Browse the corpus

WARNING: LOSS OF BONE MINERAL DENSITY Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1) ]. It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1) ]. Medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1) ]. WARNING: LOSS OF BONE MINERAL DENSITY See full prescribing information for complete boxed warning . Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. ( 5.1 ) It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. ( 5.1 ) Medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. ( 1 , 5.1 )

1 INDICATIONS AND USAGE Medroxyprogesterone acetate injectable suspension is indicated for use by females of reproductive potential to prevent pregnancy. Limitations of Use : The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Medroxyprogesterone acetate injectable suspension is a progestin indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use : The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. ( 1 , 5.1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. ( 2.1 ) 2.1 Prevention of Pregnancy Both the 1 mL vial and the 1 mL prefilled syringe of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep intramuscular (IM) injection using strict aseptic technique in the gluteal or deltoid muscle, rotating the sites with every injection. As with any IM injection, to avoid an inadvertent subcutaneous injection, body habitus should be assessed prior to each injection to determine if a longer needle is necessary particularly for gluteal IM injection. Use for longer than 2 years is not recommended (unless other birth control methods are considered inadequate) due to the impact of long-term medroxyprogesterone acetate injectable suspension treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1) ] . Dosage does not need to be adjusted for body weight [see Clinical Studies (14.1) ] . To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first 5 days of a normal menstrual period or within the first 5-days post-partum. In post-partum mothers who exclusively breastfeed, administer medroxyprogesterone acetate injectable suspension during or after the sixth post-partum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration. 2.2 Switching from Other Methods of Contraception When switching from other contraceptive methods, medroxyprogesterone acetate injectable suspension should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of medroxyprogesterone acetate injectable suspension on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

3 DOSAGE FORMS AND STRENGTHS Sterile Aqueous suspension: 150 mg/mL Prefilled syringes are packaged with 22-gauge x 1 1/2 inch Terumo ® SurGuard TM Needles. Vials containing sterile aqueous suspension: 150 mg per mL ( 3 ) Prefilled syringes: prefilled syringes are packaged with 22-gauge x 1 1/2 inch Terumo ® SurGuard TM Needles. ( 3 )

4 CONTRAINDICATIONS The use of medroxyprogesterone acetate injectable suspension is contraindicated in the following conditions: Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2) ]. Known or suspected malignancy of breast [see Warnings and Precautions (5.3) ] . Known hypersensitivity to medroxyprogesterone acetate injectable suspension or any of its other ingredients [see Warnings and Precautions (5.6) ] . Significant liver disease [see Warnings and Precautions (5.8) ] . Undiagnosed vaginal bleeding [see Warnings and Precautions (5.11) ] . Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease. ( 4 ) Known or suspected malignancy of breast. ( 4 ) Known hypersensitivity to medroxyprogesterone acetate injectable suspension (medroxyprogesterone acetate or any of its other ingredients). ( 4 ) Significant liver disease. ( 4 ) Undiagnosed vaginal bleeding. ( 4 )

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders: Discontinue medroxyprogesterone acetate injectable suspension in patients who develop thrombosis. ( 5.2 ) Cancer Risks: Monitor women with a strong family history of breast cancer carefully. ( 5.3 ) Meningioma: Discontinue medroxyprogesterone acetate injectable suspension if meningioma is diagnosed. Monitor patients for signs and symptoms of meningioma. ( 5.4 ) Ectopic Pregnancy: Consider ectopic pregnancy if a woman using medroxyprogesterone acetate injectable suspension becomes pregnant or complains of severe abdominal pain. ( 5.5 ) Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. ( 5.6 ) Liver Function: Discontinue medroxyprogesterone acetate injectable suspension if jaundice or disturbances of liver function develop. ( 5.8 ) Carbohydrate Metabolism: Monitor diabetic patients carefully. ( 5.13 ) 5.1 Loss of Bone Mineral Density Use of medroxyprogesterone acetate injectable suspension reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess the reversibility of loss of BMD in adolescents was conducted with medroxyprogesterone acetate injectable suspension. After discontinuing medroxyprogesterone acetate injectable suspension in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.3) ] . Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [see Clinical Studies (14.2) ] . The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use medroxyprogesterone acetate injectable suspension long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods should be considered in the risk/benefit analysis for the use of medroxyprogesterone acetate injectable suspension in women with osteoporosis risk factors. Medroxyprogesterone acetate injectable suspension can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). 5.2 Thromboembolic Disorders There have been reports of serious thrombotic events in women using medroxyprogesterone acetate injectable suspension (150 mg). However, medroxyprogesterone acetate injectable suspension has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate injectable suspension should discontinue treatment unless she has no other acceptable options for birth control.

ectable suspension has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate injectable suspension should discontinue treatment unless she has no other acceptable options for birth control. Do not re-administer medroxyprogesterone acetate injectable suspension pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer Women who have or have had a history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate injectable suspension, because breast cancer may be hormonally sensitive [see Contraindications (4) ]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies assessing the association between depo-medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US study 1 evaluated the recency and duration of use and found a statistically significantly increased risk of breast cancer in recent users (defined as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with results of a previous study 2 . Figure 1. Risk estimates for breast cancer in DMPA users Odds ratio estimates were adjusted for the following covariates: Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography. Based on the published SEER-18 2011 incidence rate (age-adjusted to the 2000 US Standard Population) of breast cancer for US women, all races, age 20 to 49 years, a doubling of risk would increase the incidence of breast cancer in women who use medroxyprogesterone acetate injectable suspension from about 72 to about 144 cases per 100,000 women. Cervical Cancer A statistically nonsignificant increase in relative risk (RR) estimates of invasive squamous-cell cervical cancer has been associated with the use of medroxyprogesterone acetate injectable suspension in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant RR of invasive squamous-cell cervical cancer in women who ever used medroxyprogesterone acetate injectable suspension was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. Other Cancers Long-term case-controlled surveillance of users of medroxyprogesterone acetate injectable suspension found no overall increased risk of ovarian or liver cancer. Figure 1 Risk estimates for breast cancer in DMPA users 5.4 Meningioma Cases of meningiomas have been reported following repeated administration of medroxyprogesterone acetate, primarily with long term use. Monitor patients on medroxyprogesterone acetate injectable suspension for signs and symptoms of meningioma. Discontinue medroxyprogesterone acetate injectable suspension if a meningioma is diagnosed.

iomas have been reported following repeated administration of medroxyprogesterone acetate, primarily with long term use. Monitor patients on medroxyprogesterone acetate injectable suspension for signs and symptoms of meningioma. Discontinue medroxyprogesterone acetate injectable suspension if a meningioma is diagnosed. 5.5 Ectopic Pregnancy Be alert to the possibility of an ectopic pregnancy among women using medroxyprogesterone acetate injectable suspension who become pregnant or complain of severe abdominal pain. 5.6 Anaphylaxis and Anaphylactoid Reaction Anaphylaxis and anaphylactoid reaction have been reported with the use of medroxyprogesterone acetate injectable suspension. Institute emergency medical treatment if an anaphylactic reaction occurs. 5.7 Injection Site Reactions Injection site reactions have been reported with use of medroxyprogesterone acetate injectable suspension [see Adverse Reactions (6.2) ] . Persistent injection site reactions may occur after administration of medroxyprogesterone acetate injectable suspension due to inadvertent subcutaneous administration or release of the drug into the subcutaneous space while removing the needle [see Dosage and Administration (2.1) ]. 5.8 Liver Function Discontinue medroxyprogesterone acetate injectable suspension use if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and medroxyprogesterone acetate injectable suspension causation has been excluded. 5.9 Convulsions There have been a few reported cases of convulsions in patients who were treated with medroxyprogesterone acetate injectable suspension. Association with drug use or pre-existing conditions is not clear. 5.10 Depression Monitor patients who have a history of depression and do not re-administer medroxyprogesterone acetate injectable suspension if depression recurs. 5.11 Bleeding Irregularities Most women using medroxyprogesterone acetate injectable suspension experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting, prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if abnormal bleeding persists or is severe, and institute appropriate treatment. As women continue using medroxyprogesterone acetate injectable suspension, fewer experience irregular bleeding and more experience amenorrhea. In clinical studies of medroxyprogesterone acetate injectable suspension, by month 12 amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using medroxyprogesterone acetate injectable suspension. 5.12 Weight Gain Women tend to gain weight while on therapy with medroxyprogesterone acetate injectable suspension. From an initial average body weight of 136 lb, women who completed 1 year of therapy with medroxyprogesterone acetate injectable suspension gained an average of 5.4 lb. Women who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain. 5.13 Carbohydrate Metabolism A decrease in glucose tolerance has been observed in some patients on medroxyprogesterone acetate injectable suspension treatment. Monitor diabetic patients carefully while receiving medroxyprogesterone acetate injectable suspension.

ge-scale clinical trial because of excessive weight gain. 5.13 Carbohydrate Metabolism A decrease in glucose tolerance has been observed in some patients on medroxyprogesterone acetate injectable suspension treatment. Monitor diabetic patients carefully while receiving medroxyprogesterone acetate injectable suspension. 5.14 Fluid Retention Because progestational drugs including medroxyprogesterone acetate injectable suspension may cause some degree of fluid retention, monitor patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction. 5.15 Return of Fertility Return to ovulation and fertility is likely to be delayed after stopping medroxyprogesterone acetate injectable suspension. In a large US study of women who discontinued use of medroxyprogesterone acetate injectable suspension to become pregnant, data are available for 61% of them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception for those who do conceive is 10 months following the last injection with a range of 4 to 31 months, and is unrelated to the duration of use. No data are available for 39% of the patients who discontinued medroxyprogesterone acetate injectable suspension to become pregnant and who were lost to follow-up or changed their mind. 5.16 Sexually Transmitted Infections Patients should be counseled that medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted infections. 5.17 Monitoring A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare professional for a blood pressure check and for other indicated healthcare. 5.18 Interference with Laboratory Tests The use of medroxyprogesterone acetate injectable suspension may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins [see Drug Interactions (7.2) ].

6 ADVERSE REACTIONS The following important adverse reactions observed with the use of medroxyprogesterone acetate injectable suspension are discussed in greater detail in the Warnings and Precautions section ( 5 ): Loss of Bone Mineral Density [see Warnings and Precautions (5.1) ] Thromboembolic disease [see Warnings and Precautions (5.2) ] Breast Cancer [see Warnings and Precautions (5.3) ] Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.6) ] Bleeding Irregularities [see Warnings and Precautions (5.11) ] Weight Gain [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence >5%): menstrual irregularities (bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal pain/discomfort 11%, weight gain >10 lb at 24 months 38%, dizziness 6%, headache 17%, nervousness 11%, decreased libido 6%. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Clinical trials are conducted under widely varying conditions; therefore, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the two clinical trials with medroxyprogesterone acetate injectable suspension, over 3,900 women, who were treated for up to 7 years, reported the following adverse reactions, which may or may not be related to the use of medroxyprogesterone acetate injectable suspension. The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and 4.9% Unknown race. The patients received 150 mg medroxyprogesterone acetate injectable suspension every 3-months (90 days). The median study duration was 13 months with a range of 1 to 84 months. Fifty-eight percent of patients remained in the study after 13 months and 34% after 24 months. Table 1. Adverse Reactions that Were Reported by More than 5% of Subjects * Body System represented from COSTART medical dictionary. Body System* Adverse Reactions [Incidence (%)] Body as a Whole Headache (16.5%) Abdominal pain/discomfort (11.2%) Metabolic/Nutritional Increased weight >10 lb at 24 months (37.7%) Nervous Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) Reproductive (Urogenital*) Menstrual irregularities: bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) Table 2. Adverse Reactions that Were Reported by between 1 and 5% of Subjects * Body System represented from COSTART medical dictionary. Body System* Adverse Reactions [Incidence (%)] Body as a Whole Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) Digestive Nausea (3.3%) Bloating (2.3%) Metabolic/Nutritional Edema (2.2%) Musculoskeletal Leg cramps (3.7%) Arthralgia (1.0%) Nervous Depression (1.5%) Insomnia (1.0%) Skin and Appendages Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) Reproductive (Urogenital*) Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) Adverse reactions leading to study discontinuation in ≥2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension.

st pain (2.8%) Vaginitis (1.2%) Adverse reactions leading to study discontinuation in ≥2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking medroxyprogesterone acetate injectable suspension. Table 3. Adverse Reactions Reported during Post-Marketing Experience * Body System represented from COSTART medical dictionary. † Injection site abscess and injection site infections have been reported; therefore, strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension in order to avoid injection site infections [see Dosage and Administration (2.1) ] . Body System* Adverse Reactions Body as a Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess † , Injection site infection † , Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swelling Cardiovascular Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins Digestive Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding Hematologic and Lymphatic Anemia, Blood dyscrasia Musculoskeletal Osteoporosis Neoplasms Cervical cancer, Breast cancer Nervous Paralysis, Facial palsy, Paresthesia, Drowsiness Respiratory Dyspnea and asthma, Hoarseness Skin and Appendages Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma, Melasma, Chloasma Reproductive (Urogenital*) Lack of return to fertility, Unexpected pregnancy, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Increased libido, Uterine hyperplasia, Vaginal cysts, Genitourinary infections, Dyspareunia

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 1. Adverse Reactions that Were Reported by More than 5% of Subjects </caption><colgroup><col width="32.88%"/><col width="67.12%"/></colgroup><tfoot><tr><td colspan="2">^* Body System represented from COSTART medical dictionary. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System*</content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reactions [Incidence (%)]</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole</content> </td><td styleCode="Rrule" valign="top">Headache (16.5%) Abdominal pain/discomfort (11.2%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Metabolic/Nutritional</content> </td><td styleCode="Rrule" valign="top">Increased weight &gt;10 lb at 24 months (37.7%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous</content> </td><td styleCode="Rrule" valign="top">Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Reproductive (Urogenital*)</content> </td><td styleCode="Rrule" valign="top">Menstrual irregularities: bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) </td></tr></tbody></table>

ased (5.5%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Reproductive (Urogenital*)</content> </td><td styleCode="Rrule" valign="top">Menstrual irregularities: bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 2. Adverse Reactions that Were Reported by between 1 and 5% of Subjects </caption><colgroup><col width="32.66%"/><col width="67.34%"/></colgroup><tfoot><tr><td colspan="2">* Body System represented from COSTART medical dictionary. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System*</content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reactions [Incidence (%)]</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole</content> </td><td styleCode="Rrule" valign="top">Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Digestive</content> </td><td styleCode="Rrule" valign="top">Nausea (3.3%) Bloating (2.3%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Metabolic/Nutritional</content> </td><td styleCode="Rrule" valign="top">Edema (2.2%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal</content> </td><td styleCode="Rrule" valign="top">Leg cramps (3.7%) Arthralgia (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous</content> </td><td styleCode="Rrule" valign="top">Depression (1.5%) Insomnia (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Skin and Appendages</content> </td><td styleCode="Rrule" valign="top">Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Reproductive (Urogenital*)</content> </td><td styleCode="Rrule" valign="top">Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) </td></tr></tbody></table>

eCode="Rrule" valign="top">Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Reproductive (Urogenital*)</content> </td><td styleCode="Rrule" valign="top">Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3. Adverse Reactions Reported during Post-Marketing Experience </caption><colgroup><col width="34.5%"/><col width="65.5%"/></colgroup><tfoot><tr><td colspan="2">^* Body System represented from COSTART medical dictionary. ^&#x2020; Injection site abscess and injection site infections have been reported; therefore, strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension in order to avoid injection site infections <content styleCode="italics">[see <linkHtml href="#Section_2.1">Dosage and Administration (2.1)</linkHtml>]</content>.

ons have been reported; therefore, strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension in order to avoid injection site infections <content styleCode="italics">[see <linkHtml href="#Section_2.1">Dosage and Administration (2.1)</linkHtml>]</content>. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"><content styleCode="bold">Body System*</content> </td><td styleCode="Rrule" align="left" valign="middle"><content styleCode="bold">Adverse Reactions</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Body as a Whole</content> </td><td styleCode="Rrule" align="justify" valign="top">Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess^&#x2020;, Injection site infection^&#x2020;, Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swelling </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Cardiovascular</content> </td><td styleCode="Rrule" valign="top">Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Digestive</content> </td><td styleCode="Rrule" valign="top">Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Hematologic and Lymphatic</content> </td><td styleCode="Rrule" valign="top">Anemia, Blood dyscrasia </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Musculoskeletal</content> </td><td styleCode="Rrule" valign="top">Osteoporosis </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Neoplasms</content> </td><td styleCode="Rrule" valign="top">Cervical cancer, Breast cancer </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Nervous</content> </td><td styleCode="Rrule" valign="top">Paralysis, Facial palsy, Paresthesia, Drowsiness </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Respiratory</content> </td><td styleCode="Rrule" valign="top">Dyspnea and asthma, Hoarseness </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Skin and Appendages</content> </td><td styleCode="Rrule" valign="top">Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma, Melasma, Chloasma </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold"><content styleCode="bold">Reproductive (Urogenital*)</content></content> </td><td styleCode="Rrule" valign="top">Lack of return to fertility, Unexpected pregnancy, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Increased libido, Uterine hyperplasia, Vaginal cysts, Genitourinary infections, Dyspareunia </td></tr></tbody></table>

7 DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of contraceptive drug products. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. ( 7.1 ) 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration of HIV protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Laboratory Test Interactions The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including medroxyprogesterone acetate injectable suspension: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Gonadotropin levels are decreased. (c) Sex-hormone-binding-globulin concentrations are decreased. (d) Protein-bound iodine and butanol extractable protein-bound iodine may increase. T 3 -uptake values may decrease. (e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. (f) Sulfobromophthalein and other liver function test values may be increased. (g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue if pregnancy occurs. ( 8.1 ) Lactation: Detectable amounts of drug have been identified in the milk of mothers receiving Medroxyprogesterone acetate injectable suspension. ( 8.2 ) Pediatric Patients: Medroxyprogesterone acetate injectable suspension is not indicated before menarche. ( 8.4 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, medroxyprogesterone acetate injectable suspension should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 8.2 Lactation Risk Summary Although medroxyprogesterone acetate is detectable in the milk of mothers receiving medroxyprogesterone acetate injectable suspension, milk composition, quality, and amount do not appear to be adversely affected. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in mothers who exclusively breastfeed, initiate medroxyprogesterone acetate injectable suspension during or after the sixth post-partum week [see Dosage and Administration (2.1) ]. No adverse effects in breastfed infants would be expected with maternal use of progestins. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied and no adverse effects have been noted. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for medroxyprogesterone acetate injectable suspension and any potential adverse effects on the breastfed child from medroxyprogesterone acetate injectable suspension or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Medroxyprogesterone acetate injectable suspension is indicated for the prevention of pregnancy and would therefore be expected to impair female fertility until cessation of treatment. Women may experience a delay in return to ovulation and fertility (conception) following discontinuation of medroxyprogesterone acetate injectable suspension [see Warnings and Precautions (5.15) ] . 8.4 Pediatric Use Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women. 8.5 Geriatric Use This product has not been studied in post-menopausal women and is not indicated in this population.

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, medroxyprogesterone acetate injectable suspension should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.4 Pediatric Use Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women.

11 DESCRIPTION Medroxyprogesterone acetate injectable suspension, USP contains medroxyprogesterone acetate USP, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate USP is active by the parenteral and oral routes of administration. It is a white to almost white microcrystalline powder that is stable in air and that melts between 205.0°C and 209.0°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-,(6α-). The structural formula is as follows: Medroxyprogesterone acetate injectable suspension, USP for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile, white to off white suspension 150 mg/mL. Medroxyprogesterone acetate injectable suspension, USP vials and prefilled syringes: Each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.9 mg Polysorbate 80 2.41 mg Sodium chloride 8.68 mg Methylparaben 1.37 mg Propylparaben 0.150 mg Water for injection quantity sufficient When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. medroxyprogesterone-str.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Medroxyprogesterone acetate injectable suspension (medroxyprogesterone acetate [MPA]) inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect. 12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted with medroxyprogesterone acetate injectable suspension. 12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Elimination Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate injectable suspension is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.

12.1 Mechanism of Action Medroxyprogesterone acetate injectable suspension (medroxyprogesterone acetate [MPA]) inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect.

12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Elimination Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate injectable suspension is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.

14 CLINICAL STUDIES 14.1 Contraception In five clinical studies using medroxyprogesterone acetate injectable suspension, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate injectable suspension was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of medroxyprogesterone acetate injectable suspension is dependent on the patient returning every 3 months (13 weeks) for reinjection. 14.2 Bone Mineral Density Changes in Women Treated with Medroxyprogesterone Acetate Injectable Suspension In a controlled, clinical study, adult women using medroxyprogesterone acetate injectable suspension (150 mg) for up to 5 years showed spine and hip bone mineral density (BMD) mean decreases of 5 to 6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. After stopping use of medroxyprogesterone acetate injectable suspension, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table 4 shows the change in BMD in women after 5 years of treatment with medroxyprogesterone acetate injectable suspension and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available. Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) * The treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for 5 years and were then followed for 2 years post-use (total time in study of 7 years). ** The control group consisted of women who did not use hormonal contraception and were followed for 7 years. Time in Study Spine Total Hip Femoral Neck Medroxyprogesterone acetate* Control** Medroxyprogesterone acetate* Control** Medroxyprogesterone acetate* Control** 5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106 7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63 14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Medroxyprogesterone Acetate Injectable Suspension The impact of medroxyprogesterone acetate injectable suspension (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of medroxyprogesterone acetate injectable suspension was associated with a significant decline from baseline in BMD. Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per medroxyprogesterone acetate injectable suspension user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

gesterone acetate injectable suspension user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of BMD. Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort Duration of Treatment Medroxyprogesterone Acetate I njectable Suspension (150 mg IM) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) 113 73 28 -2.75 -5.40 -6.40 166 109 84 1.22 2.19 1.71 Femoral Neck BMD Week 60 Week 120 Week 240 113 73 28 -2.96 -5.30 -5.40 166 108 84 1.75 2.83 1.94 Lumbar Spine BMD Week 60 Week 120 Week 240 114 73 27 -2.47 -2.74 -2.11 167 109 84 3.39 5.28 6.40 BMD Recovery Post-Treatment in Adolescents Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of medroxyprogesterone acetate injectable suspension. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received medroxyprogesterone acetate injectable suspension for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with medroxyprogesterone acetate for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period (data not shown) [see Warnings and Precautions (5.1) ]. Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone Acetate Injectable Suspension Use (2 Years or Less vs. More than 2 Years) Duration of Treatment 2 years or less More than 2 years N Mean % Change from baseline N Mean % Change from baseline Total Hip BMD End of Treatment 49 -1.5% 49 -6.2% 12 M post-treatment 33 -1.4% 24 -4.6% 24 M post-treatment 18 0.3% 17 -3.6% 36 M post-treatment 12 2.1% 11 -4.6% 48 M post-treatment 10 1.3% 9 -2.5% 60 M post-treatment 3 0.2% 2 -1.0% Femoral Neck BMD End of Treatment 49 -1.6% 49 -5.8% 12 M post-treatment 33 -1.4% 24 -4.3% 24 M post-treatment 18 0.5% 17 -3.8% 36 M post-treatment 12 1.2% 11 -3.8% 48 M post-treatment 10 2.0% 9 -1.7% 60 M post-treatment 3 1.0% 2 -1.9% Lumbar Spine BMD End of Treatment 49 -0.9% 49 -3.5% 12 M post-treatment 33 0.4% 23 -1.1% 24 M post-treatment 18 2.6% 17 1.9% 36 M post-treatment 12 2.4% 11 0.6% 48 M post-treatment 10 6.5% 9 3.5% 60 M post-treatment 3 6.2% 2 5.7% 14.4 Bone Fracture Incidence in Women Treated with Medroxyprogesterone Acetate Injectable Suspension A retrospective cohort study to assess the association between medroxyprogesterone acetate injectable suspension and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between medroxyprogesterone acetate injectable suspension users and contraceptive users who had no recorded use of medroxyprogesterone acetate injectable suspension. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47).

rates of fracture were compared between medroxyprogesterone acetate injectable suspension users and contraceptive users who had no recorded use of medroxyprogesterone acetate injectable suspension. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to medroxyprogesterone acetate injectable suspension use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to medroxyprogesterone acetate injectable suspension was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use. There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in medroxyprogesterone acetate injectable suspension users compared to non-users. Importantly, this study could not determine whether use of medroxyprogesterone acetate injectable suspension has an effect on fracture rate later in life.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) </caption><colgroup><col width="7.18%"/><col width="20.3%"/><col width="10.64%"/><col width="20.3%"/><col width="10.64%"/><col width="20.3%"/><col width="10.64%"/></colgroup><tfoot><tr><td colspan="7"> ^*The treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for 5 years and were then followed for 2 years post-use (total time in study of 7 years). ^**The control group consisted of women who did not use hormonal contraception and were followed for 7 years. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Time in Study</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Spine</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Total Hip</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Femoral Neck</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Medroxyprogesterone acetate*</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Control**</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Medroxyprogesterone acetate*</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Control**</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Medroxyprogesterone acetate*</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Control**</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">5 years</content><content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="top">-5.38% n=33 </td><td styleCode="Rrule" align="center" valign="top">0.43% n=105 </td><td styleCode="Rrule" align="center" valign="top">-5.16% n=21 </td><td styleCode="Rrule" align="center" valign="top">0.19% n=65 </td><td styleCode="Rrule" align="center" valign="top">-6.12% n=34 </td><td styleCode="Rrule" align="center" valign="top">-0.27% n=106 </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">7 years</content><content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="top">-3.13% n=12 </td><td styleCode="Rrule" align="center" valign="top">0.53% n=60 </td><td styleCode="Rrule" align="center" valign="top">-1.34% n=7 </td><td styleCode="Rrule" align="center" valign="top">0.94% n=39 </td><td styleCode="Rrule" align="center" valign="top">-5.38% n=13 </td><td styleCode="Rrule" align="center" valign="top">-0.11% n=63 </td></tr></tbody></table>

er" valign="top">0.53% n=60 </td><td styleCode="Rrule" align="center" valign="top">-1.34% n=7 </td><td styleCode="Rrule" align="center" valign="top">0.94% n=39 </td><td styleCode="Rrule" align="center" valign="top">-5.38% n=13 </td><td styleCode="Rrule" align="center" valign="top">-0.11% n=63 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving &#x2265;4 Injections per 60-week Period, by Skeletal Site and Cohort </caption><colgroup><col width="25.8%"/><col width="14.14%"/><col width="23%"/><col width="12.3%"/><col width="24.76%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Duration of Treatment</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Medroxyprogesterone Acetate I</content><content styleCode="bold">njectable Suspension</content> <content styleCode="bold">(150 mg IM)</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Unmatched, Untreated Cohort</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mean % Change</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mean % Change</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Total Hip BMD</content> Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) </td><td styleCode="Rrule" align="center" valign="middle">113 73 28 </td><td styleCode="Rrule" align="center" valign="middle">-2.75 -5.40 -6.40 </td><td styleCode="Rrule" align="center" valign="middle">166 109 84 </td><td styleCode="Rrule" align="center" valign="middle">1.22 2.19 1.71 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Femoral Neck BMD</content> Week 60 Week 120 Week 240 </td><td styleCode="Rrule" align="center" valign="middle">113 73 28 </td><td styleCode="Rrule" align="center" valign="middle">-2.96 -5.30 -5.40 </td><td styleCode="Rrule" align="center" valign="middle">166 108 84 </td><td styleCode="Rrule" align="center" valign="middle">1.75 2.83 1.94 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Lumbar Spine BMD</content> Week 60 Week 120 Week 240 </td><td styleCode="Rrule" align="center" valign="middle">114 73 27 </td><td styleCode="Rrule" align="center" valign="middle">-2.47 -2.74 -2.11 </td><td styleCode="Rrule" align="center" valign="middle">167 109 84 </td><td styleCode="Rrule" align="center" valign="middle">3.39 5.28 6.40 </td></tr></tbody></table>

eek 240 </td><td styleCode="Rrule" align="center" valign="middle">114 73 27 </td><td styleCode="Rrule" align="center" valign="middle">-2.47 -2.74 -2.11 </td><td styleCode="Rrule" align="center" valign="middle">167 109 84 </td><td styleCode="Rrule" align="center" valign="middle">3.39 5.28 6.40 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone Acetate Injectable Suspension Use (2 Years or Less vs.

eek 240 </td><td styleCode="Rrule" align="center" valign="middle">114 73 27 </td><td styleCode="Rrule" align="center" valign="middle">-2.47 -2.74 -2.11 </td><td styleCode="Rrule" align="center" valign="middle">167 109 84 </td><td styleCode="Rrule" align="center" valign="middle">3.39 5.28 6.40 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone Acetate Injectable Suspension Use (2 Years or Less vs. More than 2 Years) </caption><colgroup><col width="26.02%"/><col width="11.38%"/><col width="26.04%"/><col width="9.22%"/><col width="27.34%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Duration of Treatment</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">2 years or less</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">More than 2 years</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mean % Change from baseline</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mean % Change from baseline</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="center" valign="middle"><content styleCode="bold">Total Hip BMD</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">End of Treatment</content> </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-1.5% </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-6.2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">12 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">33 </td><td styleCode="Rrule" align="center" valign="middle">-1.4% </td><td styleCode="Rrule" align="center" valign="middle">24 </td><td styleCode="Rrule" align="center" valign="middle">-4.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">24 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">0.3% </td><td styleCode="Rrule" align="center" valign="middle">17 </td><td styleCode="Rrule" align="center" valign="middle">-3.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">36 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">12 </td><td styleCode="Rrule" align="center" valign="middle">2.1% </td><td styleCode="Rrule" align="center" valign="middle">11 </td><td styleCode="Rrule" align="center" valign="middle">-4.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">48 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">10 </td><td styleCode="Rrule" align="center" valign="middle">1.3% </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">-2.5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">60 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">0.2% </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">-1.0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="center" valign="middle"><content styleCode="bold">Femoral Neck BMD</content> </td></tr><tr

er" valign="middle">0.2% </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">-1.0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="center" valign="middle"><content styleCode="bold">Femoral Neck BMD</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">End of Treatment</content> </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-1.6% </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-5.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">12 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">33 </td><td styleCode="Rrule" align="center" valign="middle">-1.4% </td><td styleCode="Rrule" align="center" valign="middle">24 </td><td styleCode="Rrule" align="center" valign="middle">-4.3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">24 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">0.5% </td><td styleCode="Rrule" align="center" valign="middle">17 </td><td styleCode="Rrule" align="center" valign="middle">-3.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">36 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">12 </td><td styleCode="Rrule" align="center" valign="middle">1.2% </td><td styleCode="Rrule" align="center" valign="middle">11 </td><td styleCode="Rrule" align="center" valign="middle">-3.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">48 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">10 </td><td styleCode="Rrule" align="center" valign="middle">2.0% </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">-1.7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">60 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">1.0% </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">-1.9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="center" valign="middle"><content styleCode="bold">Lumbar Spine BMD</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">End of Treatment</content> </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-0.9% </td><td styleCode="Rrule" align="center" valign="middle">49 </td><td styleCode="Rrule" align="center" valign="middle">-3.5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">12 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">33 </td><td styleCode="Rrule" align="center" valign="middle">0.4% </td><td styleCode="Rrule" align="center" valign="middle">23 </td><td styleCode="Rrule" align="center" valign="middle">-1.1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">24 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">2.6% </td><td styleCode="Rrule" align="center" valign="middle">17 </td><td styleCode="Rrule" align="center" valign="middle">1.9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">36 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">12 </td><td

center" valign="middle">2.6% </td><td styleCode="Rrule" align="center" valign="middle">17 </td><td styleCode="Rrule" align="center" valign="middle">1.9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">36 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">12 </td><td styleCode="Rrule" align="center" valign="middle">2.4% </td><td styleCode="Rrule" align="center" valign="middle">11 </td><td styleCode="Rrule" align="center" valign="middle">0.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">48 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">10 </td><td styleCode="Rrule" align="center" valign="middle">6.5% </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">3.5% </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">60 M post-treatment </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">6.2% </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">5.7% </td></tr></tbody></table>

15 REFERENCES Li CI, Beaber EF, Tang, MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012;72:2028-2035. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989; 299:759-62.

16 HOW SUPPLIED/STORAGE AND HANDLING Medroxyprogesterone acetate sterile suspension, 150 mg/mL Medroxyprogesterone acetate injectable suspension, USP is a sterile, white to off white suspension and is supplied in the following package configurations: 150 mg per mL: 1 mL Single-Dose Vial Packaged Individually NDC 55150-329-01 1 mL Single-Dose Vials in a Carton of 25 NDC 55150-329-25 Vials MUST be stored upright at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Medroxyprogesterone acetate prefilled syringes packaged with 22-gauge x 1 1/2 inch Terumo ® SurGuard™ Medroxyprogesterone acetate injectable suspension, USP is a sterile, white to off white aqueous suspension and is supplied in the following package configurations: 150 mg per mL: 1 mL prefilled syringe NDC 55150-330-01 Packaged individually in a carton with 22-gauge x 1 1/2 inch Terumo ® SurGuard TM Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. The vial stopper and plunger rubber stopper are not made with natural rubber latex.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with medroxyprogesterone acetate injectable suspension continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use medroxyprogesterone acetate injectable suspension [see Warnings and Precautions (5.3) ]. Counsel patients with a history of meningioma about the possible risk of worsening meningioma [see Warnings and Precautions (5.4) ]. Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections. Counsel patients on Warnings and Precautions associated with use of medroxyprogesterone acetate injectable suspension. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. This product’s labeling may have been updated. For the most recent prescribing information, please visit eugiaus.com. For more medical information please visit eugiaus.com or call 1-866-850-2876 Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

Patient Information Medroxyprogesterone Acetate (med ROX ee proe JES ter one AS e tate) Injectable Suspension Read this Patient Information carefully before you decide if medroxyprogesterone acetate injectable suspension is right for you. This information does not take the place of talking with your gynecologist or other healthcare professional who specializes in women’s health. If you have any questions about medroxyprogesterone acetate injectable suspension, ask your healthcare professional. You should also learn about other birth control methods to choose the one that is best for you. What is the most important information I should know about medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension can cause serious side effects, including: Use of medroxyprogesterone acetate injectable suspension may cause you to lose calcium stored in your bone and decrease your bone mass. The longer you use medroxyprogesterone acetate injectable suspension, the greater your loss of calcium from your bones. Your bones may not recover completely when you stop using medroxyprogesterone acetate injectable suspension. If you use medroxyprogesterone acetate injectable suspension continuously for a long time (for more than 2 years), it may increase the risk of weak, porous bones (osteoporosis) that could increase the risk of broken bones, especially after menopause. You should not use medroxyprogesterone acetate injectable suspension for more than two years unless you cannot use other birth control methods. It is not known if your risk of developing osteoporosis is greater if you are a teenager or young adult when you start to use medroxyprogesterone acetate injectable suspension (see “What are the possible side effects of medroxyprogesterone acetate injectable suspension?”). Medroxyprogesterone acetate injectable suspension is intended to prevent pregnancy. Medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). What is medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is a progestin hormone birth control method that is given by injection (a shot) to prevent pregnancy. How well does medroxyprogesterone acetate injectable suspension work? Your chance of getting pregnant depends on how well you follow the directions for taking your medroxyprogesterone acetate injectable suspension. The more carefully you follow the directions (such as returning every 3 months for your next injection), the less chance you have of getting pregnant. In clinical studies, about 1 out of 100 women got pregnant during the first year that they used medroxyprogesterone acetate injectable suspension. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. How should I take medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is given by your healthcare professional as a shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm 1 time every 3 months.

trol and are trying to get pregnant. How should I take medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is given by your healthcare professional as a shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm 1 time every 3 months. At the end of the 3 months, you will need to return to your healthcare professional for your next injection in order to continue your protection against pregnancy . To make sure that you are not pregnant before you take medroxyprogesterone acetate injectable suspension, the first injection should be given only: ◦ during the first 5 days of a normal menstrual period, or ◦ within the first 5 days after giving birth, if you are not breastfeeding , or ◦ at the 6th week after giving birth, if you are feeding your baby only breastmilk. Medroxyprogesterone acetate injectable suspension may be given at other times than those listed above, but you will likely need to have a pregnancy test first to show that you are not pregnant. During treatment with medroxyprogesterone acetate injectable suspension, you should see your healthcare professional every year for a blood pressure check and other healthcare needs. Who Should Not Use medroxyprogesterone acetate injectable suspension? Do not use medroxyprogesterone acetate injectable suspension if you: have bleeding from your vagina that has not been explained have breast cancer now or in the past, or think you have breast cancer have had a stroke ever had blood clots in your arms, legs or lungs have problems with your liver or liver disease are allergic to medroxyprogesterone acetate or any of the other ingredients in medroxyprogesterone acetate injectable suspension. See the end of this leaflet for a complete list of ingredients in medroxyprogesterone acetate injectable suspension. What should I tell my healthcare professional before taking medroxyprogesterone acetate injectable suspension? Before taking medroxyprogesterone acetate injectable suspension, tell your healthcare professional if you have: risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or smoke regularly, anorexia nervosa, or a strong family history of osteoporosis irregular or lighter than usual menstrual periods breast cancer now or in the past, or think you have breast cancer a family history of breast cancer an abnormal mammogram (breast X-ray), lumps in your breasts, or bleeding from your nipples have or have ever had a type of usually benign brain tumor called a meningioma kidney problems high blood pressure had a stroke had blood clots in your arms, legs or lungs migraine headaches asthma epilepsy (convulsions or seizures) diabetes depression or a history of depression any other medical conditions If you are breastfeeding or plan to breastfeed, medroxyprogesterone acetate can pass into your breast milk. Talk to your healthcare professional about the best way to feed your baby if you take medroxyprogesterone acetate injectable suspension. Tell your healthcare professional about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Medroxyprogesterone acetate injectable suspension and certain other medicines may affect each other, causing serious side effects. Sometimes the doses of other medicines may need to be changed while you are taking medroxyprogesterone acetate injectable suspension. Some medicines may make medroxyprogesterone acetate injectable suspension less effective at preventing pregnancy, including those listed below. Especially tell your healthcare professional if you take: medicine to help you sleep bosentan medicine for seizures griseofulvin an antibiotic medicine for HIV (AIDS) St. John’s wort Know the medicines you take.

esterone acetate injectable suspension less effective at preventing pregnancy, including those listed below. Especially tell your healthcare professional if you take: medicine to help you sleep bosentan medicine for seizures griseofulvin an antibiotic medicine for HIV (AIDS) St. John’s wort Know the medicines you take. Keep a list of your medicines with you to show your healthcare professional or pharmacist before you first start taking medroxyprogesterone acetate injectable suspension or when you get a new medicine. Follow your healthcare professional’s instructions about using a back-up method of birth control if you are taking medicines that may make medroxyprogesterone acetate injectable suspension less effective. What are the possible side effects of medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension can cause serious side effects, including: Effect on the bones: See “What is the most important information I should know about medroxyprogesterone acetate injectable suspension?”. Teenage years are the most important years to gain bone strength. The decrease in calcium in your bones is of most concern if you are a teenager or have the following problems: bone disease an eating disorder (anorexia nervosa) a strong family history of osteoporosis you take a drug that can lower the amount of calcium in your bones (drugs for epilepsy or steroid drugs) you drink a lot of alcohol (more than 2 drinks a day) you smoke If you need a birth control method for more than 2 years, your healthcare professional may switch you to another birth control method instead of using medroxyprogesterone acetate injectable suspension. If you continue using medroxyprogesterone acetate injectable suspension, your healthcare professional may ask you to have a bone test, especially if you have other risks for weak bones. When medroxyprogesterone acetate injectable suspension is stopped, your bones may start to regain calcium. However, in a study of teenage girls who used medroxyprogesterone acetate injectable suspension for more than 2 years, their hip bones did not completely recover by 5 years after they stopped using medroxyprogesterone acetate injectable suspension. Taking calcium and Vitamin D and exercising daily may lessen the loss of calcium from your bones. possible increased risk of breast cancer. Women who use medroxyprogesterone acetate injectable suspension may have a slightly increased risk of breast cancer compared to non-users. blood clots in your arms, legs, lungs, and eyes stroke a pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. allergic reactions. Severe allergic reactions have been reported in some women using medroxyprogesterone acetate injectable suspension. loss of vision or other eye problems migraine headaches possible increased risk for growth of a meningioma (a usually benign brain tumor), primarily when the product is used for a long time.

ic reactions. Severe allergic reactions have been reported in some women using medroxyprogesterone acetate injectable suspension. loss of vision or other eye problems migraine headaches possible increased risk for growth of a meningioma (a usually benign brain tumor), primarily when the product is used for a long time. depression convulsions or seizures liver problems Call your healthcare professional right away if you have: sharp chest pain, coughing up blood, or sudden shortness of breath (indicating a possible clot in the lung) sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) severe pain or swelling in the calf (indicating a possible clot in the leg) sudden blindness, partial or complete (indicating a possible clot in the blood vessels of the eye) unusually heavy vaginal bleeding severe pain or tenderness in the lower abdominal area persistent pain, pus, or bleeding at the injection site yellowing of the eyes or skin hives difficulty breathing swelling of the face, mouth, tongue or neck The most common side effects of medroxyprogesterone acetate injectable suspension include: irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or continued spotting weight gain. You may experience weight gain while you are using medroxyprogesterone acetate injectable suspension. About two-thirds of the women who used medroxyprogesterone acetate injectable suspension in the clinical trials reported a weight gain of about 5 pounds during the first year of use. You may continue to gain weight after the first year. Women who used medroxyprogesterone acetate injectable suspension for 2 years gained an average of 8 pounds over those 2 years. abdominal pain headache weakness tiredness nervousness dizziness Tell your healthcare professional if you have any side effect that bothers you or does not go away. These are not all the possible side effects of medroxyprogesterone acetate injectable suspension. For more information, ask your healthcare professional or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What other information should I know before choosing medroxyprogesterone acetate injectable suspension? Pregnancy . When you take medroxyprogesterone acetate injectable suspension every 3 months, your chance of getting pregnant is very low. You could miss a period or have a light period and not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see your healthcare professional as soon as possible. You should not use medroxyprogesterone acetate injectable suspension if you are pregnant. However, medroxyprogesterone acetate injectable suspension taken by accident during pregnancy does not seem to cause birth defects. Nursing Mothers . Although medroxyprogesterone acetate can be passed to the nursing baby in the breast milk, no harmful effects on babies have been found. Medroxyprogesterone acetate injectable suspension does not stop the breasts from producing milk, so it can be used by nursing mothers. However, to minimize the amount of medroxyprogesterone acetate injectable suspension that is passed to the baby in the first weeks after birth, you should wait until your baby is 6 weeks old before you start using medroxyprogesterone acetate injectable suspension for birth control. How will medroxyprogesterone acetate injectable suspension change my periods? Change in normal menstrual cycle . The side effect reported most frequently by women who use medroxyprogesterone acetate injectable suspension for birth controls is a change in their normal menstrual cycle.

table suspension for birth control. How will medroxyprogesterone acetate injectable suspension change my periods? Change in normal menstrual cycle . The side effect reported most frequently by women who use medroxyprogesterone acetate injectable suspension for birth controls is a change in their normal menstrual cycle. During the first year of using medroxyprogesterone acetate injectable suspension, you might have one or more of the following changes: ◦ irregular or unpredictable bleeding or spotting ◦ an increase or decrease in menstrual bleeding ◦ no bleeding at all . In clinical studies of medroxyprogesterone acetate injectable suspension, 55% of women reported no menstrual bleeding (amenorrhea) after one year of use and 68% of women reported no menstrual bleeding after two years of use. Missed period . During the time you are using medroxyprogesterone acetate injectable suspension for birth controls, you may skip a period, or your periods may stop completely. If you have been receiving your shot of medroxyprogesterone acetate injectable suspension regularly every 3 months, then you are probably not pregnant. However, if you think that you may be pregnant, see your healthcare professional. Unusually heavy or continuous bleeding is not a usual effect of medroxyprogesterone acetate injectable suspension and if this happens you should see your healthcare professional right away. With continued use of medroxyprogesterone acetate injectable suspension, bleeding usually decreases and many women stop having periods completely. When you stop using medroxyprogesterone acetate injectable suspension your menstrual period will usually, in time, return to its normal cycle. What if I want to become pregnant? Because medroxyprogesterone acetate injectable suspension is a long-acting birth control method, it takes some time after your last shot for its effect to wear off. Most women who try to get pregnant after using medroxyprogesterone acetate injectable suspension get pregnant within 18 months after their last shot. The length of time you use medroxyprogesterone acetate injectable suspension has no effect on how long it takes you to become pregnant after you stop using it. General Information about medroxyprogesterone acetate injectable suspension Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. This leaflet summarizes the most important information about medroxyprogesterone acetate injectable suspension. If you would like more information, talk with your healthcare professional. You can ask your healthcare professional for information about medroxyprogesterone acetate injectable suspension that is written for healthcare professionals. What are the ingredients in medroxyprogesterone acetate injectable suspension? Active ingredient: medroxyprogesterone acetate Inactive ingredients: polyethylene glycol 3350, polysorbate 80, sodium chloride, methylparaben, propylparaben, and water for injection. When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. This Patient Information has been approved by the U.S. Food and Drug Administration. This product’s labeling may have been updated. For the most recent prescribing information, please visit eugiaus.com. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India Revised: January 2026 Chart

WARNING: LOSS OF BONE MINERAL DENSITY Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1)] . It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1)] . Medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1)] . WARNING: LOSS OF BONE MINERAL DENSITY See full prescribing information for complete boxed warning . Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. (5.1) It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. (5.1) Medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. (1, 5.1)

1 INDICATIONS AND USAGE Medroxyprogesterone acetate injectable suspension is indicated for use by females of reproductive potential to prevent pregnancy. Limitations of Use: The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Medroxyprogesterone acetate is a progestin indicated for use by females of reproductive potential to prevent pregnancy. (1) Limitations of Use: The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. (1, 5.1)

2 DOSAGE AND ADMINISTRATION The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. (2.1) 2.1 Prevention of Pregnancy The 1 mL prefilled syringe of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep intramuscular (IM) injection using strict aseptic technique in the gluteal or deltoid muscle, rotating the sites with every injection. As with any IM injection, to avoid an inadvertent subcutaneous injection, body habitus should be assessed prior to each injection to determine if a longer needle is necessary particularly for gluteal IM injection. Use for longer than 2 years is not recommended (unless other birth control methods are considered inadequate) due to the impact of long-term medroxyprogesterone acetate injectable suspension treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1)] . Dosage does not need to be adjusted for body weight [ see Clinical Studies ( 14.1 )] . To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration. 2.2 Switching From Other Methods of Contraception When switching from other contraceptive methods, medroxyprogesterone acetate injectable suspension should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of medroxyprogesterone acetate injectable suspension on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

3 DOSAGE FORMS AND STRENGTHS Prefilled syringe is available packaged with 22-gauge x 1 1/2 inch Terumo SurGuard ® Needles. (3) Prefilled syringe: prefilled syringe is available packaged with 22-gauge x 1 1/2 inch Terumo SurGuard ® Needles. ( 3 )

4 CONTRAINDICATIONS The use of medroxyprogesterone acetate injectable suspension is contraindicated in the following conditions: Known or suspected pregnancy or as a diagnostic test for pregnancy. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease [ see Warnings and Precautions ( 5.2 ) ]. Known or suspected malignancy of breast [ see Warnings and Precautions ( 5.3 ) ]. Known hypersensitivity to medroxyprogesterone acetate injectable suspension or any of its other ingredients [ see Warnings and Precautions ( 5.5 ) ]. Significant liver disease [ see Warnings and Precautions ( 5. 7) ]. Undiagnosed vaginal bleeding [ see Warnings and Precautions ( 5. 10) ]. Known or suspected pregnancy or as a diagnostic test for pregnancy. ( 4 ) Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease. ( 4 ) Known or suspected malignancy of breast. ( 4 ) Known hypersensitivity to medroxyprogesterone acetate injectable suspension or any of its other ingredients. ( 4 ) Significant liver disease. ( 4 ) Undiagnosed vaginal bleeding. ( 4 )

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders: Discontinue medroxyprogesterone acetate injectable suspension in patients who develop thrombosis. ( 5.2 ) Cancer Risks: Monitor women with a strong family history of breast cancer carefully. ( 5.3 ) Ectopic Pregnancy: Consider ectopic pregnancy if a woman using medroxyprogesterone acetate injectable suspension becomes pregnant or complains of severe abdominal pain. ( 5.4 ) Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. ( 5.5 ) Liver Function: Discontinue medroxyprogesterone acetate injectable suspension if jaundice or disturbances of liver function develop. ( 5. 7) Carbohydrate Metabolism: Monitor diabetic patients carefully. ( 5.1 2) 5.1 Loss of Bone Mineral Density Use of medroxyprogesterone acetate injectable suspension reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess the reversibility of loss of BMD in adolescents was conducted with medroxyprogesterone acetate injectable suspension. After discontinuing medroxyprogesterone acetate injectable suspension in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.3)]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [See Clinical Studies (14.2)]. The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use medroxyprogesterone acetate injectable suspension long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods should be considered in the risk/benefit analysis for the use of medroxyprogesterone acetate injectable suspension in women with osteoporosis risk factors. Medroxyprogesterone acetate injectable suspension can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). 5.2 Thromboembolic Disorders There have been reports of serious thrombotic events in women using medroxyprogesterone acetate injectable suspension (150 mg). However, medroxyprogesterone acetate injectable suspension has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate injectable suspension should discontinue treatment unless she has no other acceptable options for birth control.

ectable suspension has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate injectable suspension should discontinue treatment unless she has no other acceptable options for birth control. Do not re-administer medroxyprogesterone acetate injectable suspension pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer Women who have or have had a history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate injectable suspension, because breast cancer may be hormonally sensitive [see Contraindications ( 4 )]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies 1, 2 assessing the association between depo-­medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US study 1 evaluated the recency and duration of use and found a statistically significantly increased risk of breast cancer in recent users (defined as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with results of a previous study. Odds ratio estimates were adjusted for the following covariates: Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography. Based on the published SEER-18 2011 incidence rate (age-adjusted to the 2000 U.S. Standard Population) of breast cancer for U.S. women, all races, age 20 to 49 years, a doubling of risk would increase the incidence of breast cancer in women who use medroxyprogesterone acetate injectable suspension from about 72 to about 144 cases per 100,000 women. Cervical Cancer A statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of medroxyprogesterone acetate injectable suspension in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical cancer in women who ever used medroxyprogesterone acetate injectable suspension was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. Other Cancers Long-term case-controlled surveillance of users of medroxyprogesterone acetate injectable suspension found no overall increased risk of ovarian or liver cancer. spl-medroxy-fig1 5.4 Ectopic Pregnancy Be alert to the possibility of an ectopic pregnancy among women using medroxyprogesterone acetate injectable suspension who become pregnant or complain of severe abdominal pain. 5.5 Anaphylaxis and Anaphylactoid Reaction Anaphylaxis and anaphylactoid reaction have been reported with the use of medroxyprogesterone acetate injectable suspension. Institute emergency medical treatment if an anaphylactic reaction occurs.

njectable suspension who become pregnant or complain of severe abdominal pain. 5.5 Anaphylaxis and Anaphylactoid Reaction Anaphylaxis and anaphylactoid reaction have been reported with the use of medroxyprogesterone acetate injectable suspension. Institute emergency medical treatment if an anaphylactic reaction occurs. 5.6 Injection Site Reactions Injection site reactions have been reported with use of medroxyprogesterone acetate injectable suspension [see Adverse Reactions (6.2)] . Persistent injection site reactions may occur after administration of medroxyprogesterone acetate injectable suspension due to inadvertent subcutaneous administration or release of the drug into the subcutaneous space while removing the needle [see Dosage and Administration (2.1)]. 5.7 Liver Function Discontinue medroxyprogesterone acetate injectable suspension use if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and medroxyprogesterone acetate injectable suspension causation has been excluded. 5.8 Convulsions There have been a few reported cases of convulsions in patients who were treated with medroxyprogesterone acetate injectable suspension. Association with drug use or pre-existing conditions is not clear. 5.9 Depression Monitor patients who have a history of depression and do not re-administer medroxyprogesterone acetate injectable suspension if depression recurs. 5.10 Bleeding Irregularities Most women using medroxyprogesterone acetate injectable suspension experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting, prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if abnormal bleeding persists or is severe, and institute appropriate treatment. As women continue using medroxyprogesterone acetate injectable suspension, fewer experience irregular bleeding and more experience amenorrhea. In clinical studies of medroxyprogesterone acetate injectable suspension, by month 12 amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using medroxyprogesterone acetate injectable suspension. 5.11 Weight Gain Women tend to gain weight while on therapy with medroxyprogesterone acetate injectable suspension. From an initial average body weight of 136 lb, women who completed 1 year of therapy with medroxyprogesterone acetate injectable suspension gained an average of 5.4 lb. Women who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain. 5.12 Carbohydrate Metabolism A decrease in glucose tolerance has been observed in some patients on medroxyprogesterone acetate injectable suspension treatment. Monitor diabetic patients carefully while receiving medroxyprogesterone acetate injectable suspension. 5.13 Lactation Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. In nursing mothers treated with medroxyprogesterone acetate injectable suspension, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted.

g mothers treated with medroxyprogesterone acetate injectable suspension, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted. 5.14 Fluid Retention Because progestational drugs including medroxyprogesterone acetate injectable suspension may cause some degree of fluid retention, monitor patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction. 5.15 Return of Fertility Return to ovulation and fertility is likely to be delayed after stopping medroxyprogesterone acetate injectable suspension. In a large U.S. study of women who discontinued use of medroxyprogesterone acetate injectable suspension to become pregnant, data are available for 61% of them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception for those who do conceive is 10 months following the last injection with a range of 4 to 31 months, and is unrelated to the duration of use. No data are available for 39% of the patients who discontinued medroxyprogesterone acetate injectable suspension to become pregnant and who were lost to follow-up or changed their mind. 5.16 Sexually Transmitted Diseases Patients should be counseled that medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 5.17 Pregnancy Although medroxyprogesterone acetate injectable suspension should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development. 5.18 Monitoring A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.19 Interference With Laboratory Tests The use of medroxyprogesterone acetate injectable suspension may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. [See Drug Interactions ( 7.2 ).]

6 ADVERSE REACTIONS The following important adverse reactions observed with the use of medroxyprogesterone acetate injectable suspension are discussed in greater detail in the Warnings and Precautions section ( 5 ): Loss of Bone Mineral Density [ see Warnings and Precautions ( 5.1 ) ] Thromboembolic disease [ see Warnings and Precautions ( 5.2 ) ] Breast Cancer [ see Warnings and Precautions ( 5.3 ) ] Anaphylaxis and Anaphylactoid Reactions [ see Warnings and Precautions ( 5.5 ) ] Bleeding Irregularities [ see Warnings and Precautions ( 5. 10) ] Weight Gain [ see Warnings and Precautions ( 5. 11) ] Most common adverse reactions (incidence >5%) are: menstrual irregularities (bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal pain/discomfort 11%, weight gain > 10 lbs at 24 months 38%, dizziness 6%, headache 17%, nervousness 11%, decreased libido 6%. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the two clinical trials with medroxyprogesterone acetate injectable suspension, over 3,900 women, who were treated for up to 7 years, reported the following adverse reactions, which may or may not be related to the use of medroxyprogesterone acetate injectable suspension. The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and 4.9% Unknown race. The patients received 150 mg medroxyprogesterone acetate injectable suspension every 3-months (90 days). The median study duration was 13 months with a range of 1 to 84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months. Table 1 Adverse Reactions that Were Reported by More than 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Headache (16.5%) Abdominal pain/discomfort (11.2%) Metabolic/Nutritional Increased weight> 10lbs at 24 months (37.7%) Nervous Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) Urogenital Menstrual irregularities: (bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) * Body System represented from COSTART medical dictionary. Table 2 Adverse Reactions that Were Reported by between 1 and 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) Digestive Nausea (3.3%) Bloating (2.3%) Metabolic/Nutritional Edema (2.2%) Musculoskeletal Leg cramps (3.7%) Arthralgia (1.0%) Nervous Depression (1.5%) Insomnia (1.0%) Skin and Appendages Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) Urogenital Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) * Body System represented from COSTART medical dictionary. Adverse reactions leading to study discontinuation in ≥ 2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension.

from COSTART medical dictionary. Adverse reactions leading to study discontinuation in ≥ 2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking medroxyprogesterone acetate injectable suspension. Table 3 Adverse Reactions Reported during Post-Marketing Experience Body System Body System represented from COSTART medical dictionary. Adverse Reactions Body as a Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess Injection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension in order to avoid injection site infections [see Dosage and Administration (2.1)]. , Injection site infection , Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swelling Cardiovascular Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins Digestive Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding Hematologic and Lymphatic Anemia, Blood dyscrasia Musculoskeletal Osteoporosis Neoplasms Cervical cancer, Breast cancer Nervous Paralysis, Facial palsy, Paresthesia, Drowsiness Respiratory Dyspnea and asthma, Hoarseness Skin and Appendages Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma Urogenital Lack of return to fertility, Unexpected pregnancy, Prevention of lactation, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Melasma, Chloasma, Increased libido, Uterine hyperplasia, Genitourinary infections, Vaginal cysts, Dyspareunia

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="50%"/><col width="50%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System* </content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reactions [Incidence (%)] </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole </content> </td><td styleCode="Rrule" valign="top">Headache (16.5%) Abdominal pain/discomfort (11.2%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Metabolic/Nutritional </content> </td><td styleCode="Rrule" valign="middle">Increased weight&gt; 10lbs at 24 months (37.7%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous </content> </td><td styleCode="Rrule" valign="top">Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital </content> </td><td styleCode="Rrule" valign="top">Menstrual irregularities: (bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) </td></tr></tbody></table>

) Libido decreased (5.5%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital </content> </td><td styleCode="Rrule" valign="top">Menstrual irregularities: (bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="98%"><colgroup><col width="46.58%"/><col width="53.42%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System* </content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reactions [Incidence (%)] </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole </content> </td><td styleCode="Rrule" valign="top">Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Digestive </content> </td><td styleCode="Rrule" valign="top">Nausea (3.3%) Bloating (2.3%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Metabolic/Nutritional </content> </td><td styleCode="Rrule" valign="middle">Edema (2.2%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal </content> </td><td styleCode="Rrule" valign="top">Leg cramps (3.7%) Arthralgia (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous </content> </td><td styleCode="Rrule" valign="top">Depression (1.5%) Insomnia (1.0%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Skin and Appendages </content> </td><td styleCode="Rrule" valign="top">Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital </content> </td><td styleCode="Rrule" valign="top">Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) </td></tr></tbody></table>

> </td><td styleCode="Rrule" valign="top">Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital </content> </td><td styleCode="Rrule" valign="top">Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0"><caption>Table 3 Adverse Reactions Reported during Post-Marketing Experience </caption><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System<footnote ID="fn10719">Body System represented from COSTART medical dictionary.

e cellspacing="0" cellpadding="0" border="0"><caption>Table 3 Adverse Reactions Reported during Post-Marketing Experience </caption><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body System<footnote ID="fn10719">Body System represented from COSTART medical dictionary. </footnote></content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reactions </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole </content> </td><td styleCode="Rrule" align="justify" valign="top">Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess<footnote ID="fn10721">Injection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension in order to avoid injection site infections [see Dosage and Administration (2.1)].</footnote>, Injection site infection<footnoteRef IDREF="fn10721"/>, Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swelling </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular </content> </td><td styleCode="Rrule" align="justify" valign="top">Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Digestive </content> </td><td styleCode="Rrule" align="justify" valign="top">Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Hematologic and Lymphatic </content> </td><td styleCode="Rrule" align="justify" valign="middle">Anemia, Blood dyscrasia </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Musculoskeletal </content> </td><td styleCode="Rrule" align="justify" valign="middle">Osteoporosis </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Neoplasms </content> </td><td styleCode="Rrule" align="justify" valign="middle">Cervical cancer, Breast cancer </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Nervous </content> </td><td styleCode="Rrule" align="justify" valign="middle">Paralysis, Facial palsy, Paresthesia, Drowsiness </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Respiratory </content> </td><td styleCode="Rrule" align="justify" valign="middle">Dyspnea and asthma, Hoarseness </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Skin and Appendages </content> </td><td styleCode="Rrule" align="justify" valign="top">Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital </content> </td><td styleCode="Rrule" align="justify" valign="top">Lack of return to fertility, Unexpected pregnancy, Prevention of lactation, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Melasma, Chloasma, Increased libido, Uterine hyperplasia, Genitourinary infections, Vaginal cysts, Dyspareunia </td></tr></tbody></table>

7 DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of contraceptive drug products. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. ( 7.1 ) 7.1 Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of coadministration of HIV protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Laboratory Test Interactions The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including medroxyprogesterone acetate injectable suspension: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Gonadotropin levels are decreased. (c) Sex-hormone-binding-globulin concentrations are decreased. (d) Protein-bound iodine and butanol extractable protein-bound iodine may increase. T3-uptake values may decrease. (e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. (f) Sulfobromophthalein and other liver function test values may be increased. (g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

8 USE IN SPECIFIC POPULATIONS Nursing Mothers : Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. ( 8.3 ) Pediatric Patients : Medroxyprogesterone acetate injectable suspension is not indicated before menarche. ( 8.4 ) 8.1 Pregnancy Medroxyprogesterone acetate injectable suspension should not be administered during pregnancy. [ See Contraindications and Warnings and Precautions ( 5.1 7).] 8.3 Nursing Mothers Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. [ See Warnings and Precautions ( 5.1 3) .] 8.4 Pediatric Use Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women. 8.5 Geriatric Use This product has not been studied in post-menopausal women and is not indicated in this population. 8.6 Renal Impairment The effect of renal impairment on medroxyprogesterone acetate injectable suspension pharmacokinetics has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on medroxyprogesterone acetate injectable suspension pharmacokinetics has not been studied. Medroxyprogesterone acetate injectable suspension should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur. [ See Contraindications ( 4 ) and Warnings and Precautions ( 5. 7) .]

11 DESCRIPTION Medroxyprogesterone acetate injectable suspension, USP, a contraceptive injection, contains medroxyprogesterone acetate, USP a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white or almost white, crystalline powder that is stable in air and that melts between 205°C and 209°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α-). The structural formula is as follows: Medroxyprogesterone acetate injectable suspension, USP for IM injection is available in prefilled syringe containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. For Medroxyprogesterone acetate injectable suspension prefilled syringe, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.90 mg Polysorbate 80 2.41 mg Sodium chloride 8.68 mg Methylparaben 1.37 mg Propylparaben 0.15 mg Water for injection quantity sufficient When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. spl-medroxy-structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Medroxyprogesterone acetate (MPA) injectable suspension, inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect. 12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted with medroxyprogesterone acetate injectable suspension. 12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21- positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate injectable suspension is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.

12.1 Mechanism of Action Medroxyprogesterone acetate (MPA) injectable suspension, inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect.

12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21- positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate injectable suspension is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.

14 CLINICAL STUDIES 14.1 Contraception In five clinical studies using medroxyprogesterone acetate injectable suspension, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate injectable suspension was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of medroxyprogesterone acetate injectable suspension is dependent on the patient returning every 3 months (13 weeks) for reinjection. 14.2 Bone Mineral Density Changes in Adult Women Treated with Medroxyprogesterone Acetate Injectable Suspension In a controlled, clinical study, adult women using medroxyprogesterone acetate injectable suspension (150 mg) for up to 5 years showed spine and hip bone mineral density (BMD) mean decreases of 5 to 6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. After stopping use of medroxyprogesterone acetate injectable suspension, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table 4 shows the change in BMD in women after 5 years of treatment with medroxyprogesterone acetate injectable suspension and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2 year post-treatment data were available. Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) Time in Study Spine Total Hip Femoral Neck Medroxyprogesterone Acetate Injectable Suspension The treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for 5 years and were then followed for 2 years post-use (total time in study of 7 years). Control The control group consisted of women who did not use hormonal contraception and were followed for 7 years. Medroxyprogesterone Acetate Injectable Suspension Control Medroxyprogesterone Acetate Injectable Suspension Control 5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106 7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63 14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Medroxyprogesterone Acetate Injectable Suspension The impact of medroxyprogesterone acetate injectable suspension (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of medroxyprogesterone acetate injectable suspension was associated with a significant decline from baseline in BMD. Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per medroxyprogesterone acetate injectable suspension user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

gesterone acetate injectable suspension user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of BMD. Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort Duration of Treatment Medroxyprogesterone Acetate Injectable Suspension (150 mg IM) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) 113 73 28 -2.75 -5.40 -6.40 166 109 84 1.22 2.19 1.71 Femoral Neck BMD Week 60 Week 120 Week 240 113 73 28 -2.96 -5.30 -5.40 166 108 84 1.75 2.83 1.94 Lumbar Spine BMD Week 60 Week 120 Week 240 114 73 27 -2.47 -2.74 -2.11 167 109 84 3.39 5.28 6.40 BMD Recovery Post-Treatment in Adolescents Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of medroxyprogesterone acetate injectable suspension. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received medroxyprogesterone acetate injectable suspension for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with medroxyprogesterone acetate injectable suspension for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period (data not shown) [see Warnings and Precautions (5.1)] . Table 6: BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone Acetate Injectable Suspension Use (2 Years or Less vs. More than 2 Years) Duration of Treatment 2 years or less More than 2 years N Mean % Change from baseline N Mean % Change from baseline Total Hip BMD End of Treatment 49 -1.5% 49 -6.2% 12 M post-treatment 33 -1.4% 24 -4.6% 24 M post-treatment 18 0.3% 17 -3.6% 36 M post-treatment 12 2.1% 11 -4.6% 48 M post-treatment 10 1.3% 9 -2.5% 60 M post-treatment 3 0.2% 2 -1.0% Femoral Neck BMD End of Treatment 49 -1.6% 49 -5.8% 12 M post-treatment 33 -1.4% 24 -4.3% 24 M post-treatment 18 0.5% 17 -3.8% 36 M post-treatment 12 1.2% 11 -3.8% 48 M post-treatment 10 2.0% 9 -1.7% 60 M post-treatment 3 1.0% 2 -1.9% Lumbar Spine BMD End of Treatment 49 -0.9% 49 -3.5% 12 M post-treatment 33 0.4% 23 -1.1% 24 M post-treatment 18 2.6% 17 1.9% 36 M post-treatment 12 2.4% 11 0.6% 48 M post-treatment 10 6.5% 9 3.5% 60 M post-treatment 3 6.2% 2 5.7% 14.4 Bone Fracture Incidence in Women Treated with Medroxyprogesterone Acetate Injectable Suspension A retrospective cohort study to assess the association between medroxyprogesterone acetate injectable suspension and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the U.K. The incidence rates of fracture were compared between medroxyprogesterone acetate injectable suspension users and contraceptive users who had no recorded use of medroxyprogesterone acetate injectable suspension . The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47).

tes of fracture were compared between medroxyprogesterone acetate injectable suspension users and contraceptive users who had no recorded use of medroxyprogesterone acetate injectable suspension . The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to medroxyprogesterone acetate injectable suspension use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to medroxyprogesterone acetate injectable suspension was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use. There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in medroxyprogesterone acetate injectable suspension users compared to non-users. Importantly, this study could not determine whether use of medroxyprogesterone acetate injectable suspension has an effect on fracture rate later in life.

<table cellspacing="0" cellpadding="0" border="0" width="129.01"><caption>Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) </caption><colgroup><col width="8%"/><col width="21%"/><col width="9%"/><col width="22%"/><col width="9%"/><col width="20%"/><col width="8%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom"> <content styleCode="bold">Time in Study </content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Spine</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Total Hip</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Femoral Neck</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Medroxyprogesterone Acetate Injectable Suspension<footnote ID="fn10722">The treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for 5 years and were then followed for 2 years post-use (total time in study of 7 years).</footnote></content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Control<footnote ID="fn10723">The control group consisted of women who did not use hormonal contraception and were followed for 7 years.</footnote><sup/></content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Medroxyprogesterone Acetate Injectable Suspension<footnoteRef IDREF="fn10722"/></content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Control<footnoteRef IDREF="fn10723"/><sup/></content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Medroxyprogesterone Acetate Injectable Suspension<footnoteRef IDREF="fn10722"/></content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Control<footnoteRef IDREF="fn10723"/><sup/></content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> 5 years </td><td styleCode="Rrule" align="center" valign="middle"> -5.38% n=33 </td><td styleCode="Rrule" align="center" valign="middle"> 0.43% n=105 </td><td styleCode="Rrule" align="center" valign="middle"> -5.16% n=21 </td><td styleCode="Rrule" align="center" valign="middle"> 0.19% n=65 </td><td styleCode="Rrule" align="center" valign="middle"> -6.12% n=34 </td><td styleCode="Rrule" align="center" valign="middle"> -0.27% n=106 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> 7 years </td><td styleCode="Rrule" align="center" valign="middle"> -3.13% n=12 </td><td styleCode="Rrule" align="center" valign="middle"> 0.53% n=60 </td><td styleCode="Rrule" align="center" valign="middle"> -1.34% n=7 </td><td styleCode="Rrule" align="center" valign="middle"> 0.94% n=39 </td><td styleCode="Rrule" align="center" valign="middle"> -5.38% n=13 </td><td styleCode="Rrule" align="center" valign="middle"> -0.11% n=63 </td></tr></tbody></table>

0.53% n=60 </td><td styleCode="Rrule" align="center" valign="middle"> -1.34% n=7 </td><td styleCode="Rrule" align="center" valign="middle"> 0.94% n=39 </td><td styleCode="Rrule" align="center" valign="middle"> -5.38% n=13 </td><td styleCode="Rrule" align="center" valign="middle"> -0.11% n=63 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="25%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="18%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Duration of Treatment</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Medroxyprogesterone Acetate Injectable Suspension</content> <content styleCode="bold">(150 mg IM)</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Unmatched, Untreated Cohort</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom"/><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Mean % Change</content> </td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Mean % Change</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Total Hip BMD</content> Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) </td><td styleCode="Rrule" align="center" valign="bottom">113 73 28 </td><td styleCode="Rrule" align="center" valign="bottom">-2.75 -5.40 -6.40 </td><td styleCode="Rrule" align="center" valign="bottom">166 109 84 </td><td styleCode="Rrule" align="center" valign="bottom">1.22 2.19 1.71 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Femoral Neck BMD</content> Week 60 Week 120 Week 240 </td><td styleCode="Rrule" align="center" valign="bottom">113 73 28 </td><td styleCode="Rrule" align="center" valign="bottom">-2.96 -5.30 -5.40 </td><td styleCode="Rrule" align="center" valign="bottom">166 108 84 </td><td styleCode="Rrule" align="center" valign="bottom">1.75 2.83 1.94 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Lumbar Spine BMD</content> Week 60 Week 120 Week 240 </td><td styleCode="Rrule" align="center" valign="bottom">114 73 27 </td><td styleCode="Rrule" align="center" valign="bottom">-2.47 -2.74 -2.11 </td><td styleCode="Rrule" align="center" valign="bottom">167 109 84 </td><td styleCode="Rrule" align="center" valign="bottom">3.39 5.28 6.40 </td></tr></tbody></table>

eek 240 </td><td styleCode="Rrule" align="center" valign="bottom">114 73 27 </td><td styleCode="Rrule" align="center" valign="bottom">-2.47 -2.74 -2.11 </td><td styleCode="Rrule" align="center" valign="bottom">167 109 84 </td><td styleCode="Rrule" align="center" valign="bottom">3.39 5.28 6.40 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="29%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> <content styleCode="bold"> Duration of Treatment </content></td><td styleCode="Rrule" colspan="2" align="left" valign="middle"> <content styleCode="bold">2 years or less</content></td><td styleCode="Rrule" colspan="2" align="left" valign="middle"> <content styleCode="bold">More than 2 years</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> <content styleCode="bold"/></td><td styleCode="Rrule" align="left" valign="middle"> <content styleCode="bold"> N</content></td><td styleCode="Rrule" align="left" valign="middle"> <content styleCode="bold"> Mean % Change </content> <content styleCode="bold">from baseline</content></td><td styleCode="Rrule" align="left" valign="middle"> <content styleCode="bold">N</content></td><td styleCode="Rrule" align="left" valign="middle"> <content styleCode="bold"> Mean % Change </content> <content styleCode="bold">from baseline</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="left" valign="middle"> <content styleCode="bold">Total Hip BMD</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> <content styleCode="bold"> End of Treatment </content></td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -1.5% </td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -6.2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 12 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 33 </td><td styleCode="Rrule" align="left" valign="middle"> -1.4% </td><td styleCode="Rrule" align="left" valign="middle"> 24 </td><td styleCode="Rrule" align="left" valign="middle"> -4.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 24 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 18 </td><td styleCode="Rrule" align="left" valign="middle"> 0.3% </td><td styleCode="Rrule" align="left" valign="middle"> 17 </td><td styleCode="Rrule" align="left" valign="middle"> -3.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 36 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 12 </td><td styleCode="Rrule" align="left" valign="middle"> 2.1% </td><td styleCode="Rrule" align="left" valign="middle"> 11 </td><td styleCode="Rrule" align="left" valign="middle"> -4.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 48 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 10 </td><td styleCode="Rrule" align="left" valign="middle"> 1.3% </td><td styleCode="Rrule" align="left" valign="middle"> 9 </td><td styleCode="Rrule" align="left" valign="middle"> -2.5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 60 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 3 </td><td styleCode="Rrule" align="left" valign="middle"> 0.2% </td><td styleCode="Rrule" align="left" valign="middle"> 2 </td><td styleCode="Rrule" align="left" valign="middle">

rule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 60 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 3 </td><td styleCode="Rrule" align="left" valign="middle"> 0.2% </td><td styleCode="Rrule" align="left" valign="middle"> 2 </td><td styleCode="Rrule" align="left" valign="middle"> -1.0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="left" valign="middle"> <content styleCode="bold">Femoral Neck BMD</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> <content styleCode="bold"> End of Treatment </content></td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -1.6% </td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -5.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 12 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 33 </td><td styleCode="Rrule" align="left" valign="middle"> -1.4% </td><td styleCode="Rrule" align="left" valign="middle"> 24 </td><td styleCode="Rrule" align="left" valign="middle"> -4.3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 24 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 18 </td><td styleCode="Rrule" align="left" valign="middle"> 0.5% </td><td styleCode="Rrule" align="left" valign="middle"> 17 </td><td styleCode="Rrule" align="left" valign="middle"> -3.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 36 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 12 </td><td styleCode="Rrule" align="left" valign="middle"> 1.2% </td><td styleCode="Rrule" align="left" valign="middle"> 11 </td><td styleCode="Rrule" align="left" valign="middle"> -3.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 48 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 10 </td><td styleCode="Rrule" align="left" valign="middle"> 2.0% </td><td styleCode="Rrule" align="left" valign="middle"> 9 </td><td styleCode="Rrule" align="left" valign="middle"> -1.7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 60 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 3 </td><td styleCode="Rrule" align="left" valign="middle"> 1.0% </td><td styleCode="Rrule" align="left" valign="middle"> 2 </td><td styleCode="Rrule" align="left" valign="middle"> -1.9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" align="left" valign="middle"> <content styleCode="bold">Lumbar Spine BMD</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> <content styleCode="bold"> End of Treatment </content></td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -0.9% </td><td styleCode="Rrule" align="left" valign="middle"> 49 </td><td styleCode="Rrule" align="left" valign="middle"> -3.5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 12 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 33 </td><td styleCode="Rrule" align="left" valign="middle"> 0.4% </td><td styleCode="Rrule" align="left" valign="middle"> 23 </td><td styleCode="Rrule" align="left" valign="middle"> -1.1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 24 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 18 </td><td styleCode="Rrule" align="left" valign="middle"> 2.6% </td><td styleCode="Rrule" al

td styleCode="Rrule" align="left" valign="middle"> -1.1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 24 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 18 </td><td styleCode="Rrule" align="left" valign="middle"> 2.6% </td><td styleCode="Rrule" al ign="left" valign="middle"> 17 </td><td styleCode="Rrule" align="left" valign="middle"> 1.9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 36 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 12 </td><td styleCode="Rrule" align="left" valign="middle"> 2.4% </td><td styleCode="Rrule" align="left" valign="middle"> 11 </td><td styleCode="Rrule" align="left" valign="middle"> 0.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> 48 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 10 </td><td styleCode="Rrule" align="left" valign="middle"> 6.5% </td><td styleCode="Rrule" align="left" valign="middle"> 9 </td><td styleCode="Rrule" align="left" valign="middle"> 3.5% </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="middle"> 60 M post-treatment </td><td styleCode="Rrule" align="left" valign="middle"> 3 </td><td styleCode="Rrule" align="left" valign="middle"> 6.2% </td><td styleCode="Rrule" align="left" valign="middle"> 2 </td><td styleCode="Rrule" align="left" valign="middle"> 5.7% </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Medroxyprogesterone acetate injectable suspension, USP is supplied as follows: Package Configuration Strength NDC Medroxyprogesterone acetate injectable suspension, USP, 150 mg/mL, 1 mL Prefilled Syringe packed with 22 gauge x 1 1/2 inch Terumo SurGuard ® Needles 1 mL prefilled syringe 150 mg/mL NDC 62756-091-40 Stored at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="41%"/><col width="23%"/><col width="34%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Package Configuration </td><td styleCode="Rrule" valign="bottom">Strength </td><td styleCode="Rrule" valign="bottom">NDC </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" valign="top"><content styleCode="bold">Medroxyprogesterone acetate injectable suspension, USP, 150 mg/mL, 1 mL Prefilled Syringe packed with 22 gauge x 1 1/2 inch Terumo SurGuard^&#xAE; Needles</content> </td></tr><tr><td styleCode="Lrule Rrule" valign="top">1 mL prefilled syringe </td><td styleCode="Rrule" valign="middle">150 mg/mL </td><td styleCode="Rrule" valign="top">NDC 62756-091-40 </td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION "See FDA-approved patient labeling (Patient Information)." Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with medroxyprogesterone acetate injectable suspension continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use medroxyprogesterone acetate injectable suspension [ see Warnings and Precautions ( 5.3 ) ]. Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Counsel patients on Warnings and Precautions associated with use of medroxyprogesterone acetate injectable suspension. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Limited Halol-Baroda Highway, Halol-389 350, Gujarat, India.

PATIENT INFORMATION Medroxyprogesterone Acetate (med ROX ee proe JES ter one AS e tate) Injectable Suspension, USP Read this Patient Information carefully before you decide if medroxyprogesterone acetate injectable suspension is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women's health. If you have any questions about medroxyprogesterone acetate injectable suspension, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. What is the most important information I should know about medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension can cause serious side effects, including: Use of medroxyprogesterone acetate injectable suspension may cause you to lose calcium stored in your bone and decrease your bone mass. The longer you use medroxyprogesterone acetate injectable suspension, the greater your loss of calcium from your bones. Your bones may not recover completely when you stop using medroxyprogesterone acetate injectable suspension. If you use medroxyprogesterone acetate injectable suspension continuously for a long time (for more than 2 years), it may increase the risk of weak, porous bones (osteoporosis) that could increase the risk of broken bones, especially after menopause. You should not use medroxyprogesterone acetate injectable suspension for more than two years unless you cannot use other birth control methods. It is not known if your risk of developing osteoporosis is greater if you are a teenager or young adult when you start to use medroxyprogesterone acetate injectable suspension (see "What are the possible side effects of medroxyprogesterone acetate injectable suspension?"). Medroxyprogesterone acetate injectable suspension is intended to prevent pregnancy. Medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted diseases (STDs). What is medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is a progestin hormone birth control method that is given by injection (a shot) to prevent pregnancy. How well does medroxyprogesterone acetate injectable suspension work? Your chance of getting pregnant depends on how well you follow the directions for taking your medroxyprogesterone acetate injectable suspension. The more carefully you follow the directions (such as returning every 3 months for your next injection), the less chance you have of getting pregnant. In clinical studies, about 1 out of 100 women got pregnant during the first year that they used medroxyprogesterone acetate injectable suspension. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. How should I take medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is given by your healthcare provider as a shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm 1 time every 3 months.

control and are trying to get pregnant. How should I take medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension is given by your healthcare provider as a shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm 1 time every 3 months. At the end of the 3 months, you will need to return to your healthcare provider for your next injection in order to continue your protection against pregnancy . To make sure that you are not pregnant before you take medroxyprogesterone acetate injectable suspension, the first injection should be given only: during the first 5 days of a normal menstrual period, or within the first 5 days after giving birth, if you are not breastfeeding , or at the 6 th week after giving birth, if you are feeding your baby only breastmilk. Medroxyprogesterone acetate injectable suspension may be given at other times than those listed above, but you will likely need to have a pregnancy test first to show that you are not pregnant. During treatment with medroxyprogesterone acetate injectable suspension, you should see your healthcare provider every year for a blood pressure check and other healthcare needs. Who should not use medroxyprogesterone acetate injectable suspension? Do not use medroxyprogesterone acetate injectable suspension if you: are pregnant or think you might be pregnant have bleeding from your vagina that has not been explained have breast cancer now or in the past, or think you have breast cancer have had a stroke ever had blood clots in your arms, legs or lungs have problems with your liver or liver disease are allergic to medroxyprogesterone acetate or any of the other ingredients in medroxyprogesterone acetate injectable suspension. See the end of this leaflet for a complete list of ingredients in medroxyprogesterone acetate injectable suspension. What should I tell my healthcare provider before taking medroxyprogesterone acetate injectable suspension? Before taking medroxyprogesterone acetate injectable suspension, tell your healthcare provider if you have: risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or smoke regularly, anorexia nervosa, or a strong family history of osteoporosis irregular or lighter than usual menstrual periods breast cancer now or in the past, or think you have breast cancer a family history of breast cancer an abnormal mammogram (breast X-ray), lumps in your breasts, or bleeding from your nipples kidney problems high blood pressure had a stroke had blood clots in your arms, legs or lungs migraine headaches asthma epilepsy (convulsions or seizures) diabetes depression or a history of depression any other medical conditions If you are breastfeeding or plan to breastfeed, medroxyprogesterone acetate can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take medroxyprogesterone acetate injectable suspension. Tell your healthcare provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Medroxyprogesterone acetate injectable suspension and certain other medicines may affect each other, causing serious side effects. Sometimes the doses of other medicines may need to be changed while you are taking medroxyprogesterone acetate injectable suspension. Some medicines may make medroxyprogesterone acetate injectable suspension less effective at preventing pregnancy, including those listed below. Especially tell your healthcare provider if you take: medicine to help you sleep bosentan medicine for seizures griseofulvin an antibiotic medicine for HIV (AIDS) St. John's wort Know the medicines you take.

progesterone acetate injectable suspension less effective at preventing pregnancy, including those listed below. Especially tell your healthcare provider if you take: medicine to help you sleep bosentan medicine for seizures griseofulvin an antibiotic medicine for HIV (AIDS) St. John's wort Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider or pharmacist before you first start taking medroxyprogesterone acetate injectable suspension or when you get a new medicine. Follow your healthcare provider's instructions about using a back-up method of birth control if you are taking medicines that may make medroxyprogesterone acetate injectable suspension less effective. What are the possible side effects of medroxyprogesterone acetate injectable suspension? Medroxyprogesterone acetate injectable suspension can cause serious side effects, including: Effect on the bones: See "What is the most important information I should know about medroxyprogesterone acetate injectable suspension?" Teenage years are the most important years to gain bone strength. The decrease in calcium in your bones is of most concern if you are a teenager or have the following problems: bone disease an eating disorder (anorexia nervosa) a strong family history of osteoporosis you take a drug that can lower the amount of calcium in your bones (drugs for epilepsy or steroid drugs) you drink a lot of alcohol (more than 2 drinks a day) you smoke If you need a birth control method for more than 2 years, your healthcare provider may switch you to another birth control method instead of using medroxyprogesterone acetate injectable suspension. If you continue using medroxyprogesterone acetate injectable suspension, your healthcare provider may ask you to have a bone test, especially if you have other risks for weak bones. When medroxyprogesterone acetate injectable suspension is stopped, your bones may start to regain calcium. However, in a study of teenage girls who used medroxyprogesterone acetate injectable suspension for more than 2 years, their hip bones did not completely recover by 5 years after they stopped using medroxyprogesterone acetate injectable suspension. Taking calcium and Vitamin D and exercising daily may lessen the loss of calcium from your bones. possible increased risk of breast cancer. Women who use medroxyprogesterone acetate injectable suspension may have a slightly increased risk of breast cancer compared to non-users. blood clots in your arms, legs, lungs, and eyes stroke a pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. allergic reactions. Severe allergic reactions have been reported in some women using medroxyprogesterone acetate injectable suspension.

de of your uterus (ectopic pregnancy). Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death. allergic reactions. Severe allergic reactions have been reported in some women using medroxyprogesterone acetate injectable suspension. loss of vision or other eye problems migraine headaches depression convulsions or seizures liver problems Call your healthcare provider right away if you have: sharp chest pain, coughing up blood, or sudden shortness of breath (indicating a possible clot in the lung) sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) severe pain or swelling in the calf (indicating a possible clot in the leg) sudden blindness, partial or complete (indicating a possible clot in the blood vessels of the eye) unusually heavy vaginal bleeding severe pain or tenderness in the lower abdominal area persistent pain, pus, or bleeding at the injection site yellowing of the eyes or skin hives difficulty breathing swelling of the face, mouth, tongue or neck The most common side effects of medroxyprogesterone acetate injectable suspension include: irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or continued spotting weight gain. You may experience weight gain while you are using medroxyprogesterone acetate injectable suspension. About two-thirds of the women who used medroxyprogesterone acetate injectable suspension in the clinical trials reported a weight gain of about 5 pounds during the first year of use. You may continue to gain weight after the first year. Women who used medroxyprogesterone acetate injectable suspension for 2 years gained an average of 8 pounds over those 2 years. abdominal pain headache weakness tiredness nervousness dizziness Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of medroxyprogesterone acetate injectable suspension. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What other information should I know before choosing medroxyprogesterone acetate injectable suspension? Pregnancy . When you take medroxyprogesterone acetate injectable suspension every 3 months, your chance of getting pregnant is very low. You could miss a period or have a light period and not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see your healthcare provider as soon as possible. You should not use medroxyprogesterone acetate injectable suspension if you are pregnant. However, medroxyprogesterone acetate injectable suspension taken by accident during pregnancy does not seem to cause birth defects. Nursing Mothers . Although Medroxyprogesterone acetate injectable suspension can be passed to the nursing baby in the breast milk, no harmful effects on babies have been found. Medroxyprogesterone acetate injectable suspension does not stop the breasts from producing milk, so it can be used by nursing mothers. However, to minimize the amount of medroxyprogesterone acetate injectable suspension that is passed to the baby in the first weeks after birth, you should wait until your baby is 6 weeks old before you start using medroxyprogesterone acetate injectable suspension for birth control. How will medroxyprogesterone acetate injectable suspension change my periods? Change in normal menstrual cycle . The side effect reported most frequently by women who use medroxyprogesterone acetate injectable suspension for birth controls is a change in their normal menstrual cycle.

table suspension for birth control. How will medroxyprogesterone acetate injectable suspension change my periods? Change in normal menstrual cycle . The side effect reported most frequently by women who use medroxyprogesterone acetate injectable suspension for birth controls is a change in their normal menstrual cycle. During the first year of using medroxyprogesterone acetate injectable suspension, you might have one or more of the following changes: irregular or unpredictable bleeding or spotting an increase or decrease in menstrual bleeding no bleeding at all . In clinical studies of medroxyprogesterone acetate injectable suspension, 55% of women reported no menstrual bleeding (amenorrhea) after one year of use and 68% of women reported no menstrual bleeding after two years of use. Missed period . During the time you are using medroxyprogesterone acetate injectable suspension for birth controls, you may skip a period, or your periods may stop completely. If you have been receiving your shot of medroxyprogesterone acetate injectable suspension regularly every 3 months, then you are probably not pregnant. However, if you think that you may be pregnant, see your healthcare provider. Unusually heavy or continuous bleeding is not a usual effect of medroxyprogesterone acetate injectable suspension and if this happens you should see your healthcare provider right away. With continued use of medroxyprogesterone acetate injectable suspension, bleeding usually decreases and many women stop having periods completely. When you stop using medroxyprogesterone acetate injectable suspension your menstrual period will usually, in time, return to its normal cycle. What if I want to become pregnant? Because medroxyprogesterone acetate injectable suspension is a long-acting birth control method, it takes some time after your last shot for its effect to wear off. Most women who try to get pregnant after using Medroxyprogesterone acetate injectable suspension get pregnant within 18 months after their last shot. The length of time you use medroxyprogesterone acetate injectable suspension has no effect on how long it takes you to become pregnant after you stop using it. General Information about medroxyprogesterone acetate injectable suspension Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. This leaflet summarizes the most important information about medroxyprogesterone acetate injectable suspension. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about medroxyprogesterone acetate injectable suspension that is written for healthcare providers. What are the ingredients in medroxyprogesterone acetate injectable suspension? Active ingredient: medroxyprogesterone acetate Inactive ingredients: polyethylene glycol 3350, polysorbate 80, sodium chloride, methylparaben, propylparaben, and water for injection. When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. This Patient Information has been approved by the U.S. Food and Drug Administration. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Limited Halol-Baroda Highway, Halol-389 350, Gujarat, India. 5221314 ISS. 06/2021 spl-medroxy-pil

Rx only WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia . ) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders . ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use . ) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS , Malignant Neoplasm, Breast Cancer . ) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia . ) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders . ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use . ) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS , Malignant Neoplasm, Breast Cancer . ) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. What is the most important information I should know about medroxyprogesterone acetate tablets (a progestin hormone)? Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with medroxyprogesterone acetate.

DESCRIPTION Medroxyprogesterone acetate tablets, USP contain medroxyprogesterone acetate, USP which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. The structural formula is: C 24 H 34 O 4 M.W. 386.53 Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate, USP and the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn starch, and sodium lauryl sulfate. fig1

CLINICAL PHARMACOLOGY Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate 2.5 mg tablets or a single administration of two medroxyprogesterone acetate 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one medroxyprogesterone acetate 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1. Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 x 10 mg 1.01 (0.599) 2.65 (1.41) 6.95 (3.39) 12.1 (3.49) 78024 (47220) 64110 (42662) 8 x 2.5 mg 0.805 (0.413) 2.22 (1.39) 5.62 (2.79) 11.6 (2.81) 62748 (40146) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) *Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of medroxyprogesterone acetate tablets with food increases the bioavailability of MPA. A 10 mg dose of medroxyprogesterone acetate tablets, taken immediately before or after a meal, increased MPA C max (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Specific Populations Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Renal Insufficiency The effect of renal impairment on the pharmacokinetics of medroxyprogesterone acetate has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4.

tact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Renal Insufficiency The effect of renal impairment on the pharmacokinetics of medroxyprogesterone acetate has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA.

Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate 2.5 mg tablets or a single administration of two medroxyprogesterone acetate 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one medroxyprogesterone acetate 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1. Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 x 10 mg 1.01 (0.599) 2.65 (1.41) 6.95 (3.39) 12.1 (3.49) 78024 (47220) 64110 (42662) 8 x 2.5 mg 0.805 (0.413) 2.22 (1.39) 5.62 (2.79) 11.6 (2.81) 62748 (40146) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) *Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of medroxyprogesterone acetate tablets with food increases the bioavailability of MPA. A 10 mg dose of medroxyprogesterone acetate tablets, taken immediately before or after a meal, increased MPA C max (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Specific Populations Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Renal Insufficiency The effect of renal impairment on the pharmacokinetics of medroxyprogesterone acetate has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA.

<table width="800px" cellpadding="5"><caption>Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)</caption><col width="13%"/><col width="15%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="12%"/><col width="19%"/><tbody><tr><td align="center" valign="top" styleCode=" Botrule Toprule Rrule"> <paragraph>Tablet</paragraph><paragraph>Strength</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>C_max</paragraph><paragraph>(ng/mL)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>T_max</paragraph><paragraph>(h)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Auc_0-(&#x221E;)</paragraph><paragraph>(ng&#xB7;h/mL)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>t_1/2</paragraph><paragraph>(h)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Vd/f</paragraph><paragraph>(L)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule"> <paragraph>CL/f</paragraph><paragraph>(mL/min)</paragraph></td></tr><tr><td valign="top" colspan="7" styleCode=" Botrule Toprule"> <paragraph>Single Dose</paragraph></td></tr><tr><td align="center" valign="top" styleCode=" Toprule Rrule"> <paragraph>2 x 10 mg</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule Rrule"> <paragraph>1.01 (0.599)</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule Rrule"> <paragraph>2.65 (1.41)</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule Rrule"> <paragraph>6.95 (3.39)</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule Rrule"> <paragraph>12.1 (3.49)</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule Rrule"> <paragraph>78024</paragraph><paragraph>(47220)</paragraph></td><td align="center" valign="top" styleCode=" Toprule Lrule"> <paragraph>64110</paragraph><paragraph>(42662)</paragraph></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Rrule"> <paragraph>8 x 2.5 mg</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule Rrule"> <paragraph>0.805 (0.413)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule Rrule"> <paragraph>2.22 (1.39)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule Rrule"> <paragraph>5.62 (2.79)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule Rrule"> <paragraph>11.6 (2.81)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule Rrule"> <paragraph>62748</paragraph><paragraph>(40146)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Lrule"> <paragraph>74123</paragraph><paragraph>(35126)</paragraph></td></tr><tr><td valign="top" colspan="7" styleCode=" Botrule Toprule"> <paragraph>Multiple Dose</paragraph></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Toprule Rrule"> <paragraph>10 mg *</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0.71 (0.35)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2.83 (1.83)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>6.01 (3.16)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprul

ragraph>0.71 (0.35)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2.83 (1.83)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>6.01 (3.16)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprul e Lrule Rrule"> <paragraph>16.6 (15.0)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>40564</paragraph><paragraph>(38256)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule"> <paragraph>41963</paragraph><paragraph>(38402)</paragraph></td></tr></tbody></table>

CLINICAL STUDIES Effects on the Endometrium In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic medroxyprogesterone acetate (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg medroxyprogesterone acetate plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2. Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment* Histological Results Placebo (n=119) CEE † (n=119) Medroxyprogesterone Acetate ‡ + CEE (n=118) Normal/No hyperplasia (%) 116 (97) 45 (38) 112 (95) Simple (cystic) hyperplasia (%) 1 (1) 33 (28) 4 (3) Complex (adenomatous) hyperplasia (%) 1 (1) 27 (22) 2 (2) Atypia (%) 0 14 (12) 0 Adenocarcinoma (%) 1 (1) 0 0 * Includes most extreme abnormal result † CEE = conjugated equine estrogens 0.625 mg/day ‡ Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1 to 28), plus either 5 mg cyclic medroxyprogesterone acetate or 10 mg cyclic medroxyprogesterone acetate (days 15 to 28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic medroxyprogesterone acetate (days 15 to 28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3. Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year CEE * MPA † + CEE * (n=283) MPA 5 mg (n=277) MPA 10 mg (n=272) Cystic hyperplasia (%) 55 (19) 3 (1) 0 Adenomatous hyperplasia without atypia 2 (1) 0 0 * CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. † Cyclic medroxyprogesterone acetate on days 15 to 28 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

g to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 4: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS a,b Event Relative Risk CE/MPA vs placebo (95% nCI c ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99 to 1.53) 1.28 (1.00 to 1.63) 1.10 (0.70 to 1.75) 41 31 8 34 25 8 All strokes 1.31 (1.03 to 1.68) 33 25 Ischemic stroke 1.44 (1.09 to 1.90) 26 18 Deep vein thrombosis d 1.95 (1.43 to 2.67) 26 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breast cancer e 1.24 (1.01 to 1.54) 41 33 Colorectal cancer 0.61 (0.42 to 0.87) 10 16 Endometrial cancer d 0.81 (0.48 to 1.36) 6 7 Cervical cancer d 1.44 (0.47 to 4.42) 2 1 Hip fracture 0.67 (0.47 to 0.96) 11 16 Vertebral fractures d 0.65 (0.46 to 0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59 to 0.85) 44 62 Total fractures d 0.76 (0.69 to 0.83) 152 199 Overall mortality f 1.00 (0.83 to 1.19) 52 52 Global Index g 1.13 (1.02 to 1.25) 184 165 a. Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b. Results are based on centrally adjudicated data. c. Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d. Not included in “global index”. e. Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f. All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g. A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44 to 1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years.

of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia and PRECAUTIONS , Geriatric Use ).

<table width="800px" cellspacing="0" cellpadding="5"><caption>Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment*</caption><col width="473.4pt"/><col width="473.4pt"/><col width="473.4pt"/><col width="473.4pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Histological</paragraph><paragraph>Results</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CEE^&#x2020;</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Medroxyprogesterone Acetate^&#x2021; </paragraph><paragraph>+ CEE</paragraph><paragraph>(n=118)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Normal/No hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>116 (97)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45 (38)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>112 (95)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Simple (cystic) hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33 (28)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (3)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Complex (adenomatous) hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>27 (22)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Atypia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14 (12)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adenocarcinoma (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4">^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days</td></tr></tbody></table>

e Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4">^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days</td></tr></tbody></table> <table width="800px" cellspacing="0" cellpadding="5" border="1"><caption>Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year</caption><col/><col/><col/><col/><tbody><tr><td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CEE^*</paragraph></td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA^&#x2020; + CEE^*</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>(n=283)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA 5 mg</paragraph><paragraph>(n=277)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA 10 mg</paragraph><paragraph>(n=272)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cystic hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>55 (19)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adenomatous hyperplasia without atypia</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28</paragraph></td></tr></tbody></table>

Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28</paragraph></td></tr></tbody></table> <table width="800px" cellspacing="0" cellpadding="5" border="1"><caption>Table 4: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS ^a,b</caption><col width="135.9pt"/><col width="117pt"/><col width="99pt"/><col width="121.5pt"/><tbody><tr><td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk</paragraph><paragraph>CE/MPA vs placebo</paragraph><paragraph>(95% nCI^c)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CE/MPA</paragraph><paragraph>n = 8,506</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo</paragraph><paragraph>n = 8,102</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Absolute Risk per 10,000 Women-Years</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CHD events <content styleCode="italics"> Non-fatal MI</content> <content styleCode="italics"> CHD death</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.23 (0.99 to 1.53)</paragraph><paragraph><content styleCode="italics">1.28 (1.00 to 1.63)</content></paragraph><paragraph><content styleCode="italics">1.10 (0.70 to 1.75)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph><paragraph><content styleCode="italics">31</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>34</paragraph><paragraph><content styleCode="italics">25</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>All strokes</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.31 (1.03 to 1.68)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Ischemic stroke</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.44 (1.09 to 1.90)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">26</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">18</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Deep vein thrombosis^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.95 (1.43 to 2.67)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td align="center" styleCode=" Bot

center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td align="center" styleCode=" Bot rule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Invasive breast cancer^e</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (1.01 to 1.54)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Colorectal cancer</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.61 (0.42 to 0.87)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Endometrial cancer^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.81 (0.48 to 1.36)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cervical cancer^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.44 (0.47 to 4.42)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hip fracture</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.67 (0.47 to 0.96)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vertebral fractures^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 (0.46 to 0.92)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lower arm/wrist fractures^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.71 (0.59 to 0.85)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>62</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total fractures^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.76 (0.69 to 0.83)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>152</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>199</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality^f</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.00 (0.

Rrule"><paragraph>152</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>199</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality^f</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.00 (0. 83 to 1.19)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Global Index^g</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.13 (1.02 to 1.25)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>184</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a.Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. ^b.Results are based on centrally adjudicated data. ^c.Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ^d.Not included in &#x201C;global index&#x201D;. ^e.Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. ^f.All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ^g.A subset of the events was combined in a &#x201C;global index&#x201D;, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</paragraph></td></tr></tbody></table>

INDICATIONS AND USAGE Medroxyprogesterone acetate tablets, USP are indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. They are also indicated for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving daily oral conjugated estrogens 0.625 mg tablets.

CONTRAINDICATIONS Medroxyprogesterone acetate is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected, or history of breast cancer. Known or suspected estrogen- or progesterone-dependent neoplasia. Active DVT, PE, or a history of these conditions Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. Known anaphylactic reaction or angioedema to medroxyprogesterone acetate. Known liver impairment or disease. Known or suspected pregnancy.

WARNINGS See BOXED WARNINGS . 1. Cardiovascular Disorders. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See CLINICAL STUDIES . ) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES ). Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a.

be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo (see CLINICAL STUDIES ). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups. (See CLINICAL STUDIES . ) Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller, increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year.

py in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3. Probable Dementia In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS , Geriatric Use . ) 4. Visual Abnormalities Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.

PRECAUTIONS A. General Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe medroxyprogesterone acetate. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to medroxyprogesterone acetate. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy. C.

and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum. for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance. D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS . ) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. E. Pregnancy Medroxyprogesterone acetate should not be used during pregnancy. (See CONTRAINDICATIONS . ) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established. F. Nursing Mothers Medroxyprogesterone acetate should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins. G. Pediatric Use Medroxyprogesterone acetate tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone.

conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES . ) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS , Probable Dementia . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia . )

A. General Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum. for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS . ) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

E. Pregnancy Medroxyprogesterone acetate should not be used during pregnancy. (See CONTRAINDICATIONS . ) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established.

Medroxyprogesterone acetate should not be used during pregnancy. (See CONTRAINDICATIONS . ) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established.

H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES . ) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS , Probable Dementia . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia . )

ADVERSE REACTIONS See BOXED WARNINGS , WARNINGS , and PRECAUTIONS . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions have been reported in women taking medroxyprogesterone acetate tablets, without concomitant estrogens treatment: 1. Genitourinary system Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions. 2. Breasts Breast tenderness, mastodynia or galactorrhea has been reported. 3. Cardiovascular Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported. 4. Gastrointestinal Nausea, cholestatic jaundice. 5. Skin Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported. 6. Eyes Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis. 7. Central nervous system Mental depression, insomnia, somnolence, dizziness, headache, nervousness. 8. Miscellaneous Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance. The following adverse reactions have been reported with estrogen plus progestin therapy. 1. Genitourinary system Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas. 5. Skin Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes Retinal vascular thrombosis, intolerance to contact lenses. 7. Central nervous system Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. 8. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

OVERDOSAGE Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE plus MPA together with institution of appropriate symptomatic care.

DOSAGE AND ADMINISTRATION Secondary Amenorrhea Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate therapy. Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate. Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of medroxyprogesterone acetate has not been determined.

PATIENT INFORMATION MedroxyPROGESTERone Acetate (med rox″ ee proe jes′ ter one as′ etate) Tablets Read this Patient Information before you start taking medroxyprogesterone acetate tablets and read what you get each time you refill your medroxyprogesterone acetate tablets prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about medroxyprogesterone acetate tablets (a progestin hormone)? Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. You and your healthcare provider should talk regularly about whether you still need treatment with medroxyprogesterone acetate. What are medroxyprogesterone acetate tablets? Medroxyprogesterone acetate tablet is a medicine that contains medroxyprogesterone acetate, a progestin hormone. What are medroxyprogesterone acetate tablets used for? Medroxyprogesterone acetate tablets are used to: Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your healthcare provider about whether medroxyprogesterone acetate tablets are right for you. Reduce your chances of getting cancer of the uterus (womb). In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chance of getting cancer of the uterus (womb). Who should not take medroxyprogesterone acetate tablets? Do not start taking medroxyprogesterone acetate tablets if you: have unusual vaginal bleeding currently have or have had certain cancers Estrogen plus progestin may increase your chance of getting certain types of cancers, including cancer of the breast. If you have or have had cancer, talk with your healthcare provider about whether you should use medroxyprogesterone acetate tablets. had a stroke or heart attack currently have or have had blood clots currently have or have had liver problems are allergic to medroxyprogesterone acetate tablets or any of its ingredients See the list of ingredients in medroxyprogesterone acetate tablets at the end of this leaflet. think you may be pregnant Medroxyprogesterone acetate tablets are not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use medroxyprogesterone acetate tablets if the test is positive and talk to your healthcare provider. There may be an increased risk of minor birth defects in children whose mothers take medroxyprogesterone acetate tablets during the first 4 months of pregnancy. Medroxyprogesterone acetate tablets should not be used as a test for pregnancy. What should I tell my healthcare provider before taking medroxyprogesterone acetate tablets?

an increased risk of minor birth defects in children whose mothers take medroxyprogesterone acetate tablets during the first 4 months of pregnancy. Medroxyprogesterone acetate tablets should not be used as a test for pregnancy. What should I tell my healthcare provider before taking medroxyprogesterone acetate tablets? Before you take medroxyprogesterone acetate tablets, tell your healthcare provider if you: have any other medical problems Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis (severe pelvic pain), lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium in your blood. are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop taking medroxyprogesterone acetate tablets. are breast feeding The hormone in medroxyprogesterone acetate can pass into your breast milk. Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how medroxyprogesterone acetate tablets work. Medroxyprogesterone acetate tablets may also affect how other medicines work. How should I take medroxyprogesterone acetate tablets? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. The lowest effective dose of medroxyprogesterone acetate tablets has not been determined. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with medroxyprogesterone acetate tablets. Absence of menstrual period: Medroxyprogesterone acetate tablets may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. Abnormal Uterine Bleeding: Medroxyprogesterone acetate tablets may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, medroxyprogesterone acetate tablets may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month. What are the possible side effects of medroxyprogesterone acetate tablets? The following side effects have been reported with the use of medroxyprogesterone acetate tablets alone: breast tenderness breast milk secretion breakthrough bleeding spotting (minor vaginal bleeding) irregular periods amenorrhea (absence of menstrual periods) vaginal secretions headaches nervousness dizziness depression insomnia, sleepiness, fatigue premenstrual syndrome-like symptoms thrombophlebitis (inflamed veins) blood clot itching, hives, skin rash acne hair loss, hair growth abdominal discomfort nausea bloating fever increase in weight swelling changes in vision and sensitivity to contact lenses Call your healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of medroxyprogesterone acetate with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated.

r healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of medroxyprogesterone acetate with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: heart attack stroke blood clots dementia breast cancer cancer of the uterus cancer of the ovary high blood pressure high blood sugar gallbladder disease liver problems changes in your thyroid hormone levels enlargements of benign tumors (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision and speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue memory loss or confusion Less serious, but common side effects include: headache breast pain irregular vaginal bleeding or spotting stomach or abdominal cramps, bloating nausea and vomiting hair loss fluid retention vaginal yeast infection These are not all the possible side effects of medroxyprogesterone acetate with or without estrogen. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have side effect that bothers you or does not go away. You may report side effects to Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with medroxyprogesterone acetate tablets? Talk with your healthcare provider regularly about whether you should continue taking medroxyprogesterone acetate tablets. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while taking medroxyprogesterone acetate tablets. Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chance of getting heart disease. General information about safe and effective use of medroxyprogesterone acetate tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take medroxyprogesterone acetate tablets for conditions for which it was not prescribed. Do not give medroxyprogesterone acetate tablets to other people, even if they have the same symptoms you have. It may harm them. Keep medroxyprogesterone acetate tablets out of the reach of children. This leaflet provides a summary of the most important information about medroxyprogesterone acetate tablets. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about medroxyprogesterone acetate tablets that is written for health professionals. You can get more information by calling the toll-free number, 1-888-838-2872. What are the ingredients in medroxyprogesterone acetate tablets? Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn starch, and sodium lauryl sulfate.

ents in medroxyprogesterone acetate tablets? Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn starch, and sodium lauryl sulfate. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 3/2024

<table width="800px" cellpadding="5"><caption>Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)</caption><col width="13%"/><col width="15%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="12%"/><col width="19%"/><tbody><tr><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"> <paragraph>Tablet</paragraph><paragraph>Strength</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>C _max</paragraph><paragraph>(ng/mL)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>T _max</paragraph><paragraph>(h)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>Auc _0-(&#x221E;)</paragraph><paragraph>(ng&#xB7;h/mL)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>t _1/2</paragraph><paragraph>(h)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>Vd/f</paragraph><paragraph>(L)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule" valign="top"> <paragraph>CL/f</paragraph><paragraph>(mL/min)</paragraph></td></tr><tr><td colspan="7" styleCode=" Botrule Toprule" valign="top"> <paragraph>Single Dose</paragraph></td></tr><tr><td align="center" styleCode=" Toprule Rrule" valign="top"> <paragraph>2 x 10 mg</paragraph></td><td align="center" styleCode=" Toprule Lrule Rrule" valign="top"> <paragraph>1.01 (0.599)</paragraph></td><td align="center" styleCode=" Toprule Lrule Rrule" valign="top"> <paragraph>2.65 (1.41)</paragraph></td><td align="center" styleCode=" Toprule Lrule Rrule" valign="top"> <paragraph>6.95 (3.39)</paragraph></td><td align="center" styleCode=" Toprule Lrule Rrule" valign="top"> <paragraph>12.1 (3.49)</paragraph></td><td align="center" styleCode=" Toprule Lrule Rrule" valign="top"> <paragraph>78024</paragraph><paragraph>(47220)</paragraph></td><td align="center" styleCode=" Toprule Lrule" valign="top"> <paragraph>64110</paragraph><paragraph>(42662)</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>8 x 2.5 mg</paragraph></td><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>0.805 (0.413)</paragraph></td><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>2.22 (1.39)</paragraph></td><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>5.62 (2.79)</paragraph></td><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>11.6 (2.81)</paragraph></td><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>62748</paragraph><paragraph>(40146)</paragraph></td><td align="center" styleCode=" Botrule Lrule" valign="top"> <paragraph>74123</paragraph><paragraph>(35126)</paragraph></td></tr><tr><td colspan="7" styleCode=" Botrule Toprule" valign="top"> <paragraph>Multiple Dose</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"> <paragraph>10 mg *</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>0.71 (0.35)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>2.83 (1.83)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>6.01 (3.16)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule R

<paragraph>0.71 (0.35)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>2.83 (1.83)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>6.01 (3.16)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule R rule" valign="top"> <paragraph>16.6 (15.0)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>40564</paragraph><paragraph>(38256)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule" valign="top"> <paragraph>41963</paragraph><paragraph>(38402)</paragraph></td></tr></tbody></table>

<table width="800px" cellspacing="0" cellpadding="5"><caption>Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment*</caption><col width="473.4pt"/><col width="473.4pt"/><col width="473.4pt"/><col width="473.4pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Histological</paragraph><paragraph>Results</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CEE ^&#x2020;</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Medroxyprogesterone Acetate ^&#x2021; </paragraph><paragraph>+ CEE</paragraph><paragraph>(n=118)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Normal/No hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>116 (97)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45 (38)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>112 (95)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Simple (cystic) hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33 (28)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (3)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Complex (adenomatous) hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>27 (22)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Atypia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14 (12)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adenocarcinoma (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4">^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days </td></tr></tbody></table>

Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4">^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days </td></tr></tbody></table> <table width="800px" cellspacing="0" cellpadding="5" border="1"><caption>Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year</caption><col/><col/><col/><col/><tbody><tr><td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CEE ^*</paragraph></td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA ^&#x2020; + CEE ^*</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>(n=283)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA 5 mg</paragraph><paragraph>(n=277)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>MPA 10 mg</paragraph><paragraph>(n=272)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cystic hyperplasia (%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>55 (19)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adenomatous hyperplasia without atypia</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (1)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28 </paragraph></td></tr></tbody></table>

oprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28 </paragraph></td></tr></tbody></table> <table width="800px" cellspacing="0" cellpadding="5" border="1"><caption>Table 4: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS ^a,b</caption><col width="135.9pt"/><col width="117pt"/><col width="99pt"/><col width="121.5pt"/><tbody><tr><td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Event</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Relative Risk</paragraph><paragraph>CE/MPA vs placebo</paragraph><paragraph>(95% nCI ^c) </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CE/MPA</paragraph><paragraph>n = 8,506</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Placebo</paragraph><paragraph>n = 8,102</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Absolute Risk per 10,000 Women-Years</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>CHD events <content styleCode="italics">Non-fatal MI</content> <content styleCode="italics">CHD death</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.23 (0.99 to 1.53)</paragraph><paragraph><content styleCode="italics">1.28 (1.00 to 1.63)</content></paragraph><paragraph><content styleCode="italics">1.10 (0.70 to 1.75)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph><paragraph><content styleCode="italics">31</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>34</paragraph><paragraph><content styleCode="italics">25</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>All strokes</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.31 (1.03 to 1.68)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Ischemic stroke</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">1.44 (1.09 to 1.90)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">26</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">18</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Deep vein thrombosis ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.95 (1.43 to 2.67)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td align="center" styleCode=" Bo

"center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td align="center" styleCode=" Bo trule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Invasive breast cancer ^e</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (1.01 to 1.54)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Colorectal cancer</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.61 (0.42 to 0.87)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Endometrial cancer ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.81 (0.48 to 1.36)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cervical cancer ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.44 (0.47 to 4.42)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hip fracture</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.67 (0.47 to 0.96)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vertebral fractures ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 (0.46 to 0.92)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lower arm/wrist fractures ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.71 (0.59 to 0.85)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>62</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total fractures ^d</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.76 (0.69 to 0.83)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>152</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>199</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality ^f</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>

e Lrule Rrule"><paragraph>152</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>199</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Overall mortality ^f</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> 1.00 (0.83 to 1.19)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Global Index ^g</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.13 (1.02 to 1.25)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>184</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^a.Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. ^b.Results are based on centrally adjudicated data. ^c.Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ^d.Not included in &#x201C;global index&#x201D;. ^e.Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. ^f.All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ^g.A subset of the events was combined in a &#x201C;global index&#x201D;, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. </paragraph></td></tr></tbody></table>

HOW SUPPLIED Medroxyprogesterone acetate tablets, USP are available in the following strengths and package sizes: 2.5 mg tablets (White, round, scored, biconvex tablet. Debossed with 555/872 on the scored side and stylized b on the other side) Bottles of 30: NDC 72789-043-30 Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Keep this and all medications out of the reach of children.

Rx only WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See Error! Hyperlink reference not valid. and and . ) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See and . ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See and WARNINGS , and Error! Hyperlink reference not valid., Error! Hyperlink reference not valid.. ) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See and WARNINGS Error! Hyperlink reference not valid. Error! Hyperlink reference not valid.. ) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See Error! Hyperlink reference not valid. and and . ) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See and . ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See and WARNINGS , and Error! Hyperlink reference not valid., Error! Hyperlink reference not valid.. ) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See and WARNINGS Error! Hyperlink reference not valid. Error! Hyperlink reference not valid.. ) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. What is the most important information I should know about medroxyprogesterone acetate tablets (a progestin hormone)? • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). • Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. • Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. • You and your healthcare provider should talk regularly about whether you still need treatment with medroxyprogesterone acetate.

<table ID="_RefID0EREAE" cellpadding="0.5pt" width="100%"><caption>Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA)</caption><col width="13%"/><col width="15%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="12%"/><col width="19%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph> </paragraph><paragraph>Tablet</paragraph><paragraph>Strength</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>C_max</paragraph><paragraph>(ng/mL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>T_max</paragraph><paragraph>(h)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>Auc_0-(&#x221E;)</paragraph><paragraph>(ng&#xB7;h/mL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>t_1/2</paragraph><paragraph>(h)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>Vd/f</paragraph><paragraph>(L)</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>CL/f</paragraph><paragraph>(mL/min)</paragraph></td></tr><tr><td colspan="7" styleCode="Toprule Botrule " valign="top"><paragraph> </paragraph><paragraph>Single Dose</paragraph></td></tr><tr><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph> </paragraph><paragraph>2 x 10 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>1.01 (0.599)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>2.65 (1.41)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>6.95 (3.39)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>12.1 (3.49)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>78024</paragraph><paragraph>(47220)</paragraph></td><td align="center" styleCode="Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>64110</paragraph><paragraph>(42662)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph> </paragraph><paragraph>8 x 2.5 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>0.805 (0.413)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>2.22 (1.39)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>5.62 (2.79)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>11.6 (2.81)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>62748</paragraph><paragraph>(40146)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>74123</paragraph><paragraph>(35126)</paragraph></td></tr><tr><td colspan="7" styleCode="Toprule Botrule " valign="top"><paragraph> </paragraph><paragraph>Multiple D

paragraph>62748</paragraph><paragraph>(40146)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph> </paragraph><paragraph>74123</paragraph><paragraph>(35126)</paragraph></td></tr><tr><td colspan="7" styleCode="Toprule Botrule " valign="top"><paragraph> </paragraph><paragraph>Multiple D ose</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph> </paragraph><paragraph>10 mg *</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>0.71 (0.35)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>2.83 (1.83)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>6.01 (3.16)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>16.6 (15.0)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>40564</paragraph><paragraph>(38256)</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph> </paragraph><paragraph>41963</paragraph><paragraph>(38402)</paragraph></td></tr></tbody></table>

of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See Error! Hyperlink reference not valid., Error! Hyperlink reference not valid. and PRECAUTIONS , ).

<table ID="_RefID0EYQAE" cellpadding="0.5pt" cellspacing="0pt" width="100%"><caption>Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment*</caption><col width="25%"/><col width="24%"/><col width="24%"/><col width="25%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Histological</paragraph><paragraph>Results</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>CEE^&#x2020;</paragraph><paragraph>(n=119)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Medroxyprogesterone Acetate^&#x2021; </paragraph><paragraph>+ CEE</paragraph><paragraph>(n=118)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Normal/No hyperplasia (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>116 (97)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>45 (38)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>112 (95)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Simple (cystic) hyperplasia (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33 (28)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Complex (adenomatous) hyperplasia (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27 (22)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Atypia (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Adenocarcinoma (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph>^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days</paragraph></td></tr></tbody></table>

colspan="4" styleCode="Botrule " valign="top"><paragraph>^* Includes most extreme abnormal result ^&#x2020;CEE = conjugated equine estrogens 0.625 mg/day ^&#x2021;Medroxyprogesterone acetate = medroxyprogesterone acetate tablets 10 mg/day for 12 days</paragraph></td></tr></tbody></table> <table ID="_RefID0E3UAE" cellpadding="0.5pt" cellspacing="0pt" width="100%"><caption>Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year</caption><col width="25%"/><col width="25%"/><col width="24%"/><col width="24%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>CEE^*</paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>MPA^&#x2020; + CEE^*</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>(n=283)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>MPA 5 mg</paragraph><paragraph>(n=277)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>MPA 10 mg</paragraph><paragraph>(n=272)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Cystic hyperplasia (%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>55 (19)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Adenomatous hyperplasia without atypia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28</paragraph></td></tr></tbody></table>

n="top"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>^*CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. ^&#x2020;Cyclic medroxyprogesterone acetate on days 15 to 28</paragraph></td></tr></tbody></table> <table ID="_RefID0EJYAE" cellpadding="0.5pt" cellspacing="0pt" width="100%"><caption>Table 4: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS ^a,b</caption><col width="27%"/><col width="27%"/><col width="20%"/><col width="24%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Event</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Relative Risk</paragraph><paragraph>CE/MPA vs placebo</paragraph><paragraph>(95% nCI^c)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>CE/MPA</paragraph><paragraph>n = 8,506</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo</paragraph><paragraph>n = 8,102</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Absolute Risk per 10,000 Women-Years</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>CHD events <content styleCode="italics"> Non-fatal MI</content> <content styleCode="italics"> CHD death</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.23 (0.99 to 1.53)</paragraph><paragraph><content styleCode="italics">1.28 (1.00 to 1.63)</content></paragraph><paragraph><content styleCode="italics">1.10 (0.70 to 1.75)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>41</paragraph><paragraph><content styleCode="italics">31</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>34</paragraph><paragraph><content styleCode="italics">25</content></paragraph><paragraph><content styleCode="italics">8</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>All strokes</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.31 (1.03 to 1.68)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="italics">Ischemic stroke</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="italics">1.44 (1.09 to 1.90)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="italics">26</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="italics">18</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Deep vein thrombosis^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.95 (1.43 to 2.67)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule

thrombosis^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.95 (1.43 to 2.67)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Pulmonary embolism</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.13 (1.45 to 3.11)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Invasive breast cancer^e</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.24 (1.01 to 1.54)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Colorectal cancer</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.61 (0.42 to 0.87)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Endometrial cancer^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.81 (0.48 to 1.36)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Cervical cancer^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.44 (0.47 to 4.42)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Hip fracture</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.67 (0.47 to 0.96)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Vertebral fractures^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.65 (0.46 to 0.92)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Lower arm/wrist fractures^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.71 (0.59 to 0.85)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>44</par

"Rrule Lrule Toprule Botrule " valign="top"><paragraph>Lower arm/wrist fractures^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.71 (0.59 to 0.85)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>44</par agraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>62</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Total fractures^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.76 (0.69 to 0.83)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>152</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>199</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Overall mortality^f</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.00 (0.83 to 1.19)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>52</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Global Index^g</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.13 (1.02 to 1.25)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>184</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>^a.Adapted from numerous WHI publications.

Rrule Lrule Toprule Botrule " valign="top"><paragraph>184</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>165</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>^a.Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. ^b.Results are based on centrally adjudicated data. ^c.Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ^d.Not included in &#x201C;global index&#x201D;. ^e.Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. ^f.All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ^g.A subset of the events was combined in a &#x201C;global index&#x201D;, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.</paragraph></td></tr></tbody></table>

CONTRAINDICATIONS Medroxyprogesterone acetate is contraindicated in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of breast cancer. 3. Known or suspected estrogen- or progesterone-dependent neoplasia. 4. Active DVT, PE, or a history of these conditions 5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. 6. Known anaphylactic reaction or angioedema to medroxyprogesterone acetate. 7. Known liver impairment or disease. 8. Known or suspected pregnancy.

WARNINGS See BOXED WARNINGS . 1. Cardiovascular Disorders. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See . ) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See Error! Hyperlink reference not valid. ). Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a.

be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo (see CLINICAL STUDIES ). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups. (See . ) Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller, increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year.

py in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3. Probable Dementia In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See and PRECAUTIONS , . ) 4. Visual Abnormalities Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.

PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 2. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. 3. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. 4. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 5. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. 6. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. 7. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe medroxyprogesterone acetate. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to medroxyprogesterone acetate. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 1.

al fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum. for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS . ) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. E. Pregnancy Medroxyprogesterone acetate should not be used during pregnancy. (See CONTRAINDICATIONS . ) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established. F. Nursing Mothers Medroxyprogesterone acetate should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins. G. Pediatric Use Medroxyprogesterone acetate tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone.

conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See . ) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS , . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , . )

A. General 1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. 2. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. 3. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. 4. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 5. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. 6. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. 7. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum. for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance.

H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See . ) The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS , . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , . )

DOSAGE AND ADMINISTRATION Secondary Amenorrhea Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate therapy. Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate. Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see Error! Hyperlink reference not valid. ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of medroxyprogesterone acetate has not been determined.

HOW SUPPLIED Medroxyprogesterone acetate tablets, USP are available in the following strengths and package sizes: 5 mg tablets (White, round, scored, biconvex tablet. Debossed with 555/873 on the scored side and stylized b on the other side) Bottles of 30: NDC 68788-8112-3 Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Keep this and all medications out of the reach of children. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 3/2024

PATIENT INFORMATION MedroxyPROGESTERone Acetate (med rox″ ee proe jes′ ter one as′ etate) Tablets Read this Patient Information before you start taking medroxyprogesterone acetate tablets and read what you get each time you refill your medroxyprogesterone acetate tablets prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about medroxyprogesterone acetate tablets (a progestin hormone)? • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). • Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. • Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. • You and your healthcare provider should talk regularly about whether you still need treatment with medroxyprogesterone acetate. What are medroxyprogesterone acetate tablets? Medroxyprogesterone acetate tablet is a medicine that contains medroxyprogesterone acetate, a progestin hormone. What are medroxyprogesterone acetate tablets used for? Medroxyprogesterone acetate tablets are used to: • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your healthcare provider about whether medroxyprogesterone acetate tablets are right for you. • Reduce your chances of getting cancer of the uterus (womb). In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chance of getting cancer of the uterus (womb). Who should not take medroxyprogesterone acetate tablets? Do not start taking medroxyprogesterone acetate tablets if you: • have unusual vaginal bleeding • currently have or have had certain cancers Estrogen plus progestin may increase your chance of getting certain types of cancers, including cancer of the breast. If you have or have had cancer, talk with your healthcare provider about whether you should use medroxyprogesterone acetate tablets. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to medroxyprogesterone acetate tablets or any of its ingredients See the list of ingredients in medroxyprogesterone acetate tablets at the end of this leaflet. • think you may be pregnant Medroxyprogesterone acetate tablets are not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use medroxyprogesterone acetate tablets if the test is positive and talk to your healthcare provider. There may be an increased risk of minor birth defects in children whose mothers take medroxyprogesterone acetate tablets during the first 4 months of pregnancy. Medroxyprogesterone acetate tablets should not be used as a test for pregnancy. What should I tell my healthcare provider before taking medroxyprogesterone acetate tablets?

an increased risk of minor birth defects in children whose mothers take medroxyprogesterone acetate tablets during the first 4 months of pregnancy. Medroxyprogesterone acetate tablets should not be used as a test for pregnancy. What should I tell my healthcare provider before taking medroxyprogesterone acetate tablets? Before you take medroxyprogesterone acetate tablets, tell your healthcare provider if you: • have any other medical problems Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis (severe pelvic pain), lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium in your blood. • are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop taking medroxyprogesterone acetate tablets. • are breast feeding The hormone in medroxyprogesterone acetate can pass into your breast milk. Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how medroxyprogesterone acetate tablets work. Medroxyprogesterone acetate tablets may also affect how other medicines work. How should I take medroxyprogesterone acetate tablets? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. The lowest effective dose of medroxyprogesterone acetate tablets has not been determined. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with medroxyprogesterone acetate tablets. 1. Absence of menstrual period: Medroxyprogesterone acetate tablets may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 2. Abnormal Uterine Bleeding: Medroxyprogesterone acetate tablets may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 3. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, medroxyprogesterone acetate tablets may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month. What are the possible side effects of medroxyprogesterone acetate tablets? The following side effects have been reported with the use of medroxyprogesterone acetate tablets alone: • breast tenderness • breast milk secretion • breakthrough bleeding • spotting (minor vaginal bleeding) • irregular periods • amenorrhea (absence of menstrual periods) • vaginal secretions • headaches • nervousness • dizziness • depression • insomnia, sleepiness, fatigue • premenstrual syndrome-like symptoms • thrombophlebitis (inflamed veins) • blood clot • itching, hives, skin rash • acne • hair loss, hair growth • abdominal discomfort • nausea • bloating • fever • increase in weight • swelling • changes in vision and sensitivity to contact lenses Call your healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of medroxyprogesterone acetate with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated.

r healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of medroxyprogesterone acetate with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: • heart attack • stroke • blood clots • dementia • breast cancer • cancer of the uterus • cancer of the ovary • high blood pressure • high blood sugar • gallbladder disease • liver problems • changes in your thyroid hormone levels • enlargements of benign tumors (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: • new breast lumps • unusual vaginal bleeding • changes in vision and speech • sudden new severe headaches • severe pains in your chest or legs with or without shortness of breath, weakness and fatigue • memory loss or confusion Less serious, but common side effects include: • headache • breast pain • irregular vaginal bleeding or spotting • stomach or abdominal cramps, bloating • nausea and vomiting • hair loss • fluid retention • vaginal yeast infection These are not all the possible side effects of medroxyprogesterone acetate with or without estrogen. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have side effect that bothers you or does not go away. You may report side effects to Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088. What can I do to lower my chances of a serious side effect with medroxyprogesterone acetate tablets? • Talk with your healthcare provider regularly about whether you should continue taking medroxyprogesterone acetate tablets. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). • See your healthcare provider right away if you get vaginal bleeding while taking medroxyprogesterone acetate tablets. • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chance of getting heart disease. General information about safe and effective use of medroxyprogesterone acetate tablets • Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. • Do not take medroxyprogesterone acetate tablets for conditions for which it was not prescribed. • Do not give medroxyprogesterone acetate tablets to other people, even if they have the same symptoms you have. It may harm them. Keep medroxyprogesterone acetate tablets out of the reach of children. This leaflet provides a summary of the most important information about medroxyprogesterone acetate tablets. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about medroxyprogesterone acetate tablets that is written for health professionals. You can get more information by calling the toll-free number, 1-888-838-2872. What are the ingredients in medroxyprogesterone acetate tablets? Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate.

tablets that is written for health professionals. You can get more information by calling the toll-free number, 1-888-838-2872. What are the ingredients in medroxyprogesterone acetate tablets? Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn starch, and sodium lauryl sulfate. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 3/2024 Repackaged By: Preferred Pharmaceuticals Inc.

<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td valign="top"><paragraph>Warnings and Precautions, Meningioma (<linkHtml href="#ID_1fbd4fa9-a418-4cb5-9a6d-046f510c4571">5.4</linkHtml>)</paragraph></td><td align="right" valign="bottom"><paragraph>12/2025</paragraph></td></tr></tbody></table>

WARNING: LOSS OF BONE MINERAL DENSITY • Women who use depo-subQ provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1) ] . • It is unknown if use of depo-subQ provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1) ] . • Depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1) ] . WARNING: LOSS OF BONE MINERAL DENSITY See full prescribing information for complete boxed warning . • Women who use depo-subQ provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. ( 5.1 ) • It is unknown if use of depo-subQ provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. ( 5.1 ) • Depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. ( 1 , 5.1 )

1 INDICATIONS AND USAGE Depo-subQ provera 104 is indicated in females of reproductive age for: • Prevention of pregnancy and • Management of endometriosis-associated pain. Depo-subQ provera 104 is a progestin that is indicated in females of reproductive age for: • Prevention of pregnancy. ( 1 ) • Management of endometriosis-associated pain. ( 1 ) Limitations of Use : Use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. ( 1 , 5.1 ) Limitations of Use : The use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ].

2 DOSAGE AND ADMINISTRATION • Only for healthcare professional administration. ( 2.1 ) • Prior to first injection, confirm the patient is not pregnant. ( 2.1 ) • Administer 104 mg of depo-subQ provera 104 by subcutaneous injection into the anterior thigh or abdomen, once every 12 to 14 weeks. ( 2.1 ) • See Full Prescribing Information for recommendations on switching from another contraceptive method to depo-subQ provera 104. ( 2.2 ) • See Full Prescribing Information for important preparation and administration instructions. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Depo-subQ provera 104 is only for subcutaneous administration and is only to be administered by a healthcare professional. Use for longer than 2 years is not recommended (unless other birth control methods or medical therapies for endometriosis-associated pain are considered inadequate) due to the impact of long-term depo-subQ provera 104 treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1) ] . Prior to the first injection confirm that the patient is not pregnant. For women who are sexually active and who have regular menses, administer the first injection only during the first 5 days of a normal menstrual period. For women who are breast-feeding, administer the first injection during or after the sixth post-partum week. The recommended dosage of depo-subQ provera 104 is 104 mg given subcutaneously every 12 to 14 weeks. If more than 14 weeks elapse between injections, confirm that the patient is not pregnant before the next injection. Instruct the patient that if they are unable to receive an injection within 12–14 weeks, another contraceptive method should be used until the next depo-subQ provera 104 injection. The dosage does not need to be adjusted for body weight. Inject the entire contents of the pre-filled syringe using strict aseptic technique into the upper anterior thigh or abdomen, rotating the sites with every injection [see Dosage and Administration (2.3) ] . 2.2 Switching from Another Method of Contraception When switching from another contraceptive method to depo-subQ provera 104, administer depo-subQ provera 104 in a manner that ensures continuous contraceptive coverage. Follow the respective recommendations when switching from the contraceptive methods listed below: • Combined hormonal contraceptives : administer the first injection of depo-subQ provera 104 within 7 days after the last day of using the combined hormonal contraceptive method (i.e., within 7 days after taking the last active pill). • An implant : administer the first injection of depo-subQ provera 104 on the day of implant removal. • A contraceptive vaginal ring or transdermal system : administer the first injection of depo-subQ provera 104 on the day the patient would have inserted the next ring or applied the next transdermal system. • An Intrauterine Device (IUD) or Intrauterine System (IUS) : administer the first injection of depo-subQ provera 104 on the day of IUD/IUS removal. If the IUD/IUS is not removed on the first day of the patient's menstrual cycle, instruct patients to use a non-hormonal back-up method of birth control for the first 7 days after administration of depo-subQ provera 104. • Depot medroxyprogesterone acetate injectable suspension for intramuscular use (DMPA-IM) : inject depo-subQ provera 104 12 to 14 weeks after the last dose of DMPA-IM.

trual cycle, instruct patients to use a non-hormonal back-up method of birth control for the first 7 days after administration of depo-subQ provera 104. • Depot medroxyprogesterone acetate injectable suspension for intramuscular use (DMPA-IM) : inject depo-subQ provera 104 12 to 14 weeks after the last dose of DMPA-IM. 2.3 Preparation and Administration Instructions Prior to injection: • Ensure all the components in Figure A are available and that depo-subQ provera 104 is at room temperature . • Shake the pre-filled syringe vigorously prior to injection to ensure appropriate viscosity of the suspension. • Inspect depo-subQ provera 104 visually for particulate matter and discoloration. Figure A. Components in the Package Step 1: Select & Prepare the Injection Area • Select a preferred injection area, i.e., the left or right upper thigh or the abdomen (see shaded areas , Figure B ). • Avoid selection of bony areas and the umbilicus. • Clean the skin in the injection area you have chosen with a clean cotton pad or clean paper tissue. • Rotate the injection site by injecting into a different puncture site than used for the previous injection. Figure B. Preferred injection areas: Left or right upper thigh or abdomen Step 2: Prepare Syringe • Carefully remove the needle and syringe from the packaging. • Hold the syringe firmly by the barrel, with the barrel pointing upward. • Shake the syringe vigorously for at least 1 minute to mix thoroughly ( Figure C ). Figure C. Shake vigorously for 1 minute • While holding the syringe barrel firmly, remove the protective cap from the tip of the syringe barrel by unscrewing it ( Figure D ). Figure D. • While holding the syringe barrel firmly, attach the needle to the barrel of the syringe firmly by pushing the plastic needle cover down fully and firmly with a slight twisting movement ( Figure E ). Figure E. • Move the safety shield away from the needle and toward the syringe barrel. The safety shield will remain in an open 45- to 90-degree position ( Figure F ). Figure F. • While holding the syringe barrel firmly, remove the plastic needle cover from the needle without twisting, ensuring the needle is still firmly attached to the syringe ( Figure G ). Figure G. • While holding the syringe with the needle pointing upward, gently push in the plunger until the liquid is up to the top of the syringe ( Figure H ). There should be no air within the barrel. Figure H. Step 3: Injecting depo-Sub Q provera 104 • Gently grasp and squeeze a large area of skin in the chosen injection area between the thumb and forefinger, pulling it away from the body ( Figure I ). • Insert the needle at a 45-degree angle so that most of the needle is in the fatty tissue. • The plastic hub of the needle should be nearly or almost touching the skin. Figure I. Inject slowly until the syringe is empty ( Figure J ). • This should take about 5 to 7 seconds. • It is important that the entire dose is given. Figure J. Inject slowly (5–7 seconds) Step 4: Remove the Needle and Activate the Safety Shield • After completing the injection, remove the needle from the skin and activate the safety shield as follows: o While positioning the shield about 40°– 45°, and with a firm quick motion, press down against a flat surface until a click is heard or felt ( Figure K ). o If uncertain that the safety shield is fully engaged, repeat this step. Figure K. • Use a clean cotton pad to press lightly on the injection area for a few seconds ( Figure L ). • Do not rub the area. Figure L. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L

3 DOSAGE FORMS AND STRENGTHS Injectable suspension (104 mg/0.65 mL) in a single-dose pre-filled syringe, packaged with a 26-gauge × 3/8-inch Terumo SurGuard ® needle. Injectable suspension: 104 mg/0.65 mL ( 3 )

4 CONTRAINDICATIONS The use of depo-subQ provera 104 is contraindicated in the following conditions: • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2) ] . • Known, suspected, or past malignancy of the breast [see Warnings and Precautions (5.3) ] . • Significant liver disease [see Warnings and Precautions (5.14) ] . • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients in depo-subQ provera 104 [see Warnings and Precautions (5.6) ] . • Undiagnosed vaginal bleeding [see Warnings and Precautions (5.12) ] . • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease. ( 4 ) • Known, suspected, or past malignancy of the breast. ( 4 ) • Significant liver disease. ( 4 ) • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients of depo-subQ provera 104. ( 4 ) • Undiagnosed vaginal bleeding. ( 4 )

5 WARNINGS AND PRECAUTIONS • Thromboembolic disorders: Discontinue depo-subQ provera 104 in patients who develop arterial or venous thrombosis. ( 5.2 ) • Breast cancer risks: Monitor women with a family history of breast cancer or a significant risk of breast cancer carefully. ( 5.3 ) • Meningioma: Discontinue depo-subQ provera 104 if meningioma is diagnosed. Monitor patients for signs and symptoms of meningioma. ( 5.4 ) • Ectopic pregnancy: Consider ectopic pregnancy if a woman becomes pregnant or complains of severe abdominal pain. ( 5.5 ) • Anaphylaxis: Provide emergency medical treatment. ( 5.6 ) • Injection site reactions (e.g., persistent atrophy, dimpling/indentation, lump/nodule and discoloration) have been reported. ( 5.11 ) • Diabetics may be at greater risk of hyperglycemia. ( 5.13 ) • Jaundice and elevated transaminase: Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. ( 5.14 ) 5.1 Loss of Bone Mineral Density Use of depo-subQ provera 104 reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of depo-subQ provera 104 by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess the reversibility of loss of BMD in adolescents was conducted with DMPA-IM. After discontinuing DMPA-IM in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.4) ] . Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [see Clinical Studies (14.3) ] . The use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use depo-subQ provera 104 long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods or therapies for endometriosis-associated pain should be considered in the risk/benefit analysis for the use of depo-subQ provera 104 in women with osteoporosis risk factors. Depo-subQ provera 104 can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). 5.2 Arterial and Venous Thromboembolic Disorders There have been reports of serious arterial and venous thrombotic events in women treated with DMPA-IM. Women with a history of thromboembolic disorders were not studied in clinical trials of depo-subQ provera 104. Although no causal relationship between the use of depo-subQ provera 104 and thrombotic events has been clearly established, patients who develop arterial or venous thrombosis while taking depo-subQ provera 104 should discontinue treatment.

embolic disorders were not studied in clinical trials of depo-subQ provera 104. Although no causal relationship between the use of depo-subQ provera 104 and thrombotic events has been clearly established, patients who develop arterial or venous thrombosis while taking depo-subQ provera 104 should discontinue treatment. Do not re-administer depo-subQ provera 104 pending examination if there is a sudden onset of a suspected vascular ocular event (e.g., partial or complete loss of vision, proptosis, or diplopia) or migraine. Do not re-administer depo-subQ provera 104 if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer The use of hormonal contraceptives, including depo sub-Q provera 104, is contraindicated in women who have or have had breast cancer because breast cancer may be sensitive to hormones [see Contraindications (4) ] . Women who have a family history of breast cancer or a significant risk of breast cancer should be monitored. The results of five large case-control studies assessing the association between DMPA-IM use and the risk of breast cancer are summarized in Figure M. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One US study 1 evaluated the timing and duration of use and found a statistically significant increased risk of breast cancer in recent DMPA-IM users (defined as last use within the past five years) who used DMPA-IM for 12 months or longer; this is consistent with results of a previous study 2 . Figure M. Risk Estimates of Breast Cancer in DMPA-IM Users Odds ratio estimates were adjusted for the following covariates: Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography. Odds Ratio [95% confidence interval (CI)] displayed on logarithmic scale Based on the published SEER-18 2015 incidence rate (age-adjusted to the 2000 US Standard Population) of breast cancer for US women, all races, age 20 to 49 years, a doubling of risk would increase the incidence of breast cancer in women who use DMPA-IM from about 73 to about 146 cases per 100,000 women. Figure M Other Cancers The relative rate of invasive squamous-cell cervical cancer in women who ever used DMPA-IM was estimated to be 1.11 (95% CI: 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. Long-term, case-controlled surveillance of users of DMPA-IM found no overall increased risk of ovarian or liver cancer. 5.4 Meningioma Cases of meningiomas have been reported following repeated administration of medroxyprogesterone acetate, primarily with long term use. Monitor patients on depo-subQ provera 104 for signs and symptoms of meningioma. Discontinue depo-subQ provera 104 if a meningioma is diagnosed. 5.5 Ectopic Pregnancy Healthcare professionals should be alert to the possibility of an ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain. 5.6 Anaphylaxis Serious anaphylactic reactions have been reported in women using depo-subQ provera 104. If an anaphylactic reaction occurs, appropriate emergency medical treatment should be administered.

ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain. 5.6 Anaphylaxis Serious anaphylactic reactions have been reported in women using depo-subQ provera 104. If an anaphylactic reaction occurs, appropriate emergency medical treatment should be administered. 5.7 Fluid Retention Because progestational drugs including depo-subQ provera 104 may cause fluid retention, monitor patients with conditions that might be affected by fluid retention. 5.8 Weight Gain Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb (1.6 kg) in the first year of use. In a small, two-year study comparing depo-subQ provera 104 to DMPA-IM, the mean weight gain observed for women using depo-subQ provera 104 [7.5 lb (3.4 kg)] was similar to the mean weight gain for women using DMPA-IM [7.6 lb (3.5 kg)]. Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on DMPA-IM may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb (5.1 kg), while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb (2.9 kg). 5.9 Delayed Return of Ovulation or Fertility Return to ovulation is likely to be delayed after stopping depo-subQ provera 104, as demonstrated in a study of 15 women who received multiple doses of depo-subQ provera 104: • Median time to ovulation was 10 months after the last injection. • Earliest return to ovulation was 6 months after the last injection. • 12 women (80%) ovulated within 1 year of the last injection. However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104; therefore, administer the next depo-subQ provera 104 12 to 14 weeks after the last injection. Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 7 women were lost to follow-up. One woman became pregnant within one year of her last injection and another woman became pregnant 443 days after her last injection. The remaining 19 women had not become pregnant; it is not known if these 19 women were still attempting to become pregnant or if they had started a new contraceptive method . 5.10 Depression Depression (3% of depo-subQ provera 104-treated patients) and other mood disorders have been reported in clinical trials of depo-subQ provera 104 [see Adverse Reactions (6.1) ] . Patients with a history of depression or who are on treatment for depression may be at increased risk for depression recurrence or exacerbation and for associated mood disorders while receiving depo-subQ provera 104. Therefore, patients should be monitored for symptoms of depression and mood changes. 5.11 Injection Site Reactions In five clinical studies of depo-subQ provera 104 involving 2325 women (282 treated for up to 6 months, 1780 treated for up to 1 year, and 263 women treated for up to 2 years), 5% of women reported injection site reactions (such as pain/tenderness, nodule/lump, lipodystrophy, discoloration), and 1% had persistent atrophy/indentation/dimpling [see Adverse Reactions (6.1) ] . These injection site reactions have also been reported in post-marketing experience. 5.12 Bleeding Irregularities Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular unpredictable spotting or bleeding, prolonged spotting or bleeding, or heavy bleeding [see Adverse Reactions (6.1) ] .

ve also been reported in post-marketing experience. 5.12 Bleeding Irregularities Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular unpredictable spotting or bleeding, prolonged spotting or bleeding, or heavy bleeding [see Adverse Reactions (6.1) ] . Fewer women experienced irregular bleeding and more experienced amenorrhea with longer term use of depo‑subQ provera 104, consistent with expected endometrial thinning effects. In three contraception trials, 39% of 2053 depo-subQ provera 104-treated women experienced amenorrhea during Month 6, and 57% experienced amenorrhea during Month 12. In two endometriosis trials using depo-subQ provera 104, 24% of 289 women experienced amenorrhea during Month 6 [see Adverse Reactions (6.1) ] . If abnormal bleeding is persistent or severe, evaluate the patient for underlying pathology or pregnancy. 5.13 Risk of Hyperglycemia in Patients with Diabetes Some patients receiving progestins may exhibit a decrease in glucose tolerance; therefore, patients with diabetes may be at greater risk of hyperglycemia. 5.14 Jaundice and Elevated Transaminase Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. Depo-subQ provera 104 may be resumed after both the jaundice and elevated transaminase levels resolve, and the healthcare professional determines that depo-subQ provera 104 did not cause the abnormalities. 5.15 Protection Against Sexually Transmitted Infections Patients should be counseled that this product does not protect against HIV infection (including AIDS) and other sexually transmitted infections.

<table styleCode="Noautorules" width="100%"><col width="100%"/><thead><tr><th align="center" valign="top"><content styleCode="bold">Figure M. Risk Estimates of Breast Cancer in DMPA-IM Users</content></th></tr></thead><tfoot><tr><td align="left" colspan="1" valign="top">Odds ratio estimates were adjusted for the following covariates: Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography.</td></tr></tfoot><tbody><tr><td align="center" valign="top"><paragraph>Odds Ratio [95% confidence interval (CI)] displayed on logarithmic scale</paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id807" referencedObject="MM13"/></td></tr></tbody></table>

6 ADVERSE REACTIONS The following important adverse reactions are described in more detail in other sections of the prescribing information: • Loss of bone mineral density [see Warnings and Precautions (5.1) ] • Arterial and venous thromboembolic disorders [see Warnings and Precautions (5.2) ] • Anaphylaxis [see Warnings and Precautions (5.6) ] • Fluid retention [see Warnings and Precautions (5.7) ] • Delayed return of ovulation or fertility [see Warnings and Precautions (5.9) ] • Depression [see Warnings and Precautions (5.10) ] • Injection site reactions [see Warnings and Precautions (5.11) ] • Bleeding irregularities [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence >5%) are dysfunctional uterine bleeding, headache, increased weight, amenorrhea, and injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Clinical trials are conducted under widely varying conditions, therefore adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to depo-subQ provera 104 in five clinical trials involving 2325 women including 2043 women who received treatment for contraception (1780 treated up to 1 year and 263 treated for up to 2 years) and 282 women for endometriosis for up to 6 months. In these pooled trials, 9% of women discontinued treatment due to an adverse reaction and the most common reason for discontinuation was dysfunctional uterine bleeding (3%). Adverse Reactions in the Contraception Adult Studies Table 1 presents frequently reported adverse reactions (>1%) in the contraception pooled studies. In these studies, the most frequently reported adverse reactions (>5%) were dysfunctional uterine bleeding (e.g., irregular, increased, decreased, or spotting), headache, increased weight, amenorrhea, and injection site reactions (e.g., pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling or lipodystrophy). The frequency reported is based on the all-causality incidence in the pooled results of the three contraception studies. Closely related "Adverse Reaction" terms were grouped but individual patients reporting two or more grouped events were only counted once. Table 1. Frequently Reported Adverse Reactions in the Contraception Studies (>1%) Adverse Reaction Frequency Dysfunctional uterine bleeding (irregular, increase, decrease, spotting) 18% Headache 9% Increased weight (see below) 7% Amenorrhea 6% Injection site reactions (such as pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling, lipodystrophy, discoloration) 6% Vaginitis, including candidiasis and bacterial 5% Abdominal pain 4% Urinary tract infections 4% Acne 4% Depression 3% Decreased libido 3% Nausea 3% Back pain 3% Breast pain/tenderness 2% Fatigue 2% Anxiety 1% Irritability 1% Dizziness 1% Dysfunctional Uterine Bleeding The extent of bleeding and spotting in the three contraception trials is presented in Figure N; data from the endometriosis trials are presented in Figure O [see Warnings and Precautions (5.1) ]. Figure N.

ain 3% Breast pain/tenderness 2% Fatigue 2% Anxiety 1% Irritability 1% Dizziness 1% Dysfunctional Uterine Bleeding The extent of bleeding and spotting in the three contraception trials is presented in Figure N; data from the endometriosis trials are presented in Figure O [see Warnings and Precautions (5.1) ]. Figure N. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Contraception Studies N=Number of subjects with bleeding or spotting during indicated month. Figure O. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Endometriosis Studies N=Number of subjects with bleeding or spotting during indicated month. Figure N Figure O Weight Gain In three large clinical trials, the mean weight gain in depo-subQ provera 104 treated patients was 3.5 lb (1.6 kg) in the first year of use. Half (50%) of women remained within 4.9 lb (2.2 kg) of their initial body weight; 12% of women lost more than 4.9 lb (2.2 kg), and 38% of women gained more than 5.1 lb (2.3 kg). In a small, 2-year study comparing depo-subQ provera 104 to DMPA-IM, the mean weight gain observed for women using depo-subQ provera 104 [7.5 lb (3.4 kg)] was similar to the mean weight gain for women using DMPA-IM [7.7 lb (3.5 kg)]. Other Adverse Reactions Observed in Contraception Clinical Trials with depo-subQ provera 104 Other adverse reactions occurring at an incidence of <1% in women who received depo-subQ provera 104 were as follows: • Neoplasms benign, malignant and unspecified (including cysts and polyps): breast lump • Blood and lymphatic system disorders: anemia • Immune system disorders: drug hypersensitivity • Metabolism and nutrition disorders: weight decreased, fluid retention • Nervous system disorders: facial palsy, syncope, paresthesia, somnolence • Cardiac disorders: tachycardia • Vascular disorders: hot flushes • Respiratory, thoracic and mediastinal disorders: asthma, dyspnea • Gastrointestinal disorders: diarrhea, abdominal distension • Skin and subcutaneous tissue disorders: urticaria, pruritus, dry skin • Reproductive system and breast disorders: dysmenorrhea, galactorrhea, dyspareunia • General disorders and administration site conditions: chest pain Adverse Reactions in the Endometriosis Adult Studies The safety profile of depo-subQ provera 104 in endometriosis clinical trials was similar to the safety profile of depo-subQ provera 104 in the contraception studies with the exception of the following adverse reactions which were more frequently reported in patients with endometriosis: abdominal pain, diarrhea, nausea, and back pain. In endometriosis studies, subjects recorded daily the occurrence and severity of hot flushes. Of the depo-subQ provera 104 users, 29% reported experiencing moderate or severe hot flushes at baseline, 36% at Month 3, and 27% at Month 6. Of the leuprolide users, 33% reported experiencing moderate or severe hot flushes at baseline, 74% at Month 3, and 69% at Month 6. Adverse Reactions in the Adolescent Contraception Study Depo-sub-Q provera 104 and DMPA-IM clinical trials reported similar safety profiles in adult study populations (see Table 1 above). Accordingly, a similar safety profile is expected for adolescents receiving depo-subQ provera 104 as for adolescents receiving DMPA-IM. The safety profile of DMPA-IM for prevention of pregnancy in adolescents was observed to be generally similar to the safety profile of adult women using DMPA-IM for prevention of pregnancy, with the exception of the following adverse reactions which were reported more frequently by adolescents: abdominal pain, diarrhea, back pain, weight increased, depression, headache, and dysmenorrhea.

ts was observed to be generally similar to the safety profile of adult women using DMPA-IM for prevention of pregnancy, with the exception of the following adverse reactions which were reported more frequently by adolescents: abdominal pain, diarrhea, back pain, weight increased, depression, headache, and dysmenorrhea. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of DMPA-IM. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Immune system disorders: anaphylactic reaction, anaphylactoid reaction, angioedema • Vascular disorders: pulmonary embolism, deep vein thrombosis, thrombophlebitis • Musculoskeletal and connective tissue disorders: osteoporosis (including osteoporotic fractures) • Reproductive system and breast disorders: prolonged anovulation, unexpected pregnancy, uterine hyperplasia • Respiratory, thoracic and mediastinal disorders: hoarseness • Skin and subcutaneous tissue disorders: increased body odor • Gastrointestinal disorders: gastrointestinal disturbances • General disorders and administration site conditions: axillary swelling, chills, thirst

<table ID="table1" width="100%"><caption>Table 1. Frequently Reported Adverse Reactions in the Contraception Studies (&gt;1%)</caption><col width="80%"/><col width="20%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Reaction</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Frequency</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dysfunctional uterine bleeding (irregular, increase, decrease, spotting)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Increased weight (see below)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Amenorrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions (such as pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling, lipodystrophy, discoloration)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vaginitis, including candidiasis and bacterial</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary tract infections</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Acne</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Depression</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased libido</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Breast pain/tenderness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botru

h></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botru le " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Irritability</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table> <table ID="_RefID0EVEAG" styleCode="Noautorules" width="100%"><caption>Figure N. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Contraception Studies</caption><col width="100%"/><tfoot><tr><td align="left" colspan="1" valign="top">N=Number of subjects with bleeding or spotting during indicated month.</td></tr></tfoot><tbody><tr><td valign="top"><renderMultiMedia ID="id1087" referencedObject="MM14"/></td></tr></tbody></table> <table ID="_RefID0EHFAG" styleCode="Noautorules" width="100%"><caption>Figure O. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Endometriosis Studies</caption><col width="100%"/><tfoot><tr><td align="left" colspan="1" valign="top">N=Number of subjects with bleeding or spotting during indicated month.</td></tr></tfoot><tbody><tr><td valign="top"><renderMultiMedia ID="id1097" referencedObject="MM15"/></td></tr></tbody></table>

7 DRUG INTERACTIONS Strong CYP3A inhibitors and inducers: Avoid concomitant use. ( 7 ) 7.1 Effect of Other Drugs on depo-SubQ provera 104 Moderate or Strong CYP3A Inducers Concomitant use with moderate or strong CYP3A inducers may decrease concentrations of medroxyprogesterone acetate which may reduce depo-subQ provera 104 efficacy. This effect is based upon the primary metabolism of medroxyprogesterone acetate by CYP3A and was not confirmed by a clinical study. Avoid coadministration of depo-subQ provera 104 with moderate or strong CYP3A inducers. Some examples of moderate CYP3A inducers are bosentan, efavirenz, etravirine, and modafinil. Some examples of strong CYP3A inducers are rifampin, carbamazepine, phenytoin, phenobarbital, mitotane, and St. John's wort (the CYP3A4 induction effect of St. John's wort varies widely and is preparation dependent). These examples are a guide and do not represent a comprehensive list of all possible drugs that may fit these categories. The use of CYP3A inducers may require using a back-up or alternate contraceptive method.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Discontinue if pregnancy occurs. ( 8.1 ) • Lactation: Detectable amounts of drug have been identified in the milk of mothers receiving depot-medroxyprogesterone acetate. ( 8.2 ) • Pediatric patients (after menarche): Bone loss is a particular concern. ( 8.4 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, depo-subQ provera 104 should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15‑20%, respectively. 8.2 Lactation Risk Summary Although medroxyprogesterone acetate is detectable in the milk of mothers receiving DMPA-IM, milk composition, quality, and amount do not appear to be adversely affected. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in mothers who exclusively breastfeed, initiate depo-subQ provera 104 during or after the sixth post-partum week [see Dosage and Administration (2.1) ] . No adverse effects in breastfed infants would be expected with maternal use of progestins. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied and no adverse effects have been noted. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for depo-subQ provera 104 and any potential adverse effects on the breastfed child from depo-subQ provera 104 or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Depo-subQ provera 104 is indicated for the prevention of pregnancy and would therefore be expected to impair female fertility until cessation of treatment. Women may experience a delay in return to ovulation and fertility (conception) following discontinuation of depo-subQ provera 104 [see Warnings and Precautions (5.9) ]. 8.4 Pediatric Use Depo-subQ provera 104 is indicated for the prevention of pregnancy and management of endometriosis-associated pain in females of reproductive age. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for users 17 years and older. Use of depo-subQ provera 104 is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence, a critical period of bone accretion. It is unknown if use of depo-subQ provera 104 by female adolescents will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. In a study of adolescent females (12–18 years of age) receiving DMPA-IM for contraception, mean BMD 2 years after starting DMPA-IM decreased 1.9% (spine), 4.3% (total hip), and 4.2% (femoral neck). In those adolescents who used DMPA-IM for more than 2 years, mean BMD at total hip and femoral neck did not return to baseline within 5 years. Depo-subQ provera 104 is not indicated before menarche. 8.5 Geriatric Use Depo-subQ provera 104 is not indicated in post-menopausal women.

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, depo-subQ provera 104 should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15‑20%, respectively.

8.4 Pediatric Use Depo-subQ provera 104 is indicated for the prevention of pregnancy and management of endometriosis-associated pain in females of reproductive age. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for users 17 years and older. Use of depo-subQ provera 104 is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence, a critical period of bone accretion. It is unknown if use of depo-subQ provera 104 by female adolescents will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. In a study of adolescent females (12–18 years of age) receiving DMPA-IM for contraception, mean BMD 2 years after starting DMPA-IM decreased 1.9% (spine), 4.3% (total hip), and 4.2% (femoral neck). In those adolescents who used DMPA-IM for more than 2 years, mean BMD at total hip and femoral neck did not return to baseline within 5 years. Depo-subQ provera 104 is not indicated before menarche.

11 DESCRIPTION Depo-subQ provera 104 contains medroxyprogesterone acetate (MPA), a derivative of progesterone, as its active ingredient. MPA is a white to off-white, odorless crystalline powder that is stable in air and that melts between 205°C and 209°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for MPA is 17-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate. The structural formula is as follows: Depo-subQ provera 104 for subcutaneous use is available in pre-filled syringes, each containing 0.65 mL (104 mg) of sterile medroxyprogesterone acetate injectable suspension. Each 0.65 mL contains the following inactive ingredients: Methylparaben 1.040 mg Propylparaben 0.098 mg Sodium Chloride 5.200 mg Polyethylene Glycol 18.688 mg Polysorbate 80 1.950 mg Monobasic Sodium Phosphate H 2 O 0.451 mg Dibasic Sodium Phosphate 12H 2 O 0.382 mg Methionine 0.975 mg Povidone 3.250 mg Water for Injection qs When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both. Chemical Structure

<table styleCode="Noautorules" width="75%"><col width="56%"/><col width="30%"/><tbody><tr><td align="justify" valign="top"><paragraph> Methylparaben</paragraph></td><td align="justify" valign="top"><paragraph>1.040 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Propylparaben</paragraph></td><td align="justify" valign="top"><paragraph>0.098 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Sodium Chloride</paragraph></td><td align="justify" valign="top"><paragraph>5.200 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Polyethylene Glycol</paragraph></td><td align="justify" valign="top"><paragraph>18.688 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Polysorbate 80</paragraph></td><td align="justify" valign="top"><paragraph>1.950 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Monobasic Sodium Phosphate H₂O</paragraph></td><td align="justify" valign="top"><paragraph>0.451 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Dibasic Sodium Phosphate 12H₂O</paragraph></td><td align="justify" valign="top"><paragraph>0.382 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Methionine</paragraph></td><td align="justify" valign="top"><paragraph>0.975 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Povidone</paragraph></td><td align="justify" valign="top"><paragraph>3.250 mg</paragraph></td></tr><tr><td align="justify" valign="top"><paragraph> Water for Injection</paragraph></td><td align="justify" valign="top"><paragraph>qs</paragraph></td></tr></tbody></table>

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Depo-subQ provera 104 inhibits the secretion of gonadotropins, which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect. Suppression of serum estradiol concentrations is likely to be responsible for the therapeutic effect on endometriosis-associated pain. 12.2 Pharmacodynamics The following laboratory tests are expected to be affected by progestins including depo-subQ provera 104: • Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). • Gonadotropin levels are decreased. • Sex-hormone-binding-globulin concentrations are decreased. • Histology specimens may demonstrate changes consistent with progestin effects. The following laboratory tests may be affected by depo-subQ provera 104, however the clinical significance is unknown: • Protein-bound iodine and butanol extractable protein-bound iodine may increase. • T 3 -uptake values may decrease. • Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. • Sulfobromophthalein and other liver function test values may be increased. • The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies. 12.3 Pharmacokinetics The pharmacokinetic parameters of MPA following a single subcutaneous injection of depo-subQ provera 104 in healthy women (n=42) are shown in Table 2 and Figure P. Table 2. Pharmacokinetic Parameters of MPA after a Single Subcutaneous Injection of depo-subQ provera 104 in Healthy Women C max (ng/mL) T max (day) C 91 (ng/mL) AUC 0–91 (ng∙day/mL) AUC 0–∞ (ng∙day/mL) t½ (day) Abbreviations: C max =peak serum concentration; T max =time when C max is observed; C 91 =serum concentration at 91 days; AUC 0–91 and AUC 0–∞ =area under the concentration-time curve over 91 days or infinity, respectively; t½=terminal half-life. Mean 1.56 8.8 0.402 66.98 92.84 43 Min 0.53 2.0 0.133 20.63 31.36 16 Max 3.08 80.0 0.733 139.79 162.29 114 Following subcutaneous administration of single depo-subQ provera 104 doses ranging from 50 to 150 mg (0.48 and 1.4 times the recommended dose, respectively), the AUC and C min (Day 91) increased with higher doses, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but C max did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity. Absorption Following a single subcutaneous injection of depo-subQ provera 104 in healthy women, serum MPA concentrations reached ≥0.2 ng/mL within 24 hours. The mean T max was attained approximately 1 week after injection. Figure P. Serum Concentration-Time Profile of MPA Mean (SD) after a Single Injection of depo-subQ provera 104 to Healthy Women In a study to assess accumulation and the achievement of steady state following multiple subcutaneous administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration.

dy to assess accumulation and the achievement of steady state following multiple subcutaneous administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12, and 24 months, respectively. Depo-subQ provera 104 was administered subcutaneously into the anterior thigh or the abdomen to evaluate effects of injection site location on the MPA concentration-time profile. MPA trough concentrations (C min ; Day 91) were similar for the two injection site locations. Figure P Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Elimination Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 were generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after subcutaneous administration. Most MPA metabolites were excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Specific Populations Racial Groups There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after subcutaneous administration of depo-subQ provera 104 in African-American, Caucasian, and Asian women. Effect of Body Weight Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women [n=42, body mass index (BMI) ranged from 18.2 to 46.7 kg/m 2 ]. The AUC 0–91 values for MPA were 71.6, 67.9, and 46.3 ng∙day/mL in women with BMI categories of ≤28 kg/m 2 , >28–38 kg/m 2 , and >38 kg/m 2 , respectively. The mean MPA C max was 1.74 ng/mL in women with BMI ≤28 kg/m 2 , 1.53 ng/mL in women with BMI >28–38 kg/m 2 , and 1.02 ng/mL in women with BMI >38 kg/m 2 , respectively. The MPA trough (C min ) concentrations had a tendency to be lower in women with BMI >38 kg/m 2 .

12.1 Mechanism of Action Depo-subQ provera 104 inhibits the secretion of gonadotropins, which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect. Suppression of serum estradiol concentrations is likely to be responsible for the therapeutic effect on endometriosis-associated pain.

12.2 Pharmacodynamics The following laboratory tests are expected to be affected by progestins including depo-subQ provera 104: • Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). • Gonadotropin levels are decreased. • Sex-hormone-binding-globulin concentrations are decreased. • Histology specimens may demonstrate changes consistent with progestin effects. The following laboratory tests may be affected by depo-subQ provera 104, however the clinical significance is unknown: • Protein-bound iodine and butanol extractable protein-bound iodine may increase. • T 3 -uptake values may decrease. • Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. • Sulfobromophthalein and other liver function test values may be increased. • The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

12.3 Pharmacokinetics The pharmacokinetic parameters of MPA following a single subcutaneous injection of depo-subQ provera 104 in healthy women (n=42) are shown in Table 2 and Figure P. Table 2. Pharmacokinetic Parameters of MPA after a Single Subcutaneous Injection of depo-subQ provera 104 in Healthy Women C max (ng/mL) T max (day) C 91 (ng/mL) AUC 0–91 (ng∙day/mL) AUC 0–∞ (ng∙day/mL) t½ (day) Abbreviations: C max =peak serum concentration; T max =time when C max is observed; C 91 =serum concentration at 91 days; AUC 0–91 and AUC 0–∞ =area under the concentration-time curve over 91 days or infinity, respectively; t½=terminal half-life. Mean 1.56 8.8 0.402 66.98 92.84 43 Min 0.53 2.0 0.133 20.63 31.36 16 Max 3.08 80.0 0.733 139.79 162.29 114 Following subcutaneous administration of single depo-subQ provera 104 doses ranging from 50 to 150 mg (0.48 and 1.4 times the recommended dose, respectively), the AUC and C min (Day 91) increased with higher doses, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but C max did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity. Absorption Following a single subcutaneous injection of depo-subQ provera 104 in healthy women, serum MPA concentrations reached ≥0.2 ng/mL within 24 hours. The mean T max was attained approximately 1 week after injection. Figure P. Serum Concentration-Time Profile of MPA Mean (SD) after a Single Injection of depo-subQ provera 104 to Healthy Women In a study to assess accumulation and the achievement of steady state following multiple subcutaneous administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12, and 24 months, respectively. Depo-subQ provera 104 was administered subcutaneously into the anterior thigh or the abdomen to evaluate effects of injection site location on the MPA concentration-time profile. MPA trough concentrations (C min ; Day 91) were similar for the two injection site locations. Figure P Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Elimination Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 were generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after subcutaneous administration. Most MPA metabolites were excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Specific Populations Racial Groups There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after subcutaneous administration of depo-subQ provera 104 in African-American, Caucasian, and Asian women.

in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Specific Populations Racial Groups There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after subcutaneous administration of depo-subQ provera 104 in African-American, Caucasian, and Asian women. Effect of Body Weight Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women [n=42, body mass index (BMI) ranged from 18.2 to 46.7 kg/m 2 ]. The AUC 0–91 values for MPA were 71.6, 67.9, and 46.3 ng∙day/mL in women with BMI categories of ≤28 kg/m 2 , >28–38 kg/m 2 , and >38 kg/m 2 , respectively. The mean MPA C max was 1.74 ng/mL in women with BMI ≤28 kg/m 2 , 1.53 ng/mL in women with BMI >28–38 kg/m 2 , and 1.02 ng/mL in women with BMI >38 kg/m 2 , respectively. The MPA trough (C min ) concentrations had a tendency to be lower in women with BMI >38 kg/m 2 .

<table ID="_RefID0EDTAG" width="100%"><caption>Table 2. Pharmacokinetic Parameters of MPA after a Single Subcutaneous Injection of depo-subQ provera 104 in Healthy Women</caption><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="15%"/><col width="15%"/><col width="14%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Toprule " valign="top">C_max (ng/mL)</th><th align="center" styleCode="Rrule Botrule Toprule " valign="top">T_max (day)</th><th align="center" styleCode="Rrule Botrule Toprule " valign="top">C₉₁ (ng/mL)</th><th align="center" styleCode="Rrule Botrule Toprule " valign="top">AUC_0&#x2013;91 (ng&#x2219;day/mL)</th><th align="center" styleCode="Rrule Botrule Toprule " valign="top">AUC_{0&#x2013;&#x221E;} (ng&#x2219;day/mL)</th><th align="center" styleCode="Botrule Toprule " valign="top">t&#xBD; (day)</th></tr></thead><tfoot><tr><td align="left" colspan="7" valign="top">Abbreviations: C_max=peak serum concentration; T_max=time when C_max is observed; C₉₁=serum concentration at 91 days; AUC_0&#x2013;91 and AUC_{0&#x2013;&#x221E;}=area under the concentration-time curve over 91 days or infinity, respectively; t&#xBD;=terminal half-life.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Mean</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>1.56</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8.8</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.402</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>66.98</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>92.84</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>43</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Min</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.53</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.133</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20.63</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>31.36</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Max</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.08</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>80.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.733</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>139.79</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>162.29</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>114</paragraph></td></tr></tbody></table>

agraph>0.733</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>139.79</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>162.29</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>114</paragraph></td></tr></tbody></table> <table ID="_RefID0EBYAG" styleCode="Noautorules" width="100%"><caption>Figure P. Serum Concentration-Time Profile of MPA Mean (SD) after a Single Injection of depo-subQ provera 104 to Healthy Women</caption><col width="100%"/><tbody><tr><td valign="top"><renderMultiMedia ID="id1452" referencedObject="MM17"/></td></tr></tbody></table>

14 CLINICAL STUDIES 14.1 Contraception Studies In three open label clinical studies, depo-SubQ provera 104 (104 mg given every three months subcutaneously), was administered to healthy, sexually-active, nonpregnant women 18 to 49 years of age who desired long-term contraception. In these three studies, no pregnancies were detected among 2042 women treated with depo-subQ provera 104 for up to 1 year. In women less than 36 years of age (at baseline), the Pearl Index pregnancy rate in cycles in which no other contraceptive methods were used, was 0 pregnancies per 100 women-years of use (upper 95% CI = 0.25). 14.2 Endometriosis Studies The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies in pre-menopausal women 18 to 49 years of age with laparoscopically diagnosed endometriosis and persistent endometriosis pain symptoms (i.e., Studies 268 and 270). Each study assessed endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment. Subjects were treated for six months with depo-subQ provera 104 [104 mg given subcutaneously every 3 months (2 injections)] or leuprolide [11.25 mg given subcutaneously every 3 months (2 injections) or 3.75 mg given subcutaneously every month (6 injections)]. Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 subjects received depo-subQ provera 104 and 138 subjects received leuprolide). Study 270 was conducted in South America, Europe, and Asia, and enrolled 299 subjects (153 subjects received depo-subQ provera 104 and 146 subjects received leuprolide). Reduction in endometriosis pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (i.e., dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (i.e., pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure Q). Figure Q. Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Patients with Endometriosis in Studies 268 and 270 Favorable Response = reduction in severity of symptom or sign of ≥1 point on a scale of 0 to 3, as compared to baseline. Additionally, scores from each of the five categories were combined into a composite score that was considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, the mean changes in the composite score met the protocol-defined criterion for improvement for the depo-subQ provera 104 and leuprolide treatment groups. In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available. Figure Q 14.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception In a study that compared changes in bone mineral density (BMD) in adult women using depo-subQ provera 104 or DMPA-IM for contraception, both treatments showed BMD reductions in the lumbar spine, total hip, and femoral neck.

.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception In a study that compared changes in bone mineral density (BMD) in adult women using depo-subQ provera 104 or DMPA-IM for contraception, both treatments showed BMD reductions in the lumbar spine, total hip, and femoral neck. Mean percent changes in BMD in depo-subQ provera 104-treated women are shown in Table 3. Table 3. BMD Mean Percent Change from Baseline in Women Using depo-subQ provera 104 for Contraception Time on Treatment Lumbar Spine Total Hip Femoral Neck Mean % Change (95% CI) Mean % Change (95% CI) Mean % Change (95% CI) 1 year (n=166) -2.7 (-3.1 to -2.3) -1.7 (-2.1 to -1.3) -1.9 (-2.5 to -1.4) 2 years (n=106) - 4.1 (-4.6 to -3.5) -3.5 (-4.2 to -2.7) -3.5 (-4.3 to -2.6) BMD Recovery Post-Treatment in Women Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, BMD recovery post-treatment is also expected to be similar. In a controlled clinical study that compared changes in BMD in adult women using DMPA-IM for contraception or no hormonal contraception, the 2-year post-treatment follow-up demonstrated incomplete recovery of BMD following the last injection of DMPA-IM. Table 4 shows the change in BMD in women after 5 years of treatment with DMPA-IM and in the control group, as well as the extent of BMD recovery in the subset of women for whom 2-year post-treatment data were available. Table 4. BMD Mean Percent Change from Baseline in Women by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) Time in Study Spine Total Hip Femoral Neck DMPA-IM Women who received DMPA-IM for 5 years and were then followed for 2 years post-treatment (total time in study of 7 years). Control Women who did not use hormonal contraception and were followed for 7 years. DMPA-IM Control DMPA-IM Control 5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106 7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63 14.4 Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age) Treated with DMPA-IM The effect of DMPA-IM on BMD in adolescents is described below, and the effect of depo-subQ provera 104 on BMD in adolescents is expected to be similar. The impact of DMPA-IM use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of DMPA-IM was associated with a significant decline from baseline in BMD. Partway through the trial, DMPA-IM administration was stopped (at 120 weeks). The mean number of injections per DMPA-IM user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD, and other factors that influence the rate of acquisition of BMD. Table 5.

l neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD, and other factors that influence the rate of acquisition of BMD. Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort Duration of Treatment DMPA-IM (150 mg) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) 113 -2.75 166 1.22 Week 120 (2.3 years) 73 -5.40 109 2.19 Week 240 (4.6 years) 28 -6.40 84 1.71 Femoral Neck BMD Week 60 113 -2.96 166 1.75 Week 120 73 -5.30 108 2.83 Week 240 28 -5.40 84 1.94 Lumbar Spine BMD Week 60 114 -2.47 167 3.39 Week 120 73 -2.74 109 5.28 Week 240 27 -2.11 84 6.40 BMD Recovery Post-Treatment in Adolescents Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of DMPA-IM. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received DMPA-IM for two years or less compared to more than two years. Post-treatment follow-up showed that, in adolescents treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with DMPA-IM for more than two years did not recover to their baseline BMD level at the femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period [see Warnings and Precautions (5.1) ] . Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs. More than 2 Years) Duration of Treatment (Months) 2 Years or Less More than 2 Years N Mean % Change from baseline N Mean % Change from baseline Total Hip BMD End of Treatment 49 -1.5% 49 -6.2% 12 M post-treatment 33 -1.4% 24 -4.6% 24 M post-treatment 18 0.3% 17 -3.6% 36 M post-treatment 12 2.1% 11 -4.6% 48 M post-treatment 10 1.3% 9 -2.5% 60 M post-treatment 3 0.2% 2 -1.0% Femoral Neck BMD End of Treatment 49 -1.6% 49 -5.8% 12 M post-treatment 33 -1.4% 24 -4.3% 24 M post-treatment 18 0.5% 17 -3.8% 36 M post-treatment 12 1.2% 11 -3.8% 48 M post-treatment 10 2.0% 9 -1.7% 60 M post-treatment 3 1.0% 2 -1.9% Lumbar Spine BMD End of Treatment 49 -0.9% 49 -3.5% 12 M post-treatment 33 0.4% 23 -1.1% 24 M post-treatment 18 2.6% 17 1.9% 36 M post-treatment 12 2.4% 11 0.6% 48 M post-treatment 10 6.5% 9 3.5% 60 M post-treatment 3 6.2% 2 5.7% 14.5 Bone Fracture Incidence in Women Treated with Depo-medroxyprogesterone acetate for Contraception A retrospective cohort study to assess the association between DMPA-IM injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA-IM users and contraceptive users who had no recorded use of DMPA-IM. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to DMPA-IM use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to DMPA-IM was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.

s who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use. There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA-IM users compared to non-users. Importantly, this study could not determine whether use of DMPA-IM has an effect on fracture rate later in life. Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, bone fracture incidence may also be expected to be similar. 14.6 Bone Mineral Density in Women Treated with depo-SubQ provera 104 for Endometriosis In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment (104 mg subcutaneously every 3 months) were compared to 6 months of leuprolide treatment (either 11.25 mg given subcutaneously every 3 months or 3.75 mg given subcutaneously every month). Subjects were then observed after treatment completion, for an additional 12 months. See Table 7 for the results. Table 7. BMD Mean Percent Change from Baseline after Therapy for Endometriosis with depo-subQ provera 104 or Leuprolide for 6 Months, and 6- and 12-Months Post-Therapy (Studies 268 and 270 Combined) Time of BMD Measurement Lumbar Spine Total Hip depo-subQ provera 104 Leuprolide depo-subQ provera 104 Leuprolide N Mean % Change N Mean % Change N Mean % Change N Mean % Change Month 6 of treatment (End of Treatment) 208 -1.20 229 -4.10 207 -0.03 227 -1.83 6 months post-treatment 168 -1.06 180 -2.75 169 -0.05 181 -1.59 12 months post-treatment 124 -0.54 133 -1.48 125 0.39 134 -1.15

<table ID="_RefID0ES6AG" styleCode="Noautorules" width="100%"><caption>Figure Q. Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Patients with Endometriosis in Studies 268 and 270</caption><col width="100%"/><tfoot><tr><td align="left" colspan="1" valign="top">Favorable Response = reduction in severity of symptom or sign of &#x2265;1 point on a scale of 0 to 3, as compared to baseline.</td></tr></tfoot><tbody><tr><td valign="top"><renderMultiMedia ID="id1596" referencedObject="MM18"/></td></tr></tbody></table>

idth="100%"/><tfoot><tr><td align="left" colspan="1" valign="top">Favorable Response = reduction in severity of symptom or sign of &#x2265;1 point on a scale of 0 to 3, as compared to baseline.</td></tr></tfoot><tbody><tr><td valign="top"><renderMultiMedia ID="id1596" referencedObject="MM18"/></td></tr></tbody></table> <table ID="_RefID0E5ABG" width="100%"><caption>Table 3. BMD Mean Percent Change from Baseline in Women Using depo-subQ provera 104 for Contraception</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Time on Treatment</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Lumbar Spine</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Total Hip</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Femoral Neck</content></th></tr><tr><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content> <content styleCode="bold">(95% CI)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content> <content styleCode="bold">(95% CI)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content> <content styleCode="bold">(95% CI)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 year (n=166)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-2.7 (-3.1 to -2.3)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-1.7 (-2.1 to -1.3)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-1.9 (-2.5 to -1.4)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2 years (n=106)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>- 4.1 (-4.6 to -3.5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-3.5 (-4.2 to -2.7) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-3.5 (-4.3 to -2.6)</paragraph></td></tr></tbody></table>

yleCode="Rrule Botrule " valign="top"><paragraph>- 4.1 (-4.6 to -3.5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-3.5 (-4.2 to -2.7) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-3.5 (-4.3 to -2.6)</paragraph></td></tr></tbody></table> <table ID="_RefID0EKEBG" width="100%"><caption>Table 4. BMD Mean Percent Change from Baseline in Women by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up)</caption><col width="15%"/><col width="15%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="15%"/><col width="15%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Time in Study</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Spine</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Total Hip</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Femoral Neck</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top">DMPA-IM<footnote ID="_Refft1">Women who received DMPA-IM for 5 years and were then followed for 2 years post-treatment (total time in study of 7 years).</footnote></th><th align="center" styleCode="Rrule Botrule " valign="top">Control<footnote ID="_Refft2">Women who did not use hormonal contraception and were followed for 7 years.</footnote></th><th align="center" styleCode="Rrule Botrule " valign="top">DMPA-IM<footnoteRef IDREF="_Refft1"/></th><th align="left" styleCode="Rrule Botrule " valign="top">Control<footnoteRef IDREF="_Refft2"/></th><th align="center" styleCode="Rrule Botrule " valign="top">DMPA-IM<footnoteRef IDREF="_Refft1"/></th><th align="center" styleCode="Rrule Botrule " valign="top">Control<footnoteRef IDREF="_Refft2"/></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 years</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-5.38% n=33</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.43% n=105</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-5.16% n=21</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.19% n=65</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-6.12% n=34</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-0.27% n=106</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7 years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-3.13% n=12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.53% n=60</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.34% n=7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.94% n=39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-5.38% n=13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-0.11% n=63</paragraph></td></tr></tbody></table>

></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.94% n=39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-5.38% n=13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-0.11% n=63</paragraph></td></tr></tbody></table> <table ID="_RefID0EOJBG" width="100%"><caption>Table 5.

></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.94% n=39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-5.38% n=13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-0.11% n=63</paragraph></td></tr></tbody></table> <table ID="_RefID0EOJBG" width="100%"><caption>Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving &#x2265;4 Injections per 60-week Period, by Skeletal Site and Cohort</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Duration of Treatment</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">DMPA-IM (150 mg)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Unmatched, Untreated Cohort</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Total Hip BMD</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/><td styleCode="Rrule Toprule " valign="top"/><td styleCode="Rrule Toprule " valign="top"/><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Week 60 (1.2 years)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>113</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.75</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>166</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.22</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Week 120 (2.3 years)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>73</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-5.40</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>109</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.19</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 240 (4.6 years)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-6.40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>84</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.71</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Femoral Neck BMD</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Week 60</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>113</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.96</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>166</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.75</paragraph></td></tr><tr><td styleCode="Rrule Lrule " vali

aragraph>113</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.96</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>166</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.75</paragraph></td></tr><tr><td styleCode="Rrule Lrule " vali gn="top"><paragraph>Week 120</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>73</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-5.30</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>108</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.83</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Week 240</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-5.40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>84</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.94</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Lumbar Spine BMD</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Week 60</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>114</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.47</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>167</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.39</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Week 120</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>73</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.74</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>109</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.28</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Week 240</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-2.11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>84</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.40</paragraph></td></tr></tbody></table>

ragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-2.11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>84</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.40</paragraph></td></tr></tbody></table> <table ID="_RefID0EAQBG" width="100%"><caption>Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs.

ragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-2.11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>84</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.40</paragraph></td></tr></tbody></table> <table ID="_RefID0EAQBG" width="100%"><caption>Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs. More than 2 Years)</caption><col width="25%"/><col width="25%"/><col width="17%"/><col width="17%"/><col width="17%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Duration of Treatment</content> <content styleCode="bold">(Months)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">2 Years or Less</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">More than 2 Years</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change from baseline</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change from baseline</content></th></tr></thead><tbody><tr><td align="center" colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Total Hip BMD</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">End of Treatment</content></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-6.2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>12 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-4.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>24 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-3.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>36 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-4.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>48 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60 M post-treatment</

styleCode="Rrule " valign="top"><paragraph>1.3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-2.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60 M post-treatment</ paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.0%</paragraph></td></tr><tr><td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Femoral Neck BMD</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">End of Treatment</content></paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-5.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>12 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-4.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>24 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-3.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>36 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-3.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>48 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.0%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60 M post-treatment</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.0%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.9%</paragraph></td></tr><tr><td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Lumbar Spine BMD</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">End of Treatment</content></paragraph></td><td align="center" styleCode=

tr><td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Lumbar Spine BMD</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">End of Treatment</content></paragraph></td><td align="center" styleCode= "Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-0.9%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-3.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>12 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>-1.1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>24 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>36 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>48 M post-treatment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6.5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>60 M post-treatment</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.7%</paragraph></td></tr></tbody></table>

<paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.7%</paragraph></td></tr></tbody></table> <table ID="table7" width="100%"><caption>Table 7.

<paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.7%</paragraph></td></tr></tbody></table> <table ID="table7" width="100%"><caption>Table 7. BMD Mean Percent Change from Baseline after Therapy for Endometriosis with depo-subQ provera 104 or Leuprolide for 6 Months, and 6- and 12-Months Post-Therapy (Studies 268 and 270 Combined)</caption><col width="18%"/><col width="18%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><col width="9%"/><thead><tr><th align="left" rowspan="3" styleCode="Rrule Lrule Toprule " valign="top"><content styleCode="bold">Time of BMD Measurement</content></th><th align="center" colspan="4" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Lumbar Spine</content></th><th align="center" colspan="4" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Total Hip</content></th></tr><tr><th align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">depo-subQ provera 104</content></th><th align="center" colspan="2" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Leuprolide</content></th><th align="center" colspan="2" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">depo-subQ provera 104</content></th><th align="center" colspan="2" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Leuprolide</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Mean % Change</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Month 6 of treatment (End of Treatment)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>208</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-1.20</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>229</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-4.10</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>207</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-0.03</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>227</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>-1.83</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 months post-treatment</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>168</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.06</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>180</paragraph></td><td align="cente

post-treatment</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>168</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.06</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>180</paragraph></td><td align="cente r" styleCode="Rrule Botrule " valign="top"><paragraph>-2.75</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>169</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-0.05</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>181</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.59</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>12 months post-treatment</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>124</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-0.54</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>133</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.48</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>125</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.39</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>134</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>-1.15</paragraph></td></tr></tbody></table>

15 REFERENCES 1. Li CI, Beaber EF, Tang MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012; 72:2028-2035. 2. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989; 299:759-62.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Depo-subQ provera 104 medroxyprogesterone acetate injectable suspension (104 mg/0.65 mL) is available in a single dose, disposable pre-filled syringe and is packaged with a 26-gauge × 3/8-inch Terumo SurGuard ® needle. NDC 0009-4709-13 16.2 Storage Store at controlled room temperature 20° C to 25° C (68° F to 77°F) [see USP]. Do not refrigerate.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) . Loss of Bone Mineral Density Advise the patient that the use of depo-subQ provera 104 decreases BMD [see Warnings and Precautions (5.1) ]. Arterial and Venous Thromboembolic Disorders Advise the patient that serious arterial and venous thrombotic events have been seen in women treated with depot medroxyprogesterone acetate (DMPA) [see Warnings and Precautions (5.2) ]. Anaphylaxis Counsel patients on the importance of seeking urgent medical attention if they experience symptoms of anaphylaxis [see Warnings and Precautions (5.6) ]. Ectopic Pregnancy Advise patients to tell their healthcare professional right away if they become pregnant or experience severe abdominal pain to exclude a diagnosis of ectopic pregnancy [see Warnings and Precautions (5.5) ]. Bleeding Irregularities Advise patients at the beginning of treatment that their menstrual cycle may be disrupted, resulting in irregular and unpredictable bleeding or spotting. Explain that bleeding and spotting irregularities usually decrease to the point of amenorrhea as treatment with depo-subQ provera 104 continues and does not require other therapy [see Warnings and Precautions (5.12) ]. Delayed Return of Ovulation and Fertility Advise patients that return to ovulation and fertility is likely to be delayed after stopping depo-subQ provera 104 [see Warnings and Precautions (5.9) ]. Risks of Breast Cancer Counsel patients about the possible increased risk of breast cancer in women who use depo-subQ provera 104 [see Warnings and Precautions (5.3) ]. Meningioma Counsel patients with a history of meningioma about the possible risk of worsening meningioma [see Warnings and Precautions (5.4) ]. Depression Counsel patients about the possible risk of depression and mood disorders. Advise patients with a history of depression or who are receiving treatment for depression to be alert to any mood changes or worsening of their depression. Counsel patients to follow up with their healthcare professional accordingly [see Warnings and Precautions (5.10) ]. Risk of Hyperglycemia in Patients with Diabetes Advise diabetic patients that some patients receiving progestins may exhibit a decrease in glucose tolerance and hyperglycemia [see Warnings and Precautions (5.13) ]. Liver Dysfunction Advise patients to seek medical advice if they experience symptoms of liver problems such as jaundice [see Warnings and Precautions (5.14) ]. Fluid Retention Counsel patients with conditions that may be influenced by fluid retention to inform their healthcare professional if they experience symptoms of fluid retention [see Warnings and Precautions (5.7) ]. Injection Site Reactions Counsel patients that injection site reactions including site dimpling, scarring or discoloration may occur [see Warnings and Precautions (5.11) ]. Sexually Transmitted Infections Counsel patients that depo-subQ provera 104 does not protect against HIV infection (AIDS) and other sexually transmitted infections [see Warnings and Precautions (5.15) ]. Drug Interactions Counsel patients to contact their healthcare professional if they start a medication that is a CYP3A enzyme inducer [see Drug Interactions (7) ]. Advise patients that taking a medication that is a CYP3A enzyme inducer may require using a back-up or alternate contraceptive method.

PATIENT INFORMATION DEPO-SUBQ PROVERA 104 ® (deh-poh' sub-cue' pro-ver-ah' one-oh-four) (medroxyprogesterone acetate injectable suspension) for subcutaneous use WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT depo-subQ provera 104? Use of depo-subQ provera 104 may cause you to lose calcium stored in your bones. The longer you use depo-subQ provera 104 the more calcium you are likely to lose. The calcium may not return completely once you stop using depo-subQ provera 104. Loss of calcium may cause weak, porous bones (osteoporosis) that could increase the risk that your bones might break, especially after menopause. It is not known whether your risk of developing osteoporosis may be greater if you are a teenager when you start to use depo-subQ provera 104. You should use depo-subQ provera 104 long-term (for example, more than 2 years) only if other methods of birth control or other treatments for endometriosis pain are not right for you. Depo-subQ provera 104 does not protect you from HIV (AIDS) and other sexually transmitted infections (STIs). WHAT IS depo-subQ provera 104? Depo-subQ provera 104 is a drug for birth control. It also helps relieve pain related to endometriosis (en-do-ME-tree-OH-sis) . Symptoms of endometriosis arise when cells normally inside your uterus grow outside the uterus. The cells respond to menstrual cycle hormones, and may cause painful periods, pelvic pain, and painful sex. Depo-subQ provera 104 contains a hormone called medroxyprogesterone acetate (MPA). It is given as a shot (injection) every 3 months. Three months is the same as 12 to 14 weeks. HOW WELL DOES depo-subQ provera 104 WORK FOR PREVENTING PREGNANCY? When you use depo-subQ provera 104 correctly, the chance of getting pregnant is very low. In studies, no women became pregnant during the year they used depo-subQ provera 104 injection. The list below estimates the chances of getting pregnant using different types of birth control. The numbers are based on typical use. Typical use includes people who use the method correctly and people who use the method incorrectly. The list shows the number of women out of 100 women who will likely get pregnant if they use the method for 1 year. Method Typical Chance of Getting Pregnant in 1 year (Number of pregnancies in 100 women) Shot Implant Female sterilization Male sterilization IUD (copper IUD and levonorgestrel IUD) Less than 1 Pill 5 Condom alone (male) 14 Withdrawal 19 Diaphragm with spermicides 20 Condom alone (female) 21 Periodic abstinence 25 Spermicides alone 26 Vaginal sponge or Cervical cap with spermicide 20 to 40 HOW WILL I GET depo-subQ provera 104? Depo-subQ provera 104 is given as a shot just under the skin on your thigh or belly. You get it once every 3 months. For Birth Control First shot: Your healthcare professional will want to be sure that you are not pregnant before you get your first shot. Normally, you get the shot by the 5th day from the START of your menstrual period. You get it whether or not you are still bleeding. If you are breast-feeding, you may have your first shot as early as 6 weeks after you deliver your baby. After the first shot: It is very important to keep getting depo-subQ provera 104 every 3 months. If you wait more than 14 weeks between shots, you could become pregnant. Your healthcare professional must make sure you are not pregnant before you get your next shot. When you get your shot, make an appointment for your next shot. Mark it on your calendar.

portant to keep getting depo-subQ provera 104 every 3 months. If you wait more than 14 weeks between shots, you could become pregnant. Your healthcare professional must make sure you are not pregnant before you get your next shot. When you get your shot, make an appointment for your next shot. Mark it on your calendar. If you need a birth control method for more than two years, your healthcare professional may ask you to have a test of your bones or ask you to switch to another birth control method before continuing depo-subQ provera 104, especially if you have other risks for weak bones. For Endometriosis If you have regular periods, you will get depo-subQ provera 104 the same way as described above for birth control. If your periods have stopped or are not regular, your healthcare professional must test to make sure you are not pregnant before you get your first shot. It is not recommended that you receive depo-subQ provera 104 for treatment of endometriosis for longer than 2 years. If your painful symptoms return after stopping treatment, your healthcare professional should ask you to have a test of your bones before restarting treatment. WHAT IF I MISS A SHOT? If you miss a shot, or wait longer than 14 weeks between shots, you could get pregnant. The longer you wait, the greater the risk of getting pregnant. Talk with your healthcare professional to find out when to restart depo-subQ provera 104. You should be tested to be sure you are not pregnant. Use another kind of non-hormonal birth control, such as condoms, until you start depo-subQ provera 104 again. DO NOT TAKE depo-subQ provera 104 IF YOU… • Have any unexplained vaginal bleeding • Have or have ever had breast cancer or think you have breast cancer • Ever had serious blood clots, such as blood clots in your legs (deep venous thrombophlebitis), lungs (pulmonary embolism), heart (heart attack), or head (stroke) • Have liver disease • Are allergic to anything in depo-subQ provera 104. There is a list of what is in depo-subQ provera 104 at the end of this leaflet. BEFORE TAKING depo-subQ provera 104 Your healthcare professional may do a physical examination and check your blood and urine. Tell your healthcare professional about all your medical conditions. Most importantly, tell your healthcare professional if you: • Are pregnant or might be pregnant. You should not get depo-subQ provera 104 if you are pregnant. • Plan to become pregnant in the next year. After you stop getting depo-subQ provera 104, it takes time for your body to be able to get pregnant. It can be as early as 1 week after the last shot wears off. Most likely it will take up to 1 year or longer for you to get pregnant. • Have or have ever had breast cancer, or think you have breast cancer • Have breast cancer in your family • Have an abnormal mammogram (breast X-ray), lumps in your breast, or bleeding from your nipples • Have or have ever had a type of usually benign brain tumor called a meningioma • Have irregular, light, or heavy menstrual periods • Have or had any of the following medical problems: o Kidney problems o High blood pressure o Migraine headaches o Asthma o Seizures o Diabetes, or if it runs in your family o Depression o Heart attack, stroke, or blood clots o Bone disease o Anorexia nervosa (an eating disorder) o A strong family history of osteoporosis o Use of a drug that can lower the amount of calcium in bones (drugs for epilepsy or steroids) o Drinking a lot of alcohol or smoking a lot It is important to see your healthcare professional regularly if you have any of these conditions.

o Anorexia nervosa (an eating disorder) o A strong family history of osteoporosis o Use of a drug that can lower the amount of calcium in bones (drugs for epilepsy or steroids) o Drinking a lot of alcohol or smoking a lot It is important to see your healthcare professional regularly if you have any of these conditions. Some medicines may make depo-subQ provera 104 less effective at preventing pregnancy, including those listed below: • Bosentan (used to treat pulmonary arterial hypertension) • Efavirenz, etravirine (HIV medicines) • Modafinil (used to improve wakefulness) • Mitotane (used to treat adrenal cortical carcinoma) • Phenytoin, carbamazepine, phenobarbital (used to treat seizures) • Rifampin (an antibiotic) • St. John's Wort (herbal medicinal product) Tell your healthcare professional about all the medicines you take. This includes prescription and over-the-counter medicines, vitamins, and herbal products. WHAT ELSE SHOULD I KNOW ABOUT TAKING depo-subQ provera 104? Other Birth Control. If you can't take birth control pills or can't use a birth control patch or ring, you may be able to use depo-subQ provera 104. Ask your healthcare professional. Pregnancy. When you take depo-subQ provera 104 every 3 months, your chance of getting pregnant is very low. You could miss a period or have a light period and not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see your healthcare professional as soon as possible. You should not use depo-subQ provera 104 if you are pregnant. However, depo-subQ provera 104 taken by accident during pregnancy does not seem to cause birth defects. Pregnancy in your fallopian tubes (Ectopic Pregnancy). If you have severe pain low in your belly, tell your healthcare professional right away. Infrequently, a baby may start to grow outside the uterus, most often in the tubes. Nursing a baby. Wait at least 6 weeks after your baby is born to start depo-subQ provera 104. You can use depo-subQ provera 104 if you are nursing. It does not lower the amount of milk you can make. It can pass through breast milk into your baby, but it is not harmful. Blood or urine tests. Depo-subQ provera 104 may affect blood or urine test results. Tell your healthcare professional you are taking depo-subQ provera 104 if you are going to have blood or urine tests. Liver problems. Your healthcare professional may stop depo-subQ provera 104 if you have liver problems. Some signs of liver problems are yellow skin or eyes, feeling like you have the flu, feeling more tired than usual, and itching. Tell your healthcare professional if you have these symptoms. WHAT ARE THE MOST SERIOUS RISKS OF depo-subQ provera 104? Losing calcium from your bones. Depo-subQ provera 104 use may decrease the amount of calcium in your bones. The longer you use depo-subQ provera 104, the more calcium you are likely to lose. This increases the risk of your bones weakening if you use depo-subQ provera 104 continuously for a long time (for example, if you use depo-subQ provera 104 for more than 2 years). The loss of calcium may increase your risk of osteoporosis and broken bones, particularly after your menopause. Calcium is generally added to the bones during teenage years.

nes weakening if you use depo-subQ provera 104 continuously for a long time (for example, if you use depo-subQ provera 104 for more than 2 years). The loss of calcium may increase your risk of osteoporosis and broken bones, particularly after your menopause. Calcium is generally added to the bones during teenage years. The decrease of calcium in your bones is of most concern if you are a teenager or have the following risk factors: • Bone disease • Anorexia nervosa (an eating disorder) • A strong family history of osteoporosis • Using a drug that can lower the amount of calcium in bones (drugs for epilepsy or steroids), or • Drinking a lot of alcohol or smoking a lot If you need a birth control method for more than 2 years, your healthcare professional may ask you to have a test of your bones or ask you to switch to another birth control method before continuing depo-subQ provera 104, especially if you have other risks for weak bones. When depo-subQ provera 104 is stopped, the calcium in your bones begins to come back. The lost calcium may not return completely once you stop using depo-subQ provera 104. Abnormal or very heavy bleeding. If you start having very heavy or very long periods, tell your healthcare professional. Allergic reaction. Allergic reactions to depo-subQ provera 104 have been reported. If you have hives, problems breathing, swelling of the face, mouth, tongue, or neck, or just do not feel right after your shot, call your healthcare professional or go to the Emergency Room right away. Serious blood clots. Call your healthcare professional immediately if you: • Have sharp chest pain, cough blood, or suddenly have trouble breathing • Have a sudden severe headache with vomiting, blindness or trouble talking, weakness, or numbness in an arm or leg, or get dizzy or faint • Have swelling or severe pain in your leg Depression. If you suffer from depression or have a history of depression, inform your healthcare professional if you notice any worsening of your depression while taking depo-subQ provera 104. Meningioma (a type of usually benign brain tumor). Possible increased risk for growth of a meningioma, primarily when the product is used for a long time. WHAT ARE COMMON SIDE EFFECTS OF depo-subQ provera 104? The most common side effects are: • Changes in your monthly periods. You may not know when you will bleed, your periods may not be regular, you may have heavy bleeding, or you may have spotting. You may have more days of bleeding during the first 2 or 3 months after you start depo-subQ provera 104. Over time, you may have less and less bleeding. Many women stop having periods by the end of 1 year. Your periods will come back eventually after you stop using depo-subQ provera 104. • Headache. • Weight gain. In studies, women gained an average of 3 to 4 pounds during the first year they used depo-subQ provera 104. After 2 years of using depo-subQ provera 104, women gained an average of 7 to 8 pounds. Some women gained more, some gained less, some lost, and some stayed the same. Weight changes beyond 2 years of use with depo-subQ provera 104 have not been studied. Women who used a similar birth control product for 5 years gained on average 5 pounds more than women who did not use a hormone contraceptive product. • Skin reaction where you got the shot. Lumps, skin dimpling, or pain may occur. Scarring and discoloration are uncommon, but may happen. If there is swelling or your skin gets hot, has pus or looks bruised 1 or more days after your shot, call your healthcare professional.

o did not use a hormone contraceptive product. • Skin reaction where you got the shot. Lumps, skin dimpling, or pain may occur. Scarring and discoloration are uncommon, but may happen. If there is swelling or your skin gets hot, has pus or looks bruised 1 or more days after your shot, call your healthcare professional. Women using depo-subQ provera 104 for birth control or endometriosis had these less common side effects: Vaginal inflammation, vaginal thrush, abdominal pain, urinary tract infections, acne, depression, less sex drive, nausea, back pain, breast pain/tenderness, fatigue, anxiety, being irritable, dizziness, hot flushes and fluid retention. If you feel you are having other side effects, talk with your healthcare professional. DOES depo-subQ provera 104 CAUSE CANCER? There have been several studies of women who use birth control like depo-subQ provera 104. • Women who use depo-subQ provera 104 may have a slightly increased risk of breast cancer compared to non-users. • The risk of cancer of the ovary, liver, or cervix did not change. WHAT IF I WANT TO BECOME PREGNANT? Plan ahead. The effect of depo-subQ provera 104 can last for a long time after you stop getting shots. Although you may be able to get pregnant quickly, it is more likely to take a year or longer after your last shot before you get pregnant. It's best to see your healthcare professional for a pre-pregnancy check-up. Your healthcare professional may also tell you to take a vitamin called folic acid every day if you are planning to become pregnant. GENERAL ADVICE ABOUT depo-subQ provera 104 For more information about depo-subQ provera 104, ask your healthcare professional or pharmacist. WHAT IS IN depo-subQ provera 104? Active ingredient: medroxyprogesterone acetate. Inactive ingredients: methylparaben, propylparaben, sodium chloride, polyethylene glycol, polysorbate 80, monobasic sodium phosphate∙H2O, dibasic sodium phosphate∙12H2O, methionine, povidone, water for shot. When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both. This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . LAB-0298-12.0 Revised December 2025 logo

<table width="100%"><col width="50%"/><col width="50%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Method</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Typical Chance of Getting Pregnant in 1 year</content> <content styleCode="bold">(Number of pregnancies in 100 women)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Shot Implant Female sterilization Male sterilization IUD (copper IUD and levonorgestrel IUD)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Less than 1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pill</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Condom alone (male)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Withdrawal</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diaphragm with spermicides</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Condom alone (female)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>21</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Periodic abstinence</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Spermicides alone</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>26</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Vaginal sponge or Cervical cap with spermicide</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 to 40</paragraph></td></tr></tbody></table>