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DESCRIPTION Tretinoin Cream, USP are used for the topical treatment of acne vulgaris. Tretinoin Cream, USP contains tretinoin in either of three strengths, 0.1%, 0.05% or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: structure

CLINICAL PHARMACOLOGY Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

INDICATIONS AND USAGE Tretinoin cream is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established.

PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of tretinoin cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. Tretinoin acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of tretinoin is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% tretinoin applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin.

mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with tretinoin has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical dose adjusted for total body surface area). Pregnancy Teratogenic Effects Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietale incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin.

in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic Effects Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tretinoin is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical studies of tretinoin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of tretinoin cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. Tretinoin acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of tretinoin is begun.

Carcinogenesis, Mutagenesis, Impairment to Fertility In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% tretinoin applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with tretinoin has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical dose adjusted for total body surface area).

Pregnancy Teratogenic Effects Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietale incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic Effects Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tretinoin is administered to a nursing woman.

Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical studies of tretinoin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

ADVERSE REACTIONS The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin cream. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin cream. To date, all adverse effects of tretinoin cream have been reversible upon discontinuance of therapy (see Dosage and Administration). To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

DOSAGE AND ADMINISTRATION Tretinoin cream, USP should be applied once a day, before retiring to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alterations of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with tretinoin acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (see PRECAUTIONS.)

HOW SUPPLIED Tretinoin Cream, USP are supplied as: NDC Code Strength Quantity 21922-077-25 0.1% 20 g 21922-077-06 0.1% 45 g 21922-078-25 0.05% 20 g 21922-078-06 0.05% 45 g 21922-079-25 0.025% 20 g 21922-079-06 0.025% 45 g Storage Conditions: Tretinoin Cream, USP 0.1%, 0.05% and 0.025%: store below 80°F. Rx only Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, North Carolina (NC) 27713, United States (USA) Revised: 03/2026

<table width="100%"><col width="34%" align="left" valign="middle"/><col width="33%" align="left" valign="middle"/><col width="33%" align="left" valign="middle"/><thead align="center"><tr><th styleCode="Toprule" align="justify"><content styleCode="bold"> NDC Code</content></th><th styleCode="Toprule" align="justify"><content styleCode="bold"> Strength</content></th><th styleCode="Toprule" align="justify"><content styleCode="bold"> Quantity</content></th></tr></thead><tbody><tr><td align="justify"><paragraph> 21922-077-25</paragraph></td><td align="justify"><paragraph> 0.1%</paragraph></td><td valign="top" align="justify"><paragraph> 20 g</paragraph></td></tr><tr><td align="justify"><paragraph> 21922-077-06</paragraph></td><td align="justify"><paragraph> 0.1%</paragraph></td><td valign="top" align="justify"><paragraph> 45 g</paragraph></td></tr><tr><td align="justify"><paragraph> 21922-078-25</paragraph></td><td align="justify"><paragraph> 0.05%</paragraph></td><td valign="top" align="justify"><paragraph> 20 g</paragraph></td></tr><tr><td align="justify"><paragraph> 21922-078-06</paragraph></td><td align="justify"><paragraph> 0.05%</paragraph></td><td valign="top" align="justify"><paragraph> 45 g</paragraph></td></tr><tr><td align="justify"><paragraph> 21922-079-25</paragraph></td><td align="justify"><paragraph> 0.025%</paragraph></td><td valign="top" align="justify"><paragraph> 20 g</paragraph></td></tr><tr><td styleCode="Botrule" align="justify"><paragraph> 21922-079-06</paragraph></td><td styleCode="Botrule" align="justify"><paragraph> 0.025%</paragraph></td><td styleCode="Botrule" valign="top" align="justify"><paragraph> 45 g</paragraph></td></tr></tbody></table>

PATIENT INSTRUCTIONS Tretinoin Cream, USP For Topical Use Only Acne Treatment IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT TRETINOIN ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with tretinoin may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in tretinoin cream, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with tretinoin should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using tretinoin. If you do become sunburned, stop your therapy with tretinoin until your skin has recovered. Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with tretinoin may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinue the use of tretinoin and consult your physician. There have been reports that, in some patients, areas treated with tretinoin developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to tretinoin or therapy was discontinued. Use other medications only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully.

normal either when the skin was allowed to adjust to tretinoin or therapy was discontinued. Use other medications only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with tretinoin which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of tretinoin in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using this medication. AND WHILE YOU’RE ON TRETINOIN THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing . Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild, bland soap. Two or three times a day should be sufficient. Pat skin dry with a towel. Let the face dry 20 to 30 minutes before applying tretinoin. Remember, excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE TRETINOIN To get the best results with tretinoin therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when tretinoin is used properly , many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOUR DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. Apply tretinoin once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying tretinoin every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. Tretinoin Cream : Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with tretinoin cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT Tretinoin works deep inside your skin and this takes time.

it over the entire affected area. Smooth gently into the skin. It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT Tretinoin works deep inside your skin and this takes time. You cannot make tretinoin work any faster by applying more than one dose each day, but an excess amount of tretinoin may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to tretinoin and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using tretinoin. If tretinoin is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of tretinoin until your physician instructs otherwise. IF YOU HAVE QUESTIONS All questions of a medical nature should be taken up with your doctor. For more information about tretinoin, call Encube Ethicals Pvt. Ltd.at 1-833-285-4151. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, North Carolina (NC) 27713, United States (USA) Revised: 03/2026 image-1

For Topical Use Only Manufactured for: Northstar RxLLC Memphis, TN 38141. Toll Free Number: 1-800-206-7821 Manufactured by: Taro Pharmaceuticals Inc. Brampton, Ontario, Canada L6T 1C1. Issued: February 2022 5228784 42

Description Tretinoin Cream USP, 0.05% is used for the topical treatment of acne vulgaris. Tretinoin Cream contains tretinoin in 0.05% by weight, in a hydrophilic cream vehicle of butylated hydroxytoluene, isopropyl myristate, polyoxyl stearate type II, purified water, sorbic acid, stearic acid, stearyl alcohol and xanthan gum. Chemically, tretinoin is all-trans -retinoic acid and has the following structure: Chemical Structure

Clinical Pharmacology Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

Indications and Usage Tretinoin cream is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established.

Precautions General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of tretinoin cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. Tretinoin acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin. It also is advisable to "rest" a patient's skin until the effects of such preparations subside before use of tretinoin is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% tretinoin applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin.

mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with tretinoin has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical dose adjusted for total body surface area). Pregnancy Teratogenic effects Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin.

in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tretinoin is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical studies of tretinoin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

Drug Interactions Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with tretinoin. It also is advisable to "rest" a patient's skin until the effects of such preparations subside before use of tretinoin is begun.

Pregnancy Teratogenic effects Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic effects Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

Nonteratogenic effects Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Adverse Reactions The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin. To date, all adverse effects of tretinoin have been reversible upon discontinuance of therapy (see Dosage and Administration Section).

Overdosage If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

Dosage and Administration Tretinoin Cream should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with tretinoin acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions )

PATIENT INSTRUCTIONS Tretinoin Cream USP, 0.05% For Topical Use Only Acne Treatment IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT TRETINOIN ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR'S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS Keep out of reach of children. Keep tube tightly closed. Do not expose to heat. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with tretinoin may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in Tretinoin Cream, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced . There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with tretinoin should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using tretinoin. If you do become sunburned, stop your therapy with tretinoin until your skin has recovered. Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with tretinoin may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinue the use of tretinoin and consult your physician. There have been reports that, in some patients, areas treated with tretinoin developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to tretinoin or therapy was discontinued. Use other medication only on your physician's advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary.

present. The pigment in these areas returned to normal either when the skin was allowed to adjust to tretinoin or therapy was discontinued. Use other medication only on your physician's advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician's instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with tretinoin which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of tretinoin in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU'RE ON TRETINOIN THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn't caused by dirt, so no matter how hard you scrub, you can't wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20 to 30 minutes before applying tretinoin. Remember, excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE TRETINOIN To get the best results with tretinoin therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when tretinoin is used properly , many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON'T START AND STOP THERAPY ON YOUR OWN – IF YOU HAVE QUESTIONS, ASK YOUR DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. Apply tretinoin once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying tretinoin every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won't give faster or better results. Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying . Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with tretinoin cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash.

y with tretinoin cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT Tretinoin works deep inside your skin and this takes time. You cannot make tretinoin work any faster by applying more than one dose each day, but an excess amount of tretinoin may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to tretinoin and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using tretinoin. If tretinoin is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don't be discouraged if you see no immediate improvement. Don't stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of tretinoin until your physician instructs otherwise. IF YOU HAVE QUESTIONS All questions of a medical nature should be taken up with your doctor. For more information about tretinoin, call our toll-free number: 1-800-206-7821. Manufactured for: Northstar RxLLC, Memphis, TN 38141. Manufactured by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1. Issued: February 2022 5228784 42 Figure

1 INDICATIONS AND USAGE Tretinoin gel (microsphere) is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. Tretinoin gel (microsphere) is a retinoid indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION For topical use only. Not for oral, ophthalmic, or intravaginal use. Prior to tretinoin gel (microsphere) use, thoroughly cleanse area(s) with a mild, non-medicated cleanser then pat the skin dry. When applying tretinoin gel (microsphere), keep away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Apply a thin layer of tretinoin gel (microsphere) (0.06%, or 0.08%) to skin where acne lesions appear (cover the entire affected area), once daily in the evening. Do not apply more than a thin layer [see Warning and Precautions ( 5.1 )]. Improvements in acne lesions may be noticed after two weeks of tretinoin gel (microsphere) therapy, but more than seven weeks of therapy may be needed for sustained benefit. If tretinoin gel (microsphere) was temporarily discontinued due to local adverse reactions, tretinoin gel (microsphere) therapy may be resumed upon resolution of local adverse reactions. For topical use only. Not for oral, ophthalmic, or intravaginal use. ( 2 ) Keep away from eyes, mouth, paranasal creases of the nose, and mucous membranes. ( 2 ) Apply a thin layer of tretinoin gel (microsphere) to skin where acne lesions appear (cover the entire affected area) (0.06%, or 0.08%) once daily in the evening ( 2 ).

5 WARNINGS AND PRECAUTIONS Local Skin Irritation : Tretinoin gel (microsphere) can cause local skin irritation, including excessive dryness, redness, swelling, peeling, itching, blistering, burning, or stinging ( 5.1 ) Avoid use on eczematous skin or during weather extremes, such as severe wind or cold. To reduce the risk of local skin irritation, wash the treated skin gently, using a mild, non-medicated soap, avoid washing the treated skin too often or scrubbing it hard when washing, and apply a topical moisturizer. If severe local skin irritation occurs, discontinue use temporarily or permanently. Initial Worsening of Inflammatory Acne Vulgaris : During the early weeks of tretinoin gel (microsphere) treatment, an apparent exacerbation of inflammatory lesions may occur. If tretinoin gel (microsphere) is tolerated, this should not be considered a reason to discontinue therapy. ( 5.2 ) Photosensitivity : Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to UV light, including sunlight and sunlamps. Advise patients to use sunscreen (SPF ≥15) and sun-protective clothing if UV light exposure cannot be avoided. Avoid use on sunburn skin. ( 5.3 ) 5.1 Local Irritation Tretinoin gel (microsphere) can cause local skin irritation, including excessive dryness, redness, swelling, peeling, itching, blistering, burning, or stinging [see Adverse Reactions ( 6.1 )] . Use of tretinoin gel (microsphere) in greater than the recommended dosage (more frequent than once daily application or excessive application) will not result in more rapid or improved acne results and may result in marked redness, peeling, or discomfort. Tretinoin has been reported to cause severe local skin irritation on eczematous skin. Weather extremes, such as severe wind or cold, may increase the risk of skin irritation in patients using tretinoin gel (microsphere). To reduce the risk of local skin irritation, instruct tretinoin gel (microsphere) - treated patients to: Avoid use of tretinoin gel (microsphere) in areas affected by eczema. Minimize or avoid use of tretinoin gel (microsphere) with weather extremes. Wash the treated skin gently, using a mild, non-medicated soap, pat it dry, and avoid washing the treated skin too often or scrubbing it hard when washing. Tretinoin gel (microsphere) is not recommended with concomitant use of medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, spices, or lime peels. Apply a topical moisturizer. Advise patients that concomitant use of topical over the counter (OTC) acne products containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with tretinoin gel (microsphere) may increase the risk for local skin irritation including dryness, erythema, and peeling. Consider withholding the use of topical OTC acne products if signs of skin irritation develop. Advise patients to allow the skin irritation effects of the topical OTC acne products to subside before initiation of tretinoin gel (microsphere) treatment . If severe local skin irritation occurs, discontinue tretinoin gel (microsphere) use temporarily or permanently. Efficacy of tretinoin gel (microsphere) at reduced frequencies of application has not been established.

of the topical OTC acne products to subside before initiation of tretinoin gel (microsphere) treatment . If severe local skin irritation occurs, discontinue tretinoin gel (microsphere) use temporarily or permanently. Efficacy of tretinoin gel (microsphere) at reduced frequencies of application has not been established. 5.2 Initial Worsening of Inflammatory Acne Vulgaris During the early weeks of tretinoin gel (microsphere) treatment, an apparent exacerbation of inflammatory acne vulgaris lesions may occur. If tretinoin gel (microsphere) is tolerated, initial worsening of inflammatory acne vulgaris lesions should not be considered a reason to discontinue therapy. 5.3 Photosensitivity Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel (microsphere). Advise patients with sunburn to not use tretinoin gel (microsphere) until the sunburn fully recovers. Advise patients, especially those who may be required to have extended periods of UV light exposure (e.g., due to occupation or sports), those with inherent sensitivity to the sun, or those using drugs that cause photosensitivity, to use sun protection daily in the form of sunscreen (sun protection factor [SPF] ≥ 15) and sun- protective clothing, when UV exposure cannot be avoided, even on days when it is not sunny or inside activities are expected.

5.3 Photosensitivity Tretinoin gel (microsphere) can cause photosensitivity. Advise patients to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel (microsphere). Advise patients with sunburn to not use tretinoin gel (microsphere) until the sunburn fully recovers. Advise patients, especially those who may be required to have extended periods of UV light exposure (e.g., due to occupation or sports), those with inherent sensitivity to the sun, or those using drugs that cause photosensitivity, to use sun protection daily in the form of sunscreen (sun protection factor [SPF] ≥ 15) and sun- protective clothing, when UV exposure cannot be avoided, even on days when it is not sunny or inside activities are expected.

6 ADVERSE REACTIONS Most common adverse reactions were skin irritation, skin burning, erythema, peeling, dryness, itching, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 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 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. Tretinoin gel (microsphere), 0.1% The safety of tretinoin gel (microsphere), 0.1% for the treatment of acne vulgaris was evaluated in two multicenter, double-blind, randomized, vehicle-controlled clinical trials (Studies 1 and 2). A total of 347 subjects with acne vulgaris were treated in Studies 1 and 2 in which 172 subjects received tretinoin gel (microsphere), 0.1% and 175 subjects received vehicle, applied topically once daily in the evening, for 12 weeks. Mean age was 19 years (range 11-40) and 55% were female [see Clinical Studies (14.1) ]. Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. In Studies 1 and 2, subjects treated with tretinoin gel (microsphere), 0.1% had increased cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching that peaked during the initial two weeks of therapy and decreased thereafter, compared to those treated with vehicle [see Warnings and Precautions (5.1) ]. During the 12-week treatment period, no more than 3% of tretinoin gel (microsphere), 0.1%-treated subjects had cutaneous irritation scores indicative of severe cutaneous irritation and 6% (14/224) of tretinoin gel (microsphere) 0.1%-treated subjects discontinued treatment due to cutaneous irritation. Of these 14 subjects, four had severe cutaneous irritation after 3 to 5 days of treatment, with blistering in one subject. Tretinoin gel (microsphere), 0.04% The safety of tretinoin gel (microsphere), 0.04% for the treatment of acne vulgaris was evaluated in two multicenter, double-blind, randomized, vehicle-controlled clinical trials (Studies 3 and 4). A total of 451 subjects with acne vulgaris were treated in Studies 3 and 4 in which 225 subjects received tretinoin gel (microsphere), 0.04% and 226 subjects received vehicle, applied once daily in the evening, for 12 weeks. Mean age was 19 years (range 11-49) and 57% were female [see Clinical Studies (14.2) ]. Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. In Studies 3 and 4, subjects treated with tretinoin gel (microsphere), 0.04% had increased cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching that peaked during the initial two weeks of therapy and decreased thereafter, compared to those treated with vehicle [see Warnings and Precautions (5.1) ]. Approximately half of the 225 subjects in the tretinoin gel (microsphere), 0.04%-treated group had cutaneous irritation at Week 2. Of the subjects who experienced cutaneous irritation, most had signs or symptoms that were mild in severity (severity was ranked on a 4-point ordinal scale: 0=none, 1=mild, 2=moderate, and 3=severe).

ely half of the 225 subjects in the tretinoin gel (microsphere), 0.04%-treated group had cutaneous irritation at Week 2. Of the subjects who experienced cutaneous irritation, most had signs or symptoms that were mild in severity (severity was ranked on a 4-point ordinal scale: 0=none, 1=mild, 2=moderate, and 3=severe). Less than 10% of tretinoin gel (microsphere), 0.04%-treated subjects experienced moderate cutaneous irritation, and none had severe cutaneous irritation at Week 2. In Studies 3 and 4, during the 12-week treatment period, the majority of tretinoin gel (microsphere), 0.04%-treated subjects experienced cutaneous irritation (mild, moderate, or severe), of which, 1% (2/225) of subjects had cutaneous irritation scores indicative of a severe irritation and 1.3% (3/225) of subjects discontinued treatment due to cutaneous irritation, which included dryness in one subject and peeling and urticaria in another. Tretinoin gel (microsphere), 0.04% and 0.1% In a double-blind trial, 156 subjects with acne vulgaris were treated for 12-weeks with tretinoin gel (microsphere) 0.04% (n=78) or 0.1% (n=78) topically once daily. In this trial, the most frequently reported adverse events affected the skin and subcutaneous tissue (15% in the 0.04% group, and 21% in the 0.1% group). The most prevalent events in the 0.04% group were skin irritation (6%); and in the 0.1% group, skin burning (8%), erythema (5%), skin irritation (4%), and dermatitis (4%). In this trial, 63% of the adverse events were of mild intensity, and 34% were of moderate intensity. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tretinoin gel (microsphere) and other topical tretinoin products. 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: Hyper- or hypopigmentation has been reported with repeated application of tretinoin.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published prospective observational studies and retrospective cohort studies over decades of use of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . In animal reproduction studies with pregnant rats, alterations in the vertebrae and ribs of offspring were observed with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 5 to 10 times the maximum recommended human dose (MRHD). In animal reproduction studies with pregnant rabbits, fetal malformations, such as domed head and hydrocephaly, were observed in the offspring with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 10 to 19 times the MRHD [ see Data ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US 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. Data Human Data: Published data from prospective observational studies and retrospective cohort studies on the use of topical tretinoin products during pregnancy have not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including potential misclassification of exposure, small sample size and in some cases, lack of physical exam by an expert in birth defects. Animal Data: For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of tretinoin gel (microsphere), 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight). Pregnant rats were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 6-15. Alterations were seen in the vertebrae and ribs of the affected offsprings at 0.5 mg/kg/day tretinoin, 5 to 10 times the MRHD based on body surface area (BSA) comparison. Pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species were observed at doses of 0.5 and 1 mg/kg/day. Similar malformations were not observed in the offspring at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. In a second rabbit study, pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.5 or 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for six hours per day while pregnant rabbits were restrained in stocks to prevent ingestion. The offspring of pregnant rabbits exposed to 0.5 or 1 mg/kg/day tretinoin did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison).

ere restrained in stocks to prevent ingestion. The offspring of pregnant rabbits exposed to 0.5 or 1 mg/kg/day tretinoin did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison). Malformations (shortened or kinked tail) were observed in the offspring of pregnant rats treated with topical tretinoin at doses greater than 1 mg/kg/day during the period of organogenesis (10 times the MRHD based on BSA comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported in offspring when 10 mg/kg/day was topically applied to pregnant rats during the period of organogenesis. Supernumerary ribs have been a consistent finding in newborn rats when dams were treated topically or orally with retinoids. Oral administration of tretinoin during organogenesis has been shown to cause malformations in the offspring of rats, mice, rabbits, hamsters, and nonhuman primates. Fetal malformations and death were observed when tretinoin was orally administered to pregnant rats during organogenesis at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). Fetal malformations were reported at doses of 10 mg/kg/day or greater when administered to pregnant cynomolgus monkeys, but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses. Dose-dependent increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. In peri- and postnatal development studies in rats with oral tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison). Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison. 8.2 Lactation Risk Summary There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tretinoin gel (microsphere) and any potential adverse effects on the breastfed infant from the tretinoin gel (microsphere) or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the infant via human milk, during breastfeeding, use tretinoin gel (microsphere) on the smallest area of skin with acne and for the shortest duration possible. Advise breastfeeding women not to apply tretinoin gel (microsphere) directly to the nipple and areola to avoid direct infant exposure. 8.4 Pediatric Use The safety and effectiveness of tretinoin gel (microsphere) for topical application for the treatment of acne vulgaris have been established in pediatric patients aged 12 years and older [see Clinical Studies (14) ] . The safety and effectiveness of tretinoin gel (microsphere) have not been established in pediatric patients younger than 12 years of age. 8.5 Geriatric Use Clinical trials of tretinoin gel (microsphere) did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger adult subjects. Acne vulgaris is largely a disease of pediatric and young adult patients.

c patients younger than 12 years of age. 8.5 Geriatric Use Clinical trials of tretinoin gel (microsphere) did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger adult subjects. Acne vulgaris is largely a disease of pediatric and young adult patients. Clinical studies of tretinoin gel (microsphere) did not include patients 65 years of age and older.

8.1 Pregnancy Risk Summary Available data from published prospective observational studies and retrospective cohort studies over decades of use of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . In animal reproduction studies with pregnant rats, alterations in the vertebrae and ribs of offspring were observed with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 5 to 10 times the maximum recommended human dose (MRHD). In animal reproduction studies with pregnant rabbits, fetal malformations, such as domed head and hydrocephaly, were observed in the offspring with daily topical dosing of 0.1% tretinoin gel (microsphere) during organogenesis at 10 to 19 times the MRHD [ see Data ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US 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. Data Human Data: Published data from prospective observational studies and retrospective cohort studies on the use of topical tretinoin products during pregnancy have not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including potential misclassification of exposure, small sample size and in some cases, lack of physical exam by an expert in birth defects. Animal Data: For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of tretinoin gel (microsphere), 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight). Pregnant rats were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 6-15. Alterations were seen in the vertebrae and ribs of the affected offsprings at 0.5 mg/kg/day tretinoin, 5 to 10 times the MRHD based on body surface area (BSA) comparison. Pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.2, 0.5, and 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species were observed at doses of 0.5 and 1 mg/kg/day. Similar malformations were not observed in the offspring at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. In a second rabbit study, pregnant rabbits were treated with 0.1% tretinoin gel (microsphere) at daily dermal doses of 0.5 or 1 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for six hours per day while pregnant rabbits were restrained in stocks to prevent ingestion. The offspring of pregnant rabbits exposed to 0.5 or 1 mg/kg/day tretinoin did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison).

ere restrained in stocks to prevent ingestion. The offspring of pregnant rabbits exposed to 0.5 or 1 mg/kg/day tretinoin did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison). Malformations (shortened or kinked tail) were observed in the offspring of pregnant rats treated with topical tretinoin at doses greater than 1 mg/kg/day during the period of organogenesis (10 times the MRHD based on BSA comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported in offspring when 10 mg/kg/day was topically applied to pregnant rats during the period of organogenesis. Supernumerary ribs have been a consistent finding in newborn rats when dams were treated topically or orally with retinoids. Oral administration of tretinoin during organogenesis has been shown to cause malformations in the offspring of rats, mice, rabbits, hamsters, and nonhuman primates. Fetal malformations and death were observed when tretinoin was orally administered to pregnant rats during organogenesis at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). Fetal malformations were reported at doses of 10 mg/kg/day or greater when administered to pregnant cynomolgus monkeys, but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses. Dose-dependent increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. In peri- and postnatal development studies in rats with oral tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison). Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison.

8.2 Lactation Risk Summary There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tretinoin gel (microsphere) and any potential adverse effects on the breastfed infant from the tretinoin gel (microsphere) or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the infant via human milk, during breastfeeding, use tretinoin gel (microsphere) on the smallest area of skin with acne and for the shortest duration possible. Advise breastfeeding women not to apply tretinoin gel (microsphere) directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use The safety and effectiveness of tretinoin gel (microsphere) for topical application for the treatment of acne vulgaris have been established in pediatric patients aged 12 years and older [see Clinical Studies (14) ] . The safety and effectiveness of tretinoin gel (microsphere) have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Clinical trials of tretinoin gel (microsphere) did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger adult subjects. Acne vulgaris is largely a disease of pediatric and young adult patients. Clinical studies of tretinoin gel (microsphere) did not include patients 65 years of age and older.

10 OVERDOSAGE Oral ingestion of large amounts of tretinoin gel (microsphere) may lead to the same adverse reactions as those associated with excessive oral intake of Vitamin A. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdose recommendations.

11 DESCRIPTION Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1- cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. Tretinoin is a retinoid and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C20H28O2 and the following chemical structure Tretinoin gel (microsphere) is for topical use. Each gram of tretinoin gel (microsphere): 0.06%, contains 0.6 mg of tretinoin 0.08%, contains 0.8 mg of tretinoin The formulation uses acrylate copolymer microsphere system to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, propylene glycol dicaprylate/dicaprate, purified water, sorbic acid, and trolamine. str.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms. The exact mechanism of action of topical tretinoin for treatment of acne vulgaris is unknown. Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. 12.2 Pharmacodynamics The pharmacodynamics of tretinoin gel (microsphere) is unknown. 12.3 Pharmacokinetics Absorption Tretinoin is a metabolite of Vitamin A. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy males and females after single and repeated daily tretinoin applications up to 28 days of 500 mg of a 0.1% tretinoin gel product. In this assessment, estimates of in vivo bioavailability, mean (SD) were 0.82 (0.11)% and 1.41 (0.54)%, for single and multiple daily topical applications, respectively. The plasma concentrations of tretinoin and its metabolites, 13- cis - retinoic acid, all- trans -4-oxo-retinoic acid, and 13- cis -4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of tretinoin gel (microsphere), 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with tretinoin gel (microsphere), 0.08%, 0.06% and 0.04%.

12.1 Mechanism of Action Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms. The exact mechanism of action of topical tretinoin for treatment of acne vulgaris is unknown. Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

12.3 Pharmacokinetics Absorption Tretinoin is a metabolite of Vitamin A. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy males and females after single and repeated daily tretinoin applications up to 28 days of 500 mg of a 0.1% tretinoin gel product. In this assessment, estimates of in vivo bioavailability, mean (SD) were 0.82 (0.11)% and 1.41 (0.54)%, for single and multiple daily topical applications, respectively. The plasma concentrations of tretinoin and its metabolites, 13- cis - retinoic acid, all- trans -4-oxo-retinoic acid, and 13- cis -4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of tretinoin gel (microsphere), 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with tretinoin gel (microsphere), 0.08%, 0.06% and 0.04%.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dermal carcinogenicity testing has not been performed with tretinoin gel (microsphere), 0.04%, 0.06%, 0.08%, or 0.1%. In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-dependent incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photo carcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [ see Warnings and Precautions (5.3) ]. The genotoxic potential of tretinoin was evaluated in the Ames assay and an in vivo mouse micronucleus assay. Both tests were negative. The components of the microspheres have shown potential for genetic toxicity and fetal malformation. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in an in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and an in vivo mouse micronucleus assay. In fertility studies in rats with oral tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dermal carcinogenicity testing has not been performed with tretinoin gel (microsphere), 0.04%, 0.06%, 0.08%, or 0.1%. In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-dependent incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photo carcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [ see Warnings and Precautions (5.3) ]. The genotoxic potential of tretinoin was evaluated in the Ames assay and an in vivo mouse micronucleus assay. Both tests were negative. The components of the microspheres have shown potential for genetic toxicity and fetal malformation. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in an in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and an in vivo mouse micronucleus assay. In fertility studies in rats with oral tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

14 CLINICAL STUDIES 14.1 Clinical Studies of tretinoin gel (microsphere), 0.1% The efficacy of tretinoin gel (microsphere), 0.1% was evaluated in two double-blind, randomized, vehicle-controlled trials in adult and pediatric subjects 11 years of age and older with acne vulgaris (Studies 1 and 2). Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. Tretinoin gel (microsphere), 0.1%, applied topically once daily in the evening, was superior to vehicle gel, applied topically once daily, in reducing the acne lesion counts. The mean reduction in lesion counts from baseline after treatment for 12 weeks are shown in Table 1: Table 1: Mean Percent Reduction in Lesion Counts in Subjects with Acne Vulgaris at Week 12 in Studies 1 and 2 Study 1 Study 2 Tretinoin gel (microsphere),0.1% (n=72) Vehicle Gel (n=71) Tretinoin gel (microsphere), 0.1% (n=72) Vehicle Gel (n=67) Non-inflammatory lesion counts 49% 22% 32% 3% Inflammatory lesion counts 37% 18% 29% 24% Total lesion counts 45% 23% 32% 16% Efficacy was also assessed by the investigator’s global evaluation, which included categories of “excellent”, “good”, “fair”, “no change”, and “poor”. Tretinoin gel (microsphere), 0.1%, was significantly superior (p<0.001) to the vehicle in the investigator's global evaluation of the clinical response: In Study #1, 35% of tretinoin gel (microsphere), 0.1% - treated subjects achieved an “excellent” result, as compared to 11% of vehicle-treated subjects. In Study #2, 28% of tretinoin gel (microsphere), 0.1% - treated subjects achieved an “excellent” result, as compared to 9% of vehicle-treated subjects. 14.2 Clinical Studies with tretinoin gel (microsphere), 0.04% In two vehicle-controlled clinical trials in adult and pediatric subjects 11 years of age and older with acne vulgaris (Studies 3 and 4). Tretinoin gel (microsphere) is not approved for use in pediatric patients younger than 12 years of age [see Indications and Usage (1) ]. Tretinoin gel (microsphere), 0.04%, applied topically once daily in the evening, was more effective (p<0.05) than vehicle gel, applied topically once daily, in reducing the acne lesion counts. The mean reduction in lesion counts from baseline after treatment for 12 weeks are shown in Table 2: Table 2: Mean Percent Reduction in Lesion Counts in Subjects with Acne Vulgaris at Week 12 in Studies 3 and 4 Study 3 Study 4 Tretinoin gel (microsphere) 0.04% (n=108) Vehicle Gel (n=111) Tretinoin gel (microsphere) 0.04% (n=110) Vehicle Gel (n=103) Non-inflammatory lesion counts 37% -2%* 29% 14% Inflammatory lesion counts 44% 13% 41% 30% Total lesion counts 40% 8% 35% 20% * -2% represents a mean percent increase of 2% Efficacy was also assessed by the investigator’s global evaluation, which included categories of “excellent”, “good”, “fair”, “no change”, and “poor”. Tretinoin gel (microsphere) 0.04% was superior (p<0.05) to the vehicle in the investigator's global evaluation of the clinical response: In Study #3, 14% of tretinoin gel (microsphere) 0.04%-treated subjects achieved an “excellent” result, as compared to 5% of vehicle-treated subjects. In Study #4, 19% of tretinoin gel (microsphere) 0.04%-treated subjects achieved an “excellent” result, as compared to 9% of vehicle-treated subjects.

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Botrule Lrule Rrule Toprule"/><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Study</content><content styleCode="bold"/><content styleCode="bold"> 1</content></th><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Study</content><content styleCode="bold"/><content styleCode="bold"> 2</content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph/></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Tretinoin gel</content></paragraph><paragraph><content styleCode="bold">(microsphere),0.1% (n=72)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Vehicle</content><content styleCode="bold"/><content styleCode="bold"> Gel </content><content styleCode="bold">(n=71)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Tretinoin gel (microsphere), 0.1% (n=72)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Vehicle</content><content styleCode="bold"/><content styleCode="bold"> Gel </content><content styleCode="bold">(n=67)</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Non-inflammatory lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>49%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>22%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>32%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Inflammatory lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>37%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>18%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>29%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Total lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>45%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>23%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>32%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>16%</paragraph></td></tr></tbody></table>

><paragraph>45%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>23%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>32%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>16%</paragraph></td></tr></tbody></table> <table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Botrule Lrule Rrule Toprule"/><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Study</content><content styleCode="bold"/><content styleCode="bold"> 3</content></th><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Study</content><content styleCode="bold"/><content styleCode="bold"> 4</content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph/></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Tretinoin gel (microsphere) </content><content styleCode="bold">0.04% </content><content styleCode="bold">(n=108)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Vehicle</content><content styleCode="bold"/><content styleCode="bold"> Gel </content><content styleCode="bold">(n=111)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Tretinoin gel (microsphere) </content><content styleCode="bold">0.04% </content><content styleCode="bold">(n=110)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Vehicle</content><content styleCode="bold"/><content styleCode="bold"> Gel </content><content styleCode="bold">(n=103)</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Non-inflammatory lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>37%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>-2%*</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>29%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Inflammatory lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>44%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>13%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>41%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Total lesion counts</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>40%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>8%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>35%</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>20%</paragraph></td></tr><tr><td colspan="5" styleCode="Botrule Lrule Rrule" valign="top"><paragraph>* -2% represents a mean percent increase of 2%</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Tretinoin gel (microsphere) is opaque and white to very pale yellow in color and is supplied as follows: Strength Amount of Tretinoin in One Gram of Gel Quantity/Package Type NDC 0.06% 0.6 mg 50 gram pump 21922-042-40 0.08% 0.8 mg 50 gram pump 21922-043-40 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store pump upright.

<table width="100%"><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><thead align="center"><tr><th styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"> Strength</content></th><th styleCode="Botrule Rrule Toprule"><content styleCode="bold"> Amount</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> Tretinoin in</content><content styleCode="bold"/><content styleCode="bold"> One</content><content styleCode="bold"/><content styleCode="bold"> Gram</content><content styleCode="bold"/><content styleCode="bold">of</content><content styleCode="bold"/><content styleCode="bold"> Gel</content></th><th styleCode="Botrule Rrule Toprule"><content styleCode="bold"> Quantity/Package</content><content styleCode="bold"/><content styleCode="bold"> Type</content></th><th styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">NDC</content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph> 0.06%</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph> 0.6 mg</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph> 50 gram pump</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph> 21922-042-40</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph> 0.08%</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph> 0.8 mg</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph> 50 gram pump</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph> 21922-043-40</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Administration Instruct the patient to [see Dosage and Administration (2) ] : Thoroughly cleanse treatment area(s) with a mild, non-medicated cleanser then pat the skin dry prior to application of tretinoin gel (microsphere). Avoid contact with eyes, mouth, paranal creases of nose, and mucous membranes when applying tretinoin gel (microsphere). Apply a thin layer of tretinoin gel (microsphere) to cover the affected area(s). Local Skin Irritation: Advise the patient that use of tretinoin gel (microsphere) greater than the recommended dosage will not result in more rapid of improved acne results and may result in marked redness, peeling or discomfort [see Warnings and Precautions (5.1) ]. To reduce the risk of local skin irritation, advise the patient to: Minimize or avoid use of tretinoin gel (microsphere) during weather extremes, such as severe wind or cold. Wash the treated skin gently, using a mild, non-medicated soap, and pat it dry, and avoid washing the treated skin too often or scrubbing it hard when washing. Not use medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, spices, and lime peels while using tretinoin gel (microsphere). Apply a topical moisturizer when using tretinoin gel (microsphere). Advise the patient that concomitant use of topical OTC acne products containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with tretinoin gel (microsphere) may increase the risk of local skin irritation. Advise the patient to withhold the use of topical OTC acne products if signs of skin irritation develop. Advise the patient to allow the skin irritation effects of the topical OTC acne products to subside before initiation of tretinoin gel (microsphere) [see Warning and Precautions (5.1) ]. Photosensitivity Advise the patient to avoid or minimize unnecessary exposure to ultraviolet (UV) light, including sunlight and sunlamps, while using tretinoin gel (microsphere). Advise the patient to not use tretinoin gel (microsphere) on sunburn skin. Advise the patient to use sun protection in the form of sunscreen (SPF ≥15) and sun-protective clothing if UV exposure cannot be avoided [see Warnings and Precautions (5.3) ]. Lactation Advise the female patient to use tretinoin gel (microsphere) on the smallest area of skin with acne vulgaris and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, instruct the patient who is breastfeeding not to apply tretinoin gel (microsphere) directly to the nipple and areola [see Use in Specific Populations (8.2) ] . Made in Italy, formulated in India. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, NC 27713 USA Revised: 10/2025

PATIENT INFORMATION Patient Information Tretinoin gel (microsphere) (truh·ti·now·uhn) Tretinoin gel (microsphere), 0.08% and 0.06% for topical use Important information Tretinoin gel (microsphere ) is for use on skin (topical use) only. Keep tretinoin gel (microsphere) away from your eyes, mouth, vagina, or the corners of your nose. What is tretinoin gel (microsphere) ? Tretinoin gel (microsphere) is a prescription medicine used on the skin (topical) to treat acne in adults and children 12 years of age and older. Acne is a condition in which the skin has blackheads, whiteheads, and other pimples. It is not known if tretinoin gel (microsphere) is safe and effective in children under 12 years of age. Before using tretinoin gel (microsphere), tell your healthcare provider about all of your medical conditions, including if you: have a skin condition called eczema. have a sunburn. You should not use tretinoin gel (microsphere) until your skin has healed. are pregnant or plan to become pregnant. It is not known if tretinoin gel (microsphere) will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if tretinoin gel (microsphere) passes into your breast milk. If you breastfeed during treatment with tretinoin gel (microsphere), use tretinoin gel (microsphere) on the smallest area of the skin with acne and for the shortest time possible. Do not apply tretinoin gel (microsphere) directly to the nipple and areola to avoid contact with your baby. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you use any skin products that contain benzoyl peroxide, sulfur, resorcinol, or salicylic acid. Using these topical skin products may increase the irritation of your skin when used with tretinoin gel (microsphere). How should I use tretinoin gel (microsphere) ? Use tretinoin gel (microsphere) exactly as your healthcare provider tells you to use it. Before you apply tretinoin gel (microsphere), gently wash the affected skin area with a mild, non-medicated soap. Rinse and pat your skin dry. Apply a thin layer of tretinoin gel (microsphere) to the affected area 1 time a day in the evening. Do not use more tretinoin gel (microsphere) than you need to cover the affected area and do not apply tretinoin gel (microsphere) more than 1 time a day. Using too much tretinoin gel (microsphere) or using it too often will not give you faster or better results, and you may get skin redness, peeling, or discomfort. You may use moisturizers after applying tretinoin gel (microsphere). Early in your treatment, you may get new pimples. At this stage, it is important to continue using tretinoin gel (microsphere). Your acne may not get better right away. Improvement in your acne may be noticed after 2 weeks of tretinoin gel (microsphere) treatment, but more than 7 weeks of treatment may be needed before you get the full benefit. Wash your hands after applying tretinoin gel (microsphere). Tretinoin gel (microsphere) taken by mouth in large amounts may lead to the same side effects as those seen with large amounts of Vitamin A taken by mouth. Call the Poison Help line at 1-833-285-4151 if tretinoin gel (microsphere) is taken by mouth. What should I avoid while using tretinoin gel (microsphere) ? You should avoid sunlamps, tanning beds, and ultraviolet light during treatment with tretinoin gel (microsphere).

en with large amounts of Vitamin A taken by mouth. Call the Poison Help line at 1-833-285-4151 if tretinoin gel (microsphere) is taken by mouth. What should I avoid while using tretinoin gel (microsphere) ? You should avoid sunlamps, tanning beds, and ultraviolet light during treatment with tretinoin gel (microsphere). Minimize exposure to sunlight. If you have to be in the sunlight, are sensitive to sunlight, or are using medicine that cause sensitive to sunlight, use a sunscreen with sun protection factor (SPF) of 15 or more. Wear a wide-brimmed hat or other protective clothing to cover the treated areas, even on days when it is not sunny, or you are inside. Do not use tretinoin gel (microsphere) on sunburn skin until your skin has healed. What are the possible side effects of tretinoin gel (microsphere)? Tretinoin gel (microsphere) can cause serious side effects, including: Skin irritation. Tretinoin gel (microsphere) can cause skin dryness, redness, swelling, peeling, itching, blistering, burning, or stinging. If you develop these symptoms, your healthcare provider may temporarily stop or completely stop your treatment with tretinoin gel (microsphere). To help reduce the risk of skin irritation with tretinoin gel (microsphere): Avoid use of tretinoin gel (microsphere) in skin areas affected by eczema. Minimize or avoid use of tretinoin gel (microsphere) with weather extremes, such as severe wind or cold. Avoid washing the treated skin too often or scrubbing it hard when washing. Tretinoin gel (microsphere) is not recommended with use of medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high amounts of alcohol, astringents, spices, or lime peels. Apply a topical moisturizer when using tretinoin gel (microsphere). It is not known if tretinoin gel (microsphere) is effective when used less than 1 time a day. Sensitivity to sunlight. See “What should I avoid while using tretinoin gel (microsphere) ?” The most common side effects of tretinoin gel (microsphere) include skin redness, pain, and itching. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of tretinoin gel (microsphere). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store tretinoin gel (microsphere) ? Store tretinoin gel (microsphere) at room temperature between 68°F to 77°F (20°C to 25°C). Store tretinoin gel (microsphere) pump upright. Keep tretinoin gel (microsphere) and all medicines out of the reach of children. General information about the safe and effective use of tretinoin gel (microsphere) . Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tretinoin gel (microsphere) for a condition for which it was not prescribed. Do not give tretinoin gel (microsphere) to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tretinoin gel (microsphere) that is written for health professionals. What are the ingredients of tretinoin gel (microsphere)? Active ingredient: tretinoin Inactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, propylene glycol dicaprylate/dicaprate, purified water, sorbic acid and trolamine. Made in Italy, formulated in India. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc.

stearate, propylene glycol, propylene glycol dicaprylate/dicaprate, purified water, sorbic acid and trolamine. Made in Italy, formulated in India. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, NC 27713 USA For more information, call 1-833-285-4151. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 10/2025

<table width="100%"><col width="100%" align="left" valign="middle"/><thead align="center"><tr><th styleCode="Botrule Lrule Rrule Toprule" align="center"><content styleCode="bold">Patient</content><content styleCode="bold"/><content styleCode="bold"> Information</content><content styleCode="bold">Tretinoin gel (microsphere) (truh&#xB7;ti&#xB7;now&#xB7;uhn)</content><content styleCode="bold">Tretinoin gel (microsphere), 0.08% and 0.06% </content><content styleCode="bold">for topical use</content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top" align="justify"><paragraph><content styleCode="bold"> Important</content><content styleCode="bold"/><content styleCode="bold"> information</content> Tretinoin gel (microsphere<content styleCode="bold">) </content>is for use on skin (topical use) only. Keep tretinoin gel (microsphere) away from your eyes, mouth, vagina, or the corners of your nose.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold"> What</content><content styleCode="bold"/><content styleCode="bold"> is</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">?</content></paragraph><paragraph>Tretinoin gel (microsphere) is a prescription medicine used on the skin (topical) to treat acne in adults and children 12 years of age and older. Acne is a condition in which the skin has blackheads, whiteheads, and other pimples.</paragraph><paragraph> It is not known if tretinoin gel (microsphere) is safe and effective in children under 12 years of age.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold">Before</content><content styleCode="bold"/><content styleCode="bold"> using</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere),</content><content styleCode="bold"/><content styleCode="bold"> tell</content><content styleCode="bold"/><content styleCode="bold"> your</content><content styleCode="bold"/><content styleCode="bold"> healthcare</content><content styleCode="bold"/><content styleCode="bold"> provider</content><content styleCode="bold"/><content styleCode="bold"> about</content><content styleCode="bold"/><content styleCode="bold"> all</content><content styleCode="bold"/><content styleCode="bold"> of your</content><content styleCode="bold"/><content styleCode="bold"> medical</content><content styleCode="bold"/><content styleCode="bold"> conditions,</content><content styleCode="bold"/><content styleCode="bold"> including</content><content styleCode="bold"/><content styleCode="bold"> if </content><content styleCode="bold">you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have a skin condition called eczema.</item><item>have a sunburn. You should not use tretinoin gel (microsphere) until your skin has healed.</item><item>are pregnant or plan to become pregnant. It is not known if tretinoin gel (microsphere) will harm your unborn baby.</item><item>are breastfeeding or plan to breastfeed. It is not known if tretinoin gel (microsphere) passes into your breast milk. If you breastfeed during treatment with tretinoin gel (microsphere), use tretinoin gel (microsphere) on the smallest area of the skin with acne and for the shortest time possible.

born baby.</item><item>are breastfeeding or plan to breastfeed. It is not known if tretinoin gel (microsphere) passes into your breast milk. If you breastfeed during treatment with tretinoin gel (microsphere), use tretinoin gel (microsphere) on the smallest area of the skin with acne and for the shortest time possible. Do not apply tretinoin gel (microsphere) directly to the nipple and areola to avoid contact with your baby.</item></list><paragraph><content styleCode="bold"> Tell</content><content styleCode="bold"/><content styleCode="bold"> your</content><content styleCode="bold"/><content styleCode="bold"> healthcare</content><content styleCode="bold"/><content styleCode="bold"> provider</content><content styleCode="bold"/><content styleCode="bold"> about</content><content styleCode="bold"/><content styleCode="bold"> all</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> the</content><content styleCode="bold"/><content styleCode="bold"> medicines</content><content styleCode="bold"/><content styleCode="bold"> you</content><content styleCode="bold"/><content styleCode="bold"> take,</content><content styleCode="bold"/> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Especially tell your healthcare provider if you use any skin products that contain benzoyl peroxide, sulfur, resorcinol, or salicylic acid. Using these topical skin products may increase the irritation of your skin when used with tretinoin gel (microsphere).</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold"> How</content><content styleCode="bold"/><content styleCode="bold"> should</content><content styleCode="bold"/><content styleCode="bold"> I</content><content styleCode="bold"/><content styleCode="bold"> use</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Use tretinoin gel (microsphere) exactly as your healthcare provider tells you to use it.</item><item>Before you apply tretinoin gel (microsphere), gently wash the affected skin area with a mild, non-medicated soap. Rinse and pat your skin dry.</item><item>Apply a thin layer of tretinoin gel (microsphere) to the affected area 1 time a day in the evening.</item><item>Do not use more tretinoin gel (microsphere) than you need to cover the affected area and do not apply tretinoin gel (microsphere) more than 1 time a day. Using too much tretinoin gel (microsphere) or using it too often will not give you faster or better results, and you may get skin redness, peeling, or discomfort.</item><item>You may use moisturizers after applying tretinoin gel (microsphere).</item><item>Early in your treatment, you may get new pimples. At this stage, it is important to continue using tretinoin gel (microsphere).</item><item>Your acne may not get better right away. Improvement in your acne may be noticed after 2 weeks of tretinoin gel (microsphere) treatment, but more than 7 weeks of treatment may be needed before you get the full benefit.</item></list><paragraph> Wash your hands after applying tretinoin gel (microsphere).</paragraph><list listType="unordered" styleCode="Disc"><item>Tretinoin gel (microsphere) taken by mouth in large amounts may lead to the same side effects as those seen with large amounts of Vitamin A taken by mouth.

the full benefit.</item></list><paragraph> Wash your hands after applying tretinoin gel (microsphere).</paragraph><list listType="unordered" styleCode="Disc"><item>Tretinoin gel (microsphere) taken by mouth in large amounts may lead to the same side effects as those seen with large amounts of Vitamin A taken by mouth. Call the Poison Help line at 1-833-285-4151 if tretinoin gel (microsphere) is taken by mouth.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold"> What</content><content styleCode="bold"/><content styleCode="bold"> should</content><content styleCode="bold"/><content styleCode="bold"> I</content><content styleCode="bold"/><content styleCode="bold"> avoid</content><content styleCode="bold"/><content styleCode="bold"> while</content><content styleCode="bold"/><content styleCode="bold"> using</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">?</content></paragraph><list listType="unordered" styleCode="Disc"><item>You should avoid sunlamps, tanning beds, and ultraviolet light during treatment with tretinoin gel (microsphere).</item><item>Minimize exposure to sunlight.</item><item>If you have to be in the sunlight, are sensitive to sunlight, or are using medicine that cause sensitive to sunlight, use a sunscreen with sun protection factor (SPF) of 15 or more. Wear a wide-brimmed hat or other protective clothing to cover the treated areas, even on days when it is not sunny, or you are inside.</item><item>Do not use tretinoin gel (microsphere) on sunburn skin until your skin has healed.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold">What are the possible side effects of tretinoin gel (microsphere)? Tretinoin gel (microsphere) can</content><content styleCode="bold"/><content styleCode="bold"> cause</content><content styleCode="bold"/><content styleCode="bold"> serious</content><content styleCode="bold"/><content styleCode="bold"> side</content><content styleCode="bold"/><content styleCode="bold"> effects,</content><content styleCode="bold"/><content styleCode="bold"> including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Skin</content><content styleCode="bold"/><content styleCode="bold"> irritation.</content><content styleCode="bold"/> Tretinoin gel (microsphere) can cause skin dryness, redness, swelling, peeling, itching, blistering, burning, or stinging. If you develop these symptoms, your healthcare provider may temporarily stop or completely stop your treatment with tretinoin gel (microsphere).</item></list><paragraph> To help reduce the risk of skin irritation with tretinoin gel (microsphere):</paragraph><list listType="unordered" styleCode="Circle"><item>Avoid use of tretinoin gel (microsphere) in skin areas affected by eczema.</item></list><list listType="unordered" styleCode="Circle"><item>Minimize or avoid use of tretinoin gel (microsphere) with weather extremes, such as severe wind or cold.</item><item>Avoid washing the treated skin too often or scrubbing it hard when washing.

tretinoin gel (microsphere) in skin areas affected by eczema.</item></list><list listType="unordered" styleCode="Circle"><item>Minimize or avoid use of tretinoin gel (microsphere) with weather extremes, such as severe wind or cold.</item><item>Avoid washing the treated skin too often or scrubbing it hard when washing. Tretinoin gel (microsphere) is not recommended with use of medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high amounts of alcohol, astringents, spices, or lime peels.</item><item>Apply a topical moisturizer when using tretinoin gel (microsphere).</item></list><paragraph> It is not known if tretinoin gel (microsphere) is effective when used less than 1 time a day.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Sensitivity</content><content styleCode="bold"/><content styleCode="bold"> to</content><content styleCode="bold"/><content styleCode="bold"> sunlight.</content><content styleCode="bold"/> See<content styleCode="bold"> &#x201C;What</content><content styleCode="bold"/><content styleCode="bold"> should</content><content styleCode="bold"/><content styleCode="bold"> I</content><content styleCode="bold"/><content styleCode="bold"> avoid</content><content styleCode="bold"/><content styleCode="bold"> while</content><content styleCode="bold"/><content styleCode="bold"> using</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">?&#x201D;</content></item></list><paragraph><content styleCode="bold">The most common side effects of tretinoin gel (microsphere) include </content>skin redness, pain, and itching. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of tretinoin gel (microsphere).</paragraph><paragraph> Call your doctor for medical advice about side effects.

crosphere) include </content>skin redness, pain, and itching. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of tretinoin gel (microsphere).</paragraph><paragraph> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top" align="justify"><paragraph><content styleCode="bold"> How</content><content styleCode="bold"/><content styleCode="bold"> should</content><content styleCode="bold"/><content styleCode="bold"> I</content><content styleCode="bold"/><content styleCode="bold"> store</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store tretinoin gel (microsphere) at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Store tretinoin gel (microsphere) pump upright.</item></list><paragraph><content styleCode="bold">Keep</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere) and</content><content styleCode="bold"/><content styleCode="bold"> all</content><content styleCode="bold"/><content styleCode="bold"> medicines</content><content styleCode="bold"/><content styleCode="bold"> out</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> the</content><content styleCode="bold"/><content styleCode="bold"> reach</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> children.</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold"> General</content><content styleCode="bold"/><content styleCode="bold"> information</content><content styleCode="bold"/><content styleCode="bold"> about</content><content styleCode="bold"/><content styleCode="bold"> the</content><content styleCode="bold"/><content styleCode="bold"> safe</content><content styleCode="bold"/><content styleCode="bold"> and</content><content styleCode="bold"/><content styleCode="bold"> effective</content><content styleCode="bold"/><content styleCode="bold"> use</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)</content><content styleCode="bold">.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tretinoin gel (microsphere) for a condition for which it was not prescribed. Do not give tretinoin gel (microsphere) to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider</paragraph><paragraph> for information about tretinoin gel (microsphere) that is written for health professionals.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What</content><content styleCode="bold"/><content styleCode="bold"> are</content><content styleCode="bold"/><content styleCode="bold"> the</content><content styleCode="bold"/><content styleCode="bold"> ingredients</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)?

tyleCode="bold"> are</content><content styleCode="bold"/><content styleCode="bold"> the</content><content styleCode="bold"/><content styleCode="bold"> ingredients</content><content styleCode="bold"/><content styleCode="bold"> of</content><content styleCode="bold"/><content styleCode="bold"> tretinoin gel (microsphere)? Active ingredient: </content>tretinoin</paragraph><paragraph><content styleCode="bold"> Inactive</content><content styleCode="bold"/><content styleCode="bold"> ingredients:</content><content styleCode="bold"/> benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, propylene glycol dicaprylate/dicaprate, purified water, sorbic acid and trolamine.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold"> Made in Italy, formulated in India.</content></paragraph><paragraph> Manufactured by:</paragraph><paragraph><content styleCode="bold"> Encube Ethicals Pvt. Ltd.</content></paragraph><paragraph> Plot No. C-1, Madkaim Industrial Estate,</paragraph><paragraph> Madkaim, Post: Mardol, Ponda, Goa - 403 404, India.</paragraph><paragraph/><paragraph> Distributed by:</paragraph><paragraph><content styleCode="bold"> Encube Ethicals, Inc.</content></paragraph><paragraph> 200 Meredith Drive, Suite 202,</paragraph><paragraph>Durham, NC 27713 USA</paragraph><paragraph> For more information, call 1-833-285-4151.</paragraph></td></tr></tbody></table>

For Topical Use Only Manufactured for: Northstar RxLLC Memphis, TN 38141. Toll Free Number: 1-800-206-7821 Manufactured by: Taro Pharmaceuticals Inc. Brampton, Ontario, Canada L6T 1C1. Issued: February 2022 5228205 41

Description Tretinoin Cream USP, 0.1% is used for the topical treatment of acne vulgaris. Tretinoin Cream contains tretinoin in 0.1% by weight, in a hydrophilic cream vehicle of butylated hydroxytoluene, isopropyl myristate, polyoxyl stearate type II, purified water, sorbic acid, stearic acid, stearyl alcohol and xanthan gum. Chemically, tretinoin is all-trans -retinoic acid and has the following structure: Chemical Structure

<table width="50%" styleCode="Noautorules"><colgroup><col align="left" valign="middle" width="10%"/><col align="left" valign="top" width="30%"/><col align="left" valign="top" width="60%"/></colgroup><tbody><tr><td/><td><list listType="unordered" styleCode="Disc"><item>20g</item></list></td><td><list listType="unordered"><item>68071-3889-2</item></list></td></tr></tbody></table>

PATIENT INSTRUCTIONS Tretinoin Cream USP, 0.1% For Topical Use Only Acne Treatment IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT TRETINOIN ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR'S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS Keep out of reach of children. Keep tube tightly closed. Do not expose to heat. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with tretinoin may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in Tretinoin Cream, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced . There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with tretinoin should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using tretinoin. If you do become sunburned, stop your therapy with tretinoin until your skin has recovered. Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with tretinoin may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinue the use of tretinoin and consult your physician. There have been reports that, in some patients, areas treated with tretinoin developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to tretinoin or therapy was discontinued. Use other medication only on your physician's advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary.

y with tretinoin cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT Tretinoin works deep inside your skin and this takes time. You cannot make tretinoin work any faster by applying more than one dose each day, but an excess amount of tretinoin may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to tretinoin and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using tretinoin. If tretinoin is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don't be discouraged if you see no immediate improvement. Don't stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of tretinoin until your physician instructs otherwise. IF YOU HAVE QUESTIONS All questions of a medical nature should be taken up with your doctor. For more information about tretinoin, call our toll-free number: 1-800-206-7821. Manufactured for: Northstar RxLLC, Memphis, TN 38141. Manufactured by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1. Issued: February 2022 5228205 41 Image

WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)] . Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe Differentiation Syndrome until resolution [see Warnings and Precautions (5.2)] . WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Embryo-Fetal Toxicity: tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose. (5.1, 8.1, 8.3) Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe Differentiation Syndrome until resolution. (5.2)

1 INDICATIONS AND USAGE Tretinoin capsules are indicated for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Tretinoin capsules are a retinoid indicated for induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL), characterized by presence of t(15;17) translocation or presence of PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.

2 DOSAGE AND ADMINISTRATION The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission. ( 2.2 ) Discontinue 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. ( 2.2 ) 2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] . 2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose. 2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] . 2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose.

4 CONTRAINDICATIONS Tretinoin capsules are contraindicated in patients with a known hypersensitivity to tretinoin capsules, any of its components, or other retinoids. Reactions have included rash, pruritus, face edema, and dyspnea [see Adverse Reactions ( 6.1 )]. Hypersensitivity to tretinoin capsules, any of its components, or other retinoids

5 WARNINGS AND PRECAUTIONS Patients Without t(15;17) Translocation or PML/RARα Fusion: Tretinoin capsules may be initiated based on morphological diagnosis of APL. Confirm diagnosis by detection of the t(15;17) translocation or PML/RARα fusion. ( 5.3 ) Leukocytosis: Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. ( 5.4 ) Intracranial Hypertension: Tretinoin capsules have been associated with benign intracranial hypertension, especially in pediatric patients. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. ( 5.5 ) Lipid Abnormalities: Patients experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. ( 5.6 ) Hepatotoxicity: Monitor liver function test results at baseline and during treatment as clinically indicated. ( 5.7 ) Thromboembolic Events: Venous and arterial events have been reported; these events may occur during the first month of treatment with tretinoin capsules. ( 5.8 , 7.4 ) 5.1 Embryo-Fetal Toxicity Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)] . Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis. This syndrome generally occurs during the first month of treatment, as early as following the first dose. Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure. At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions ( 6.1 )] .

examethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions ( 6.1 )] . 5.3 Patients Without t(15;17) Translocation or PML/RARα Fusion Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques. Tretinoin capsules are not recommended for use in patients without these genetic markers [see Indications and Usage ( 1 )] . 5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [see Adverse Reactions ( 6.1 )] . Patients who present with a baseline white blood cell count (WBC) > 5 × 10 9 /L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. 5.5 Intracranial Hypertension Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension [see Drug Interactions ( 7.2 )] . 5.6 Lipid Abnormalities Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. 5.7 Hepatotoxicity Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment. Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than 5 times the upper limit of normal values until resolution. 5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules [see Adverse Reactions ( 6.2 )]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [see Drug Interactions ( 7.4 )] .

Adverse Reactions ( 6.2 )]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [see Drug Interactions ( 7.4 )] . 5.1 Embryo-Fetal Toxicity Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)] . Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis. This syndrome generally occurs during the first month of treatment, as early as following the first dose. Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure. At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions ( 6.1 )] . 5.3 Patients Without t(15;17) Translocation or PML/RARα Fusion Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques. Tretinoin capsules are not recommended for use in patients without these genetic markers [see Indications and Usage ( 1 )] .

of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques. Tretinoin capsules are not recommended for use in patients without these genetic markers [see Indications and Usage ( 1 )] . 5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [see Adverse Reactions ( 6.1 )] . Patients who present with a baseline white blood cell count (WBC) > 5 × 10 9 /L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. 5.5 Intracranial Hypertension Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension [see Drug Interactions ( 7.2 )] . 5.6 Lipid Abnormalities Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.

treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. 5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules [see Adverse Reactions ( 6.2 )]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk. Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [see Drug Interactions ( 7.4 )] .

5.7 Hepatotoxicity Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment. Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than 5 times the upper limit of normal values until resolution.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.2 )] Leukocytosis [see Warnings and Precautions ( 5.4 )] Intracranial hypertension [see Warnings and Precautions (5.5)] Lipid abnormalities [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Thromboembolic events [see Warnings and Precautions (5 .8 )] The most common adverse reactions (≥30%) are headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 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 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. Acute Promyelocytic Leukemia The safety of tretinoin capsules was evaluated in patients with APL who received tretinoin capsules at a dose of 22.5 mg/m 2 orally twice daily [see Clinical Studies ( 14 )] . The most common adverse reactions (≥30%) were headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain. Table 1 summarizes the adverse reactions for patients with APL. Table 1.

mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain. Table 1 summarizes the adverse reactions for patients with APL. Table 1. Adverse Reactions (≥ 10%) Occurring in Patients with APL Who Received Tretinoin Capsules Adverse Reaction Tretinoin Capsules All Grades (%) Nervous system disorders Headache 86 Dizziness 20 Paresthesias 17 Anxiety 17 Insomnia 14 Depression 14 Confusion 11 General disorders Fever 83 Skin/mucous membrane dryness 77 Malaise 66 Shivering 63 Peripheral edema 52 Pain 37 Chest discomfort 32 Edema 29 Mucositis 26 Weight increase 23 Anorexia 17 Weight decrease 17 Musculoskeletal and connective tissue disorders Bone pain 77 Myalgia 14 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders 63 Dyspnea 60 Respiratory insufficiency 26 Pleural effusion 20 Rales 14 Expiratory wheezing 14 Pneumonia 14 Vascular disorders Hemorrhage 60 Gastrointestinal hemorrhage 34 Flushing 23 Hypotension 14 Hypertension 11 Phlebitis 11 Infections and infestations Infections 58 Gastrointestinal disorders Nausea/vomiting 57 Abdominal pain 31 Other gastrointestinal disorders 26 Diarrhea 23 Constipation 17 Dyspepsia 14 Abdominal distention 11 Skin and subcutaneous tissue disorders Rash 54 Pruritus 20 Increased sweating 20 Alopecia 14 Skin changes 14 Blood and lymphatic system disorders Leukocytosis 49 Differentiation syndrome 1 26 Disseminated intravascular coagulation 26 Ear and labyrinth disorders Earache or feeling of fullness in the ears 23 Cardiac disorders Arrhythmias 23 Eye disorders Visual disturbances 17 Ocular disorders 17 Renal and urinary disorders Renal insufficiency 11 1 Differentiation syndrome can be associated with other commonly reported events such as fever, leukocytosis, dyspnea, pneumonia, pleural effusion, pericardial effusion, hypotension, edema, weight gain, and renal failure. Adverse reactions that occurred in <10% of patients who received tretinoin capsules include: Hepatobiliary disorders: Hepatosplenomegaly (9%), hepatitis (3%), unspecified liver disorder (3%). Musculoskeletal and connective tissue disorders: Flank pain (9%), bone inflammation (3%). Nervous system disorders: Agitation (9%), cerebral hemorrhage (9%), intracranial hypertension (9%), hallucination (6%), abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, stroke, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech (3% each). Renal and urinary disorders: Dysuria (9%), acute renal failure, micturition frequency, renal tubular necrosis, and enlarged prostate (3% each). Respiratory, thoracic and mediastinal disorders: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma, pulmonary edema, larynx edema, and unspecified pulmonary disease (3% each). Infections and infestations: Cellulitis (8%). Blood and lymphatic system disorders: Lymph disorders (6%). Cardiovascular disorders: Cardiac failure (6%), cardiac arrest, myocardial infarction, enlarged heart, heart murmur, myocarditis, pericarditis, and secondary cardiomyopathy (3% each). Ear and labyrinth disorders: Hearing loss and other unspecified auricular disorders (6%), irreversible hearing loss (<1%). General disorders: Face edema (6%), pallor (6%), hypothermia (3%). Metabolism and nutrition disorders: Fluid imbalance (6%), acidosis (3%). Eye disorders: Changed visual acuity (6%), visual field defects (3%).

rinth disorders: Hearing loss and other unspecified auricular disorders (6%), irreversible hearing loss (<1%). General disorders: Face edema (6%), pallor (6%), hypothermia (3%). Metabolism and nutrition disorders: Fluid imbalance (6%), acidosis (3%). Eye disorders: Changed visual acuity (6%), visual field defects (3%). Gastrointestinal disorders: Ascites, ulcer (3% each). Vascular disorders: Ischemia and pulmonary hypertension (3% each). 6.2 Postmarketing Experience 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. Erythema nodosum, basophilia and hyperhistaminemia, Sweet’s Syndrome, organomegaly, hypercalcemia, pancreatitis, myositis, thrombosis (both venous and arterial), thrombocytosis, genital ulceration and vasculitis, predominantly involving the skin.

<table width="387.667px"><col/><col/><tbody><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content> </td><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Tretinoin Capsules</content></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph><content styleCode="bold"> All Grades</content></paragraph><content styleCode="bold">(%)</content></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Headache</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 86</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Dizziness</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 20</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Paresthesias</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Anxiety</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Insomnia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Depression</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Confusion</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">General disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Fever</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 83</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Skin/mucous membrane dryness</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 77</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Malaise</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 66</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Shivering</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 63</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Peripheral edema</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 52</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Pain</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 37</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Chest discomfort</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 32</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Edema</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 29</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Mucositis</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Weight increase</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Anorexia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Weight decrease</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr>

e Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Weight decrease</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr> <tr><td styleCode=" Botrule Toprule Lrule Rrule"> Bone pain</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 77</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Myalgia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Upper respiratory tract disorders</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 63</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Dyspnea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 60</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Respiratory insufficiency</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Pleural effusion</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 20</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Rales</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Expiratory wheezing</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Pneumonia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Vascular disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Hemorrhage</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 60</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Gastrointestinal hemorrhage</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 34</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Flushing</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Hypotension</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Hypertension</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Phlebitis</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Infections and infestations</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Infections</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 58</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Nausea/vomiting</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 57</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Abdominal pain</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 31</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Other gastrointestinal disorders</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Diarrhea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Constipation</td><td align="center" styleCode=" Botrul

rs</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Diarrhea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Constipation</td><td align="center" styleCode=" Botrul e Toprule Lrule Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Dyspepsia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Abdominal distention</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Rash</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 54</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Pruritus</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 20</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Increased sweating</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 20</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Alopecia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Skin changes</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 14</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Blood and lymphatic system disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Leukocytosis</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 49</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Differentiation syndrome¹</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Disseminated intravascular coagulation</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Ear and labyrinth disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Earache or feeling of fullness in the ears</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Cardiac disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Arrhythmias</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 23</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Eye disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Visual disturbances</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Ocular disorders</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 17</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Renal and urinary disorders</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Renal insufficiency</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11</td></tr></tbody></table>

7 DRUG INTERACTIONS Strong CYP3A Inhibitors and Inducers: Avoid coadministration with strong CYP3A inhibitors and inducers. ( 7.1 ) Concomitant Use of Products Known to Cause Intracranial Hypertension : Avoid concomitant use with other products that can cause intracranial hypertension. ( 7.2 ) Vitamin A : Avoid concomitant use with vitamin A. ( 7.3 ) Anti-fibrinolytic Agents : Avoid concomitant use with anti-fibrinolytic agents. ( 7.4 ) 7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible. 7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [see Warnings and Precautions ( 5.5 )] . 7.3 Vitamin A The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A. 7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )].

amin A. 7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )]. 7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible. 7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [see Warnings and Precautions ( 5.5 )] . 7.3 Vitamin A The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A. 7.4 Anti-fibrinolytic Agents Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions ( 5.8 )].

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )], tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. 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. Data Human Data Tretinoin capsules are a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero . Animal Data Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m 2 basis). 8.2 Lactation There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for 1 week after the last dose. 8.3 Use in Females and Males of Reproductive Potential Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin capsules with a sensitivity of at least 50 mIU/mL. Contraception Females Advise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed.

raception during treatment with tretinoin capsules and for 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed. Males Advise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for 1 week after the last dose. Infertility Males Based on testicular toxicities observed in dogs, tretinoin capsules may impair male fertility [see Nonclinical Toxicology ( 13.1 )] . The reversibility of effect on fertility is unknown. 8.4 Pediatric Use Safety and effectiveness of tretinoin capsules have been established in pediatric patients 1 year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and a lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions. Safety and effectiveness in pediatric patients less than 1 year of age have not been established. 8.5 Geriatric Use Across clinical studies of tretinoin capsules, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )], tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. 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. Data Human Data Tretinoin capsules are a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero . Animal Data Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m 2 basis).

8.2 Lactation There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for 1 week after the last dose.

8.4 Pediatric Use Safety and effectiveness of tretinoin capsules have been established in pediatric patients 1 year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and a lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions. Safety and effectiveness in pediatric patients less than 1 year of age have not been established.

8.5 Geriatric Use Across clinical studies of tretinoin capsules, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

10 OVERDOSAGE In case of overdose with tretinoin capsules, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects. There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in a special hematological unit.

11 DESCRIPTION Tretinoin is a retinoid. The chemical name is all-trans retinoic acid. The molecular formula is C 20 H 28 O 2 and the molecular weight is 300.44 g/mol. The structural formula is: It is a yellow to light orange, crystalline powder with melting point at about 182°C (with decomposition). Tretinoin is practically insoluble in water, sparingly soluble in methylene chloride, and slightly soluble in ethanol (96%). Tretinoin capsules are available as capsules containing 10 mg tretinoin for oral use. Each capsule also contains butylated hydroxyanisole, edetate disodium, soybean oil, hydrogenated vegetable oils, medium chain triglycerides, soya lecithin, and yellow beeswax. The gelatin capsule shell contains gelatin, glycerin, yellow iron oxide, red iron oxide and titanium dioxide. Capsules are printed with edible black ink, which consist of propylene glycol, iron oxide black, polyvinyl acetate phthalate and polyethylene glycol 400. The molecular formula for Tretinoin.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tretinoin induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo . In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin capsules have not been characterized. 12.3 Pharmacokinetics Following the administration of tretinoin capsules 22.5 mg/m 2 orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL. Absorption Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin capsules was approximately 50%. Effect of Food The effect of food on the absorption of tretinoin capsules has not been characterized. Food increases the absorption of retinoids, as a class. Distribution The apparent volume of distribution of tretinoin has not been determined. Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL. Elimination The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. Metabolism Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9- cis retinoic acid, 13- cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. Excretion Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m 2 ), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days. Specific Populations The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown. Drug Interaction Studies Clinical Studies and Post Marketing Experience Strong CYP3A inhibitors: Tretinoin AUC increased by 72% following concomitant use with ketoconazole (strong CYP3A inhibitor). Increased tretinoin toxicity has also been reported post-marketing with strong CYP3A inhibitors including certain antimycotics. Moderate CYP3A Inhibitors: Increased tretinoin toxicity following concomitant use of tretinoin capsules with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing. In Vitro Studies Effect of Tretinoin on Transporters: Tretinoin does not inhibit P-gp and BCRP in vitro .

12.1 Mechanism of Action Tretinoin induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo . In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

12.3 Pharmacokinetics Following the administration of tretinoin capsules 22.5 mg/m 2 orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL. Absorption Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin capsules was approximately 50%. Effect of Food The effect of food on the absorption of tretinoin capsules has not been characterized. Food increases the absorption of retinoids, as a class. Distribution The apparent volume of distribution of tretinoin has not been determined. Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL. Elimination The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. Metabolism Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9- cis retinoic acid, 13- cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. Excretion Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m 2 ), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days. Specific Populations The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown. Drug Interaction Studies Clinical Studies and Post Marketing Experience Strong CYP3A inhibitors: Tretinoin AUC increased by 72% following concomitant use with ketoconazole (strong CYP3A inhibitor). Increased tretinoin toxicity has also been reported post-marketing with strong CYP3A inhibitors including certain antimycotics. Moderate CYP3A Inhibitors: Increased tretinoin toxicity following concomitant use of tretinoin capsules with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing. In Vitro Studies Effect of Tretinoin on Transporters: Tretinoin does not inhibit P-gp and BCRP in vitro .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a carcinogen diethylnitrosamine (DEN, intraperitoneal 50 mg/kg and 100 mg/kg) received dietary supplement of all-trans-retinoic acid (tretinoin) for 12 months. Tretinoin at a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m 2 basis) was shown to increase the rate of DEN-induced mouse hepatocellular carcinomas. Tretinoin in combination with 50 mg/kg of DEN also increased the incidence of hemangiomas and hemangiosarcomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A 2-fold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m 2 basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m 2 ).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a carcinogen diethylnitrosamine (DEN, intraperitoneal 50 mg/kg and 100 mg/kg) received dietary supplement of all-trans-retinoic acid (tretinoin) for 12 months. Tretinoin at a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m 2 basis) was shown to increase the rate of DEN-induced mouse hepatocellular carcinomas. Tretinoin in combination with 50 mg/kg of DEN also increased the incidence of hemangiomas and hemangiosarcomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A 2-fold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m 2 basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m 2 ).

14 CLINICAL STUDIES The efficacy of tretinoin capsules has been evaluated in 114 previously treated patients and in 67 previously untreated (“de novo”) patients with APL in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). Patients received tretinoin capsules 22.5 mg/m 2 orally twice daily for up to 90 days following the first dose or 30 days following achievement of complete remission. Efficacy results are shown Table 2. Table 2. Efficacy Results in a Controlled Clinical Trial (MSKCC) and Compassionate Use MSK CC NCI Cohort 1 NCI Cohort 2 Relapsed N = 20 De Novo n = 15 Relapsed* N = 48 De Novo n = 14 Relapsed n = 46 De Novo † n = 38 Complete Remission 16 (80%) 11 (73%) 24 (50%) 5 (36%) 24 (52%) 26 (68%) Median Survival (months) 10.8 NR 5.8 0.5 8.8 NR Median Follow-up (months) 9.9 42.9 5.6 1.2 8.0 13.1 NR = Not Reached NA = Not Available * Including 9 chemorefractory patients † Including 8 patients who received chemotherapy but failed to enter remission The median time to complete remission was between 40 and 50 days (range: 2 to 120 days). Most patients received cytotoxic chemotherapy during the remission phase. Ten of 15 pediatric cases achieved complete remission (8 of 10 males and 2 of 5 females).

<table width="714.667px"><col/><col/><col/><col/><col/><col/><col/><tbody><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"> </td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">MSK</content><content styleCode="bold">CC</content></paragraph></td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">NCI Cohort 1</content></td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">NCI Cohort 2</content></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">Relapsed</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">N = 20</content></content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">De Novo</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">n = 15</content></content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">Relapsed*</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">N = 48</content></content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">De Novo</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">n = 14</content></content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">Relapsed</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">n = 46</content></content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> <content styleCode="bold">De Novo^&#x2020;</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">n = 38</content></content></paragraph></td></tr><tr><td align="right" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> Complete Remission</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 16 (80%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 11 (73%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 24 (50%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5 (36%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 24 (52%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 26 (68%)</td></tr><tr><td align="right" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Survival</paragraph><paragraph>(months)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 10.8</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> NR</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5.8</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 0.5</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 8.8</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> NR</td></tr><tr><td align="right" styleCode=" Botrule Toprule Lrule Rrule"><paragraph> Median Follow-up</paragraph><paragraph>(months)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 9.9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 42.9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5.6</td><td align="center" styleCode=" Bot

"><paragraph> Median Follow-up</paragraph><paragraph>(months)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 9.9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 42.9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 5.6</td><td align="center" styleCode=" Bot rule Toprule Lrule Rrule"> 1.2</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 8.0</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 13.1</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Tretinoin capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side. Supplied in high-density polyethylene, opaque bottles of 100 capsules available in: 100 count bottles with child-resistant closure NDC 10370-268-01 Store at 20ºC to 25ºC (68ºF to 77ºF); [see USP Controlled Room Temperature]. Keep bottle tightly closed. Protect from light.

17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 , 8.3 )] . Advise females of reproductive potential to use 2 methods of effective contraception during treatment with tretinoin capsules and for 1 month after the last dose [see Use in Specific Populations ( 8.3 )] . Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations ( 8.3 )] . Differentiation Syndrome Advise patients that tretinoin capsules can cause differentiation syndrome. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Warnings and Precautions ( 5.2 )] . Patients Without t(15;17) Translocation or PML/RARα Fusion Advise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RARα fusion [see Warnings and Precautions ( 5.3 )] . Leukocytosis Inform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [see Warnings and Precautions ( 5.4 )] . Intracranial Hypertension Advise patients that tretinoin capsules can cause intracranial hypertension, especially in pediatric patients. Ask patients to immediately report any symptoms suggestive of intracranial hypertension, such as headache, nausea, vomiting, and visual disturbances [see Warnings and Precautions ( 5.5 )] . Lipid Abnormalities Inform patients that hypercholesterolemia and/or hypertriglyceridemia can occur during treatment with tretinoin capsules. Advise patients on the need for monitoring fasting triglycerides and cholesterol [see Warnings and Precautions ( 5.6 )] . Hepatotoxicity Advise patients that tretinoin capsules can cause elevated liver function tests. Advise patients on the need for monitoring of liver function tests [see Warnings and Precautions ( 5.7 )] . Thromboembolic Events Inform patients that venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct can occur during treatment with tretinoin capsules [see Warnings and Precautions ( 5.8 )] . Lactation Advise women not to breastfeed during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )]. Administration Instructions Advise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration ( 2.2 )] .

ot to take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration ( 2.2 )] . Effects on Ability to Drive and Use Machines Advise patients that the ability to drive or operate machinery might be impaired when treated with tretinoin capsules, particularly if patients are experiencing dizziness or severe headache. Manufactured for: Par Health USA Rochester, MI 48307 Made in France © 2026 Par Health, Inc. or one of its affiliates. Revised: 03/2026