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FOR INTRAVAGINAL USE ONLY NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE Clinical Studies In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received metronidazole vaginal gel daily for 5 days, the clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 (53%) and 109/190 (57%), respectively. Manufactured for: Northstar Rx LLC Memphis, TN 38141 Manufactured by: Glenmark Pharmaceuticals Limited Colvale-Bardez, Goa 403513, India June 2022

e clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 (53%) and 109/190 (57%), respectively. Manufactured for: Northstar Rx LLC Memphis, TN 38141 Manufactured by: Glenmark Pharmaceuticals Limited Colvale-Bardez, Goa 403513, India June 2022 Metronidazole Vaginal Gel, 0.75% DIRECTIONS FOR USE 1. Filling the applicator • Remove cap and puncture metal seal on tube with the pointed tip of cap (see Figure 1). • Screw end of applicator onto tube (see Figure 2). • Slowly squeeze gel out of tube and into applicator. Plunger will stop when the applicator is full (see Figure 3). • Unscrew applicator and replace cap on tube. 2. Inserting the applicator • The applicator may be inserted while lying on your back with your knees bent or in any comfortable position. • Hold filled applicator by barrel, and gently insert into vagina as far as it will comfortably go (see Figure 4). • Slowly press the plunger until it stops to deposit gel into vagina and then withdraw the applicator. 3. Care of the applicator If physician prescribes twice-a-day dosing: • After use, pull the plunger out of the barrel (see Figure 5). • Wash both plunger and barrel in warm soapy water and rinse thoroughly. • To reassemble applicator, gently push plunger back into barrel. IMPORTANT For once-a-day dosing, apply one applicator full at bedtime. For twice-a-day dosing, apply one applicator full each morning and evening for 5 days, or as directed by physician. WARNINGS • If significant irritation develops from the use of this medication, discontinue use and consult your physician. • Do not use during pregnancy except under the supervision of a physician. • Keep this and all medications out of reach of children. • For vaginal use only. Not for use in the eyes, on the skin or in the mouth. Store at room temperature. Avoid exposure to extreme heat or cold. See end of carton and bottom of tube for lot number and expiration date. Manufactured for: Northstar Rx LLC Memphis, TN 38141 Manufactured by: Glenmark Pharmaceuticals Limited Colvale-Bardez, Goa 403513, India June 2022 figure1.jpg figure2.jpg figure3.jpg figure4.jpg figure5.jpg

DESCRIPTION Metronidazole Vaginal Gel is the intravaginal dosage form of the synthetic antibacterial agent, metronidazole, USP at a concentration of 0.75%. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical formula of C 6 H 9 N 3 O 3 , a molecular weight of 171.15 g/mol, and has the following structure: Metronidazole Vaginal Gel is a gelled, purified water solution, containing metronidazole, USP at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains carbomer 974P, edetate disodium, methylparaben, propylparaben, propylene glycol, and sodium hydroxide. Each applicator full of 5 grams of vaginal gel contains approximately 37.5 mg of metronidazole, USP. Structure.jpg

CLINICAL PHARMACOLOGY Normal Subjects Following a single, intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole) to 12 normal subjects, a mean maximum serum metronidazole concentration of 237 ng/mL was reported (range: 152 to 368 ng/mL). This is approximately 2% of the mean maximum serum metronidazole concentration reported in the same subjects administered a single, oral 500 mg dose of metronidazole (mean C max = 12,785 ng/mL, range: 10,013 to 17,400 ng/mL). These peak concentrations were obtained in 6 to 12 hours after dosing with metronidazole vaginal gel and 1 to 3 hours after dosing with oral metronidazole. The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole), was approximately 4% of the AUC of a single oral 500 mg dose of metronidazole (4977 ng-hr/mL and approximately 125,000 ng-hr/mL, respectively). Dose-adjusted comparisons of AUCs demonstrated that, on a mg to mg comparison basis, the absorption of metronidazole, when administered vaginally, was approximately half that of an equivalent oral dosage. Patients with Bacterial Vaginosis Following single and multiple 5 g doses of metronidazole vaginal gel to 4 patients with bacterial vaginosis, a mean maximum serum metronidazole concentration of 214 ng/mL on day 1 and 294 ng/mL (range: 228 to 349 ng/mL) on day five were reported. Steady-state metronidazole serum concentrations following oral dosages of 400 to 500 mg BID have been reported to range from 6,000 to 20,000 ng/mL. Microbiology The intracellular targets of action of metronidazole on anaerobes are largely unknown. The 5-nitro group of metronidazole is reduced by metabolically active anaerobes, and studies have demonstrated that the reduced form of the drug interacts with bacterial DNA. However, it is not clear whether interaction with DNA alone is an important component in the bactericidal action of metronidazole on anaerobic organisms. Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis (see INDICATIONS AND USAGE ). Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis , Mobiluncus spp., and Mycoplasma hominis , has not been defined. Nonetheless, metronidazole is an antimicrobial agent active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis: Bacteroides spp. Gardnerella vaginalis Mobiluncus spp . Peptostreptococcus spp.

INDICATIONS AND USAGE Metronidazole vaginal gel is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis). NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells. Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis , Chlamydia trachomatis , N. gonorrhoeae , Candida albicans , and Herpes simplex virus should be ruled out.

CONTRAINDICATIONS Metronidazole vaginal gel is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives.

WARNINGS Convulsive Seizures and Peripheral Neuropathy Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral or intravenous metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be administered with caution to patients with central nervous system diseases. Psychotic Reactions Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients who have taken disulfiram within the last 2 weeks.

PRECAUTIONS Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUCs) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. Data from well-controlled trials directly comparing metronidazole administered orally to metronidazole administered vaginally are not available. General Patients with severe hepatic disease metabolize metronidazole slowly. This results in the accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, metronidazole vaginal gel should be administered cautiously. Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with metronidazole vaginal gel. Approximately 6 to 10% of patients treated with metronidazole vaginal gel developed symptomatic Candida vaginitis during or immediately after therapy. Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be excluded. Metronidazole vaginal gel contains ingredients that may cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water. Information for the Patient The patient should be cautioned about drinking alcohol while being treated with metronidazole vaginal gel. While blood levels are significantly lower with metronidazole vaginal gel than with usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded. The patient should be instructed not to engage in vaginal intercourse during treatment with this product. Drug Interactions Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole vaginal gel is prescribed for patients on this type of anticoagulant therapy. In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity. Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma clearance of metronidazole. Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7. Carcinogenesis, Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis.

340 nm) and metronidazole (322 nm) at pH 7. Carcinogenesis, Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 500 mg/kg/day), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Several long-term oral dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. These studies have not been conducted with 0.75% metronidazole vaginal gel, which would result in significantly lower systemic blood levels than those obtained with oral formulations. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals ( in vivo ) have failed to demonstrate a potential for genetic damage. Fertility studies have been performed in mice up to six times the recommended human oral dose (based on mg/m 2 ) and have revealed no evidence of impaired fertility. Pregnancy: Teratogenic Effects There has been no experience to date with the use of metronidazole vaginal gel in pregnant patients. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at six times the recommended human dose (based on mg/m 2 ); however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Specific studies of metronidazole levels in human milk following intravaginally administered metronidazole have not been performed. However, metronidazole is secreted in human milk in concentrations similar to those found in plasma following oral administration of metronidazole. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established.

General Patients with severe hepatic disease metabolize metronidazole slowly. This results in the accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, metronidazole vaginal gel should be administered cautiously. Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with metronidazole vaginal gel. Approximately 6 to 10% of patients treated with metronidazole vaginal gel developed symptomatic Candida vaginitis during or immediately after therapy. Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be excluded. Metronidazole vaginal gel contains ingredients that may cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.

Information for the Patient The patient should be cautioned about drinking alcohol while being treated with metronidazole vaginal gel. While blood levels are significantly lower with metronidazole vaginal gel than with usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded. The patient should be instructed not to engage in vaginal intercourse during treatment with this product.

Drug Interactions Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole vaginal gel is prescribed for patients on this type of anticoagulant therapy. In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity. Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma clearance of metronidazole. Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 500 mg/kg/day), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Several long-term oral dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. These studies have not been conducted with 0.75% metronidazole vaginal gel, which would result in significantly lower systemic blood levels than those obtained with oral formulations. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals ( in vivo ) have failed to demonstrate a potential for genetic damage. Fertility studies have been performed in mice up to six times the recommended human oral dose (based on mg/m 2 ) and have revealed no evidence of impaired fertility.

Pregnancy: Teratogenic Effects There has been no experience to date with the use of metronidazole vaginal gel in pregnant patients. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at six times the recommended human dose (based on mg/m 2 ); however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers Specific studies of metronidazole levels in human milk following intravaginally administered metronidazole have not been performed. However, metronidazole is secreted in human milk in concentrations similar to those found in plasma following oral administration of metronidazole. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE EVENTS Clinical Trials There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 non-pregnant women who received metronidazole vaginal gel. In a randomized, single-blind clinical trial of 505 non-pregnant women who received metronidazole vaginal gel once or twice a day, 2 patients (one from each regimen) discontinued therapy early due to drug-related adverse events. One patient discontinued drug because of moderate abdominal cramping and loose stools, while the other patient discontinued drug because of mild vaginal burning. These symptoms resolved after discontinuation of drug. Medical events judged to be related, probably related, or possibly related to administration of metronidazole vaginal gel once or twice a day were reported for 195/505 (39%) patients. The incidence of individual adverse reactions were not significantly different between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%: Reproductive: Vaginal discharge (12%), Symptomatic Candida cervicitis/vaginitis (10%), Vulva/vaginal irritative symptoms (9%), Pelvic discomfort (3%). Gastrointestinal: Gastrointestinal discomfort (7%), Nausea and/or vomiting (4%), Unusual taste (2%), Diarrhea/loose stools (1%), Decreased appetite (1%), Abdominal bloating/gas; thirsty, dry mouth. Neurologic: Headache (5%), Dizziness (2%), Depression. Dermatologic: Generalized itching or rash. Other: Unspecified cramping (1%), Fatigue, Darkened urine. In previous clinical trials submitted for approved labeling of metronidazole vaginal gel the following was also reported: Laboratory: Increased/decreased white blood cell counts (1.7%). Other Metronidazole Formulations Other effects that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients. Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUC) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole: Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Central Nervous System: (See WARNINGS ) Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, insomnia. Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages. Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis. Hematopoietic: Reversible neutropenia, reversible thrombocytopenia. Hypersensitivity Reactions: Urticaria; erythematous rash; flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

poietic: Reversible neutropenia, reversible thrombocytopenia. Hypersensitivity Reactions: Urticaria; erythematous rash; flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine. To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

OVERDOSAGE There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects (see WARNINGS ).

DOSAGE AND ADMINISTRATION The recommended dose is one applicator full of metronidazole vaginal gel (approximately 5 grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once-a-day dosing, metronidazole vaginal gel should be administered at bedtime.

HOW SUPPLIED Metronidazole Vaginal Gel, 0.75% is supplied in a 70 g tube and packaged with 5 vaginal applicators. The NDC number for the 70 g tube is 16714-557-01. Store at controlled room temperature 15°C to 30°C (59°F to 86°F). Protect from freezing.

1 INDICATIONS AND USAGE NUVESSA is indicated for the treatment of bacterial vaginosis in females 12 years of age and older. NUVESSA is a nitroimidazole antimicrobial indicated for the treatment of bacterial vaginosis in females 12 years of age and older. ( 1 )​

2 DOSAGE AND ADMINISTRATION A single-dose, pre-filled disposable applicator (which delivers approximately 5 g of gel containing 65 mg of metronidazole) administered once intravaginally. NUVESSA should be administered at bedtime. NUVESSA is not for ophthalmic, dermal or oral use. A single-dose, pre-filled disposable applicator administered once intravaginally at bedtime. ( 2 ) NUVESSA is not for ophthalmic, dermal, or oral use. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Vaginal gel (1.3%) containing 65 mg of metronidazole in 5 grams of gel in a pre-filled applicator. Vaginal gel: 65 mg of metronidazole in 5 grams of gel (1.3%) in a prefilled applicator ( 3 )

4 CONTRAINDICATIONS History of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives ( 4.1 ) Concomitant use of disulfiram or within 2 weeks of disulfiram ( 4.2 , 7.1 ) Concomitant use of alcohol ( 4.3 , 7.2 ) 4.1 Hypersensitivity NUVESSA is contraindicated in persons who have shown hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives. 4.2 Use of Disulfiram Psychotic reactions have been reported with co-administration of disulfiram and oral metronidazole. Do not administer concurrently with or within 2 weeks of disulfiram. 4.3 Concomitant Alcohol Disulfiram-like reactions to alcohol have been reported with co-administration of oral metronidazole; do not consume ethanol or propylene glycol, during and for at least 24 hours following treatment.

5 WARNINGS AND PRECAUTIONS Central and peripheral nervous system effects: Convulsive seizures and peripheral neuropathy have been reported in patients treated with oral or intravenous metronidazole. Discontinue promptly if abnormal neurologic signs develop ( 5.1 ) Interference with laboratory tests: Metronidazole may interfere with certain serum chemistry laboratory values. ( 5.3 ) 5.1 Central and Peripheral Nervous System Effects Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral or intravenous metronidazole. NUVESSA should be administered with caution to patients with central nervous system diseases. Discontinue promptly if abnormal neurologic signs develop. 5.2 Carcinogenicity in Animals Metronidazole has been shown to be carcinogenic at high doses administered orally in mice and rats [see Nonclinical Toxicology ( 13.1 )] . Unnecessary use of metronidazole should be avoided. Use of NUVESSA should be reserved for the treatment of bacterial vaginosis [see Indications and Usage ( 1 )]. 5.3 Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions observed in adult clinical studies (incidence ≥1%) were vulvovaginal candidiasis, headache, vulvovaginal pruritus, nausea, diarrhea, and dysmenorrhea. The most common adverse reactions observed in pediatric clinical studies (incidence ≥1%) was vulvovaginal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc., at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical Trial Experience in Adult Subjects The safety of NUVESSA was evaluated in a randomized, double-blind, vehicle-controlled study in subjects with bacterial vaginosis. A total of 321 non-pregnant females with a mean age of 33.4 years (range 18 to 67 years) received NUVESSA. Subjects were primarily Black/African American (58.3%) or White (39.3%). Subjects administered a single dose of NUVESSA at bedtime on the first day of the study. There were no deaths or serious adverse reactions in this trial. Adverse reactions were reported by 19.0% of subjects treated with NUVESSA versus 16.1% of subjects treated with Vehicle Gel. Adverse reactions occurring in ≥1% of subjects receiving NUVESSA were: vulvovaginal candidiasis (5.6%), headache (2.2%), vulvovaginal pruritus (1.6%), nausea (1.6%), diarrhea (1.2%), and dysmenorrhea (1.2%). No subjects discontinued treatment due to adverse reactions. Clinical Trial Experience in Pediatric Subjects The safety of NUVESSA was evaluated in a multicenter, open-label study evaluating the safety and tolerability of NUVESSA in 60 pediatric subjects between the ages of 12 and less than 18 years old all of whom were treated with a single dose of NUVESSA administered once at bedtime intravaginally. Most subjects in this study were either Black/African-American, non-Hispanic (47%) or Hispanic (35%). Safety in pediatric female subjects aged 12 to less than 18 years old was comparable to adult women. No deaths occurred and no subjects discontinued treatment due to adverse reactions. Adverse reactions occurring in ≥ 1% of pediatric subjects included: vulvovaginal discomfort (2%). 6.2 Other Metronidazole Formulations Other Vaginal Formulations Other reactions that have been reported in association with the use of other formulations of metronidazole vaginal gel include: unusual taste and decreased appetite. Topical (Dermal) Formulations Other reactions that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse reactions exceeded an incidence of 2% of patients. Oral and Parenteral Formulations The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole: Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Nervous System: The most serious adverse reactions reported in patients treated with oral metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity.

e seen in electrocardiographic tracings. Nervous System: The most serious adverse reactions reported in patients treated with oral metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia [see Warnings and Precautions ( 5.1 )]. Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, "furry" tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages. Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis. Hematopoietic: Reversible neutropenia, reversible thrombocytopenia. Hypersensitivity Reactions: Urticaria; erythematous rash; Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains [see Contraindications ( 4 )]. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

7 DRUG INTERACTIONS The intravaginal administration of a single dose of NUVESSA results in lower systemic exposure to metronidazole that is approximately 2% to 4% of that achieved following oral administration of 500 mg metronidazole tablets [see Clinical Pharmacology ( 12.3 )] . The following drug interactions were reported for oral metronidazole. Warfarin and other coumarin anticoagulants: Prolonged anticoagulant effects of warfarin and other coumarin anticoagulants have been reported with co-administration of oral metronidazole. ( 7.3 ) Lithium: Elevated plasma lithium concentrations have been reported with oral metronidazole. ( 7.4 ) 7.1 Disulfiram Use of oral metronidazole has been associated with psychotic reactions in alcoholic patients who are using disulfiram concurrently. NUVESSA should not be used by patients who have taken disulfiram within the last two weeks [see Contraindications ( 4.2 )] . 7.2 Alcoholic Beverages Use of oral metronidazole has been associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) to alcohol. Alcoholic beverages and preparations containing ethanol or propylene glycol should not be consumed during and for at least 24 hours after NUVESSA therapy [see Contraindications ( 4.3 )]. 7.3 Coumarin and Other Oral Anticoagulants Use of oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when NUVESSA is prescribed for patients on this type of anticoagulant therapy. 7.4 Lithium Short-term use of oral metronidazole has been associated with elevation of plasma lithium concentrations and, in a few cases, signs of lithium toxicity in patients stabilized on relatively high doses of lithium. 7.5 Cimetidine Use of oral metronidazole with cimetidine may prolong the half-life and decrease plasma clearance of metronidazole. No dose adjustment of NUVESSA is necessary.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating patient may pump and discard breast milk during treatment and for 48 hours after the last dose. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no data available on the use of NUVESSA in pregnant women. Metronidazole usage in pregnancy has been associated with certain congenital anomalies (see Data ) . In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally, during organogenesis to pregnant rats and rabbits at up to 30 times and 60 times the recommended human dose based on body surface area comparison, respectively (see Data ) . The estimated 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 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 Blood levels following NUVESSA vaginal administration are lower than those achieved with oral metronidazole. Following a single intravaginal 5 g dose of NUVESSA, mean maximum concentration (C max ) and total exposure (AUC 0 -∞ ) are approximately 2% and 4%, respectively, of those following a single oral 500 mg dose of metronidazole tablets [see Clinical Pharmacology ( 12.3 )] . Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero ; however, these findings were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Animal Data No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rabbits at up to 200 mg/kg (about 60 times the maximum human dose based on body surface area comparison). Similarly, no fetotoxic or teratogenic effects were observed in five studies in rats where dosing was administered orally in the diet or by gastric intubation at doses up to 200 mg/kg (about 30 times the maximum human dose based on body surface area comparison). As well, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at doses up to 100 mg/kg (about 7 times the maximum human dose based on body surface area comparison). However, some intrauterine deaths were observed in Swiss Webster mice administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1 times the maximum human dose based on body surface area comparison).

at doses up to 100 mg/kg (about 7 times the maximum human dose based on body surface area comparison). However, some intrauterine deaths were observed in Swiss Webster mice administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1 times the maximum human dose based on body surface area comparison). The relationship of these intraperitoneal findings in mice to the vaginal use of NUVESSA is unknown. 8.2 Lactation Risk Summary There are no data on the presence of metronidazole in human milk following intravaginal administration. Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to those found in plasma ( see Data ). The metronidazole vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral metronidazole dose [see Clinical Pharmacology ( 12.3 )] . The published literature reports no adverse effects in infants exposed through breastmilk to maternal orally administered metronidazole. There are no data on the effects on milk production. Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice [see Nonclinical Toxicology ( 13.1 )] . The clinical relevance of these findings is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NUVESSA, and any potential adverse effects on the breastfed child from NUVESSA or from the underlying maternal condition. Alternatively, a lactating patient may interrupt breastfeeding and choose to pump and discard breastmilk during treatment with NUVESSA and for 48 hours after the last dose and feed her infant previously stored human milk or formula. Data In a study of lactating women receiving oral metronidazole 600 mg (n=11) or 1200 mg (n=4) daily, mean maternal plasma concentrations were 5.0 and 12.5 mcg/mL respectively, within 2 hours following administration; the milk: maternal plasma ratio was approximately 1. 8.4 Pediatric Use The safety and effectiveness of NUVESSA have been established in pediatric subjects between the ages of 12 and less than 18 years old. Use of NUVESSA in this age group is supported by evidence from a multicenter, open-label safety and tolerability study in 60 pediatric patients with bacterial vaginosis [see Adverse Reactions ( 6.1 )] and, evidence from adequate and well-controlled studies in adult women. The safety and effectiveness of NUVESSA in pediatric subjects below the age of 12 years have not been established. 8.5 Geriatric Use Clinical studies with NUVESSA did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects.

8.1 Pregnancy Risk Summary There are no data available on the use of NUVESSA in pregnant women. Metronidazole usage in pregnancy has been associated with certain congenital anomalies (see Data ) . In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally, during organogenesis to pregnant rats and rabbits at up to 30 times and 60 times the recommended human dose based on body surface area comparison, respectively (see Data ) . The estimated 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 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 Blood levels following NUVESSA vaginal administration are lower than those achieved with oral metronidazole. Following a single intravaginal 5 g dose of NUVESSA, mean maximum concentration (C max ) and total exposure (AUC 0 -∞ ) are approximately 2% and 4%, respectively, of those following a single oral 500 mg dose of metronidazole tablets [see Clinical Pharmacology ( 12.3 )] . Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero ; however, these findings were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Animal Data No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rabbits at up to 200 mg/kg (about 60 times the maximum human dose based on body surface area comparison). Similarly, no fetotoxic or teratogenic effects were observed in five studies in rats where dosing was administered orally in the diet or by gastric intubation at doses up to 200 mg/kg (about 30 times the maximum human dose based on body surface area comparison). As well, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at doses up to 100 mg/kg (about 7 times the maximum human dose based on body surface area comparison). However, some intrauterine deaths were observed in Swiss Webster mice administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1 times the maximum human dose based on body surface area comparison). The relationship of these intraperitoneal findings in mice to the vaginal use of NUVESSA is unknown.

8.4 Pediatric Use The safety and effectiveness of NUVESSA have been established in pediatric subjects between the ages of 12 and less than 18 years old. Use of NUVESSA in this age group is supported by evidence from a multicenter, open-label safety and tolerability study in 60 pediatric patients with bacterial vaginosis [see Adverse Reactions ( 6.1 )] and, evidence from adequate and well-controlled studies in adult women. The safety and effectiveness of NUVESSA in pediatric subjects below the age of 12 years have not been established.

10 OVERDOSAGE There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied NUVESSA could be absorbed in sufficient amounts to produce systemic effects [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6.2 )].

11 DESCRIPTION NUVESSA contains 1.3% metronidazole, USP in a single-dose prefilled disposable applicator. It is intended for intravaginal use. Metronidazole is a nitroimidazole antimicrobial. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. Its structural formula is: The molecular formula is C 6 H 9 N 3 O 3 with a molecular weight of 171.16. NUVESSA is an aqueous gel containing metronidazole at a concentration of 13 mg/g (1.3%). The gel is formulated at pH 4.0. The gel also contains benzyl alcohol, methylparaben, polycarbophil, polyethylene glycol 400, propylene glycol, propylparaben, and purified water. Each applicator contains approximately 65 mg of metronidazole in 5 g of vaginal gel. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Metronidazole is an antimicrobial drug [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics Following a single, intravaginal 5 g dose of NUVESSA (equivalent to 65 mg of metronidazole) to 20 healthy female subjects, a mean maximum serum metronidazole concentration (C max ) of 239 ng/mL was observed (range: 114 to 428 ng/mL). The average time to achieve this C max was 7.3 hours (range: 4 to 18 hours). This C max is approximately 2% of the mean maximum serum concentration reported in healthy subjects administered a single, oral 500 mg dose of metronidazole tablets (mean C max = 12,785 ng/mL). The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of NUVESSA (equivalent to 65 mg of metronidazole), was 5,434 ng∙hr/mL (range: 1382 to 12744 ng∙hr/mL). This AUC 0-∞ is approximately 4% of the reported AUC of metronidazole following a single oral 500 mg dose of metronidazole (approximately 125,000 ng∙hr/mL). 12.4 Microbiology Mechanism of Action Metronidazole is a nitroimidazole antimicrobial agent that acts primarily against anaerobic bacteria and selected protozoa. The 5-nitro group on the metronidazole molecule is reduced by metabolically active anaerobes to its active state by the bacterial nitro-reductase enzyme after it diffuses into the bacterial cell. This results in the production of cytotoxic compounds that disrupt the helical structure of bacterial DNA thereby inhibiting bacterial nucleic acid synthesis which leads to cell death. Resistance The mechanism of resistance, like for other nitroimidazoles, appears to be multifactorial that include decreased uptake of the drug, higher efflux activity, and/or altered nitroreductase activity. Antibacterial Activity Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Clinical Studies ( 14 )] . The following in vitro data are available, but their clinical significance is unknown. Metronidazole is active in vitro against most isolates of the following organisms reported to be associated with bacterial vaginosis: Bacteroides spp. Gardnerella vaginalis Mobiluncus spp. Peptostreptococcus spp.

12.3 Pharmacokinetics Following a single, intravaginal 5 g dose of NUVESSA (equivalent to 65 mg of metronidazole) to 20 healthy female subjects, a mean maximum serum metronidazole concentration (C max ) of 239 ng/mL was observed (range: 114 to 428 ng/mL). The average time to achieve this C max was 7.3 hours (range: 4 to 18 hours). This C max is approximately 2% of the mean maximum serum concentration reported in healthy subjects administered a single, oral 500 mg dose of metronidazole tablets (mean C max = 12,785 ng/mL). The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of NUVESSA (equivalent to 65 mg of metronidazole), was 5,434 ng∙hr/mL (range: 1382 to 12744 ng∙hr/mL). This AUC 0-∞ is approximately 4% of the reported AUC of metronidazole following a single oral 500 mg dose of metronidazole (approximately 125,000 ng∙hr/mL).

12.4 Microbiology Mechanism of Action Metronidazole is a nitroimidazole antimicrobial agent that acts primarily against anaerobic bacteria and selected protozoa. The 5-nitro group on the metronidazole molecule is reduced by metabolically active anaerobes to its active state by the bacterial nitro-reductase enzyme after it diffuses into the bacterial cell. This results in the production of cytotoxic compounds that disrupt the helical structure of bacterial DNA thereby inhibiting bacterial nucleic acid synthesis which leads to cell death. Resistance The mechanism of resistance, like for other nitroimidazoles, appears to be multifactorial that include decreased uptake of the drug, higher efflux activity, and/or altered nitroreductase activity. Antibacterial Activity Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Clinical Studies ( 14 )] . The following in vitro data are available, but their clinical significance is unknown. Metronidazole is active in vitro against most isolates of the following organisms reported to be associated with bacterial vaginosis: Bacteroides spp. Gardnerella vaginalis Mobiluncus spp. Peptostreptococcus spp.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Pulmonary tumors were reported in several mouse studies in which mice were dosed orally at 75 mg/kg and above (about 6 or more times the maximum recommended human dose based on mg/m 2 ). Malignant lymphoma was reported at 66 mg/kg and above (about 5 or more times the maximum recommended human dose based on mg/m 2 ). These tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). All these effects were statistically significant. There were statistically significant increases in the incidence of mammary tumors, among female rats administered metronidazole at 270 mg/kg and above (about 40 times the maximum human dose based on mg/m 2 ). Hepatic adenomas and carcinomas were observed in rats administered 300 mg/kg (about 45 times the maximum human dose based on mg/m 2 ). Two lifetime oral tumorigenicity studies in hamsters have been performed and reported to be negative at doses up to 80 mg/kg (about 10 times the maximum human dose based on mg/m 2 ). Carcinogenesis studies have not been conducted with NUVESSA. Although metronidazole has shown in vitro mutagenic activity in bacterial reverse mutation tests, it was negative in in vitro mammalian mutation systems including CHO/HGPRT and CH V79 lung cell assays. Metronidazole was not clastogenic in vitro chromosome aberration tests in CHO cells up to 5000 µg/mL but was positive in human and monkey peripheral blood lymphocytes at 0.1 µg/mL. In general, numerous micronucleus studies in rats and mice have failed to demonstrate a potential for genetic damage up to single oral doses 3000 mg/kg in mice (about 225 times the maximum human dose based on mg/m 2 ). However, a dose dependent increase in the frequency of micronuclei was observed in CFW mice after intraperitoneal injections of up to 160 mg/kg (about 12 times the maximum human dose based on mg/m 2 ). Fertility studies have been performed in mice orally dosed up to 500 mg/kg (about 37 times the maximum human dose based on mg/m 2 ) revealed no evidence of impaired fertility. While no effects on fertility were observed in female rats dosed intraperitoneally at doses up to 1000 mg/kg (about 300 times the maximum human dose based on mg/m 2 ), studies in male rats resulted in effects on testes and sperm production at oral doses of 100 mg/kg and above (about 30 times the maximum human dose based on mg/m 2 ).

13.1 Carcinogenesis Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Pulmonary tumors were reported in several mouse studies in which mice were dosed orally at 75 mg/kg and above (about 6 or more times the maximum recommended human dose based on mg/m 2 ). Malignant lymphoma was reported at 66 mg/kg and above (about 5 or more times the maximum recommended human dose based on mg/m 2 ). These tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). All these effects were statistically significant. There were statistically significant increases in the incidence of mammary tumors, among female rats administered metronidazole at 270 mg/kg and above (about 40 times the maximum human dose based on mg/m 2 ). Hepatic adenomas and carcinomas were observed in rats administered 300 mg/kg (about 45 times the maximum human dose based on mg/m 2 ). Two lifetime oral tumorigenicity studies in hamsters have been performed and reported to be negative at doses up to 80 mg/kg (about 10 times the maximum human dose based on mg/m 2 ). Carcinogenesis studies have not been conducted with NUVESSA. Although metronidazole has shown in vitro mutagenic activity in bacterial reverse mutation tests, it was negative in in vitro mammalian mutation systems including CHO/HGPRT and CH V79 lung cell assays. Metronidazole was not clastogenic in vitro chromosome aberration tests in CHO cells up to 5000 µg/mL but was positive in human and monkey peripheral blood lymphocytes at 0.1 µg/mL. In general, numerous micronucleus studies in rats and mice have failed to demonstrate a potential for genetic damage up to single oral doses 3000 mg/kg in mice (about 225 times the maximum human dose based on mg/m 2 ). However, a dose dependent increase in the frequency of micronuclei was observed in CFW mice after intraperitoneal injections of up to 160 mg/kg (about 12 times the maximum human dose based on mg/m 2 ). Fertility studies have been performed in mice orally dosed up to 500 mg/kg (about 37 times the maximum human dose based on mg/m 2 ) revealed no evidence of impaired fertility. While no effects on fertility were observed in female rats dosed intraperitoneally at doses up to 1000 mg/kg (about 300 times the maximum human dose based on mg/m 2 ), studies in male rats resulted in effects on testes and sperm production at oral doses of 100 mg/kg and above (about 30 times the maximum human dose based on mg/m 2 ).

14 CLINICAL STUDIES A single, randomized, double-blind, vehicle-controlled clinical trial was conducted to evaluate the efficacy of NUVESSA. Subjects had a clinical diagnosis of bacterial vaginosis defined by the presence of a homogenous vaginal discharge that (a) had a pH ≥ 4.7, (b) emitted a "fishy" amine odor when mixed with a 10% KOH solution ("whiff" test), and (c) contained clue cells ≥ 20% of the total vaginal epithelial cells. In addition, to be eligible for analysis subjects must have had a Gram stain Nugent score ≥ 4 and have been negative for N. gonorrhoeae and C. trachomatis . Non-pregnant females at least 18 years of age were randomized 1:1 to either NUVESSA or Vehicle Gel and instructed to administer study drug once at bedtime. Two hundred ninety-two (292) NUVESSA subjects and 285 Vehicle Gel subjects were eligible for the analysis. Clinical cure was defined as (a) return of normal physiologic discharge, (b) negative KOH "whiff" test, and (c) clue cell < 20% of the total vaginal epithelial cells at the Test of Cure visit (between 21 to 30 days post-treatment). Bacteriological Cure was defined as a Nugent score of < 4 and Therapeutic cure was defined as clinical cure and bacteriological cure. NUVESSA demonstrated statistically significantly higher cure rates over Vehicle Gel as measured by clinical cure, bacteriological cure and therapeutic cure (Table 1). Table 1. The Efficacy of NUVESSA for the Treatment of Bacterial Vaginosis in a Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study Outcome NUVESSA N = 292 n (%) Vehicle Gel N = 285 n (%) Treatment Difference (%) [95% Confidence Interval] Test of Cure (Day 21 to 30) Clinical Cure 108 (37.0) 76 (26.7) 10.3 (2.8, 17.9) Bacteriological Cure 57 (19.5) 22 (7.7) 11.8 (6.3, 17.3) Therapeutic Cure 49 (16.8) 18 (6.3) 10.5 (5.3, 15.6) Clinical Cure and Bacteriological Cure were also assessed at Day 7. Clinical Cure at Day 7 was achieved by a statistically significantly greater proportion of subjects in the NUVESSA group compared to subjects in the Vehicle Gel group (41.1% vs. 20.0%). Bacteriological Cure at Day 7 was achieved by a statistically significantly greater proportion of subjects in the NUVESSA group compared to subjects in the Vehicle Gel group (33.9% vs. 6.3%).

<table width="65%"><caption>Table 1. The Efficacy of NUVESSA for the Treatment of Bacterial Vaginosis in a Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study</caption><col width="20%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="30%" align="left" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule">Outcome</th><th align="center" styleCode="Lrule Rrule">NUVESSA N = 292 n (%) </th><th align="center" styleCode="Lrule Rrule">Vehicle Gel N = 285 n (%) </th><th align="center" styleCode="Lrule Rrule">Treatment Difference (%) [95% Confidence Interval] </th></tr><tr><th colspan="4" styleCode="Lrule Rrule"> Test of Cure (Day 21 to 30)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Clinical Cure</td><td styleCode="Rrule">108 (37.0)</td><td styleCode="Rrule">76 (26.7)</td><td styleCode="Rrule">10.3 (2.8, 17.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bacteriological Cure</td><td styleCode="Rrule">57 (19.5)</td><td styleCode="Rrule">22 (7.7)</td><td styleCode="Rrule">11.8 (6.3, 17.3)</td></tr><tr><td styleCode="Lrule Rrule"> Therapeutic Cure</td><td styleCode="Rrule">49 (16.8)</td><td styleCode="Rrule">18 (6.3)</td><td styleCode="Rrule">10.5 (5.3, 15.6)</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING NUVESSA is available in cartons containing one single-dose, prefilled disposable applicator delivering 5 g of vaginal gel containing approximately 65 mg of metronidazole: 5 g disposable applicator (NDC 0642-7466-05). Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F) [ see USP Controlled Room temperature ]. Do not freeze. Do not refrigerate.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Interaction with Alcohol Instruct the patient not to consume alcoholic beverages and preparations containing ethanol or propylene glycol during and for at least 24 hours after treatment with NUVESSA [see Contraindications ( 4.3 ) and Drug Interactions ( 7.2 )]. Drug Interactions Instruct the patient not to use NUVESSA if disulfiram had been used within the last two weeks [see Contraindications ( 4.2 )] , and to inform their healthcare provider if they are taking oral anticoagulants, or lithium [see Drug Interactions ( 7.3 , 7.4 )]. Vaginal Intercourse and Use with Vaginal Products Instruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) following the single administration of NUVESSA. Lactation A patient may choose to pump and discard breast milk during treatment with NUVESSA and for 48 hours after last dose, and feed her infant previously stored human milk or formula [see Use in Specific Populations ( 8.2 )]. Vaginal Irritation Inform the patient to discontinue use and consult a healthcare provider if vaginal irritation occurs with use of NUVESSA. Administration of Drug Instruct the patient that NUVESSA is supplied as a single dose in a pre-filled applicator.

PATIENT INFORMATION NUVESSA ® (nue-ve-sa) (metronidazole vaginal gel 1.3%) For intravaginal use only. Do not use in the eyes, mouth or skin. What is NUVESSA? NUVESSA is a prescription medicine used to treat bacterial vaginal infections in females 12 years and older. It is not known if Nuvessa is safe and effective in female children younger than 12 years of age. Do not use NUVESSA if you: are allergic to metronidazole, parabens, nitroimidazole derivatives, or any of the ingredients in NUVESSA. See the end of this leaflet for a complete list of ingredients in NUVESSA. take or have taken a medicine called Antabuse (disulfiram) in the last 2 weeks. drink alcohol. Do not drink alcohol while you use NUVESSA and for at least 24 hours after you stop using it. It can increase your chances of getting serious side effects. Before you use NUVESSA, tell your healthcare provider about all your medical conditions, including if you: have or had central nervous system diseases. are pregnant or plan to become pregnant. It is not known if NUVESSA will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with NUVESSA. are breastfeeding or plan to breastfeed. NUVESSA can pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using NUVESSA. Tell your healthcare provider all about the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. How should I use NUVESSA? See the " Instructions for Use " at the end of this Patient Information leaflet for detailed instructions about how to use NUVESSA. Use NUVESSA exactly as your healthcare provider tells you to. NUVESSA is used one time at bedtime. If you get NUVESSA in your eyes, rinse your eyes with cool tap water and call your healthcare provider. What should I avoid while using NUVESSA? Do not have vaginal intercourse or use other vaginal products (such as tampons or douches). What are the possible side effects of NUVESSA? The most common side effects of NUVESSA include: yeast infections, headache, vaginal itching, nausea, diarrhea, and pain with menstrual cycle and vaginal pain or discomfort. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of NUVESSA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about NUVESSA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NUVESSA for a condition for which it was not prescribed. Do not give NUVESSA 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 NUVESSA that is written for health professionals. What are the ingredients in NUVESSA? Active ingredient: metronidazole Inactive ingredients: polyethylene glycol 400, propylene glycol, benzyl alcohol, methylparaben, propylparaben, purified water, and polycarbophil

<table width="100%"><colgroup><col align="left" valign="middle" width="100%"/></colgroup><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule"><content styleCode="bold">PATIENT INFORMATION NUVESSA ^&#xAE; (nue-ve-sa) </content> (metronidazole vaginal gel 1.3%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">For intravaginal use only. Do not use in the eyes, mouth or skin.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">What is NUVESSA?</content> NUVESSA is a prescription medicine used to treat bacterial vaginal infections in females 12 years and older. It is not known if Nuvessa is safe and effective in female children younger than 12 years of age. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Do not use NUVESSA if you: </content><list listType="unordered" styleCode="Disc"><item>are allergic to metronidazole, parabens, nitroimidazole derivatives, or any of the ingredients in NUVESSA. See the end of this leaflet for a complete list of ingredients in NUVESSA.</item><item>take or have taken a medicine called Antabuse (disulfiram) in the last 2 weeks.</item><item>drink alcohol. Do not drink alcohol while you use NUVESSA and for at least 24 hours after you stop using it. It can increase your chances of getting serious side effects.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Before you use NUVESSA, tell your healthcare provider about all your medical conditions, including if you:</content><list listType="unordered" styleCode="Disc"><item>have or had central nervous system diseases.</item><item>are pregnant or plan to become pregnant. It is not known if NUVESSA will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with NUVESSA.</item><item>are breastfeeding or plan to breastfeed. NUVESSA can pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using NUVESSA.</item></list><content styleCode="bold">Tell your healthcare provider all about the medicines you take,</content> including prescription and over-the-counter medicines, vitamins and herbal supplements. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">How should I use NUVESSA?</content><list listType="unordered" styleCode="Disc"><item>See the &quot; <linkHtml href="#IFU">Instructions for Use</linkHtml>&quot; at the end of this Patient Information leaflet for detailed instructions about how to use NUVESSA. </item><item>Use NUVESSA exactly as your healthcare provider tells you to.</item><item>NUVESSA is used one time at bedtime.</item><item>If you get NUVESSA in your eyes, rinse your eyes with cool tap water and call your healthcare provider.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">What should I avoid while using NUVESSA?</content> <content styleCode="bold">Do not</content> have vaginal intercourse or use other vaginal products (such as tampons or douches). </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">What are the possible side effects of NUVESSA?</content> <content styleCode="bold">The most common side effects of NUVESSA</content> include: yeast infections, headache, vaginal itching, nausea, diarrhea, and pain with menstrual cycle and vaginal pain or discomfort.

<td styleCode="Lrule Rrule"><content styleCode="bold">What are the possible side effects of NUVESSA?</content> <content styleCode="bold">The most common side effects of NUVESSA</content> include: yeast infections, headache, vaginal itching, nausea, diarrhea, and pain with menstrual cycle and vaginal pain or discomfort. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of NUVESSA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General information about NUVESSA</content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NUVESSA for a condition for which it was not prescribed. Do not give NUVESSA 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 NUVESSA that is written for health professionals. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">What are the ingredients in NUVESSA?</content> <content styleCode="bold">Active ingredient:</content> metronidazole <content styleCode="bold">Inactive ingredients:</content> polyethylene glycol 400, propylene glycol, benzyl alcohol, methylparaben, propylparaben, purified water, and polycarbophil </td></tr></tbody></table>

INSTRUCTIONS FOR USE NUVESSA ® (metronidazole vaginal gel 1.3%) For vaginal use only. You will need the following supplies (See Figure A ) Figure A Step 1: Remove the pre-filled applicator and plunger from the foil package (See Figure B ) Tear open the foil packet just before using. Remove the pre-filled applicator and plunger from the foil packaging. Figure B Step 2: Insert the plunger into the open end of the pre-filled applicator (See Figure C ) With the pink cap still on, push the tip of the plunger into the open end of the pre-filled applicator. Figure C Step 3: Remove the pink cap (See Figure D ) Pull the pink cap straight off the top of the pre-filled applicator. Figure D Step 4: Prepare to insert the pre-filled applicator (See Figure E ) The pre-filled applicator may be inserted while lying on your back with your knees bent or in any comfortable position. Figure E Step 5: Insert the pre-filled applicator (See Figure F ) Hold the pre-filled applicator by the barrel and gently insert the rounded tip into your vagina as far as it will comfortably go, then pull back slightly. Figure F Step 6: Push the plunger (See Figure G ) While holding the barrel in place, slowly press the plunger until it stops to release the gel into your vagina. Figure G Step 7: Remove the pre-filled applicator from your vagina and throw it away in your household trash. How should I store NUVESSA? Store NUVESSA at room temperature between 68°F to 77°F (20°-25°C). Do not freeze. Do not refrigerate. Keep NUVESSA and all medicines out of the reach of children. This Patient Information and Instructions for Use have been approved by the US Food and Drug Administration. Rx only Distributed By: Exeltis USA, Inc.. 180 Park Ave., Florham Park, NJ 07932 © 2022 Exeltis USA, Inc. All rights reserved. NUVESSA ® and its design are trademarks of Exeltis Healthcare S.L. Revised: 04/2022 Figure A Figure B Figure C Figure D Figure E Figure F Figure G

<table width="100%" ID="FigureA" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM2"/></td></tr><tr><td>Figure A</td></tr></tbody></table> <table width="100%" ID="FigureB" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM3"/></td></tr><tr><td>Figure B</td></tr></tbody></table> <table width="100%" ID="FigureC" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM4"/></td></tr><tr><td>Figure C</td></tr></tbody></table> <table width="100%" ID="FigureD" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM5"/></td></tr><tr><td>Figure D</td></tr></tbody></table> <table width="100%" ID="FigureE" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM6"/></td></tr><tr><td>Figure E</td></tr></tbody></table> <table width="100%" ID="FigureF" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM7"/></td></tr><tr><td>Figure F</td></tr></tbody></table> <table width="100%" ID="FigureG" styleCode="Noautorules"><colgroup><col align="center" valign="top" width="100%"/></colgroup><tbody><tr><td><renderMultiMedia referencedObject="MM8"/></td></tr><tr><td>Figure G</td></tr></tbody></table>

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLAGYL ® and other antibacterial drugs, FLAGYL ® should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . LAB-0163-20.0 Revised: 07/2025 Logo

WARNING Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS ). Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGE section below.

DESCRIPTION FLAGYL (metronidazole) capsules, 375 mg is an oral formulation of the synthetic nitroimidazole antimicrobial agent, 2-methyl-5-nitro-1 H -imidazole-1-ethanol, which has the following structural formula: FLAGYL (metronidazole) capsules, 375 mg, (indicated below as FLAGYL 375 capsules) contain 375 mg of metronidazole USP. Inactive ingredients include corn starch, magnesium stearate, gelatin, black iron oxide, titanium dioxide, FD&C Green No. 3, and D&C Yellow No. 10. Chemical Structure

CLINICAL PHARMACOLOGY Absorption Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. FLAGYL 375 capsules have been shown to have a rate and extent of absorption similar to metronidazole tablets (FLAGYL) and were bioequivalent at an equal single dose of 750 mg. In a study conducted with 23 adult, healthy, female volunteers, oral administration of two 375 mg FLAGYL capsules under fasted conditions produced a mean (±1 SD) peak plasma concentration (C max ) of 21.4 (±2.8) mcg/mL with a mean T max of 1.6 (± 0.7) hours and a mean area under the plasma concentration-time curve (AUC) of 223 (±44) mcg∙hr/mL. In the same study, three 250 mg FLAGYL tablets produced a mean C max of 20.4 (± 3.8) mcg/mL with a mean T max of 1.4 (± 0.4) hours and a mean AUC of 218 (± 50) mcg∙hr/mL. Administration of FLAGYL 375 capsules with food does not affect the extent of absorption of metronidazole; however, the presence of food results in a lower C max and a delayed T max compared to fasted conditions. In a study of 14 healthy, adult, female volunteers, administration of FLAGYL 375 capsules under fasting conditions produced a mean C max of 10.9 (± 1.5) mcg/mL, a mean T max of 1.5 (± 1.4) hours, and a mean AUC of 110 (± 34) mcg∙hr/mL compared to a mean C max of 8.6 (± 1.6) mcg/mL, a mean T max of 4.2 (± 1.7) hours, and a mean AUC of 99 (± 14) mcg∙hr/mL under fed conditions. Distribution Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. Metabolism/Excretion The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity against most strains of anaerobic bacteria and in vitro trichomonacidal activity. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m 2 . The average elimination half-life of metronidazole in healthy subjects is eight hours. Renal Impairment Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CL CR =8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CL CR =126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS ).

idazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CL CR =126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS ). Effect of Dialysis Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION ). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD. Hepatic Impairment Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC 24 of hydroxy-metronidazole in these hepatically impaired patients. Pharmacokinetic modeling and simulation indicates the metronidazole dosage in amebiasis should be reduced by 50% and the dosage interval for trichomoniasis should be increased from every 12 hours to every 24 hours in patients with severe (Child-Pugh C) hepatic impairment. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with hepatic impairment should be monitored for metronidazole associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Geriatric Patients Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS ). Pediatric Patients In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours. Microbiology Mechanism of Action Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria.

e of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear. Resistance A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair. Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Antimicrobial activity Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive anaerobes: Clostridium species Eubacterium species Peptococcus species Peptostreptococcus species Gram-negative anaerobes: Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus) Fusobacterium species Protozoal parasites: Entamoeba histolytica Trichomonas vaginalis The following in vitro data are available, but their clinical significance is unknown. Metronidazole exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most (≥90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-negative anaerobes Bacteroides fragilis group ( B. caccae, B. uniformis ) Prevotella species ( P. bivia, P. buccae, P. disiens ) Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

Microbiology Mechanism of Action Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear. Resistance A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair. Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Antimicrobial activity Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive anaerobes: Clostridium species Eubacterium species Peptococcus species Peptostreptococcus species Gram-negative anaerobes: Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus) Fusobacterium species Protozoal parasites: Entamoeba histolytica Trichomonas vaginalis The following in vitro data are available, but their clinical significance is unknown. Metronidazole exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most (≥90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-negative anaerobes Bacteroides fragilis group ( B. caccae, B. uniformis ) Prevotella species ( P. bivia, P. buccae, P. disiens ) Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

INDICATIONS AND USAGE Symptomatic Trichomoniasis . FLAGYL 375 capsules are indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis . FLAGYL 375 capsules are indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Sexual Partners . T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her sexual partner is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the sexual partner should be treated with metronidazole in cases of reinfection. Amebiasis . FLAGYL 375 capsules are indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, FLAGYL 375 capsules therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections . FLAGYL 375 capsules are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with FLAGYL therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to FLAGYL 375 capsules. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus ), Clostridium species, Eubacterium species, Peptococcus species, or Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, or Fusobacterium species. GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species , Peptostreptococcus species, or Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group or Clostridium species. BONE AND JOINT INFECTIONS (as adjunctive therapy) caused by Bacteroides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B.

ides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLAGYL 375 capsules and other antibacterial drugs, FLAGYL 375 capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS Hypersensitivity FLAGYL 375 capsules are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. In patients with trichomoniasis, FLAGYL 375 capsules are contraindicated during the first trimester of pregnancy (see PRECAUTIONS ). Psychotic Reaction with Disulfiram Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS, Drug Interactions ). Interaction with Alcohol Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS, Drug Interactions ). Cockayne Syndrome FLAGYL 375 capsules are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (see ADVERSE REACTIONS ) .

WARNINGS Hypersensitivity Reactions Hypersensitivity reactions including severe cutaneous adverse reactions (SCARs) can be serious and potentially life threatening (see ADVERSE REACTIONS ). Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue FLAGYL capsules immediately and institute appropriate therapy. Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS ).

PRECAUTIONS General Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. The FLAGYL 375 capsules dosage or the frequency of administration should be reduced in patients with severe (Child-Pugh C) hepatic impairment. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed. Patients with hepatic impairment should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Renal Impairment Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY ). Fungal Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with FLAGYL 375 capsules and requires treatment with a candidacidal agent. Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leucopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy. Drug-Resistant Bacteria and Parasites Prescribing FLAGYL 375 capsules in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites. Information for patients Interaction with Alcohol Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking FLAGYL 375 capsules and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions ). Treatment of Bacterial and Parasitic Infections Patients should be counseled that FLAGYL 375 should only be used to treat bacterial and parasitic infections. They do not treat viral infections (e.g., the common cold). When FLAGYL 375 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FLAGYL 375 in the future. Severe Cutaneous Adverse Reactions Advise patients that FLAGYL capsules may increase the risk of serious and sometimes fatal dermatologic reactions, including TEN, SJS, and DRESS. Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop FLAGYL capsules immediately if they develop any type of rash and seek medical attention. Drug interactions Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS ).

evelop any type of rash and seek medical attention. Drug interactions Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS ). Alcoholic Beverages Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS ). Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL 375 capsules is prescribed for patients on this type of anticoagulant therapy prothrombin time and INR should be carefully monitored. Lithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication. Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. Drugs that Inhibit CYP450 Enzymes The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Drugs that Induce CYP450 Enzymes The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported. Drugs that Prolong the QT interval QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD + ⇆ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7. Carcinogenesis, Mutagenesis, Impairment of Fertility Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters. Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m 2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice.

tion during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m 2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage. Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (similar to the maximum recommended clinical dose based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period. Pregnancy: Teratogenic effects: There are no adequate and well-controlled studies of FLAGYL 375 capsules in pregnant women. There are published data from case-control studies, cohort studies, and 2‑meta‑analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero ; however, these finding were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital abnormalities or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole. Nursing mothers Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. There are no data on the effects of metronidazole on milk production. Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility ). This drug is not intended to be administered chronically; therefore, the clinical relevance of the findings of the animal studies is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLAGYL and any potential adverse effects on the breastfed infant from FLAGYL or from the underlying maternal condition. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of FLAGYL therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula.

for FLAGYL and any potential adverse effects on the breastfed infant from FLAGYL or from the underlying maternal condition. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of FLAGYL therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula. Geriatric use In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION ). Pediatric use Safety and effectiveness in pediatric patients have not been established, except in the treatment of amebiasis.

General Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. The FLAGYL 375 capsules dosage or the frequency of administration should be reduced in patients with severe (Child-Pugh C) hepatic impairment. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed. Patients with hepatic impairment should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Renal Impairment Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY ). Fungal Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with FLAGYL 375 capsules and requires treatment with a candidacidal agent. Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leucopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy. Drug-Resistant Bacteria and Parasites Prescribing FLAGYL 375 capsules in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

Information for patients Interaction with Alcohol Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking FLAGYL 375 capsules and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions ). Treatment of Bacterial and Parasitic Infections Patients should be counseled that FLAGYL 375 should only be used to treat bacterial and parasitic infections. They do not treat viral infections (e.g., the common cold). When FLAGYL 375 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FLAGYL 375 in the future. Severe Cutaneous Adverse Reactions Advise patients that FLAGYL capsules may increase the risk of serious and sometimes fatal dermatologic reactions, including TEN, SJS, and DRESS. Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop FLAGYL capsules immediately if they develop any type of rash and seek medical attention.

Drug interactions Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS ). Alcoholic Beverages Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS ). Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL 375 capsules is prescribed for patients on this type of anticoagulant therapy prothrombin time and INR should be carefully monitored. Lithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication. Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. Drugs that Inhibit CYP450 Enzymes The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Drugs that Induce CYP450 Enzymes The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported. Drugs that Prolong the QT interval QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD + ⇆ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters. Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m 2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage. Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (similar to the maximum recommended clinical dose based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Pregnancy: Teratogenic effects: There are no adequate and well-controlled studies of FLAGYL 375 capsules in pregnant women. There are published data from case-control studies, cohort studies, and 2‑meta‑analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero ; however, these finding were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital abnormalities or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Teratogenic effects: There are no adequate and well-controlled studies of FLAGYL 375 capsules in pregnant women. There are published data from case-control studies, cohort studies, and 2‑meta‑analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero ; however, these finding were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital abnormalities or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Nursing mothers Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. There are no data on the effects of metronidazole on milk production. Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility ). This drug is not intended to be administered chronically; therefore, the clinical relevance of the findings of the animal studies is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLAGYL and any potential adverse effects on the breastfed infant from FLAGYL or from the underlying maternal condition. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of FLAGYL therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula.

Geriatric use In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS The following reactions have been reported during treatment with metronidazole: Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS ). Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; abdominal cramping; and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic: Dermatitis bullous, fixed drug eruption, erythematous rash and pruritus. Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. Hypersensitivity: Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS ), urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) (see CONTRAINDICATIONS ). Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling "serum sickness." Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved indication for FLAGYL 375 capsules.

OVERDOSAGE Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day. Treatment of Overdosage: There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

DOSAGE AND ADMINISTRATION Trichomoniasis In the Female: Seven-day course of treatment (375 mg two times daily for seven consecutive days). A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain treatment. Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS and PRECAUTIONS ). When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment. In the Male: Treatment should be individualized as it is for the female. Amebiasis: Adults: For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. For amebic liver abscess: 750 mg orally three times daily for 5 to 10 days. Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days. Anaerobic Bacterial Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every 6 hours (approximately 500 mg for a 70 kg adult). A maximum of 4 g should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Dosage Adjustments Patients with Severe Hepatic impairment For amebiasis patients with severe (Child-Pugh C) hepatic impairment, pharmacokinetic modeling and simulation indicate that the FLAGYL 375 capsules dose should be reduced by 50%. Therefore, the dosage regimen of FLAGYL 375 capsules in Child Pugh C patients with amebiasis is 375 mg q8h for 5 to 10 days (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). For trichomoniasis patients with severe (Child-Pugh C) hepatic impairment, pharmacokinetic modeling and simulation indicate that the frequency of metronidazole administration should be reduced from every 12 hours to every 24 hours. Therefore, the dosage regiment of FLAGYL 375 capsules in Child Pugh C patients with trichomoniasis is 375 mg q24h for 7 days (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient's clinical situation (see CLINICAL PHARMACOLOGY ).

HOW SUPPLIED FLAGYL 375 capsules have an iron gray opaque body imprinted with 375 mg and a light green opaque cap imprinted with FLAGYL, supplied as: NDC Number Size 0025-1942-34 Carton of 100 unit dose Storage and Stability: Store at controlled room temperature 15–25°C (59–77°F). Dispense in a well-closed container with a child-resistant closure.

DESCRIPTION: METROCREAM ® Topical Cream contains metronidazole, USP, at a concentration of 7.5 mg per gram (0.75%) in an emollient cream consisting of benzyl alcohol, emulsifying wax, glycerin, isopropyl palmitate, purified water, sorbitol solution, lactic acid and/or sodium hydroxide to adjust pH. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and anti-bacterial agent. Chemically, metronidazole is 2-methyl-5-nitro-1 H- imidazole-1-ethanol. The molecular formula is C 6 H 9 N 3 O 3 and molecular weight is 171.16. Metronidazole is represented by the following structural formula:

CONTRAINDICATIONS: METROCREAM ® (metronidazole topical cream) Topical Cream is contraindicated in individuals with a history of hypersensitivity to metronidazole, or other ingredients of the formulation.

PRECAUTIONS: General: Topical metronidazole has been reported to cause tearing of the eyes. Therefore, contact with the eyes should be avoided. If a reaction suggesting local irritation occurs, patients should be directed to use the medication less frequently or discontinue use. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of blood dyscrasia. Information for patients: This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. Drug interactions: Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and coumarin anticoagulants, resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin time is not known. Carcinogenesis, mutagenesis, impairment of fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but not in studies involving hamsters. Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-response increase in the frequency of micronuclei was observed in mice after intraperitoneal injections and an increase in chromosome aberrations have been reported in patients with Crohn’s disease who were treated with 200-1200 mg/day of metronidazole for 1 to 24 months. However, no excess chromosomal aberrations in circulating human lymphocytes have been observed in patients treated for 8 months. Pregnancy: Teratogenic effects: Pregnancy category B: There are no adequate and well-controlled studies with the use of METROCREAM ® (metronidazole topical cream) Topical Cream in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral metronidazole in rats or mice. However, because animal reproduction studies are not always predictive of human response and since oral metronidazole has been shown to be a carcinogen in some rodents, this drug should be used during pregnancy only if clearly needed. Nursing mothers: After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels are significantly lower with topically applied metronidazole than those achieved after oral administration of metronidazole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use: Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS: In controlled clinical trials, the total incidence of adverse reactions associated with the use of METROCREAM ® Topical Cream was approximately 10%. Skin discomfort (burning and stinging) was the most frequently reported event followed by erythema, skin irritation, pruritus and worsening of rosacea. All individual events occurred in less than 3% of patients. The following additional adverse experiences have been reported with the topical use of metronidazole: dryness, transient redness, metallic taste, tingling or numbness of extremities and nausea.

DOSAGE AND ADMINISTRATION: Apply and rub in a thin layer of METROCREAM ® (metronidazole topical cream) Topical Cream twice daily, morning and evening, to entire affected areas after washing. Areas to be treated should be washed with a mild cleanser before application. Patients may use cosmetics after application of METROCREAM ® (metronidazole topical cream) Topical Cream.

HOW SUPPLIED: METROCREAM ® (metronidazole topical cream) Topical Cream, 0.75% is supplied in a 45 g aluminum tube - NDC 0299-3836-45. Storage conditions : STORE AT CONTROLLED ROOM TEMPERATURE, 68° to 77°F (20° to 25°C), EXCURSIONS PERMITTED BETWEEN 59° AND 86°F (15° - 30°C). Marketed by: GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA Made in Canada All trademarks are the property of their respective owners. P53314-0 Revised: January 2017

FOR TOPICAL USE ONLY NOT FOR OPHTHALMIC USE Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada Noritate is a trademark of Bausch Health Companies Inc. or its affiliates. © 2020 Bausch Health Companies Inc. or its affiliates 9468004 Rev. 06/2020

DESCRIPTION Noritate ® (metronidazole cream) Cream, 1%, contains metronidazole USP. Chemically, metronidazole is 2-methyl-5-nitro-1 H -imidazole-1-ethanol. The molecular formula for metronidazole is C 6 H 9 N 3 O 3 . It has the following structural formula: Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has a solubility in water of 10 mg/mL at 20°C. Metronidazole is a member of the imidazole class of antibacterial agents and is classified as an antiprotozoal and antibacterial agent. Noritate is an emollient cream; each gram contains 10 mg micronized metronidazole USP, in a base of glycerin USP, glyceryl monostearate NF, methylparaben NF, propylparaben NF, purified water USP, stearic acid NF and trolamine NF. Noritate Chemical Structure

CLINICAL PHARMACOLOGY Pharmacokinetics: When a one gram dose of Noritate Cream, 1%, was applied in a single application to the face of 16 healthy volunteers, low concentrations of metronidazole were detected in the plasma of 7 of the volunteers. The mean±SD C max of metronidazole was 27.6±7.3 ng/mL, which is about 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (T max ) in the volunteers with detectable metronidazole was 8-12 hours after topical application. Pharmacodynamics: The mechanisms by which metronidazole acts in reducing inflammatory lesions of rosacea are unknown. Clinical Studies: Safety and efficacy of Noritate were evaluated in two randomized vehicle-controlled clinical studies for the treatment of rosacea, which excluded patients who had nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema or ocular involvement and those who had a history of not responding to metronidazole therapy for rosacea. Of the patients included in the efficacy database (n=416), there were 142 men and 274 women. Endpoint efficacy data comparisons for patients treated with daily Noritate or vehicle applications are listed below. Inflammatory Lesion Counts and Erythema Severity Scores in Two Clinical Trials for Rosacea Noritate Vehicle Study 1 Study 2 Study 1 Study 2 N Result N Result N Result N Result Papules + Pustules Count Baseline 89 15 92 19 50 18 49 17 Week 10 80 7* 82 8 45 15 41 12 Reduction 49%* 58%* 17% 30% Papules Count Baseline 89 13 92 17 50 15 49 15 Week 10 80 7* 82 7 45 12 41 11 Reduction 41%* 55%* 14% 28% Erythema Score Baseline 89 2.2 92 2.3 50 2.2 49 2.2 Week 10 80 1.3* 82 1.4* 45 1.7 40 1.8 Reduction 42%* 40%* 25% 19% *Statistically significant differences between Noritate and vehicle groups with p≤0.05. Erythema scores: 0=none, 1=mild, 2=moderate and 3=severe. Safety Studies: Studies of contact sensitization (n=258), phototoxicity (n=21), and photocontact sensitization (n=29) of Noritate were conducted. No evidence of sensitization or phototoxicity was seen in these studies.

Clinical Studies: Safety and efficacy of Noritate were evaluated in two randomized vehicle-controlled clinical studies for the treatment of rosacea, which excluded patients who had nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema or ocular involvement and those who had a history of not responding to metronidazole therapy for rosacea. Of the patients included in the efficacy database (n=416), there were 142 men and 274 women. Endpoint efficacy data comparisons for patients treated with daily Noritate or vehicle applications are listed below. Inflammatory Lesion Counts and Erythema Severity Scores in Two Clinical Trials for Rosacea Noritate Vehicle Study 1 Study 2 Study 1 Study 2 N Result N Result N Result N Result Papules + Pustules Count Baseline 89 15 92 19 50 18 49 17 Week 10 80 7* 82 8 45 15 41 12 Reduction 49%* 58%* 17% 30% Papules Count Baseline 89 13 92 17 50 15 49 15 Week 10 80 7* 82 7 45 12 41 11 Reduction 41%* 55%* 14% 28% Erythema Score Baseline 89 2.2 92 2.3 50 2.2 49 2.2 Week 10 80 1.3* 82 1.4* 45 1.7 40 1.8 Reduction 42%* 40%* 25% 19% *Statistically significant differences between Noritate and vehicle groups with p≤0.05. Erythema scores: 0=none, 1=mild, 2=moderate and 3=severe. Safety Studies: Studies of contact sensitization (n=258), phototoxicity (n=21), and photocontact sensitization (n=29) of Noritate were conducted. No evidence of sensitization or phototoxicity was seen in these studies.

<table ID="_RefID0EYCAC" width="100%"><caption>Inflammatory Lesion Counts and Erythema Severity Scores in Two Clinical Trials for Rosacea</caption><col width="20%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><col width="10%"/><thead><tr><th align="left" styleCode="Lrule Toprule " valign="top"/><th align="center" colspan="4" styleCode="Toprule " valign="top"><content styleCode="bold">Noritate</content></th><th align="center" colspan="4" styleCode="Rrule Toprule " valign="top"><content styleCode="bold">Vehicle</content></th></tr><tr><th align="left" styleCode="Lrule " valign="top"/><th align="left" colspan="2" valign="top"><content styleCode="bold">Study 1</content></th><th align="left" colspan="2" valign="top"><content styleCode="bold">Study 2</content></th><th align="left" colspan="2" valign="top"><content styleCode="bold">Study 1</content></th><th align="left" colspan="2" styleCode="Rrule " valign="top"><content styleCode="bold">Study 2</content></th></tr><tr><th align="left" styleCode="Lrule Botrule " valign="top"/><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">N</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">Result</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">N</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">Result</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">N</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">Result</content></th><th align="left" styleCode="Botrule " valign="top"><content styleCode="bold">N</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Result</content></th></tr></thead><tbody><tr><td colspan="9" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Papules + Pustules Count</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Baseline</paragraph></td><td valign="top"><paragraph>89</paragraph></td><td valign="top"><paragraph>15</paragraph></td><td valign="top"><paragraph>92</paragraph></td><td valign="top"><paragraph>19</paragraph></td><td valign="top"><paragraph>50</paragraph></td><td valign="top"><paragraph>18</paragraph></td><td valign="top"><paragraph>49</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>17</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Week 10</paragraph></td><td valign="top"><paragraph>80</paragraph></td><td valign="top"><paragraph>7*</paragraph></td><td valign="top"><paragraph>82</paragraph></td><td valign="top"><paragraph>8</paragraph></td><td valign="top"><paragraph>45</paragraph></td><td valign="top"><paragraph>15</paragraph></td><td valign="top"><paragraph>41</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph> Reduction</paragraph></td><td valign="top"/><td valign="top"><paragraph>49%*</paragraph></td><td valign="top"/><td valign="top"><paragraph>58%*</paragraph></td><td valign="top"/><td valign="top"><paragraph>17%</paragraph></td><td valign="top"/><td styleCode="Rrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td colspan="9" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Papules Count</content

d valign="top"><paragraph>58%*</paragraph></td><td valign="top"/><td valign="top"><paragraph>17%</paragraph></td><td valign="top"/><td styleCode="Rrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td colspan="9" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Papules Count</content ></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Baseline</paragraph></td><td valign="top"><paragraph>89</paragraph></td><td valign="top"><paragraph>13</paragraph></td><td valign="top"><paragraph>92</paragraph></td><td valign="top"><paragraph>17</paragraph></td><td valign="top"><paragraph>50</paragraph></td><td valign="top"><paragraph>15</paragraph></td><td valign="top"><paragraph>49</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Week 10</paragraph></td><td valign="top"><paragraph>80</paragraph></td><td valign="top"><paragraph>7*</paragraph></td><td valign="top"><paragraph>82</paragraph></td><td valign="top"><paragraph>7</paragraph></td><td valign="top"><paragraph>45</paragraph></td><td valign="top"><paragraph>12</paragraph></td><td valign="top"><paragraph>41</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph> Reduction</paragraph></td><td valign="top"/><td valign="top"><paragraph>41%*</paragraph></td><td valign="top"/><td valign="top"><paragraph>55%*</paragraph></td><td valign="top"/><td valign="top"><paragraph>14%</paragraph></td><td valign="top"/><td styleCode="Rrule " valign="top"><paragraph>28%</paragraph></td></tr><tr><td colspan="9" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Erythema Score</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Baseline</paragraph></td><td valign="top"><paragraph>89</paragraph></td><td valign="top"><paragraph>2.2</paragraph></td><td valign="top"><paragraph>92</paragraph></td><td valign="top"><paragraph>2.3</paragraph></td><td valign="top"><paragraph>50</paragraph></td><td valign="top"><paragraph>2.2</paragraph></td><td valign="top"><paragraph>49</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>2.2</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Week 10</paragraph></td><td valign="top"><paragraph>80</paragraph></td><td valign="top"><paragraph>1.3*</paragraph></td><td valign="top"><paragraph>82</paragraph></td><td valign="top"><paragraph>1.4*</paragraph></td><td valign="top"><paragraph>45</paragraph></td><td valign="top"><paragraph>1.7</paragraph></td><td valign="top"><paragraph>40</paragraph></td><td styleCode="Rrule " valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph> Reduction</paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"><paragraph>42%*</paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"><paragraph>40%*</paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"><paragraph>25%</paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr></tbody></table>

PRECAUTIONS General: If a reaction suggesting local skin irritation occurs, patients should be directed to discontinue use of the medication. Conjunctivitis associated with topical use of metronidazole on the face has been reported. Contact with the eyes should be avoided. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia. Information for Patients: Patients using Noritate should receive the following information and instructions: 1. This medication is to be used as directed. 2. It is for external use only. 3. Avoid contact with the eyes. 4. Cleanse affected area(s) before applying Noritate . 5. This medication should not be used for any disorder other than that for which it is prescribed. 6. Patients should report any adverse reaction to their physician. Drug Interactions: Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when Noritate is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. (See CLINICAL PHARMACOLOGY , Pharmacokinetics .) Carcinogenesis, Mutagenesis, Impairment of Fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but not in studies involving hamsters. In several long-term studies in mice, oral doses of approximately 225 mg/m 2 /day or greater (approximately 37 times the human topical dose on a mg/m 2 basis) were associated with an increase in pulmonary tumors and lymphomas. Several long-term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m 2 /day (144 times the topical human dose). Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn’s disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn’s disease treated with the drug for 8 months. In one published study, using albino hairless mice, intraperitoneal administration of metronidazole at a dose of 45 mg/m 2 /day (approximately 7 times the human topical dose on a mg/m 2 basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with Noritate or any marketed metronidazole formulations. Pregnancy: Teratogenic Effects: There are no adequate and well-controlled studies with the use of Noritate in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents.

nant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, Noritate should be used during pregnancy only if clearly needed. Nursing Mothers: After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the risk to the infant. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

General: If a reaction suggesting local skin irritation occurs, patients should be directed to discontinue use of the medication. Conjunctivitis associated with topical use of metronidazole on the face has been reported. Contact with the eyes should be avoided. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia.

Information for Patients: Patients using Noritate should receive the following information and instructions: 1. This medication is to be used as directed. 2. It is for external use only. 3. Avoid contact with the eyes. 4. Cleanse affected area(s) before applying Noritate . 5. This medication should not be used for any disorder other than that for which it is prescribed. 6. Patients should report any adverse reaction to their physician.

Drug Interactions: Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when Noritate is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. (See CLINICAL PHARMACOLOGY , Pharmacokinetics .)

Carcinogenesis, Mutagenesis, Impairment of Fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but not in studies involving hamsters. In several long-term studies in mice, oral doses of approximately 225 mg/m 2 /day or greater (approximately 37 times the human topical dose on a mg/m 2 basis) were associated with an increase in pulmonary tumors and lymphomas. Several long-term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m 2 /day (144 times the topical human dose). Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn’s disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn’s disease treated with the drug for 8 months. In one published study, using albino hairless mice, intraperitoneal administration of metronidazole at a dose of 45 mg/m 2 /day (approximately 7 times the human topical dose on a mg/m 2 basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with Noritate or any marketed metronidazole formulations.

Pregnancy: Teratogenic Effects: There are no adequate and well-controlled studies with the use of Noritate in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, Noritate should be used during pregnancy only if clearly needed.

Teratogenic Effects: There are no adequate and well-controlled studies with the use of Noritate in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, Noritate should be used during pregnancy only if clearly needed.

Nursing Mothers: After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the risk to the infant.

ADVERSE REACTIONS Safety data from 302 patients who used Noritate (n=200) or vehicle control (n=102) once daily in clinical trials and experienced an adverse event considered to be treatment related include: application site reaction ( Noritate 1, vehicle 1), condition aggravated ( Noritate 1, vehicle 0), paresthesia ( Noritate 0, vehicle 1), acne ( Noritate 1, vehicle 0), dry skin ( Noritate 0, vehicle 2). The majority of adverse reactions were mild to moderate in severity. Two patients treated with Noritate once daily discontinued treatment because of adverse events: one for a severe flare of comedonal acne and one for rosacea aggravated. Additional clinical adverse effects reported spontaneously since the drug was marketed are uncommon and include tingling or numbness of extremities, allergic reactions, skin and eye irritation, rash, headache, nausea and dry mouth. To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION Areas to be treated should be cleansed before application of Noritate . Apply and rub in a thin film of Noritate once daily to entire affected area(s). Patients may use cosmetics after application of Noritate .