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CLINICAL PHARMACOLOGYPharmacokinetics: When one gram dose of NORITATE (metronidazole) 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 Cmax 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 (Tmax) 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 (metronidazole) 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 (metronidazole) 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 (metronidazole) 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 (metronidazole) were conducted. No evidence of sensitization or phototoxicity was seen in these studies.

CLINICAL PHARMACOLOGY Normal Subjects Following a single, intravaginal 5 gram 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 Cmax = 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 gram 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 gram 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. Clinical Studies In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received METROGEL-VAGINAL 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.

CLINICAL PHARMACOLOGY Mechanism of Action The mechanism of action of metronidazole in the treatment of rosacea is unknown. Pharmacodynamics The pharmacodynamics of metronidazole in association with the treatment of rosacea are unknown. Pharmacokinetics Topical administration of a one gram dose of METROGEL (metronidazole) to the face of 13 patients with moderate to severe rosacea once daily for 7 days resulted in a mean ± SD Cmax of metronidazole of 32 ± 9 ng/mL. The mean ± SD AUC(0-24) was 595 ± 154 ng*hr/mL. The mean Cmax and AUC(0-24) are less than 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) was 6-10 hours after topical application. Clinical Studies In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel, 1% or gel vehicle once daily for 10 weeks. Most subjects had “moderate” rosacea at baseline. Efficacy was determined by recording reduction in inflammatory lesion counts and success rate in the Investigator Global Assessment (percentage of subjects “clear” and “almost clear” of rosacea at the end of the study). The scale is based on the following definitions: Table 3: Investigator Global Assessment Scale Score Grade Definition 0 Clear No signs or symptoms present; at most, mild erythema 1 Almost Clear Very mild erythema present. Very few small papules/pustules 2 Mild Mild erythema. Several small papules/pustules 3 Moderate Moderate erythema. Several small or large papules/pustules, and up to 2 nodules 4 Severe Severe erythema. Numerous small and/or large papules/pustules, up to several nodules The results are shown in the following table: Table 4: Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea Metronidazole Gel, 1% Vehicle N Results N (%) N Results N (%) Inflammatory lesions 557 189 Baseline, mean count 18.3 18.4 Week-10, mean count 8.9 12.8 Reduction 9.4 (50.7) 5.6 (32.6) Investigator Global Assessment 557 189 Subject clear or almost clear 214 (38.42) 52 (27.51) Subject with no change 159 (28.5) 77 (40.7) Subjects treated with metronidazole gel, 1% experienced a mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 lesions. The contribution to efficacy of individual components of the vehicle has not been established.

CLINICAL PHARMACOLOGY Absorption Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between one and two hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower. 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 sidechain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl5nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic 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. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m². The average elimination halflife of metronidazole in healthy subjects is eight hours. Renal Impairment Decreased renal function does not alter the singledose-pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CLCR = 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 hydroxyl-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR = 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 AUC24 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 AUC24 of hydroxylmetronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate 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 hydroxymetronidazole (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 halflife, 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 halflives 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 intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a shortlived 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. Drug 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. Activity In Vitro And In Clinical Infections 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 (MIC's) 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 wellcontrolled clinical trials. Gram-negative Anaerobes Bacteroides fragilis group (B. caccae, B. uniformis) Prevotella species (P. bivia, P. buccae, P. disiens) Susceptibility Tests When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial or communityacquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. For Anaerobes Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference broth and/or agar method1,2. The MIC values should be interpreted according to the criteria provided in the following Table Susceptibility Test Interpretive Criteria for Metronidazole against Anaerobes*† MIC (mcg/mL) Interpretation ≤ 8 Susceptible (S) 16 Intermediate (I) ≥ 32 Resistant (R) *Agar dilution method is recommended for all anaerobes †Broth dilution method is recommended for testing of Bacteroides fragilis group only; for this group, MIC values by agar and broth dilution methods are considered equivalent A report of “Susceptible” (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” (I) implies that an infection due to the isolate may be appropriately treated in the body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. A report of “Resistant” (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard metronidazole powder should provide a value within the MIC ranges noted in the following table: Acceptable Quality Control Ranges for Metronidazole against Anaerobes Quality control strain Minimum Inhibitory Concentration (mcg/mL) Agar Broth Bacteroides fragilis ATCC 25285 0.25-1.0 0.25-2.0 Bacteroides thetaiotaomicron ATCC 29741 0.5-2.0 0.5-4.0 Clostridium difficile ATCC 700057 0.125-0.5 - Eggerthella lenta ATCC 43055 - 0.125-0.5 For protozoal parasites Standardized tests do not exist for use in clinical microbiology laboratories. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. CLSI document M11A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twentyfifth Informational Supplement, CLSI document M100S25. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Find Lowest Prices on NORITATE™ (metronidazole) Cream, 1% FOR TOPICAL USE ONLY (NOT FOR OPHTHALMIC USE) DESCRIPTION NORITATE™ (metronidazole cream) Cream, 1%, contains metronidazole, USP. Chemically, metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. 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 anti-bacterial agents and is classified as an antiprotozoal and anti-bacterial agent. NORITATE (metronidazole) is an emollient cream; each gram contains 10 mg micronized metronidazole USP, in a base of purified water USP, stearic acid NF, glyceryl monostearate NF, glycerin USP, methylparaben NF, trolamine NF and propylparaben NF.

MetroGel-Vaginal® (metronidazole) 0.75% Vaginal Gel FOR INTRAVAGINAL USE ONLY NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE DESCRIPTION METROGEL-VAGINAL 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 C6H9N3O3, a molecular weight of 171.16, and has the following structure: METROGEL-VAGINAL is a gelled, purified water solution, containing metronidazole at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains carbomer 934P, 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.

Find Lowest Prices on METROGEL® (metronidazole) Gel, 1% For topical use only. DESCRIPTION METROGEL contains metronidazole, USP. Chemically, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. 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 solubility in water of 10 mg/mL at 20°C. Metronidazole belongs to the nitroimidazole class of compounds. METROGEL is an aqueous gel; each gram contains 10 mg of metronidazole in a base of betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.

Find Lowest Prices on FLAGYL® (metronidazole) tablets To reduce the development of drugresistant 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. 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) tablets, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula: FLAGYL (metronidazole) tablets contain 250 mg or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, and titanium dioxide.

INDICATIONSNORITATE (metronidazole) is indicated for the topical treatment of inflammatory lesions and erythema of rosacea. DOSAGE AND ADMINISTRATIONAreas to be treated should be cleansed before application of NORITATE (metronidazole) . Apply and rub in a thin film of NORITATE (metronidazole) once daily to entire affected area(s). Patients may use cosmetics after application of NORITATE (metronidazole) . HOW SUPPLIEDCream - 30 gram aluminum tube NDC 0066-9850-30. Keep out of the reach of children. Storage Conditions: Store at controlled room temperature: 20 to 25°C (68 to 77°F). Manufactured by: PanGeo Quebec Pharma Inc. Montreal, Quebec, Canada Marketed by: Dermik Laboratories, Inc. Berwyn, PA 19312 USA Made in Canada

INDICATIONS METROGEL-VAGINAL 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 &ldqou;fishy&rdqou; 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. DOSAGE AND ADMINISTRATION The recommended dose is one applicator full of METROGEL-VAGINAL (approximately 5 grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once a day dosing, METROGEL-VAGINAL should be administered at bedtime. HOW SUPPLIED METROGEL-VAGINAL (metronidazole vaginal gel) 0.75% Vaginal Gel is supplied in a 70 gram tube and packaged with 5 vaginal applicators. The NDC number for the 70 gram tube is 99207-130-70. Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from freezing. Manufactured for: Medicis, The Dermatology Company, Scottsdale, AZ 85256. by: DPT Laboratories, Inc., San Antonio, TX 78215, 129800. Revised: Dec 2011

INDICATIONS METROGEL® (metronidazole) is indicated for the topical treatment of inflammatory lesions of rosacea. DOSAGE AND ADMINISTRATION Apply and rub in a thin film of METROGEL (metronidazole) once daily to affected area(s). A gentle cleanser may be used before the application of METROGEL (metronidazole) . Cosmetics may be applied after the application of METROGEL (metronidazole) . Not for oral, ophthalmic or intravaginal use. HOW SUPPLIED Dosage Forms And Strengths Gel, 1%. Clear, colorless to pale yellow gel. Storage And Handling METROGEL® (metronidazole) is supplied as follows: 60 gram tube – NDC 0299-3820-60 Storage Conditions: Store at controlled room temperature: 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F). Manufactured by: Galderma Production Canada Inc. Baie d'Urfé, QC, H9X 3S4 Canada. Made in Canada. Marketed by: Galderma Laboratories, L.P. Fort Worth, Texas 76177 USA

INDICATIONS Symptomatic Trichomoniasis FLAGYL is 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 is 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 FLAGYL in cases of reinfection. Amebiasis FLAGYL is indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, FLAGYL therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections FLAGYL is 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. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intraabdominal 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, and Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tuboovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and 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. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. To reduce the development of drugresistant 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 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. DOSAGE AND ADMINISTRATION Trichomoniasis In The Female One-day-treatment – two grams of FLAGYL, given either as a single dose or in two divided doses of one gram each, given in the same day. Seven-day course of treatment – 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other. Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS). In pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy). 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 retreatment. 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: 500 mg or 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 six hours (approx. 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 patients with severe hepatic impairment (Child-Pugh C), the dose of FLAGYL should be reduced by 50% (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 the 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 250-mg tablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; supplied as bottles of 50 and 100. NDC Number Size 0025-1831-50 bottle of 50 0025-1831-31 bottle of 100 FLAGYL 500-mg tablets are oblong, blue, film coated, with FLAGYL debossed on one side and 500 on the other side; bottles of 50 and 100. NDC Number Size 0025-1821-50 bottle of 50 0025-1821-31 bottle of 100 Storage And Stability Store below 77°F (25°C) and protect from light. Distributed by: G.D. Searle, Division of Pfizer Inc., NY, NY, 10017. Revised: July 2016

PATIENT INFORMATION DIRECTIONS FOR USE 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) Gently squeeze the tube from the bottom to fill applicator. Plunger will stop when the applicator is full. (See Figure 3) Unscrew applicator and replace cap on tube. Figure 1, 2 and 3 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. Figure 4 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. Figure 5 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 five 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.

PATIENT INFORMATION Interaction With Alcohol Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking FLAGYL 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 should only be used to treat bacterial and parasitic infections. FLAGYL does not treat viral infections (e.g., the common cold). When FLAGYL 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 in the future.

OVERDOSE 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.) CONTRAINDICATIONS METROGEL-VAGINAL is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives.

OVERDOSE There are no reported human experiences with overdosage of METROGEL. Topically applied metronidazole can be absorbed in sufficient amount to produce systemic effects. CONTRAINDICATIONS METROGEL (metronidazole) is contraindicated in patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation.

OVERDOSE 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. CONTRAINDICATIONS Hypersensitivity FLAGYL Tablets is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. In patients with trichomoniasis, FLAGYL Tablets is 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).

SIDE EFFECTSSafety data from 302 patients who used NORITATE (metronidazole) (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 (metronidazole) 1, vehicle 1), condition aggravated (NORITATE (metronidazole) 1, vehicle 0), paresthesia (NORITATE (metronidazole) 0, vehicle 1), acne (NORITATE (metronidazole) 1, vehicle 0), dry skin (NORITATE (metronidazole) 0, vehicle 2). The majority of adverse reactions were mild to moderate in severity. Two patients treated with NORITATE (metronidazole) once daily discontinued treatment because of adverse events: one for a severe flare of comedonal acne and one for rosacea aggravated. 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 (metronidazole) 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 section) Carcinogenesis, Mutagenesis and 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/m2/day or greater (approximately 37 times the human topical dose on a mg/m2 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/m2/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/m2/day (approximately 7 times the human topical dose on a mg/m2 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: Pregnancy Category B. There are no adequate and well controlled studies with the use of NORITATE (metronidazole) 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 (metronidazole) 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.

SIDE EFFECTS 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 METROGEL-VAGINAL. In a randomized, single-blind clinical trial of 505 non-pregnant women who received METROGELVAGINAL 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 METROGEL-VAGINAL 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 METROGEL-VAGINAL 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. METROGEL-VAGINAL 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, &ldqou;furry&rdqou; 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. 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.

SIDE EFFECTS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a controlled clinical trial, 557 patients used metronidazole gel, 1% and 189 patients used the gel vehicle once daily for up to 10 weeks. The following table summarizes selected adverse reactions that occurred at a rate of ≥ 1%: Table 1: Adverse Reactions That Occurred at a Rate of ≥ 1% System Organ Class/Preferred Term Metronidazole Gel, 1% N= 557 Gel Vehicle N= 189 Patients with at least one AE Number (%) of Patients 186 (33.4) 51 (27.0) Infections and infestations 76 (13.6) 28 (14.8) Bronchitis 6 (1.1) 3 (1.6) Influenza 8 (1.4) 1 (0.5) Nasopharyngitis 17 (3.1) 8 (4.2) Sinusitis 8 (1.4) 3 (1.6) Upper respiratory tract infection 14 (2.5) 4 (2.1) Urinary tract infection 6 (1.1) 1 (0.5) Vaginal mycosis 1 (0.2) 2 (1.1) Musculoskeletal and connective tissue disorders 19 (3.4) 5 (2.6) Back pain 3 (0.5) 2 (1.1) Neoplasms 4 (0.7) 2 (1.1) Basal cell carcinoma 1 (0.2) 2 (1.1) Nervous system disorders 18 (3.2) 3 (1.6) Headache 12 (2.2) 1 (0.5) Respiratory, thoracic and mediastinal disorders 22 (3.9) 5 (2.6) Nasal congestion 6 (1.1) 3 (1.6) Skin and subcutaneous tissue disorders 36 (6.5) 12 (6.3) Contact dermatitis 7 (1.3) 1 (0.5) Dry skin 6 (1.1) 3 (1.6) Vascular disorders 8 (1.4) 1 (0.5) Hypertension 6 (1.1) 1 (0.5) Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline Sign/Symptom Metronidazole Gel, 1% N= 544 Gel Vehicle N= 184 Dryness 138 (25.4) 63 (34.2) Mild 93 (17.1) 41 (22.3) Moderate 42 (7.7) 20 (10.9) Severe 3 (0.6) 2 (1.1) Scaling 134 (24.6) 60 (32.6) Mild 88 (16.2) 32 (17.4) Moderate 43 (7.9) 27 (14.7) Severe 3 (0.6) 1 (0.5) Pruritus 86 (15.8) 35 (19.0) Mild 53 (9.7) 21 (11.4) Moderate 27 (5.0) 13 (7.1) Severe 6 (1.1) 1 (0.5) Stinging/burning 56 (10.3) 28 (15.2) Mild 39 (7.2) 18 (9.8) Moderate 7 (1.3) 9 (4.9) Severe 10 (1.8) 1 (0.5) The following additional adverse experiences have been reported with the topical use of metronidazole: skin irritation, transient redness, metallic taste, tingling or numbness of extremities, and nausea. Post Marketing Experience The following adverse reaction has been identified during post approval use of topical metronidazole: peripheral neuropathy. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. 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 METROGEL (metronidazole) is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.

SIDE EFFECTS 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, 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; and 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 Erythematous rash and pruritus. Hematopoietic Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular Flattening of the T-wave may be seen in electrocardiographic tracings. Hypersensitivity Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, 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. 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.  Crohn's disease is not an approved indication for FLAGYL tablets. 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 two 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 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. 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.

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 two weeks. PRECAUTIONS METROGEL-VAGINAL 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 6-10% of patients treated with METROGELVAGINAL 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. METROGEL-VAGINAL 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 METROGEL-VAGINAL 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. 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/m²) and have revealed no evidence of impaired fertility. Pregnancy Teratogenic Effects Pregnancy Category B There has been no experience to date with the use of METROGEL-VAGINAL 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/m²); 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Neurologic Disease Peripheral neuropathy, characterized by numbness or paresthesia of an extremity has been reported in patients treated with systemic metronidazole. Although not evident in clinical trials for topical metronidazole, peripheral neuropathy has been reported with the post approval use. The appearance of abnormal neurologic signs should prompt immediate reevaluation of METROGEL therapy. Metronidazole should be administered with caution to patients with central nervous system diseases. Blood Dyscrasias Metronidazole is a nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia. Contact Dermatitis Irritant and allergic contact dermatitis have been reported. If dermatitis occurs, patients may need to discontinue use. Eye Irritation Topical metronidazole has been reported to cause tearing of the eyes. Avoid contact with the eyes. Nonclinical Toxicology 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/m²/day or greater (approximately 37 times the human topical dose on a mg/m² 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/m²/day (144 times the 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/m²/day (approximately 7 times the human topical dose on a mg/m² basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with METROGEL or any marketed metronidazole formulations. Use In Specific Populations Pregnancy Teratogenic Effects - Pregnancy Category B There are no adequate and well-controlled studies with the use of METROGEL in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole in 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, METROGEL (metronidazole) 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. Geriatric Use Sixty-six subjects aged 65 years and older were treated with metronidazole gel, 1% in the clinical study. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS 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. For patients with severe hepatic impairment (ChildPugh C), a reduced dose of FLAGYL is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients 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 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 leukopenia 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 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 drugresistant bacteria and parasites. Carcinogenesis, Mutagenesis, Impairment Of Fertility Tumors affecting the liver, lungs, 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 weredosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m² (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 at 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 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 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. 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. 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula. Geriatric Use In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY, 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 for the treatment of amebiasis.