Prescription Drugs

CLINICAL PHARMACOLOGY Bioavailability studies on the topical administration of 1 gram of Rosadan® (metronidazole) Gel (7.5 mg of metronidazole) to the face of 10 rosacea patients showed a maximum serum concentration of 66 nanograms per milliliter in one patient. This concentration is approximately 100 times less than concentrations afforded by a single 250 mg oral tablet. The serum metronidazole concentrations were below the detectable limits of the assay at the majority of time points in all patients. Three of the patients had no detectable serum concentrations of metronidazole at any time point. The mean dose of gel applied during clinical studies was 600 mg which represents 4.5 mg of metronidazole per application. Therefore, under normal usage levels, the formulation affords minimal serum concentrations of metronidazole. The mechanisms by which Rosadan® (metronidazole) Gel acts in the treatment of rosacea are unknown, but appear to include an anti-inflammatory effect.

CLINICAL PHARMACOLOGY The mechanisms by which metronidazole acts in the treatment of rosacea are unknown, but appear to include an anti-inflammatory effect.

Rosadan® (metronidazole) Gel, USP 0.75% FOR TOPICAL USE ONLY (NOT FOR OPHTHALMIC USE) DESCRIPTION Rosadan® (metronidazole) Gel contains metronidazole, USP, at a concentration of 7.5 mg per gram (0.75%) in a gel consisting of carbomer homopolymer NF, edetate disodium, methylparaben, propylene glycol, propylparaben, purified water, and sodium hydroxide. Metronidazole is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is named 2-methyl-5-nitro-1H-imidazole-1-ethanol and has the following structure:

Rosadan® (metronidazole) Topical Cream, 0.75% DESCRIPTION Rosadan® (metronidazole) Topical Cream contains metronidazole, USP, at a concentration of 7.5 mg per gram (0.75%) in an emollient cream consisting of emulsifying wax, sorbitol solution, glycerin, isopropyl palmitate, benzyl alcohol, lactic acid and/or sodium hydroxide to adjust pH, and purified water. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The molecular formula is C6H9N3O3 and molecular weight is 171.16. Metronidazole is represented by the following structural formula:

INDICATIONS Rosadan® (metronidazole) Gel is indicated for topical application in the treatment of inflammatory papules and pustules of rosacea. DOSAGE AND ADMINISTRATION Apply and rub in a thin film of Rosadan® (metronidazole) Gel twice daily, morning and evening, to entire affected areas after washing. Areas to be treated should be cleansed before application of Rosadan® (metronidazole) Gel. Patients may use cosmetics after application of Rosadan® (metronidazole) Gel. HOW SUPPLIED Rosadan® (metronidazole) Gel is supplied in a 45 g tube – NDC 43538-182-45. Storage Conditions Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Manufactured by: G&W Laboratories, Inc. South Plainfield, NJ 07080. Revised: June 2013

INDICATIONS Rosadan® (metronidazole) Topical Cream is indicated for topical application in the treatment of inflammatory papules and pustules of rosacea. DOSAGE AND ADMINISTRATION Apply and rub in a thin layer of Rosadan® (metronidazole) 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 Rosadan® (metronidazole) Topical Cream. HOW SUPPLIED Rosadan® (metronidazole) Topical Cream, 0.75% is supplied in a 45 g tube - NDC 43538-180-45. Storage Conditions Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from Freezing. Manufactured for: Medimetriks Pharmaceuticals, Inc.,  383 Route 46 West, Fairfield, NJ 07004-2402 USA. Manufactured by: G&W Laboratories, Inc., South Plainfield, NJ 07080. Revised: Dec 2014

PATIENT INFORMATION This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.

OVERDOSE No Information Provided CONTRAINDICATIONS Rosadan® (metronidazole) Gel is contraindicated in individuals with a history of hypersensitivity to metronidazole, parabens, or other ingredients of the formulation.

OVERDOSE No information provided. CONTRAINDICATIONS Rosadan® (metronidazole) Topical Cream is contraindicated in individuals with a history of hypersensitivity to metronidazole, or other ingredients of the formulation.

SIDE EFFECTS The following adverse experiences have been reported with the topical use of metronidazole: burning, skin irritation, dryness, transient redness, metallic taste, tingling or numbness of extremities and nausea. DRUG INTERACTIONS Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin time is not known.

SIDE EFFECTS In controlled clinical trials, the total incidence of adverse reactions associated with the use of topical metronidazole 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. To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc. at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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.

WARNINGS No Information Provided PRECAUTIONS General Metronidazole Gel 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. 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 has been no experience to date with the use of Metronidazole Gel in pregnant patients. 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 Metronidazole Gel blood levels 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

WARNINGS No information provided. 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. Pregnancy Teratogenic Effects Pregnancy Category B There are no adequate and well-controlled studies with the use of Rosadan® (metronidazole) 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.