MetroLotion

MetroLotion® (metronidazole lotion) Topical Lotion, 0.75% is supplied in the following size:

2 fl. oz. (59 mL) plastic bottle - NDC 0299-3838-02

Storage

Store at controlled room temperature 68° to 77°F (20° - 25°C). Protect from freezing.

Marketed by: GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177, USA. Manufactured by: Galderma Production Canada, Inc. Montreal, QC H9X 3N7 Canada. Revised: August 2003. FDA Rev date: 5/11/2004

MetroLotion® (metronidazole lotion) Topical Lotion is indicated for topical application in the treatment of inflammatory papules and pustules of rosacea.

Apply a thin layer to entire affected areas after washing. Use morning and evening or as directed by physician. Avoid application close to the eyes. Patients may use cosmetics after waiting for the MetroLotion® (metronidazole lotion) Topical Lotion to dry (not less than 5 minutes).

MetroLotion® (metronidazole lotion) Topical Lotion is contraindicated in individuals with a history of hypersensitivity to metronidazole or to other ingredients of the formulation.

WARNINGS

No information provided.

PRECAUTIONS

General: Topical metronidazole formulations have 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 nitroim-idazole and should be used with care in patients with evidence 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. Neither carcinogenicity nor photocarcinogenicity studies have been performed by the topical route with MetroLotion® Topical Lotion or any marketed metronidazole formulations.

In several long-term studies in mice, oral doses of approximately 198 mg/m²/day or greater (approximately 29 to 71 times the human topical dose on a mg/m² basis) were associated with an increase in lung tumors in male mice and lymphomas in female mice.

Several long-term studies by the oral route in rats have shown statistically significant increases in mammary and hepatic tumors in female rats and testicular tumors and pituitary adenomas in male rats at doses (in feed) of 1593 mg/m²/day or greater (approximately 230 to 573 times the human topical dose on a mg/m² basis). In another oral study (by gavage), mammary tumors in female rats were observed with a dose of 177 mg/m²/day (approximately 26 to 64 times the human topical dose on a mg/m² basis).

In a published study, the ultraviolet radiation-induced carcinogenesis was enhanced in albino hairless mice by intraperitoneal administration of 45 mg/m² metronidazole, as shown by a decreased latency period to the development of skin neoplasms. The concentration of metronidazole in the skin following the intraperitoneal administration was not determined. This study did not distinguish whether metronidazole must be present during the exposure to ultraviolet radiation in order to enhance tumor formation or whether metronidazole could promote tumor formation from preexisting ultraviolet radiation-initiated cells. The significance of these results in the topical use of metronidazole for the treatment of rosacea is unclear.

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. An increase in chromosome aberrations in peripheral blood lymphocytes was reported in patients with Crohn's disease who were treated with 200-1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no excess chromosomal aberrations in circulating human lymphocytes were observed in patients treated for 8 months.

In rats, oral metronidazole at doses of 1770 mg/m²/day (approximately 255 to 637 times the human topical dose on a mg/m² basis) induced inhibition of spermatogenesis and severe testicular degeneration. In two strains of mice (ICR and CF1), conflicting results have been reported indicating either no effect or a similar effect to that reported in rats.

Pregnancy

Teratogenic Effects: Pregnancy Category B

There are no adequate and well-controlled studies with the use of MetroLotion® Topical Lotion 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. 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 metronida-zole 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.

SIDE EFFECTS

In a controlled clinical trial, safety data from 141 patients who used MetroLotion® (metronidazole lotion) Topical Lotion (n=71), or the lotion vehicle (n=70), twice daily and experienced a local cutaneous adverse event which may or may not have been related to the treatments include: local allergic reaction, MetroLotion® (metronidazole lotion) Topical Lotion 2 (3%), lotion vehicle 0; contact dermatitis, MetroLotion® (metronidazole lotion) Topical Lotion 2 (3%), lotion vehicle 1 (1%); pruritus, MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 0; skin discomfort (burning and stinging), MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 2 (3%); erythema, MetroLotion® (metronidazole lotion) Topical Lotion 4 (6%), lotion vehicle 0; dry skin, MetroLotion® (metronidazole lotion) Topical Lotion 0, lotion vehicle 1 (1%); and worsening of rosacea, MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 7 (10%). 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.

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.

Teratogenic Effects: Pregnancy Category B

There are no adequate and well-controlled studies with the use of MetroLotion® Topical Lotion 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. 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.

In a controlled clinical trial, safety data from 141 patients who used MetroLotion® (metronidazole lotion) Topical Lotion (n=71), or the lotion vehicle (n=70), twice daily and experienced a local cutaneous adverse event which may or may not have been related to the treatments include: local allergic reaction, MetroLotion® (metronidazole lotion) Topical Lotion 2 (3%), lotion vehicle 0; contact dermatitis, MetroLotion® (metronidazole lotion) Topical Lotion 2 (3%), lotion vehicle 1 (1%); pruritus, MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 0; skin discomfort (burning and stinging), MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 2 (3%); erythema, MetroLotion® (metronidazole lotion) Topical Lotion 4 (6%), lotion vehicle 0; dry skin, MetroLotion® (metronidazole lotion) Topical Lotion 0, lotion vehicle 1 (1%); and worsening of rosacea, MetroLotion® (metronidazole lotion) Topical Lotion 1 (1%), lotion vehicle 7 (10%). 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.

No information provided.

Absorption of metronidazole after topical application of MetroLotion® (metronidazole lotion) Topical Lotion is less complete and more prolonged than after oral administration. Detectable plasma levels were found in all subjects following the administration of a 1 gram dose of MetroLotion® Topical Lotion (containing 7.5 mg of metronidazole) applied every morning and evening for 4 days to the faces of 8 patients. The highest concentration (96 ng/mL) seen following the morning dose on Day 5 was approximately 80 times lower than the peak concentrations produced by a single 250 mg tablet of metronidazole. The mean (±SD) AUC_0-24 after twice daily administration was 962±373 ng.hr/mL.