Action And Clinical Pharmacology: Metronidazole topical preparations are particularly effective against the inflammatory, papulopustular component of rosacea. The mechanisms by which topical metronidazole acts in reducing inflammatory lesions of rosacea are unknown, but may include an anti-bacterial and/or an anti-inflammatory effect.
Pharmacokinetics: Metronidazole is rapidly and nearly totally absorbed after oral administration. The drug is not significantly bound to serum proteins and distributes well to all body compartments with the lowest concentration found in fat. Metronidazole is excreted primarily in the urine as parent drug, oxidative metabolites, and conjugates.
Studies on the topical administration of 1 g of topical gel to the face (7.5 mg of metronidazole) of 10 rosacea patients showed a maximum serum concentration of 66 ng/mL in 1 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 (25 ng/mL) 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.
An in vitro study with 0.75% metronidazole topical cream and gel demonstrates that the penetration of metronidazole into the layers of the skin is comparable.
Indications And Clinical Uses: For topical application in the treatment of inflammatory papules, pustules, and erythema of rosacea. Patients with dry or sensitive skin may prefer using the cream formulation.
Contra-Indications: In individuals with a history of hypersensitivity to metronidazole, or other ingredients of the formulations.
Manufacturers’ Warnings In Clinical States: Avoid contact with the eyes. Topical metronidazole has been reported to cause tearing of the eyes. It should not be used in or close to the eye. If contact does occur, flush with water.
Children: Safety and effectiveness in children have not been established.
Pregnancy: There has been no experience to date with the use of metronidazole 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, this drug should be used during pregnancy only after careful assessment of the risk/benefit ratio.
Lactation: Even though metronidazole blood levels are significantly lower after topical than after oral administration 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. After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma.
Mutagenicity and Carcinogenicity: Information from preclinical studies indicates that metronidazole and its principal metabolite are mutagenic in bacteria and that tumors were observed in animal studies after oral administration of metronidazole. The relevance of these findings to the topical use of metronidazole in humans is unknown. The anaerobic or hypoxic conditions that might lead to the production of genotoxic compounds are unlikely to occur in topical use. There is no conclusive evidence after 30 years of clinical use of systemic metronidazole for either a genotoxic or carcinogenic potential.
Exposure to Sun: Exposure to excessive sunlight, including sunlamps and tanning beds, should be avoided when using the topical gel or cream (based on studies in hairless mice treated with intraperitoneal metronidazole).
Precautions: Because of the minimal absorption of metronidazole, and consequently its insignificant plasma concentration after topical administration, the systemic adverse experiences reported with the oral form of the drug should not be expected with the metronidazole topical gel or cream.
General: Avoid contact with the eyes. Topical metronidazole has been reported to cause tearing of the eyes. If contact with the eyes does occur, flush with water. If a reaction suggesting local irritation occurs, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use until further instructions. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or a history of, blood dyscrasia. Although rosacea is a chronic disease, data on the long-term use of the topical gel or cream in rosacea is not available. In controlled clinical trials, patients were treated for 12 weeks (see Dosage).
Drug Interactions: Drug interactions are less likely with topical administration but should be kept in mind when metronidazole is prescribed for patients who are receiving anticoagulant treatment. Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. Oral metronidazole also interacts with alcohol, producing a disulfiram-like reaction. Although this adverse reaction has not been reported with topical application of metronidazole, a drug interaction of metronidazole-alcohol is a possibility.
Dermatological Sensitivity: There were no reports of contact dermatitis attributed to the topical gel or cream during clinical trials. However, there have been reports of contact dermatitis/allergic reaction reported as post marketing adverse experiences (see Adverse Effects). Physicians should be aware of the possibility of skin sensitivity reactions and of cross-sensitization with other imidazole preparations, such as clotrimazole and tioconazole.
Adverse Reactions: The patient safety database included 114 evaluable patients that participated in controlled and uncontrolled metronidazole topical gel trials.
In controlled clinical trials with MetroCream, the patient safety database included 71 evaluable patients.
Since commercialization of MetroGel, the following post marketing adverse experiences have been reported: contact dermatitis/allergic reaction; local irritation, redness, itching and burning; treatment failure (worsening of rosacea); watery eyes (tearing); metallic taste; tingling or numbness of the extremities; nausea; other (zoster lesion, pustules on nose and vesicular bullous eruptions). A causal relationship with topical metronidazole has not been unequivocally established for these adverse experiences.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no human experience with overdosage of metronidazole.
Massive ingestion may produce vomiting and slight disorientation. There is no specific antidote. Ipecac syrup or gastric lavage; then activated charcoal followed by a saline cathartic is suggested. Treatment should include symptomatic and supportive therapy.
Dosage And Administration: Apply and rub in a thin film of the topical gel or cream twice daily, morning and evening, to entire affected areas after washing. Significant therapeutic results should be noticed within 3 weeks. Clinical studies have demonstrated continuing improvement through 9 weeks of therapy. The dosage required for long-term administration is uncertain (see Precautions).
Areas to be treated should be cleansed before application of metronidazole. Patients may use cosmetics after application of metronidazole.
Availability And Storage: MetroCream: The white, smooth, emollient cream, contains: metronidazole 0.75%. Nonmedicinal ingredients: emulsifying wax, glycerin, isopropyl palmitate, purified water, sorbitol, lactic acid and/or sodium hydroxide with benzyl alcohol as preservative. Tubes of 45 g.
MetroGel: The clear, colorless gel, contains: metronidazole 0.75%. Nonmedicinal ingredients: carbopol 940, edetate disodium, propylene glycol, purified water and sodium hydroxide with methylparaben and propylparaben as preservatives. Tubes of 30 g.
Store at room temperature (15 to 30°C).
METROCREAM METROGEL® Galderma Metronidazole Antirosacea Agent