METROGEL® (metronidazole gel), 1% 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 a solubility in water of 10 mg/mL at 20°C. Metronidazole is a member of the imidazole class of antibacterial agents and is classified as an antiprotozoal and anti-bacterial agent.

METROGEL® (metronidazole gel), 1% 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.

METROGEL® (metronidazole gel), 1% is indicated for the topical treatment of inflammatory lesions of rosacea.

Areas to be treated should be cleansed before application of METROGEL® (metro-nidazole gel), 1%. Apply and rub in a thin film of METROGEL® (metronidazole gel), 1% once daily to entire affected area(s). Patients may use cosmetics after application of METROGEL® (metronidazole gel), 1%.

METROGEL® (metronidazole gel), 1% is available in a 45-gram tube.

45 gram tube - NDC 0299-3820-45

Keep out of the reach of children.

Storage Conditions: Store at controlled room temperature: 20° to 25°C (68° to 77°F), excursions permitted between

59° and 86°F (15°-30°C).

Prescribing Information as of June 2005. Manufactured by: Galderma Production Canada Inc. Montreal, QC H9X 3N7 Canada. Marketed by: Galderma Laboratories, L.P. Fort Worth, Texas 76177, USA. FDA Rev date: 11/14/2005

In a controlled clinical trial, 557 patients used METROGEL® (metronidazole gel), 1% and 189 patients used the gel vehicle once daily. The following table summarizes adverse reactions that occur at a rate of ≥ 1% in the clinical trials:

The following table summarizes the highest scores of local cutaneous signs and symptoms of irritation that were worse than baseline:

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.

Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and war-farin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL® (metronidazole gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.

No information provided.

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 skin irritation occurs, patients should be directed to use the medication less often 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 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 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 to1200 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® (metronidazole gel), 1% or any marketed metronidazole formulations.

Pregnancy: Teratogenic Effects: Pregnancy Category B. There are no adequate and well-controlled studies with the use of METROGEL® (metronidazole gel), 1% 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 gel), 1% 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: While specific clinical trials in the geriatric population have not been conducted, sixty-six patients aged 65 years and older treated with METROGEL® (metronidazole gel), 1% over ten weeks showed comparable safety and efficacy as compared to the general study population.

There are no reported human experiences with overdosage of METROGEL® (metronidazole gel), 1%. Topically applied metronidazole can be absorbed in sufficient amount to produce systemic effects.

METROGEL® (metronidazole gel), 1% is contraindicated in those patients with a history of hypersensitivity to metro-nidazole or to any other ingredient in this formulation.

The contribution to efficacy of individual components of the vehicle has not been established.

Pharmacokinetics

Topical administration of a one gram dose of METROGEL® (metronidazole gel), 1% 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.

Pharmacodynamics

The mechanisms by which metronidazole acts are unknown.

Clinical Studies

Clinical Studies: Safety and efficacy of METROGEL® (metronidazole gel), 1% have been demonstrated in a 10-week, randomized, vehicle-controlled trial in 746 patients with rosacea. Patients were treated once daily for ten weeks with METROGEL® (metronidazole gel), 1%, or with gel vehicle. Most patients 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:

Investigator Global Assessment Scale

The results are shown in the following table:

Inflammatory Lesion Counts and Global Scores in a Clinical Trial for Rosacea

Patients treated with METROGEL® (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.

Safety Studies

Studies of cumulative irritation (n=35), contact sensitization-repeat insult patch test (n=230), photo-toxicity (n=29), and photoallergy (n=30) of METROGEL® (metronidazole gel), 1% were conducted. No significant evidence of irritation, sensitization, phototoxicity or photoallergy was found in these studies.

Patients using METROGEL® (metronidazole gel), 1% should receive the following information and instructions:

1. This medication is to be used as directed.
2. It is for external use only.
3. Avoid contact with the eyes.
4. Cleanse affected area(s) before applying METROGEL® (metronidazole gel), 1%.
5. This medication should not be used for any other condition than that for which it is prescribed.
6. Patients should report any adverse reaction to their physicians.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

METRONIDAZOLE - TOPICAL

(meh-troh-NID-uh-zole)

COMMON BRAND NAME(S): Metrocream, Metrogel, Metrolotion, Noritate

USES: This medication is used on the skin to treat a certain skin disorder known as rosacea, a type of adult acne. It may help to decrease redness, swelling and the number of pimples caused by rosacea.

This medication is an antibiotic. For the treatment of rosacea, metronidazole is believed to work by decreasing swelling (inflammation).

HOW TO USE: Use this medication on the skin only. Wash and dry your hands before and after applying this medication. Wash and dry the area to be treated. Wait 15 minutes, then apply a thin layer of medication usually once or twice daily, or as directed by your doctor. Wait 5 minutes before applying cosmetics.

Avoid using this medication around the eye area, unless directed by your doctor. Watery eyes or tearing of the eyes may occur if this medication is applied too close to the eyes. Avoid getting this medication in your eyes. If this occurs, rinse your eyes with large amounts of cool water.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day.

It may take about three weeks before any improvement is seen, and up to nine weeks for full benefit. If no improvement is seen after three weeks, consult your doctor.

SIDE EFFECTS: Stinging, burning, skin irritation, dryness, redness, metallic taste, nausea, or headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if you have this unlikely but serious side effect: tingling or numbness of the hands and feet.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using metronidazole, tell your doctor or pharmacist if you are allergic to it; or to other nitroimidazole antibiotics (e.g., tinidazole); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders (blood dyscrasias).

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Breast-feeding while using this medication is not recommended. Consult with your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medicine may be harmful if swallowed.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in those cases.

Avoid certain triggers that may worsen rosacea such as excessive sunlight, wind, hot beverages, spicy foods, alcohol, and extreme cold. Discuss with your doctor.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. If using the lotion, do not freeze. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.