P50742 metrogel 1% pi

HIGHLIGHTS OF PRESCRIBING
INFORMATION
These highlights do not include all
5.2 Blood Dyscrasias
information
METROGEL (metronidazole) Gel, 1%
• Metronidazole is a nitroimidazole and Metronidazole is a nitroimidazole; use with care in patients with evidence of, safely and effectively. See full pre-
scribing information for METROGEL
5.3 Contact Dermatitis
(metronidazole) Gel, 1%.
Irritant and allergic contact dermatitis have been reported. If dermatitis METROGEL® (metronidazole) gel, 1%
occurs, patients may need to discontinue use.
For topical use.
5.4 Eye Irritation
Initial U.S. Approval: 1963
Topical metronidazole has been reported to cause tearing of the eyes. Avoid reported to cause tearing of the eyes.
--------INDICATIONS AND USAGE------
ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, ----------ADVERSE REACTIONS------
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.
---DOSAGE AND ADMINISTRATION---
In a controlled clinical trial, 557 patients used metronidazole gel, 1% and • Not for oral, ophthalmic or intravagi- To report SUSPECTED ADVERSE RE-
189 patients used the gel vehicle once daily for up to 10 weeks. The following ACTIONS, contact Galderma Labora-
table summarizes selected adverse reactions that occurred at a rate of ≥1%: tories, L.P. at 1-866-735-4137 or
Table 1: Adverse Reactions That Occurred at a Rate of ≥1%
FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
System Organ Class/Preferred Term
Metronidazole Gel, 1%
Gel Vehicle
----------DRUG INTERACTIONS------
Patients with at least one AE
Number (%) of Patients
186 (33.4)
51 (27.0)
to potentiate the anticoagulant effect of --DOSAGE FORMS AND STRENGTHS-
Infections and infestations
76 (13.6)
28 (14.8)
----------CONTRAINDICATIONS--------
---WARNINGS AND PRECAUTIONS-
• Peripheral neuropathy, characterized
See 17 for PATIENT COUNSELING
INFORMATION
Musculoskeletal and
connective tissue disorders
in clinical trials for topical metronida- Neoplasms
Revised: 10/2011
reported with the post approval use.
Nervous system disorders
FULL PRESCRIBING INFORMATION: CONTENTS*
INDICATIONS AND USAGE
OVERDOSAGE
Respiratory, thoracic and
DOSAGE AND ADMINISTRATION
DESCRIPTION
mediastinal disorders
DOSAGE FORMS AND
CLINICAL PHARMACOLOGY
STRENGTHS
CONTRAINDICATIONS
Skin and subcutaneous
WARNINGS AND PRECAUTIONS
tissue disorders
NONCLINICAL TOXICOLOGY
CLINICAL STUDIES
Vascular disorders
ADVERSE REACTIONS
HOW SUPPLIED/STORAGE AND
HANDLING
PATIENT COUNSELING
DRUG INTERACTIONS
INFORMATION
Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline
USE IN SPECIFIC POPULATIONS
Metronidazole Gel, 1%
Gel Vehicle
Sign/Symptom
138 (25.4)
63 (34.2)
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
METROGEL® is indicated for the topical treatment of inflammatory lesions of 134 (24.6)
60 (32.6)
DOSAGE AND ADMINISTRATION
Apply and rub in a thin film of METROGEL once daily to affected area(s).
A gentle cleanser should be used before the application of METROGEL.
Cosmetics may be applied after the application of METROGEL.
Pruritus
86 (15.8)
35 (19.0)
Not for oral, ophthalmic or intravaginal use.
DOSAGE FORMS AND STRENGTHS
Gel, 1%. METROGEL is a clear, colorless to pale yellow gel. Each gram of METROGEL contains 10 mg (1%) of metronidazole.
CONTRAINDICATIONS
METROGEL is contraindicated in patients with a history of hypersensitivity Stinging/burning
56 (10.3)
28 (15.2)
to metronidazole or to any other ingredient in the formulation.
WARNINGS AND PRECAUTIONS
5.1 Neurologic Disease
Peripheral neuropathy, characterized by numbness or paresthesia of an extremity has been reported in patients treated with systemic metronidazole.
The following additional adverse experiences have been reported with the Although not evident in clinical trials for topical metronidazole, peripheral topical use of metronidazole: skin irritation, transient redness, metallic taste, neuropathy has been reported with the post approval use. The appearance of tingling or numbness of extremities, and nausea.
abnormal neurologic signs should prompt immediate reevaluation of 6.2 Post Marketing Experience
METROGEL therapy. Metronidazole should be administered with caution to The following adverse reaction has been identified during post approval use patients with central nervous system diseases.
of topical metronidazole: peripheral neuropathy. Because this reaction is reported voluntarily from a population of uncertain size, it is not always in patients with Crohn’s disease treated with the drug for 8 months.
possible to reliably estimate the frequency or establish a causal relationship In one published study, using albino hairless mice, intraperitoneal administra- tion of metronidazole at a dose of 45 mg/m2/day (approximately 7 times the DRUG INTERACTIONS
human topical dose on a mg/m2 basis) was associated with an increase in Oral metronidazole has been reported to potentiate the anticoagulant effect ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinoge- of coumarin and warfarin, resulting in a prolongation of prothrombin time.
nicity nor photocarcinogenicity studies have been performed with Drug interactions should be kept in mind when METROGEL is prescribed for METROGEL or any marketed metronidazole formulations.
patients who are receiving anticoagulant treatment, although they are less CLINICAL STUDIES
likely to occur with topical metronidazole administration because of low In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel, 1% or gel vehicle once daily for 10 weeks.
USE IN SPECIFIC POPULATIONS
Most subjects had “moderate” rosacea at baseline. Efficacy was determined 8.1 Pregnancy
by recording reduction in inflammatory lesion counts and success rate in the Teratogenic Effects: Pregnancy Category B.
Investigator Global Assessment (percentage of subjects “clear” and “almost There are no adequate and well-controlled studies with the use of METROGEL clear” of rosacea at the end of the study). The scale is based on the in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration Table 3: Investigator Global Assessment Scale
of metronidazole in rats or mice at 200 and 20 times, respectively, the expected Score Grade
Definition
clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of No signs or symptoms present; at most, mild erythema human response, METROGEL should be used during pregnancy only if clearly Very mild erythema present. Very few small papules/pustules Mild erythema. Several small papules/pustules 8.3 Nursing Mothers
After oral administration, metronidazole is secreted in breast milk in concen- Moderate erythema. Several small or large papules/pustules, and up to 2 trations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those Severe erythema. Numerous small and/or large papules/pustules, up to achieved after oral metronidazole a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the The results are shown in the following table: importance of the drug to the mother and the risk to the infant.
8.4 Pediatric Use
Table 4: Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea
Safety and effectiveness in pediatric patients have not been established.
8.5 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 Inflammatory lesions
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.
OVERDOSAGE
Investigator Global Assessment
There are no reported human experiences with overdosage of METROGEL.
Topically applied metronidazole can be absorbed in sufficient amount to DESCRIPTION
METROGEL (metronidazole) Gel, 1% contains metronidazole, USP. Chemi- Subjects treated with metronidazole gel, 1% experienced a mean reduction cally, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a molecular formula for metronidazole is C H N O . It has the following struc- reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 The contribution to efficacy of individual components of the vehicle has not HOW SUPPLIED/STORAGE AND HANDLING
METROGEL® is clear, colorless to pale yellow in color, and supplied as follows: Metronidazole has a molecular weight of 171.16. It is a white to pale yellow 60 gram tube – NDC 0299-3820-60
crystalline powder. It is slightly soluble in alcohol and has solubility in water 55 gram pump – NDC 0299-3820-01
of 10 mg/mL at 20˚C. Metronidazole belongs to the nitroimidazole class of 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).
METROGEL is a clear, colorless to pale yellow, aqueous gel; each gram con- PATIENT COUNSELING INFORMATION
tains 10 mg of metronidazole in a base of betadex, edetate disodium, Patients using METROGEL should receive the following information and hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propy- lene glycol, propylparaben and purified water.
1. This medication is to be used as directed.
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of metronidazole in the treatment of rosacea is 4. Cleanse affected area(s) before applying METROGEL.
5. This medication should not be used for any condition other than that for 12.2 Pharmacodynamics
The pharmacodynamics of metronidazole in association with the treatment 7. Patients should report any adverse reaction to their physicians.
12.3 Pharmacokinetics
Topical administration of a one gram dose of METROGEL 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 Manufactured by:
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.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Metronidazole has shown evidence of carcinogenic activity in a number of studies Marketed by:
involving chronic, oral administration in mice and rats, but not in studies involving 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

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