MetroCream: Indications, Dosage, Precautions, Adverse Effects
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MetroCream - Product Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Erythema (Skin Rash), Perioral Dermatitis, Rosacea
Class: Topical anti-rosacea agents
Form: Cream, Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: metronidazole, benzyl alcohol, emulsifying wax, glycerin, isopropyl palmitate, lactic acid and/or sodium hydroxide, sorbitol solution, purified water

Summary Product Information

Route of Administration Dosage Form ⁄ Strength Clinically Relevant Nonmedicinal Ingredients*
Topical metronidazole gel USP, 0.75%
metronidazole gel Galderma Std, 1%
metronidazole cream, 0.75%
metronidazole lotion, 0.75%
methylparaben, propylparaben, propylene glycol, phenoxyethanol

*For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

METROGEL (0.75% & 1%), METROCREAM (0.75%), and METROLOTION (0.75%) (metronidazole topical gel, cream, and lotion) are indicated 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 or lotion formulation (i.e., METROCREAM or METROLOTION).

Geriatrics (≥ 65 years of age)

While specific clinical trials in the geriatric population have not been conducted, 66 patients aged 65 years and older treated with METROGEL 1% over 10 weeks showed comparable safety and efficacy as compared to the general study population.

Pediatrics

Safety and effectiveness in pediatrics have not been established.

Contradications

METROGEL, METROCREAM, and METROLOTION (metronidazole topical gel, cream, and lotion) are contraindicated:

  • in individuals with a history of hypersensitivity to metronidazole, or other ingredients of the formulations. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

Warning and Precautions

General

Because of the minimal absorption of metronidazole, and consequently its insignificant plasma concentration after topical administration, the systemic adverse reactions reported with the oral form of the drug should not be expected with METROGEL, METROCREAM, or METROLOTION (metronidazole topical gel, cream, or lotion).

Physicians should consider the most appropriate formulation (gel, cream, or lotion) for their patients.

Although rosacea is a chronic disease, data on the long-term use of METROGEL, METROCREAM, or METROLOTION in rosacea is not available. In controlled clinical trials, patients were treated for up to 12 weeks (see Dosage and Administration section).

Carcinogenesis and Mutagenesis

Information from preclinical studies indicates that metronidazole and its principal metabolite are mutagenic in bacteria and that tumours were observed in animal studies after oral administration of metronidazole (see Toxicology section). 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.

Hematologic

Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia.

Ophthalmologic

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.

Conjunctivitis associated with topical use of metronidazole on the face has been reported.

Sensitivity⁄Resistance

Exposure to excessive sunlight, including sunlamps and tanning beds, should be avoided when using METROGEL, METROCREAM, or METROLOTION [based on studies in hairless mice treated with intraperitoneal metronidazole (see Toxicology section).

Skin

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.

There were no reports of contact dermatitis attributed to METROGEL and METROCREAM, during clinical trials. However, there have been reports of contact dermatitis/allergic reaction reported during METROLOTION clinical trials and as post marketing adverse reactions (see Adverse Reactions section). Physicians should be aware of the possibility of skin sensitivity reactions and of cross-sensitization with other imidazole preparations, such as clotrimazole and tioconazole.

Special Populations

Pregnant Women

There has been no experience to date with the use of METROGEL, METROCREAM, or METROLOTION (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 only be used during pregnancy after careful assessment of the risk/benefit ratio.

Nursing Woman

Even though metronidazole blood levels are significantly lower after topical application 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.

Adverse Reactions

Adverse Drug Reaction Overview

The safety profile of METROGEL (metronidazole topical gel 0.75% and 1%), METROCREAM (metronidazole topical cream 0.75%) and METROLOTION (metronidazole topical lotion 0.75%) has been established in clinical trials. The results of the safety analyses indicate topical application of metronidazole is well tolerated.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Metronidazole Topical Gel 1%

In a 10-week controlled clinical trial in patients with rosacea, 557 patients used METROGEL (metronidazole gel), 1% and 189 patients used the gel vehicle once daily. Among the treatment groups, the adverse reactions considered related to treatment were low with comparable frequencies. The majority of the adverse reactions were mild or moderate in severity.

Adverse reactions considered related to once daily treatment with METROGEL 1% were reported at a frequency of <1% and are summarized in the table below.

Table 1: Adverse Reactions Attributed to METROGEL 1% (metronidazole topical gel)
System Organ Class⁄Adverse Reactions Incidence (No. of Patients) Severity (No. of Patients) Follow-Up Treatment
Skin and subcutaneous tissue disorders
Dry Skin 0.9% (5) mild (2)
mild
mild
moderate
treatment required
none required
none required*
none required**
Erythema 0.7% (4) moderate (3)
severe
none required*
treatment required*
Pruritus 0.5% (3) mild
moderate
severe
none required*
none required*
treatment required*
Skin burning sensation 0.2% (1) mild none required**
Skin irritation 0.2% (1) severe treatment required*
Rash papular 0.4% (2) mild
moderate
none required
none required*
Skin desquamation 0.2% (1) moderate none required*
Skin tightness 0.4% (2) mild< none required**
Facial oedema 0.2% (1) severe treatment required*
Urticaria 0.2% (1) moderate treatment required*
Eve Disorders
Conjunctivitis 0.4% (2) mild
mild
treatment required
treatment required*
Eye irritation 0.2% (1) mild none reqiured
Gastrointestinal Disorders
Dyspepsia 0.2% (1) mild treatment required

MedDRA version 9.0 has been used for coding of adverse reactions.
* drug discontinued
** therapy interrupted/reduced

Metronidazole Topical Gel 0.75%

The patient safety database included 114 evaluable patients that participated in controlled and uncontrolled METROGEL (metronidazole topical gel) trials. Adverse reactions attributed to the use of METROGEL are summarized in the table below.

Table 2: Adverse Reactions Attributed to METROGEL 0.75% (metronidazole topical gel)
System Organ Class⁄Adverse Reactions Incidence (No. of Patients) Severity Follow-Up Treatment
Skin and subcutaneous disorders
Skin irritation 1.8% (2) mild none required
Dry Skin 1.8% (2) mild none required
Erythema 1.8% (2) mild none required
Burning Sensation 0.9% (1) mild none required
Eye disorders
Lacrimation Increased 0.9% (1) mild none required

Metronidazole Topical Cream

In controlled clinical trials with METROCREAM (metronidazole topical cream), the patient safety database included 71 evaluable patients. Adverse reactions attributed to the use of METROCREAM are summarized in the table below.

Table 3: Adverse Reactions Attributed to METROCREAM (metronidazole topical cream)
System Organ Class⁄Adverse Reactions Incidence (No. of Patients) Severity Follow-Up Treatment
Skin and subcutaneous disorders
Skin discomfort (burning and stinging) 2.8% (2) moderate
moderate
none required
drug discontinued
Rosacea 1.4% (1) mild drug discontinued
Erythema 1.4% (1) moderate drug discontinued
Skin irritation 1.4% (1) moderate drug discontinued
Pruritus 1.4% (1) moderate none required

Metronidazole Topical Lotion

During controlled clinical trials with METROLOTION (metronidazole topical lotion), the patient safety database included 72 evaluable patients. Adverse reactions attributed to the use of METROLOTION are summarized in the following table.

Table 4: Adverse Reactions Attributed to METROLOTION (metronidazole topical lotion)
System Organ Class⁄Adverse Reactions Incidence (No. of Patients) Severity Follow-Up Treatment
Skin and subcutaneous disorders
Hypersensivity 2.8% (2) moderate drug discontinued
Dermatitis contact 1.4% (1)
1.4% (1)
mild
moderate
therapy interrupted temporarily
drug discontinued
Erythema 2.8% (2)
2.8% (2)
mild
moderate
none required
drug discontinued
Rosacea 1.4% (1) mild drug discontinued

Post-Market Adverse Drug Reactions

Since commercialization of METROGEL (0.75%, 1%), METROCREAM and METROLOTION, the following post marketing adverse reactions have been reported.

A causal relationship with topical metronidazole has not been unequivocally established for these adverse drug reactions.

Post Marketing Adverse Drug Reactions by System Organ Class, MedDRA preferred term for METROGEL, METROCREAM and METROLOTION:

Blood and lymphatic disorders: Leucopenia

Eye disorders: Lacrimation increased

Gastrointestinal disorders: Dysgeusia, nausea

General disorders and administration: Condition aggravated

Immune system disorders: Hypersensitivity

Nervous system disorders: Paraesthesia

Skin and subcutaneous tissue disorders: Dermatitis contact, dry skin, erythema, pruritis, rashpustular, dermatitis bullous, skin burning sensation, skin irritation

Drug Interactions

Drug-Drug Interactions

Table 5: Established or Potential Drug-Drug Interactions
Metronidazole Ref Comment Clinical Comment
Coumarin and warfarin C⁄CT Potentiate the anticoagulant effect 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.
Alcohol T (topical)
C (oral)
Disulfiram-like reaction. 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.
Other imidazole preparations such as clotrimazole and tioconazole T Skin sensitivity Physicians should be aware of the possibility of skin sensitivity reactions and of cross-sensitization with other imidazole preparations.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Dosage And Administration

Recommended Dose and Dosage Adjustment

METROGEL 1%: Apply and rub in a thin film once daily to entire affected area(s).

METROGEL 0.75%, METROCREAM 0.75%, AND METROLOTION 0.75%: Apply and rub in a thin film twice daily, morning and evening, to entire affected areas.

Significant therapeutic results should be noticed within three weeks. Clinical studies have demonstrated continuing improvement through nine weeks of therapy. The dosage required for long-term administration is uncertain (see Warnings section).

Administration

Areas to be treated should be cleansed before application of METROGEL, METROCREAM, or METROLOTION. The face must be dry before applying medication. Patients may use cosmetics after application of METROGEL, METROCREAM, or METROLOTION. The medication should have absorbed into the skin ("dry") before the cosmetics are applied.

Overdosage

There is no human experience with overdosage of METROGEL, METROCREAM, or METROLOTION (metronidazole topical gel, cream, or lotion). Topically applied metronidazole can be absorbed in sufficient amount to produce systemic effects.

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.

Action And Clinical Farmacology

Mechanism of Action

METROGEL, METROCREAM, and METROLOTION (metronidazole topical gel, cream, and lotion) preparations are particularly effective against the inf1ammatory, 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 (see Detailed Pharmacology section).

Pharmacinetics

Serum metronidazole levels have been shown to be below detection limits (<25 ng⁄mL) at the majority of time points after administration of topical metronidazole. At the time points that it could be detected, topical metronidazole produced blood levels (Cmax 40.6 ng⁄mL) that were approximately 80% less than a similar dose administered orally (Cmax 212 ng⁄mL). Therefore, with normal usage, topical metronidazole results in minimal blood levels of metronidazole.

Storage and Stability

METROGEL 1% (metronidazole topical gel): Store at room temperature (15° to 30°C).
METROGEL 0.75% and METROCREAM (metronidazole topical gel and cream): Store at 15° to 30°C.

METROLOTION (metronidazole topical lotion): Store at room temperature (15° to 30°C). Protect from freezing.

Dosage Forms, Composition and Packaging

METROGEL 1% is supplied in a 55 g high-density polyethylene (HDPE) bottle with a polypropylene (PP) pump.

METROGEL 0.75% (metronidazole topical gel) is supplied in 60 g aluminum tubes.

METROCREAM (metronidazole topical cream) is supplied in 60 g aluminum tubes.

METROLOTION (metronidazole topical lotion) is supplied in 120 mL oval plastic bottles.

Composition

METROGEL 1%

METROGEL (metronidazole topical gel) is an aqueous gel containing metronidazole 1%.

Non-medicinal ingredients: betadex, edetate disodium, hydroxyethyl cellulose 250 HHX, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben, and purified water.

METROGEL 0.75%

METROGEL (metronidazole topical gel) is a clear, colourless gel containing metronidazole 0.75%.

Non-medicinal ingredients: carbopol 940, edetate disodium, methylparaben, propylene glycol, propylparaben, sodium hydroxide and purified water.

METROCREAM

METROCREAM (metronidazole topical cream) is a white, smooth, emollient cream containing metronidazole 0.75%.

Non-medicinal ingredients: benzyl alcohol, emulsifying wax, glycerin, isopropyl palmitate, lactic acid and/or sodium hydroxide, sorbitol solution and purified water.

METROLOTION

METROLOTION (metronidazole topical lotion) is a fluid, emollient lotion containing metronidazole 0.75%.

Non-medicinal ingredients: benzyl alcohol, carbomer 941, cyclomethicone, glycerin, glyceryl stearate, light mineral oil, polyethylene glycol 100 stearate, polyethylene glycol 400, potassium sorbate, sodium hydroxide and/or lactic acid, stearyl alcohol, steareth-21 and purified water.