New Zealand Datasheet

Name of Medicine

ROZEX cream

Metronidazole

Presentation

Contains 0.75% w/w metronidazole as the active ingredient in an oil-in-water cream base containing benzyl alcohol, isopropyl palmitate, glycerol, sorbitol 70% (non-crystallising), emulsifying wax, lactic acid or sodium hydroxide solutions to adjust pH and purified water.

Actions

Metronidazole is an antiprotozoal (trichomoniasis, amoebiasis, giardiasis) and anaerobic antibacterial agent. However the mechanisms by which ROZEX cream acts in reducing inflammatory lesions of rosacea are unknown.

Pharmacokinetics

Following a single topical 1 gram application of ROZEX cream to the face of twelve normal human subjects, a mean maximum serum metronidazole concentration of 32.9ng.ml-1 was reported (range: 14.8 to 54.4 ng.ml-1). This is less than 0.5% of the mean maximum metronidazole concentration reported in the same subjects administered a single oral 250 mg tablet of metronidazole (mean Cmax = 7248 ng.ml-1, range: 4270 to 13970 ng.ml-1). The Tlag and Tmax for metronidazole after topical administration of the cream formulation were significantly (p<0.05) prolonged when compared with oral administration. In comparison to the oral tablet the mean Tmax for the topical formulation occurred 7.0 hours later (95% confidence interval: 2.7 to 11.3 hours). The hydroxymetabolite (2-hydroxymethylmetronidazole) Cmax after the 250 mg oral dose ranged from 626 to 1788 ng. ml-1 and peaked betweem 4 and 12 hours. Following topical application of ROZEX cream the hydroxymetabolite serum concentrations were below the quantifiable limit of the assay (<9.6 ng. ml-1) at the majority of time points. The hydroxymetabolite Cmax after topical administration of the cream ranged from below the quantifiable limit to 17.6 ng.ml-1. The extent of exposure area under the curve (AUC.) from a 1gram application of metronidazole administered topically was 1.2% of the AUC.of a single oral 250mg metronidazole dose (mean = 912.7 ng.hr ml-1 and approximately 67207 ng.hr ml-1 and respectively).

Dosage and Administration

ROZEX cream should be applied in a thin layer to the affected areas of the skin twice daily, morning and evening. Areas to be treated should be washed with a mild cleanser before application. Patients may use non-comedogenic and non-astringent cosmetics after application of ROZEX cream. The dosage does not need to be adjusted for elderly patients. Safety and effectiveness in paediatric patients have not been established. The average period of treatment is three to four months. If a clear benefit has been demonstrated continued therapy for a further three to four months period may be considered by the prescribing physician depending upon the severity of the condition. Clinical experience with ROZEX cream over prolonged periods is limited at present. Patients should be monitored to ensure that clinical benefit continues and that no local or systemic events occur. In the absence of a clear clinical improvement therapy should be stopped. ROZEX cream should not be used in or close to the eyes. The use of a sunscreen is recommended when exposure to sunlight cannot be avoided

Contraindications

Contraindicated in individuals with a history of hypersensitivity to metronidazole or other ingredients of the formulation.

Warnings and Precautions

ROZEX cream has been reported to irritate the eyes (watering), therefore contact with the eyes should be avoided, as well as with mucous membranes. 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 compound and should be used with care in patients with evidence or a history of blood dyscrasia. Patients should be advised to avoid or minimize exposure of areas treated with topical metronidazole to sunlight or other sources of UV light (see section: carcinogenicity, mutagenicity and impairment of fertility). Unnecessary or prolonged use of this medication should be avoided as the long term safety of topical metronidazole is unknown.

Use in Pregnancy

(Category B2) The potential adverse effects of ROZEX cream on pregnancy have not been determined however oral metronidazole is known to cross the placental barrier and enter the foetal circulation rapidly. There is no conclusive evidence of fetotoxicity or teratogenicity in animal studies with metronidazole nor has clinical experience to date with the use of metonidazole in pregnant women revealed evidence of a fetotoxic or teratogenic effect of the drug. Because there are no well controlled studies of therapy with ROZEX cream in pregnant women ROZEX cream should not be used during pregnancy.

Use in Lactation

After oral administration metronidazole is excreted in breast milk in concentrations similar to those found in the plasma. Metronidazole blood levels from topical application are significantly lower than those achieved after oral metronidazole. A decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Use in Children

ROZEX cream has not been studied in children. Rosacea is a skin disorder which principally affects adults.

Carcinogenicity, Mutagenicity and Impairment of Fertility

Animal studies with oral metronidazole showed increased incidences of tumour in the lung, liver, testes, reticulum, mammary gland and pituitary gland in certain rodent species. Evidence of photocarcinogenicity of metronidazole has also been reported in mice. Although there is no evidence to date of a carcinogenic effect in humans it is prudent to avoid unnecessary and prolonged use of ROZEX cream and to avoid or to minimise exposure of sites treated with ROZEX cream to the sun. Metronidazole has shown evidence of mutagenic activity in several bacterial systems. In addition, a dose response increase in the frequency of micronuclei was observed in mice after intraperitoneal injection and an increase in chromosome aberrations has been found in human lymphocyte cultures. The benefit/risk ratio should therefore be carefully assessed in each case particularly in relation to the severity of the disease and the age of the patient. Oral metronidazole caused hypospermatogenesis, infertility and abnormal spermatozoa in mice and rats with a NOEL in rats being about 200 times the estimated human metronidazole dose contained in the ROZEX cream, based on body surface area.

Interactions

Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application of ROZEX cream is low. Nevertheless it should be mentioned that a disulfiram-like reaction has been reported in a small number of patients taking oral metronidazole and alcohol concomitantly. Oral metronidazole has also been reported to potentiate the effect of warfarin and other coumarin anticoagulants resulting in a prolongation of prothrombin time. However the effect of topical metronidazole on prothrombin is not known.

Overdosage

There is no human experience with overdosage of ROZEX cream.

Pharmaceutical Precautions

Store below 25degC (room temperature)

Medicine Classification

Prescription Medicine.

Package Quantities

Cream: 5g, 30g.

Further Information

Clinical Studies

One multicentre randomised, double-blind, placebo-controlled clinical study was conducted to evaluate ROZEX Cream for the treatment of rosacea. All of the patients included in the trial had moderate to severe (Stage 2) rosacea. The prescribed therapy was applied daily for 12 weeks with follow up at weeks 3, 6, 9 and 12. The results are tabulated below. Table 1: Inflammatory lesion counts in the ITT population at baseline and endpoint.

There were no significant differences between the treatment groups in the reduction of erythema or telangiectasis. For a subgroup within the ROZEX cream group who had dry skin there was a significant reduction in erythema (59.6% vs 30.4%, p=0.05). In another randomised single-blind multicentre study (n=100) in which the gel and cream formulations were compared, there were no significant differences in lesion counts or global assessment of improvement at weeks 4, 8 and 12. All patients recruited to the study had moderate to severe stage 2 rosacea. The percent reduction in mean lesion count from baseline to week 12 was 61.3% (MZ cream) vs 63.5% (MZ gel), p= n.s.

Name and Address

Date of Preparation

1 May 2006 [Marketing Authorisation Number: AUST R 72393 Approved for marketing by the Therapeutic Goods Administration on 27thFebruary 2002. Latest update March 2004