Rozex Gel

Metronidazole Ph. Eur 0.75% w/w

Gel

Indicated in the treatment of inflammatory papules, pustules and erythema of rosacea

For topical administration only.

Adults: Apply and rub in a film of Gel twice daily, morning and evening, to entire affected area after washing.

Elderly: The dosage recommended in the elderly is the same as that recommended in adults.

Children: Not recommended

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

Rozex Gel has been reported to cause lacrimation of the eyes, therefore, contact with the eyes should be avoided. 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 history of, blood dyscrasia. Exposure of treated sites to ultraviolet or strong sunlight should be avoided during use of metronidazole. Unnecessary and prolonged use of this medication should be avoided.

Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application of Rozex Gel is low. Oral metronidazole has been reported to potentiate the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin is not known. However, very rare cases of modification of the INR values have been reported with concomitant use of Rozex and coumarin anticoagulants.

There is no experience to date with the use of Rozex Gel in pregnancy. Metronidazole crosses the placental barrier and rapidly enters the foetal circulation. There is inadequate evidence of the safety of Metronidazole in human pregnancy. In animals, Metronidazole was not teratogenic or embryotoxic unless administered at extremely high doses. Rozex Gel should only be used in pregnancy where there is no safer alternative.

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

Not applicable

Because of the minimal absorption of metronidazole and consequently its insignificant plasma concentration after topical administration, the adverse experiences reported with the oral form of the drug have not been reported with Rozex Gel. Adverse reactions reported with Rozex Gel have been only local and mild, and include skin discomfort (burning and stinging), erythema, pruritis, skin irritation, worsening of rosacea, nausea, metallic taste and tingling or numbness of the extremities, and watery eyes if applied too closely to this area.

No data exists about overdosage in humans. Acute oral toxicity studies with a topical gel formulation containing 0.75% w/w metronidazole in rats have shown no toxic action with doses of up to 5 g of finished product per kilogram body weight, the highest dose used. This dose is equivalent to the oral intake of 12 tubes of 30g packaging Rozex Gel for an adult weighing 72 kg, and 2 tubes of Gel for a child weighing 12 kg.

Metronidazole is an antiprotozoal and antibacterial agent which is active against a wide range of pathogenic micro-organisms. The mechanisms of action of metronidazole in rosacea are unknown but available evidence suggests that the effects may be antibacterial and/or anti-inflammatory.

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 the fat. Metronidazole is excreted primarily in the urine as parent drug, oxidative metabolites and conjugates.

Bioavailability studies with Rozex Gel in rosacea patients treated with 7.5 mg metronidazole applied topically to the face resulted in maximum serum concentrations of 66 ng/ml which is approximately 100 times less than those attained after a single oral dose of 250 mg. In most patients at most time points after Rozex Gel application, serum concentrations of metronidazole were below the detectable limits of the assay (25 ng/ml).

The toxicity studies conducted with the Metronidazole 0.75% Topical Gel formulation demonstrate that the product is non-toxic in rats after acute oral administration 5g/kg and produced no ocular irritation in rabbit eyes. The formulation produced no observable effects in rabbits after dermal application of 13 mg /kg for 90 days.

No compound-related dermal or systemic effects were observed in a 13-week cutaneous route toxicity study, in which Rozex gel containing Metronidazole 0.75% w/w was applied daily to rabbits at doses ranging between 0.13 and 13 mg/kg.

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.

One study showed a significant enhancement of UV induced skin tumours in hairless mice treated with Metronidazole intraperitoneally (15μg per g body weight and per day for 28 weeks). Although the significance of these studies to man is not clear, patients should be advised to avoid or minimise exposure of metronidazole treated sites to sun.

Metronidazole has shown mutagenic activity in several in vitro bacterial assay 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 have been reported in patients with Crohn's disease who were treated with 200 to 1200mg/day of metronidazole for 1 to 24 months. However, no excess chromosomal aberrations in circulating human lymphocytes have been observed in patients treated for 8 months.

Carbomer 940 (Carbopol 980) Ph. Eur

Disodium Edetate Ph. Eur.

Methyl Hydroxybenzoate Ph. Eur.

Propyl Hydroxybenzoate Ph. Eur.

Propylene Glycol Ph. Eur.

Sodium Hydroxide Ph. Eur.

Purified Water Ph. Eur.

None known

Rozex Gel has a shelf life when unopened of 36 months

Store at a temperature not exceeding 25°C, away from direct heat. Do not freeze.

Aluminium tubes with epoxy phenolic lining, and white polypropylene or polyethylene screw caps; pack sizes: 5, 30g, 40g & 50.

Not applicable

Galderma (UK.) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts.

WD17 1DS

UK

PL 10590/0016

16/03/2006

February 2006