Galderma (U.K) Ltd

Rozex 7.5 mg/g Gel

Each gram of gel contains 7.5mg metronidazole equivalent to metronidazole 0.75% w/w

Excipients:

Propylene glycol 30 mg/g

Propyl parahydroxybenzoate (E216) 0.2 mg/g

Methyl parahydroxybenzoate (E218) 0.8 mg/g

For full list of excipients, see section 6.1.

Gel

A clear colourless to light yellow viscous single phase gel.

In the management of acute inflammatory exacerbations of rosacea.

For topical administration only.

The average period of treatment is three to four months. The recommended duration of treatment should not be exceeded. However, 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 on the severity of the condition. In clinical studies, topical metronidazole therapy for rosacea has been continued for up to 2 years. In the absence of a clear clinical improvement, therapy should be stopped.

Adults: A thin film of preparation is applied to the affected area twice daily. 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 Gel.

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

Children: Not recommended. Safety and efficacy have not been established.

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

1. If a reaction suggesting local irritation occurs, patients should be directed to use the medication less frequently or discontinue use temporarily and to contact their physician concerning further use if necessary.

2. Contact with eyes and mucous membranes should be avoided. This product has been reported to cause tearing of the eyes.

3. Exposure to ultraviolet or strong sunlight should be avoided during use of metronidazole.

4. Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of, or history of, blood dyscrasias.

5. Unnecessary and prolonged use of this medication should be avoided.

6. This product contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed). This product contains propylene glycol which may cause skin irritation.

7. Evidence suggests that metronidazole is carcinogenic in certain animal species. There is no evidence to date of a carcinogenic effect in human (see section 5.3).

Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application of Rozex Gel is low.

Nevertheless, it should be mentioned that disulfiram-like reactions has been reported in small number of patients taking metronidazole and alcohol concomitantly.

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 time 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 evidence to date with the use of Rozex Gel in pregnant patients. Metronidazole crosses the placenta barrier and rapidly enters the foetal circulation. No foetotoxicity was observed after oral metronidazole in rats or mice. However, because of animal reproduction studies are not always predictive of human response, and since oral metronidazole has been shown to be carcinogenic in some rodents, Rozex Gel should only be used in pregnancy if it is considered essential by the physician.

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

Based upon the pharmacodynamic profile and clinical experience performance related to driving and using machines should not be affected.

The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention:

Very common (1/10)

Common (1/100, < 1/10)

Uncommon ( 1/ 1,000, < 1/100)

Rare (1/10,000, < 1/1,000)

Very rare (<1/10,000), including isolated reports

Skin and subcutaneous tissue disorders:

Common: dry skin, erythema, pruritus, skin discomfort (burning, pain of skin/stinging), skin irritation, worsening of rosacea.

Unknown frequency: contact dermatitis

Nervous System disorders:

Uncommon: hypothesia, paraesthesia, dysgeusia (metallic taste)

Gastrointestinal disorders:

Uncommon: nausea

There is no human experience with overdosage of Rozex Gel. The acute oral toxicity of Rozex Gel was determined to be greater than 5g/kg (the highest dose given) in albino rats. No toxic effects were observed at this dose. This dose is equivalent to the intake of 12 30g tubes of Rozex 7.5 mg/g gel for an adult weighing 72 kg, and 2 tubes 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 Metronidazole 0.75% Topical Gel formulation demonstrate that the product is non-toxic in rats after acute oral administration of 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 13mg/kg.

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

Disodium edetate

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Propylene glycol

Sodium hydroxide (for pH-adjustment)

Purified water

Not Applicable

3 years

Do not store above 25^°C. Do not freeze.

Aluminium tubes with epoxy phenolic lining; pack sizes; 50 g, 40 g, 30 g and 5 g Physicians Sample.

Not all pack sizes may be marketed

No special requirements.

Galderma (UK) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts

WD17 1DS

UK

PA590/10/1

Date of first authorisation: 26^th June 1991

Date of last renewal: 26^th June 2001

July 2011