Rozex Cream

Metronidazole Ph. Eur 0.75% w/w

Cream

Indicated in the treatment of inflammatory papules, pustules and erythema 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: 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.

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, or other ingredients of the formulation.

Contact with mucous membranes should be avoided.

Rozex Cream 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 or discontinue use temporarily and to seek medical advice if necessary. 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 (e.g. solarium, sun-lamp) or strong sunlight (including sun-bathing) should be avoided during use of metronidazole. Unnecessary and prolonged use of this medication should be avoided.

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 Cream is low. Nevertheless, it should be mentioned that disulfiram-like reactions have been reported in a 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 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 Cream in pregnancy. In case of oral administration, metronidazole crosses the placental barrier and rapidly enters the foetal circulation. No foetotoxicity was observed after oral metronidazole in either rats or mice. However because animal reproduction studies are not always predictive of human response and since oral metronidazole has been shown to be a carcinogen in some rodents this drug should be used in pregnancy only if clearly needed.

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.

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 Cream. Adverse reactions reported with Rozex Cream have been only local and mild.

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

Watery eyes have been reported 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 Cream for an adult weighing 72 kg, and 2 tubes of Cream 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 a topical 1g application of Rozex Cream to the face of normal subjects resulted in mean maximum serum concentrations of 32.9ng/ml (range 14.8 to 54.4ng/ml) which is approximately 100 times less than those attained after a single oral dose of 250 mg (mean Cmax = 7248ng/ml; range 4270 – 13970ng/ml). The peak concentration occurred between 0.25 – 4 hours after oral dosing, and 6 to 24 hours after cutaneous application of Rozex Cream.

Following topical application of Rozex Cream, serum concentrations of the major metabolite (the hydroxymetabolite 2-hydroxymethylmetronidazole) were below the quantifiable limit of the assay (<9.6ng/ml) at most of the time points, ranging to a maximum of 17.5ng/ml peak concentration between 8 and 24 hours after application. In comparison, the peak concentration following a 250mg oral dose ranged from 626 to 1788ng/ml between 4 and 12 hours after dosing.

The extent of exposure (Area under the curve, AUC) from a 1g application of metronidazole administered topically was 1.36% of the AUC of a single oral 250mg metronidazole dose (mean + 912.7ng.hr/ml and approximately 67207ng.ml/hr respectively).

No evidence for a primary dermal irritation was observed in rabbits following a single 24-hour cutaneous application of Rozex Cream to abraded and non-abraded skin, under occlusion.

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 oral metronidazole for 1 to 24 months. However, the preponderance of evidence from these studies suggests that although metronidazole has a potential for producing mutations, this should not occur in well oxygenated mammalian cells, i.e., under normal aerobic conditions.

The carcinogenicity of metronidazole by the oral route of administration has been evaluated in rats, mice and hamsters. These studies showed that oral metronidazole caused an increased incidence of pulmonary tumours in mice and possibly other tumours, including liver tumours, in the rat. Conversely, two lifetime studies in hamsters produced negative results. Moreover, 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 results to the cutaneous use of metronidazole for the treatment of rosacea is unclear, patients should be advised to avoid or minimise exposure of metronidazole cream-treated sites to sun. After several decades of systemic use, no evidence has been published to suggest that metronidazole is associated with carcinogenic potential in humans.

Emulsifying Wax, Benzyl alcohol, Isopropyl palmitate, Glycerol, Sorbitol 70% (non-crystallising), lactic acid and/or Sodium Hydroxide, Purified Water.

None known

Rozex Cream has a shelf life when unopened of 36 months

Store at a temperature not exceeding 25°C. Do not refrigerate.

Aluminium tubes with epoxy phenolic lining, fitted with white polypropylene screw caps; pack sizes: 30g, 40g & 50g

Replace cap tightly after use.

Galderma (UK.) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts.

WD17 1DS

UK

PL 10590/0028

18^th June 1997

December 2010