Rozex 0.75% W/W Cutaneous Emulsion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rozex 0.75% w/w Cutaneous Emulsion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Metronidazole 0.75% w/w (7.5mg/g)
Excipients with known effect Stearyl alcohol 2.0% w/w (20mg/g)
Potassium sorbate 0.2% w/w (2mg/g).
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Cutaneous emulsion White to off-white lotion
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Indicated in the treatment of inflammatory papules, pustules and erythema of rosacea.
4.2 Posology and method of administration
For topical administration only.
The average period of treatment is 3 to 4 months. If a clear benefit has been demonstrated, continued therapy for a further 3 to 4 months period may be considered by the prescribing physician depending upon the severity of the condition. In clinical studies topical metronidazole therapy has been continued for up to 2 years. In the absence of a clear clinical improvement, therapy should be stopped.
Adults: A thin layer of emulsion is applied to the affected areas of 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 cutaneous emulsion.
Elderly: The dosage recommended in the elderly is the same as that recommended in adults.
Paediatric Population : Not recommended.
Safety and efficacy have not been established in individuals under 18 years of age.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Contact with mucous membranes should be avoided.
Rozex Emulsion 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 either use the medication less frequently or to discontinue its use and seek medical advice.
Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of, or history of, blood dyscrasia. Unnecessary and prolonged use of this medication should be avoided.
Exposure of treated sites to ultraviolet or strong sunlight should be avoided during use of metronidazole. Metronidazole transforms into inactive metabolite due to UV exposure, therefore its efficacy decreases significantly. Phototoxic side-effects haven’t been reported in clinical trials in relation to metronidazole.
Rozex Emulsion contains stearyl alcohol and potassium sorbate which may cause local skin reactions (e.g. contact dermatitis).
4.5 Interaction with other medicinal products and other forms of fnteraction
Oral metronidazole has been reported to potentiate the anti-coagulant effect of dicoumarin and warfarin, resulting in a prolongation of prothrombin time.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is no experience to date with the use of Rozex cutaneous emulsion in pregnancy. Following oral administration, 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 cutaneous emulsion should only be used in pregnancy when there is no safer alternative.
Breastfeeding
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.
4.7 Effects on ability to drive and use machines
Rozex cutaneous emulsion has no influence on the ability to drive and use machines.
4.8 Undesirable effects
The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency.
|
System Organ Class |
Frequency |
Adverse drug reaction |
|
Skin and subcutaneous tissue disorders |
Common ( > 1/100, < 1/10) |
Dry skin, erythema, pruritus, skin discomfort (burning, pain of skin/stinging), skin irritation, worsening of rosacea. |
|
Unknown frequency |
Contact dermatitis, swelling face, skin exfoliation | |
|
Nervous system disorders |
Uncommon (> 1/ 1,000, < 1/100) |
Hypoesthesia, paraesthesia, dysgeusia (metallic taste) |
|
Gastrointestinal disorders |
Uncommon (> 1/ 1,000, < 1/100) |
Nausea |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard .
Watery eyes have been reported if applied too closely to this area.
4.9 Overdose
There is no human experience with overdosage of Rozex cutaneous emulsion. The acute oral toxicity of a gel formulation was determined to be greater than 5 g/kg (the highest dose given) in albino rats. No toxic effects were observed at this dose. This dose is equivalent to the intake of more than seven 50g tubes of Rozex cutaneous emulsion for an adult weighing 72 kg, and one tube for a child weighing 12 kg.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Chemotherapeutics for external use ATC code: D06BX01
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.
5.2 Pharmacokinetic properties
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 cutaneous emulsion to the face of 12 normal subjects resulted in mean maximum serum concentrations of 34.4 ng/mL (range 19.7 to 63.8 ng/mL) which is less than 0.5% of the mean maximum serum metronidazole concentration reported in the same subjects administered a single oral dose of 250 mg (mean Cmax = 7248 ng/mL; range 4270 - 13970 ng/mL). The Tlag and Tmax for metronidazole after topical administration of the emulsion formulation were significantly (p < 0.05) prolonged as compared with oral administration. In relation to the oral tablet, the mean Tmax occurred 7.8 hours (95% confidence interval: 3.6 to 12.1 hours) later with the emulsion formulation.
Following topical application of Rozex cutaneous emulsion, serum concentrations of the major metabolite (the hydroxy metabolite 2-hydroxymethylmetronidazole) were below the quantifiable limit of the assay (<9.6 ng/mL) at most of the time points. Cmax ranged from below the quantifiable limit to a maximum of 17.3 ng/mL peak concentration between 8 and 24 hours after application. In comparison, the peak concentration following a 250mg oral dose ranged from 626 to 1788 ng/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 1.4% of the AUC of a single oral 250 mg metronidazole dose (mean + 971.1 ng.hr/mL and approximately 67207 ng.hr/mL respectively).
5.3 Preclinical safety data
No evidence for a primary dermal irritation was observed in rabbits following a single 24-hour cutaneous application of Rozex cutaneous emulsion to abraded and non-abraded skin, under occlusion.
Metronidazole has shown mutagenic activity in several in vitro bacterial assay systems. In vivo, metronidazole did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of mice treated either intraperitoneally or orally at doses up to 1500 and 2000 mg.kg-1 respectively, treatments at which clear signs of clinical toxicity were apparent. In the induction of chromosome aberrations study in cultured human peripheral blood lymphocytes, metronidazole did not induce aberrations in cultured human peripheral blood lymphocytes when tested to a maximum concentration of 10 mM in the absence and presence of metabolic activation.
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 (15 pg 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 treated sites to sun. After several decades of systemic use no evidence has been published to suggest that metronidazole is associated with a carcinogenic potential in humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Carbomer 941 Benzyl alcohol (E1519)
Glycerol Macrogol 400 Steareth-21
Glyceryl stearate/PEG-100 stearate Stearyl alcohol Light liquid paraffin Cyclomethicone Potassium sorbate (E202)
Lactic acid and/or sodium hydroxide solutions to adjust pH and purified water.
6.2 Incompatibilities
Not applicable
6.3
Shelf life
2 years
Shelf life after first opening: 60 days
6.4 Special precautions for storage
Do not store above 25°C.
Do not refrigerate or freeze.
6.5 Nature and contents of container
HDPE tubes with polypropylene screw caps.
Pack sizes: 15, 30 and 50g.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements for disposal.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Galderma (UK) Limited, Meridien House 69-71 Clarendon Road Watford Herts. WD17 1DS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 10590/0036
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/05/2013
10 DATE OF REVISION OF THE TEXT
24/01/2016