This information is intended for use by health professionals

1. Name of the medicinal product

ROSICED 7.5 mg/g Cream

2. Qualitative and quantitative composition

1 g of cream contains 7.5 mg of metronidazole (0.75% m/m)

For excipients, see 6.1.

3. Pharmaceutical form

Cream

Smooth white to off-white cream.

4. Clinical particulars
4.1 Therapeutic indications

For the topical treatment of inflammatory papulo-pustules rosacea related.

4.2 Posology and method of administration

Cutaneous use

Adults and elderly

Apply and gently rub the cream into the affected skin of the face in a thin film twice daily for a usual duration of treatment of 6 to 12 weeks. If necessary, treatment may be continued (see section 4.4). In the absence of any clinical improvement therapy should be stopped.

Children and adolescents

There is no adequate clinical data on efficacy and safety of Rosiced® cream in children; therefore Rosiced® cream should not be applied to children.

Areas to be treated should be cleansed before application of the cream. Patients may use non-comedogenic and non-astringent cosmetics after application of the cream.

4.3 Contraindications

ROSICED 7.5 mg/g Cream is contraindicated during the first third of pregnancy.

ROSICED 7.5 mg/g Cream must not be taken by patients with hypersensitivity to medicinal products containing metronidazole or other 5-nitroimidazoles as does ROSICED 7.5 mg/g Cream. Sole exception is in cases of life-threatening infections and if other medicines are inefficacious.

ROSICED 7.5 mg/g Cream is contraindicated in patients with hypersensitivity to any of the excipients.

In patients with severe liver damage, dyshaematopoiesis, and diseases of the central or peripheral nervous system a careful risk-benefit assessment is necessary prior to treatment with ROSICED 7.5 mg/g Cream.

4.4 Special warnings and precautions for use

Avoid contact with the eyes or any mucocutaneous application. If contact occurs, the cream should be washed out carefully with water.

If irritation does occur the patient should be advised to use Rosiced® cream less frequently or to stop temporarily and to seek medical advice if necessary.

UV exposure (sunbathing, solarium, sunlamp) should be avoided during the therapy with Rosiced® cream.

The recommended duration of therapy should not be exceeded. If required, the therapy could be repeated, however the interval of 6 weeks in between should be considered.

There is no adequate clinical data on efficacy and safety of Rosiced® cream in children; therefore Rosiced® cream should not be applied to children

ROSICED 7.5 mg/g Cream should be used with caution in patients with evidence or history of blood dyscrasia.

Unnecessary or 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.

ROSICED 7.5 mg/g Cream contains propylene glycol which may cause skin irritation.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions with other topically applied medicinal products are not known.

Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application of Rosiced® cream 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 unknown.

4.6 Pregnancy and lactation

The safety of the use of metronidazole during pregnancy is not sufficiently proven.

Contradictory reports are available especially regarding early pregnancy. Some studies have yielded indications of an increased rate of malformations. The risk of possible sequelae, including a carcinogenic risk, is not yet clarified.

In case of unrestricted use of nitroimidazoles by the mother, the foetus and/or neonate is exposed to a carcinogenic or genotoxic risk. So far, there is no proven evidence of a damage to embryo or foetus. In animal experimental studies, metronidazole did not exhibit any teratogenic properties (see. 5.3)

ROSICED 7.5 mg/g Cream is contraindicated during the first third of pregnancy. During the middle and the last third of pregnancy ROSICED 7.5 mg/g Cream should only be administered if other treatments have been unsuccessful.

Metronidazole passes into maternal milk. After oral administration, up to 100% of the plasma value can be reached. Following topical application of ROSICED 7.5 mg/g Cream the plasma levels are lower than after oral administration of metronidazole. Nevertheless, during lactation breast-feeding should either be interrupted or the treatment with ROSICED 7.5 mg/g Cream should be discontinued.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

Immune system disorders:

Rare: anaphylaxis

Skin and subcutaneous tissue disorders:

Common: contact dermatitis, dry skin, erythema, pruritus, rash, skin discomfort (burning and stinging), skin irritation, worsening of rosacea

Rare: angio-edema

Nervous system disorder:

Uncommon: hypothesia, paraesthesia

General disorders and administration site conditions:

Common: pain

Gastrointestinal disorders:

Rare: metallic taste, 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

4.9 Overdose

Overdose is extremely unlikely. The cream should be removed by washing with warm water.

No data exist about overdose in humans. Acute oral toxicity studies with topical gel formulation containing 0.75% w/w metronidazole in rats have shown no toxic action with doses of up to 5g 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 metronidazole cream 0.75% for an adult weighing 72 kg and 2 tubes of cream for a child weighing 12 kg.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Chemotherapeutics for topical use

ATC-code: D06BX01

When applied topically metronidazole is active against the inflammatory aspect of rosacea.

Metronidazole belongs to the group of nitroimidazoles. It is reduced in sensitive protozoa and strictly anaerobic bacteria with formation of acetamide and N-(2-hydroxyethyl)-oxamid acid. Interaction with DNA leads to inhibition of the nucleic acid synthesis of the micro-organisms concerned, which results in the death of these agents.

There is no parallel resistance to other antibacterial substances.

5.2 Pharmacokinetic properties

The systemic concentration of metronidazole following topical administration of ROSICED 7.5 mg/g Cream to 18 healthy volunteers ranged from 19 ng/ml to 107 ng/ml with a mean Cmax of 49 ng/ml i.e. 600 times lower than after 2 g oral administration.

The tmax for the topical formulation was 8.9 hours. The absorption rate-limited half life for metronidazole is 33 hours. The oral half life of metronidazole is approximately 8 hours.

Following oral administration, metronidazole is absorbed speedily and almost completely with maximum serum levels after 1-2 hours. If administered rectally, approximately 80% of the substance is available systematically and the serum maximum is reached after approximately 4 hours. Following vaginal administration only approximately 20% are found in the serum; in this case the maximum is reached later, after 8 – 24 hours. The serum half life is about 8 (6 to 10) hours. Several metabolites are formed in the human organism; the hydroxymetabolite (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole) and the “acidic” metabolite (2-methyl-5-nitroimidazole-1-yl-acetic acid) are the main metabolites.

Approximately 80% of the substance is excreted renally, the not metabolised share being less than 10%. Small amounts (ca.6%) are also excreted via the liver. Renal insufficiency prolongs excretion only insignificantly. In the case of severe hepatic insufficiency a delayed elimination must be expected. In patients with highly reduces liver function the half-life can be prolonged to up to 30 hours. Protein binding is less than 20%. The apparent volume of distribution is ca. 36 l.

5.3 Preclinical safety data

a) Acute toxicity

Acute toxicity was tested in mice in two different routes of administration. If administered orally, the LD50 values were 3 800 mg/kg body weight and if administered intraperitoneally they were 3 950 mg/kg body weight. Thus, acute toxicity is very low.

No cases of acute toxicity in humans were known. The toxic blood level is stated to be 200 µg/ml, which is 10-fold higher than taken according to the intended oral use.

b) Subacute toxicity

In chronic toxicity studies no side effects could be observed in rats after administration of metronidazole for 26 to 80 weeks. Only at doses of 300 to 600 mg/kg body weight and day did testis dystrophy and prostate atrophy occur. Toxic effects in dogs receiving 75 mg/kg body weight and day were expressed as ataxia and tremor. Investigations in monkeys showed a dose-dependent increase in hepatic cell degeneration after administration of 45, 100 and/or 225 mg/kg body weight and day for one year.

18 mg/kg/day were stated as being the lowest toxic dose at 8 weeks continuous oral administration to humans. Cholestatic hepatosis and peripheral neuropathy are generally rare side effects.

c) Mutagenic and tumorigenic potential

Mutagenicity

Following nitroreduction, metronidazole acts mutagenic in bacteria. Methodologically valid investigation yielded non indication of a mutagenic effect in mammalian cells in vitro and in vivo. Investigation in lymphocytes of patients treated with metronidazole yielded no relevant indications of DNA-damaging effects.

Carcinogenicity

There are indications that metronidazole has tumorigenic effects in rats and mice. The increase rate of lung tumours after oral administration to mice is especially worth mentioning. There does not appear to be a connection with genotoxic mechanism of action since no increased mutation rates were observed in various organs including the lung of transgenic mice after administration of high doses of metronidazole.

After intra peritoneal administration of metronidazole (15 µg/g body weight) to hairless mice for 4 weeks an increase in UV-induced skin tumours was observed.

The significance of these carcinogenicity findings for cutaneous treatment of rosacea with ROSICED 7.5 mg/g Cream in humans remains unclear, especially as decades of systemic use of metronidazole in humans have yielded no indications of an increase risk of cancer. Nevertheless, patients should be advised to avoid direct exposure of the treated skin areas to sun light if possible.

d) Reproductive toxicity

Animal experiments did not show any teratogenic or other embryotoxic effects in rats at doses of up to 200 mg/kg body weight and in rabbits up to 150 mg/kg body weight per day.

e) Local tolerance

In a local tolerance study ROSICED 7.5 mg/g Cream was considered slightly irritant, without any systemic toxicity. Skin sensitisation power of ROSICED 7.5 mg/g Cream has been found to be very low, and no phototoxicity or photosensitization has been observed.

6. Pharmaceutical particulars
6.1 List of excipients

Glyceryl monolaurate

Glyceryl monomyristate

Propylene glycol

Citric acid anhydrous

(pH adjuster)

Sodium hydroxide

(pH adjuster)

Carbomers

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

After first opening: 8 weeks

6.4 Special precautions for storage

Do not store above 30°C.

Do not refrigerate or freeze.

6.5 Nature and contents of container

MDPE tubes fitted with polypropylene caps containing 25 g, 30 g, 40 g or 50 g of cream.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

PIERRE FABRE DERMATOLOGIE

45 PLACE ABEL GANCE

92100 BOULOGNE

FRANCE

8. Marketing authorisation number(s)

PL 20693/0007

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 05/12/2001 Date of renewal: 06/06/2007

10. Date of revision of the text

25/03/2015