TRAVODERMAL TOPICAL CREAM

Each 100 mg of TRAVODERMAL contains

0.1 g (0.1%) of diflucortolone valerate, 1 g (1%) of isoconazole nitrate.

Excipients with known effects: cetostearyl alcohol.

For the full list of excipients, see section 6.1.

Topical Cream

4.1 Therapeutic Indications

Initial or interim treatment of those superficial fungal infections of the skin which are accompanied by highly inflammatory or eczematous skin conditions, e.g. in the region of the hands, the interdigital spaces of the feet and in the inguinal and genital regions.

4.2 Posology and method of administration

Cutaneous use

TRAVODERMAL should be applied twice daily to the diseased areas of skin.

Treatment with TRAVODERMAL must be terminated after regression of the inflammatory or eczematous skin conditions or at the latest after 2 weeks and therapy continued or followed up with a glucocorticoid-free anti-fungal preparation. This applies in particular for use in the inguinal and genital regions.

Paediatric population:

Dose adjustments are not required when TRAVODERMAL is administered to children aged 2 years or older and adolescents.

Only limited data on the safety of TRAVODERMAL in children aged below 2 years are available, for more details see section 5.1.

4.3 Contraindications

Tuberculous or syphilitic processes in the area to be treated; virus diseases (e.g. varicella, herpes zoster), rosacea, perioral dermatitis and postvaccination skin reactions in the area to be treated.

Hypersensitivity to the active substances or to any of the excipients.

In general, TRAVODERMAL should be used without occlusion.

4.4 Special warnings and precautions for use

Specific additional therapy is required for bacterial infections of the skin.

TRAVODERMAL should not be allowed to come into contact with the eyes when being applied to the face. Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Extensive application of topical glucocorticoids to large areas of the body or for prolonged periods of time, in particular under occlusion, may increase the risk of systemic side effects.

As known from systemic glucocorticoids, glaucoma may also develop from using local glucocorticoids (e.g. after large-dosed or extensive application over a prolonged period, occlusive dressing techniques, or application to the skin around the eyes).

The physician should advise the patients on hygienic measures during the treatment.

If TRAVODERMAL is applied to the genital regions, the excipients liquid paraffin and soft paraffin may cause damage of latex products for barrier methods such as condoms and diaphragms used concomitantly, thus impairing their effectiveness.

This medicinal product contains cetostearyl alcohol which may cause local skin reactions (e.g. contact dermatitis).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of isoconazole nitrate/diflucortolon valerate in pregnant women

TRAVODERMAL should be avoided during the first trimester of pregnancy. In particular, treating large areas, prolonged use or occlusive dressings should be avoided during the whole of pregnancy.

Epidemiological studies suggest that there could possibly be an increased risk of oral clefts among newborns of women who were treated with glucocorticoids during the first trimester of pregnancy.

Breast-feeding

It is unknown whether isoconazole nitrate/diflucortolone valerate are excreted in human milk. A risk to the suckling child cannot be excluded.

Nursing mothers should not be treated on the breasts. Treating large areas, prolonged use or occlusive dressings should be avoided during lactation.

The clinical indication for treatment with TRAVODERMAL must be carefully reviewed and the benefits weighed against the risks in lactating women.

Fertility

Preclinical data did not indicate any risk on fertility.

4.7 Effects on ability to drive and use machines

There was no effect on the ability to drive and use machines in patients treated with TRAVODERMAL.

4.8 Undesirable effects

In clinical studies, most frequently observed adverse reactions included application site irritation and application site burning.

Frequencies of adverse reactions observed in clinical studies and given in the table below are defined according to the MedDRA frequency convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

As with other glucocorticoids for topical application, the following local adverse reactions may occur (frequency not known): Skin atrophy, application site folliculitis, hypertrichosis, telangiectasia, perioral dermatitis, skin discoloration, acne, and/or allergic skin reactions to any of the ingredients of the formulation. Systemic effects due to absorption may occur when topical preparations containing glucocorticoids are applied.

Adverse reactions cannot be excluded in neonates whose mothers have been treated extensively or for a prolonged period of time during pregnancy or while lactating (for example, reduced adrenocortical function, immunosuppression).

Reporting Suspected Adverse Effects

Reporting suspected adverse reactions after registration 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 at EPVC email “pv.report@edaegypt.gov.eg or company PhV email: pv@multicare-eg.com

4.9 Overdose

Results from acute toxicity studies do not indicate that any risk of acute intoxication is to be expected following a single dermal application of an overdose (application over a large area under conditions favourable to absorption) or inadvertent oral ingestion

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Imidazole and triazole derivatives, combinations

ATC Code: D01AC20

Isoconazole nitrate is for use in the treatment of superficial fungal diseases of the skin. It displays a very broad spectrum of antimicrobial action. It is effective against dermatophytes and yeasts, yeast-like fungi (including the causative organism of pityriasis versicolor) and molds, as well against gram-positive bacteria in-vitro and against the causative organism of erythrasma.

Diflucortolone valerate suppresses inflammation in inflammatory and allergic skin conditions and alleviates the subjective complaints such as pruritus, burning and pain.

5.2 Pharmacokinetic properties

Isoconazole nitrate:

Isoconazole penetrates rapidly into human skin from TRAVODERMAL cream and maximum drug concentrations in the horny layer and in the living skin are present 1 hour after application. High concentrations were maintained for at least 7 hours (horny layer: approx. 3500 μg/ml (corresponding to 7 mmol/l), living epidermis approx. 20 μg/ml (40 μmol/l), dermis approx. 3 μg/ml (6 μmol/l). Removal of the horny layer prior to the application increased isoconazole concentrations in the living skin approximately by a factor of 2. Drug concentrations in the horny layer and the epidermis exceeded minimum inhibitory and biocidal antimycotic concentrations (MIC) of most important pathogens (dermatophytes, molds and yeasts) several-fold and reached MIC values in the dermis.

In a further study, isoconazole nitrate could still be detected above the MIC in the stratum corneum and the hair follicles at one week after termination of a two-week application period. In some subjects, isoconazole nitrate could even be detected 14 days after the last application.

After topical application to rabbits of the antimycotic concentrations were obtained in the skin as compared to the corticosteroid-free preparation. This was interpreted as a retardation of percutaneous absorption of isoconazole nitrate as a consequence of the vasoconstrictive effect of the corticosteroid.

Furthermore, the concentration ratio between antimycotic and corticosteroid in the skin is increased, indicating that antimycotic efficacy is not impaired by the corticosteroid.

Isoconazole is not metabolically inactivated in the skin. Systemic load due to percutaneous absorption is low. Even after removal of the horny layer less than 1 % of the applied dose has reached the systemic circulation within 4 hours exposure time.

The percutaneous absorbed portion was too low to investigate the fate of isoconazole nitrate within the human organism. Therefore 0.5 mg of 3H-labelled isoconazole nitrate was injected intravenously. Isoconazole is completely metabolized and rapidly eliminated.

2,4-Dichloromandelic acid and 2-(2,6-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)-acetic acid were characterised as

quantitatively most important metabolites. A third of the labelled substances was excreted with the urine and two thirds with the bile; 75% of the total dose was already excreted within 24 hours.

Diflucortolone valerate:

Isoconazole does not influence penetration and percutaneous absorption of diflucortolone valerate. Diflucortolone valerate penetrates rapidly into the skin leading to horny layer levels of approximately 150 μg/ml (= 300 μmol/l) after one hour. Those levels are maintained for at least seven hours. Corticosteroid levels in the deeper epidermis were about 0.15 μg/ml (= 0.3 μmol/l).

Diflucortolone valerate is partly hydrolysed in the skin to the likewise effective diflucortolone. The portion of the corticosteroid which is percutaneously absorbed is low. Within four hours exposure time, less than 1 % of the topically applied TRAVODERMAL dose has been percutaneously absorbed.

Entering the systemic circulation, diflucortolone valerate is hydrolysed to diflucortolone and the corresponding fatty acid within minutes. Besides diflucortolone, 11- keto – diflucortolone and two further metabolites have been detected in the plasma. Diflucortolone and all metabolites are eliminated from the plasma with half-lives of 4 – 5 hours and approximately 9 hours respectively (half-lives after i.v. injection) and are excreted in a ratio of 75:25 with urine and faeces.

6.1 List of excipients

Polysorbate 60, sorbitan stearate, cetostearyl alcohol, Heavy liquid paraffin, White soft paraffin, disodium edetate and purified water.

6.2 Shelf life

3 years.

6.3 Special precautions for storage

Store at temperature not exceed 30ºC.

6.4 Nature and contents of container

Carton box containing aluminium tube of 15 gm and an inner leaflet.

Carton box containing aluminium tube of 30 gm and an inner leaflet.

6.5 MARKETING AUTHORISATION HOLDER

Manufacturer

Misr Company For Pharmaceutical Industries, Egypt. 

Licensor

PharmaCare Egypt for Trading Agency, Egypt.