TRAVOCORT Cream Ref.[8251] Active ingredients: Diflucortolone Isoconazole

Isoconazole nitrate

Isoconazole penetrates rapidly into human skin from Travocort 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 as compared to a ratio of 10:1 present in Travocort cream, 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 metabolised 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 Travocort 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.

In systemic tolerance studies following repeated dermal and subcutaneous administration, the effect of diflucortolone valerate was that of a typical glucocorticoid. Following repeated dermal application of the active substance combination only those effects typical of glucocorticoids were observed. It can be derived from these results that no side effects other than these which are typical of glucocorticoids are to be expected following therapeutic use of Travocort under extreme conditions such as application over large areas and/or occlusion. There were no indications of possible interaction with isoconazole nitrate. The results from repeated dose systemic tolerance studies on isoconazole nitrate do not suggest that systemic effects of the antimycotic have to be expected under therapy with Travocort.

Embryotoxicity studies with Travocort led to results typical for glucocorticoids, i.e. embryolethal and/or teratogenic effects are induced in the appropriate test system. In view of these findings, particular care should be taken when prescribing Travocort during pregnancy. The results of epidemiological studies are summarized under section "4.6 Fertility, pregnancy and lactation"

In a series of special reproduction toxicity studies, isoconazole exerted no adverse effects on any phase of the reproductive cycle. In particular, the active ingredient showed no teratogenic potential. Although no controlled clinical studies have been carried out, experience in the use of preparations containing isoconazole nitrate during pregnancy does not indicate any risk of embryotoxic effects.

In vitro and in vivo investigations for detection of gene-, chromosome- and genome mutations have not given any indications of a mutagenic potential of diflucortolone valerate or isoconazole nitrate.

Specific tumorigenicity studies have neither been carried out with diflucortolone valerate nor with isoconazole nitrate. On the basis of the pharmacodynamic action pattern, the lack of evidence of a genotoxic potential, the structural properties and the results of chronic toxicity tests (no indication of proliferative changes), there is no suspicion of a tumorigenic potential of either of the active substances. Since systemically effective immunosuppressive dosages will not be reached after dermal application of Travocort if used as directed, no influence on the occurrence of tumours is to be expected.

According to the results from local tolerance studies following repeated dermal administration of diflucortolone valerate alone and in combination with isoconazole nitrate, no dermal changes further to the side-effects already known for topical preparations containing glucocorticoids are to be expected from therapy with Travocort.

Results from mucosal tolerance investigations on the rabbit eye show that a slight irritative effect is to be expected on the conjunctiva following inadvertent contamination of the eyes with Travocort.