Full Prescribing Info Contents Isoconazole nitrate, diflucortolone valerate. Description 1 g Isoconazole nitrate + Diflucortolone valerate (Travocort) contains 10 mg (1 %) isoconazole nitrate and 1 mg (0.1 %) diflucortolone valerate. Excipients/Inactive Ingredients: Cetostearyl alcohol, Disodium edetate, Liquid paraffin, White soft paraffin, Polysorbate 60, Sorbitan stearate, Purified water. Action Pharmacotherapeutic group: Imidazole and triazole derivatives, combinations. ATC Code: D01AC20. Pharmacology: Pharmacodynamics: 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 as 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. Pharmacokinetics: Isoconazole nitrate: Isoconazole penetrates rapidly into human skin from Isoconazole nitrate + Diflucortolone valerate (Travocort) cream and reaches maximum drug concentrations in the horny layer and in the living skin already 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 higher 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 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 the Isoconazole nitrate + Diflucortolone valerate (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-labeled 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 characterized as quantitatively most important metabolites. A third of the labeled 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 hydrolyzed in the skin to the likewise effective diflucortolone. The portion of the corticosteroid, which is percutaneously absorbed, is low. Within four hour exposure time, less than 1 % of the topically applied Isoconazole nitrate + Diflucortolone valerate (Travocort) dose have been percutaneously absorbed. Entering the systemic circulation, diflucortolone valerate is hydrolyzed 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 respectively all metabolites are eliminated from the plasma with half-lives of 4 - 5 hours and approx. 9 hours, respectively (half-lives after i.v. injection) and are excreted in a ratio of 75:25 with urine and feces. Toxicology: Preclinical safety data: 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 further to those which are typical of glucocorticoids are to be expected following therapeutic use of Isoconazole nitrate + Diflucortolone valerate (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 Isoconazole nitrate + Diflucortolone valerate (Travocort). Embryotoxicity studies with Isoconazole nitrate + Diflucortolone valerate (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 Isoconazole nitrate + Diflucortolone valerate (Travocort) during pregnancy. The results of epidemiological studies are summarized under Use in Pregnancy & Lactation. Specific investigations into reproduction toxicology gave no indications of restrictive influence of the various reproductive phases due to isoconazole nitrate. 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 dosages will not be reached after dermal application of Isoconazole nitrate + Diflucortolone valerate (Travocort) if used as directed, no influence on the occurrence of tumors 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 Isoconazole nitrate + Diflucortolone valerate (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 Isoconazole nitrate + Diflucortolone valerate (Travocort). Indications/Uses 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. Dosage/Direction for Use Method of administration: Cutaneous use. Dosage regimen: Isoconazole nitrate + Diflucortolone valerate (Travocort) should be applied twice daily to the diseased areas of skin. The treatment with Isoconazole nitrate + Diflucortolone valerate (Travocort) must be terminated after regression of the inflammatory or eczematous skin condition, at the latest, however, after 2 weeks, and the therapy continued or followed up with a glucocorticoid free anti-fungal preparation. This applies in particular for use in the inguinal and genital regions. Additional information on special populations: Pediatric patients: Dose adjustments are not required when Isoconazole nitrate + Diflucortolone valerate (Travocort) is administered to children aged 2 years or older and adolescents. Only limited data on the safety of Isoconazole nitrate + Diflucortolone valerate (Travocort) in children aged below 2 years are available. Overdosage 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 favorable to absorption) or inadvertent oral ingestion. 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. Special Precautions Specific additional therapy is required for bacterial infections of the skin. Isoconazole nitrate + Diflucortolone valerate (Travocort) should not be allowed to come into contact with the eyes when being applied to the face. 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 Isoconazole nitrate + Diflucortolone valerate (Travocort) 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. Effects on ability to drive or use machines: No effects on ability to drive and use machines have been observed in patients treated with Isoconazole nitrate + Diflucortolone valerate (Travocort). Use In Pregnancy & Lactation Pregnancy: There are no data from the use of isoconazole nitrate/diflucortolone valerate in pregnant women. Studies in animals (mice, rats and rabbits) have shown reproductive toxicity for diflucortolone valerate (see Pharmacology: Toxicology: Preclinical safety data under Actions). In general, the use of topical preparations containing glucocorticoids should be avoided during the first trimester of pregnancy. In particular, treating large areas, prolonged use or occlusive dressings should be avoided during 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. The clinical indication for treatment with Isoconazole nitrate + Diflucortolone valerate (Travocort) must be carefully reviewed and the benefits weighed against the risks in pregnant women. Lactation: 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 Isoconazole nitrate + Diflucortolone valerate (Travocort) must be carefully reviewed and the benefits weighed against the risks in lactating women. Fertility: Preclinical data did not indicate any risk on fertility. Adverse Reactions Summary of the safety profile: In clinical studies, most frequently observed adverse reactions included application site irritation and application site burning. Tabulated list of adverse reactions: Frequencies of adverse reactions observed in clinical studies and given in the table as follows 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). (See table.) Click on icon to see table/diagram/image Description of selected adverse reactions: 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). View ADR Monitoring Form Drug Interactions No interaction studies have been performed. Caution For Usage Incompatibilities: Not applicable. Instructions for use/handling: No special requirements. Storage Store all drugs properly. Store at temperatures not exceeding 30°C. Shelf life: 36 months.