- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Active substance:Tazarotene ........................................................ 0.05 g
Excipients with known effect:Butylhydroxyanisole......................................... 0.05 gButylhydroxytoluene........................................ 0.05 g For 100 g of gel For the full list of excipients, see section 6.1.
PosologyZORAC gel is available in two concentrations.To initiate a treatment with ZORAC, it is advisable to start with ZORAC 0.05% in order to evaluate the skin response and tolerance before progressing to ZORAC 0.1% if necessary.Treatment with the lower concentration gel is associated with a somewhat lower incidence of local adverse events (see sections 4.8 Undesirable effects and 5. Pharmacological Properties).Treatment with the higher concentration gel gives a faster and numerically higher response rate. The physician should choose the concentration to be used based on clinical circumstances and the principle of using the least concentration of drug to achieve the desired effect.Individual variations with respect to efficacy and tolerability are possible. It is thus advisable for patients to consult their physician on a weekly basis when initiating therapy.
Paediatric populationThe safety and efficacy of ZORAC gel in children under the age of 18 years has not been established.
Method of administrationA thin film of the gel should be applied once daily in the evening; care should be taken to apply it only to areas of affected skin, avoiding application to healthy skin or in skin folds. Treatment is limited to 10% body surface area (approximately equivalent to the total skin area of one arm).If the patient experiences more drying or irritation, an effective greasy emollient (without pharmaceutically active ingredients) can be applied to the areas of the skin to be treated to improve tolerability. Healthy skin around the psoriatic plaques can be covered by using zinc paste, for example, to prevent irritation.Usually, the treatment period is up to 12 weeks. Clinical experience, particularly on tolerability, is available on periods of use of up to 12 months.
PregnancyZORAC gel is contraindicated in women who are or may become pregnant (see 4.3). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient apprised of the potential hazard to the foetus. Women of child-bearing potential should be warned of the potential risk and use adequate birth control measures when ZORAC gel is used. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test having a sensitivity down to at least 50 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeks prior to ZORAC gel therapy, which should begin during a normal menstrual period. Although in animals no malformations were observed after dermal application, skeletal alterations were seen in the foetuses, which may be attributable to systemic retinoid effects. Teratogenic effects were observed after oral administration.
LactationAlthough no data are available on the excretion of tazarotene in human milk, animal data indicate that excretion into milk is possible. For that reason ZORAC gel should not be used during breast-feeding.
|Skin and subcutaneous tissue disorders|
|Very common:||Pruritus, burning, erythema, and irritation|
|Common:||Desquamation, non-specific rash, irritant contact dermatitis, skin pain, worsening of psoriasis, stinging and inflamed and dry skin.|
Post-marketing ExperienceThe following adverse reactions have been identified during post-marketing use of ZORAC gel in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship.
Skin and subcutaneous tissue disordersBlister, skin discoloration (including skin hyperpigmentation or skin hypopigmentation).
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard.
AbsorptionResults of a pharmacokinetic study of single topical application of 0.1% 14C-tazarotene gel show that approximately 5% is absorbed when applied to normal skin under occlusion.After a single topical application of tazarotene gel to 20% body surface area for 10 hours in healthy volunteers, tazarotene was not detectable in the plasma. Maximum plasma levels for the active metabolite tazarotenic acid of 0.3 ± 0.2 ng/ml (for the 0.05% strength) and 0.5 ± 0.3 ng/ml (0.1% gel) were measured after approximately 15 hours. The AUC was 40% higher for the 0.1% gel compared with the 0.05% gel. Thus, the two strengths of the gel are not strictly dose proportional with respect to systemic absorption. Repeated topical application of the 0.1% gel over 7 days led to maximum plasma levels for tazarotenic acid of 0.7 ± 0.6 ng/ml after 9 hours.
BiotransformationAfter dermal application, tazarotene undergoes esterase hydrolysis to form its free acid, tazarotenic acid, and oxidative metabolism to form inactive sulphoxide and sulphone derivatives.
EliminationSecondary metabolites of tazarotenic acid (the sulphoxide, the sulphone and an oxygenated derivative of tazarotenic acid) have been detected in human urine and faeces. The elimination half-life of tazarotenic acid after dermal application of tazarotene is approximately 18 hours in normal and psoriatic subjects.After intravenous administration, the half-life of tazarotene was approximately 6 hours and that of tazarotenic acid 14 hours.b) Characteristics after use in patientsAfter single topical application of 0.1% 14C-tazarotene gel for 10 hours to psoriatic lesions (without occlusion), 4.5% of the dose was recovered in the stratum corneum and 2.4% in the epidermal/dermal layers. Less than 1% of the dose was absorbed systemically. More than 75% of drug elimination was completed within 72 hours.In a small five patient study, repeated topical application of tazarotene 0.1% gel over 13 days results in a mean peak plasma level of tazarotenic acid of 12 ± 8 ng/ml. These patients had psoriatic lesions on 8-18% of body surface area. In a larger 24 psoriatic patient study, tazarotene 0.05% and 0.1% gels were applied for 3 months and yielded a Cmax of 0.45 ± 0.78 ng/ml and 0.83 ± 1.22 ng/ml, respectively.In a 1 year clinical study with 0.05% and 0.1% tazarotene gel, tazarotene was detected in 3 out of 112 patients at plasma concentrations below 1 ng/ml, while its active metabolite tazarotenic acid was found in 31 patients. Only four patients had plasma concentrations of tazarotenic acid greater than or equal to 1 ng/ml (maximum 2.8 ng/ml).
Subacute / Chronic toxicityThe safety of daily dermal application of tazarotene gel was tested in mouse, rat and mini-pig over periods of up to one year. The main observation was reversible skin irritation. In the case of the mini-pig, an incomplete healing of the dermal irritation was observed after an 8 week recovery period. The rat appears to be the most sensitive species to tazarotene, as is the case with other retinoids. Here, dermal application induced severe skin reactions and clinically significant retinoid-like systemic effects. No adverse systemic effects were observed in the other species.After oral administration of 0.025 mg/kg/day for 1 year in the cynomolgus monkey, no toxic effects were observed. At higher doses, typical symptoms of retinoid toxicity were seen.
Reproductive toxicitySafety of use during pregnancy has not been established. Teratogenic and embryotoxic effects were observed after oral administration in the rat and rabbit. In dermal application studies during foetal development, skeletal alterations and decreased pup weight at birth and at the end of the lactation period were observed.Animal tests suggest that tazarotene or its active metabolite is excreted in breast milk and passes the placenta barrier.No effects on fertility are reported after topical application in the male and female rat.
Mutagenicity / carcinogenicityNo evidence of a mutagenic potential of tazarotene has been reported in in vitro and in vivo trials.In long term investigations of the effects of dermal and oral administration in animals, no carcinogenic effects were observed.There was an increased incidence of photocarcinogenic effects in the hairless mouse when exposed to UV light after topical application of tazarotene.
Local tolerabilityTazarotene gel has a considerable irritative potential on skin in all animal species investigated.Instillation of tazarotene gel in the eye of the rabbit resulted in irritation with marked hyperaemia of the conjunctiva, but there was no corneal damage.
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