INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ZORAC® GEL

SCHEDULING STATUS:
Schedule 3

PROPRIETARY NAME
(and dosage form):

ZORAC® GEL
ZORAC®0,05% Gel and ZORAC®0,1% Gel

COMPOSITION:
ZORAC® 0,05% Gel: Tazarotene 0,5 mg/g of gel
ZORAC® 0,1% Gel: Tazarotene 1 mg/g of gel

Preservative: Benzyl alcohol 1,0% (m/m)
Antioxidants: Ascorbic acid 0,5% (m/m)
  Butylhydroxyanisole 0,5% (m/m)
  Butylhydroxytoluene 0,5% (m/m)

PHARMACOLOGICAL CLASSIFICATION
A 13.9.1 Dermatological preparations. Preparations for psoriasis

PHARMACOLOGICAL ACTION
Tazarotene is a member of the acetylenic class of retinoids. Tazarotene is a retinoid prodrug which is converted to its active form, M1 ("tazarotenic acid'), by rapid de-esterification in most biological systems. "Tarazotenic acid" binds to and regulates gene expression through all three members of the RAR family of retinoid nuclear receptors, RAR
alpha, RARbeta and RARgamma. Within the RAR family, "tazarotenic acid" shows selectivity for RARbeta and RARgamma. "Tazarotenic acid" does not bind to or activate the RXR family of receptors. In addition, both cellular and in vivo studies show that, like tretinoin, tazarotene modulates cell differentiationand proliferation in a wide range of tissues.
Among its specific pharmacological activities, topical tazarotene blocks induction of epidermal ornithine decarboxylase (ODC) activity in the hairless mouse by the tumour promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). ODC catalyzes the first step in polyamine synthesis and is associated with cell proliferation and hyperplasia; both ODC activity and hyperplasia are elevated in the epidermal layer of the psoriatic plaque.
In cultured human keratinocytes, tazarotene suppresses expression of MRP8, an inflammatory marker present in psoriatic epidermis at high levels and blocks the synthesis of cornified envelopes and envelope precursors. Cornified envelope build-up is an element of psoriatic scale. Tazarotene, therefore, has multiple effects on keratinocyte differentiation and proliferation, as well as on inflammatory processes which contribute to the pathogenesis of psoriasis.
Tazarotene has been shown to be inactive in a series of animal tests for effects on CNS activity, analgesia, body temperature, digestive tract function, respiratory function, circulatory function and kidney function.

PHARMACOKINETICS
Absorption
: Controlled pharmacokinetic studies with 0.1%
14C tazarotene gel indicate that less than 1% of the dose is absorbed when applied topically (unoccluded) to psoriatic plaques and approximately 5% of the dose is absorbed after application to normal skin under occlusion.
After a 7-day dermal dosing period with tazarotene 0.1% gel to normal skin over 20% of the body surface area (0,1 mg/kg/day), the mean maximum plasma concentration was 0,72 + 0,58 ng/mL at 9 hours and the area under the plasma concentration time curve over a 24-hour time period was 10,1 + 7,2 ng hr/mL.
During clinical trials for the treatment of psoriasis with 0.1% or 0.5% gels, plasma concentrations of tazarotene were detected sporadically in only 1% of patients at very low levels (< 0,79 ng/mL). Plasma concentrations of the primary metabolite, “tazarotenic acid”, ranged from < 0,05 ng/mL (below the limit of quantitation) to 6,1 ng/mL, with a median plasma concentration of 0,27 ng/mL. The majority of patients with detectable “tazarotenic acid”had concentrations less than 1 ng/mL. Nine percent of patients tested had plasma concentrations of “tazarotenic acid”greater than 1 ng/mL.
The apparent plasma half-life of "tazarotenic acid" after topical administration of tazarotene was approximately 18 hours, supporting a once-daily dosing regimen. “Tazarotenic acid" is the only metabolite of tazarotene known to have retinoid activity.
Distribution: Dosing topically under occlusion, on normal skin, approximately 5% and 0,5% of the dose were recovered in the stratum corneum and epidermis-dermis layers, respectively, whereas in psoriatic patients, 1,4% of the dermal dose applied without occlusion was recovered in the stratum corneum and 2,4% in the epidermis-dermis layers.
Tazarotene and "tazarotenic acid" are extensively bound (more than 99%) to human plasma and albumin.
Metabolism: After topical administration to healthy subjects,
14C-tazarotene underwent esterase hydrolysis to "tazarotenic acid" and oxidative metabolism to inactive sulfoxide and sulfone derivatives. Secondary metabolites of "tazarotenic acid" (the sulfoxide, the sulfone and an oxygenated derivative of "tazarotenic acid") were detected in human urine and faeces.
Rapid systemic metabolism limits the propensity for tissue distribution and body exposure to tazarotene.
Excretion: Tazarotene was not excreted unchanged. Following a topical non-occluded dose to psoriatic patients, 0,3% of the dose was excreted in the urine and 0,4% excreted in the faeces. Greater than 75% of total drug excretion was completed within 72 hours after drug removal, with equal excretion of the radioactivity in urine and faeces.

INDICATIONS
ZORAC
® 0,1%/ZORAC® 0,05% are indicated for the topical treatment of plaque psoriasis.

CONTRA-INDICATIONS
ZORAC
® 0,1%/ZORAC® 0,05%are contra-indicated in individuals who have shown hypersensitivity to any of its components.
Retinoids should not be used on eczematous skin, as they may cause severe irritation.
Paediatric use: The safety and efficacy of tazarotene have not been established in paediatric patients under the age of 12 years.
ZORAC should not be used during pregnancy, in women planning a pregnancy or in lactating women.

WARNINGS
The safety of use over more than 20% of body surface area has not been established.
Use in pregnancy: Safety in humans during pregnancy has not been established.
Tazarotene was found to be non-teratogenic and non-foetotoxic when applied topicallyat the maximumtolerated doses in rats and rabbits. In experimental studies with animals, tazarotene, like other retinoids, was found to be teratogenic when administered orally at high doses. There are no adequate and well-controlled studies in pregnant women. Topical tazarotene should be used by women of childbearing years only after contraceptive counselling.
Marked skin irritation, possibly contributing to enhancement of photocarcinogenesis, was observed in hairless mice following chronic dermal dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0,001%, 0,005% and 0,01% for up to 40 weeks.
Relevance of these studies in humans has not been established.

DOSAGE AND DIRECTIONS FOR USE
For dermatological (cutaneous) use only.

General: Application may cause a feeling of burning or stinging. If this occurs, the dosage may be altered by choosing the lower drug concentration or temporarily reducing the frequency of application.

Apply ZORAC® 0,1%/ZORAC® 0,05%once a day, in the evening, to psoriatic lesions, using enough to cover only the lesions with a thin film. If a bath or shower is taken prior to application, the skin should be dry before applying the gel. If emollients are used, they should be applied and allowed to absorb into the skin before application of ZORAC® 0,1%/ZORAC® 0,05%. Because unaffected skin may be more susceptible to irritation, application of tazarotene to these areas should be carefully avoided. In clinical trials, ZORAC® 0,1%/ZORAC® 0,05%was used for a period of 12 weeks.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The most frequent adverse reactions (> 5%) reported during clinical trials with ZORAC® 0,1% / ZORAC® 0,05% in the treatment of psoriases included pruritus, burning/stinging, erythema, skin irritation, skin pain, worsening of psoriasis and rash. Reported less frequently (1% - 5%) were desquamation, contact irritant dermatitis, skin inflammation and dry skin. The following reactions were reported rarely (< 1%) by study subjects: fissuring of the skin, bleeding, skin discharge, increased skin fragility and localised oedema. The incidence and severity of adverse reactions appear to be dose related.
In human dermal safety studies, tazarotene 0.1% and 0,05% gels were moderately irritating under exaggerated conditions of the studies but did not induce contact sensitisation, phototoxicity or photoallergy.
Special precautions: Excessive itching, pruritus, burning, skin redness or peeling may occur. When this occurs, the medication should be discontinued until the integrity of the skin is restored.
Drug interactions: Concomitant dermatological medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of ZORAC® 0,1%/ZORAC® 0,05%is begun.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Excessive topical use of ZORAC® 0,1%/ZORAC® 0,05% may lead to marked redness, peeling or discomfort.
Inadvertent oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of vitamin A (hypervitaminosis A) or other retinoids.

IDENTIFICATION
ZORAC® 0,1%/ZORAC® 0,05%is a colourless to light yellow, translucent to cloudy, homogenous, aqueous gel packed in collapsible aluminium tubes with a tamper-evident aluminium membrane over the opening and a white screw cap.

PRESENTATION
ZORAC® 0,1%/ZORAC® 0,05% is packaged in tubes containing 30 g gel.

STORAGE INSTRUCTIONS
ZORAC® 0,1%/ZORAC® 0,05% should be stored at or below 30 C.
Keep tube tightly closed when not in use. Do not allow to freeze.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER
ZORAC® 0,1%: 31/13.9.1/0180
ZORAC® 0,05%: 31/13.9.1/0179

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Allergan Pharmaceuticals (Pty) Ltd
30 New Road (Entrance off Bavaria Road)
Randjespark Ext 11, Midrand, 1682
Johannesburg, Gauteng
South Africa

DATE OF PUBLICATION OF THIS PACKAGE INSERT
13 June 1997

New addition to this site: September 2009
Source: Pharmaceutical Industry

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