Consumer medicine information

Zorac Cream

Tazarotene

BRAND INFORMATION

Brand name

Zorac Cream

Active ingredient

Tazarotene

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zorac Cream.

What is in this leaflet

This leaflet answers some common questions about ZORAC® cream. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ZORAC® cream against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ZORAC® cream is used for

ZORAC® 0.5 mg/g and 1.0 mg/g (0.05% w/w and 0.1% w/w) cream is used to treat plaque psoriasis. In addition, 1.0 mg/g is used to treat facial acne.

Acne is characterised by inflamed pimples and non-inflamed pimples on the skin.

Psoriasis is characterised by inflamed red skin with red, thickened areas often with silvery scales called plaques.

ZORAC® cream contains tazarotene as the active ingredient which is a retinoid. The exact mechanisms of action for psoriasis and acne are not known. It is thought to act by helping skin cells to grow normally as well as having an anti-inflammatory effect in psoriasis and acne.

ZORAC® cream is only available with a doctor's prescription from pharmacies. Your doctor may have prescribed ZORAC® cream for another reason.

Ask your doctor if you have any questions about why ZORAC® cream has been prescribed for you.

Before you use ZORAC® cream

When you must not use it

Do not use ZORAC® cream if:

  • you have an allergy to tazarotene or any of the ingredients listed at the end of this leaflet.
  • you are pregnant or plan to become pregnant.
  • you have a skin condition called eczema. ZORAC® cream may cause severe irritation if used on eczematous skin.
  • the tube/packaging shows signs of tampering.
  • the product does not look quite right.
  • the expiry date on the tube has passed.
    If you use this medicine after the expiry date has passed, it may not work effectively.

It is not known whether ZORAC® cream is safe and useful for children and adolescents under 18 years, in psoriasis or under 12 years in acne.

This cream is for topical use only. Avoid contact with eyes, eyelids and mouth.

Before you start to use it

Tell your doctor if

  • you have had an allergy to any medicines or any other substances, such as foods, preservatives or dyes.
  • if you are pregnant or intend to become pregnant.
    Like many medicines, ZORAC® cream should not be used during pregnancy. Talk to your doctor about effective birth control if you are a woman who is able to become pregnant.
    Talk to your doctor about a time period after which pregnancy can be contemplated after using ZORAC® cream.
    If you become pregnant while using this medicine, stop using it and contact your doctor immediately as this product may cause birth defects.
  • you are breast feeding or intend to breast feed.
  • you have sunburn. You should wait until your skin has finally recovered from the sunburn before using ZORAC® cream.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor or pharmacist if you are taking medicines that are known to cause sun sensitivity e.g. thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides.

If you take these medicines while using ZORAC® cream, your skin may become more sensitive to the sun.

Watch your reaction to ZORAC® cream carefully if you are also using other skin products with a strong drying effect or high amounts of alcohol, astringents, spices, lime peel, medicated soaps or shampoos, permanent wave solution, electrolysis, hair depilatories or waxes or other products or processes that may dry or irritate the skin.

Ask your doctor or pharmacist if you have any concerns about using ZORAC® cream as well as other medications.

How to use ZORAC® cream

How much to use

Your doctor will tell you how much cream you need to use each day. Use ZORAC® cream only as prescribed by your doctor.

For psoriasis: apply ZORAC® cream once a day, in the evening, to the psoriatic lesions using enough to cover only the lesions with a thin film.

For acne: apply a thin film of ZORAC® 1.0 mg/g cream once a day in the evening to the skin where acne lesions appear.

Follow all directions given to you by your doctor carefully. The directions may differ from the information contained in this leaflet.

Use ZORAC® cream every day, at about the same time each day, unless your doctor tells you otherwise.

How to use it

Psoriasis:
Remove makeup (if present) before applying ZORAC® cream. If you wash your face prior to application, you should allow your skin to dry before applying ZORAC® cream.

After the skin is dry, apply a thin layer of ZORAC® cream once a day to the areas of your skin with psoriasis.

Carefully avoid application of the cream to other areas that are not affected by psoriasis. If the cream is applied to areas that are not required to be treated wash the cream off.

Follow your doctor or pharmacists' directions for other routine skin care and the use of make-up.

Wash your hands after applying medication unless you are treating your hands for psoriasis. If you are treating hands, avoid contact with the eyes.

Do not use more ZORAC® cream than instructed or more often than instructed.

While using ZORAC® cream, weather extremes, such as wind or cold may irritate your skin more than usual. Application of the cream may cause burning or stinging for a short time. If this persists, talk to your doctor or pharmacist. You should avoid using a solarium and when outside you should use a sunscreen with an SPF of at least 15 and protective clothing during the day.

Ask your doctor or pharmacist any questions you may have.

How to use it

Acne:
Remove makeup (if present) before applying ZORAC® cream. If you wash your face prior to application, you should allow your skin to dry before applying ZORAC® cream.

After the skin is dry, apply a thin layer of ZORAC® cream once a day to the skin where the acne lesions appear.

Use enough to cover the entire affected area. All skin prone to acne should be treated.

Carefully avoid application of the cream to other areas that are not affected by acne. If the cream is applied to areas that are not required to be treated, wash the cream off.

Follow your doctor or pharmacists' directions for other routine skin care and the use of make-up. You should talk to your doctor or pharmacist about the use of sunscreens, moisturisers and cosmetics.

If emollients or a moisturiser are used, they can be applied before or after ZORAC® cream but whichever one is applied first should be allowed to absorb into the skin before the next one is applied.

Wash your hands after applying medication. If the cream is applied to areas that are not required to be treated, wash the cream off.

Keep ZORAC® cream away from your eyes and mouth. If the cream gets in your eyes, wash them with large amounts of cool water. Contact your doctor if eye irritation continues.

While using ZORAC® cream, weather extremes, such as wind or cold, may irritate your skin more than usual.

Application of the cream may cause burning or stinging for a short time. If this persists, talk to your doctor or pharmacist. You should avoid using a solarium and when outside you should use a sunscreen with an SPF of at least 15 and protective clothing during the day.

Ask your doctor or pharmacist any questions you may have.

How long to use it

Continue using ZORAC® cream for as long as your doctor prescribes.

If you forget to use it

If you miss a dose, do not try to make it up. Continue your normal schedule.

Do not use double the amount to make up for the dose that you missed.

If you use too much (overdose)

If you accidentally put ZORAC® cream in your eye(s), immediately rinse your eye(s) with large amounts of cool water. Contact your doctor if eye irritation continues.

If you think that you or anyone else may have swallowed ZORAC® cream, immediately telephone your doctor or Poisons Information Centre (Australia: telephone 13 11 26; New Zealand: telephone 0800 POISON or 0800 764 766) for advice or go to casualty at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

While you are using ZORAC® cream

Things you must do

You should use adequate contraception (e.g. the pill, condoms) while using ZORAC® cream.

If you become pregnant while using ZORAC® cream, stop use and tell your doctor immediately.

Tell your doctor if your condition gets worse or does not get better while using ZORAC® cream.

If you are about to start any new medicine, tell your doctor or pharmacist that you are using ZORAC® cream.

Things you must not do

Do not give ZORAC® cream to anyone else, even if they have the same condition as you.

Side effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using ZORAC® cream.

Check with your doctor or pharmacist as soon as possible if you have any problems while using ZORAC® cream, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Ask your doctor or pharmacist to answer any questions you may have.

Side effects in psoriasis:

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • itching
  • redness of the skin
  • burning

Less often the following effects have been seen:

  • irritation of the skin
  • peeling of the skin
  • stinging
  • skin rash
  • eczema (a skin condition with itching, redness and a burning feeling and often include blisters that weep and become crusted.)
  • worsening of psoriasis
  • skin pain
  • high triglycerides levels in the blood
  • dry skin
  • skin inflammation
  • general swelling

Rarely:
Cracking of the skin, flaking of the skin, bleeding skin, weeping skin, erosion of the skin, blistering rash, skin rash with pus filled blisters, redness of the nose and cheeks, skin reaction, hives (itchy rash), allergic skin rash, skin blisters, eyelid irritation, redness of the eyelids, pain, chills, headache, infection, itchy scalp, high cholesterol in the blood, swelling, SGOT and SGPT enzyme levels increased, mouth ulcers, nausea, aching muscles not caused by exercise and sleeplessness.

Side effects in acne:

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • peeling of the skin
  • dry skin
  • redness of the skin
  • burning sensation

Less often the following effects have been seen:

  • itching
  • irritation of the skin
  • stinging of the skin
  • face pain

Rarely:
Acne, skin discolouration, rash, worsening acne, sun-induced redness of the skin, flaking of the skin, eczema (a skin condition with itching, redness and a burning feeling which often includes blisters that weep and become crusted), skin pain, lumps on the skin and tightness of the skin, skin blisters, pain, infection, headache, cracking or inflammation of the lips, sore throat (discomfort when swallowing) and diminished sensitivity.

After using ZORAC® cream

Storage

Keep your ZORAC® cream in a cool place where the temperature stays below 25°C.

Do not put it in the refrigerator or freezer.

Keep the tube where children cannot reach it.

Do not leave the top/lid off the tube for any length of time to avoid contaminating the cream.

Disposal

Throw out any remaining cream after 12 months from the date of opening.

If your doctor tells you to stop using the cream or it has passed the expiry date, ask your pharmacist what to do with any remaining cream.

Product description

What ZORAC® cream looks like

A white to off white cream in collapsible aluminium tube with tamper-evident opening and screw cap.

Ingredients

Active ingredient:

Tazarotene 1.0 mg/g (0.1%w/w) or

Tazarotene 0.5 mg/g (0.05%w/w)

Preservative:

Benzyl alcohol

Inactive ingredients:

Sodium thiosulfate pentahydrate

Disodium edetate

Liquid paraffin

Medium chain triglycerides

Carbomer 1342

Sorbitan mono-oleate

Carbomer 934P

Sodium hydroxide

Purified water

Manufactured by Allergan

Supplier

Allergan Australia Pty Ltd.
810 Pacific Highway,
Gordon NSW 2072
ABN 85 000 612 831

ZORAC® cream can be identified by registration numbers:

ZORAC® 0.5 mg/g (0.05% w/w) cream - AUST R 101328

ZORAC® 1.0 mg/g (0.1% w/w) cream - AUST R 101327

Date of preparation:

September 2018

® marks owned by Allergan, Inc.

© 2018 Allergan, Inc.

Published by MIMS November 2018

BRAND INFORMATION

Brand name

Zorac Cream

Active ingredient

Tazarotene

Schedule

S4

 

1 Name of Medicine

Tazarotene.

2 Qualitative and Quantitative Composition

Zorac 0.05% w/w cream contains 0.5 mg/g of tazarotene.
Zorac 0.1% w/w cream contains 1 mg/g of tazarotene.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zorac is a topical cream.

4 Clinical Particulars

4.1 Therapeutic Indications

For the topical treatment of plaque psoriasis. For the topical treatment of facial acne (0.1% concentration only; see Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

For dermatological (cutaneous) use only.

General.

Application may cause a transitory feeling of burning or stinging. If irritation becomes problematic, the dosage may be altered by choosing the lower drug concentration (in psoriasis only) or temporarily reducing the frequency of application (in psoriasis and acne). Efficacy has not been established for less than once daily dosing frequencies. Application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance.
If the face is washed or a bath or shower is taken prior to application, the skin should be dry before applying the cream. If emollients or moisturisers are used, they can be applied either before or after tazarotene cream but whichever one is applied first should be allowed to absorb into the skin before the next one is applied.

Psoriasis.

Apply Zorac cream once a day in the evening to psoriatic lesions, using enough (2 mg/cm2) to cover only the lesions with a thin film.
Treatment may start with Zorac 0.05% w/w cream, with the strength increased to 0.1% if tolerated and medically indicated. Zorac 0.1% w/w cream was generally more effective than the 0.05% w/w concentration in reducing the severity of the individual signs of disease.
If irritation becomes problematic, the dosage may be altered by choosing the lower drug concentration or temporarily reducing the frequency of application. Efficacy has not been established for less than once daily dosing frequencies. Application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance.

Acne.

Cleanse the skin thoroughly. After the skin is dry, apply a thin film of Zorac 0.1% w/w cream once a day in the evening to the skin where acne lesions appear. Use enough to cover the entire affected area. If any makeup is present it should be removed before applying Zorac cream to the face.

4.3 Contraindications

Zorac cream is contraindicated in individuals who have shown hypersensitivity to any of its components. Zorac cream is contraindicated in pregnancy and in women planning a pregnancy.
Retinoids should not be used on eczematous skin, as they may cause severe irritation.

4.4 Special Warnings and Precautions for Use

General.

Zorac cream should only be applied to affected areas. For external use only. Avoid contact with eyes, eyelids and mouth. If contact with eyes occurs, rinse thoroughly with water.
Some individuals may experience excessive itching, pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored or the dosing should be adjusted to a level or interval the patient can tolerate.
Patients should be advised to avoid excessive exposure to UV light (use of a solarium or PUVA therapy) during treatment with Zorac cream.
Patients should be warned to use sunscreens (minimum SPF of 15) and protective clothing when using Zorac cream. Patients with sunburn should be advised not to use Zorac cream until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using Zorac cream.
Zorac cream has not been studied in patients with actinic keratosis or basal cell carcinoma.
Zorac cream should be administered with caution if the patient is also taking drugs known to be photosensitisers (e.g. thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented photosensitivity.
Weather extremes, such as wind or cold, may be more irritating to patients using Zorac cream.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of tazarotene in psoriasis have not been established in patients under the age of 18 years.
The safety and efficacy of tazarotene in acne have not been established in patients under the age of 12 years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interaction studies have been conducted.
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 cream is begun.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No impairment of fertility occurred in male or female rats following topical application of tazarotene at dermal doses of up to 0.125 mg/kg/day (associated with plasma AUC of 1.2 times that maximally anticipated in patients treated with 2 mg/cm2 of 0.1% w/w Zorac cream over 15% body surface area). However, following oral administration, decreases in sperm count, sperm density and relative weights of the seminal vesicles and prostate gland were evident in male rats dosed at 3 mg/kg/day, with a No observable Effect level (NOEL) of 1 mg/kg/day. Reductions in implantations, live litter size and foetal bodyweight were observed in female rats dosed at 2 mg/kg/day, with a NOEL of 1 mg/kg/day. The NOEL of 1 mg/kg/day in male and female rats was associated with a plasma AUC value of 3.7 and 6.7 times, respectively, that maximally anticipated in patients treated with 2 mg/cm2 of 0.1% w/w Zorac cream over 15% body surface area.
(Category D)
As with other retinoids, tazarotene may cause foetal harm when used during pregnancy.
Tazarotene is teratogenic in rats and rabbits. Following topical dermal application at 0.25 mg/kg/day during organogenesis, tazarotene was associated with reduced foetal bodyweight and reduced skeletal ossification in rats, and an increased incidence of known retinoid malformations (including spina bifida, hydrocephaly and heart anomalies) in rabbits. Following oral administration at doses greater than 0.1 and 0.05 mg/kg/day in rats and rabbits, respectively, tazarotene caused developmental delays in rats, and teratogenic effects and postimplantation loss in both rats and rabbits.
There are no adequate and well controlled studies of Zorac cream treatment in pregnant women. Tazarotene is contraindicated in women who are or may become pregnant. If Zorac cream is used during pregnancy, or if the patient becomes pregnant while using Zorac cream, treatment should be discontinued and the patient apprised of the potential hazard to the foetus. Women of childbearing potential should be warned of the potential risk and use adequate contraception when Zorac cream is used.
It is difficult to determine the exact time frame in which a patient's system would be completely free of tazarotenic acid, the active form of tazarotene. However, if the patient has normal hepatic and renal function, based on the 18 hour half-life, one could assume that nearly all of the active metabolite would be gone after approximately 7 days following the last application. In seven days, over 9 half-lives will have been completed. It takes about 5 half-lives for 97% of a drug to be eliminated and 7 half-lives for about 99% of a drug to be eliminated. In human pharmacokinetic studies, no active metabolite of tazarotene could be detected after 7 days.
 Tazarotene and/or its metabolites have been detected in the milk of lactating rats following topical administration with a tazarotene gel formulation. It is not known whether tazarotene and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if tazarotene cream is used in a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Pre-marketing clinical trials.

In human dermal safety studies, tazarotene 0.1% w/w and 0.05% w/w creams were moderately irritating under the exaggerated conditions of the studies but did not induce contact sensitisation, phototoxicity or photoallergy. In psoriasis it may be difficult to distinguish some of the common adverse events of tazarotene (such as pruritus, erythema, burning skin, skin irritation and desquamation) from the signs and symptoms of the disease. See Table 1.
Adverse events (< 0.5%) include cheilitis, excoriated skin, headache, eczema, sun-induced erythema, hypoesthesia, infection, papules, pharyngitis, skin pain, skin tightness and worsened acne. See Table 2.
Adverse events (< 0.5%) include arm pain, leg pain, oedema, chills, headache, infection, abdominal pain, knee pain, pelvic pain, nausea, mouth ulcer, SGOT inc, SGPT inc, insomnia, rash pustular, urticaria, pruritus scalp, hypercholesterolaemia, myalgia, dermatitis atopic, rash vesicular bullous, skin reaction, rosacea, eyelid erythema, eyelid irritation, foot pain, hyperlipemia, skin oedema focal, skin tightness, ear infection, genital oedema, cellulitis, bilirubinaemia, hyperglycaemia, joint disease, tingling, skin discolouration and eye irritation.

Post-marketing experience.

There have been isolated reports of patients using Zorac cream experiencing bullous eruptions (with or without fever).

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Excessive topical use of Zorac cream 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. If oral ingestion occurs, the patient should be monitored and appropriate supportive measures should be administered as necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tazarotene is a member of the acetylenic class of retinoids.
Tazarotene is a retinoid prodrug which is converted to its biologically active form tazarotenic acid by de-esterification in animals and man. Tazarotenic acid binds to and regulates gene expression through all three members of the RAR family of retinoid nuclear receptors, RARα, RARβ and RARγ. Within the RAR family, tazarotenic acid shows relative selectivity for RARβ and RARγ. 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 differentiation and proliferation in a wide range of tissues.
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.

Psoriasis.

The exact mechanism of tazarotene action in psoriasis is unknown. Improvement in psoriatic patients appears to occur in association with restoration of normal cutaneous morphology, reduction of the inflammatory markers ICAM-1 and HLA-DR and the diminution of markers of epidermal hyperplasia and abnormal differentiation such as elevated keratinocyte transglutaminase, involucrin and keratin16.
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 catalyses 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 buildup is an element of psoriatic scale formation. Tazarotene also induces the expression of TIG3 (tazarotene induced gene 3), a putative tumour suppressor, which may inhibit epidermal hyperproliferation in treated plaques. Tazarotene, therefore, has multiple effects on keratinocyte differentiation and proliferation, as well as on inflammatory processes which contribute to the pathogenesis of psoriasis.

Acne.

Although the exact mechanism of action of tazarotene in acne remains undefined, retinoids are recognised as fundamental mediators of cell differentiation and proliferation.
Directly or indirectly, tazarotene is thought to act against several of the factors that contribute to acne vulgaris. Its primary mechanism of action may be to normalize the keratinisation pattern in acne and decrease the coherence of follicular keratinocytes, thus achieving a comedolytic effect against existing comedones and preventing the development of new microcomedones. Tazarotene may also have direct or indirect activity against inflammatory acne.

Clinical trials.

Psoriasis.

In two 12 week vehicle controlled clinical studies in patients with stable plaque psoriasis (excluding those with deteriorating disease), tazarotene 0.05% w/w and 0.1% w/w creams were significantly more effective than vehicle in reducing the severity of plaque psoriasis. The primary endpoint, clinical success, was defined as an overall lesional assessment (OLA) of none, minimal or mild. It was rated on a 6 point scale from none (0) to very severe (5) and included the three key signs of psoriasis: plaque elevation, scaling and erythema.
Tazarotene creams demonstrated effectiveness as early as 1 week after starting treatment, and initial treatment success (global response to treatment of moderate, marked, almost cleared or completely cleared) was reached significantly earlier than vehicle. Treatment success rates with the 0.1% w/w cream were generally superior (numerically) to those with the 0.05% w/w cream. During these studies, the number of patients with none, minimal or mild overall disease was significantly greater with tazarotene 0.05% w/w and 0.1% w/w cream vs vehicle at most follow-up visits.
Improvements in plaque elevation, scaling and erythema were generally significantly greater with tazarotene cream 0.1% w/w and 0.05% w/w than with vehicle. Tazarotene cream 0.1% w/w cream was generally more effective than the 0.05% concentration in reducing the severity of the individual signs of disease. However, tazarotene 0.1% w/w cream was associated with a somewhat greater degree of local irritation than the 0.05% w/w cream. See Table 3.
The secondary evaluation criteria were plaque elevation (which is the most distinctive feature of plaque psoriasis), scaling, erythema and treatment success at week 12 (see Table 4).

Acne.

In two 12 week vehicle controlled studies, tazarotene 0.1% w/w cream was significantly more effective than vehicle in reducing the total number of lesions, the number of inflammatory lesions and the number of noninflammatory lesions. Tazarotene 0.1% w/w cream demonstrated effectiveness in reducing the total number of lesions as early as 4 weeks after starting treatment.
The primary efficacy variable in the studies was the percentage reduction from baseline in the total number of facial lesions (the sum of all noninflammatory and inflammatory lesions). The reduction in the total number of lesions provided an objective measure of improvement in the key characteristic of acne. Secondary variables were the reductions in noninflammatory (sum of open and closed comedones) and inflammatory (sum of papules, pustules and nodules) lesions separately, providing information about the responses of the different types of acne lesions. The secondary efficacy variables also included an overall acne assessment (none, minimal, mild, moderate, severe and very severe) and a global response to treatment (completely cleared, almost cleared, marked response, moderate response, slight response, condition unchanged and condition worsened).
After 12 weeks, the number of patients whose overall acne assessment improved from baseline by one or more grades (clinical improvement rate) was significantly greater with tazarotene 0.1% w/w cream than with vehicle.
Tazarotene 0.1% w/w cream was also associated with a significantly higher treatment success rate, based upon numbers of patients with a moderate response to treatment or better, than vehicle cream. See Tables 5 and 6.
In general, the rates of irritation adverse events reported during psoriasis studies with Zorac 0.1% w/w cream were 1 to 4 percentage points higher than those reported for Zorac 0.05% w/w cream.
In acne, tazarotene cream has only been studied in the treatment of facial lesions.
No studies of treatment duration longer than 12 weeks have been conducted to assess the efficacy and safety of tazarotene cream in acne and psoriasis.

5.2 Pharmacokinetic Properties

Absorption.

When tazarotene was administered intravenously to healthy volunteers (N = 8), it had a half-life of 6 hours. The half-life of the active metabolite, tazarotenic acid, was 14 hours.
In a pharmacokinetic study in psoriatic patients, tazarotene 0.1% w/w cream was applied once daily to the psoriatic lesions (5-35% of body surface area) at a standard (clinical) dosing of 2 mg/cm2 or an exaggerated dosing of 10 mg/cm2 to different groups of patients for 14 days. At 14 days, the systemic bioavailability was approximately 3% and 2% of the applied dose, respectively.
In the same pharmacokinetic study, the mean (range) plasma tazarotenic acid Cmax value was 2.31 nanogram/mL (range 1.02-6.85 nanogram/mL) at the standard dosing rate. Values of Cmax at the exaggerated dosing level were higher, but not proportionately so. Values of Cmax in a pharmacokinetic study in acne patients were lower than in the psoriatic study, even at an exaggerated dosing schedule.
Following topical application, tazarotene rapidly undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound can be detected in the plasma.
Across all pharmacokinetic and therapeutic drug level monitoring studies, there is no evidence to suggest that plasma tazarotenic acid concentrations are dependent on gender, age or bodyweight.

Distribution.

Tazarotene and tazarotenic acid are extensively bound (more than 99%) to human plasma proteins which is linear binding. The blood to plasma ratio of 14C-tazarotene was less than one, indicating a higher affinity toward plasma proteins than red blood cells.

Metabolism.

After tazarotene gel was topically applied to healthy subjects, 14C-tazarotene underwent esterase hydrolysis to produce 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.

The half-life of tazarotenic acid following topical application of tazarotene gel or cream was similar in normal subjects and patients with psoriasis or acne, approximately 18 hours.
Tazarotene was not excreted unchanged. After dermal dosing with 14C-tazarotene gel under occlusion to healthy volunteers, 2.6% of the dose was excreted in urine and 2.7% of the dose was excreted in faeces over a 7 day period. Following a topical nonoccluded 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 removal of residual gel from the skin surface using gauze pads wetted with isopropanol. There was equal excretion of the radioactivity in urine and faeces.

5.3 Preclinical Safety Data

Genotoxicity.

Tazarotene was negative in a standard battery of in vitro and in vivo genotoxicity tests.

Carcinogenicity.

The carcinogenic potential of tazarotene was studied in mice following topical dermal application and in rats following oral administration. No increase in tumour incidence was apparent in either mice or rats at plasma AUC levels of up to 7.8 and 1.4 times, respectively, that maximally anticipated in patients treated with 2 mg/cm2 of Zorac 0.1% w/w cream over 15% body surface area.
A reduction in median time to onset of ultraviolet radiation induced tumour formation was observed in hairless mice following topical dermal application of a tazarotene gel formulation. The cause of this effect is unknown. The potential photocarcinogenicity of the Zorac cream formulation has not been examined. Exposure of Zorac cream treated areas to the sun should be avoided.

6 Pharmaceutical Particulars

6.1 List of Excipients

Benzyl alcohol, sodium thiosulfate pentahydrate, disodium edetate, liquid paraffin, medium chain triglycerides, carbomer 1342, sorbitan mono-oleate, carbomer 934P, sodium hydroxide and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years in the unopened container.
Keep tube tightly closed when not in use.

6.4 Special Precautions for Storage

Store at or below 25°C.

6.5 Nature and Contents of Container

1.0 mg/g and 0.5 mg/g white to off white cream in collapsible aluminum tubes with tamper-evident opening and screw cap in 3.5 g, 30 g and 60 g sizes.
Zorac 0.05% w/w cream AUST R 101328.
Zorac 0.1% w/w cream AUST R 101327.

6.6 Special Precautions for Disposal

Unused contents of the tube should be discarded 12 months after opening.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

118292-40-3.
Molecular weight: 351.46. Chemical Name: Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate. Empirical formula: C21H21NO2S.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes