SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Atralin 0.05% w/w Gel.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tretinoin 0.05% w/w.

Excipients: butylhydroxytoluene (E321), methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), ethyl parahydroxybenzoate (E214), butyl parahydroxybenzoate, and isobutyl parahydroxybenzoate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Pale yellow gel.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of mild to moderate acne vulgaris.

4.2 Posology and method of administration

Atralin Gel is for cutaneous use only.

Atralin Gel should be applied once daily, after washing in the evening, to the skin where acne lesions appear, using enough to lightly cover the entire

affected area. Application of excessive amounts of gel will not provide incremental efficacy, but may increase the potential for irritation.

The gel should be applied using clean finger tips, cotton wool or a gauze swab, avoiding the mucous regions of the eyes, mouth, and nose.

A transitory feeling of warmth or slight stinging may be noted on application.

Therapeutic results may be noticed after two weeks, but four or more weeks of therapy are required before consistent beneficial effects are observed.

Patients treated with Atralin Gel may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied. Astringent toiletries should be avoided.

Children

Use of Atralin Gel in children under 10 years of age has not been investigated.

Elderly

Safety and effectiveness in a geriatric population have not been established. Clinical studies of Atralin Gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

4.3 Contraindications

Atralin Gel is contraindicated in individuals with a history of sensitivity reactions to any of its components. Use should be discontinued if hypersensitivity to any of its ingredients is noted.

Atralin Gel is contraindicated in patients with a personal or familial history of cutaneous epithelioma.

Tretinoin has been reported to cause severe irritation on eczematous skin and Atralin Gel should not be used in patients with acute eczema.

Atralin Gel should not be used to treat rosacea and perioral dermatitis.

Atralin Gel is contraindicated in pregnancy.

4.4 Special warnings and precautions for use

Application of excessive amounts of gel will not provide increased efficacy, but may increase the potential for irritation. Even at the recommended usage, the skin of certain individuals may become excessively dry, red, or swollen. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use altogether. Excessive skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful.

Unprotected exposure to excessive sunlight or UV exposure, including sunlamps and solaria, should be minimized during the use of Atralin Gel. Patients with sunburn should be advised not to use the product on the affected areas until fully recovered because of heightened susceptibility to additional irritation to patients under treatment with tretinoin. Patients who may have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas are recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.

Atralin Gel should be kept away from the mucous regions of the eyes, mouth, and nose. If contact with these areas occurs, wash carefully with water.

There is evidence that, at least in some animal models, tretinoin may have photocarcinogenic potential, although some studies have suggested that tretinoin inhibits photocarcinogenesis. The relevance of this finding to use in man is uncertain. It is however advisable that patients avoid or minimise exposure to sunlight.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of other topical or oral retinoid medications is to be avoided. The use of medicated or abrasive soaps and cleansers, products that have a strong drying effect, and products with high concentrations of alcohol, alpha-hydroxy acids or astringents should be used with caution because of possible interaction with tretinoin.

Caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulphur, resorcinol, or salicylic acid with Atralin Gel. Before applying Atralin Gel to areas treated with these products, it is advisable to allow the irritant effects of such preparations to subside.

4.6 Fertility, Pregnancy and lactation

There are no adequate data from the use of topically applied tretinoin in women.

Animal studies with topically applied Atralin Gel did not show any toxicity to reproduction (see section 5.3), although literature data indicate that high doses of topically applied tretinoin may be fetotoxic.

Atralin Gel should not be used in pregnancy.

It is not known whether tretinoin is secreted in breast milk. Caution should be exercised when Atralin Gel is administered to breastfeeding mothers.

4.7 Effects on ability to drive and use machines

None known. The topical administration of Atralin Gel is not considered likely to affect the patient’s ability to drive or use machines.

4.8 Undesirable effects

In clinical studies of Atralin Gel, the majority of adverse events were associated with the system organ class Skin and Subcutaneous Tissues. The majority of these events (such as erythema, burning, stinging, dryness and peeling) were mild in intensity occurred early during therapy and generally decreased over the course of therapy.

Common (>1/100):

Skin: Erythrema, reddening, peeling, scaling, exfoliative dermatitis, dry skin, pruritus, warmth, burning, rashes, stinging reaction or pain.

Temporary hypo- and hyper-pigmentation.

Uncommon (1/100-1/1000):

Skin: Blistering and crusting of the skin, oedema Eyes: Eye irritation.

True contact allergy to cutaneous tretinoin is rare. Increased susceptibility to sunlight or other UVB sources has been reported. Studies of Atralin Gel in volunteers indicate a low potential for the induction of allergic contact dermatitis, photoallergy or phototoxicity.

4.9 Overdose

Atralin Gel is intended for cutaneous use only. If medication is applied excessively, marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A (e.g. dry skin, pruritus, arthralgias, vomiting, anorexia).

If the gel is accidentally ingested, and if this ingestion is recent, measures to promote rapid gastric emptying should be used.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Retinoids for topical use in acne.

ATC Code: D10AD01

The precise mechanism of action of tretinoin in the treatment of acne is not known. However, biochemical and pharmacological profile studies have clearly demonstrated that tretinoin is a potent modulator of cellular differentiation and keratinisation processes which are abnormally present in the pathology of acne vulgaris.

Atralin Gel has been investigated in a total of 960 patients. Of these, 674 patients were included in two large randomised, placebo (vehicle) controlled, investigator blinded studies of safety and efficacy. These studies were of 12 weeks duration and included male and female mild to moderate acne vulgaris patients from 10 to 65 years of age.

In the two clinical studies described above, Atralin Gel was shown to be significantly more effective than its vehicle in reducing both inflammatory and non-inflammatory lesions associated with acne vulgaris. For the combined study populations, at 12 weeks Atralin Gel produced a mean percentage reduction in inflammatory and noninflammatory acne lesions of 33.2% and 38.9%, respectively, compared to 18.4% and 19.7%, respectively, for vehicle (p < 0.001). The analysis of the dichotomized global severity score at Week 12 resulted in a significant treatment effect in favour of Atralin Gel, compared to its vehicle (p=0.002).

The adverse event profile observed in the studies was consistent with the known profile for topical tretinoin products - See section 4.8.

Relapse rates following treatment of acne with topical tretinoin have not been studied.

5.2 Pharmacokinetic properties

Tretinoin is a metabolite of Vitamin A. Systemic absorption was evaluated in a total of twenty-eight male and female acne patients, 13 to 37 years of age. The plasma concentrations of tretinoin and its metabolites, 13-cA-retinoic acid and 4-oxo-13-cAretinoic acid, ranged from 0.6 to 6.2 ng/mL and were essentially unaltered after fourteen daily applications of 4 g daily doses of Atralin Gel, relative to baseline levels.

In a Phase III twelve-week study of 936 acne patients, the plasma concentrations of tretinoin and its metabolites, 13-cA-retinoic acid and 4-oxo-13-cA-retinoic acid were evaluated at Baseline and Week 12. The plasma concentrations of tretinoin and its metabolites, 13-cA-retinoic acid and 4-oxo-13-cA-retinoic acid, ranged from 0.5 to 5.3 ng/mL and were essentially unaltered after twelve weeks of daily application of Atralin Gel.

5.3 Preclinical safety data

Local tolerance, repeat dose testing and dermal sensitisation studies with Atralin Gel revealed only minor signs of irritation at the application sites.

There is no evidence of genotoxicity of tretinoin in standard in vitro and in vivo tests.

The weight of evidence indicates that topically applied tretinoin is not carcinogenic. In a lifetime study of CD-1 mice treated with a proprietary topical tretinoin product, a low incidence of skin tumours occurred at doses of 100 and 200 times the estimated clinical dose. No such tumours were seen in the study controls, but the incidence in treated animals fell within the historic control range for CD-1 mice.

In animal studies topically applied Atralin Gel (at doses higher than the proposed human dose) has not produced any measurable effect on systemic levels of tretinoin or its metabolites; nor did it have any teratogenic effects. Topically applied Atralin Gel did not produce evidence of fetotoxicity in the rat. However, literature data suggest that very high levels topically applied tretinoin may cause fetotoxicity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water

Glycerol Soluble collagen Sodium hyaluronate Carbomer 940 Butylhydroxytoluene Octoxynol 9 Trolamine

Methyl parahydroxybenzoate Propyl parahydroxybenzoate Ethyl parahydroxybenzoate Butyl parahydroxybenzoate Isobutyl parahydroxybenzoate Benzyl alcohol Phenoxyethanol

6.2 Incompatibilities

None known.

6.3 Shelf life

Three years.

After opening: three months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Collapsible epoxy-lined aluminium tube with polypropylene cap containing 20 or 45 g of gel.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Beechmere Pharmaceuticals Ltd

Merlin Place

Milton Road

Cambridge

CB4 0DP

8    MARKETING AUTHORISATION NUMBER(S)

PL 19661/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/10/2007

DATE OF REVISION OF THE TEXT

14/11/2012