Retin-A Gel 0.025%

1. Name Of The Medicinal Product

RETIN-A^® Gel 0.025% w/w.

2. Qualitative And Quantitative Composition

Tretinoin 0.025% w/w.

Excipients:

Butylated hydroxytoluene.

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gel.

Retin-A Gel 0.025% is a clear yellow gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of acne vulgaris.

Retin-A Gel is suitable for use on oily skin.

4.2 Posology And Method Of Administration

Adults

Retin-A should be applied once or twice daily to the area of skin where acne lesions occur.

Only apply sufficient to cover the affected areas lightly, using a gauze swab, cotton wool or the tips of clean fingers. Avoid over-saturation to the extent that excess medication could run into the eyes, angles of the nose or other areas where treatment is not intended.

Initial application may cause transitory stinging and a feeling of warmth. The correct frequency of administration should produce a slight erythema similar to that of mild sunburn.

If Retin-A is applied excessively, no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur. Should this occur accidentally or through over enthusiastic use, application should be discontinued for a few days.

Patience is needed in this treatment, since the therapeutic effects will not usually be observed until after 6-8 weeks of treatment. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen comedones and papules.

Once the acne lesions have responded satisfactorily, it should be possible to maintain the improvement with less frequent applications.

Moisturisers and cosmetics may be used during treatment with Retin-A but should not be applied to the skin at the same time. The skin should be thoroughly washed before application of Retin-A. Astringent toiletries should be avoided.

Children

The safety and efficacy of tretinoin in children aged less than 10 years has not been established.

Method of administration

Cutaneous use.

4.3 Contraindications

Retin-A is contraindicated in patients with:

- A history of sensitivity/hypersensitivity reactions to any of the components

- Pregnancy

- Personal or familial history of cutaneous epithelioma

- Acute eczemas (as tretinoin has been reported to cause severe irritation on eczematous skin)

- Rosacea and perioral dermatitis.

4.4 Special Warnings And Precautions For Use

Local irritation

The presence of cutaneous irritative signs (eg erythema, peeling, pruritus, sunburn, etc) should prohibit initiation or recommencement of treatment with Retin-A until the symptoms resolve.

In certain sensitive individuals, topical use may induce severe local erythema, swelling, pruritus, warmth, burning or stinging, blistering, crusting and/or peeling at the site of application. If the degree of local irritation warrants, the patient should be directed to apply the medication less frequently or discontinue its use temporarily. If a patient experiences severe or persistent irritation, the patient should be advised to discontinue application of Retin-A completely and, if necessary, consult a physician.

Weather extremes, such as wind or cold, also may be irritating to patients being treated with Retin-A.

Exposure to sunlight, including ultraviolet sunlamps, should be avoided or minimised during the use of tretinoin. Patients with sunburn should be advised not to use the product until fully recovered because of potential severe irritation to skin. A patient who experiences considerable sun exposure due to occupational duties and/or anyone inherently sensitive to the sun should exercise particular caution. When exposure to sunlight cannot be avoided, use of sunscreen products and protective clothing over treated areas is recommended.

General precautions for use:

Before application of Retin-A, areas to be treated should be cleansed thoroughly.

Abstain from washing the treated area frequently: twice daily is sufficient. Use of mild soap is recommended. Dry skin without rubbing.

Avoid contact with eyes, eyelids, nostrils, mouth and mucous membranes. If contact in these areas occurs, careful washing with water is recommended.

Warning:

The weight of evidence indicates that topical tretinoin is not carcinogenic. In a lifetime study of CD-1 mice, a low incidence of skin tumours was seen at 100 and 200 times the estimated clinical dose but, although no such tumours were seen in the study controls, the incidence in these treated animals was within the historic control range for CD-1 mice.

Studies in hairless albino mice suggest that tretinoin may accelerate the tumorigenic potential of UVB light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVB light, the photocarcinogenic effects of tretinoin were not observed. Due to significantly different experimental conditions, no strict comparison of this disparate data is possible. Although the significance of these studies in man is not clear, patients should avoid or minimise exposure to sunlight.

The weight of evidence indicates that topical tretinoin is not mutagenic. The mutagenic potential of tretinoin was evaluated in the Ames assay and the in vivo mouse micronucleus assay, both of which showed negative findings.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Retin-A should be used with caution in the presence of:

− concomitant topical medications

− toiletry preparations having a strong drying, abrasive or desquamative effect.

Following prolonged use of a peeling agent it is advisable to 'rest' a patient's skin until the effects of the peeling agent subside before the use of Retin-A is begun. When Retin-A and peeling agents are alternated contact dermatitis may result and the frequency of application may have to be reduced.

4.6 Pregnancy And Lactation

The topical human dose used in a 50 kg adult applying a maximum volume of 500 mg of 0.05% Retin-A cream is 0.005 mg/kg. In animal reproductive studies, oral tretinoin is known to be teratogenic and has been shown to be foetotoxic in rats when given in doses 500 times the topical human dose. In reproduction studies in rats and rabbits, topical tretinoin, when used at doses 500 and 320 times the topical human dose, respectively, induced minor skeletal abnormalities, eg irregularly contoured or partially ossified skull bones. These changes may be considered variants of normal development and are usually corrected after weaning. Retin-A should not be used during pregnancy.

It is not known whether tretinoin is excreted in human milk, therefore caution should be exercised when Retin-A is administered to a nursing mother.

4.7 Effects On Ability To Drive And Use Machines

Retin-A is administered topically and is unlikely to have an effect on one's ability to drive or operate machinery.

4.8 Undesirable Effects

Local reactions frequently reported during therapy included: dry or peeling skin, burning, stinging, warmth, erythema, pruritus, rash and temporary hypo- and hyper-pigmentation. These skin reactions were usually mild to moderate and were generally well-tolerated. They usually occurred early in therapy and, except for dry or peeling skin which persisted during therapy, generally decreased over the course of therapy.

Rarely reported undesirable effects are blistering and crusting of the skin, eye irritation and oedema.

True contact allergy to topical tretinoin is rarely encountered. Heightened susceptibility to either sunlight or other sources of UVB light has been reported.

4.9 Overdose

Excessive application of Retin-A does not improve the results of treatment and may induce marked irritation, eg erythema, peeling, pruritus, etc. Oral ingestion of Retin-A may lead to the same effects associated with excessive oral intake of vitamin A (eg pruritus, dry skin, arthralgias, anorexia, vomiting). In the event of accidental ingestion, if the ingestion is recent an appropriate method of gastric emptying should be used as soon as possible.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Retinoids for topical use in acne

ATC code: D10AD01

Tretinoin (β-all trans retinoic acid, vitamin A acid) produces profound metabolic changes in keratinizing epithelia. Tretinoin increases the proliferative activity of epidermal cells in in vivo and in vitro studies, and cellular differentiation (keratinization and cornification) is also altered.

5.2 Pharmacokinetic Properties

Absorption

Tretinoin is an endogenous metabolite of Vitamin A metabolism in man. Upon topical application, tretinoin is minimally absorbed, penetrating both the epidermis and dermis.

Percutaneous absorption of tretinoin, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in healthy men and women after single and/or repeated daily applications of a 0.05%, 0.1% or 0.5% tretinoin cream formulation or a 0.01% tretinoin gel formulation, at doses of 100, 150 or 500 mg. The mean percutaneous absorption ranged from 1.0 to 4.3%. Endogenous plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid and 13-cis-4-oxo-retinoic acid were essentially unaltered after either single or multiple daily applications relative to baseline levels.

Distribution

Approximately 80% of tretinoin applied remains on the skin surface, whereas its penetration through the stratum corneum and the hair follicle is vehicle-dependent. After the initial diffusion into the stratum corneum that occurs within a few minutes, further diffusion into epidermis and dermis proceeds more slowly.

Metabolism

Topically-applied tretinoin is metabolized by CYP2S1 and CYP26. Metabolites are 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid and 13-cis-4-oxo-retinoic acid.

Elimination

After application of radiolabelled tretinoin emollient cream or cream, urinary excretion occurred mainly in the first 48 hours, whereas radioactivity was eliminated in the faeces throughout the 7 days after dose application. On average 1 – 1.5% of the radioactivity was recovered in urine and less than 1 % was recovered in feces.

Paediatric Population

Although there is limited data available, it is considered likely that the pharmacokinetic behaviour of tretinoin topical formulations and drug-drug interactions with tretinoin topical formulations will be similar to those in adults. In a study in 20 adolescent patients with moderate to severe acne treated for 12 weeks with tretinoin gel, none of the plasma samples obtained at Week 12 of the treatment period contained quantifiable tretinoin levels.

5.3 Preclinical Safety Data

See Sections 4.4 (Special warnings and precautions) and 4.6 (Pregnancy and lactation).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Butylated hydroxytoluene

Hydroxypropyl cellulose

Undenatured ethanol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube with polypropylene cap.

Aluminium tube may contain 10, 15, 20 or 60 g of gel per pack.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0268

9. Date Of First Authorisation/Renewal Of The Authorisation

1 September 1995/21 May 2003

10. Date Of Revision Of The Text

26 October 2011