1. The frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance.

2. The presence of cutaneous irritative signs (e.g. erythema, peeling, pruritus, sunburn, etc) should prohibit initiation or recommencement of treatment with Optimal^® until the symptoms resolve.

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

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

5. 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 Optimal^® completely and if necessary, consult a physician.

Weather extremes, such as wind or cold and low humidity, may also be irritating to skin being treated with Optimal^® and may increase its dryness.

Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

Patients will be able to remove hair as usual (e.g. plucking, electrolysis, depilatories) but should avoid these procedures before applying Optimal^® as they might result in skin irritation.

Permanent wave solutions, waxing preparations, medicated soaps and shampoos can sometimes irritate even normal skin. Caution should be used so that these products do not come into contact with skin treated with Optimal^®

Exposure to sunlight

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.

6. 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 suggested that tretinoin may accelerate the tumorigenic potential of UVB light from a solar simulator.

In other studies, when light 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 indicated that topical tretinoin is not mutagenic. The mutagenic potential of tretinoin was evaluated in the Ames assay and in-vivo mouse micronucleus assay, both of which showed negative findings.

7. History of sensitivity/hypersensitivity to any of the components as part of the combined statement in Contraindications.

The following products or medications should be used with caution because of possible interaction with tretinoin. It is advised to allow the effects of such preparations to subside before use of Optimal^® is begun:

• concomitant topical medication

• preparations containing benzoyl peroxide

• toiletry preparations having an abrasive, drying, or desquamative effect, including soaps, shampoos, cosmetics, and products with high concentrations of alcohol, astringents, spices or lime.

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 of 500 and 320 times the topical human dose, respectively, induced minor skeletal abnormalities e.g. irregularly contoured or partially ossified skull bones.

These changes may be considered variants of normal development and are usually corrected after weaning. Optimal^® should not be used during pregnancy. It is not known whether tretinoin is excreted in human milk, therefore caution should be exercised when Optimal^® is administered to a nursing mother.

Optimal^® is administered topically and is unlikely to have an effect on one's ability to drive or operate machinery.

The safety of tretinoin topical formulations including Optimal^® was evaluated in 4160 patients (of whom 3035 were treated with topical tretinoin and 1125 received placebo) who participated in 23 clinical trials, including 4 open-label and 19 double-blind, placebo-controlled clinical trials. The 23 clinical trials evaluated the safety of tretinoin in male and female patients, aged 10 to 79 years, with photodamaged skin or acne vulgaris.

The table below displays ADRs that have been reported with the use of tretinoin topical formulations from the 23 clinical trials and from post marketing experience.

The displayed frequency categories use the following convention:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).

Table: Adverse Drug Reactions Reported in Clinical Trials and Postmarketing Experience for RETIN-A

Excessive application of Optimal^® does not improve the results of treatment and may induce marked irritation, e.g. erythema, peeling, pruritus etc. Oral ingestion of Optimal^® may lead to the same effects associated with excessive oral intake of vitamin A (e.g. 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.

Pharmacotherapeutic group: Retinoids for topical use in acne

ATC code: D10AD01

Tretinoin (ß-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.

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 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 gel, urinary excretion occurred mainly in the first 48 hours, whereas radioactivity was eliminated in the feces 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

It is expected that pharmacokinetic behavior 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.

Topical administration of Optimal^® products produces dose-dependent erythema, peeling and irritation and excessive use of the products should be avoided. Optimal^® 0.1% w/w did not produce an allergic response when tested in 160 subjects by the Draize test.

No systemic toxic effects have been reported following topical application of Optimal^® formulations

Store below 30°C.