TOLAK

Posology Tolak should be applied once daily in an amount sufficient to cover the whole area of involved actinic skin of the face and/or ears and/or scalp where AK lesions have been identified with a thin film, using the fingertips to gently massage the medication uniformly into the skin.

When assessing options to treat recurrent lesions, the physician should consider that repeated treatment with Tolak in case of recurrence has not been formally assessed. 4 months). Number of retreatments with Tolak is at the decision of the treating physician.

Duration of treatment Apply Tolak for a period of 4 weeks as tolerated. The development of an inflammatory response is associated with the pharmacological action of 5-FU on dysplastic AK cells. 8). These local reactions are essentially mild to moderate with a peak at 4 weeks of treatment.

4). In case of severe discomfort during treatment or for skin reactions lasting more than 4 weeks, symptomatic treatment (such as emollient or topical corticosteroids) should be offered. Evaluation of the therapeutic effect can be assessed approximately 4 weeks after the end of the treatment.

Method of administration Prior to application of Tolak, wash, rinse, and dry the treatment areas. 4) Special populations Pediatric population There is no relevant use of Tolak in the pediatric population. No data are available in the pediatric population since children do not have actinic keratosis.

Elderly population No dedicated studies in elderly patients have been conducted. 1).

Hepatic and renal impairment:

No dosage adjustment is required for patients with hepatic or renal impairment

Summary of the safety profile The most frequently reported events in subjects treated with Tolak in the primary clinical studies were application site reactions. 1). Local reactions related to tolerability, associated with the pharmacological action of 5-FU included erythema, scaling/dryness, oedema, crusting, erosions, stinging/burning, and pruritus with an incidence of 62% to 99% by symptom.

These local reactions were mild with an incidence of 17% to 37% by symptom, moderate with an incidence of 22% to 44% by symptom and severe with an incidence of 6% to 38% by symptom. 4). Aside from application site reactions, insomnia, nasal discomfort, pharyngitis, nausea, periorbital oedema, impetigo, rash, and lip blister were reported at a frequency below 1%.

Tabulated list of adverse reactions The following table gives the adverse reactions reported in AK patients treated with Tolak once daily for 4 weeks during the primary clinical studies and reported spontaneously. Their frequency is defined using the following conventions: 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); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Preferred MedDRA terms FrequencySystem Organ Class Common Uncommon Not known Infections and infestations Impetigo Pharyngitis Immune system disorders Hypersensitivity reactions Psychiatric disorders Insomnia Eye disorders Eye irritation Eye swelling Periorbital oedema Lacrimation increased Respiratory, thoracic and mediastinal disorders Nasal discomfort Gastrointestinal disorders Lip blister Nausea Skin and subcutaneous tissue disorders Rash General disorders and administration site conditions Application site disorders: - Irritation - pain - reaction - erythema - pruritus - inflammation - oedema Application site disorders: - haemorrage - erosion - dermatitis - discomfort - dryness - paraesthesia - photosensitivity reaction Description of selected adverse reactions Hypersensitivity reactions Although no case has been reported in the primary clinical trials of Tolak, allergic contact dermatitis (delayed type hypersensitivity reaction) has been reported with topical 5-FU drugs and with Tolak since first marketing authorization.

Do not apply Tolak directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur. Should such contact occur, the cream is to be washed off with plenty of water. Tolak should not be applied to open wounds or damaged skin where the skin barrier is compromised.

The normal pattern of response includes: an early inflammatory phase (typically characterised by erythema, which may become intense and blotchy), an apoptotic phase (characterised by skin erosion) and finally healing (when epithelialisation occurs).

The clinical manifestation of response usually occurs in the second week of treatment. 8). 2). Occlusive dressing may increase inflammatory reactions of the skin. Ophthalmic Adverse Reactions Corneal and conjunctival disorders have occurred with topical 5-FU.

Avoid application to the periocular area. To avoid transfer of the drug into the eyes and/or contact lenses and to the periocular area, patients should wash hands well after applying Tolak. If accidental exposure occurs, the patient should flush eye(s) with large amounts of water.

Hypersensitivity Reactions Allergic contact dermatitis (delayed type hypersensitivity reaction) has been noted for topical 5-FU drugs. Delayed type hypersensitivity should be suspected in the event of severe pruritus or eczema at the application site or at a distant site.

Although the potential for a delayed hypersensitivity reaction to 5-FU exists, patch testing to confirm hypersensitivity may be inconclusive. Photosensitivity Topical 5-FU is associated with photosensitivity reactions. Exposure to ultraviolet rays including sunlight, sun lamps, and tanning beds should be avoided during treatment with Tolak.

Dihydropyrimidine dehydrogenase (DPD) deficiency Significant systemic drug toxicity is unlikely via percutaneous absorption of fluorouracil when Tolak is administered as per the approved prescribing information. g. cuts), if the product is applied under an occlusive dressing, and/or in individuals with deficiency in dihydropyrimidine dehydrogenase (DPD).

1. 6) • In coadministration with brivudine, sorivudine and analogues as they may lead to a substantial increase in plasma levels of 5-FU and associated toxicity. 5).