4.1. Therapeutic indications

Tolak is indicated for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade I and II) of the face, ears, and/or scalp in adults.

4.2. Posology and method of administration

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. The duration between initial treatment and retreatment with Tolak in clinical studies ranged between 7 and 13 months (mean: 9.4 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. The clinical manifestation of response is characterised by local skin reactions including erythema, scaling, crusting, pruritus, burning, oedema and erosions (see section 4.8). These local reactions are essentially mild to moderate with a peak at 4 weeks of treatment. They are transient and resolve within 2-4 weeks after the end of treatment (see also normal pattern of response in section 4.4).

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.

Thoroughly wash hands following Tolak cream application (see section 4.4).

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. No dose adjustment is required for elderly patients (65 years and older) based on the results of the clinical studies (see section 5.1).

Hepatic and renal impairment:

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

4.3. Contraindications

Tolak is contraindicated:

• In patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• In patients with allergy to peanut or soya (see section 6.1)

• During pregnancy (see section 4.6)

• During breastfeeding (see section 4.6)

• In coadministration with brivudine, sorivudine and analogues as they may lead to a substantial increase in plasma levels of 5-FU and associated toxicity. The antiviral nucleoside drugs brivudine and sorivudine are potent inhibitors of dihydropyrimidine dehydrogenase (DPD), a 5-FU metabolising enzyme (see section 4.4 and 4.5).

4.4. Special warnings and precautions for use

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. However, these treatment effects can sometimes be more severe (see section 4.8). 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 (see section 4.2).

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. However, the likelihood of this is increased if the product is used on skin areas in which the barrier function is impaired (e.g. cuts), if the product is applied under an occlusive dressing, and/or in individuals with deficiency in dihydropyrimidine dehydrogenase (DPD). DPD is a key enzyme involved in metabolising and eliminating fluorouracil. Determination of DPD activity may be considered where systemic drug toxicity is confirmed or suspected. There have been reports of increased toxicity in patients who have reduced activity of the enzyme dihydropyrimidine dehydrogenase. In the event of suspected systemic drug toxicity, Tolak treatment should be stopped.

Patients with a known DPD deficiency should be intensively monitored for signs and symptoms of systemic toxicity during treatment with topical 5-FU.

Treatment with the antiviral nucleoside analogues Brivudine or sorivudine and topical cutaneous application of Tolak should be separated by an interval of at least four weeks.

Tolak contains:

• Butylhydroxytoluene (E 321) which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

• Cetyl alcohol and stearyl alcohol which may cause local skin reactions (e.g. contact dermatitis)

• Methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed)

4.5. Interaction with other medicinal products and other forms of interaction

The antiviral nucleoside analogues brivudine and sorivudine are potent inhibitors of DPD, metabolising enzyme of 5-FU (see Section 4.4). The concomitant use of these drugs with Tolak is contraindicated (See Section 4.3).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of topical 5-FU in pregnant women. Studies in animals have shown that 5-FU is teratogenic (see section 5.3).

The potential risk for humans is unknown, hence Tolak must not be used during pregnancy (see section 4.3).

If a pregnancy occurs during treatment, the treatment must be interrupted, and the patient should be advised about the risk for the child of adverse effects associated with the treatment, and genetic counselling is recommended.

Contraception in males and females

Due to the genotoxic potential of fluorouracil, women of childbearing potential should not become pregnant during topical 5-FU therapy and must use an effective method of contraception during treatment with 5-FU therapy and for 6 months following completion of treatment.

Men must use an effective method of contraception and not father a child during treatment with 5-FU therapy and for 3 months following completion of treatment.

Breast-feeding

No information is available on the excretion of 5-FU into breast milk. Studies in animals have shown the 5-FU is teratogenic (see section 5.3). A risk to the suckling child cannot be excluded, so Tolak must not be used in nursing mothers (see section 4.3). If use during breastfeeding is absolutely necessary, breastfeeding must be discontinued.

Fertility

No clinical data in humans are available on the effects of topical 5-FU on fertility.

Experiments in various species revealed an impairment of the fertility and reproductive performance of systemic 5-FU. The use of topical 5-FU may impair female and male fertility. Topical 5-FU is not recommended in women and men attempting to have a child.

4.7. Effects on ability to drive and use machines

It is unlikely that treatment will have any effect on the ability to drive and use machines when used according to the dosage instructions.

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported events in subjects treated with Tolak in the primary clinical studies were application site reactions. An evaluation of application site tolerability was performed in the primary clinical studies (see section 5.1). 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. They were transient with a peak at 4 weeks of treatment and resolved within 2-4 weeks after the end of treatment (see also normal pattern of response in section 4.4).

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).

System Organ Class

Preferred MedDRA terms

Frequency

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.

Photosensitivity

Topical 5-FU is associated with photosensitivity reactions including severe sunburn. Photosensitivity reaction was reported in one subject (0.3%) in the primary clinical studies of Tolak. It should be noted that photosensitivity reaction was also reported by a subject in the vehicle group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

When applied on the skin as recommended, systemic intoxication with 5-FU is unlikely. Application of significantly higher doses than recommended may result in an increase of frequency of reactions at the application site and their severity.

There is no known clinical case of accidental ingestion of Tolak, however if this occurs signs of 5-FU overdosage may include nausea, vomiting, diarrhea and stomatitis.

Blood dyscrasias may occur in severe cases. Daily white cell counts should be performed and appropriate measures should be taken accordingly for the prevention of systemic infection.