4.1. Therapeutic indications

This medicine is used for the topical treatment of superficial pre-malignant and malignant skin lesions; keratoses including senile, actinic and arsenical forms; keratoacanthoma; Bowen's disease; superficial basal-cell carcinoma. Deep, penetrating or nodular basal cell and squamous cell carcinomas do not usually respond to fluorouracil therapy. It should be used only as a palliative therapy in such cases where no other form of treatment is possible.

4.2. Posology and method of administration

Posology

Adults

This medicine is for topical application.

Pre-malignant conditions

The cream should be applied thinly to the affected area once or twice daily; an occlusive dressing is not essential.

Malignant conditions

The cream should be applied once or twice daily under an occlusive dressing where this is practicable.

The cream should not harm healthy skin. Treatment should be continued until there is marked inflammatory response from the treated area, preferably with some erosion in the case of pre-malignant conditions. Severe discomfort may be alleviated by the use of topical steroid cream. The usual duration of treatment for an initial course of therapy is three to four weeks, but this may be prolonged. Lesions on the face usually respond more quickly than those on the trunk or lower limbs whilst lesions on the hands and forearms respond more slowly. Healing may not be complete until one or two months after therapy is stopped.

Special population

Elderly

Many of the conditions for which fluorouracil is indicated are common in the elderly. No special precautions are necessary.

Paediatric population

In view of the lack of clinical data available, fluorouracil is not recommended for use in children.

Method of application

The hands should be washed carefully after applying this medicine. Also care should be taken to avoid contact with mucous membranes or the eyes when applying the cream.

The total area of skin being treated with this medicine at any one time should not exceed 500 cm2 (approximately 23 x 23 cm). Larger areas should be treated a section at a time.

4.3. Contraindications

This medicine is contraindicated in patients with known hypersensitivity to fluorouracil or any of the excipients listed in section 6.1. Coadministration of fluorouracil with antiviral nucleoside drugs (e.g. brivudine and analogues) may lead to a substantial increase in plasma levels of fluorouracil and associated toxicity and is contraindicated. Brivudine and analogues are potent inhibitors of DPD, a fluorouracil metabolising enzyme (see section 4.4 and 4.5)

Use of fluorouracil during pregnancy and in breast-feeding mothers is contraindicated.

4.4. Special warnings and precautions for use

The normal pattern of response includes: early and severe inflammatory phases (typically characterised by erythema, which may become intense and blotchy), a necrotic phase (characterised by skin erosion) and finally healing (when epithelialisation occurs). The clinical manifestation of response usually occurs in the second week of fluorouracil treatment. However these treatment effects can sometimes be more severe and include pain, blistering and ulceration (see section 4.8). Occlusive dressing may increase inflammatory reactions of the skin. There is a possibility of increased absorption through ulcerated or inflamed skin (see section 5.2). Further application of fluorouracil cream should be avoided in cases of severe skin inflammation including ulceration and blistering.

Instruct patients not to smoke or go near naked flames - risk of severe burns. Fabric (clothing, bedding, dressings etc) that has been in contact with this product burns more easily and is a serious fire hazard. Washing clothing and bedding may reduce product build-up but not totally remove it.

Exposure to UV-radiation (e.g. natural sunlight, tanning salon) should be avoided.

Pre-existing subclinical lesions may become apparent following fluorouracil use.

Any severe skin discomfort during treatment with fluorouracil may be alleviated by the use of an appropriate topical steroid cream.

When used according to the approved prescribing information this medicine should have minimal effect on healthy skin.

Significant systemic drug toxicity is unlikely via percutaneous absorption of fluorouracil when this medicine 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, fluorouracil treatment should be stopped.

An interval of at least four weeks should elapse between treatment with brivudine, sorivudine or analogues and subsequent administration of fluorouracil.

The excipients stearyl alcohol and propylene glycol may cause local skin irritations (e.g. contact dermatitis); the excipients methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

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

Although no significant drug interactions with fluorouracil have been reported, potential drug interactions are possible as indicated below.

Brivudine, sorivudine and analogues are potent inhibitors of DPD, a fluorouracil metabolising enzyme (see section 4.4). For this reason concomitant administration of these drugs with fluorouracil is contraindicated (See section 4.3)

4.6. Fertility, pregnancy and lactation

Contraception in males and females

Due to the genotoxic potential of fluorouracil, women of childbearing potential should use effective contraceptive measures while being treated with fluorouracil and for 6 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child while receiving fluorouracil and for 3 months following completion of treatment.

Pregnancy

There are no adequate data from the use of topical fluorouracil in pregnant women.

Studies in animals have shown that fluorouracil is teratogenic (see section 5.3). The potential risk for humans is unknown, hence fluorouracil should not be used during pregnancy (see section 4.3).

Women of childbearing potential should not become pregnant during topical fluorouracil therapy and should use effective method of contraception during treatment with fluorouracil therapy. If a pregnancy occurs during treatment the patient should be advised about the risk for the child of adverse effects associated with the treatment and genetic counselling is recommended.

Breast-feeding

No information is available on the excretion of fluorouracil into breast milk. Studies in animals have shown the fluorouracil is teratogenic (see section 5.3). A risk to the suckling g child cannot be excluded, so fluorouracil should 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 fluorouracil on fertility.

Experiments in various species revealed an impairment of the fertility and reproductive performance of systemic 5-fluorouracil. The reduced systemic exposure to 5-FU following its topical administration will reduce the potential toxicity. The use of topical 5-fluorouracil may impair female and male fertility. Topical fluorouracil is not recommended in men attempting to father 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

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories:

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)

Frequency not known (cannot be estimated from the available data)

Adverse reactions associated with exacerbations of normal pattern of response (see section 4.4) which are related to pharmacological activity of fluorouracil on the skin are the most frequently reported reactions. Allergic type skin reactions and reactions related to systemic drug toxicity are very rarely reported.

Blood and lymphatic system disorders

Very rare: Haematological disorders, associated with systemic drug toxicity, e.g. pancytopenia, neutropenia, thrombocytopenia, leukocytosis.

Immune system disorders

Very rare: Allergic conditions (e.g., Hypersensitivity and Type IV hypersensitivity).

Nervous system disorders

Frequency not known: Dysgeusia, headache, dizziness.

Eye disorders

Frequency not known: Conjunctival irritation, keratitis, increased lacrimation.

Gastrointestinal disorders

Very rare: Diarrhoea haemorrhagic, diarrhoea, vomiting, abdominal pain, stomatitis, associated with systemic drug toxicity.

Frequency not known: Nausea.

Skin and subcutaneous tissue disorders

Very rare: Pruritus, urticaria, rash (usually local but also generalised if associated with systemic drug toxicity); erythemas including erythema multiforme; dermal and epidermal conditions (such as skin burning sensation, skin exfoliation, skin swelling); skin and subcutaneous skin ulcerations; dermatitis and eczema conditions (such as contact dermatitis, skin irritation); blisters, and alopecia.

Exposure to sunlight may increase the intensity of the reaction.

See also normal pattern of response in section 4.4.

General disorders and administration site conditions

Very rare: Pyrexia, chills and mucosal inflammation, associated with systemic drug toxicity.

Frequency not known: Application site haemorrhage

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google play or Apple App Store.

4.9. Overdose

If this medicine is accidentally ingested, signs of fluorouracil overdosage may include nausea, vomiting and diarrhoea. Stomatitis and blood dyscrasias may occur in severe cases. Appropriate measures should be taken for the prevention of systemic infection and daily white cell counts should be performed.