ACTIKERALL Cutaneous solution Ref.[50747] Active ingredients: Fluorouracil Salicylic acid

DPD enzyme

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Inhibition, deficiency or decreased activity of this enzyme can result in accumulation of fluorouracil. However, as percutaneous absorption of fluorouracil is negligible when Actikerall is administered as per the approved prescribing information, no differences in the safety profile of Actikerall are expected in this sub-population and no dose adjustments are considered necessary.

Sensory disturbances

In patients with sensory disturbances (e.g. those with diabetes mellitus) close medical monitoring of the treatment area is required.

Sun exposure

Actinic keratosis is due to chronic UV damage. Any local irritation where Actikerall has been applied may worsen with sun exposure. Patients should be counselled to protect the skin against further excessive or cumulative exposure, especially in the area being actively treated.

Other skin conditions

There is no experience in treating actinic keratoses in an area that is also affected by another skin disease and the clinician should take into account that the outcome of treatment may differ.

No experience exists for the treatment of basal cell carcinoma (BCC) and Bowen’s disease, which should therefore not be treated with the product.

General

Actikerall contains the cytostatic agent fluorouracil.

Actikerall should not be used on bleeding lesions.

The bottle should be closed tightly after use or the solution will dry up quickly and can no longer be used correctly.

The solution should not be used if crystals occur.

Actikerall solution should not come into contact with textiles or acrylics (e.g. acrylic bathtubs) as the solution may cause permanent stains.

Caution flammable: keep away from fire and do not use near an open flame, lit cigarette or some devices (e.g. hairdryers).

This medicinal product contains dimethyl sulfoxide which may be irritant to the skin.

This medicine contains 160 mg of alcohol (ethanol) in each gram. It may cause burning sensation on damaged skin.

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Antiviral nucleoside analogues such as brivudine and sorivudine may lead to a drastic increase in plasma concentrations of fluorouracil or other fluoropyrimidines and thus an associated increase in toxicity. For this reason, an interval of at least 4 weeks between the use of fluorouracil and brivudine, sorivudine and analogues should be observed.

In case of accidental administration of nucleoside analogues such as brivudine and sorivudine to patients who are being treated with fluorouracil, effective measures for reducing fluorouracil toxicity should be taken. Admission to a hospital may be indicated. All necessary measures for protection from systemic infections and dehydration should be introduced.

Elevated plasma levels of phenytoin leading to symptoms of phenytoin intoxication have been reported with the concomitant administration of systemic fluorouracil and phenytoin.

There is no evidence for relevant systemic absorption of salicylic acid, however absorbed salicylic acid may interact with methotrexate and sulphonylureas.

Pregnancy

There are no data from the use of topical fluorouracil in pregnant women. A teratogenic effect of systemically administered fluorouracil has been observed in animals (see section 5.3). Salicylic acid can adversely influence the outcome of pregnancy in rodents.

Actikerall is contraindicated during pregnancy (see section 4.3).

Breastfeeding

It is unknown whether fluorouracil or its metabolites are excreted in human milk after topical application. A risk to the suckling child cannot be excluded.

Actikerall is contraindicated during lactation (see section 4.3).

Fertility

Fertility studies with systemic fluorouracil resulted in transient male infertility and in reduction of pregnancy rates in female rodents. However, this is unlikely to be of relevance to human, due to the very limited absorption of active compounds after cutaneous administration of Actikerall.

Actikerall has no influence on the ability to drive and use machines.

Summary of the safety profile

Mild to moderate irritation and inflammation at the application site occurred in the majority of patients treated with the solution for actinic keratosis. In case of severe reactions frequency of treatment may be reduced.

As the medicinal product has a very strong softening effect on the stratum corneum, whitish discolorations and scaling of the skin may occur, particularly in the area surrounding the actinic keratosis.

Due to its salicylic acid content, use of this medicinal product may cause slight signs of irritation, such as dermatitis and contact allergic reactions, in predisposed patients. Such contact allergy reactions may be manifested in the form of itching, reddening and small blisters even outside the area of application.

Tabulated list of adverse reactions

Adverse reactions according to MedDRA system organ class and in decreasing frequency are listed below. Frequencies are defined as 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); and not known (cannot be estimated from the available data).

Description of selected adverse reactions

Application site reactions are frequently reported with Actikerall treatment and are expected to occur, because these are related to the pharmacological activity of the active substances fluorouracil and salicylic acid on the skin. Severe application site reactions can be managed by dose reduction (see section 4.2). In case of bleeding stop treatment until adverse reaction improves (see section 4.4). When surface of contiguous application increases (field up to 25cm2), administration site adverse reactions frequency may increase. In particular frequency of dermatitis, scab, erosion, bleeding, oedema may be Very common, while frequency of ulcer may be Common.

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.

Not applicable.