HYFTOR Gel Ref.[50985] Active ingredients: Sirolimus

Immunosupressed patients

Although systemic exposure is much lower following topical treatment with Hyftor than after systemic treatment with sirolimus, the gel should not be used in immunocompromised adults and children as a precautionary measure.

Mucous membranes and damaged skin

Hyftor should not be used on wounds, irritated skin or skin with a clinically confirmed diagnosis of infection as well as in patients with known skin barrier defects.

Contact with eyes or mucous membranes (mouth, nose) should be avoided. Therefore, the gel should not be applied around the eyes and on the eyelids.

Photosensitivity

Photosensitivity reactions have been observed in patients treated with Hyftor (see sections 4.8 and 5.3). Therefore, patients should avoid exposure to natural or artificial sunlight during the treatment period. Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing and/or headgear.

Skin cancer

Skin cancer has been observed after long-term treatment with oral sirolimus in preclinical studies (see section 5.3) and in patients treated systemically for immunosuppression. Although systemic exposure is much lower during treatment with sirolimus gel than with systemically administered sirolimus, patients should minimise or avoid exposure to natural or artificial sunlight during therapy using the same measures as mentioned above, to prevent photosensitivity.

Lymphoproliferative disorders

Lymphoproliferative disorders secondary to chronic systemic use of immunosuppressive agents have been reported in patients.

Severe hepatic impairment

Sirolimus is metabolised in the liver and blood concentrations are low following topical administration. As a precautionary measure in patients with severe hepatic impairment, treatment should be discontinued in case any potential systemic side effects are observed.

Hyperlipidaemia

Increased serum levels of cholesterol or triglycerides have been observed during treatment with sirolimus, in particular after oral administration. Patients with established hyperlipidaemia should regularly monitor lipid blood levels during treatment with sirolimus gel.

Excipients with known effect

Ethanol

This medicinal product contains 458 mg ethanol in each gram. This may cause burning sensation on damaged skin.

No interaction studies have been performed.

Sirolimus is extensively metabolised by the CYP3A4 isoenzyme, and it is a substrate for the multidrug efflux pump P-glycoprotein (P-gp). In addition, sirolimus has been shown to inhibit human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro. In the light of the low systemic exposure after topical administration it is not expected that clinical relevant interactions will occur, but Hyftor should be used with caution in patients taking respective concomitant medicinal products. Potential adverse reactions should be monitored and in case observed, treatment should be interrupted.

Except for sunscreens, no other topical treatments should be used on the facial angiofibroma lesions while treatment is ongoing.

Vaccination

During treatment with Hyftor, vaccinations may be less effective. Vaccination with live vaccines should be avoided during treatment.

Oral contraceptives

No interactions studies with Hyftor and oral contraceptives have been performed. Low systemic exposure to sirolimus during topical treatment with Hyftor makes pharmacokinetic drug interactions unlikely. The possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Hyftor cannot be fully excluded. For this reason, patients should be advised to use non-hormonal contraceptive measures during treatment.

Pregnancy

There are no or limited amount of data from the use of Hyftor in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3).

Hyftor should not be used during pregnancy, unless the clinical condition of the woman requires treatment with sirolimus.

Breast-feeding

Available pharmacokinetic data in rats have shown excretion of systemically administred sirolimus in milk. It is unknown whether sirolimus is excreted in human milk, although clinical data have shown that systemic exposure is low following administration of Hyftor.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Hyftor therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Impairments of sperm parameters have been observed among some patients treated systemically with sirolimus. These effects were reversible upon discontinuation of systemic sirolimus treatment in most cases.

Hyftor has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions were skin irritation events, including application site irritation (34.7%), dry skin (33.7%), acne (19.4%), and pruritus (11.2%). These events were generally mild or moderate in intensity, nonserious, and did not lead to treatment discontinuation.

Tabulated list of adverse reactions

Adverse reactions reported from the clinical studies are listed in table 1 by system organ class and frequency using 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), very rare (<1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions:

Description of selected adverse reactions

Application site irritation

Application site irritation of mild or moderate intensity occurred in 34.7% of patients treated with sirolimus gel in clinical studies. Application site irritation did not require discontinuation of treatment with the medicinal product.

Dry skin

Dry skin of mild or moderate intensity occurred in 33.7% of patients treated with sirolimus gel in clinical studies. Dry skin did not require discontinuation of treatment with the medicinal product.

Acne

Acne was reported in 19.4% of patients overall treated with sirolimus gel in clinical studies. Acne was of mild or moderate intensity; no severe acne was reported. Acne/dermatitis acneiform did not require discontinuation of treatment with the medicinal product.

Pruritus

Mild or moderate intensity pruritus occurred in 11.2% of patients treated with sirolimus gel in clinical studies. Pruritus did not require discontinuation of treatment with the medicinal product.

Paediatric population

In clinical development, no difference was seen in the safety between paediatric patients aged 6 years and older and adult patients included in a Phase III study including 27 patients ≤ 18 years (Hyftor: n=13) and a long-term study including 50 patients ≤ 18 years (Hyftor: all).

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 national reporting system listed in Appendix V.

Not applicable.