Acitretina IFC

- Extensive and severe refractory forms of psoriasis;

- Pustulous psoriasis of the hands and feet;

- Severe congenital ichthyosis and ichthyosiform dermatitis;

- Lichen ruber planus of skin and mucous membranes;

- Other severe and refractory forms of dermatitis characterised by dyskeratosis and/or hyperkeratosis.

Acitretina IFC should only be prescribed by doctors, who have experience in treatment with systemic retinoids and who are aware of the teratogenic risk associated with Acitretina IFC.

The dosage is based on the clinical appearance of the disorder and the tolerability of the product. The treating physician must determine the dosage individually for each patient. The following information can serve as a guide.

This product is available in two strengths:

Acitretina IFC 10 mg capsules

Acitretina IFC 25 mg capsules

Adults

An initial daily dose of 25 or 30 mg Acitretina IFC (i.e. 1 capsule of Acitretina IFC 25 mg or 3 capsules of Acitretina IFC 10 mg) for 2 to 4 weeks is recommended. After this initial phase, it may be necessary in some cases to increase the dose up to a maximum of 75 mg Acitretina IFC per day (i.e. 3 capsules of Acitretina IFC 25 mg). This maximum dose should not be exceeded.

In patients with Darier's disease a starting dose of 10mg may be appropriate. The dose should be increased cautiously as isomorphic reactions may occur.

The maintenance dose must be adjusted to the therapeutic response and the tolerability. In general, a daily dose of 30 mg Acitretina IFC for a further 6 to 8 weeks allows an optimum therapeutic effect to be achieved in psoriasis. In keratinisation disorders, the maintenance dose should be kept as low as possible (possibly less than 10 mg Acitretina IFC per day). It should not on any account exceed 30 mg Acitretina IFC per day.

Therapy can generally be discontinued in patients with psoriasis whose lesions have improved sufficiently. Long-term therapy is not recommended in psoriasis patients. Relapses are treated in the same way.

Patients with severe congenital ichthyosis and severe Darier's disease may require therapy beyond 3 months. The lowest effective dosage, not exceeding 50mg/day, should be given.

Elderly

Dosage recommendations are the same as for other adults.

Combination therapy:

If the administration of Acitretina IFC is combined with other forms of treatment, it may be possible to reduce the dose of Acitretina IFC according to the therapeutic result. Other dermatological therapy, particularly with keratolytics, should normally be stopped before administration of Acitretina IFC. However, the use of topical corticosteroids or bland emollient ointment may be continued if indicated.

Additional topical treatments, including purely skincare treatments, during the administration of Acitretina IFC must be discussed with the doctor.

Method of administration

Acitretina IFC hard capsules are for oral administration.

The hard capsules are taken whole once daily with meals or with milk. It is absolutely essential to keep to the dose of Acitretina IFC calculated by the doctor.

PREGNANCY: Acitretina IFC, the active substance of Acitretina IFC, is highly teratogenic and must not be used during pregnancy. The same applies to all women of childbearing potential, unless strict contraception is practiced 4 weeks before, during and for 3 years after treatment.

LACTATION: Acitretina IFC is contraindicated during the period of breast-feeding.

Acitretina IFC is not indicated in hepatic and renal dysfunction (liver and kidney failure), severe hyperlipaemia, concurrent use of vitamin A or other retinoids and during co-medication with methotrexate. Since Acitretina IFC and tetracyclines can cause an increase in intracranial pressure, they must not be given concurrently.

Acitretina IFC must not be used concomitantly with low dose progesterone-only products (minipills).

Acitretina IFC must not be used in patients with hypersensitivity to the active substance “Acitretina IFC” or other retinoids or to any of the excipients.

Acitretina IFC is highly teratogenic and hence contraindicated in women of childbearing potential unless pregnancy is reliably prevented 4 weeks before, during and for 3 years after the completion of therapy.

Full patient information about the teratogenic risk and the strict pregnancy prevention measures should be given by the physician to all patients, both male and female.

Clinical evidence has shown that etretinate can be formed with concurrent ingestion of Acitretina IFC and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than Acitretina IFC. Women of childbearing age must therefore not consume alcohol (in drinks, food or medicines) during treatment with Acitretina IFC and for 2 months after cessation of Acitretina IFC therapy. Contraceptive measures and pregnancy tests must also be taken for 3 years after completion of Acitretina IFC treatment.

Women of childbearing potential must not receive blood from patients being treated with Acitretina IFC. Donation of blood by a patient being treated with Acitretina IFC is prohibited during and for 3 years after completion of treatment with Acitretina IFC.

Due to the risk of foetal malformations, the medicine must not be passed on to other people. Unused or expired products should be returned to a pharmacy for disposal.

In view of possible effects on liver function, this must be monitored regularly during treatment. Hepatic function should be checked before starting treatment with Acitretina IFC, every 1 - 2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, Acitretina IFC must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months.

Serum cholesterol and serum triglycerides (fasting values) must be monitored, especially in high-risk patients (disturbances of lipid metabolism, diabetes mellitus, obesity, alcoholism) and during long-term treatment.

In diabetic patients, retinoids can alter glucose tolerance. Blood sugar levels should therefore be checked more frequently than usual at the beginning of the treatment period.

Before and during long-term therapy, x-rays (e.g. of the vertebral column, long bones, including ankles and wrists) must be taken at regular intervals (every year) in view of possible ossification abnormalities. In the event of hyperostosis, the discontinuation of therapy must be discussed with the patient. The risks must be carefully weighed against the therapeutic benefit to be expected.

Since there have been occasional reports of bone changes in children, including premature epiphyseal closure, fractures, skeletal hyperostosis and extraosseous calcification after long-term treatment with etretinate, these effects may be expected with its active metabolite Acitretina IFC. Acitretina IFC therapy in children is not, therefore, recommended unless, in the opinion of the physician, the benefits significantly outweigh the risks and all other alternative treatments have failed. If, in exceptional circumstances, such therapy is undertaken the child should be regularly monitored for any abnormalities of musculo-skeletal development and growth. Any symptoms that suggest possible bone changes (restricted mobility, bone pain) should be carefully investigated. As soon as the medical condition allows, the use of Acitretina IFC should be interrupted.

The dosage should be based on bodyweight (b.w.). An initial daily dose of 0.5 mg Acitretina IFC per kg b.w. is recommended. Higher doses up to 1 mg Acitretina IFC per kg b.w. per day may be necessary for a limited period in some cases. The maximum dose of 35 mg Acitretina IFC per day should not be exceeded.

The fixed-dose capsule formulations of 10 and 25 mg may not provide sufficient flexibility to cover the proposed paediatric dosing schedule per kg b.w. In this case preparation of a suitable dosage form (e.g. powders or capsules) made of the capsule content of Acitretina IFC by qualified pharmaceutical personnel in a public or hospital pharmacy is suggested.

The mean maintenance dose lies at 0.1 mg Acitretina IFC per kg b.w. per day. The maintenance dose should be kept as low as possible and should generally not exceed 0.2 mg Acitretina IFC per kg b.w. per day (dosing every other day may be considered).

The effects of UV light are enhanced by retinoid therapy, therefore patients should avoid excessive exposure to sunlight and the unsupervised use of sun lamps.

Decreased night vision has been reported with Acitretina IFC therapy. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored.

Wearing of contact lenses might become impossible due to dryness of the eyes. Patients who wear contact lenses should be excluded from treatment or wear glasses throughout the treatment period.

Very rare cases of Capillary Leak Syndrome / retinoic acid syndrome have been reported from world-wide post marketing experience.

Very rare cases of Exfoliative dermatitis have been reported from world-wide post marketing experience.

Acitretina IFC has moderate influence on the ability to drive and use machines.

Decreased night vision has been reported with Acitretina IFC therapy. In rare cases, this has continued after the treatment has stopped. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night or in a tunnel. Visual problems should be carefully monitored.

Possible side effects of Acitretina IFC occur in varying degrees from patient to patient. Most of the side effects are dose-related and usually reversible with reduction of dosage or discontinuation of therapy.

At the start of treatment with Acitretina IFC there may be a transient worsening of the psoriasis symptoms.

The skin and mucous membranes are most commonly affected, and it is recommended that patients should be so advised before treatment is commenced.

The reported adverse reactions are listed below by system organ class and by frequency.

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)

Not known (frequency cannot be estimated from the available data)

Skin and subcutaneous tissue disorders:

Not all the consequences of long-term therapy with Acitretina IFC can be estimated as yet.

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. Health professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Overdose of Acitretina IFC leads to the signs and symptoms of acute hypervitaminosis A, with headache, nausea and/or vomiting, drowsiness, irritability and pruritus.

In the event of acute overdose, the use of Acitretina IFC must be stopped. No further specific measures are necessary because of the low acute toxicity of the product.

Pharmacotherapeutic group: Antipsoriatics, retinoids for treatment of psoriasis

ATC code: D05BB02

Retinol (Vitamin A) is known to be essential for normal epithelial growth and differentiation, though the mode of this effect is not yet established. Both retinol and retinoic acid are capable of reversing hyperkeratotic and metaplastic skin changes. However, these effects are generally only obtained at dosages associated with considerable local or systemic toxicity.

Acitretina IFC, the active ingredient of Acitretina IFC, is a synthetic aromatic analogue of retinoic acid and the main metabolite of etretinate, which has been used with success for a number of years in the treatment of psoriasis and other disorders of keratinisation.

Clinical studies have confirmed that, in psoriasis and dyskeratosis, Acitretina IFC brings about a normalisation of epidermal cell proliferation, differentiation and keratinisation in doses at which the side effects are generally tolerable. The effect of Acitretina IFC is purely symptomatic: the mechanism of action is still largely unknown.

In the case of keratinisation disorders, experience for up to 2 years is available.

Absorption

Acitretina IFC reaches peak plasma concentration 1 - 4 hours after ingestion of the drug. Bioavailability of orally administered Acitretina IFC is enhanced by food. Bioavailability of a single dose is approximately 60%, but inter-patient variability is considerable (36 95%).

Distribution

Acitretina IFC is highly lipophilic and penetrates readily into body tissues. Protein binding of Acitretina IFC exceeds 99%. In animal studies, Acitretina IFC passed the placental barrier in quantities sufficient to produce foetal malformations. Due to its lipophilic nature, it can be assumed that Acitretina IFC passes into breast milk in considerable quantities.

Metabolism

Acitretina IFC is metabolised by isomerisation into its 13-cis isomer (cis Acitretina IFC), by glucuronidation and cleavage of the side chain.

Elimination

Multiple-dose studies in patients aged 21 - 70 years showed an elimination half-life of approximately 50 hours for Acitretina IFC and 60 hours for its main metabolite in plasma, cis Acitretina IFC, which is also a teratogen. From the longest elimination half-life observed in these patients for Acitretina IFC (96 hours) and cis Acitretina IFC (123 hours), and assuming linear kinetics, it can be predicted that more than 99% of the drug is eliminated within 36 days after cessation of long-term therapy. Furthermore, plasma concentrations of Acitretina IFC and cis Acitretina IFC dropped below the sensitivity limit of the assay (< 6ng/ml) within 36 days following cessation of treatment. Acitretina IFC is excreted entirely in the form of its metabolites, in approximately equal parts via the kidneys and the bile.

Clinical evidence has shown that etretinate can be formed with concurrant ingestion of Acitretina IFC and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than Acitretina IFC.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential.

Not applicable.

Any unused product or waste material should be disposed of in accordance with local requirements.