- 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.
Acitren should only be prescribed by doctors, who have experience in treatment with systemic retinoids and who are aware of the teratogenic risk associated with Acitren.
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:
Acitren 10 mg capsules
Acitren 25 mg capsules
An initial daily dose of 25 or 30 mg Acitren (i.e. 1 capsule of Acitren 25 mg or 3 capsules of Acitren 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 Acitren per day (i.e. 3 capsules of Acitren 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 Acitren 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 Acitren per day). It should not on any account exceed 30 mg Acitren 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.
Dosage recommendations are the same as for other adults.
If the administration of Acitren is combined with other forms of treatment, it may be possible to reduce the dose of Acitren according to the therapeutic result. Other dermatological therapy, particularly with keratolytics, should normally be stopped before administration of Acitren. 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 Acitren must be discussed with the doctor.
Method of administration
Acitren 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 Acitren calculated by the doctor.
PREGNANCY: Acitren, the active substance of Acitren, 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: Acitren is contraindicated during the period of breast-feeding.
Acitren 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 Acitren and tetracyclines can cause an increase in intracranial pressure, they must not be given concurrently.
Acitren must not be used concomitantly with low dose progesterone-only products (minipills).
Acitren must not be used in patients with hypersensitivity to the active substance â€œAcitrenâ€ or other retinoids or to any of the excipients.
Acitren 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 Acitren and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than Acitren. Women of childbearing age must therefore not consume alcohol (in drinks, food or medicines) during treatment with Acitren and for 2 months after cessation of Acitren therapy. Contraceptive measures and pregnancy tests must also be taken for 3 years after completion of Acitren treatment.
Women of childbearing potential must not receive blood from patients being treated with Acitren. Donation of blood by a patient being treated with Acitren is prohibited during and for 3 years after completion of treatment with Acitren.
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 Acitren, 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, Acitren 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 Acitren. Acitren 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 Acitren should be interrupted.
The dosage should be based on bodyweight (b.w.). An initial daily dose of 0.5 mg Acitren per kg b.w. is recommended. Higher doses up to 1 mg Acitren per kg b.w. per day may be necessary for a limited period in some cases. The maximum dose of 35 mg Acitren 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 Acitren by qualified pharmaceutical personnel in a public or hospital pharmacy is suggested.
The mean maintenance dose lies at 0.1 mg Acitren per kg b.w. per day. The maintenance dose should be kept as low as possible and should generally not exceed 0.2 mg Acitren 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 Acitren 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.
Acitren has moderate influence on the ability to drive and use machines.
Decreased night vision has been reported with Acitren 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 Acitren 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 Acitren 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:
over 80% of patients experienced: hypervitaminosis A as e.g. dry lips and possibly inflamed lips (using moisturisers or 'emollients' from the start of treatment can help to relieve dry skin problems.)
40 - 80% of patients experienced: dry mucous membranes of mouth and nose, peeling of skin, especially the palms of the hands and soles of the feet, rhinitis.
10 - 40% of patients experienced: nose bleed, scaling and thinning of healthy skin with increased sensitivity, erythema, pruritus, sensation of â€œburning skinâ€, sensation of â€œsticky skinâ€, dermatitis, hair loss, inflammation of the nail wall, nail fragility.
up to 10% of patients experienced: development of rhagades, inflammation of oral mucosa and gingiva associated with taste disturbances, blistering of the skin, change in pigmentation of the skin and hair, change in growth rate of hair, change in hair structure.
Marked dose dependence has been observed especially with regard to
- dry skin and mucous membranes, especially of the lips and nose,
- increased sensitivity of the skin and mucous membranes and
- hair loss.
Side effects of the skin and mucous membranes occur rather soon (a few days) after start of treatment, hair loss cannot be expected until several weeks into the treatment.
These side effects are reversible after altering the dose or discontinuation of treatment. However, new growth of hair will take some months, due to the hair growth cycle.
Increased sensitivity of the skin to light, as a result of which a sunburn can occur after only brief exposure to the sun. In these cases, care must be taken to wear adequate sun protection.
Madarosis and exfoliative dermatitis.
Wearing of contact lenses might become impossible. For this reason, patients should wear glasses during treatment with Acitren.
Inflammation or ulcers of the cornea.
Respiratory, thoracic and mediastinal disorders
Musculoskeletal and connective tissue disorders
Myalgia, arthralgia and bone pain.
Gastrointestinal tract disorders
Gastrointestinal symptoms (e.g. nausea, vomiting, abdominal pain, diarrhoea, dyspepsia).
Hepatitis and jaundice.
Reproductive system and breast disorders
During treatment with Acitren an increase in vulvovaginitis caused by Candida albicans has been observed.
Thirst and feeling of cold (10 to 40%).
Peripheral oedema, sensation of heat, dysgeusia, headache.
In addition to a possible increase in liver function values, an elevation of blood lipids has also been observed during treatment with Acitren.
The following changes in laboratory values occurred in patients during clinical trials:
- Elevation of triglycerides, total cholesterol, SGPT, creatine phosphokinase, SGOT, Î³-GT, alkaline phosphatase, direct bilirubin, lactate dehydrogenase and uric acid
- Lowering of HDL cholesterol.
Occasionally an increase in creatinine, BUN and total bilirubin was observed.
Nervous system disorders
An increase of intracranial pressure (pseudotumor cerebri) may occur, which may be accompanied by severe headache, lightheadedness, nausea, vomiting, dizziness or visual disturbances, but subsides after discontinuation of treatment. If these symptoms occur the treating physician should be consulted immediately.
Immune system disorders
Type 1 hypersensitivity.
Capillary Leak Syndrome / retinoic acid syndrome.
Not all the consequences of long-term therapy with Acitren 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 Acitren 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 Acitren 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.
Acitren, the active ingredient of Acitren, 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, Acitren brings about a normalisation of epidermal cell proliferation, differentiation and keratinisation in doses at which the side effects are generally tolerable. The effect of Acitren 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.
Acitren reaches peak plasma concentration 1 - 4 hours after ingestion of the drug. Bioavailability of orally administered Acitren is enhanced by food. Bioavailability of a single dose is approximately 60%, but inter-patient variability is considerable (36 95%).
Acitren is highly lipophilic and penetrates readily into body tissues. Protein binding of Acitren exceeds 99%. In animal studies, Acitren passed the placental barrier in quantities sufficient to produce foetal malformations. Due to its lipophilic nature, it can be assumed that Acitren passes into breast milk in considerable quantities.
Acitren is metabolised by isomerisation into its 13-cis isomer (cis Acitren), by glucuronidation and cleavage of the side chain.
Multiple-dose studies in patients aged 21 - 70 years showed an elimination half-life of approximately 50 hours for Acitren and 60 hours for its main metabolite in plasma, cis Acitren, which is also a teratogen. From the longest elimination half-life observed in these patients for Acitren (96 hours) and cis Acitren (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 Acitren and cis Acitren dropped below the sensitivity limit of the assay (< 6ng/ml) within 36 days following cessation of treatment. Acitren 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 Acitren and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than Acitren.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential.<
Any unused product or waste material should be disposed of in accordance with local requirements.