Acitren: composition and dosage form
One hard capsule contains 10 mg or 25 mg of acitretin. The two strengths exist because the spread of daily doses is wide: for some indications the count runs to tens of milligrams, for others the maintenance dose is under ten.
The capsule is swallowed whole, once a day, with food or with milk — this is not a matter of taste but a condition of absorption. The dose the doctor sets is followed without exception. And there is one rule almost no other medicine carries: the drug must not be passed on to anyone else, and unused or expired capsules are returned to the pharmacy for destruction.
How Acitren works
The starting point is vitamin A. Retinol is a necessary growth factor that affects above all the growth and differentiation of epithelial cells, and its mechanism of action has not been fully explained. Both retinol and retinoic acid can reverse skin changes of the hyperkeratosis and tumour-formation type, but these effects usually appear only at doses with considerable local or systemic toxicity.
Acitretin is a synthetic aromatic analogue of retinoic acid and the main metabolite of etretinate, which was used successfully for years in psoriasis and other disorders of keratinisation. Clinical studies confirmed that in psoriasis and dyskeratosis acitretin normalises the multiplication of epithelial cells and the processes of their differentiation and keratinisation — and does so at doses at which the unwanted effects are on the whole tolerable. At the same time the product information warns plainly: the action of the medicine is purely symptomatic, and its mechanism remains largely unexplained.
Indications
There are five indications, and all of them are about one thing — severe disorders of keratinisation that do not respond to other treatment. First: extensive and severe forms of psoriasis resistant to treatment. Second: pustular psoriasis of the palms and soles. Third: severe congenital ichthyosis and ichthyosiform dermatitis.
Fourth is lichen planus of the skin and mucous membranes. The fifth is phrased as an open category: other severe, treatment-resistant forms of skin inflammation with abnormal or excessive keratinisation. What all five share are the words "severe" and "resistant": a medicine with this safety profile is not prescribed where simpler remedies work.
Method of administration and dosage
The first condition concerns not the dose but the prescriber: acitretin may be prescribed only by a doctor experienced in systemic retinoids and fully aware of the teratogenic risk. The dose is chosen individually according to the clinical picture and tolerance. Adults are advised to start at 25–30 mg a day for 2–4 weeks; an increase up to the maximum of 75 mg a day may then be needed, and that ceiling must not be exceeded. In Darier's disease a starting 10 mg may be enough, and the dose is raised cautiously because of the risk of isomorphic reactions.
The maintenance dose depends on the response and on tolerance. In psoriasis optimal efficacy is usually reached at 30 mg a day over the following 6–8 weeks, and once improvement is sufficient the treatment is stopped: long-term therapy is not recommended in psoriasis, and relapses are treated the same way. In disorders of keratinisation the maintenance dose should be as low as possible — even below 10 mg — and under no circumstances above 30 mg. In severe congenital ichthyosis or severe Darier's disease treatment may last longer than three months at the lowest effective dose, no higher than 50 mg a day. In the elderly the dose is the same as in adults. In children the dose is calculated by body weight: start at 0.5 mg per kilogram a day, if necessary temporarily up to 1 mg, but no more than 35 mg a day; maintenance averages 0.1 mg per kilogram and is usually no more than 0.2 mg, down to dosing every other day. Ready-made capsules do not always allow such a calculation, and the dose is then prepared by the pharmacist.
Contraindications
The main contraindication is pregnancy, and the wording leaves no room for interpretation: acitretin is highly teratogenic and must not be used in pregnant women. The same applies to women of childbearing age unless they use effective methods of pregnancy prevention for 4 weeks before treatment starts, throughout it, and for 3 years afterwards. Breastfeeding belongs here too.
The remaining prohibitions fall into two groups. Organ-related: severe impairment of liver and kidney function, chronically raised plasma lipid concentrations. And drug-related — three combinations, each with its own reason. Tetracyclines are ruled out because of a possible rise in intracranial pressure. Methotrexate, because the risk of hepatitis was shown for its combination with etretinate. Vitamin A and other retinoids, because of the risk of hypervitaminosis A. The list closes with hypersensitivity to the active substance or to the excipients.
Special warnings and precautions
Treatment with acitretin means regular laboratory tests. Liver function is checked before the start, then every 1–2 weeks for the first two months, and every 3 months thereafter; if values deviate, monitoring becomes weekly, and if they do not return to normal or grow worse, treatment is stopped and the liver is followed for at least 3 months more. Fasting cholesterol and triglycerides are checked before the start, after a month and then every 3 months. In diabetes, alcohol dependence, obesity or with cardiovascular risk factors, lipids, glucose and blood pressure are monitored more often; in people with diabetes retinoids may either improve or worsen glucose tolerance. If in high-risk patients the values do not normalise, a dose reduction or withdrawal is considered.
The second group of warnings concerns what the patient notices personally. Cases of impaired night vision have been described, so visual disturbances are mentioned in advance and driving after dark is not advised; in rare cases this persisted even after treatment ended. Benign intracranial hypertension was noted rarely: with severe headache, nausea, vomiting and visual disturbances the drug is stopped and a neurologist consulted. In adults on long-term treatment the bones are checked periodically for ossification disorders, and in children growth and bone development are followed: long-term etretinate treatment produced premature closure of the growth plates, hyperostosis and extraosseous calcification, and these are possible on acitretin as well. Retinoids amplify the effect of ultraviolet light: intense sun and tanning beds are avoided, and protection of at least SPF 15 is used where needed. Large doses may change mood as far as irritability, aggression and depression. Dry eyes may make contact lenses impossible to wear: such patients are either not given the drug or are asked to wear glasses. And one point is made separately: all the consequences of long-term acitretin use are not known today.
Interaction with other medicines
Three combinations are listed among the contraindications and are confirmed here: methotrexate, tetracyclines, vitamin A and other retinoids. The most unexpected interaction is with alcohol, and it explains much in the rules of use. In studies in healthy volunteers, taking a single dose of acitretin together with alcohol led to the formation of etretinate, which is strongly teratogenic and has a half-life of about 120 days. That is why women of childbearing age are forbidden alcohol in any form — in drinks, food or medicines — during treatment and for 2 months afterwards. The mechanism of this conversion has not been established, which means other interactions cannot be ruled out either.
The rest is shorter. Preparations with low doses of progesterone, that is the mini-pill, may prove an insufficiently reliable contraceptive method during acitretin treatment. No interactions were observed with combined oestrogen-progestogen contraceptives. When taken with phenytoin it should be remembered that acitretin partly reduces the ability of phenytoin to bind to proteins, although the clinical significance of this is unknown. With other substances — digoxin, cimetidine — no interactions were recorded, and protein-binding studies of coumarin anticoagulants, including warfarin, revealed no interaction.
Pregnancy and breastfeeding
Retinoids are capable of causing severe malformations in humans — craniofacial, of the central nervous system, of the circulatory system, of the skeletal system, of the thymus. Acitretin has a strong teratogenic action and causes fetal deformities in various animal species even at the low doses recommended in humans. The risk of a child being born with malformations is exceptionally high if the drug was used before or during pregnancy, regardless of the timing and the dose. The medicine is therefore contraindicated in any woman of childbearing age unless all the conditions are met: a severe disorder of keratinisation resistant to other treatment; understanding of the doctor's instructions and a commitment to follow them strictly; the ability to use reliable methods of pregnancy prevention.
| When | What is required |
| 4 weeks before the start | begin continuous contraception, preferably by two complementary methods |
| Before the first dose | pregnancy test with sensitivity from 25 mIU/ml, no more than 3 days earlier, negative result |
| Start of treatment | only on the 2nd or 3rd day of the next normal menstrual period |
| During treatment | tests every 28 days; for a prescription at the appointment, a negative test no older than 3 days |
| During and 2 months after | a total ban on alcohol — in drinks, food and medicines |
| 3 years after the last dose | continue contraception, tests every 1–3 months, no blood donation |
The main contraceptive method is considered to be an oral contraceptive or an intrauterine device combined with a condom or a cap; the mini-pill is not recommended. If pregnancy does occur, the risk of severe malformations is high and the rate of spontaneous miscarriage is increased; this applies above all to the treatment period and the two months after it. Over the three years following the end of treatment the risk is lower — particularly in women who do not drink alcohol — but it cannot be excluded entirely because of the possible formation of etretinate. Breastfeeding is forbidden. And a rule that is easy to forget: women of childbearing age must not be transfused with blood from patients who have taken acitretin, and they themselves are forbidden to donate blood. In men, data on acitretin levels in semen indicate that the teratogenic risk is minimal, if it exists at all.
Adverse effects
The section opens with an honest admission: unwanted effects are seen in the majority of patients taking acitretin. They usually pass after a dose reduction or the end of treatment, and at the start of treatment there is sometimes a temporary worsening of psoriasis symptoms. The commonest reactions are in essence signs of hypervitaminosis A, and the first among them is a dry mouth, eased with a greasy ointment.
Very often there is dryness and inflammation of the mucous membranes: conjunctivitis and dry eyes to the point of lens intolerance, nosebleeds and rhinitis, dry mouth and thirst. Skin manifestations are very common as well — inflammation of the vermilion border of the lips, itching, hair loss, peeling of the skin especially on the palms and soles, fragile and sticky skin, dermatitis, weakened nails, redness — as are deviations in liver tests: a transient and usually reversible rise in aminotransferases and alkaline phosphatase. Often recorded are headache, blurred vision and night blindness, gastritis and digestive disorders, muscle and joint pain, skin fissures, peripheral oedema. Uncommonly — dizziness, inflammation of the gums, taste disturbances, hepatitis, bullous dermatitis, photosensitivity, bone pain. Rarely — peripheral neuropathy, benign intracranial hypertension, ulcerative keratitis, jaundice. Very rarely — exostoses: maintenance treatment may cause progression of vertebral hyperostosis and new extraskeletal calcifications. With unknown frequency, vulval and vaginal candidiasis, type I hypersensitivity, hearing disorders, hot flushes, capillary leak syndrome, dysphonia, pyogenic granuloma, exfoliative dermatitis and loss of eyelashes have been described.
Overdose
In acute overdose, treatment with acitretin is stopped at once. The manifestations are the same as in the acute form of hypervitaminosis A: pain, dizziness, nausea or vomiting, drowsiness, irritability and itching.
The product information provides for no additional measures and explains why: the acute toxicity of the medicine is low. That does not mean it is safe in general: the danger of acitretin lies not in a single excess but in the teratogenic action, which persists for years after the last capsule.
How to get a prescription for Acitren online
Acitretin has one feature that determines everything else: it is highly teratogenic, and for women of childbearing age treatment is possible only inside a pregnancy prevention programme — with contraception from 4 weeks before, tests every 28 days and three years of follow-up afterwards. The questionnaire here is not a formality but the first step of that programme. On e-zdrowie.com you fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and with it any Polish pharmacy will dispense the capsules.
In the questionnaire name the diagnosis and state what you have already been treated with and why it did not help: the indication requires a severe and resistant form. Women of childbearing age need to answer separately about contraception — which method and since when — about the date of the last menstrual period, about their readiness to take tests every 28 days and to give up alcohol. Be sure to report liver and kidney disease, raised cholesterol and triglycerides, diabetes and cardiovascular risk factors, and whether you wear contact lenses. List your medicines separately: methotrexate, tetracyclines, vitamin A and retinoids are incompatible with acitretin, and the mini-pill is unreliable while taking it. And bear in mind: blood must not be donated during treatment or for three years afterwards.
