Acitretine

Uses

Acitretine is used for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, this should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, this should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically used, have produced efficacy results similar to the initial course of therapy.

Acitretine is also used to associated treatment for these conditions: Keratinization disorders, Severe Psoriasis

How Acitretine works

The mechanism of action of acitretin is unknown, however it is believed to work by targeting specific receptors (retinoid receptors such as RXR and RAR) in the skin which help normalize the growth cycle of skin cells.

Dosage

Acitretine dosage

It is recommended that Acitretine be given only by, or under supervision of, a dermatological specialist. Acitretine capsules are for oral administration. The capsules should be taken once daily with meals or with milk. There is a wide variation in the absorption and rate of metabolism of Acitretine. This necessitates individual adjustment of dosage. For this reason the following dosage recommendations can serve only as a guide.

Adult: Initial daily dose should be 25 mg or 30 mg for 2 to 4 weeks. After this initial treatment period the involved areas of the skin should show a marked response and/or side-effects should be apparent. Following assessment of the initial treatment period, titration of the dose upwards or downwards may be necessary to achieve the desired therapeutic response with the minimum of side-effects. In general, a daily dosage of 25–50 mg taken for a further 6–8 weeks achieves optimal therapeutic results. However, it may be necessary in some cases to a maximum of 75 mg/day. Therapy can be discontinued in patients with psoriasis whose lesions have improved sufficiently.

In patients with Darier’s disease a starting dose of 10 mg may be appropriate. The dose should be increased cautiously as isomorphic reactions may occur. Patients with severe congenital ichthyosis and severe Darier's disease may require therapy beyond 3 months. The lowest effective dosage, not exceeding 50 mg/day, should be given.

Continuous use beyond 6 months is contraindicated as only limited clinical data are available on patients treated beyond this length of time.

Children: Acitretine is contra-indicated in children unless the benefits significantly outweigh the risks, in view of possible severe side-effects associated with long-term treatment. The dosage should be established according to bodyweight. The daily dosage is about 0.5 mg/kg. Higher doses (up to 1 mg/kg daily) may be necessary in some cases for limited periods, but only up to a maximum of 35 mg/day. The maintenance dose should be kept as low as possible in view of possible long-term side-effects.

Elderly: Dosage recommendations are the same as for other adults.

Side Effects

Most of the clinical side-effects of Acitretine are dose-related and are usually well-tolerated at the recommended dosages. However, the toxic dose of Acitretine is close to the therapeutic dose and most patients experience some side-effects during the initial period whilst dosage is being adjusted. They are usually reversible with reduction of dosage or discontinuation of therapy.

Toxicity

Oral, rat: LD₅₀ = >4000 mg/kg. Symptoms of overdose include headache and vertigo.

Precaution

Acitretine should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with Acitretine therapy. The risk of giving birth to a deformed child is exceptionally high if Acitretine is taken before or during pregnancy, no matter for how long or at what dosage. Foetal exposure to Acitretine always involves a risk of congenital malformation. Donation of blood by a patient being treated with Acitretine is prohibited during and for two year after completion of treatment.

Interaction

Concurrent intake of Acitretine with ethanol led to the formation of Etretinate. However, Etretinate formation without concurrent alcohol intake cannot be excluded. Therefore, since the elimination half-life of Etretinate is 120 days the post-therapy contraception period in women of childbearing potential must be 2 years. An increased risk of hepatitis has been reported following the concomitant use of Methotrexate and Etretinate. Consequently, the concomitant use of Methotrexate and Acitretine should be avoided. The effect of Acitretine on the protein binding of anticoagulants e.g. warfarin revealed no interaction.

Food Interaction

• Avoid alcohol. Women of childbearing age should avoid ingesting any alcohol during treatment and two months after discontinuation of acitretin. Alcohol intake increases the duration of risk for birth defects to beyond three years post acitretin discontinuation.
• Take with food. Taking acitretin with the main meal of the day improves oral absorption.

[Major] CONTRAINDICATED: Ethanol consumption with acitretin leads to the formation of etretinate, which has a much longer half-life than acitretin.

Major human fetal abnormalities have been associated with the administration of acitretin, etretinate, and other retinoids.

The longer elimination half-life of etretinate relative to acitretin increases the duration of teratogenic potential for female patients.

In one case report of a patient with apparent sporadic ethanol intake, etretinate was present in plasma and fat for 52 months after acitretin was discontinued.

MANAGEMENT: Female patients should be warned that ethanol is contraindicated during active treatment with acitretin and for two months after cessation of therapy.

Acitretine Alcohol interaction

[Major] CONTRAINDICATED:

Ethanol consumption with acitretin leads to the formation of etretinate, which has a much longer half-life than acitretin.

[Major human fetal abnormalities have been associated with the administration of acitretin, etretinate, and other retinoids.

The longer elimination half-life of etretinate relative to acitretin increases the duration of teratogenic potential for female patients.

In one case report of a patient with apparent sporadic ethanol intake, etretinate was present in plasma and fat for 52 months after acitretin was discontinued.

Female patients should be warned that ethanol is contraindicated during active treatment with acitretin and for two months after cessation of therapy.

Acitretine Cholesterol interaction

[Major] Acitretine is contraindicated in patients with chronic abnormally elevated blood lipid values.

It is recommended to evaluate lipid status in patients before initiation of therapy and periodically until the lipid response to the drug is established.

Care should be taken in subjects with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism, obesity, or a familial history of these conditions.

Serum lipids must be more closely monitored in high-risk patients and during long-term treatment with acitretin.

Dietary modifications, reduction in dose of acitretin, or drug therapy should be employed to control significant elevations of triglycerides, and if hypertriglyceridemia and low HDL levels persist, discontinuation of acitretin should be considered.

Acitretine Drug Interaction

Unknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, fluticasone nasal, fluticasone nasal, sodium iodide, sodium iodide, pregabalin, pregabalin, esomeprazole, esomeprazole, apremilast, apremilast, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Acitretine Disease Interaction

Major: hyperlipidemia, liver disease, renal dysfunction, intracranial hypertension, psychiatric disordersModerate: alcoholism, diabetes, ophthalmologic effects, liver disease

Elimination Route

Oral absorption of acitretin is optimal when given with food, and is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.

Half Life

49 hours (range 33 to 96 hours)

Elimination Route

Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%).

Pregnancy & Breastfeeding use

Acitretine is contra-indicated during pregnancy and in women who are breast feeding as it is a known human teratogen. It is also contra-indicated in women of childbearing potential unless specific criteria are met.

Contraindication

Acitretine is contra-indicated in cases of hypersensitivity to it or excipients or to other retinoids. Its use is contra-indicated in pregnant women and women who might become pregnant during or within 2 years of the cessation of treatment. It is also contra-indicated in patients with hepatic or renal impairment and in patients with chronic abnormally elevated blood lipid values.

Storage Condition

Store in a cool and dry place. Protect from light.

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