Acitretin

Key points

• Acitretin’s terminal elimination half-life is 49 hours, and that of its related compound cis-acitretin is 63 hours under the same conditions.
• Altered mood and psychotic disorder are listed among acitretin’s adverse effects at a frequency the SmPC labels “not known”, the label’s term for a rate that cannot be estimated from the available data.

How it works

The way acitretin works is not fully established. The UK SmPC for acitretin classifies it as a retinoid in the antipsoriatic group, and explains that retinol (Vitamin A) is essential for normal epithelial growth and differentiation, although the mode of this effect is not yet established. Retinol and retinoic acid can reverse hyperkeratotic and metaplastic skin changes, but the SmPC notes that such effects are generally only seen at dosages associated with considerable local or systemic toxicity. Clinical studies have confirmed that acitretin normalises epidermal cell proliferation, differentiation and keratinisation in psoriasis and dyskeratosis, at doses where side effects are generally tolerable.

Safety specific to Acitretin

Acitretin carries an FDA boxed warning, its strongest safety alert, addressing the risk of severe birth defects. Every part of it is set out below, unsoftened, as the US prescribing information for acitretin states it.

1. Acitretin must not be used by women who are pregnant, who intend to become pregnant during treatment or at any time for at least three years after stopping, or who cannot use reliable contraception throughout that time. Acitretin is a metabolite of etretinate (TEGISON), and major human foetal abnormalities have been reported with both drugs: any exposed foetus can potentially be affected. Concurrent ethanol intake has been linked to the formation of etretinate, which has a significantly longer elimination half-life than acitretin, so ethanol must not be taken by female patients of childbearing potential during treatment or for two months after stopping. Acitretin has been shown to be embryotoxic and/or teratogenic in animal studies. Reported human foetal abnormalities linked to acitretin and/or etretinate include meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactyly, absence of terminal phalanges, malformations of the hip, ankle and forearm, low-set ears, high palate, decreased cranial volume, cardiovascular malformation, and alterations of the skull and cervical vertebrae; acitretin should be prescribed only by those with special competence in diagnosing and treating severe psoriasis, who are experienced in the use of systemic retinoids and understand the teratogenicity risk. Because of this risk, a dedicated pregnancy prevention and education programme (EPPA) has been developed for women of childbearing potential and their healthcare providers, to help prevent pregnancy during treatment and for three years afterwards. Acitretin should be considered only for women with severe psoriasis unresponsive to other therapies, or whose clinical condition contraindicates other treatments, and a prescription must not be given to a woman of reproductive potential until pregnancy is excluded and every one of the programme’s conditions, set out below, is met.
2. Before her first acitretin prescription, a woman of reproductive potential must have two negative pregnancy tests: an initial screening test taken when treatment is decided, and a confirmation test taken during the first five days of her next menstrual period, or, for a patient with amenorrhoea, at least eleven days after her last act of unprotected intercourse without two effective forms of contraception. If the confirmation test is negative, treatment should begin within seven days of that sample being taken, and acitretin should be limited to a monthly supply.
3. During treatment, a pregnancy test must be repeated every month, with a negative result required before each prescription and a monthly supply used to support compliance; for at least three years after stopping treatment, testing must continue every three months.
4. Patients must have chosen and committed to using two effective forms of contraception simultaneously, at least one of them a primary method, unless the patient practises absolute abstinence, has had a hysterectomy, or is clearly postmenopausal.
5. Two effective forms of contraception must be used simultaneously starting at least one month before treatment, throughout treatment, and for at least three years after stopping, with counselling on contraception and pregnancy-risk behaviours repeated monthly during treatment and every three months afterwards. Primary methods include tubal ligation, a partner’s vasectomy, intrauterine devices, birth control pills, and injectable, implantable, insertable or topical hormonal contraceptives; secondary methods include condoms, diaphragms and cervical caps used with spermicide, and vaginal sponges. Any birth control method can fail, so using two forms simultaneously is critical: a pharmacokinetic interaction between acitretin and combined oral contraceptives has not been established, but acitretin is known to interfere with the contraceptive effect of microdosed progestin-only “minipill” preparations, which are not recommended during acitretin therapy, and it is not known whether other progestin-only methods such as implants and injectables are adequate. Patients should also be cautioned against self-medicating with St John’s wort, since a possible interaction with hormonal contraceptives has been suggested from reports of breakthrough bleeding and reported pregnancies.
6. Female patients must sign a Patient Agreement or Informed Consent covering the risk of birth defects if a foetus is exposed, the possibility of contraceptive failure, the requirement not to take ethanol during treatment and for two months afterwards, and the need to prevent pregnancy during treatment and for at least three years after stopping. If pregnancy does occur during treatment or within three years of stopping, the prescriber and patient should discuss the known effects: acitretin, the active metabolite of etretinate, is teratogenic and contraindicated in pregnancy, and the risk of severe foetal malformation from systemic retinoids taken in pregnancy is well established. Because the threshold blood concentration below which risk falls is not established for acitretin in humans, and elimination rates vary between patients, the length of contraception needed after stopping cannot be calculated precisely; continuing contraception for at least three years after stopping is strongly recommended, based on the elimination considerations set out below.
7. If etretinate is not formed, more than 98% of a dose of acitretin would be eliminated within two months, based on a mean elimination half-life of 49 hours.
8. Etretinate can be formed, however, as has been demonstrated when acitretin is taken together with ethanol.
9. Where etretinate is formed, more than 98% of it would be eliminated within two years, based on a mean elimination half-life of 120 days.
10. On the longest elimination half-life demonstrated for etretinate, 168 days, more than 98% of it would be eliminated within three years. However, etretinate was detected in the plasma and subcutaneous fat of one patient with reported sporadic alcohol intake, 52 months after she stopped acitretin therapy.
11. Severe birth defects have been reported both where conception occurred during treatment with acitretin and/or etretinate, and where conception occurred after therapy was completed. These cases have been reported both before and after the pregnancy outcome was known, and are listed without judging whether they represent retinoid-induced embryopathy.
12. Of 318 prospectively reported pregnancies involving etretinate, acitretin, or both, 238 involved conception after the last dose of etretinate (103 cases), acitretin (126 cases), or both (9 cases). Outcome was unknown for roughly half of these, including 62 terminations and 14 spontaneous abortions; of the 118 cases with a known outcome, 15 were abnormal, including absent hand or wrist, clubfoot, gastrointestinal malformation, hypocalcaemia, hypotonia, limb malformation, neonatal apnoea or anaemia, neonatal ichthyosis, placental disorder or death, undescended testicle, and five cases of premature birth. Among the 126 acitretin-only conceptions, 43 occurred at least one year but less than two years after the last dose, with three abnormal outcomes (limb malformation, gastrointestinal tract malformation, and premature birth); none of the four conceptions occurring at least two years after the last dose had a reported birth defect.
13. A further 35 retrospectively reported conceptions occurred at least one year after the last dose of etretinate, acitretin, or both. Three birth defects were reported among conceptions one to two years after the last dose of acitretin (heart malformations, Turner’s Syndrome, and unspecified congenital malformations), and four among conceptions two or more years after the last dose of acitretin (foot malformation, two cases of cardiac malformation, and an unspecified neonatal and infancy disorder); three further abnormal outcomes were reported at least two years after the last dose of etretinate (chromosome disorder, forearm aplasia, and stillbirth).
14. Patients who have previously taken TEGISON (etretinate) must continue to follow TEGISON’s own contraceptive recommendations. TEGISON is no longer marketed in the United States.
15. Patients, male and female, should not donate blood during treatment or for at least three years afterwards, because a woman of childbearing potential must not receive blood from someone being treated with acitretin.
16. Acitretin has been detected in the seminal fluid of male patients treated with the drug, at a maximum observed level equivalent to only about 1 in 200,000 of a single 25 mg capsule transferred per ejaculate. Although this suggests residual acitretin in semen poses little if any risk to a foetus, the no-effect limit for teratogenicity is unknown, and there is no birth defect registry for acitretin. Conception has been reported in 25 cases where the male partner was taking acitretin, with the pregnancy outcome known in 13 of those.

Beyond the boxed warning, the label and SmPC set out further points specific to acitretin:

• Liver effects. In clinical trials, acitretin was associated with raised liver function test results, raised triglyceride levels, and hepatitis; 20 of 525 subjects in US trials (3.8%) stopped treatment because of elevated liver function test results.
• Liver, kidney and lipid contraindications. Acitretin is contraindicated in patients with severely impaired liver or kidney function, and in those with chronically and abnormally elevated blood lipid values.
• Methotrexate. Combining acitretin with methotrexate is contraindicated, reflecting an increased risk of hepatitis reported when methotrexate is combined with etretinate.
• Tetracyclines. Acitretin must not be given together with tetracyclines, since both can raise intracranial pressure.
• Breastfeeding. Acitretin is contraindicated during breastfeeding.
• Skin and nails. Thinning of the skin, skin fragility and scaling can occur all over the body, particularly on the palms and soles, and nail fragility is frequently observed.

Further reading

• ACITRETIN capsule
• Acitretin 25 mg Capsules