Etretinate

(BAN, USAN, rINN)
Etretinate Chemical formula
Synonyms: Etretinaatti; Etretinat; Étrétinate; Etretinato; Etretinatum; Ro-109359. Ethyl 3-methoxy-15-apotrans)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona2,4,6,8-tetra-enoate.
Cyrillic synonym: Этретинат.

💊 Chemical information

Chemical formula: C23H30O3 = 354.5.
CAS — 54350-48-0.
ATC — D05BB01.
ATC Vet — QD05BB01.

💊 Adverse Effects and Precautions

As for Isotretinoin. Donation of blood should be avoided for at least 2 years after cessation of treatment. The period of time during which pregnancy must be avoided after stopping treatment has not been determined; detectable plasma-etretinate concentrations have been reported nearly 3 years after the last dose.

Carcinogenicity.

A report of 2 patients who developed lymphomas while receiving etretinate1 prompted a report of 3 other malignancies in patients taking etretinate.2
1. Woll PJ, et al. Lymphoma in patients taking etretinate. Lancet 1987; ii: 563–4
2. Harrison PV. Retinoids and malignancy. Lancet 1987; ii: 801.

Effects on the kidneys.

Rare cases of impaired renal function associated with etretinate have been described.1,2 In one report1it was also noted that in manufacturer-sponsored studies the mean serum-creatinine concentration had been raised in patients receiving etretinate.
1. Horber FF, et al. Impaired renal function and hypercalcaemia associated with etretinate. Lancet 1984; ii: 1093
2. Cribier B, et al. Renal impairment probably induced by etretinate. Dermatology 1992; 185: 266–8.

Oedema.

A report of generalised oedema after treatment with etretinate.1 Five other cases had been reported in the literature and rechallenge in 4 patients had provoked a recurrence. Generalised oedema as part of the capillary leak syndrome has been reported with acitretin.
1. Allan S, Christmas T. Severe edema associated with etretinate. J Am Acad Dermatol 1988; 19: 140.

Pregnancy.

For further information on the teratogenicity of etretinate, see under Acitretin.

💊 Interactions

As for Isotretinoin.

Anticoagulants.

Etretinate has been reported to reduce the therapeutic efficacy of warfarin.

Antiepileptics.

Etretinate was ineffective and none of its characteristic mucocutaneous adverse effects occurred in a patient with pityriasis rubra pilaris who was already taking carbamazepine and valproate for epilepsy. However, there was a clinical response after the carbamazepine had been withdrawn, suggesting that it may have reduced the bioavailability or increased the metabolism of etretinate.1
1. Mohammed KN. Unresponsiveness to etretinate during anticonvulsant therapy. Dermatology 1992; 185: 79.

Antineoplastics.

The risk of developing hepatotoxicity may be increased when etretinate is used with methotrexate.

Hormonal contraceptives.

For discussion of the potential interactions of retinoids with oral hormonal contraceptives, and the effect this might have on contraceptive choice during retinoid treatment.

💊 Pharmacokinetics

The mean bioavailability of etretinate is about 40% after oral doses but there is a large interindividual variation. Absorption can be increased if taken with milk or fatty food. Etretinate undergoes significant first-pass metabolism and plasma concentrations of the active carboxylic acid metabolite, acitretin, may be detected before those of the parent drug; acitretin may itself be metabolised to etretinate. Both etretinate and acitretin are extensively bound to plasma protein. Etretinate appears to accumulate in adipose tissue after repeated dosing and has a prolonged elimination half-life of about 120 days; detectable serum concentrations have been observed up to 3 years after stopping therapy. Up to 75% of a dose is excreted in the faeces mainly as unchanged drug. Etretinate is also excreted in the urine as metabolites. Etretinate crosses the placenta. Although it is not known whether etretinate is distributed into breast milk, this would be expected because of its lipophilicity; acitretin, a metabolite of etretinate, has been found in breast milk when it was given to a lactating woman.
1. Lucek RW, Colburn WA. Clinical pharmacokinetics of the retinoids. Clin Pharmacokinet 1985; 10: 38–62
2. DiGiovanna JJ, et al. Etretinate: persistent serum levels after long-term therapy. Arch Dermatol 1989; 125: 246–51
3. Larsen FG. Pharmacokinetics of etretinate and acitretin with special reference to treatment of psoriasis. Acta Derm Venereol (Stockh) 1994; 190 (suppl): 1–33
4. Wiegand UW, Chou RC. Pharmacokinetics of acitretin and etretinate. J Am Acad Dermatol 1998; 39 (suppl): S25–S33.

💊 Uses and Administration

Etretinate is a retinoid and is a derivative of tretinoin. It has been given orally for the treatment of severe, extensive psoriasis that has not responded to other treatment, especially generalised and palmo-plantar pustular psoriasis. It has also been used in severe congenital ichthyosis, severe Darier’s disease (keratosis follicularis) as well as other disorders of keratinisation, and oral lichen planus. Acitretin is now preferred to etretinate. Therapy is generally started at doses of 0.75 to 1 mg/kg daily in divided oral doses. A maximum dose of 1.5 mg/kg daily should not be exceeded (some licensed product information has suggested a maximum of 75 mg daily). Erythrodermic psoriasis may respond to lower initial doses of 250 micrograms/kg daily, increased at weekly intervals by 250 micrograms/kg daily until optimal response occurs. After the initial response, generally after 8 to 16 weeks of therapy, maintenance doses of 500 to 750 micrograms/kg daily have been given. Therapy should be stopped once lesions have sufficiently resolved.
1. Magis NLJ, et al. The treatment of psoriasis with etretinate and acitretin: a follow up of actual use. Eur J Dermatol 2000; 10: 517–21
2. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years’ experience on 23 patients. Br J Dermatol 2006; 154: 267–76.

💊 Preparations

Proprietary Preparations

Jpn: Tigason.
Published December 10, 2018.