ACITRETIN
Drugs in Pregnancy and Lactation.
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Name: ACITRETIN
Class: Vitamin/Psoralen
Risk Factor: XM
Fetal Risk Summary Acitretin, an oral active synthetic retinoid and vitamin A derivative, is the active metabolite of etretinate (see also Etretinate). It is used for the treatment of severe psoriasis resistant to other forms of therapy and for severe congenital ichthyosis and keratosis follicularis (Darier's disease).
Similar to vitamin A and its derivatives, acitretin may cause congenital defects at human dosage levels in various animal species, including the mouse, rat, and rabbit (1). Fertility of rats was not impaired at the highest dose tested (3 mg/kg/day, or about 3 times the maximum recommended human dose). Chronic administration to male dogs (30 mg/kg/day) produced testicular changes: reversible mild to moderate spermatogenic arrest and the appearance of multinucleated giant cells (1).
After oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to 13-cis-acitretin (1). When consumed with alcohol, acitretin may be converted back to etretinate, a retinoid with a very long elimination half-life (mean 120 days, but may be as long as 168 days). Because the prolonged elimination would increase the teratogenic potential for women of childbearing age (see also Etretinate), the manufacturer states that alcohol must not be ingested during therapy with acitretin and for 2 months after cessation of therapy because of the long elimination period of acitretin (1).
In a 1994 Reference, the concentrations of etretinate, acitretin, and 13-cis-acitretin were measured in plasma and subcutaneous fat samples from 37 women of childbearing age (2). Twenty of the women were receiving acitretin and 17 had stopped. Sixteen of the 20 women, current acitretin users, had taken etretinate, but had stopped that drug a mean 45 ± 17 months before sampling, whereas four women had never received etretinate. Among current acitretin users, detectable etretinate levels in the plasma and subcutaneous fat were found in 45% and 83%, respectively. The 17 women who had stopped taking acitretin had been off the drug a mean 12 ± 10 months. Eleven of these women had also used etretinate but had stopped a mean 43 ± 14 months before sampling. The six women who had never taken etretinate stopped acitretin 17 ± 9 months before testing. Among these 17 women, etretinate was detected in 18% and 86%, respectively, of the plasma and subcutaneous fat samples. In some cases, acitretin and/or etretinate were detectable in plasma or subcutaneous fat up to 29 months after acitretin therapy had ceased. Thus, plasma concentrations correlated poorly with concentrations in fat. The findings led the authors to conclude that the recommended contraception period of 2 years after acitretin treatment (in 1994) was too short to avoid the risk of teratogenicity (2). Currently, the manufacturer recommends a contraception period of 3 years, but the human threshold concentration of acitretin below which the drug is not teratogenic has not been established (1).
A detailed case report of a pregnancy exposed to acitretin starting 10 days after conception and throughout the 1st trimester was published in 1995 (3). The 34-year-old woman was treated with acitretin (50 mg/day) for severe palmoplantar epidermolytic keratoderma. Pregnancy was diagnosed 6 weeks after stopping acitretin therapy. The pregnancy was terminated at 20 weeks' gestation with delivery of a stillborn, 210-g, 24-cm long male fetus with severe symmetric defects of the upper and lower limbs and craniofacial malformations (3). The extremity defects included bilateral short arms with pterygium formation in the elbows, shortened thumbs and little fingers without nails, contractures of both lower limbs in the groins and knees, irregularly thickened femora and tibiae, and point-shaped feet with only two small toes without nails (3). X-ray of the limbs revealed bilateral humeroradial synostosis and bone defects in the hands and feet. Craniofacial malformations included underdeveloped maxilla and mandibula, a small mouth with a high, arched and narrow palate, low-set ears, bilateral microtia, agenesis of the external ear canals, and bilateral preauricular tags (3). Except for an atrioventricular septal defect type II, no other anomalies were discovered on autopsy. Concentrations of acitretin, 12-cis-acitretin, and etretinate, in the maternal plasma, fetal brain and liver, and amniotic fluid 48 days after stopping therapy, were either undetectable (<0.3 ng/mL) or unquantifiable. An attempted chromosomal analysis of the fetus failed. Because the authors could find no other explanation for the malformations, including potential genetic defects, and the craniofacial malformations were similar to previous cases of retinoic acid embryopathy (e.g., see Isotretinoin), they concluded that the defects were caused by acitretin (3). In addition, the authors were aware of the poor correlation between plasma and fat concentrations of the vitamin A derivatives (see Reference 2 above), so that the failure to detect the retinoids in the plasma did not affect their conclusion (3).
Authors of a study published in 1994 attempted to determine if there was a threshold dose or plasma concentration of acitretin below which there was no teratogenic risk in females (4). In various species, the highest non-teratogenic oral doses (mg/kg/day) were 1 (mouse), 7.5 (rat), and 0.2 (rabbit). No data were available for cynomolgus monkeys or humans. The authors also summarized the outcomes of pregnancies that had occurred during or after acitretin therapy and that had been reported to the manufacturer since human therapy with the drug began in 1983. A total of 75 women were either exposed to acitretin during pregnancy (N=8) or before pregnancy (N=67) (median time before pregnancy 5 months, range 6 weeks to 23 months). Among those exposed during pregnancy, there were four spontaneous abortions, one induced abortion (no information on the fetus), one induced abortion with typical malformations, one newborn with a non-typical anomaly, and one normal newborn. The mother of the fetus with typical malformations took 50 mg/day of acitretin during the first 19 weeks of gestation. Malformations in the fetus were microtia and defects of the face and extremities. The mother of the infant with a non-typical anomaly took acitretin (20 mg/day) during the first 8 months of pregnancy. The infant had a hearing impairment for high frequencies. The outcomes of the 67 pregnancies exposed before conception were 9 spontaneous abortions, 18 induced abortions (15 fetuses with no information, 3 normal fetuses), 4 newborns with non-typical abnormalities, and 36 normal newborns. One of the mothers who delivered an infant with non-typical malformations had received 1 week of acitretin, 25 mg/day, 18 months before conception. The abnormalities, considered incompatible with life, included macrocephaly, low-set ears, microphthalmia, low-inserted thumb, ventricular and atrial septal defects, total duodenal obstruction, and cystic kidneys. The malformations were thought to be due to a chromosomal abnormality (partial trisomy 1) and a history of maternal drug abuse (4). The nontypical abnormalities in the other three newborns were transitory neonatal icterus and hypocalcemia, left testis ectopia, and slight transitory hypotonia.
In 1999, a brief report from the manufacturer summarized the worldwide data relating to acitretin and human pregnancy exposures that had been reported to the manufacturer since acitretin became available (5). Some of these data may have also been reported in the study discussed above. There were 123 reports of acitretin exposure either before or during pregnancy, 88 of which were prospective reports. Details on malformations were provided in only one case. Outcomes that did not involve congenital malformations were classified as “other abnormalities,” defined as pregnancy-related, placental, perinatal, or neonatal disorders, such as hyperbilirubinemia, abnormal growth, and delayed motor skills (5). There were 11 exposures during pregnancy, five reported prospectively and six retrospectively. Among the prospective cases, there was one spontaneous abortion (no information on the fetus), three induced abortions (no information on the fetuses), and one newborn with malformations (no details provided, but Reference #3 above was included whereas Reference #4 was not). Among those reported retrospectively, there was one spontaneous abortion (no information), three induced abortions (two with malformations, and one with other adverse conditions), and two newborns with other adverse conditions. For exposures that occurred 0–2 years before pregnancy, there were 97 cases, 77 of them prospective. Outcomes in these cases were 8 spontaneous abortions (1 normal embryo/fetus, and 7 with no information), 25 induced abortions (3 normal, 2 with malformations, and 20 with no information), and 44 newborns (41 normal, 1 with n undescended testicle, 1 hypotonic, and 1 with hypocalcemia and jaundice). The outcomes in the 20 retrospective cases were 5 spontaneous abortions (no information), 4 induced abortions (1 normal, 1 with malformations, and 2 with no information), and 11 newborns (9 normal, 2 with malformations). Two of the five cases in which exposure occurred more than 2 years before pregnancy were prospective. Their outcomes were one spontaneous abortion (no information) and one normal newborn. The three retrospective cases all involved newborns with malformations. Finally, 10 cases involved exposure at an unknown time before conception, 4 of which were prospective. The outcomes were one spontaneous abortion (no information), one induced abortion (no information), and two normal neonates. For the six retrospective cases, there was one spontaneous abortion (no information), two induced abortions (one normal, one with no information), and three normal newborns.
An interaction between acitretin and a very low dose progestin contraceptive (levonorgestrel 0.03 mg) was observed in one woman undergoing treatment with acitretin 0.4 mg/kg/day (6). Her plasma progesterone level increased from 2.15 ng/mL before acitretin or contraceptive to 3.87–13.46 ng/mL while receiving both drugs. The increase in plasma concentration was thought to indicate failure of contraception and development of a corpus luteum after ovulation (6). No interaction, as evidenced by a rise in plasma progesterone concentration, was observed in nine other women who received combined oral contraceptives (normal or mini-dose).
Acitretin has been measured in the seminal fluid of men consuming either acitretin or etretinate (1). In men administered 30 to 50 mg/day for at least 12 weeks, the sperm count, concentration, motility, and morphology were unchanged. In addition, no adverse effects on testosterone production, LH, FSH, or on the hypothalamic-pituitary axis were observed (1). The maximum concentration of acitretin found in seminal fluid was 12.5 ng/mL. The amount of acitretin transferred in semen, assuming an ejaculate volume of 10 mL, would be 125 ng or 1/200,000 of a single 25 mg capsule (1). Of five pregnancies in which the father was receiving acitretin therapy, two ended in spontaneous abortion, one fetus had bilateral cystic hygromas and multiple cardiopulmonary anomalies, one normal newborn was delivered, and one was lost to follow-up (1). The relationship between acitretin and the fetal malformations is unknown (1). However, no teratogenicity was observed in the offspring of male rats treated with 5 mg/kg/day (about 5 times the maximum recommended human dose) for 10 weeks (approximate duration of one spermatogenic cycle) before and during mating with untreated females (1).
In summary, like all retinoids, acitretin, the active metabolite of etretinate, is a potent teratogen. It represents not only a significant fetal risk during pregnancy, but also a risk for an unknown time after therapy has ceased. This added fetal risk results because acitretin can be converted back to the parent drug, etretinate, which can persist, along with acitretin and 13-cis-acitretin, in subcutaneous fat for prolonged periods, perhaps for longer than 3 years. Measuring plasma levels of the retinoids does not appear to be beneficial in determining the risk of fetal harm. Effective contraception must be used for at least 1 month before beginning acitretin, during therapy, and for at least 3 years after acitretin therapy (1). Women of childbearing age who are considering treatment with acitretin must be informed of this very slow elimination and the possibility of adverse pregnancy outcome if they conceive within 3 years of therapy.
Breast Feeding Summary
No reports describing the use of acitretin during human lactation have been located. The drug is excreted into the milk of lactating rats (1). Vitamin A is excreted into human breast milk and the excretion of acitretin should be expected. Because of the potential for serious adverse reactions, breast feeding while consuming acitretin is not recommended. The plasma elimination half-lives of acitretin and 13-cis-acitretin may be as long as 96 and 157 hours, respectively (1). Because of storage in subcutaneous fat, the actual elimination of these compounds may take much longer. The manufacturer recommends a contraception period of 3 years after acitretin therapy is stopped, but a similar recommendation for breast feeding has not been made.
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References
- Product information. Soriatane. Roche Laboratories, 2000.
- Sturkenboom MCJM, DeJong-Van Den Berg LTW, Van Voorst-Vader PC, Cornel MC, Stricker BHCH, Wesseling H. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994;38:229–35.
- De Die-Smulders CEM, Sturkenboom MCJM, Veraart J, Van Katwijk C, Sastrowijoto P, Van Der Linden E. Severe limb defects and craniofacial anomalies in a fetus conceived during acitretin therapy. Teratology 1995;52:215–9.
- Geiger JM, Baudin M, Saurat JH. Teratogenic risk with etretinate and acitretin treatment. Dermatology 1994;189:109–16.
- Maradit H, Geiger JM. Potential risk of birth defects after acitretin discontinuation. Dermatology 1999;198:3–4.
- Berbis Ph, Bun H, Geiger JM, Rognin C, Durand A, Serradimigni A, Hartmann D, Privat Y. Acitretin (RO10-1670) and oral contraceptives: interaction study. Arch Dermatol Res 1988;280:388–9.
Q&A about Acitretin
sine i have to take a double dose of acitretin what side affects are moslty likely to kick in.?
i ahve to have a double dose becuase there's something wrong with my liver.
i ahve to have a double dose becuase there's something wrong with my liver.
The side affects would be like taking a few more pills of Vit A then normal. Maybe mild head ache and a little blurred vision. If you do have something wrong with your liver, you really shouldn't be taking Acitretin since this medicine can easily make it worse. Also, you should not take a double dose of something just because you missed a dose, that can be very dangerous. Acitretin stays in your system for a couple of days so missing a dose is not the end of the world.
can acitretin kill you.?
since i have something wrong with my liver i have to take acitretin so is it bad or is all of the side affects alright and not very seroous.
since i have something wrong with my liver i have to take acitretin so is it bad or is all of the side affects alright and not very seroous.
Acitretin is a very strong medication used in the treatment psoriasis. Psoriasis is, by the way, a skin condition which causes flaking of skin cells Acitretin is not recommended in pregnancy and in fact has several side effects. One of the side effects is hypoglycaemia, or low blood sugar. This can lead to loss of consciousness or coma Yes, it can kill.
