Anticonvulsant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Oxcarbazepine is embryo and fetal toxic and teratogenic in some animal species. Mild facial defects have been observed with oxcarbazepine and, a closely related agent carbamazepine has been associated with neural tube defects and minor craniofacial malformations (see Carbamazepine). The human data are too limited to assess the risk to the embryo–fetus. The effect of oxcarbazepine on folic acid levels or metabolism is unknown (1). Until this information is available, the safest course is to give folic acid supplementation with oxcarbazepine, as is done with other antiepileptic agents. In addition, metabolism of oxcarbazepine does not result in epoxide metabolites (1–3). Because these intermediate arene oxide metabolites have been associated with teratogenicity (see Carbamazepine, Phenytoin, and Valproic Acid), this may indicate a lower risk of teratogenicity with oxcarbazepine compared with the other agents.
FETAL RISK SUMMARY
Oxcarbazepine is an orally active anticonvulsant agent used as either monotherapy or adjunctive therapy in the treatment of partial seizures. The chemical structure of oxcarbazepine is closely related to that of another anticonvulsant, carbamazepine. Oxcarbazepine is rapidly metabolized to an active 10-monohydroxy metabolite (10-hydroxy-10,11-dihydrocarbamazepine; MHD) that is primarily responsible for the anticonvulsant activity (4).
In fertility studies with the active metabolite MHD, an oral dose, 2 times the maximum recommended human dose based on BSA (MRHD) administered to rats before and during mating and during early gestation caused disruption of the estrous cyclicity and a reduction in the numbers of corpora lutea, implantations, and live embryos. In pregnant rats, the administration of oral oxcarbazepine during organogenesis, at doses approximately 1.2 and 4 times the MRHD, caused increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations. Developmental toxicity (embryo–fetal death and growth restriction) was observed with oxcarbazepine at 4 times the MRHD. Oxcarbazepine (0.6 times the MRHD) or its active metabolite (equal to the MRHD) given during the latter part of gestation and throughout lactation were associated with persistent reductions in offspring body weights and, in the case of oxcarbazepine, altered behavior (decreased activity). Embryo and fetal death but no birth defects were observed in rabbits given oral doses of the active metabolite (1.5 times the MRHD) during organogenesis (4).
In a strain of mice susceptible to the teratogenic effects of carbamazepine, the highest tolerable oral dose of oxcarbazepine (1100 mg/kg/day) produced a lower incidence of teratogenicity (8% vs. 5% in controls; ns) than the epoxide metabolite of carbamazepine (14%–27% vs. 6% in controls; p <0.05). Concurrent treatment with phenobarbital did not increase the incidence of congenital malformations over that observed with oxcarbazepine alone (5).
In agreement with the molecular weight (about 252) of the parent drug, oxcarbazepine and its metabolite have been found in the fetus (2,6). In a woman who was taking oxcarbazepine monotherapy (300 mg 3 times daily) throughout gestation, maternal and term newborn plasma concentrations of the drug and its metabolite MHD were approximately equal (6). The healthy 3700-g female infant had mild facial dysmorphism with a discrete epicanthus and a broad nasal bridge. Her development at 13 months of age was normal without signs of mental retardation or neurologic deficit.
In three women taking oxcarbazepine (600–1800 mg/day; time of last dose not specified), maternal and cord blood were obtained at delivery and analyzed for the parent drug, active metabolite MHD, and the inactive metabolite of MHD (2). The three agents were detected in all samples. In another part of the study, oxcarbazepine was metabolized to MHD in a dual recirculating human placental perfusion system, suggesting that the same metabolic process occurs in vivo. MHD, however, was not metabolized to the inactive metabolite by the placenta. No placental metabolism of carbamazepine was observed in the perfusion system (2).
The author of a 1994 report very briefly reviewed the pregnancy outcomes of 27 women treated with oxcarbazepine (7). The outcomes included 1 infant born with “some dysmorphic features” (which disappeared later in life), 3 spontaneous abortions (SABs), 1 infant with spina bifida (whose mother also received valproate), 1 newborn with “amniotic bands,” and 22 normal infants (including 1 set of twins).
A 1996 review discussed the effects of oxcarbazepine and other anticonvulsants (1). Compared with carbamazepine, oxcarbazepine causes less induction of the cytochrome P450 enzyme system. However, oxcarbazepine may compromise the efficacy of hormonal contraception. The outcomes of 12 pregnancies treated with oxcarbazepine (3 SABs and 9 normal newborns) were listed without further details (1).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997 (8). The final report was published in July 2010. The Registry is now closed. Among 34 prospectively enrolled pregnancies exposed to oxcarbazepine and lamotrigine, with or without other anticonvulsants, 31 were exposed in the 1st trimester resulting in 27 live births without defects, 2 SABs, and 2 birth defects. There were three exposures in the 2nd/3rd trimesters resulting in live births without defects (8).
A 2006 review of prophylactic therapy of bipolar disorder briefly described the effects in pregnancy and breastfeeding of a number of drugs, including oxcarbazepine (9). Untreated pregnant and nursing women with the disorder are at an increased risk of poor obstetrical outcomes and relapse of affective symptoms. Although the limited data prevented conclusions on the relative safety of the drugs, the author did state that each case needed to be considered separately (9).
BREASTFEEDING SUMMARY
Only one published report describing the use of oxcarbazepine during human lactation has been located. In a woman who took oxcarbazepine (900 mg/day) throughout gestation and during lactation (see case discussion above), the milk:plasma ratios of the drug and its active metabolite MHD were 0.5 (6). No adverse effects in the nursing infant from the exposure were mentioned. The manufacturer also states that the milk:plasma ratio for both agents is 0.5 (4). Nursing infants should be monitored for poor suckling, vomiting, and sedation (10). However, because the American Academy of Pediatrics classifies carbamazepine as compatible with breastfeeding (see Carbamazepine), oxcarbazepine can probably be similarly classified.
References
1.Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 1996;37(Suppl 6): S34–44.
2.Pienimaki P, Lampela E, Hakkola J, Arvela P, Raunio H, Vahakangas K. Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta. Epilepsia 1997;38:309–16.
3.Grant SM, Faulds D. Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992;43:873–88.
4.Product information. Trileptal. Novartis Pharmaceuticals, 2001.
5.Bennett GD, Amore BM, Finnell RH, Wlodarczyk B, Kalhorn TF, Skiles GL, Nelson SD, Slattery JT. Teratogenicity of carbamazepine-10,11-epoxide and oxcarbazepine in the SWV mouse. J Pharmacol Exp Ther 1996;279:1237–42.
6.Bulau P, Paar WD, von Unruh GE. Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother. Eur J Clin Pharmacol 1988;34:311–3.
7.Andermann E. Pregnancy and oxcarbazepine. Epilepsia 1994;35 (Suppl 3):S26.
8.The Lamotrigine Pregnancy Registry. Final Report. 1 September 1992 through 31 March 2010. GlaxcoSmithKline, July 2010.
9.Gentile S. Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers. Bipolar Disord 2006;8:207–20.
10.Bar-Oz, B, Nulman I, Koren G, Ito S. Anticonvulsants and breast feeding—a critical review. Paediatr Drugs 2000;2:113–26.