Anticonvulsant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Tiagabine was not teratogenic or embryo–fetal toxic in experimental animals at doses that did not cause maternal toxicity. However, the no–observed-effect levels were much <10 times the MRHD. The human data are too limited to determine the risk magnitude this agent represents to the embryo–fetus. Of concern, however, metabolism of tiagabine results in epoxide metabolites. As noted above, these intermediate arene oxide metabolites from other anticonvulsants have been associated with human teratogenicity. Therefore, the safest course is to avoid tiagabine, if possible, during the 1st trimester, but there is no evidence that exposure during organogenesis or at any other time during gestation will result in fetal harm. If tiagabine is required, monotherapy using the lowest effective dose is preferred, but because of its status as adjunctive therapy, this may not be possible. In addition, folic acid 4–5 mg/day should be taken with tiagabine.
FETAL RISK SUMMARY
The oral anticonvulsant tiagabine enhances the activity of γ-aminobutyric acid, the major inhibitory neurotransmitter, in the central nervous system. It is not known if this relates to its anticonvulsant activity. Tiagabine is indicated as adjunctive therapy in the treatment of partial seizures. Its elimination half-life is 7–9 hours, but is decreased to 4–7 hours in patients who are concurrently receiving hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). A 1996 review stated that the elimination half-life was 4–13 hours (mean 7 hours) and decreased to 2–3 hours when combined with enzyme-inducing anticonvulsants (2). In plasma, 96% is bound to albumin and α1-acid glycoprotein (1,2). Although not all of the metabolites have been identified, at least one is inactive (1). Of particular interest, a 1996 review stated that metabolism of tiagabine (based on data from a manufacturer) results in arene oxide metabolites (3). These intermediate free radicals have been associated with human teratogenicity (see Carbamazepine, Phenytoin, and Valproic Acid).
Reproduction studies with tiagabine have been conducted in rats and rabbits. In pregnant rats treated during organogenesis, maternal toxic (weight loss/reduced weight gain) doses approximately 16 times the maximum recommended human dose based on BSA (MRHD) were associated with an increased incidence of fetal malformations (craniofacial, appendicular, and visceral defects) and growth restriction. When this dose was given during late gestation and throughout parturition and lactation, maternal toxicity (decreased weight gain), stillbirths, and decreased postnatal offspring viability and growth were observed. No maternal or fetal adverse effects were observed at 3 times the MRHD. In pregnant rabbits, a dose 8 times the MRHD caused maternal toxicity (decreased weight gain), embryo death, and fetal variations. The no-effect dose for maternal, embryo, and fetal toxicity was approximately equivalent to the MRHD (1).
In rats, high doses (36–100 times the plasma exposure [AUC] obtained with the maximum recommended human dose of 56 mg/day) for 2 years were carcinogenic (hepatocellular adenomas in females and Leydig cell tumors of the testis in males). In an in vitro test, tiagabine, in the absence of metabolic activation, caused increased structural chromosome aberration frequency in human lymphocytes. This toxicity, however, was not observed in the assay in the presence of metabolic activation. Similarly, no genetic toxicity was observed in several other in vitro or in vivo assays (1).
It is not known if tiagabine crosses the human placenta. The molecular weight (376 for the free base) is low enough that exposure of the embryo–fetus should be expected. The moderately long elimination half-life will result in prolonged concentrations of the drug at the maternal blood–placenta interface, thus increasing the opportunity for embryo–fetal exposure.
A 1996 report described the outcomes of 23 human pregnancies exposed to tiagabine (3). Among the pregnancies exposed in a preclinical trial, there was one maternal death (unrelated to therapy), four spontaneous abortions (SABs), eight elective abortions (EABs) (including one blighted ovum and one ectopic pregnancy), eight normal outcomes, and one infant with unspecified malformations (also receiving other unspecified anticonvulsants). Specific data relating to the exposures (e.g., dose, duration, timing) were not provided.
In a 1999 analysis of 53 clinical trials involving tiagabine, 2531 epileptic patients were treated, including 22 pregnancies (4). Some data from this report also might have been reported in the above reference. The pregnancy outcomes were: four SABs, seven EABs (includes one blighted ovum and one ectopic pregnancy), eight normal outcomes, one infant with hip displacement related to a breech presentation, and one ongoing pregnancy. In the last case, the mother, who had taken tiagabine only during the first 2 months of pregnancy, had a seizure and drowned in her bathtub. Autopsy revealed a normal fetus with growth consistent to the gestational age (4).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997. The final report was published in July 2010 (5). The Registry is now closed. In five prospectively enrolled pregnancies exposed in the 1st trimester to tiagabine and lamotrigine, with or without other anticonvulsants, the outcomes were four live births without birth defects and one SAB (5).
The effect of tiagabine on folic acid levels and metabolism is unknown (3). Although not specifically referring to tiagabine, a 2003 review recommended that to reduce the risk of birth defects from anticonvulsants, women should start multivitamins with folic acid before conception (6). Although the recommendation did not specify the amount of folic acid, a recent study found that multivitamin supplements with folic acid (typically 0.4 mg) did not reduce the risk of congenital malformations from four first-generation anticonvulsants (see Carbamazepine, Phenytoin, Phenobarbital, or Primidone). Therefore, until further information is available, the best course is to start folic acid supplementation before conception. Although a specific dosage recommendation has not been determined for patients receiving anticonvulsants, 4 mg/day appears to be reasonable.
BREASTFEEDING SUMMARY
No studies describing the use of tiagabine during human lactation have been located. The molecular weight (about 376 for the free base) and the moderately long elimination half-life (as long as 13 hours) suggest that excretion into breast milk should be expected. The effect on the nursing infant from exposure to tiagabine in milk is unknown.
References
1.Product information. Gabitril. Cephalon, 2003.
2.Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Clin Pharmacokinet 1996;31:29–46.
3.Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 1996;37(Suppl 6):S34–44.
4.Leppik IE, Gram L, Deaton R, Sommerville KW. Safety of tiagabine: summary of 53 trials. Epilepsy Res 1999;33:235–46.
5.The Lamotrigine Pregnancy Registry. Final Report. September 1, 1992 through March 31, 2010. GlaxcoSmithKline, July 2010.
6.Yerby MS. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Epilepsia 2003;44(Suppl 3):33–40.