Anticonvulsant
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports of human pregnancy experience have been located. Lacosamide was not teratogenic in two animal species but, in one, was associated with developmental neurobehavioral toxicity at plasma exposures close to those obtained in humans. Moreover, in vitro studies have shown that lacosamide interferes with the activity of collapsin response mediator protein-2 (CRMP-2), which is involved in neuronal differentiation and control of axonal outgrowth (1). Thus, lacosamide could cause adverse effects on CNS development if used in pregnancy. Until human data are available, the safest course is to avoid this drug in pregnancy.
FETAL RISK SUMMARY
Chemically, lacosamide is a functionalized amino acid that was approved by the FDA in 2008 as an anticonvulsant. It is available in both oral and IV formulations. The oral tablets are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged ≥17 years. IV injection is indicated in the same population when oral administration is temporarily not feasible. It is partially metabolized before elimination into an inactive metabolite. Plasma protein binding is minimal (about 15%), but the elimination half-life (about 13 hours) is prolonged (1).
Reproduction studies have been conducted in rats and rabbits. In rats, oral doses given during organogenesis that resulted in plasma exposures that were about twice the human exposure (AUC) from the maximum recommended dose of 400 mg/day (MRHD) caused maternal toxicity and embryo–fetal death. No teratogenic effects were observed. This dose, when given throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights in the offspring. The no-effect dose for prenatal and postnatal developmental toxicity produced plasma concentrations approximately equal to the MRHD. In rabbits, oral doses that produced plasma exposures about equal to the MRHD caused maternal toxicity but no teratogenicity (1).
Oral lacosamide also was given to rats during the neonatal and juvenile periods because the early postnatal period is thought to correspond to the 3rd trimester in humans in terms of brain development (1). This exposure resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance and deficits in learning and memory). The no-effect dose for developmental neurotoxicity was plasma concentrations about 0.5 times the MRHD (1).
Lacosamide was not carcinogenic in 2-year studies in mice and rats at doses producing plasma exposures up to about one and three times, respectively, the MRHD. Two of three mutagenicity studies were negative. In fertility studies, no adverse effects were observed on fertility or reproduction in male or female rats (1).
It is not known if lacosamide crosses the human placenta. The molecular weight (about 250), low plasma protein binding, and long elimination half-life suggest that it will cross to the embryo–fetus.
The manufacturer has established the UCB AED Pregnancy Registry in which either the healthcare provider or the patient can initiate enrollment by calling 1-888-537-7734. The manufacturer also recommends that patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334. (This must be done by the patients themselves.) (1).
BREASTFEEDING SUMMARY
No reports describing the use of lacosamide during human lactation have been located. The molecular weight (about 250), low plasma protein binding (about 15%), and long elimination half-life (about 13 hours) suggest that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown. However, consideration should be given to the neurobehavioral toxicity observed in neonatal rats at clinically relevant plasma exposures. Until human data are available, the safest course is for women taking this drug to not breastfeed.
Reference
1.Product information. Vimpat. UCB, 2008.