Anticonvulsant
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of pregabalin in human pregnancy have been located. The animal reproduction data suggest moderate risk, but the absence of human pregnancy experience prevents an assessment of the embryo–fetal risk. Until human pregnancy experience is available, the best course is to avoid pregabalin during gestation.
FETAL RISK SUMMARY
Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). However, it does not directly bind to GABA or benzodiazepine receptors, augment GABA responses, alter rat brain GABA concentrations, or have acute effects on GABA uptake or degradation. Pregabalin is indicated as oral adjunctive therapy for adult patients with partial-onset seizures. It is also indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is freely soluble in water and in both acidic and basic aqueous solutions. It undergoes minimal metabolism and the elimination half-life is about 6 hours. The drug is not bound to plasma proteins (1).
Reproduction studies have been conducted in rats and rabbits. Skull alterations secondary to abnormally advanced ossification were observed in the embryos of rats given an oral dose of pregabalin during organogenesis that produced plasma exposures (AUC) about 42 times the human exposure at the maximum recommended dose of 600 mg/day (HE-MRD). Doses producing exposures about 17–85 times the HE-MRD resulted in increased incidences of skeletal variations and retarded ossification. Decreased fetal body weights were observed at about 85 times the HE-MRD. A no-effect dose for rat embryo–fetal developmental toxicity was not established (1).
When rats were dosed throughout gestation and lactation, offspring growth and survival were decreased at exposures about ≥4 and ≥10 times the HE-MRD, respectively. Mortality was 100% at exposures about 85 times the HE-MRD. Neurobehavioral deficits (decreased auditory startle response) and reproductive impairment (decreased fertility and litter size) were observed in the adult offspring of rats given doses producing exposures about ≥10 and 42 times the HE-MRD, respectively. The no-effect dose for prenatal and postnatal developmental toxicity in rats produced a plasma exposure about 2 times the HE-MRD (1).
In pregnant rabbits given doses during organogenesis that produced plasma exposures about 40 times the HE-MRD, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed. The no-effect dose for developmental toxicity was about 16 times the HE-MRD (1).
Pregabalin produced dose-related carcinogenicity (hemangiosarcomas) in two strains of mice. The lowest dose resulting in the malignant vascular tumors was about equal to the HE-MRD; a no-effect dose in mice was not established. No carcinogenic effects were observed in rats. Mutagenic and clastogenic effects were not observed in various assays (1).
Pregabalin caused reproductive toxicity in male rats: decreased sperm counts and motility, increased sperm abnormalities, and reduced fertility. When the males were mated with untreated females, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities were observed. The no-effect dose for male reproductive toxicity was about 3 times the HE-MRD. Adverse effects were also noted on male reproductive organs (testes, epididymides) histopathology. The no-effect dose for male fertility toxicity produced plasma exposures about 8 times the HE-MRD. Pregabalin also impaired the fertility of female rats (disrupted estrous cyclicity) and increased the number of days to mating at exposures as low as 9 times the HE-MRD. A no-effect dose for female fertility toxicity was not established (1).
It is not known if pregabalin crosses the human placenta. The low molecular weight (about 159), minimal metabolism, lack of plasma protein binding, and the moderately long elimination half-life suggest that the drug will reach the embryo and fetus.
BREASTFEEDING SUMMARY
No reports describing the use of pregabalin during lactation have been located. The molecular weight (about 159), minimal metabolism, lack of plasma protein binding, and the moderately long elimination half-life (6 hours) suggest that the drug will be excreted into breast milk. Because it is freely soluble in water, the highest concentrations of the drug should be found in fore-milk. In adults, increased incidences of several adverse effects have been observed, including dizziness and somnolence, blurred vision, peripheral edema, myopathy, and decreased platelet count. The lack of data on the excretion of pregabalin into breast milk, combined with the potential for serious toxicity in a nursing infant, suggest that the drug should not be used by women who are breastfeeding.
Reference
1.Product information. Lyrica. Parke-Davis, 2006.