Antiviral/Antiparkinson
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Amantadine is teratogenic and embryotoxic in one animal species, but the human pregnancy data are too limited for a complete risk assessment. However, complex cardiac defects were reported in three cases, and five other outcomes involved various malformations. The drug is best avoided in the 1st trimester.
FETAL RISK SUMMARY
Amantadine is indicated for the treatment of Parkinson disease and for the treatment and prophylaxis of influenza A. The plasma half-life is approximately 16–17 hours (range 10–31 hours) and the drug is moderately (about 67%) bound to plasma proteins (1). In a 1975 correspondence, one author thought the drug was a potential human teratogen and the absence of published reports at the time had more to do with its infrequent use in pregnancy than to its teratogenic potency (2).
Amantadine was teratogenic in pregnant rats at a dose that was equivalent to the estimated human dose based on BSA conversion (EHD) of 7.1 mg/kg/day and embryotoxic at a dose that was equivalent to the EHD of 14.2 mg/kg/day. No embryo or fetal harm was observed at a dose that was equivalent to the EHD of 5.3 mg/kg/day. No teratogenic or embryotoxic effects were seen in pregnant rabbits given a dose that was equivalent to the EHD of 9.6 mg/kg/day (1).
No reports describing the placental passage of amantadine in humans have been located. The low molecular weight (about 152 for the free base), moderate plasma protein binding, and long plasma half-life suggest that the drug will cross to the embryo–fetus.
A cardiovascular defect (single ventricle with pulmonary atresia) has been reported in an infant exposed to amantadine during the 1st trimester (3). The mother was taking 100 mgday for a Parkinson-like movement disorder.
A 1987 retrospective report described the use of amantadine, starting before conception in four women, one of whom had a probable molar pregnancy (4). In the remaining three cases, 1st trimester spotting was observed in one (apparently normal outcome), one newborn had an inguinal hernia (also exposed to levodopa/carbidopa), and one pregnancy aborted a fetus without apparent anomalies at 4 months (also exposed to levodopa) (4).
A 1991 report described the outcomes of consecutive pregnancies in a woman with multiple sclerosis who was treated with amantadine throughout each pregnancy (5). The infants were born at 34 and 36 weeks’, respectively, with birth weights of 2640 and 2954 g, respectively. At the time of the report, the ages of the infants were 2.8 years and 3 months, respectively, and both were physically and developmentally normal (5).
Tibial hemimelia and tetralogy of Fallot was reported in an infant born from a mother exposed during early organogenesis to amantadine (6). The 37-year-old mother had taken the drug 100 mg daily for 7 days during the fourth and sixth postconception weeks for a para-influenza virus infection. Chromosome analysis of the infant revealed a normal female karyotype. In addition to this case, the investigators reported two other pregnancies exposed to amantadine throughout, both with normal outcomes. Both children, aged 4.4 and 3.2 years, had normal growth and development (6).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 51 newborns had been exposed to amantadine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Five (9.8%) major birth defects were observed (2 expected). Among six categories of defects for which specific data were available, one cardiovascular defect (0.5 expected) and one limb reduction defect (0 expected) were observed. No cases of oral clefts, spina bifida, polydactyly, or hypospadias were recorded. Although the incidence of defects is high, the number of exposures is too small to draw any conclusions.
Rosa expanded the above communication with additional data in 1994 (7). In addition to the six types of defects surveyed, brain and eye defects were added for a new total of eight defects. Among 333,000 pregnancies, 64 had 1st trimester prescriptions for amantadine. Five defects (same as in his 1993 communication) were now linked to the drug (3.1 expected), including one cardiovascular defect, but no limb reduction defects were found in the new analysis. Because heart defects were common among nonexposed cases in Medicaid data (1 in 98 births), and considering the above reports, he cautioned that if amantadine did cause the cardiac defects, the available data suggested that the risk was not high (7).
A retrospective cohort study, covering the period 2003–2008, described 239 pregnancies that were treated with antiviral agents during pregnancy (8). Of these, 104 women received M2 ion channel inhibitors (rimantadine, amantadine, or both) and 135 received oseltamivir. The pregnancy outcomes of these patients were compared with 82,097 controls from the site’s overall obstetric patient population. The exposure timing for the combined treated groups was 13% 1st trimester, 32% 2nd trimester, and 55% 3rd trimester. There were no significant differences between the treated groups and controls in terms of maternal and delivery characteristics except that M2 inhibitors had more multiple gestations. For M2 inhibitors, oseltamivir vs. controls, there were also no differences in stillbirths (0%, 0% vs. 1%), major defects (1% [trisomy 21], 0% vs. 2%), and minor defects (19%, 15% vs. 22%). The only significant finding in the characteristics of liveborn, singleton neonates, after exclusion of twins and major anomalies, was a higher risk of necrotizing enterocolitis in both treatment groups compared to controls—1.0%, 0.8% vs. 0.02%. (8).
BREASTFEEDING SUMMARY
Amantadine is excreted into breast milk in low concentrations (1). This is consistent with its low molecular weight (about 152 for the free base), moderate plasma protein binding, and long plasma half-life. Although no reports of adverse effects in nursing infants have been located, one manufacturer recommended that the drug be used with caution in lactating mothers because of the potential for urinary retention, vomiting, and skin rash in a nursing infant (9). The current manufacturer recommends that amantadine should not be used during breastfeeding (1).
References
1.Product information. Symmetrel. Endo Pharmaceuticals, 2000.
2.Coulson AS. Amantadine and teratogenesis. Lancet 1975;2:1044.
3.Nora JJ, Nora AH, Way GL. Cardiovascular maldevelopment associated with maternal exposure to amantadine. Lancet 1975;2:607.
4.Golbe LI. Parkinson’s disease and pregnancy. Neurology 1987;37:1245–9.
5.Levy M, Pastuszak A, Koren G. Fetal outcome following intrauterine amantadine exposure. Reprod Toxicol 1991;5:79–81.
6.Pandit PB, Chitayat D, Jefferies AL, Landes A, Qamar IU, Koren G. Tibial hemimelia and tetralogy of Fallot associated with first trimester exposure to amantadine. Reprod Toxicol 1994;8:89–92.
7.Rosa F. Amantadine pregnancy experience. Reprod Toxicol 1994;8:531.
8.Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol 2010;115:711–6.
9.Product information. Symmetrel. Du Pont Pharmaceuticals, 1985.