PRIMIDONE
Drugs in Pregnancy and Lactation.
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Name: PRIMIDONE
Class: Anticonvulsant
Risk Factor: D
Fetal Risk Summary
Primidone, a structural analogue of phenobarbital (see also Phenobarbital), is effective against generalized convulsive seizures and psychomotor attacks. The epileptic patient on anticonvulsant medication is at a higher risk for having a child with congenital defects than the general population (1,2,3,4,5,6 and 7). A total of 323 infants who were exposed to primidone during the 1st trimester have been noted in various publications (4,8,9,10,11,12,13,14,15,16 and 17). Of the 41 malformed infants described in these reports, only 3 infants were exposed to primidone alone during gestation (8,15,16). The anomalies observed in these three infants were similar to those observed in the fetal hydantoin syndrome (see Phenytoin).
Acardia, a rare congenital defect, was described in 1996 case report (18). The 28-year-old mother with two healthy children and a long history of epilepsy had taken primidone (500 mg/day) until the 3rd month of pregnancy. She stopped the drug at this time because of concern for malformations. Her pregnancy history included three epileptic seizures in months 4, 5, and 8. She had no prenatal care during the pregnancy until she presented at term. An ultrasound revealed a twin pregnancy. A cesarean section was performed to deliver a normal 2300-g female infant and a female acardiac acephalic monster. Both were in a single amniotic cavity. The normal female infant did well with no problems in the neonatal period. Genetic studies on the anomalous twin could not be conducted because of delay in receiving permission to study it. At autopsy, the head and upper extremities were totally absent and the major internal organs (heart, lungs, liver, spleen, pancreas, and the upper gastrointestinal tract) could not be identified. Structures that were identified included the small intestine with a blind proximal ending, colon with an anal opening, two adrenal glands, two hypoplastic kidneys and ureters, bladder, uterus and tubes, two ovaries, and a single umbilical artery and vein. The cause of the rare defect could not be determined.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 36 newborns had been exposed to primidone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.8%) major birth defect was observed (two expected). Details were not available on the single case, but no anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
The effects of exposure (at any time during the 2nd or 3rd month after the last menstrual period) to folic acid antagonists on embryo/fetal development were evaluated in a large, multicenter, case-control surveillance study published in 2000 (19). The report was based on data collected between 1976 and 1998 from 80 maternity or tertiary care hospitals. Mothers were interviewed within 6 months of delivery about their use of drugs during pregnancy. Folic acid antagonists were categorized into two groups: group I–dihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim); group II–agents that affect other enzymes in folate metabolism, impair the absorption of folate, or increase the metabolic breakdown of folate (carbamazepine, phenytoin, primidone, and phenobarbital) (18). The case subjects were 3,870 infants with cardiovascular defects, 1,962 with oral clefts, and 1,100 with urinary tract malformations. Infants with defects associated with a syndrome were excluded, as were infants with coexisting neural tube defects (NTDs; known to be reduced by maternal folic acid supplementation). Too few infants with limb-reduction defects were identified to be analyzed. Controls (N=8,387) were infants with malformations other than oral clefts and cardiovascular, urinary tract, and limb-reduction defects and NTDs, but included infants with chromosomal and genetic defects. The risk of malformations in control infants would not have been reduced by vitamin supplementation, and none of the controls used folic acid antagonists. For group I cases, the relative risks (RRs) of cardiovascular defects and oral clefts were 3.4 (95% confidence interval [CI] 1.8–6.4) and 2.6 (95% CI 1.1–6.1), respectively. For group II cases, the RRs of cardiovascular and urinary tract defects, and oral clefts were 2.2 (95% CI 1.4–3.5), 2.5 (95% CI 1.2–5.0), and 2.5 (95% CI 1.5–4.2), respectively. Maternal use of multivitamin supplements reduced the risks in group I cases, but not in group II cases (19).
A prospective study published in 1999 described the outcomes of 517 pregnancies of epileptic mothers identified at one Italian center from 1977 (20). Excluding genetic and chromosomal defects, malformations were classified as severe structural defects, mild structural defects, and deformations. Minor anomalies were not considered. Spontaneous (N=38) and early (N=20) voluntary abortions were excluded from the analysis, as were 7 pregnancies that delivered at other hospitals. Of the remaining 452 outcomes, 427 were exposed to anticonvulsants of which 313 involved monotherapy: primidone (N=35), carbamazepine (N=113), phenobarbital (N=83), valproate (N=44), phenytoin (N=31), clonazepam (N=6), and other (N=1). There were no defects in the 25 pregnancies not exposed to anticonvulsants. Of the 42 (9.3%) outcomes with malformations, 24 (5.3%) were severe, 10 (2.2%) were mild, and 8 (1.8%) were deformities. There were three malformations with primidone monotherapy: two (5.7%) were severe (intraventricular defect and hypospadias), and one (2.8%) was mild (undescended testis and inguinal hernia). The investigators concluded that the anticonvulsants were the primary risk factor for an increased incidence of congenital malformations (see also Carbamazepine, Clonazepam, Phenobarbital, Phenytoin, and Valproic Acid) (20).
There are other potential complications associated with the use of primidone during pregnancy. Neurologic manifestations in the newborn, such as overactivity and tumors, have been associated with use of primidone in pregnancy (16,21). Neonatal hemorrhagic disease with primidone alone or in combination with other anticonvulsants has been reported (14,22,23,24,25 and 26). Suppression of vitamin K1–dependent clotting factors is the proposed mechanism of the hemorrhagic effect (14,22). Administration of prophylactic vitamin K1 to the infant immediately after birth is recommended (see Phytonadione, Phenytoin, and Phenobarbital).
Breast Feeding Summary
Primidone is excreted into breast milk (27). Because primidone undergoes limited conversion to phenobarbital, breast milk concentrations of phenobarbital should also be anticipated (see Phenobarbital). A milk:plasma ratio of 0.8 for primidone has been reported (27). The amount of primidone available to the nursing infant is small, with milk concentrations of 2.3 µg/mL. No reports linking adverse effects to the nursing infant have been located; however, patients who breast-feed should be instructed to watch for potential sedative effects in the infant. In the American Academy of Pediatrics' 1994 statement, primidone is classified as an agent that may produce significant adverse effects in the nursing infant, and, thus, should be used with caution in the lactating woman (28).
References
- Hill RB. Teratogenesis and antiepileptic drugs. N Engl J Med 1973;289:1089–90.
- Bodendorfer TW. Fetal effect of anticonvulsant drugs and seizure disorders. Drug Intell Clin Pharm 1978;12:14–21.
- Committee on Drugs, American Academy of Pediatrics. Anticonvulsants and pregnancy. Pediatrics 1977;63:331–3.
- Nakane Y, Okuma T, Takahashi R, Sato Y, Wada T, Sato T, Fukushima Y, Kumashiro H, Ono T, Takahashi T, Aoki Y, Kazamatsuri H, Inami M, Komai S, Seino M, Miyakoshi M, Tanimura T, Hazama H, Kawahara R, Otuski S, Hosokawa K, Inanaga K, Nakazawa Y, Yamamoto K. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 1980;21:663–80.
- Andermann E, Dansky L, Andermann F, Loughnan PM, Gibbons J. Minor congenital malformations and dermatoglyphic alterations in the offspring of epileptic women: a clinical investigation of the teratogenic effects of anticonvulsant medication. In Epilepsy, Pregnancy and the Child. Proceedings of a Workshop held in Berlin, September 1980. New York, NY: Raven Press, 1981.
- Danksy L, Andermann F. Major congenital malformations in the offspring of epileptic patients. In Epilepsy, Pregnancy and the Child. Proceedings of a Workshop held in Berlin, September 1980. New York, NY: Raven Press, 1981.
- Janz D. The teratogenic risks of antiepileptic drugs. Epilepsia 1975;16:159–69.
- Lowe CR. Congenital malformations among infants born to epileptic women. Lancet 1973;1:9–10.
- Lander CM, Edwards BE, Eadie MJ, Tyrer JH. Plasma anticonvulsants concentrations during pregnancy. Neurology 1977;27:128–31.
- Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972;2:839–43.
- McMullin GP. Teratogenic effects of anticonvulsants. Br Med J 1971;4:430.
- Fedrick J. Epilepsy and pregnancy: a report from the Oxford Record Linkage Study. Br Med J 1973;2:442–8.
- Biale Y, Lewenthal H, Aderet NB. Congenital malformations due to anticonvulsant drugs. Obstet Gynecol 1975;45:439–42.
- Thomas P, Buchanan N. Teratogenic effect of anticonvulsants. J Pediatr 1981;99:163.
- Myhree SA, Williams R. Teratogenic effects associated with maternal primidone therapy. J Pediatr 1981;99:160–2.
- Rudd NL, Freedom RM. A possible primidone embryopathy. J Pediatr 1979;94:835–7.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:358.
- Kutlay B, Bayramoglu S, Kutlar AI, Yesildaglar N. An acardiac acephalic monster following in-utero anti-epileptic drug exposure. Eur J Obstet Gynecology Reprod Med 1996;65:245–8.
- Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608–14.
- Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, Mamoli D, Palmieri C, Molteni F, Granata T, Hassibi P, Zamperini P, Pardi G, Avanzini G. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999;40:1231–6.
- Martinez G, Snyder RD. Transplacental passage of primidone. Neurology 1973;23:381–3.
- Kohler HG. Haemorrhage in the newborn of epileptic mothers. Lancet 1966;1:267.
- Bleyer WA, Skinner AL. Fatal neonatal hemorrhage after maternal anticonvulsant therapy. JAMA 1976;235:826–7.
- Mountain KR, Hirsh J, Gallus AS. Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1970;1:265–8.
- Evans AR, Forrester RM, Discombe C. Neonatal hemorrhage following maternal anticonvulsant therapy. Lancet 1970;1:517–8.
- Margolin DO, Kantor NM. Hemorrhagic disease of the newborn: an unusual case related to maternal ingestion of antiepileptic drug. Clin Pediatr (Phila) 1972;11:59–60.
- Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979;7:624–7.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
Q&A about Primidone
This is an anti-epileptic medication
Taking primidone and mysoline for essential tremor i have had for 5 years. It seems to be necessary to keep increasing the dosage on both medications.
I believe you will find it beneficial to check out the International Essential Tremor Foundation website. You can learn a great deal there: http://www.essentialtremor.org/
Their Frequently Asked Questions page has medication information: http://www.essentialtremor.org/informati...