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THERE ARE INTRINSIC METHODOLOGIC PROBLEMS IN OBTAINING ADEQUATE DATA ON DRUG TERATOGENICITY IN HUMANS; GENETIC FACTORS OR THE EPILEPTIC CONDITION ITSELF, MAY BE MORE IMPORTANT THAN DRUG THERAPY IN CONTRIBUTING TO CONGENITAL ANOMALIES. PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES. A PATIENT WHO HAD LOW FIBRINOGEN WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH TO AN INFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED OF HEMORRHAGE. IF VALPROATE IS USED IN PREGNANCY, THE CLOTTING PARAMETERS SHOULD BE MONITORED CAREFULLY. HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF AN INFANT, HAVE BEEN REPORTED FOLLOWING THE USE OF VALPROATE DURING PREGNANCY. Animal studies have demonstrated valproate-induced teratogenicity. Increased frequencies of malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats, rabbits, and monkeys following prenatal exposure to valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental animals, but neural tube closure defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding approximately 230 µg/ mL (2.3 times the upper limit of the human therapeutic range for epilepsy) during susceptible periods of embryonic development. Text Continues Below
Administration of an oral dose of 200 mg/ kg/ day or greater (50% of the maximum human daily dose or greater on a mg/ m 2 basis) to pregnant rats during organogenesis produced malformations (skeletal, cardiac, and urogenital) and growth retardation in the offspring. These doses resulted in peak maternal plasma valproate levels of approximately 340 µg/ mL or greater (3.4 times the upper limit of the human therapeutic range for epilepsy or greater). Behavioral deficits have been reported in the offspring of rats given a dose of 200 mg/ kg/ day throughout most of pregnancy. An oral dose of 350 mg/ kg/ day (approximately 2 times the maximum human daily dose on a mg/ m 2 basis) produced skeletal and visceral malformations in rabbits exposed during organogenesis. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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