<p><strong>LD<sub>50</sub> Values</strong></p><p>Oral, mouse: 1098 mg/kg</p><p>Oral, rat: 670 mg/kg</p><p><strong>Overdose</strong></p><p>Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Official drug label" href="#label-reference">Label</a></sup></p><p><strong>Reproductive Toxicity</strong></p><p>Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Official drug label" href="#label-reference">Label</a></sup> The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED)
Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy.</p><p>There have been reports of male infertility when taking valproate.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Official drug label" href="#label-reference">Label</a></sup></p><p><strong>Lactation</strong></p><p>Valproate is excreted in human milk.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Official drug label" href="#label-reference">Label</a></sup> Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate
via breast milk.</p><p><strong>Other Toxicity Considerations</strong></p><p>Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Official drug label" href="#label-reference">Label</a></sup></p>