This syndrome resembles the well-described fetal alcohol syndrome and has been referred to as "fetal hydantoin syndrome". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively. Cancer
There is no good evidence to suggest that phenytoin is a human carcinogen. Mouth
Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a randomized controlled trial suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin. Plasma concentrations needed to induce gingival lesions have not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment. Skin
Hypertrichosis, Stevens–Johnson syndrome, purple glove syndrome, rash, exfoliative dermatitis, itching, excessive hairiness, and coarsening of facial features can be seen in those taking phenytoin. Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9.
Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. The U.S. Food and Drug Administration (FDA) notes on the phenytoin drug label that since strong evidence exists linking HLA-B*1502 with the risk of developing SJS or TEN in patients taking carbamazepine, consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele. Immune system
Phenytoin has been known to cause drug-induced lupus.Phenytoin is also associated with induction of reversible IgA deficiency. Psychological
Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide. Some case reports of acute phenytoin psychosis were already described. Bones
Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D, thus decreased vitamin D levels. Vitamin D deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density. Interactions
Phenytoin is an inducer of the CYP3A4 and CYP2C9 families of the P450 enzyme responsible for the livers degradation of various drugs.A 1981 study by the National Institutes of Health showed that antacids administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption.