Long-term use of phenytoin has been found to cause osteomalacia. Bone disease is even more likely if a combination of antiepileptic drugs is used. Patients taking phenytoin should be advised to remain physically active, take vitamin D supplements, and eat foods rich in calcium. Because some sources of calcium (such as antacids and supplements like Tums and Os-Cal) reduce absorption of phenytoin, they should not be taken within about 2 hours after the phenytoin. This restriction does not apply to food sources of calcium such as dairy products. Many doctors now recommend bone-density studies for anyone taking phenytoin.

A number of reports have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Patients should be instructed to report fever, rash, and swollen, tender lymph glands. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Serious forms of dermatitis are seen rarely, including bullous, exfoliative, or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis. It has been estimated that 2.3 to 4.5 people out of each 10,000 who take phenytoin are hospitalized for treatment of rash.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10. The FDA has provided the following information for patients, family members, and caregivers at www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm.

• Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
• Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
• Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
• Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
  • Talking or thinking about wanting to hurt yourself or end your life
  • Withdrawing from friends and family
  • Becoming depressed or having your depression get worse
  • Becoming preoccupied with death and dying
  • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Reviewed July 2008 by Steven C. Schachter, MD, epilepsy.com Editorial Board.