Phenytoin Sodium Extended

Several controlled studies have shown that long-term anticonvulsant treatment decreases blood levels of biotin. In children, a deficiency of biotin can lead to withdrawn behavior and a delay in mental development. Adults with low biotin levels might experience a loss of appetite, feelings of discomfort or uneasiness, mental depression, or hallucinations. To avoid side effects, individuals taking anticonvulsants should supplement with biotin either alone or as part of a multivitamin.

Several controlled and preliminary studies showed that multiple drug therapy for seizures results in dramatic reductions in blood carnitine levels. Further controlled research is needed to determine whether children taking anticonvulsants might benefit by supplementing with L-carnitine, since current studies yield conflicting results. For example, one controlled study indicated that children taking valproic acid and carbamazepine received no benefit from supplementing with L-carnitine. However, another small study revealed that children taking valproic acid experienced less fatigue and excessive sleepiness following L-carnitine supplementation. Despite the lack of well-controlled studies, individuals who are taking anticonvulsants and experiencing side effects might benefit from supplementing with L-carnitine.

Anticonvulsant drugs can occasionally cause birth defects when taken by pregnant women, and their toxicity might be related to low blood levels of vitamin A. One controlled study showed that taking multiple anticonvulsant drugs results in dramatic changes in the way the body utilizes vitamin A. Further controlled research is needed to determine whether supplemental vitamin A might prevent birth defects in children born to women on multiple anticonvulsant therapy. Other research suggests that ingestion of large amounts of vitamin A may promote the development of birth defects, although the studies are conflicting.

Though research results vary, long-term use of anticonvulsant drugs appears to interfere with vitamin D activity, which might lead to softening of bones (osteomalacia). One study showed that blood levels of vitamin D in males taking anticonvulsants were lower than those found in men who were not taking seizure medication. In a controlled study, bone strength improved in children taking anticonvulsant drugs who were supplemented with the activated form of vitamin D and 500 mg per day of calcium for nine months. Some research suggests that differences in exposure to sunlight—which normally increases blood levels of vitamin D—might explain why some studies have failed to find a beneficial effect of vitamin D supplementation. In one controlled study, blood vitamin D levels in children taking anticonvulsants were dramatically lower in winter months than in summer months. Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease. Consequently, people taking anticonvulsant drugs who do not receive adequate sunlight should supplement with 400 IU of vitamin D each day to help prevent osteomalacia.

Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin E levels than those who received no treatment for seizures. Though the consequences of lower blood levels of vitamin E are unknown, people taking multiple anticonvulsant drugs should probably supplement with 100 to 200 IU of vitamin E daily to prevent a deficiency.

Individuals on long-term multiple anticonvulsant therapy may develop below-normal blood levels of calcium, which may be related to drug-induced vitamin D deficiency. Two infants born to women taking high doses of phenytoin and phenobarbital while pregnant developed jitteriness and tetany (a syndrome characterized by muscle twitches, cramps, and spasm) during the first two weeks of life. Controlled research is needed to determine whether pregnant women who are taking anticonvulsant medications should supplement with additional amounts of calcium and vitamin D.

Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though many researches believe that low blood levels of folic acid are involved, the effects might be caused by a vitamin B12 deficiency. Deficiencies of folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that individuals on long-term anticonvulsant therapy, despite having no laboratory signs of anemia, had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that bathes the brain) when compared with people who were not taking seizure medications. Improvement in mental status and nerve function was observed in a majority of symptomatic individuals after taking 30 mcg of vitamin B12 daily for a few days. Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12. The results of these two studies indicate that people taking anticonvulsant drugs might experience side effects of vitamin B12 deficiency, and that the deficiency is not easily detected by the usual blood tests. Therefore, individuals taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.

Several studies have shown that multiple anticonvulsant therapy reduces blood levels of folic acid and dramatically increases homocysteine levels. Homocysteine, a potential marker for folic acid deficiency, is a compound used experimentally to induce seizures and is associated with atherosclerosis. Carbamazepine alone has also been shown to reduce blood levels of folic acid.

One preliminary study showed that pregnant women who use anticonvulsant drugs without folic acid supplementation have an increased risk of having a child with birth defects, such as heart defects, cleft lip and palate, neural tube defects, and skeletal abnormalities. However, supplementation with folic acid greatly reduces the risk. Consequently, some healthcare practitioners recommend that women taking multiple anticonvulsant drugs supplement with 5 mg of folic acid daily, for three months prior to conception and during the first trimester, to prevent folic acid deficiency-induced birth defects. Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.

One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency. In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.

Despite the apparent beneficial effects, some studies have indicated that as little as 0.8 mg of folic acid taken daily can increase the frequency and/or severity of seizures. However, a recent controlled study showed that both healthy and epileptic women taking less than 1 mg of folic acid per day had no increased risk for seizures. Until more is known about the risks and benefits of folic acid, individuals taking multiple anticonvulsant drugs should consult with their healthcare practitioner before supplementing with folic acid. In addition, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss folic acid supplementation with their practitioner.

One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood levels of vitamin B6. A nutritional deficiency of vitamin B6 can lead to an increase in homocysteine blood levels, which has been associated with atherosclerosis. Vitamin B6 deficiency is also associated with symptoms such as dizziness, fatigue, mental depression, and seizures. On the other hand, supplementation with large amounts of vitamin B6 (80–200 mg per day) has been reported to reduce blood levels of some anticonvulsant drugs, which could theoretically trigger seizures. People taking multiple anticonvulsant drugs should discuss with their doctor whether supplementing with vitamin B6 is advisable.

Some studies have shown that babies born to women taking anticonvulsant drugs have low blood levels of vitamin K, which might cause bleeding in the infant. Though some researchers recommend vitamin K supplementation prior to delivery, not all agree that supplementation for women taking anticonvulsant drugs is necessary. Until more information is available, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss vitamin K supplementation with their healthcare practitioner.