Drug Interactions:
Phenytoin

Trade Names
  • Dilantin

Phenytoin is an anticonvulsant agent used primarily to prevent seizures in conditions such as epilepsy. Drugs similar to phenytoin are ethotoin (Peganone) and mephenytoin (Mesantoin).

Other anticonvulsant agents include carbamazepine, phenobarbital, primidone, and valproic acid. In some cases, combination therapy with two or more anticonvulsant drugs may be used.

Ginkgo

Possible Harmful Interaction

The herb ginkgo (Ginkgo biloba) has been used to treat Alzheimer's disease and ordinary age-related memory loss, among many other conditions.

This interaction involves potential contaminants in ginkgo, not ginkgo itself.

A recent study found that a natural nerve toxin present in the seeds of Ginkgo biloba made its way into standardized ginkgo extracts prepared from the leaves.¹ This toxin has been associated with convulsions and death in laboratory animals.^2,3,4

Fortunately, the detected amounts of this toxic substance are considered harmless.⁵ However, given the lack of satisfactory standardization of herbal formulations in the United States, it is possible that some batches of product might contain higher contents of the toxin depending on the season of harvest.

In light of these findings, taking a ginkgo product that happened to contain significant levels of the nerve toxin might theoretically prevent an anticonvulsant from working as well as expected.

Glutamine

Possible Harmful Interaction

The amino acid glutamine is converted to glutamate in the body. Glutamate is thought to act as a neurotransmitter (a chemical that enables nerve transmission). Because anticonvulsants work (at least in part) by blocking glutamate pathways in the brain, high dosages of the amino acid glutamine might theoretically diminish an anticonvulsant's effect and increase the risk of seizures.

Ipriflavone

Possible Harmful Interaction

Ipriflavone, a synthetic isoflavone that slows bone breakdown, is used to treat osteoporosis.

Test tube studies indicate that ipriflavone might increase blood levels of the anticonvulsants phenytoin and carbamazepine when they are taken therapeutically.⁶ Ipriflavone was found to inhibit a liver enzyme involved in the body's normal breakdown of these drugs, thus allowing them to build up in the blood. Higher drug levels increase the risk of adverse effects.

Because anticonvulsants are known to contribute to the development of osteoporosis, a concern is that the use of ipriflavone for this drug-induced osteoporosis could result in higher blood levels of the drugs, with potentially serious consequences.

Individuals taking either of these drugs should use ipriflavone only under medical supervision.

Hops, Kava, Passionflower, Valerian

Possible Harmful Interaction

The herb kava (Piper methysticum) has a sedative effect and is used for anxiety and insomnia.

Combining kava with anticonvulsants, which possess similar depressant effects, could result in "add-on" or excessive physical depression, sedation, and impairment. In one case report, a 54-year-old man was hospitalized for lethargy and disorientation, side effects attributed to his having taken the combination of kava and the antianxiety agent alprazolam (Xanax) for 3 days.⁷

Other herbs having a sedative effect that might cause problems when combined with anticonvulsants include ashwagandha (Withania somnifera), calendula (Calendula officinalis), catnip (Nepeta cataria), hops (Humulus lupulus), lady's slipper (Cypripedium species), lemon balm (Melissa officinalis), passionflower (Passiflora incarnata), sassafras (Sassafras officinale), skullcap (Scutellaria lateriflora), valerian (Valeriana officinalis), and yerba mansa (Anemopsis californica).

Because of the potentially serious consequences, you should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects, unless advised by your physician.

White Willow

Possible Harmful Interaction

The herb white willow (Salix alba), also known as willow bark, is used to treat pain and fever. White willow contains a substance that is converted by the body into a salicylate similar to aspirin.

Higher doses of aspirin may increase phenytoin levels and toxicity during long-term use of both drugs.⁸ This raises the concern that white willow might have similar effects on phenytoin, though this has not been proven.

Biotin

Supplementation Possibly Helpful, but Take at a Different Time of Day

Anticonvulsants may deplete biotin, an essential water-soluble B vitamin, possibly by competing with it for absorption in the intestine. It is not clear, however, whether this effect is great enough to be harmful.

Blood levels of biotin were found to be substantially lower in 404 people with epilepsy on long-term treatment with anticonvulsants compared to 112 untreated people with epilepsy.⁹ The effect occurred with phenytoin, carbamazepine, phenobarbital, and primidone. Valproic acid appears to affect biotin to a lesser extent than other anticonvulsants.

A test tube study suggested that anticonvulsants might lower biotin levels by interfering with the way biotin is transported in the intestine.¹⁰

Biotin supplementation may be beneficial if you are on long-term anticonvulsant therapy. To avoid a potential interaction, take the supplement 2 to 3 hours apart from the drug. It has been suggested that the action of anticonvulsant drugs may be at least partly related to their effect of reducing biotin levels. For this reason, it may be desirable to take enough biotin to prevent a deficiency, but not an excessive amount.

Folate

Supplementation Possibly Helpful

Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health, including preventing neural tube birth defects and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if you are taking any medication that depletes or impairs folate even slightly, you may need supplementation.

Most drugs used for preventing seizures can reduce levels of folate in the body.^11–16

The low serum folate caused by anticonvulsants can raise homocysteine levels, a condition believed to increase the risk of heart disease.¹⁷

Adequate folate intake is also necessary to prevent neural tube birth defects such as spina bifida and anencephaly. Because anticonvulsant drugs deplete folate, babies born to women taking anticonvulsants are at increased risk for such birth defects. Anticonvulsants may also play a more direct role in the development of birth defects.¹⁸

The interaction between phenytoin and folate is fairly complex. Phenytoin appears to decrease folate levels by interfering with its absorption in the small intestine¹⁹ as well as by accelerating its normal breakdown by the body.^20,21 On the other hand, high folate levels may speed up the normal breakdown of phenytoin.^22,23 This could mean that taking extra folate might cause an increase in seizures.

For this reason, folate supplementation during phenytoin therapy should be supervised by a physician.

Calcium

Supplementation Probably Helpful, but Take at a Different Time of Day

Anticonvulsant drugs may impair calcium absorption and in this way increase the risk of osteoporosis and other bone disorders.

Calcium absorption was compared in 12 people on anticonvulsant therapy (all taking phenytoin and some also taking phenobarbital, primidone, and/or carbamazepine) and 12 people receiving no treatment.²⁴ Calcium absorption was found to be 27% lower in the treated participants.

An observational study found low calcium blood levels in 48% of 109 people taking anticonvulsants.²⁵ Other findings in this study suggested that anticonvulsants might also reduce calcium levels by directly interfering with parathyroid hormone, a substance that helps keep calcium levels in proper balance.

A low blood level of calcium can itself trigger seizures, and this might reduce the effectiveness of anticonvulsants.²⁶

Calcium supplementation may be beneficial for people taking anticonvulsant drugs. However, some studies indicate that antacids containing calcium carbonate may interfere with the absorption of phenytoin and perhaps other anticonvulsants.^27,28 For this reason, take calcium supplements and anticonvulsant drugs several hours apart if possible.

Carnitine

Supplementation Possibly Helpful

Carnitine is an amino acid that has been used for heart conditions, Alzheimer's disease, and intermittent claudication (a possible complication of atherosclerosis in which impaired blood circulation causes severe pain in calf muscles during walking or exercising).

Long-term therapy with anticonvulsant agents, particularly valproic acid, is associated with low levels of carnitine.²⁹ However, it isn't clear whether the anticonvulsants cause the carnitine deficiency or whether it occurs for other reasons. It has been hypothesized that low carnitine levels may contribute to valproic acid's damaging effects on the liver.^30,31 The risk of this liver damage increases in children younger than 24 months,³² and carnitine supplementation does seem to be protective.³³ However, in one double-blind crossover study, carnitine supplementation produced no real improvement in "well-being" as assessed by parents of children receiving either valproic acid or carbamazepine.³⁴

L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than 2 years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants.³⁵

Vitamin D

Supplementation Possibly Helpful

Anticonvulsant drugs may interfere with the activity of vitamin D. As proper handling of calcium by the body depends on vitamin D, this may be another way that these drugs increase the risk of osteoporosis and related bone disorders (see the previous Calcium topic).

Anticonvulsants appear to speed up the body's normal breakdown of vitamin D, decreasing the amount of the vitamin in the blood.³⁶ A survey of 48 people taking both phenytoin and phenobarbital found significantly lower levels of calcium and vitamin D in many of them as compared to 38 untreated individuals.³⁷ Similar but lesser changes were seen in 13 people taking phenytoin or phenobarbital alone. This effect may be apparent only after several weeks of treatment.

Another study found decreased blood levels of one form of vitamin D but normal levels of another.³⁸ Because there are two primary forms of vitamin D circulating in the blood, the body might be able to adjust in some cases to keep vitamin D in balance, at least for a time, despite the influence of anticonvulsants.³⁹

Adequate sunlight exposure may help overcome the effects of anticonvulsants on vitamin D by stimulating the skin to manufacture the vitamin.⁴⁰ Of 450 people on anticonvulsants residing in a Florida facility, none were found to have low blood levels of vitamin D or evidence of bone disease. This suggests that environments providing regular sun exposure may be protective.

Individuals regularly taking anticonvulsants, especially those taking combination therapy and those with limited exposure to sunlight, may benefit from vitamin D supplementation.

Vitamin K

Supplementation Possibly Helpful for Pregnant Women

Phenytoin, carbamazepine, phenobarbital, and primidone speed up the normal breakdown of vitamin K into inactive byproducts, thus depriving the body of active vitamin K. This can lead to bone problems such as osteoporosis. Also, use of these anticonvulsants can lead to a vitamin K deficiency in babies born to mothers taking the drugs, resulting in bleeding disorders or facial bone abnormalities in the newborns.^41,42

Mothers who take these anticonvulsants may need vitamin K supplementation during pregnancy to prevent these conditions in their newborns.

Last reviewed March 2002 by Medical Review Board

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