Phenytoin (drug interactions)
Phenytoin is an anticonvulsant medication primarily used to prevent seizures in conditions such as epilepsy. It can interact with various substances, potentially altering its effectiveness or increasing the risk of side effects. Notably, certain herbs like ginkgo, glutamine, and kava may have harmful interactions with phenytoin, either by diminishing its anticonvulsant effects or exacerbating side effects such as sedation. Additionally, nutritional supplements like biotin, calcium, and vitamin D can influence phenytoin levels, with biotin possibly being beneficial if taken separately from the medication.
Interactions with folate can be complex, as phenytoin may lower folate levels, which is crucial for preventing congenital disabilities in pregnant women. Furthermore, vitamin K supplementation may be necessary for pregnant women on phenytoin to prevent deficiencies in their newborns. Other herbs, such as St. John's wort, may inhibit the absorption of phenytoin, necessitating dosage adjustments. Overall, individuals taking phenytoin should consult healthcare providers before combining it with other medications, supplements, or herbal products to avoid adverse interactions and ensure effective seizure management.
Phenytoin (drug interactions)
DEFINITION: Phenytoin is an anticonvulsant agent used primarily to prevent seizures in conditions such as epilepsy. In some cases, combination therapy with two or more anticonvulsant drugs may be used.
INTERACTIONS: Biotin, calcium, carnitine, folate, ginkgo, glutamine, hops, ipriflavone, kava, passionflower, valerian, vitamin D, vitamin K, white willow
TRADE NAME: Dilantin, Phenytek
DRUGS IN THIS FAMILY: Carbamazepine, phenobarbital, primidone, valproic acid
RELATED DRUGS: Ethotoin (Peganone), mephenytoin (Mesantoin)
Ginkgo
Effect: 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. Seizures have been reported with the use of ginkgo leaf extract in people with previously well-controlled epilepsy; in one case, the seizures were fatal. One possible explanation is the contamination of ginkgo leaf products with ginkgo seeds. It has also been suggested that ginkgo might interfere with the effectiveness of some antiseizure medications, including phenytoin. Finally, it has been noted that the drug tacrine (also used to improve memory) has been associated with seizures, and ginkgo may affect the brain in ways similar to tacrine.
Glutamine
Effect: Possible Harmful Interaction
The amino acid glutamine is converted to glutamate in the body. Glutamate is a neurotransmitter (a chemical that enables nerve transmission) that is critical in brain function. Because anticonvulsants work (at least in part) by blocking glutamate pathways in the brain, high doses of the amino acid glutamine might diminish the anticonvulsant’s effect and increase the risk of seizures.
Ipriflavone
Effect: 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. 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. People taking either of these drugs should use ipriflavone only under medical supervision.
Hops, Kava, Passionflower, Valerian
Effect: 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 fifty-four-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 three days.
Other herbs having a sedative effect that might cause problems when combined with anticonvulsants include ashwagandha, calendula, catnip, hops, lady’s slipper, lemon balm, passionflower, sassafras, skullcap, valerian, and yerba mansa.
Because of the potentially serious consequences, one should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects, unless advised by a physician.
White Willow
Effect: 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. This raises the concern that white willow might have similar effects on phenytoin, though this has not been proven.
Biotin
Effect: 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 with 112 untreated people with epilepsy. 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.
Biotin supplementation may be beneficial for persons on long-term anticonvulsant therapy. To avoid a potential interaction, one should take the supplement two to three 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
Effect: Possible Benefits and Risks
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 congenital disabilities and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if one is taking any medication that depletes or impairs folate even slightly, one may need supplementation.
Most drugs used for preventing seizures can reduce levels of folate in the body. Phenytoin, in particular, appears to decrease folate levels by interfering with its absorption in the small intestine, as well as by accelerating its normal breakdown by the body. The low blood levels of folate caused by anticonvulsants can raise homocysteine levels, a condition believed to increase the risk of heart disease.
Adequate folate intake is also necessary to prevent neural tube congenital disabilities, such as spina bifida and anencephaly (absence of a brain). Because anticonvulsant drugs deplete folate, babies born to women taking anticonvulsants are at increased risk for such congenital disabilities. Anticonvulsants may also play a more direct role in the development of congenital disabilities.
However, there can be problems with using folate supplements. High folate levels may speed up the normal breakdown of phenytoin. This can lead to breakthrough seizures. For this reason, folate supplementation during phenytoin therapy should be supervised by a physician.
Calcium
Effect: 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 twelve people on anticonvulsant therapy (all taking phenytoin and some also taking phenobarbital, primidone, or carbamazepine) and twelve people receiving no treatment. Calcium absorption was found to be 27 percent lower in the treated participants.
An observational study found low blood calcium levels in 48 percent of 109 people taking anticonvulsants. 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 level of blood calcium can itself trigger seizures, and this might reduce the effectiveness of anticonvulsants. 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. For this reason, one should take calcium supplements and anticonvulsant drugs several hours apart if possible.
Carnitine
Effect: Supplementation Possibly Helpful
Carnitine is an amino acid critical in energy metabolism that has been used for heart conditions, Alzheimer’s disease, and intermittent claudication. Long-term therapy with anticonvulsant agents, particularly valproic acid, is associated with low levels of carnitine. However, it is unclear 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. The risk of this liver damage increases in children younger than twenty-four months, and carnitine supplementation does seem to be protective. 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.
L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than two years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants.
Vitamin D
Effect: 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. Anticonvulsants appear to speed up the body’s normal breakdown of vitamin D, decreasing the amount of the vitamin in the blood. A survey of forty-eight people taking both phenytoin and phenobarbital found significantly lower levels of calcium and vitamin D in many of them compared with thirty-eight untreated people. Similar but lesser changes were seen in thirteen 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. 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. Adequate sunlight exposure may help overcome the effects of anticonvulsants on vitamin D by stimulating the skin to manufacture the vitamin. Of 450 people on anticonvulsants residing in a Florida facility, none was 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. People regularly taking anticonvulsants, especially those taking combination therapy and those with limited exposure to sunlight, may benefit from vitamin D supplementation.
Vitamin K
Effect: 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. In addition, the use of these anticonvulsants can lead to a vitamin K deficiency in babies born to pregnant women taking the drugs, resulting in bleeding disorders or facial bone abnormalities in newborns. Women who take these anticonvulsants may need vitamin K supplementation of 10 to 20 milligrams each day during pregnancy to prevent these conditions in their newborns. In breastfeeding mothers, phenytoin may cause poor latching and slight sedation but is otherwise considered safe.
Other Interactions
Several other herbs and supplements may interact with phenytoin. St. John's wort inhibits the body’s ability to absorb phenytoin, decreasing its blood concentration. Individuals using St. John’s wort who are prescribed phenytoin should inform their doctor because their dose will need to be adjusted accordingly. Cannabis use may increase phenytoin’s side effects, including trouble concentrating, dizziness, drowsiness, difficulty concentrating, and poor judgment. Additionally, the herbs Morinda citrifolia (noni), Nigella sativa (black seed), milk thistle, and Trigonella foenum graecum (fenugreek) may also lower the effectiveness of phenytoin and should be avoided.
Bibliography
De Vivo, D. C., et al. “L-carnitine Supplementation in Childhood Epilepsy: Current Perspectives.” Epilepsia 30 (1998): 1216-25.
Granger, A. S. “Ginkgo biloba Precipitating Epileptic Seizures.” Age and Ageing 30 (2001): 523-25.
Gregory, P. J. “Seizure Associated with Ginkgo biloba?” Annals of Internal Medicine 134 (2001): 344.
Gupta, Mohit, and Jayson Tripp. “Phenytoin.” StatPearls, 10 July 2023, www.ncbi.nlm.nih.gov/books/NBK551520. Accessed 20 Sept. 2024.
Kupiec, T., and V. Raj. “Fatal Seizures Due to Potential Herb-Drug Interactions with Ginkgo biloba.” Journal of Analytical Toxicology 29 (2006): 755-58.
Preston, Claire L. Stockley’s Drug Interactions. 12th ed., Pharmaceutical Press, 2021.