Carbamazepine (drug interactions)

DEFINITION: An anticonvulsant agent used primarily to prevent seizures in conditions such as epilepsy.

INTERACTIONS: Biotin, calcium, carnitine, dong quai, folate, ginkgo, glutamine, grapefruit juice, hops, ipriflavone, kava, nicotinamide, passionflower, St. John’s wort, valerian, vitamin D, vitamin K

TRADE NAMES: Atretol, Carbatrol, Epitol, Tegretol, Tegretol XR, Equetro

DRUGS IN THIS FAMILY: Phenobarbital, phenytoin, primidone, valproic acid, oxcarbazepine, eslicarbazepine acetate

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. 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. This toxin has been associated with convulsions and death in laboratory animals.

The detected amounts of this toxic substance are considered harmless. However, given the lack of satisfactory standardization of herbal formulations in the United States, it is possible that some batches of the product might contain greater amounts 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 nerve toxin might theoretically prevent an anticonvulsant from working as well as expected.

Glutamine

Effect: Possible Harmful Interaction

The amino acid glutamine is converted to glutamate in the body. Glutamate is an excitatory neurotransmitter—a chemical that enables nerve transmission. Because anticonvulsants work, in part, by blocking glutamate pathways in the brain, high dosages of the amino acid glutamine might diminish an anticonvulsant’s effect and increase the risk of seizures.

Grapefruit Juice

Effect: Possible Harmful Interaction

Grapefruit juice slows the body’s normal breakdown of several drugs, including the anticonvulsant carbamazepine, allowing it to build up to potentially dangerous levels in the blood. A recent study indicates this effect can last for three days or more following the last glass of juice. Because of this risk, if one uses carbamazepine, the safest approach is to avoid grapefruit juice altogether.

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 carbamazepine and phenytoin 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. Persons 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 anti-anxiety agent alprazolam (Xanax) for three days.

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, one should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects unless advised by a physician.

Nicotinamide

Effect: Possible Harmful Interaction

Nicotinamide (also called niacinamide) is a compound produced by the body’s breakdown of niacin (vitamin B₃). It is a supplemental form that does not possess the flushing side effect or the cholesterol-lowering ability of niacin. Nicotinamide appears to increase blood levels of carbamazepine and primidone, possibly requiring a reduction in drug dosage to prevent toxic effects.

Carbamazepine blood levels increased in two children with epilepsy after they were given nicotinamide, but the fact that the children were on several anticonvulsant drugs clouds the issue somewhat. Similarly, nicotinamide given to three children on primidone therapy increased blood levels of primidone. It is thought that nicotinamide may interfere with the body’s normal breakdown of these anticonvulsant agents, allowing them to build up in the blood.

Dong Quai, St. John’s Wort

Effect: Possible Harmful Interaction

St. John’s wort (Hypericum perforatum) is primarily used to treat mild to moderate depression. The herb dong quai (Angelica sinensis) is often recommended for menstrual disorders such as dysmenorrhea, premenstrual syndrome (PMS), and irregular menstruation.

The anticonvulsant agents carbamazepine, phenobarbital, and valproic acid have been reported to cause increased sensitivity to the sun, amplifying the risk of sunburn or skin rash. Because St. John’s wort and dong quai may also cause this problem, taking them during treatment with these drugs might add to this risk.

Using sunscreen or wearing protective clothing during sun exposure may benefit individuals taking these herbs with anticonvulsants.

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 if one is 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: Supplementation Possibly Helpful

Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health. Carbamazepine appears to lower blood levels of folate by speeding up its normal breakdown by the body and also by decreasing its absorption. Other antiseizure drugs can also reduce levels of folate in the body.

Low folate can lead to anemia, and reduced white blood cell count, and folate supplements have been shown to help prevent these complications from being treated with carbamazepine. Adequate folate intake is necessary to prevent neural tube birth abnormalities, such as spina bifida and anencephaly. Anticonvulsants may play a direct role in developing such conditions because they deplete the body's folate reserves. Because babies born to women taking anticonvulsants are at increased risk for such congenial disabilities, many practitioners recommend women take a folic acid supplement (5mg a day) if they are pregnant or planning to become pregnant and are taking carbamazepine.

The low serum folate caused by anticonvulsants can raise homocysteine levels, a condition hypothesized to increase the risk of heart disease. However, the case for taking extra folate during anticonvulsant therapy is not as simple as it might seem. It is possible that folate supplementation itself might impair the effectiveness of anticonvulsant drugs, and physician supervision is necessary.

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 carbamazepine, phenobarbital, or primidone) and twelve people who received no treatment. Calcium absorption was found to be 27 percent lower in the treated participants.

An observational study found low calcium blood levels in 48 percent of 109 people taking anticonvulsants. Other findings in this study suggested that anticonvulsants may reduce calcium levels by directly interfering with the parathyroid hormone, which helps keep calcium levels in proper balance. A low blood level of calcium can trigger seizures, which might reduce anticonvulsants' effectiveness.

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 used for heart conditions, Alzheimer’s disease, and intermittent claudication. Intermittent claudication is 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. However, it is not 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. The risk of this liver damage increases in children younger than twenty-four months, and carnitine supplementation may 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 children under two years who have neurologic disorders and are receiving valproic acid or multiple anticonvulsants. Young children are at an increased risk of carnitine deficiency, and those taking anticonvulsants are at an even greater risk, which leads to fatigue and other side effects. Usually, this group is given 50 to 100 milligrams per kilogram of body weight daily by mouth.

Vitamin D

Effect: Supplementation Possibly Helpful

Anticonvulsant drugs may interfere with the activity of several types of vitamin D, including vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). 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 persons. 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 multiple forms of vitamin D are circulating in the blood, in some cases, the body can adjust to keep vitamin D in balance 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. Persons 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 mothers taking the drugs, resulting in bleeding disorders or facial bone abnormalities in the newborns. Mothers who take these anticonvulsants may need vitamin K supplementation during pregnancy to prevent these conditions in their newborns, particularly toward the end of their pregnancy. Additionally, newborns of mothers who took carbamazepine may require a vitamin K injection soon after they are born. However, this does not occur in all cases.

Other interactions

Alcohol increases the side effects of many medications, including carbamazepine, leading to dizziness, drowsiness, concentration difficulties, or liver damage. Because carbamazepine is an enzyme inducer, it alters how medications are absorbed in the body. This should be considered when adding any supplement, homeopathic remedy, or medicine to a carbamazepine regimen, including over-the-counter supplements and pain relievers like Tylenol. Seeking medical advice concerning the safety of these combinations is essential.

Bibliography

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Takanaga, H., et al. “Relationship Between Time After Intake of Grapefruit Juice and the Effect on Pharmacokinetics and Pharmacodynamics of Nisoldipine in Healthy Subjects.” Clinical Pharmacology and Therapeutics 67 (2000): 201-14.