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Anticonvulsants

Also indexed as: Carbamazepine, Carbatrol, Celontin, Dilantin, Epitol, Ethosuximide, Ethotoin, Felbamate, Felbatol, Fosphentyoin, Keppra, Lamictal, Lamotrigine, Levetiracetam, Mesantoin, Methsuximide, Milontin, Mysoline, Oxcarbazepine, Peganone, Phenobarbital (Anticonvulsants), Phensuximide, Phenytoin, Primidone, Tegretol, Topamax, Topiramate, Tridione, Trileptal, Trimethadione, Zarontin, Zonegran, Zonisamide

Illustration

Anticonvulsants are a family of drugs that depress abnormal nerve activity in the brain, thereby blocking seizures. Barbiturates and benzodiazepines are commonly used to prevent and treat seizure disorders, as well as other conditions. Though some people are maintained on a single drug, most take two or more anticonvulsant medications to prevent seizures. Consequently, many studies report interactions that occur in individuals taking several anticonvulsants.

Summary of Interactions with Vitamins, Herbs, and Foods
In some cases, an herb or supplement may appear in more than one category, which may seem contradictory. For clarification, read the full article for details about the summarized interactions.

Beneficial May Be Beneficial: Depletion or interference—The medication may deplete or interfere with the absorption or function of the nutrient. Taking these nutrients may help replenish them.

Biotin

Calcium

Folic acid

L-Carnitine

Vitamin A

Vitamin B12

Vitamin B6

Vitamin D

Vitamin K

Beneficial May Be Beneficial: Side effect reduction/prevention—Taking these supplements may help reduce the likelihood and/or severity of a potential side effect caused by the medication.

Folic acid

L-Carnitine

Vitamin B12

Vitamin D

Vitamin K

Beneficial May Be Beneficial: Supportive interaction—Taking these supplements may support or otherwise help your medication work better.

Folic acid

Avoid Avoid: Adverse interaction—Avoid these supplements when taking this medication because taking them together may cause undesirable or dangerous results.

Folic acid

Reduced drug absorption/bioavailability

None known

Interactions common to many, if not all, Anticonvulsants are described in this article. Interactions reported for only one or several drugs in this class may not be listed in this article. Some drugs listed in this article are linked to articles specific to that respective drug; please refer to those individual drug articles. The information in this article may not necessarily apply to drugs in this class for which no separate article exists. If you are taking an Anticonvulsant for which no separate article exists, talk with your doctor or pharmacist.

An asterisk (*) next to an item in the summary indicates that the interaction is supported only by weak, fragmentary, and/or contradictory scientific evidence.

Interactions that occur with multiple drug therapy are described on this page. For interactions involving a specific anticonvulsant, refer to the highlighted drugs listed below.

Barbiturates

Benzodiazepines

GABA Analogues

Hydantoins

  • Ethotoin (Peganone®)
  • Fosphentyoin (Mesantoin®)
  • Phenytoin (Dilantin®)

Oxazolidinediones

  • Trimethadione (Tridione®)

Phenyltriazines

  • Lamotrigine (Lamictal®)

Succinimides

  • Ethosuximide (Zarontin®)
  • Methsuximide (Celontin®)
  • Phensuximide (Milontin®)

Miscellaneous

  • Acetazolamide (Diamox®)
  • Carbamazepine (Carbatrol®, Tegretol®)
  • Felbamate (Felbatol®)
  • Levetiracetam (Keppra®)
  • Oxcarbazepine (Trileptal®)
  • Primidone (Mysoline®)
  • Topiramate (Topamax®)
  • Valproic acid (Depakene®, Depakote®)
  • Zonisamide (Zonegran®)

Interactions with Dietary Supplements

Biotin
Several controlled studies have shown that long-term anticonvulsant treatment decreases blood levels of biotin.1 2 3 4 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.

Calcium
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.5 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.6 Controlled research is needed to determine whether pregnant women who are taking anticonvulsant medications should supplement with additional amounts of calcium and vitamin D.

L-Carnitine
Several controlled and preliminary studies showed that multiple drug therapy for seizures results in dramatic reductions in blood carnitine levels.7 8 9 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.10 However, another small study revealed that children taking valproic acid experienced less fatigue and excessive sleepiness following L-carnitine supplementation.11 Despite the lack of well-controlled studies, individuals who are taking anticonvulsants and experiencing side effects might benefit from supplementing with L-carnitine.

Folic acid
Several studies have shown that multiple anticonvulsant therapy reduces blood levels of folic acid and dramatically increases homocysteine levels.12 13 14 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.15

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.16 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.17 Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.18

One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency.19 In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.20

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.21 22 23 24 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.25 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.

Vitamin A
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.26 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.

Vitamin B6
One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood levels of vitamin B6.27 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.

Vitamin B12
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.28 Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.29 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.

Vitamin D
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.30 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.31 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.32 Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease.33 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.

Vitamin E
Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin E levels than those who received no treatment for seizures.34 35 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.

Vitamin K
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.36 Though some researchers recommend vitamin K supplementation prior to delivery,37 38 not all agree that supplementation for women taking anticonvulsant drugs is necessary.39 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.

References:

1. Mock DM, Dyken ME. Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants. Neurology 1997;49:1444–7.

2. Mock DM, Mock NI, Nelson RP, Lombard KA. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr 1998;26:245–50.

3. Krause KH, Bonjour JP, Berlit P, Kochen W. Biotin status of epileptics. Ann NY Acad Sci 1985;447:297–313.

4. Krause KH, Bonjour JP, Berlit P, et al. Effect of long-term treatment with antiepileptic drugs on the vitamin status. Drug Nutr Interact 1988;5:317–43.

5. Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab 1975;41:1130–5.

6. Friis B, Sardemann H. Neonatal hypocalcaemia after intrauterine exposure to anticonvulsant drugs. Arch Dis Child 1977;52:239–41.

7. Hiraoka A, Arato T, Tominaga I. Reduction in blood free carnitine levels in association with changes in sodium valproate (VPA) disposition in epileptic patients treated with VPA and other anti-epileptic drugs. Biol Pharm Bull 1997;20:91–3.

8. Morita J, Yuge K, Yoshino M. Hypocarnitinemia in the handicapped individuals who receive a polypharmacy of antiepileptic drugs. Neuropediatrics 1986;17:203–5.

9. Hug G, McGraw CA, Bates SR, Landrigan EA. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbitol, valproic acid, phenytoin and carbamazepine in children. J Pedr 1991;119:799–802.

10. Freeman JM, Vining EP, Cost S, Singhi P. Does carnitine administration improve the symptoms attributed to anticonvulsant medications?: A double-blinded, crossover study. Pediatrics 1994;93:893–5.

11. Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Int J Vitam Nutr Res 1995;65:211–4.

12. Hendel J, Dam M, Gram L, et al. The effects of carbamazepine and valproate on folate metabolism in man. Acta Neurol Scand 1984;69:226–31.

13. Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Acta Neurol Scand 2000;101:217–23.

14. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999;40:345–50.

15. Apeland T, Mansoor MA, Strandjord RE, et al. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand 2001;103:294–9.

16. Biale Y, Lewenthal H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 1984;18:211–6.

17. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:535–44 [review].

18. Hiilesmaa VK, Teramo K, Granstrom JL, et al. Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed) 1983;287:577–9.

19. Gibberd FB, Nicholls A, Wright MG. The influence of folic acid on the frequency of epileptic attacks. Eur J Clin Pharmacol 1981;19:57–60.

20. Torres OA, Miller VS, Buist NM, Hyland K. Folinic acid-responsive neonatal seizures. J Child Neurol 1999;14:529–32.

21. Guidolin L, Vignoli A, Canger R. Worsening in seizure frequency and severity in relation to folic acid administration. Eur J Neurol 1998;5:301–3.

22. Lewis DP, Van Dyke DC, Willhite LA. Phenytoin-folic acid interaction. Ann Pharmacother 1995;29:726–35 [review].

23. Berg MJ, Rivey MP, Vern BA, et al. Phenytoin and folic acid: individualized drug-drug interaction. Ther Drug Monit 1983;5:395–9.

24. Reynolds EH. Effects of folic acid on the mental state and fit frequency of drug treated epileptic patients. Lancet 1967;1:1086.

25. Eros E, Geher P, Gomor B, Czeizel AE. Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy). Eur J Obstet Gynecol Reprod Biol 1998;80:75–8.

26. Nau H, Tzimas G, Mondry M, et al. Antiepileptic drugs alter endogenous retinoid concentrations: a possible mechanism of teratogensis of anticonvulsant therapy. Life Sci 1995;57:53–60.

27. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999;40:345–50.

28. Frenkel EP, McCall MS, Sheehan RG. Cerebrospinal fluid folate, and vitamin B12 in anticonvulsant-induced megaloblastosis. J Lab Clin Med 1973;81:105–15.

29. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999;40:345–50.

30. Telci A, Cakatay U, Kurt BB, et al. Changes in bone turnover and deoxypyridinoline levels in epileptic patients Clin Chem Lab Med 2000 38:47–50.

31. Jekovec-Vrhovsek M, Kocijancic A, Prezelj J. Effect of vitamin D and calcium on bone mineral density in children with CP and epilepsy in full-time care. Dev Med Child Neurol 2000;42:403–5.

32. Riancho JA, Del Arco C, Arteaga R, et al. Influence of solar irradiation on vitamin D levels in children on anticonvulsant drugs. Acta Neurol Scand 1989;79:296–9.

33. Williams C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J 1984;77:834.

34. Higashi A, Tamari H, Ikeda T, et al. Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol (New York) 1980;1:129–34.

35. Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E concentrations in handicapped children treated with anticonvulsants. Dev Pharmacol Ther 1982;5:109–13.

36. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923–8.

37. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:535–44 [review].

38. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993;168:884–8.

39. Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child Fetal Neonatal Ed 1999;81:F208–10.

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