CNS Drugs

, Volume 16, Issue 4, pp 263–272 | Cite as

Interactions Between Antiepileptic Drugs and Hormonal Contraception

Review Article

Abstract

An interaction between antiepileptic drugs (AEDs) and the combined oral contraceptive pill was first proposed when the dose of estradiol in the oral contraceptive pill was reduced from 100 to 50μg. There was a higher incidence of breakthrough bleeding and contraceptive failure among women with epilepsy compared with women in general.

Since then, interaction studies have been undertaken to look for possible interactions between AEDs and the combined oral contraceptive pill. Phenobarbital (phenobarbitone), phenytoin, carbamazepine, oxcarbazepine, felbamate and topiramate have been shown to increase the metabolism of ethinylestradiol and progestogens. Therefore, if a women is on one of the AEDs and wishes to take the oral contraceptive pill, she will need to take a preparation containing at least 50μg of ethinylestradiol. Levonorgestrel implants are contraindicated in women receiving these AEDs because of cases of contraceptive failure. It is recommended that medroxyprogesterone injections be given every 10 rather than 12 weeks to women who are receiving AEDs that induce hepatic microsomal enzymes.

There are no interactions between the combined oral contraceptive pill, progesterone-only pill, medroxyprogesterone injections or levonorgestrel implants and the AEDs valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide and the benzodiazepines. Therefore, normal dose contraceptive preparations can be used in patients receiving these AEDs.

Keywords

Topiramate Levetiracetam Vigabatrin Oxcarbazepine Zonisamide 

Notes

Acknowledgements

No funding was used in the preparation of this manuscript. The author has undertaken studies for and had sponsorship from GlaxoSmithKline, JanssenCilag, Novartis, Sanofi-Synthelabo, UCB, Parke-Davis and Elan Pharmaceuticals.

References

  1. 1.
    Kenyon TE. Unplanned pregnancy in an epileptic. BMJ 1972; 1: 686–7PubMedCrossRefGoogle Scholar
  2. 2.
    Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979; 20: 519–26PubMedCrossRefGoogle Scholar
  3. 3.
    Back DJ, Grimmer SFM, Orme ML, et al. Evaluation of Committee on Safety of Medicine yellow card reports on oral contraceptive interactions. Br J Pharmacokinet Pharmacol 1988; 13: 527–32Google Scholar
  4. 4.
    Park BK, Breckenridge AM. Clinical implications of enzyme induction and enzyme inhibition. Clin Pharmacokinet 1981; 6: 1–24PubMedCrossRefGoogle Scholar
  5. 5.
    Backström T, Sodergärd R. The influence of antiepileptic drugs on steroid plasma levels and binding during the menstrual cycle [abstract]. Acta Endocrinol Suppl (Copenh) 1977; Suppl. 212: 42Google Scholar
  6. 6.
    Perucca E, Hedges A, Makki KA, et al. A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in antiepileptic patients. Br J Pharmacol 1984; 11: 533–9Google Scholar
  7. 7.
    Tomson T, Svensson J, Hilton-Brown P. Relationship of inter-individual dose to plasma concentration of carbamazepine: indication of dose-dependent induction of metabolism. Ther Drug Monit 1989; 11:533–9PubMedCrossRefGoogle Scholar
  8. 8.
    Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate likelihood of metabolic pharmacodynamic interactions. Clin Pharmacokinet 1997; 32: 210–58PubMedCrossRefGoogle Scholar
  9. 9.
    Wright SA, Stevens JC. The human hepatic cytochromes 450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 1–21CrossRefGoogle Scholar
  10. 10.
    Levy RH. Cytochrome P450 isoenzymes and anti epileptic drug interactions. Epilepsia 1995; 36Suppl. 5: S8–13PubMedCrossRefGoogle Scholar
  11. 11.
    D’Arcy PF. Drug interactions with oral contraceptives. Drug Intell Clin Pharm 1986; 20: 353–62PubMedGoogle Scholar
  12. 12.
    Back DJ, Orme MLE. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18: 472–84PubMedCrossRefGoogle Scholar
  13. 13.
    Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987; 39: 1–47PubMedGoogle Scholar
  14. 14.
    Back DJ, Bates M, Bowden A, et al. The interactions of phenobarbital and other anticonvulsants with oral contraceptive therapy. Contraception 1980; 22: 495–503PubMedCrossRefGoogle Scholar
  15. 15.
    Sonnen AEH. Sodium valproate and the pill. In: Akimoto H, Kazamatsun H, Seino M, et al., editors. Advances in epileptology. Proceedings of the 13th Epilepsy International Symposium. New York: Raven Press, 1982: 429–32Google Scholar
  16. 16.
    Crawford P, Chadwick DJ, Martin C, et al. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990; 30: 892–6PubMedCrossRefGoogle Scholar
  17. 17.
    Crawford PM, Chadwick D, Cleland P, et al. The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptives. Contraception 1986; 33: 23–9PubMedCrossRefGoogle Scholar
  18. 18.
    Bartoli A, Gatti G, Cipolla G, et al. A double-blind placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers. Epilepsia 1997; 36: 702–7CrossRefGoogle Scholar
  19. 19.
    Saano V, Banield CR, Reidenberg P, et al. Effects of felbamate on the pharmacokinetics of low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523–31PubMedCrossRefGoogle Scholar
  20. 20.
    Holdich T, Whiteman P, Orme M, et al. Effect of lamotrigine on the pharmacology of the combined oral contraceptive pill. Epilepsia 1991; 32Suppl. 1: 96Google Scholar
  21. 21.
    Eldon MA, Underwood BA, Randinitis EJ, et al. Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol. Neurology 1998; 50: 1146–8PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenfeld WE, Doose DR, Walker SA, et al. Effects of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38: 317–23PubMedCrossRefGoogle Scholar
  23. 23.
    Mengel HB, Houston A, Back DJ. An evaluation of the interaction between tiagabine and oral contraceptives in female volunteers. J Pharm Med 1994; 4: 141–50Google Scholar
  24. 24.
    Klosterkov JP, Saano V, Haring P, et al. Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 1992; 33: 1149–52CrossRefGoogle Scholar
  25. 25.
    Fattore C, Cipolla G, Gatti G, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 1999; 40: 783–7PubMedCrossRefGoogle Scholar
  26. 26.
    Giuliano RA, Hiersemenzel E, Baltes G, et al. Influence of a new antiepileptic drug (Levetiracetam, ucbLO59) on the pharmacokinetics and pharmacodynamics of oral contraceptives [abstract]. Epilepsia 1996; 37Suppl. 4: 90Google Scholar
  27. 27.
    Orme M, Crawford P, Chadwick D, et al. af]Contraception, epilepsy and pharmacokinetics. In: Trimble MR, editor. Women and epilepsy. Chichester: J. Wiley & Sons, 1991: 145–58Google Scholar
  28. 28.
    Geurts TBP, Goorissen EM, Sitsen JME. Summary of drug interactions with oral contraceptives. Carnforth, Lancs: Parthenon Publishing Group, 1993: 57Google Scholar
  29. 29.
    Gilbert JC, Scott AC, Galloway DB, et al. Ethosuximide liver enzyme induction and D-glucaric acid excretion. Br J Clin Pharmacol 1974; 1: 249–52PubMedCrossRefGoogle Scholar
  30. 30.
    Kurt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 1984; 25: S118–31CrossRefGoogle Scholar
  31. 31.
    Frisium. ABPI: Compendium of data sheets. Summary of product characteristics. 1999–2000. London: Datapharm Publications Ltd., 1999: 568–9Google Scholar
  32. 32.
    Mehta DK, editor. British National Formulary — BNF40, September 2000. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2000Google Scholar
  33. 33.
    Schumacher RC, Fantel C, Kelton E, et al. Evaluation of elimination of 14C-felbamate in healthy men [abstract]. Epilepsia 1990; 31Suppl. 1: 21–2Google Scholar
  34. 34.
    Wilbur K, Ensom MHH. Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. Clin Pharmacokinet 2000; 38: 355–65PubMedCrossRefGoogle Scholar
  35. 35.
    Levy RH, Bishop F, Streeter AJ, et al. Explanation and prediction of drug interactions with topiramate using CYP450 inhibition spectrum. Epilepsia 1995; 36Suppl. 4: 47–51Google Scholar
  36. 36.
    Nicolas JM, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Dispos 1999; 27: 250–4PubMedGoogle Scholar
  37. 37.
    Nakasa H, Komiya M, Ohmori S, et al. Characterisation of human liver microsomal cytochrome P-450 responsible for reductive metabolism of zonisamide. Drug Metab Dispos 1993; 21: 777–81PubMedGoogle Scholar
  38. 38.
    Nakasa H, Nakamura H, Ono S, et al. Prediction of drug-drug interactions of zonisamide in humans from in vitro data. Eur J Clin Pharmacol 1998; 52(2): 177–83CrossRefGoogle Scholar
  39. 39.
    Betts T, Crawford P. Women and epilepsy. London: Martin Dunitz, 1998Google Scholar
  40. 40.
    Krauss GL, Brandt J, Campbell M, et al. Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians. Neurology 1996; 46: 1534–9PubMedCrossRefGoogle Scholar
  41. 41.
    Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant therapy. Contraception 1986; 33: 559–65PubMedCrossRefGoogle Scholar
  42. 42.
    Crawford P, Lee P. Gender difference in the management of epilepsy — what women are hearing. Seizure 1999; 8: 135–9PubMedCrossRefGoogle Scholar
  43. 43.
    Trussell J, Kost K. Aguide to interpreting contraceptive efficacy studies. Obstet Gynacol 1990; 76: 558–67Google Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Special Centre for Epilepsy, Department of NeurosciencesYork District HospitalYorkUK
  2. 2.Centre for Community Neurological StudiesLeeds Metropolitan UniversityLeedsUK

Personalised recommendations