Approximately 1% of the US population has epilepsy, including an estimated. Contraception for Women With Epilepsy TREATMENT REVIEW

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1 TREATMENT REVIEW Contraception for Women With Epilepsy Evren Burakgazi, MD,* Cynthia Harden, MD, John J. Kelly, MD *Department of Neurology, Virginia Commonwealth University, Richmond, VA; Department of Neurology, Epilepsy Division, University of Miami, Miami, FL; Department of Neurology, George Washington University Medical Center, Washington, DC The choice of a contraceptive drug can be challenging for women with epilepsy due to possible interactions between antiepileptic drugs (AEDs) and hormonal contraception. Enzyme-inducing AEDs can cause hormonal contraception to fail and can increase the risk of teratogenicity. Higher doses of oral contraceptives can overcome pharmacologic failure but may create additional risks. The effects of reproductive hormones on individual AEDs have recently been clarified, providing helpful guidelines for physicians and patients. Studies show that lamotrigine has a significantly increased clearance (> 50%) when used with combined oral contraceptives, which results in an increased seizure frequency in most patients. Useful alternatives to oral contraceptives include depot injections and intrauterine devices. Subdermal implants may increase the risk of pregnancy in women with epilepsy on enzyme-inducing AEDs. Depot medroxyprogesterone acetate is effective but can increase side effects. Intrauterine devices are an alternative to pharmacologic approaches because they lack drug-drug interactions and side effects. [Rev Neurol Dis. 2009;6(2):E62-E67] 2009 MedReviews, LLC Key words: Epilepsy Oral contraceptives Antiepileptic drugs Depot injections Intrauterine devices Approximately 1% of the US population has epilepsy, including an estimated 700,000 to 1.2 million women of childbearing age. About 17% of fertile women with epilepsy take combined oral contraceptive (OC) steroids, which is less than the general population of fertile women (25%). 1 Concomitant use of combined OCs with antiepileptic drugs (AEDs) creates a risk of drug interactions. Despite this risk, the effects of hormones on seizure control and the interaction between OCs and AEDs are unknown to most patients and many physicians. Approximately 50% of women with epilepsy E62 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

2 Contraception for Women With Epilepsy who take combined OCs indicate that they have never received information about this issue. In a 2002 survey of women with epilepsy who were of childbearing age, many did not recall receiving information on contraception and prepregnancy planning. 2 The potential consequences of these possible bidirectional drug interactions are risks of unintended pregnancy due to lowered oral contraceptive levels and increased seizure frequency due to lowered AED levels. Contraceptive failure can be disastrous for all women, but especially for women treated with AEDs because of the teratogenic potential of these drugs. On the other hand, loss of seizure control and recurrence of even a single seizure can have adverse medical effects for the woman and her fetus and psychosocial consequences for the family. This article will review the bidirectional interactions between AEDs and hormonal contraception, including the effects on seizure control and contraception. It will discuss the importance of patient education and counseling in the selection of effective birth control methods for women with epilepsy on AEDs. This article will also review the strengths and limitations of other methods of contraception, such as IUDs, transdermal patches, and depot injections. Effects of AEDs on Combined OCs Combined OC preparations contain 20 mg to 35 mg of ethinylestradiol and less than 1 mg of progestogen. The metabolism of ethinylestradiol has been well studied. The major part of the estrogen compound is hydroxylated to inactive metabolites by the hepatic cytochrome P450 (CYP) 3A4 or directly conjugated. AEDs that induce the CYP3A4 isoenzyme (carbamazepine, felbamate, oxcarbazepine, phenobarbital, phenytoin, and topiramate) therefore accelerate the hepatic elimination of OCs. 3-7 In a recent study, however, topiramate monotherapy in doses less than 200 mg did not affect the metabolism or clinical efficacy of OCs containing 35 mg ethinylestradiol. 8 Effects of Individual AEDs on Combined OCs Earlier data suggested that lamotrigine had no effect on combined OCs. However, in a recent pharmacokinetic study in healthy women, there was a clinically relevant influence of lamotrigine (300 mg/d) on a combined OC containing 30 mg ethinylestradiol and 150 mg levonorgestrel. The area under the curve (AUC) and the maximal plasma concentration of levonorgestrel decreased with the administration of lamotrigine. (The ethinylestradiol pharmacokinetics were unchanged.) In this study, serum progesterone levels indicated no evidence of ovulation, but contraceptive safety could not be guaranteed with higher lamotrigine doses than those tested or with other combined OCs containing different progestins. 9 A study from Finland examined use of felbamate in women taking oral contraceptives containing 30 g ethinyl estradiol and 75 g gestodene, known under the brand names Minulet or Femodene. 4 Felbamate was demonstrated to cause a 42% decrease in gestodene AUC (0-24), although without any effect on the metabolism of ethinylestradiol. 8,9 In women who use low-dose combined OCs ( 30 mg ethinylestradiol and 75 mg progesterone), ovulation suppression might not occur. Review of currently available data suggests that the newer AEDs (gabapentin, levetiracetam, tiagabine, vigabatrin, or zonisamide) do not influence the metabolism of OC and can be used without risk of contraceptive failure Benzodiazepines and ethosuximide are also in this category. In general, AEDs that do not interact with OCs are preferable for women with epilepsy. If OCs are combined with enzyme-inducer AEDs, then the ethinylestradiol dose should be increased from between 20 g and 35 g to 50 g. If breakthrough bleeding occurs, a further increase in the ethinylestradiol dose to 75 g or 100 g may be needed. 15 Even high-dose pills may not provide full protection, so a spermicidal gel or a barrier method should be used in addition to the pill to increase the level of protection. However, little is known about the metabolism of the different progestins used in combined OCs. Therefore, the findings of a drug-drug interaction study of a combined OC pill containing a specific progestin cannot be applied to other hormonal contraceptives that contain different types of progestin (Table 1). Valproate Valproate should be avoided in women of reproductive age because it is associated with a high risk of teratogenicity if taken during pregnancy. That conclusion was confirmed by similar results from different pregnancy registries. The risk of major congenital malformation varies from 6.2% in a United Kingdom pregnancy registry to 15% in an Australian pregnancy registry. 16,17 In a North American pregnancy registry, the risk of major malformation was 10.7% (95% confidence interval, 6.3%-16.9%). 18 Higher risk of major congenital malformation has corresponded with higher doses of valproate. Although valproate is a very effective drug for women with general- VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E63

3 Contraception for Women With Epilepsy continued Table 1 Antiepileptic Drugs and Combined Oral Contraceptives Antiepileptic Drugs That Can Potentially Impair Efficacy of Combined Oral Contraceptives Carbamazepine Felbamate Lamotrigine Oxcarbazepine Phenobarbital Phenytoin Primidone Rufinamide Topiramate Antiepileptic Drugs With No Effect on Combined Oral Contraceptives Benzodiazepines Ethosuximide Gabapentin Levetiracetam Pregabalin Tiagabine Valproate Vigabatrin Zonisamide Adapted with permission from O Brien MD and Guillebaud J. 30 ized epilepsies, the risks and benefits should be carefully considered and discussed with the patient. If valproate must be prescribed, the dose should be maintained at a level that is as low as possible, and certainly less than 1000 mg/d, unless there is an absolute need for higher doses to control refractory seizures. Valproate is metabolized mainly through mitochondrial oxidases and glucuronyl transferases. The glucuronyl transferases are induced by oral contraceptives. As a consequence, valproate clearance may be induced. The oral contraceptive effect on valproate clearance varies and may be of significant clinical relevance in some patients. In a study by Galimberti and colleagues, 19 during the OC intake period, total plasma clearance increased by a mean of 21.5% for total valproate and by a mean of 45.2% for unbound valproate fraction. Herzog and coworkers 20 reported on a single case in which plasma concentrations of valproate fluctuated widely during the OC cycle. The Newest AEDs and Hormonal Contraceptives The newest AEDs in the pipeline are brivaracetam, carisbamate, rufinamide, lacosamide, and eslicarbazepine. Brivaracetam is a derivative of levetiracetam, with increased selectivity for synaptovesicle protein 2. It also inhibits voltage-gated sodium channels, which may give it a broader therapeutic spectrum. It is metabolized by non-cytochrome (CYP450) dependent hydrolysis. Use at normal therapeutic doses is considered safe with OCs. 21 At doses several times higher than the therapeutic dose, brivaracetam may affect the metabolism of OCs, phenytoin, and carbamazepine. Carisbamate is a novel neuromodulator, although not enough is yet known about its mechanism of action. It has a broad therapeutic spectrum and goes through significant metabolic changes, mainly glucuronidation, hydrolysis, and oxidation. The plasma concentration of carisbamate may be reduced by 20% to 30% by OCs, possibly as a result of the induction of glucuronidation. 21 Rufinamide prolongs the inactive state of voltage-gated sodium channels. It is metabolized by enzymatic hydrolysis, independent of CYP isoenzymes, to an inactive metabolite and is primarily renally excreted. Rufinamide may increase the clearance of oral hormonal contraceptives because of weak induction of CYP3A4. 22,23 Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. There is no indication that lacosamide affects CYP isoenzymes. In 1 study, lacosamide (400 mg/d for up to 10 days) did not affect the pharmacokinetics of carbamazepine, valproate, levonorgestrel, or ethinylestradiol. 24 Eslicarbazepine acetate inhibits voltage-gated sodium channels. It is converted to its active metabolite, eslicarbazepine, after absorption. Eslicarbazepine acetate at 1200 mg/d has been shown to reduce plasma concentrations of OCs. 25 Effects of Combined OCs on AEDs The effect of AEDs on OC safety has been the focus of many drug studies. However, much less is known about the impact of hormonal contraceptives on AEDs. It is well known that combined OCs can increase the metabolism of glucuronidated drugs through induction of the uridine diphosphate glucuronosyltransferase system. AEDs that require hepatic glucuronidation and conjugation such as lamotrigine, 10-monohydroxy metabolite (MHD) of oxcarbazepine, and valproic acid are more prone to this effect. Several studies have demonstrated that lamotrigine, the most extensively studied AED, has a significantly increased clearance ( 50%) when used with combined OCs, which results in an increased seizure frequency in most patients. 26 The estrogen component of a combined OC is the main contributor to the increased metabolism of lamotrigine through induction of glucuronidation. The lack of estrogens during the pill-free week of a combined OC regimen affects the pharmacokinetics and rapidly increases the plasma E64 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

4 Contraception for Women With Epilepsy level of lamotrigine in a linear manner. 4,6-14,27-29 Therefore, blood sampling in relation to the combined OC cycle is recommended for therapeutic monitoring of lamotrigine levels. Also, up-titration of the lamotrigine dose should be avoided during the pill-free week to avoid potential tolerability problems and toxicity due to possible high levels. Patients should be informed about toxicity symptoms in particular, dizziness which may occur during the pill-free week in the high-dose lamotrigine regimen (plasma concentrations 40 mmol/l). 30,31 Other AEDs eliminated fully or partially by glucuronidation are oxcarbazepine monohydroxy derivative and valproate. This common feature with lamotrigine suggests that valproic acid and MHD of oxcarbazepine may have a similar interaction with combined OCs. In a case reported in 2005, plasma concentrations of valproate fluctuated widely during the OC cycle. This study and another report demonstrated that the plasma clearance of total valproate increased, with a mean of 21.5% during the OC intake period and of 45.2% for the unbound valproate fraction. 19,20 The OC effect on valproate clearance shows remarkable interindividual differences, likely due to genetic polymorphism. Also, the pharmacologically active monohydroxy derivate of oxcarbazepine is mainly eliminated by glucuronidation. The clinical relevance of this potential effect of OCs must be further explored. The effect of OCs on the elimination rate of AEDs shows significant interindividual variability. The variability is multifactorial and influenced by differences in dosages of the AEDs, the fraction cleared by conjugation, functional polymorphisms of glucuronosyltransferase, and OC doses and formulations. As the level of altered elimination induced by OCs is unpredictable for the individual patient, careful monitoring of the plasma level of all glucuronidated AEDs is recommended, and doses should be adjusted before and after introduction or discontinuation of OCs. 15 Contraceptive Methods Other Than OCs There is limited information on possible interactions between AEDs and progesterone-only pills, injections, implants, and intrauterine devices (Table 2). In 1 study, phenytoin caused failure of contraception in women with epilepsy with subdermal levonorgestrel implants. 32 Based on this report, these contraceptives are considered less reliable and should be avoided in women who are treated with enzyme-inducing drugs. 30 The 2 most widely used preparations are depot medroxyprogesterone acetate and norethisterone enanthate. The effect of intramuscular injection of 150 mg medroxyprogesterone acetate appears unaffected by enzyme-inducing AEDs, but the evidence is limited. Some authors recommend that the interval between each injection (eg, from 12 weeks to 10 weeks) be shortened in women on enzyme-inducing AEDs. It is likely that these high-dose, progestin-only depot preparations provide effective contraception, but they are not the first choice due to long-term side effects, such as osteoporosis, delayed return to fertility, weight gain, acne and other skin conditions, hair loss, and depressive symptoms. The decision of whether to use depot preparations in women on enzymeinducing AEDs should take into account all the risks and benefits of this contraceptive choice for the individual patient. 30,31,33-35 The classic intrauterine copper device (IUD) (or silver device) or the Table 2 Methods of Contraception Not Affected By Enzyme-Inducing Antiepileptic Drugs Barrier methods Progesterone depot injection Hormone-releasing intrauterine system Other intrauterine contraceptive devices Adapted with permission from O Brien MD and Guillebaud J. 30 newer levonorgestrel-releasing intrauterine system (IUS) (Mirena, Bayer Healthcare Pharmaceuticals, Wayne, NJ) may be an alternative for women with epilepsy who are taking enzyme-inducing AEDs. The IUS has a steroid reservoir that releases 20 mg of levonorgestrel into the uterine cavity. Over time, the release rate decreases slowly to 15 mg/d. Most of the contraceptive effect is produced via local mechanisms, such as suppression of endometrial growth by a high concentration of levonorgestrel in the endometrial tissue. Inhibited endometrial growth results in the decreased duration and amount of menstrual bleeding. It also increases cervical mucus hostility, which provides protection against the progression of sexually transmitted infections. 19,30,31 Due to local uterine mechanisms, it is very unlikely that enzyme-inducing AEDs impair the contraceptive efficacy of IUS. In an observational study of women using the IUS Mirena concurrently with AEDs and other enzyme-inducing drugs, researchers concluded that any increased pregnancy risk fell within an acceptable range. 15 Also, the levonorgestrel IUS does not seem to affect lamotrigine plasma levels (as suggested by a small observational series of 6 patients). 36 Thus, IUSs and IUDs are good alternatives VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E65

5 Contraception for Women With Epilepsy continued to the classic hormonal contraceptives in women with epilepsy, especially those who are taking enzyme inducers or lamotrigine. 36 Conclusion Contraception is a very important issue for women with epilepsy. The failure of a contraceptive method can be a devastating event because of unplanned pregnancy and/or the teratogenicity of AEDs. Hormonal contraceptives can induce metabolism of AEDs and lead to loss of seizure control, which can be very challenging in patients who had been seizurefree. The impact of bidirectional interaction between AEDs and hormonal contraception must be closely observed. Therefore, physicians must consider the type of contraception being used before prescribing an AED. The choice of which AED to use or which contraceptive method is optimal depends on a variety of factors. The potential interactions between AEDs and hormonal contraceptives must be taken into account when counseling women with epilepsy. When the use of an OC is changed, drug level monitoring is recommended whenever possible. Alternatives such as an IUD or IUS should be considered if standard hormonal contraceptives do not appear to be effective or if potential side effects limit their use. References 1. Shorvon SD, Tallis RC, Wallace HK. Antiepileptic drugs: coprescription of proconvulsant drugs and oral contraceptives: a national study of antiepileptic drug prescribing practice. J Neurol Neurosurg Psychiatry. 2002;72: Bell GS, Nashef L, Kendall S, et al. Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study. Epilepsy Res. 2002;52: 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: Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther. 1995;58: Fattore C, Cipolla G, Gatti G, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia. 1999;40: Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet. 1990;18: Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia. 1997;38: Doose DR, Wang SS, Padmanabhan M, et al. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia. 2003;44: Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol. 2006;61: Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ. Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol. Neurology. 1998; 50: Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women. Epilepsia. 2002;43: Mengel HB, Houston A, Back DJ. An evaluation of the interaction between tiagabine and oral contraceptives in female volunteers. J Pharm Med. 1994;4: Bartoli A, Gatti G, Cipolla G, et al. A doubleblind, 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;38: Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther. 2004;26: Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16: Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry. 2006;77: Vajda FJ, Hitchcock A, Graham J, et al. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust N Z J Obstet Gynaecol. 2007;47: Bromfield EB, Dworetzky BA, Wyszynski DF, et al. Valproate teratogenicity and epilepsy syndrome. Epilepsia. 2008;49: Galimberti CA, Mazzucchelli I, Arbasino C, et al. Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy. Epilepsia. 2006;47: Herzog AG, Farina EL, Blum AS. Serum valproate levels with oral contraceptive use. Epilepsia. 2005;46: Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII). Epilepsy Res. 2007;73:1-52. Main Points Concomitant use of combined oral contraceptives (OCs) with antiepileptic drugs (AEDs) creates a risk of drug interactions. The potential consequences of possible bidirectional drug interactions are risks of unintended pregnancy due to lowered oral contraceptive C levels and increased seizure frequency due to lowered AED levels. Contraceptive failure can be disastrous for all women, but especially for women treated with AEDs because of the teratogenic potential of these drugs. If OCs are combined with enzyme-inducer AEDs, then the ethinylestradiol dose should be increased from between 20 g and 35 g to 50 g. Intrauterine systems and intrauterine devices are good alternatives to the classic hormonal contraceptives in women with epilepsy, especially those who are taking enzyme inducers or lamotrigine. E66 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

6 Contraception for Women With Epilepsy 22. White HS, Franklin MR, Kupferberg HJ, et al. The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Epilepsia. 2008;49: Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70: Rosenfeld W, Fountain NB, Kaubrys G, et al. Lacosamide: an interim evaluation of long-term safety and efficacy as oral adjunctive therapy in subjects with partial-onset seizures [abstract]. Epilepsia. 2007;48(suppl 6): Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics. 2007;4: Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47: Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia. 2005;46: Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61: Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebocontrolled trial. Epilepsia. 2007;48: O Brien MD, Guillebaud J. Contraception for women with epilepsy. Epilepsia. 2006;47: Sabers A. Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure. 2008;17: Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception. 1986;33: O Brien MD, Gilmour-White SK. Management of epilepsy in women. Postgrad Med J. 2005; 81: Cromer BA, Stager M, Bonny A, et al. Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls. J Adolesc Health. 2004;35: Scholes D, Lacroix AZ, Ott SM, et al. Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol. 1999;93: Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzymeinducing drugs. J Fam Plann Reprod Health Care. 2002;28: VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E67