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1

Epilepsy & Behavior xxx (2006) xxx–xxx www.elsevier.com/locate/yebeh

2 The impact of antiepileptic drug therapy on steroidal

3 contraceptive efficacy

a,b c, d,e 4 Ian Thorneycroft , Pavel Klein *, James Simon

5 a University of South Alabama, College of Medicine, Mobile, AL, USA 6 b Bay Area Physicians for Women, Mobile, AL, USA 7 c Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA 8 d George Washington University, Washington, DC, USA 9 e The Women’s Health Research Center,Washington, DC, USA

10 Received 23 January 2006; revised 1 May 2006; accepted 3 May 2006 11 PROOF 12 Abstract

13 Women with epilepsy face unique challenges in maintaining steroidal contraceptive efficacy because some antiepileptic drugs (AEDs) 14 increase the rate of hepatic metabolism of contraceptive steroids, leading to higher potential for contraceptive failure in this population. 15 Planned pregnancy is of great clinical and social importance for women with epilepsy because of the increased risk of birth defects from 16 fetal exposure to AEDs. Current clinical guidelines for contraceptive management in women with epilepsy provide misleading informa- 17 tion by focusing on the estrogen content of the formulation, which regulates the menstrual cycle, rather than on the progestin content of 18 the formulation, which provides contraceptive efficacy. This article reviews studies of AED–contraceptive interaction and misconceptions 19 about maintaining contraceptive efficacy and makes recommendations for contraceptive management in women with epilepsy who 20 receive concomitant AED therapy. 21 Ó 2006 Published by Elsevier Inc.

22 Keywords: Antiepileptic drugs; Contraception; Efficacy; Enzyme induction; Epilepsy; Treatment guidelines; Hepatic metabolism; Steroidal contraceptives; 23 Women 24

25 1. Introduction and that women who take AEDs have a high oral contra- 36 ceptive (OC) failure rate [1]. 37 26 Women with epilepsy who are treated with antiepileptic Although more than 90% of women taking AEDs 38 27 drugs (AEDs) face unique challenges in contraception. during pregnancy will deliver a healthy child, 4–7% of 39 28 Certain AEDs can induce hepatic metabolism of steroidal fetuses exposed to certain AEDs are at increased risk 40 29 contraceptives (SCs), leading to decreased contraceptive of having birth defects [4]. Therefore, contraceptive effi- 41 30 efficacy. However, several surveys suggest that a large per- cacy is a major concern for women with epilepsy. A lack 42 31 centage of health care professionals have limited knowl- of confidence in the method of contraception can lead to 43 32 edge about optimizing contraceptive efficacy in female detrimental psychosocial stresses, including decreased 44 33 patients with epilepsy [1,2], that women of reproductive sexuality and fear of teratogenesis.[5] Women with epi- 45 34 age who are treated withUNCORRECTED enzyme-inducing AEDs do not lepsy desire treatment that offers optimal seizure control 46 35 receive information about potential drug interactions [3], together with reliable birth control, healthy pregnancies, 47 and healthy children [6]. Good counseling and pregnancy 48 planning are essential to achieving these goals. 49 * Corresponding author. Fax: +1 301 530 9177. This article reviews the published literature addressing 50 E-mail address: [email protected] (P. Klein). AED–contraceptive interaction, discusses misconceptions 51

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52 in current contraception management in women with epi- egg. If fertilization does not occur, production of estrogen 105 53 lepsy, and offers recommendations on reliable contracep- and progesterone decreases, and menstruation begins [11]. 106 54 tion methods for women to use concomitantly with In the 1950s, the initial development of SCs was based 107 55 AEDs. on the observation that progesterone is responsible for 108 the suppression of ovulation. In early tests of contracep- 109 56 2. Current contraception guidelines for women with epilepsy: tives, the use of impure progestogen samples provided 110 57 Flaws evidence that estrogen was necessary for menstrual cycle 111 regulation [12]. Analysis of bleeding patterns in women 112 58 Current guidelines for contraceptive use by women with using a number of contraceptive modalities has con- 113 59 epilepsy suggest that contraceptive efficacy is provided by firmed the necessity of estrogen for proper cycle control 114 60 the estrogen component of these agents [7,8]. In fact, it is [13]. Progestin-induced irregular menstruation may pro- 115 61 the progestin component of SCs that provides contracep- vide misleading evidence of altered hormone cycling 116 62 tive efficacy [9,10]. due to pathology [14]. Therefore, scheduled endometrial 117 63 For example, the Commission on Genetics, Pregnancy, shedding brought about by the oral intake of estrogen 118 64 and the Child, International League Against Epilepsy, may contribute to psychological well-being as well as 119 65 guidelines for the care of women of childbearing age with convenience. 120 66 epilepsy suggest that breakthrough bleeding is a sign of Currently, SCs contain either a combination of synthetic 121 67 contraceptive failure that is due to low estrogen dosage estrogen and synthetic progesterone-like steroid or a single 122 68 resulting from possible interaction between AEDs and synthetic progesterone-like component (Fig. 1) [15]. Typi- 123 69 SCs [7]. The American Academy of Neurology (AAN) cally, the synthetic estrogen component of combined SCs 124 70 Practice Parameters recognize that the risk of contraceptive comprises either ethinylestradiol or mestranol. Ethinylest- 125 71 failure may be increased as endogenously bioavailable radiol is an orally active derivative of the endogenous hor- 126 72 estrogen and progestin are reduced by the use of those mone estradiol, with the addition of an ethinyl group to the 127 73 AEDs that activate isozymes of hepatic cytochrome P450 pentane ring. Mestranol is essentially ethinylestradiol with 128 74 (CYP450) or increase production of steroid hormone-bind- a methylated hydroxyl group on the benzene ring. The pro- 129 75 ing globulins (SHBGs). AAN guidelines recommend that gesterone-like component of either combined or single- 130 76 the contraceptive formulation contain at least 50 lg of eth- agent contraceptives comprises one of a variety of synthetic 131 77 inylestradiol or mestranol to control breakthrough bleed- progestational steroids called progestins or progestogens, 132 78 ing [8]. Neither set of guidelines makes recommendations which are similar in structure to the native hormone pro- 133 79 for progestin dosage. gesterone. Norethindrone, for example, differs from pro- 134 80 Although the available guidelines recognize that some gesterone by the lack of a methyl group at position 6 and 135 81 AEDs can reduce the efficacy of SCs, they provide flawed the substitution of a hydroxyl group and an ethinyl group 136 82 guidance for providing effective contraception. Although for the ketone at position 17. Levonorgestrel differs from 137 83 estrogen levels are reduced by the action of enzyme-induc- norethindrone by the substitution of an ethyl group for 138 84 ing AEDs, it is the progestin component of the contracep- the methyl group at position 13 [16,17]. 139 85 tive that prevents ovulation. Current guidelines omit this Progestins induce four discrete contraceptive processes 140 86 crucial information. in the body. First, they inhibit production of GnRH by 141 the hypothalamus. The reduction in GnRH limits produc- 142 87 3. Steroidal contraceptive mechanism of action tion of LH and of FSH by the pituitary gland, thereby sup- 143 pressing the midcycle pulses of LH necessary to initiate 144 88 During the first stage of the menstrual cycle (follicular ovulation (Fig. 2) [18]. Second, progestins cause cervical 145 89 phase), the hypothalamus produces gonadotropin-releasing mucus to thicken, which blocks the passage of sperm. 146 90 hormone (GnRH). GnRH stimulates the pituitary gland to Third, they cause the endometrium to atrophy, making it 147 91 secrete follicle-stimulating hormone (FSH) and luteinizing unsuitable for ovum implantation. Fourth, they limit fallo- 148 92 hormone (LH), causing follicles to mature in the ovaries. pian tube cilial motility, preventing the timely transport of 149 93 Pituitary FSH secretion drives the production of estrogen, the ovum to the uterus [9,19]. 150 94 which gradually increases throughout the follicular phase. The estrogen component of combined SCs plays two 151 95 Just before ovulation, the negative feedback of estrogen important physiologic roles. First, estrogen augments the 152 96 on pituitary LH/FSH changesUNCORRECTED to positive feedback. This effects of progestins PROOF by increasing the concentration of 153 97 produces a surge in LH, as well as a surge in estradiol, intracellular progestin receptors. Estrogen also suppresses 154 98 which causes release of the oocyte from the follicle in the the release of FSH from the pituitary, further inhibiting 155 99 ovary into the fallopian tubes (ovulation). In the second the emergence of a dominant follicle. Therefore, estrogen 156 100 stage of the menstrual cycle (luteal phase), the granulosa may contribute indirectly to the efficacy of combined 157 101 cell remnants of the follicle form the corpus luteum, which SCs. Second, and more importantly, estrogen stabilizes 158 102 secretes large quantities of progesterone and, to a lesser the endometrium, minimizing breakthrough bleeding and 159 103 degree, estradiol in response to LH. These hormones pre- unscheduled endometrial shedding, which increase patient 160 104 pare the endometrium for implantation of the fertilized satisfaction and compliance [10]. 161 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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Estradiol (-19-Norpregna-1,3,5(10) triene-3,17 -diol)

Ethinylestradiol Mestranol (-19-Norpregna-1-,3,5(10) triene (-19-Norpregna-1-,3,5(10) triene 20-yne-3,17 -diol) 20-yne-17 -ol, 3-methoxy) PROOF

Progesterone (pregn-4-ene-3, 20-dione)

Norethindrone Levonorgestrel (-19-Norpregn-4-ene (D18,19- inorpregn-4-ene- 20-yne-3-one, 17 -hydroxy) 20-yne-3-one, 13-ethyl-17 -hydroxy)

Fig. 1. Chemical structures for gonadal steroids and their synthetic derivatives. Not all progestational agents are represented. Adapted, with permission, from ChemIndustry.com, Monrovia, CA, USA, and Drugs.com, Drugsite Trust, Auckland, New Zealand.

162 4. Drug interactions between AEDs and steroidal unbound fraction of the steroids being bioactive. SHBG 172 163 contraceptives is synthesized by the liver, and its synthesis is stimulated 173 by the enzyme-inducing AEDs. Therefore, enzyme-induc- 174 164 4.1. Impact of AEDs on steroidalUNCORRECTED contraceptives ing AEDs lower plasma levels of active SC by increasing 175 the rate of their catabolism and clearance and by increasing 176 165 Gonadal steroids and their synthetic derivatives are the amount of SHBG to which they bind. This can result in 177 166 metabolized by hepatic CYP450 enzymes, specifically the contraceptive failure and breakthrough bleeding when 178 167 CYP3A4 isoform group. These enzymes are induced by a serum levels of progestin and estrogen fall below effective 179 168 number of drugs, including AEDs such as phenobarbital, concentrations. 180 169 phenytoin, and carbamazepine. In addition, gonadal ste- Progestins have a bioavailability of between 80 and 181 170 roids and their synthetic derivatives are carried in the blood 100% because they do not undergo significant initial gut 182 171 largely bound to the carrier protein SHBG, with only the or hepatic metabolism. Induction of CYP3A4 by enzyme- 183 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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Fig. 2. The progestin component of steroidal contraceptives suppresses ovulation by inhibiting hormone production by the hypothalamus and pituitary gland. Adapted, with permission, from Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysiology, diagnosis, and management. Neurology 2003;61(6, Suppl. 2):S2–15.

184 inducing AEDs increases the rate of secondary progestin 42% reduction in serum ethinylestradiol [22]. Back et al. 205 185 metabolism [4], resulting in decreased serum concentra- reported that women taking phenobarbital had decreased 206 186 tions of progestins. By contrast, the bioavailability of eth- serum ethinylestradiol concentrations (64 and 72%), with 207 187 inylestradiol is generally 40–50% as a result of first-pass associated breakthrough bleeding. However, serum FSH 208 188 metabolism. Ethinylestradiol undergoes sulfation in the and progesterone levels did not change, suggesting ovula- 209 189 intestine and glucuronation or CYP3A4-catalyzed hydrox- tion did not occur in these patients [23]. In the absence of 210 190 ylation in the liver [4]. Enzyme-inducing AEDs increase information to the contrary, primidone should be consid- 211 191 secondary metabolism of both estrogens and progestins ered to have effects on SC metabolism similar to those of 212 192 by inducing CYP3A4. They further reduce free steroid lev- phenobarbital. Significant reductions in serum ethinylestra- 213 193 els by inducing the production of SHBG, which binds these diol (49%) and levonorgestrel (42%) have been observed in 214 194 steroids in the blood [20]. concurrent phenytoin and SC use [21]. 215 Of the second generation AEDs, felbamate has been 216 195 4.1.1. Inducers of hepatic enzymes shown to reduce serum gestodene by 42% and to reduce 217 196 Several first- and second-generationUNCORRECTED AEDs have signifi- ethinylestradiol PROOF by 13%, although there was no evidence 218 197 cant enzyme-inducing properties and act on a wide of ovulation among these patients [24]. In female volun- 219 198 spectrum of hepatic enzymes that metabolize the progestin teers, 300 mg/day doses of lamotrigine decreased levo- 220 199 and estrogen components of SCs (Table 1). Crawford et al. norgestrel levels by 19%, although there was no evidence 221 200 demonstrated that carbamazepine use was associated with of ovulation in these subjects and no apparent effect on eth- 222 201 a 6–66% reduction in serum ethinylestradiol concentration inylestradiol concentration [25]. Oxcarbazepine at 300 mg/ 223 202 and a 29–57% reduction in serum levonorgestrel concentra- day decreased the serum concentration of ethinylestradiol 224 203 tion [21]. In a similar study, carbamazepine use was associ- by 48% and that of levonorgestrel by 32%. However, serum 225 204 ated with a 58% reduction in serum norethindrone and a progesterone levels remained low, indicating that ovulation 226 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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Table 1 Observed effects of AEDs on steroidal contraceptive metabolism Activated enzymes Estrogen reduction (%) Progestin reduction (%) Inducers of hepatic enzymes Carbamazepine [22,28] 600 mg/day CYP1A2, CYP2C, CYP3A 42 58 Felbamate [24,28] 2400 mg/day CYP3A4 13 42 Lamotrigine [25] Not reported — 19 Oxcarbazepine [26,28] 300 mg/day CYP3A4 48 32 Phenobarbital [23,28] 60 mg/day CYP1A, CYP2A6, CYP2B, CYP2C, CYP3A 64–72 — Phenytoin [21,28] 200–300 mg/day CYP2C, CYP3A 49 42 Topiramate [22,28] 200 mg/day CYP3A4 14.7–33.0 — Non-inducers of hepatic enzymes Ethosuximide [20,28] ——— Levetiracetam [28,43] ——— Tiagabine [4,28] ——— Valproic acid [28,44] ——— Vigabatrin [28,45] ——— Zonisamide [28,46] ———

227 did not occur in these patients [26]. In doses of 100– in the postpartum period. Lamotrigine dose adjustments 262 228 400 mg/day, topiramate has been shown to decrease serum should be considered in both patient populations to ensure 263 229 ethinylestradiol levels by 630%, but topiramate had no sig- maximum seizure suppression. Further studies of the effects 264 230 nificant effect on norethindrone concentrations [27]. How- of SC use onPROOF AEDs are needed so that guidelines for dose 265 231 ever, a separate study of topiramate at 6200 mg/day adjustments during SC initiation and withdrawal can be 266 232 indicated no significant effect on ethinylestradiol or noreth- developed. 267 233 indrone serum levels [22]. 4.4. Summary 268 234 4.2. Non-inducers of hepatic enzymes The induction of CYP450 isozymes by many AEDs 269 235 Many first- and second-generation AEDs are not potent increases the metabolism of SCs, which potentially com- 270 236 inducers of hepatic enzymes. They may be less active, may promises contraceptive efficacy. Carbamazepine, felbam- 271 237 activate through less important enzyme pathways, or may ate, lamotrigine, oxcarbazepine, phenobarbital, 272 238 have no effect whatsoever. Ethosuximide, gabapentin, lev- phenytoin, and topiramate have been shown to significant- 273 239 etiracetam, tiagabine, valproic acid, vigabatrin, and zonisa- ly reduce serum concentrations of SCs, whereas ethosuxi- 274 240 mide have no appreciable enzyme-inducing action and mide, gabapentin, levetiracetam, tiagabine, valproic acid, 275 241 appear not to compromise SC efficacy [28]. vigabatrin, and zonisamide appear not to induce 276 CYP450. Conversely, SCs may impact AED efficacy 277 242 4.3. Impact of steroidal contraceptives on AEDs because SCs induce UGT activity. Serum levels of lamotri- 278 gine, in particular, may be significantly reduced in women 279 243 SCs may impact the serum concentration and efficacy of who also use SCs. 280 244 certain AEDs, most notably lamotrigine. In case studies, The potential for drug interactions between AEDs and 281 245 SCs decreased the serum level of lamotrigine by a mean SCs appears to be high. However, the available studies 282 246 49% (range: 41–64%). In these patients, seizure activity on concurrent AED and SC use have been conducted in 283 247 increased with SC use, and the side effects of lamotrigine small numbers of patients. These results need to be con- 284 248 increased when SCs were discontinued [29]. In a pilot study firmed in larger, well-designed, prospective clinical trials. 285 249 of SC impact on serum lamotrigine levels, 22 women In particular, serum concentrations of SCs need to be cor- 286 250 received lamotrigine and an SC, and 30 women received related with contraceptive failure rates so that clear guide- 287 251 lamotrigine alone. Serum lamotrigine decreased by more lines for the clinical management of drug interactions 288 252 than 50% in the women taking lamotrigine and SCs con- between AEDs and SCs can be developed. 289 253 currently [30]. These studiesUNCORRECTED suggest that the pharmacoki- 254 netics of lamotrigine are significantly altered by SC use. 5. Non-oral contraceptives 290 255 SCs induce UDP-glucuronosyltransferase (UGT), the pri- 256 mary pathway of lamotrigine elimination [30]. Therefore, Women who use enzyme-inducing AEDs and SCs con- 291 257 dose adjustments should be considered, to compensate comitantly have a higher rate of contraceptive failure than 292 258 for the marked reductions in lamotrigine that are associat- the general population [31–33]. Administering higher-dose 293 259 ed with elevated serum estrogen and progestin. Serum ste- SCs could reduce the risk of contraceptive failure by 294 260 roid levels rise in pregnancy, with a similar drop in accommodating the increased steroid metabolism caused 295 261 lamotrigine levels, followed by rise in the lamotrigine level by enzyme-inducing AEDs. For women who need alterna- 296 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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297 tives to OCs, intrauterine devices and injectable contracep- Provera 10, has been approved by the FDA. The new for- 350 298 tives appear to be the best candidates because they have mulation delivers 104 mg medroxyprogesterone acetate 351 299 not exhibited high susceptibility to enzyme-inducing AEDs and is administered every 3 months [40]. However, this 352 300 [20]. Therefore, alternative contraceptives may help low-dose formulation should not be used in patients receiv- 353 301 decrease the rate of contraceptive failure in women with ing enzyme-inducing AEDs because its efficacy may be 354 302 epilepsy. compromised by increased rates of steroid metabolism. 355

303 5.1. Intrauterine contraceptives 5.3. Transdermal contraceptives 356

304 In 2000, the U.S. Food and Drug Administration Ortho Evr is the first contraceptive patch to be approved 357 305 (FDA) approved the use of Mirena, a levonorgestrel-re- by the FDA. It delivers 150 lg of norelgestromin and 20 lg 358 306 leasing intrauterine system (LNG-IUS). The LNG-IUS ini- of ethinylestradiol daily. A new patch is applied each week 359 307 tially delivers 20 lg/day levonorgestrel and remains for 3 consecutive weeks, followed by a patch-free week that 360 308 effective for approximately 5 years [34]. Because the allows menstruation [41]. However, the risk of contracep- 361 309 LNG-IUS releases hormones locally in the uterus, the tive failure in female patients with a body mass index 362 310 potential for drug interaction through enzyme induction >27.3 kg/m2 is increased compared with that of women 363 311 is low. In a pilot study of LNG-IUS, compared with a con- with a smaller volume of distribution [42]. Therefore, it is 364 312 traceptive failure rate of 0.2/100 woman-years for women possible that the relatively low-progestin-dose contracep- 365 313 not receiving AED treatment, the rate for women receiving tive patch might also be less effective in women receiving 366 314 concurrent AED treatment was 1.1/100 woman-years, enzyme-inducing AEDs because of the resultant increased 367 315 which is less than the failure rate in women using OCs in metabolism of the SC. More studies specific to this form 368 316 combination with enzyme inducing AED treatment [35]. of SC are needed to further delineate potential interactions 369 317 The observed difference in efficacy for women receiving between these two classes of drugs. 370 318 AED treatment is perhaps due to peripheral absorption 319 of levonorgestrel from the intrauterine device, which may 5.4. Summary 371 320 decrease the viscosity of cervical mucus. Given the contra- 321 ceptive efficacy of LNG-IUS, it may prove to be a first-line Although efficacy data for alternative SCs in women 372 322 contraceptive method for women who are receiving receiving AED treatment are limited, their methods of 373 323 enzyme-inducing AEDs. Paraguard is an alternative, cop- delivery may offer clinical benefits, including a lesser degree 374 324 per intrauterine device. It provides highly effective contra- of drug interaction and improved patient compliance. 375 325 ception because copper has spermicidal properties and Transdermal contraceptives deliver low doses of progestin 376 326 local effects that prevent implantation [36]. Because the and should not be used by women receiving enzyme-induc- 377 327 copper device is not affected by steroid metabolism, it is ing AEDs. LGN-IUS and intramuscular DMPA appear to 378 328 a good contraceptive method for women receiving be attractive contraceptive choices for women receiving 379 329 enzyme-inducing AEDs. enzyme-inducing AEDs. Pilot studies show promise for 380 these agents, with potential for lower rates of contraceptive 381 330 5.2. Injection contraceptives failure in women with epilepsy. The possible anticonvul- 382 sant effect of DMPA may be an additional advantage. 383 331 In 1992, the FDA approved Depo-Provera, an injection However, the efficacy studies to date have included only 384 332 formulation of depomedroxyprogesterone acetate small numbers of patients. Well-designed, prospective stud- 385 333 (DMPA). Worldwide, approximately 8–9 million women ies need to be conducted to determine the utility of these 386 334 use this method of contraception [9]. DMPA is a proges- methods in women who are receiving concurrent AED 387 335 tin-only agent that is administered via intramuscular injec- treatment. 388 336 tion every 3 months and delivers 150 mg of 337 medroxyprogesterone acetate [37]. Pilot studies of DMPA 6. Treatment recommendations 389 338 suggest that drug interactions due to enzyme induction 339 are negligible [38]. In addition, DMPA may have an anti- Enzyme-inducing AEDs have the potential to compro- 390 340 convulsant effect. In a study of women with medically mise the efficacy of all SCs. Conversely, lamotrigine may 391 341 refractory partial seizuresUNCORRECTED and normal ovulation cycles, also compromise PROOF the efficacy of AEDs. Given how the fre- 392 342 treatment with 150 mg of depomedroxyprogesterone quency and severity of seizures impact women’s lives, epi- 393 343 resulted in a 40% average reduction in seizures [39]. The lepsy must be the treatment priority. Therefore, the most 394 344 anticonvulsant effect may be secondary to DMPA amenor- effective AED should be used to treat each type of epilepsy, 395 345 rhea. DMPA appears to be an attractive contraceptive while considering the potential effects of the AED on the 396 346 method for women receiving AED treatment, especially patient’s SC metabolism and making adjustments to ensure 397 347 for women who may be noncompliant or cognitively efficacy. At the same time, women who are considering 398 348 impaired and for those for whom estrogen use is contrain- alternative methods of steroidal contraception should be 399 349 dicated [18]. A new formulation of DMPA, Depo-SubQ advised of the risks or benefits of these agents. 400 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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Table 2 Estimates of bioavailable steroid after hepatic metabolism Steroid Dose Bioavailable steroid Minimally effective dose After 25% metabolism After 50% metabolism After 65% metabolism Norethindrone 1 mg 0.75 mg 0.5 mg 0.35 mg 0.35 mg Levonorgestrel 0.150 mg 0.113 mg 0.075 mg 0.053 mg 0.0375 mg Levonorgestrel 0.250 mg 0.188 mg 0.125 mg 0.0875 mg 0.0375 mg Ethinylestradiol 35 lg 26.5 lg 17.5 lg 12.25 lg20lg Ethinylestradiol 50 lg 37.5 lg25lg 17.5 lg20lg

401 6.1. Oral contraceptives of norethindrone should be an effective contraceptive in 419 this patient. Although the bioavailable ethinylestradiol 420 402 Table 2 illustrates the various amounts of ethinylestradi- from this combined OC would potentially be reduced by 421 403 ol, norethindrone, and levonorgestrel one would expect to 42%, the patient would still receive a higher dose than 422 404 be remaining if the administered dose had been metabo- the 20 lg in combined OCs containing lower doses of 423 405 lized 25, 50, and 65%. For comparison, the last column estrogen. 424 406 in Table 2 lists the minimum effective amounts of progestin Tables 3A,3B lists recommended SCs and notes dosag- 425 407 in FDA-approved progestin-only OCs. In combined OCs es of estrogen and progestin. Given the rates of metabol- 426 408 containing 50 lg of mestranol as the estrogen component, ic reduction for estrogen and progestin following AED 427 409 in vivo metabolism of this prodrug yields approximately interaction, biphasic and triphasic OCs are not recom- 428 410 35 lg of bioavailable ethinylestradiol. mended because the low first-phase dose of progestin 429 411 For example, in a patient treated with carbamazepine could compromisePROOF contraceptive efficacy. Similarly, all 430 412 who was also using a combined OC containing 1 mg of progestin-only OCs would be rendered ineffective and 431 413 norethindrone and 50 lg of ethinylestradiol, the progestin should be eliminated from use by individuals using 432 414 component of her OC could be reduced by 58%, and the enzyme-inducing AEDs. 433 415 estrogen component could be reduced by 42% (Table 1). Recommended OCs for women receiving AED treat- 434 416 Because the expected 58% decrease in progestin would ment include those with 1 mg of norethindrone, 0.150 mg 435 417 not reduce the dose to less than the minimally effective dose of levonorgestrel, or 0.300 mg norgestrel. All oral formula- 436 418 of 0.35 mg available as a minipill, an OC containing 1 mg tions containing 50 lg of estrogen are recommended, as 437

Table 3A Contraceptives recommended for women receiving AED treatment Registered brand name Estrogen Daily dose (lg) Progestin Daily dose (mg) Monophasic OCs [47] Ovcon 50 EE 50 NET 1 Ortho-Novum 1/50 Mestranol 50 NET 1 Norinyl 1 + 50 Mestranol 50 NET 1 Ogestrela EE 50 Norgestrel 0.5 Ortho-Novum 1/35 EE 35 NET 1 Norinyl 1 + 35 EE 35 NET 1 Loestrin 1.5/30 EE 30 NET 1.5 Loestrin Fe 1.5/30 EE 30 NET 1.5 Lo/Ovral EE 30 Norgestrel 0.3 Nordette EE 30 LNG 0.15 Loestrin 1/20 EE 20 NET 1 Loestrin Fe 1/20 EE 20 NET 1

Extended-cycle OCs [47] UNCORRECTED Seasonale EE 30 LNG 0.15

Intrauterine contraceptives [34,36] Mirena LNG 0.20 Paraguard Copper

Injection contraceptives [37] Depo-Provera (administered quarterly) MPA 150 a Generic name. EE, ethinylestradiol; LNG, levonorgestrel; MPA, medroxyprogesterone acetate; NET, norethindrone. YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

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Table 3B Contraceptives NOT recommended for women receiving AED treatmenta Registered brand name Estrogen Daily dose (lg) Progestin Daily dose (mg) Biphasic OCs [47] Ortho-Novum 10/11–28 EE 35 (Days 1–10) NET 0.5 (Days 1–10) 35 (Days 11–28) 1.0 (Days 11–28) Triphasic OCs [47] Tri-Norinyl EE 35 NET 0.5 (Week 1) 1.0 (Week 2) 0.5 (Week 3)

Progestin-only OCs [47] Nor-QD NET 0.35 Ortho Micronor NET 0.35 Ovrette Norgestrel 0.075 a Not a comprehensive list. EE, ethinylestradiol; LNG, levonorgestrel; MPA, medroxyprogesterone acetate; NET, norethindrone.

438 these contraceptives also contain relatively high doses of Given the potential for drug interactions between SCs 475 439 progestin. Therefore, patients receiving combined OCs and AEDs, we recommend combined OCs with relatively 476 440 containing 50 lg of estrogen should have effective contra- high progestin doses to ensure contraceptive efficacy. For 477 441 ception and adequate menstruation cycle control. women who seek alternatives to OCs, intrauterine devices 478 and injection contraceptives are effective and appear to 479 442 6.2. Non-oral contraceptives have less potential for drug interaction than OCs. Howev- 480 er, well-designed, prospective trials are needed before clear 481 443 The contraceptive patch should not be used by women guidelines on the administration of AEDs and SCs can 482 444 receiving AED treatment because it is a low-progestin-dose emerge. 483 445 method [38]. The 150-mg preparation of DMPA may be an 446 effective contraceptive option for women with epilepsy References 484 447 because it appears to have little or no drug interaction with 448 AEDs. Likewise, the LNG-IUS may be an effective alterna- [1] Krauss GL, Brandt J, Campbell M, et al. Antiepileptic medication 485 449 tive for women receiving AED treatment because the local- and oral contraceptive interactions: a national survey of neurologists 486 and obstetricians. Neurology 1996;46:1534–9. 487 450 ized, intrauterine delivery of steroids appears to be [2] Morrell MJ, Sarto GE, Shafer PO, et al. Health issues for women 488 451 unaffected by AED-induced enzyme metabolism. DMPA with epilepsy: a descriptive survey to assess knowledge and awareness 489 452 injections and LNG-IUS appear to have better efficacy among healthcare providers. J Womens Health Gend Based Med 490 453 than OCs and barrier methods, but studies to date are 2000;9:959–65. 491 454 based on small numbers of patients. The efficacy of these [3] Crawford P, Hudson S. Understanding the information needs of 492 women with epilepsy at different lifestages: results of the ’Ideal 493 455 alternative SCs needs to be further studied in women with World’ survey. Seizure 2003;12:502–7. 494 456 epilepsy. [4] McAuley JW, Anderson GD. Treatment of epilepsy in women of 495 reproductive age: pharmacokinetic considerations. Clin Pharmacoki- 496 457 7. Conclusion net 2002;41:559–79. 497 [5] Penovich PE, Eck KE, Economou VV. Recommendations for the 498 care of women with epilepsy. Cleve Clin J Med 2004;71(Suppl. 2): 499 458 The concern about the increased risk of teratogenicity of S49–S57. 500 459 certain AEDs makes planned pregnancy of greater concern [6] Tettenborn B, Genton P, Polson D. Epilepsy and women’s issues: an 501 460 for women with epilepsy than for women in the general update. Epileptic Disord 2002;4(Suppl. 2):S23–31. 502 461 population. The available guidelines for steroidal contra- [7] Commission on Genetics, Pregnancy, and the Child, International 503 League Against Epilepsy. Guidelines for the care of women of 504 462 ception for women with epilepsy focus misguidedly on childbearing age with epilepsy. Epilepsia 1993;34:588–9. 505 463 the estrogen component of combined SCs, which helps to [8] Practice parameter: management issues for women with epilepsy 506 464 regulate menstrual cycles, rather than the progestin compo- (summary statement). Report of the Quality Standards Subcommittee 507 465 nent, which suppresses ovulation and is responsible for of the American Academy of Neurology. Neurology 1998;51:944–8. 508 466 contraception efficacy. Low-doseUNCORRECTED SC use by women treated [9] Erkkola R, Landgren PROOF BM. Role of progestins in contraception. Acta 509 Obstet Gynecol Scand 2005;84:207–16. 510 467 with enzyme-inducing AEDs may result in contraceptive [10] Speroff L, Darney PD. A clinical guide for contraception. 3rd 511 468 failure because induction of the CYP450 enzymes responsi- ed. Philadelphia: Lippincott Williams & Wilkins; 2000. 512 469 ble for steroid metabolism increases clearance and reduces [11] Likis FE. Contraceptive applications of estrogen. J Midwifery 513 470 plasma SCs to levels insufficient for ovulation suppression. Womens Health 2002;47(3):139–56. 514 471 Conversely, SCs can impact the serum concentration of [12] Goldzieher JW, Rudel HW. How the oral contraceptives came to be 515 developed. Jama 1974;230:421–5. 516 472 AEDs by inducing UGT activity. Lamotrigine, in particu- [13] Belsey EM. Vaginal bleeding patterns among women using one 517 473 lar, appears to be susceptible to increased clearance natural and eight hormonal methods of contraception. Contraception 518 474 through SC use. 1988;38:181–206. 519 YEBEH 1183 No. of Pages 9;4C:4; Model 5+ ARTICLE IN PRESS 22 May 2006 Disk Used Faiz (CE) / Karthikeyan (TE)

I. Thorneycroft et al. / Epilepsy & Behavior xxx (2006) xxx–xxx 9

520 [14] Lobo RA. A disorder without identity: ‘‘HCA,’’ ‘‘PCO,’’ ‘‘PCOD,’’ [31] Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of 563 521 ‘‘PCOS,’’ ‘‘SLS’’. what are we to call it? Fertil Steril oral contraceptives? Epilepsia 1979;20:519–25. 564 522 1995;63:1158–60. [32] Janz D, Schmidt D. Anti-epileptic drugs and failure of oral 565 523 [15] Benagiano G, Primiero FM, Farris M. Clinical profile of contracep- contraceptives [letter]. Lancet 1974;1:1113. 566 524 tive progestins. Eur J Contracept Reprod Health Care 2004;9:182–93. [33] Kenyon IE. Unplanned pregnancy in an epileptic. Br Med J 567 525 [16] ChemIndustry.com. Monrovia, CA. 1972;1:686–7. 568 526 [17] Drugs.com. Drugsite Trust. Auckland, New Zealand. [34] MIRENAÒ [package insert]. Montville, NJ: Berlex; 2003. 569 527 [18] Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysi- [35] Bounds W, Guillebaud J. Observational series on women using the 570 528 ology, diagnosis, and management. Neurology 2003;61(6, Suppl. 2): contraceptive Mirena concurrently with anti-epileptic and other 571 529 S2–S15. enzyme-inducing drugs. J Fam Plann Reprod Health Care 572 530 [19] Rivera R, Yacobson I, Grimes D. The mechanism of action of 2002;28:78–80. 573 531 hormonal contraceptives and intrauterine contraceptive devices. Am [36] ParaguardÒ [package insert]. Tonawanda, NY: FEI Products LLC; 574 532 J Obstet Gynecol 1999;181(5, Pt. 1):1263–9. 2003. 575 533 [20] Crawford P. Interactions between antiepileptic drugs and hormonal [37] Depo-ProveraÒ [package insert]. Kalamazoo, MI: Pharmacia & 576 534 contraception. CNS Drugs 2002;16:263–72. Upjohn Co.; 2004. 577 535 [21] Crawford P, Chadwick DJ, Martin C, et al. The interaction of [38] O’Brien MD, Gilmour-White SK. Management of epilepsy in 578 536 phenytoin and carbamazepine with combined oral contraceptive women. Postgrad Med J 2005;81:278–85. 579 537 steroids. Br J Clin Pharmacol 1990;30:892–6. [39] Mattson RH, Cramer JA, Caldwell BV, et al. Treatment of seizures 580 538 [22] Doose DR, Wang SS, Padmanabhan M, et al. Effect of topiramate with medroxyprogesterone acetate: preliminary report. Neurology 581 539 or carbamazepine on the pharmacokinetics of an oral contraceptive 1984;34:1255–8. 582 540 containing norethindrone and ethinyl estradiol in healthy obese and [40] Depo-subQ provera 104ä [package insert]. New York, NY: 583 541 nonobese female subjects. Epilepsia 2003;44:540–9. Pharmacia and Upjohn Co; 2005. 584 542 [23] Back DJ, Bates M, Bowden A, et al. The interaction of phenobar- [41] ORTHO EVRAÒ [package insert]. Raritan, NJ: Ortho–McNeil 585 543 bital and other anticonvulsants with oral contraceptive steroid Pharmaceutical, Inc.; 2005. 586 544 therapy. Contraception 1980;22:495–503. [42] Holt VL, Scholes D, Wicklund KG, et al. Body mass index, weight, 587 545 [24] Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the and oral contraceptivePROOF failure risk. Obstet Gynecol 2005;105:46–52. 588 546 pharmacokinetics of a low-dose combination oral contraceptive. Clin [43] Giuliano RA, Hiersemenzel R, Baltes E, et al. Influence of a new 589 547 Pharmacol Ther 1995;58:523–31. antiepileptic drug (levetiracetam, ucb L059) on the pharmacokinetics 590 548 [25] LamictalÒ [package insert]. Greenville, NC: GlaxoSmithKline; 2005. and pharmacodynamics of oral contraceptives [abstract]. Epilepsia 591 549 [26] Klosterskov Jensen P, Saano V, Haring P, et al. Possible interaction 1996;37(Suppl. 4):90. 592 550 between oxcarbazepine and an oral contraceptive. Epilepsia [44] Crawford P, Chadwick D, Cleland P, et al. The lack of effect of 593 551 1992;33:1149–52. sodium valproate on the pharmacokinetics of oral contraceptive 594 552 [27] Rosenfeld WE, Doose DR, Walker SA, et al. Effect of topiramate on steroids. Contraception 1986;33:23–9. 595 553 the pharmacokinetics of an oral contraceptive containing norethin- [45] Bartoli A, Gatti G, Cipolla G, et al. A double-blind, placebo- 596 554 drone and ethinyl estradiol in patients with epilepsy. Epilepsia controlled study on the effect of vigabatrin on in vivo parameters of 597 555 1997;38:317–23. hepatic microsomal enzyme induction and on the kinetics of steroid 598 556 [28] Anderson GD. Pharmacogenetics and enzyme induction/inhibition oral contraceptives in healthy female volunteers. Epilepsia 599 557 properties of antiepileptic drugs. Neurology 2004;63(10, Suppl. 4) 1997;38:702–7. 600 558 :S3–8. [46] Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and 601 559 [29] Sabers A, Buchholt JM, Uldall P, et al. Lamotrigine plasma levels pharmacodynamics of a combination ethinyl estradiol–norethindrone 602 560 reduced by oral contraceptives. Epilepsy Res 2001;47:151–4. oral contraceptive in healthy women. Clin Ther 2004;26:2056–65. 603 561 [30] Sabers A, Ohman I, Christensen J, et al. Oral contraceptives reduce [47] Drugs@FDA. US Food and Drug Administration. Center for Drug 604 562 lamotrigine plasma levels. Neurology 2003;61:570–1. Evaluation and Research. Rockville, MD. 605 606

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