Pharmacokinetic Interactions Between Contraceptives and Antiepileptic Drugs

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provided by Elsevier - Publisher Connector Seizure (2008) 17, 141—144

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Pharmacokinetic interactions between contraceptives and antiepileptic drugs

Anne Sabers *

The Epilepsy Clinic, Department of Neurology, Glostrup University Hospital, Denmark

KEYWORDS Summary The occurrence of bi-directional drug interactions between antiepileptic Oral contraceptives; drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un- Epilepsy; intended pregnancy and as well as seizure deterioration. Pharmacokinetics; It is well established that several of the older AEDs (carbamazepine, phenytoin and Drug interactions phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate inﬂuence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug—drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be inﬂuenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible. # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction tions of possible drugs interactions. The main consequences of these interactions are risks of un- Combined oral contraceptive steroids (OCs) are pre- intended pregnancy or seizure deterioration. A con- scribed for 17% of fertile women with epilepsy, traceptive failure may be disastrous for all women which is almost as frequent as for the background but is of speciﬁc clinical concern for women treated population (25%).1 Co-administration of OCs and with AEDs because of the teratogenetic potential of antiepileptic drugs (AEDs) is therefore a common the drugs. On the other end of the clinical spectrum clinical situation which calls for speciﬁc considera- may recurrence of even a single seizure in a seizure- free woman have detrimental psycho-social consequences. * Correspondence address: The Epilepsy Clinic, Department of A surprising number of physicians do not have Neurology, Glostrup University Hospital, DK-2600 Glostrup, Denmark. Tel.: +45 43233029; fax: +45 43233064. adequate knowledge about potential interactions 1 E-mail addresses: [email protected], [email protected]. between their AEDs and the OCs and approximately

50% of women with epilepsy taking OC indicate that tiagabine,13 vigabatrin14 or zonisamide15 influence they have never been given information about this the metabolism of OC and can be administrated specific issue.2 A recent survey, however, has shown without risk of contraceptive failure. One study that women with epilepsy of childbearing age do not has demonstrated a modest and probably not clin- always recall being given information on contracep- ical relevant decrease of the levonorgestrel com- tion and pre-pregnant planning, which highlights pound of the OCs during lamotrigine but no change the need for regular repetitions.3 in the pharmacokinetic parameters of ethinylestra- The objective of this paper was to review the diol.16 This is in agreement with the former study by literature of the bi-directional interaction poten- Holdich et al.17 who found no effect of lamotrigine tials between AEDs and OCs and to discuss the gaps on the elimination of OCs. Similarly, it has been of current knowledge in a future perspective. demonstrated that felbamate caused a 42% decrease in gestogene AUC(0—24) but had no effect on the metabolism of ethinylestradiol.5 These stu- The effect of AEDs on the dies by Sidhu et al.16 and Saano et al.5 however, pharmacokinetics of combined OCs were performed with a moderate dose of reproduc- tive hormones, namely 35 mg ethinylestradiol and A drug interaction potential between AEDs and OCs 150 ug levonorgestrel, and 75 mg gestogene, respec- was suggested for the first time in the beginning of tively. In women who use low-dose OCs <30 mg and the 1970s about 10 years after the introduction of <75 mg progesterone, ovulation might not be sup- the combined OC. A higher incidence of break- pressed. Midcycle bleeding should therefore always through bleeding and contraceptive failure among alert the physician and the patient of the risk of women with epilepsy was observed and correlated contraceptive failure. with the time when the ethinylestradiol fraction of OCs was decreased from 50—100 to <50 mg to dimin- ish the risk of thrombo-embolic side effects. The The effect of combined OCs on the contraceptive failure, therefore, was regarded as pharmacokinetics of AED´s mainly dependent on the concentration of the estrogen fraction of the OC. OCs can increase the metabolism of glucuronidated Modern available combined OC preparations con- drugs by induction of the uridine diphosphate glu- tain 20—35 mg of ethinylestradiol and less than 1 mg curonosyltransferase system. This has been most of progestogen. The major part of the estrogen com- intensively studied for lamotrigine which is hepati- pound is hydroxylated to inactive metabolites by the cally metabolized primarily by glucuronic acid con- hepatic cytochrome P450 (CYP) 3A4 or directly conjugation. Several studies have demonstrated that jugated. AEDs that induce the CYP 3A4 isoenzyme lamotrigine is significantly and substantially (>50%) (carbamazepine,4 felbamate,5 oxcarbazepine,6 phe- increased by combined OCs16,19—21 and that this nobarbital,7 phenytoin4 and topiramate)8 may there- interaction is associated with increased seizure fre- fore accelerate the hepatic elimination of OCs. A quency in most of the cases.22 recent study of topiramate with an OC containing The contraceptive-induced pharmacokinetic 35 mg ethinyl estradiol demonstrated that topira- alteration shows a considerable inter-individual mate monotherapy in dose <200 mg did not signifi- variability based on probably both genetic factors cantly affect the clinical efficacy of OCs.9 and co-administration with other AEDs. This can be The consequences of the drug interaction are a risk exemplified by the results in a recent study that of contraceptive failure and un-intended pregnancy. revealed that the OC induction of lamotrigine elim- Women who are prescribed drugs with a enzyme ination was almost eliminated when co-admini- inducing potential, have therefore been advised to strated with valproate.23 use high-dose OCs with a dose of the estrogen com- The change in lamotrigine metabolism has pound of at least 50 mg (low-dose topiramate mono- been attributed to the estrogen rather than the therapy 35 mg) and should be advised to use progestin component of the OC19 andismostlikely additional barrier methods of contraception, espe- caused by increased drug glucuronidation.21 The cially in case of intramenstrual bleeding. lack of estrogens affects the pharmacokinetic The extent of enzyme induction is correlated to acutely and the plasma level of lamotrigine the dose of the drug but is difficult to quantify as increase in a fairly rapid and linear manner already also genetic and environmental factors influence within the ‘‘pill-free’’ week.16,21,24 The clinical the hepatic isoenzyme expression.10 consequences are not fully explored but because Data available today suggest that neither of the of the rapid and significant increase of the plasma other newer AEDs; gabapentin,11 levetiracetam,12 levels the authors suggest that the up-titration of Pharmacokinetic interactions between contraceptives & AEDs 143 lamotrigine dose should not occur in the ‘‘pill-free Intrauterine contraceptives may be an optimal week’’ in order to avoid potential titration related contraceptive choice for women treated with tolerability problems. In addition, standardization of enzyme inducing AEDs. The levonorgestrel-releasing blood sampling in relation to the OC cycles is advi- system delivers a local amount of hormone locally in sable for lamotrigine therapeutic monitoring. Perso- the uterus and systemic drug interaction potential is nal clinical experience shows that overdose low. However, one small study demonstrated that symptoms, in particular dizziness, may occur in single the contraceptive failure of this intrauterine device patients during the pill-free week on high-dose lamo- in 1.1% of women treated with AEDs compared to trigine (plasma concentrations >40 mmol/l) and that 0.2% in controls.29 Copper intrauterine devices have a dose reduction of about 25% in the OC free week can a local spermicidal effect which is not regarded to be successful. be affected by concomitant drugs. Recent results suggest that also other AEDs, eliminated fully or partly by glucuronidation, may have a similar interaction with combined OCs. Based Perspectives on a single case Herzog et al. (2005) reported that plasma concentrations of valproate fluctuated Although the potential of drug interactions between 25 widely during the OCs cycle. A subsequent paper OCs and AEDs have been recognized for many years, demonstrated that the plasma clearance of total there are still major gaps in the current knowledge valproate increased with a mean of 21.5% during OC and further explorations are needed. First of all, intake period and of 45.2% for the unbound valpro- high-dose estrogen OCs may increase the risk of 26 ate fraction. The OC effect on valproate clearance thrombo-embolic diseases and well as breast cancer. varied markedly across the subjects and may be of The extent of enzyme induction may be correlated significant clinical relevance in some patients. Also to the dose of the AEDs but it is difficult to quantify, the pharmacologically active monohydroxy derivate as genetic and environmental factors also affect of oxcarbazepine is mainly eliminated by glucuro- hepatic isoenzyme expression. Therefore, a quanti- nidation. The clinical relevance of this potential fication of the enzyme induction, based on indivi- effect of OC also needs to be further explored. dual AEDs, dosages, genotypes for relevant drug In most studies, OCs affection on AEDs elimina- metabolizing enzymes and types of co-medication, tion rate shows a great inter-individual variability. should be explored to avoid unnecessary high estro- The variability is probably multifactorial and gen exposure. However,concerning the safety of the reflects differences in dosages of the AEDs, the OCs it has always been a mantra to focus on the fraction cleared by conjugation, functional poly- estrogen compound, as discussed further in this morphisms of glucuronosyltransferases and OC doses issue it might be more relevant to ensure safe and formulations. As the level of altered elimination contraception by adequate doses of the progestin induced by OCs is unpredictable for the individual compounds. This also stresses the importance of patient, it is recommended that the plasma level of further explorations of the contraceptive safety all glucuronidated AEDs is carefully monitored and and possible interactions between AEDs and proges- doses adjusted before and after introduction or terone-only pills, injections and patches and discontinuation of OCs. implants. Data available today suggest that the newer generation of AEDs are less likely to interact with OCs, but the enzyme inducing potential of all Other contraceptives than OCs the newer AEDs have not be fully explored. Similarly there is an ongoing need to study the effects of OCs Data on possible interactions between AEDs and pro- the elimination of AEDs and/or their active meta- gesterone-only pill’s, — injections and — implants are bolites. This should especially be relevant for drugs very sparse. where the elimination involves glucuronidation pro- One study demonstrated that the subdermal levo- cesses but also other elimination pathways may norgestrel implants have a high failure risk in women affected. receiving phenytoin.27 These contraceptives are therefore generally regarded as less reliable and should not be prescribed in women who are treated Conclusion with enzyme-inducing drugs. The effect of intramuscular injection of 150 mg Treating women with epilepsy of fertile age includes medroxyprogesterone acetate seems to be unaf- systematic, ongoing and accurate counseling on fected by enzyme inducing AEDs but the evidence optimal choice of contraception. The widely avail- is very limited.28 able range of AEDs stresses the importance of being 144 A. Sabers familiar with the various properties of the drugs and 11. Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ. Gaba- to achieve a better understanding of the drug—drug pentin does not interact with a contraceptive regiment of norethindrone acetate and ethinyl estradiol. Neurology interactions and inter-individual variations. In case 1998;50(4):1146—8. of change in the use of OCs, drug monitoring is 12. Rangueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does recommended whenever possible. 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