National Medicines VOLUME 20 NUMBER 5 Information Centre 2014 ST. JAMES S HOSPITAL DUBLIN 8 TEL 01-4730589 or 1850-727-727 FAX 01-4730596 www.nmic.ie PHARMACOLOGICAL MANAGEMENT OF ADULTS WITH EPILEPSY (2) The challenge of prescribing anti-epileptic drugs (AEDs) in pregnancy is to balance the benefits of preventing major seizures during pregnancy while minimising adverse fetal effects The potential for drug-drug interactions should always be considered when prescribing concomitant medication to a patient on AEDs The metabolism of oestrogens and progestogens is increased by enzyme-inducing AEDs, which may result in reduced contraceptive efficacy The NMIC can provide up-to-date information on AED-related enquiries INTRODUCTION Anti-epileptic drugs (AEDs) are the mainstay of epilepsy treatment. A previous bulletin (NMIC 2014, Vol 20, No. 4) summarises the pharmacological management of epilepsy in adults. This bulletin reviews some of the frequent enquiries received by the NMIC such as the use of AEDs in pregnancy, AEDs and drug interactions, and AEDs and contraceptive use. The NMIC receives many other AED-related enquiries and is pleased to provide information on any specific enquiry that you may have. USE OF ANTI-EPILEPTIC DRUGS IN PREGNANCY Epilepsy is the most commonly encountered serious neurological problem in pregnancy, even though most women with epilepsy will have a normal pregnancy and delivery. 1,2 Women with epilepsy who are pregnant should be seen in a multi-disciplinary environment which includes a neurologist and obstetrician. 2 Maternal seizures, particularly generalised tonic-clonic, during pregnancy can cause harm to both the mother (increased mortality) and fetus (including prematurity, low birth weight and fetal death). 3-6 Many women with epilepsy who are considering becoming pregnant or who are pregnant require AEDs. 2,5 There are widespread concerns about the teratogenic risks posed by AEDs, however it is important to appreciate that 95% of pregnant women with epilepsy deliver a healthy baby, even under medical treatment. 1,2 Epilepsy treatment aims to achieve freedom from epileptic seizures, and in pregnant women this has to be attained without disadvantaging the fetus both in utero and in subsequent post-natal life. 4,5 Maternal effects of epilepsy: Up to two thirds of women with epilepsy are seizure-free during pregnancy. 3 Evidence suggests that if a woman with epilepsy remains seizure-free in the pre-pregnancy year her seizures appear to be appreciably less likely to recur during pregnancy than if her seizures were uncontrolled before pregnancy. 4 Various factors can affect seizure control in pregnancy including adherence to AEDs, alterations in pharmacokinetics of AEDs caused by pregnancy, sleep deprivation and vomiting in pregnancy. 4,7 In pregnancy, renal function and glomerular filtration rate are increased leading to increased clearance of AEDs such as gabapentin and levetiracetam. Increased clearance also occurs for drugs metabolised through cytochrome P450 isoenzymes, or through glucuronidation (eg lamotrigine). 4,8-10 Dose adjustments of AEDs may be required to reduce the risk of breakthrough seizures, 4,8-10 however routine monitoring of AED concentrations is not indicated and interpretation of AED blood levels is best done by a doctor specialising in the management of epilepsy. 1 Fetal effects of epilepsy: A high rate of birth defects occur in the offspring of women with epilepsy, 2,5 the cause of which is probably multi-factorial, but AEDs are considered one of the main reasons for the increased risk. 5,11 In view of the increased risk of neural tube defects and other major congenital malformations (MCM) associated with exposure to AEDs (particularly sodium valproate and carbamazepine), current guidelines recommend that a daily dose of 5mg folic acid is prescribed prior to conception and until at least the end of the first trimester for all women taking AEDs. 5,9,12,13 Other mechanisms may be involved in the increased risk of MCM, as there is some evidence to suggest that folic acid supplementation does not completely modify the effect of exposure to AEDs on MCMs. 13 Women with epilepsy who have had fetal abnormalities in a previous pregnancy may be at increased risk in a subsequent pregnancy. 4 Teratogenic effects of AEDs: Several AEDs, in particular sodium valproate are associated with MCM. 4,9,11,14-16 The teratogenic effects of sodium valproate, which include spina bifida, atrial septal defects, cleft palate and cognitive defects, appear to be dose-dependent and are increased when used in combination with others AEDs. 4,8,11,16-18 Evidence suggests that use of sodium valproate is also associated with an increased risk of autism. 19 The European Medicines Agency recently recommended that sodium valproate should not be prescribed for epilepsy (or bipolar disorder) in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. 20,21 They recommend that patients for whom sodium valproate is the only treatment option for epilepsy (or bipolar disorder) should be advised on the use of effective contraception and that treatment should be started and supervised by a doctor experienced in treating
these conditions. It is recommended that women and girls who have been prescribed sodium valproate should not stop taking their medicines without consulting their doctor as doing so could result in harm to themselves or to an unborn child. 21 The malformation risks associated with the newer AEDs, where there are less data available, are unclear. 12 However emerging evidence suggests that there is less risk of fetal abnormalities with AEDs such as levetiracetam and lamotrigine than with other AEDs. 4,16,22,23 Practical points: Women and girls (and carers as appropriate) with epilepsy must be given accurate information and counselling regarding conception and pregnancy, which should be tailored to the individual s specific needs. 1,4,12 Information regarding the risk of epilepsy, the use and risks of AEDs in pregnancy and the need for folic acid prior to conception and for at least up to 12 weeks gestation should be given to all women of child bearing potential and repeated at review appointments. 4,12 In particular, the teratogenic effects of sodium valproate should be discussed. 12,21 The challenge of prescribing AEDs in pregnancy is to balance the benefit of preventing major seizures during pregnancy while minimising adverse fetal effects. 5 If clinically possible, AEDs known to be associated with MCM and combinations of AEDs should be avoided during pregnancy and especially in the first trimester. 9,16 In the post-natal period, women with epilepsy should not be discouraged from breastfeeding because of epilepsy. 24 The risks and benefits of breastfeeding, while taking AEDs should be evaluated and discussed with the mother. The NMIC is happy to provide information on specific enquiries regarding the use of AEDs in breastfeeding. ANTI-EPILEPTIC DRUGS AND DRUG INTERACTIONS Drug-drug interactions (DDIs) occurring in patients with epilepsy can have substantial effects on clinical outcome and may often be predicted by the pharmacokinetic (PK) [absorption, distribution, metabolism and excretion] and pharmacodynamic (PD) profiles of the AEDs. 25,26 The potential for DDI is an important consideration in patients with epilepsy, as it is estimated that up to 20% of patients with epilepsy require AED polytherapy to control their seizures. In addition, many patients with epilepsy have co-morbid conditions which require non- AED concomitant medications. 25-28 AEDs are administered for prolonged periods, often for a life-time thereby increasing the probability of polypharmacy, and most AEDs have a narrow therapeutic index. 26 The AEDs as a therapeutic class are associated with more drug interactions than any other class of drugs. 28 The mechanism for drug interactions is reviewed in a previous NMIC bulletin (NMIC 2008, Vol 4, No. 8). 29 PD interactions are those where the effects are due to the mechanism of action of the drugs and may result in adverse or beneficial effects. 25,26,29 An example of a PD interaction involving AEDs is the neurotoxic effects which may occur when lamotrigine is used in combination with carbamazepine. 25,26 Most clinically important DDIs are pharmacokinetic and involve the alteration in metabolism (by induction or inhibition of enzymes) of the affected drugs. 25,26,28,29 During drug development, medicines are evaluated for their relationship with the major metabolic enzyme classes and this information is included in section 4.5 of the Summary of Product Characteristics of individual drugs. The cytochrome P450 family of enzymes plays a critical role in the metabolism of many drugs; four isoenzymes (CYP3A4, CYP2D6, CYP2C9 and CYP1A2) play a role in the metabolism of 95% all drugs and it is estimated that up to 70% of all drugs are substrates of CYP3A4. 25,29 Another group of metabolic enzymes, which are also susceptible to inhibition and induction are uridine glucuronyl transferases (UGTs) which catalyse glucuronidation e.g. UGT1A4 plays an important part in the glucuronidation of lamotrigine. 25 Enzyme induction results in increased metabolism of drugs which are substrates of the corresponding enzyme and a subsequent decrease in the plasma concentration of the affected drug. 25 For example, carbamazepine, which is an inducer of CYP3A4, may result in decreased plasma concentrations of CYP3A4 substrates such as ethosuximide, statins and hormonal contraceptives. If the affected drug has an active metabolite, enzyme induction can result in an increase in the metabolite concentration and a possible increase in drug toxicity. The time course of enzyme induction is generally gradual (days or weeks) and dose-dependent. 25,29 The effects of enzyme induction can persist for some time (days or weeks) after discontinuation; therefore it is also important to consider the possibility of an interaction occurring even after an enzyme-inducing drug has been discontinued. Enzyme inhibition, which occurs rapidly, results in a decrease in the rate of metabolism of the affected drug with a corresponding increase in plasma concentration and possible clinical toxicity. 25,29 For example, concomitant sodium valproate (enzyme inhibitor) results in an increase in lamotrigine concentration and concomitant erythromycin (enzyme inhibitor) results in an increase in carbamazepine concentration. 25,27 The probability of a DDI occurring and the associated clinical consequences are dependent on several factors including: (1) the nature of the interaction at the enzyme site, (2) the potency of the inhibition or induction, (3) the concentration of the inhibitor/inducer at the enzyme site, (4) the concentration of the affected drug and (5) the therapeutic index of the substrate. 23 Additional risk factors associated with the possibility of a DDI include increasing age, polypharmacy, the number of prescribing physicians, genetic pre-disposition and renal/hepatic dysfunction. 29 Most clinically important DDIs can be predicted from the nature of the relationship between each drug and the metabolic enzyme involved (inducer/inhibitor/substrate). Tables 1 and 2 show the most important metabolism/elimination routes of the AEDs, and the AED effects on metabolic enzymes. 30 Full information on potential DDIs is available in the Summary of Product Characteristics of each drug.
Table 1: Main routes of metabolism /elimination of antiepileptic drugs 25,28,30 Drug Older AEDS Most important route of metabolism/elimination (and, where relevant, substrates of the following enzymes:)* Table 2: Anti-epileptic drug effects on enzymes 25,28,30 Drug Older AEDS Carbamazepine CYP3A4 Carbamazepine Inducer Effect on metabolic enzymes: Inducer or inhibitor of enzymes* Ethosuximide CYP3A4 Ethosuximide No known effect Phenytoin CYP2C9/CYP2C19 Phenytoin Inducer Phenobarbital CYP2C9 Phenobarbital Inducer Primidone CYP2C9 Primidone Inducer Sodium valproate Several UGTs Sodium valproate Newer AEDs Newer AEDs Lamotrigine UGTs Lamotrigine No known effect Oxcarbazepine Renal Oxcarbazepine Inducer Gabapentin Renal Gabapentin No known effect Topiramate Renal Topiramate Inducer Levetiracetam Renal Levetiracetam No known effect Zonisamide CYP3A4 Zonisamide No known effect Vigabatrin Renal Vigabatrin No known effect Pregabalin Renal Pregabalin No known effect Tiagabine CYP3A4 Tiagabine No known effect Lacosamide CYP2C19 Lacosamide No known effect Eslicarbazepine UGTs Eslicarbazepine Inducer Perampanel CYP3A4 Perampanel Inducer Retigabine Arylamine N-acetyl transferase-2 Retigabine No known effect Rufinamide Carboxyles-terases Rufinamide Inducer CYP cytochrome P450, UGT - uridine glucuronosyl transferase *this list is for guidance only and is not exhaustive * the Summary of Product Characteristics for each medicine contains more detailed information on drug interactions Older AEDs and DDIs: The older AEDs carbamazepine, phenytoin, phenobarbital and primidone are potent inducers of CYP and UGT enzymes (Tables 1 and 2); their use can lead to reduced concentrations of many other drugs including: AEDs (e.g. sodium valproate, tiagabine, ethosuximide, lamotrigine, topiramate), psychotropics (e.g. amitriptyline, citalopram, risperidone, olanzapine), immunosuppressants (e.g. ciclosporin, tacrolimus), antineoplastics (e.g. cyclophosphamide, methotrexate) and cardiovascular drugs (e.g. propranolol, calcium antagonists, atorvastatin). 26,27,30 In addition there are many drugs (e.g. macrolide antibiotics) which can have an effect on the metabolism of the older AEDs. 27 Sodium valproate is an enzyme inhibitor and may result in increased plasma concentrations of lamotrigine and phenobarbital. 26 Newer AEDS and DDIs: Overall the new AEDs have less potential for DDI than the older AEDs, however they are not all free from DDIs (Tables 1 and 2). 25,30 Many of the new AEDs are cleared fully or partly by inducible enzymes and are a target for interactions mediated by enzyme induction (Table 1). 26 Overall, levetiracetam, gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide are associated with less pharmacokinetic reactions than lamotrigine, oxcarbazepine, topiramate and rufinamide. 29,31 It is also possible that interactions affecting new AEDS are under-recognised due to limited clinical experience with their use. 26 Practical points: If clinically possible, the risk of DDIs should be reduced by avoiding polypharmacy and by selecting medications which are less likely to interact. 26 Section 4.5 of the Summary of Product Characteristics contains useful information on the potential for drug interactions of each individual drug. ANTI-EPILEPTIC DRUGS AND CONTRACEPTION It is essential that women with epilepsy receive accurate information regarding contraception. 12 Drug interactions between AEDs and contraceptive hormones are clinically important and need to be considered due to risks including: (1) contraceptive failure, (2) potential teratogenicity of AEDs or (3) reduced seizure control. 32 The possibility of AEDs interacting with contraceptives should be discussed with each patient and
an assessment made as to the risks and benefits of individual contraceptive methods. 12,33 The UK Faculty of Sexual and Reproductive Healthcare (FSRH) is a useful resource for healthcare professionals, and provides guidance documents on contraceptive issues including AEDs and contraception; it provides a medical eligibility criteria (MEC) for the use of contraceptives in patients with medical conditions. Effect of AEDs on hormonal contraception: The metabolism of oestrogens and progestogens are increased by enzyme-inducing AEDs, which may result in reduced contraceptive efficacy of combined hormonal contraceptives [CHC] (e.g. oral, patch and ring), progestogen only pill [POP] and the progestogen-only implant. 32 AEDs which are considered enzyme inducers include carbamazepine, phenytoin, oxcarbazepine, phenobarbital and eslicarbazepine. 32,33 Evidence suggests that topiramate and perampanel are less potent inducers and may interact with CHC in a dose-dependent manner. 32-36 AEDs including sodium valproate, levetiracetam, vigabatrin, pregabalin, zonisamide, tiagabine, lacosamide, lamotrigine and gabapentin do not have a significant effect on the metabolism of oral contraceptives. 32,33 The efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) and depot medroxyprogesterone acetate (DMPA) are not affected by enzyme-inducing AEDs. All women starting enzyme-inducing AEDs should be advised to use a reliable contraceptive method unaffected by enzyme inducers (e.g. LNG-IUS, progestogen only injectable, copper IUD). 32,37 The use of enzyme-inducing AEDs and sodium valproate are associated with reduced bone mineral density (BMD). 9,38 DMPA is also associated with loss of BMD which is reversible on stopping DMPA. 32 Women should be informed about the potential effect of both drugs on BMD and offered strategies to help protect against BMD loss such as diet and exercise. The patient should be assessed for other osteoporosis risk factors and a decision to use DMPA taken on an individual basis, weighing up the potential risks of DMPA use against the risk of pregnancy. 32 The efficacy of the emergency contraceptives levonorgestrel and ulipristal acetate may be affected by enzyme-inducing AEDs, 32 therefore patients on enzyme-inducing AEDs who have unprotected sexual intercourse (UPSI) should be advised of the potential for interaction with the oral methods and offered a copper IUD. 32 If this is not possible, they should be advised to take a total of 3 mg levonorgestrel as soon as possible after the UPSI (note: this recommendation is based on limited clinical data and is unlicensed). 32 Ulipristal acetate is not recommended in women using enzyme-inducing AEDs who have UPSI. 32 Effect of contraceptives on AEDs: The plasma concentrations of some AEDs may be affected by concomitant contraceptives. 37 Ethinyl estradiol is thought to induce lamotrigine glucuronidation, which results in reduced lamotrigine levels. 32,33,37 There have been reports of increased seizures in women on lamotrigine with concomitant CHC and also reports of lamotrigine side-effects, due to increased levels of lamotrigine, during the pill free interval and on discontinuation of CHC. When combined with sodium valproate, which inhibits lamotrigine glucuronidation, lamotrigine levels are not reduced by CHC. 37 Due to the risk of drug interactions the use of lamotrigine monotherapy with CHC is considered a situation where the risks generally outweigh the benefits and an alternative method of contraception is recommended. 32,37 There is some evidence to suggest that sodium valproate levels may be affected by hormonal contraception however the clinical significance of this is unknown. 32,37 Evidence suggests that progestogen-only methods of contraception are not affected by lamotrigine, although one small study found increased levels of lamotrigine with the desogestrel-only pill. 32,38 Healthcare professionals should be aware of this possible effect and should monitor patients for lamotrigine side effects when starting the POP. 37 USEFUL RESOURCES FOR EPILEPSY National Clinical Programme for Epilepsy Ireland www.hse.ie/eng/about/who/clinical/ natclinprog/epilepsyprogramme Access to Summary of Product Characteristics for all medicines www.medicines.ie / www.hpra.ie British National Formulary (BNF) Appendix 1 (interactions) The UK Faculty of Sexual and Reproduction Healthcare www.fsrh.org Epilepsy Ireland www.epilepsy.ie/index.cfm/spkey/home.html National Medicines Information Centre www.nmic.ie FOR PERSONAL USE ONLY. NOT TO BE REPRODUCED WITHOUT PERMISSION OF THE EDITOR List of references available on request. Date of preparation: November 2014 Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue. Prescribers are recommended to refer to the individual Summary of Product Characteristics (SmPC) for specific information on a drug.
References for NMIC Bulletin on Epilepsy No. 2 1. SIGN Diagnosis and management of epilepsy in adults April 2003 2. Ahmed R et al, Epilepsy in pregnancy, Australian Family Physician, 2014;43(3):112-116 3. EURAP study, Seizure control and treatment in pregnancy, Neurology 2006;66:354-360 4. Eadie M, Treating epilepsy in pregnant women, Expert Opin Pharmacother 2014;15(6):841-850 5. Tomson T, Battino D, Teratogenic effects of antiepileptic drugs, Lancet Neurol 2012;11:803-13 6. Rauchenzauner M et al, Generalised tonic-clonic seizures and antiepileptic drugs during pregnancy - a matter of importance for the baby?, J Neurol 2013;260:484-488 7. Tomson T, Hiilesmaa V, Epilepsy in pregnancy, BMJ 2007;335:769-73 8. Perucca E, Tomson T, the pharmacological treatment of epilepsy in adults, the Lancet 2011;10:446-56 9. Schmidt D, Schachter S, Drug Treatment in Epilepsy in adults, BMJ 2014;348:g2546 10. Tomson T et al, Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications, Epilepsia 2013;54(3):405-414 11. Artama M et al, Antiepileptic drug use of women with epilepsy and congenital malformations in offspring, Neurology 2005;64:1874-1878 12. NICE clinical guideline January 2012 13. Morrow JI et al, Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK epilepsy and Pregnancy register, J Neurol Neurosurg Psychiatry 2009;80(5):506-11 14. French J, Gazzola D, New generation antiepileptic drugs: what do they offer in terms of improved tolerability? Therapeutic advances in drug safety 2011;2(4): 141-158 15. Campbell E et al, Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers, J Neurol Neurosurg Psychiatry 2014;85:1029-34 16. Harden C et al, Management issues for women with epilepsy focus on pregnancy (an evidence based review): II. Teratogenesis and perinatal outcomes, Epilepsia 2009;50(5):1237-1246 17. Vajda F et al, The teratogenic risk of antiepileptic drug polytherapy, Epilepsia 2012;51(5):805-810 18. Meador KJ et al, Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, NEJM 2009;360(16):1597-605 19. Christensen Jakob et al, Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism, JAMA 2013;309(16) 20. Pharmacovigilance Risk Assessment Committee (PRAC) statement PRAC recommends strengthening the restrictions on the use of valproate in women and girls, October 2014, http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news _detail_002184.jsp&mid=wc0b01ac058004d5c1 21. European Medicines Agency CMDh agrees to strengthen warnings on the use of valproate medicines in women and girls 21 st November 2014, http://www.ema.europa.eu/docs/en_gb/document_library/press_release/2014/11/wc50017 7638.pdf 22. Hernandez-Diaz S et al, comparative safety of antiepileptic drugs during pregnancy, Neurology 2012;78:1692-1699 23. Shallcross R et al, in utero exposure to levetiracetam vs valproate, Neurology 2014;82:213-221 24. Patsalos P, Perucca E, clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs, Lancet Neurology 2003;2:347-56 25. Perucca E, Clinically relevant drug interactions with antiepileptic drugs, British Journal of Clinical Pharmacology 2005;61(3):246-255
26. Patsalos P, Perucca E, clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs, Lancet Neurology 2003;2:473-81 27. Patsalos P, Drug Interactions with the newer antiepileptic drugs (AEDs) Part 1: pharmacokinetic and pharmacodynamics interactions between AEDs, Clin Pharmacokinet 2013;52(927-966) 28. NMIC bulletin, Drug Interactions I; how they occur, NMIC 2008;14(4) 29. Italiano D, Spina E, de Leon J, Pharmacokinetic and pharmacodynamics interactions between antiepileptics and antidepressants, Expert Opin Drug Metab Toxicol 2014;10(11):1457-1489 30. Patsalos P, Drug Interactions with the newer antiepileptic drugs (AEDs) Part 2: pharmacokinetic and pharmacodynamics interactions between AEDs and drugs used to treat non-epilepsy disorders, Clin Pharmacokinet 2013;52(927-966) 31. Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit, Antiepileptic drugs and contraception, CEU Statement January 2012, downloaded from www. On the 23 rd October 2014 32. Johnston C, Crawford P, Anti-epileptic drugs and hormonal treatments, Curr Treat Options Neurol 2014;16:288 33. John Guillebaud and Anne MacGregor book, Contraception, your questions answered, 6 th Edition 2013 34. Stockley drug interaction topiramate and oestrogen www.medicniescomplete.com 35. Stockley drug interactions perampanel and oestrogen, www.medicinescomplete.com 36. Faculty of Sexual and Reproductive Healthcare Clinical Effective Unit, Drug Interactions with hormonal contraception, January 2011 (January 2012), downloaded from www. On the 23 rd October 2014 37. Reimers A, New antiepileptic drugs and women, Seizure 2014;23:585-591 38. Miziak B et al, The problem of osteoporosis in epileptic patients taking antiepileptic drugs, Expert Opin. Drug Safety 2014;13(7):935-946