Download Vol 20 No 5 2014 (PDF 659Kb)

National Medicines
Information Centre
VOLUME 20
NUMBER 5
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 nonAED 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 drugs25,28,30
Table 2: Anti-epileptic drug effects on
enzymes25,28,30
Drug
Drug
Most important route of
metabolism/elimination
(and, where relevant, substrates
of the following enzymes:)*
Older AEDS
Effect on metabolic
enzymes:
Inducer or inhibitor of
enzymes*
Older AEDS
Carbamazepine
CYP3A4
Carbamazepine
Inducer
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
Inhibitor
Newer AEDs
Newer AEDs
Lamotrigine
UGTs
Lamotrigine
No known effect
Oxcarbazepine
Renal
Oxcarbazepine
Inducer
Inhibitor
Gabapentin
Renal
Gabapentin
No known effect
Topiramate
Renal
Topiramate
Inducer
Inhibitor
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
Inhibitor
Perampanel
CYP3A4
Perampanel
Inducer
Inhibitor
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
SIGN – Diagnosis and management of epilepsy in adults April 2003
Ahmed R et al, Epilepsy in pregnancy, Australian Family Physician, 2014;43(3):112-116
EURAP study, Seizure control and treatment in pregnancy, Neurology 2006;66:354-360
Eadie M, Treating epilepsy in pregnant women, Expert Opin Pharmacother 2014;15(6):841850
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 21st 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;82:213221
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
1.
2.
3.
4.
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 23rd
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, 6th
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
23rd 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