Medicines Q&As
Q&A 43.5
What is a suitable combined oral contraceptive pill in a patient who
is taking hepatic enzyme-inducing drugs, such as carbamazepine or
phenytoin?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Published: September 2012
Background
Combined oral contraceptives (COCs) have a higher failure rate when women are taking hepatic
enzyme-inducing drugs, such as antiepileptic drugs (AEDs). Hepatic cytochrome P450 enzymes,
mainly CYP3A4, are involved in COC metabolism in the liver; as much as 60% of an oral dose
undergoes ‘first pass metabolism’ in the liver, so only about 40% of the dose is bioavailable (1). AEDs
such as carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone, can be strong
inducers of CYP3A4 or they can be less potent inducers, such as topiramate (2;3). The resulting
enzyme induction caused by the AED increases the metabolism of the COC, resulting in a potentially
reduced clinical effect. The size of any effect on contraceptive efficacy depends upon the dose of the
hormone and the route of administration (2). Most of the commonly used COCs in the UK contain 30
micrograms of oestrogenic compounds and are likely to be ineffective in women taking hepatic enzymeinducing AEDs.(4)
Answer
It is recommended that if a woman taking a hepatic enzyme-inducing AED long-term chooses to use a
COC, a daily dose of at least 50 micrograms of oestrogen (usually ethinylestradiol (EE)) is used (2;3).
The additional use of condoms can be considered (2), but if a higher dose of EE is used, along with
tricycling and a shortened pill-free interval (see later), the most recent guidance states that additional
condom use is not essential (1). The FSRH suggest that an alternative contraceptive method, such as
depot medroxyprogesterone acetate, which is not affected by enzyme-inducing AEDs, could be used
instead of a COC (2).
Choice of therapy
There are no suitable 50 microgram preparations available in the UK. Norinyl-1 contains 50
micrograms of the EE prodrug mestranol (4). The metabolic conversion of mestranol to EE is only
about 75%, less than 40 micrograms of oestrogen is produced; which is less than the 50 microgram
recommended minimum (5;6).
Although unlicensed, a combination of lower dose pills that contain the same progestogen could be
used to obtain the required minimum of 50 micrograms of oestrogen, i.e. a 30 microgram COC plus a
20 microgram COC, or two 30 microgram COCs (1;7). The additional hormones that are taken are
metabolised to a greater extent by the liver, leaving the same amount in the body as other COC takers
would receive from one COC (7). The following combinations of monophasic COCs (4) will provide a
daily dose of 50 micrograms of ethinylestradiol:
50mcg ethinylestradiol (20mcg + 30mcg)
Progestogen
60mcg ethinylestradiol (2x30mcg)
 Loestrin 20® & Loestrin 30®
Norethisterone
 Mercilon® & Marvelon®
 Gedarel® 20/150 & Gedarel® 30/150
Desogesterol
 Femodette® & Femodene®
 Millinette®20/75 & Millinette® 30/75
 Sunya 20/75® & Katya 30/75®
Gestodene
Two tablets of one of the following
 Loestrin 30® or
 Microgynon 30® or
 Marvelone® or
 Femodene® or
 Katya 30/75®
Or two tablets of their generic equivalents.
Note that this list is not exhaustive and that the latest edition of the BNF should be consulted for currently available COCs.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
Tricycling and pill-free interval
The usual 7 day pill-free interval between packets also weakens the contraceptive effect therefore in
addition to increasing the daily dose of oestrogen, 3 or 4 cycles of monophasic tablets should be taken
without a break (“tricycling” or extended regimen) followed by a short pill-free interval (PFI) of 4 days
(1;3;4;7).
Breakthrough bleeding
Breakthrough bleeding can be an indicator of low serum hormone concentrations (1;3) . If breakthrough
bleeding occurs, it usually settles during the first two or three months cycles, if not efficacy cannot be
guaranteed and the daily dose of oestrogen may need to be increased (5). The maximum dose of
ethinylestradiol that should be used is uncertain. Guillebaud recommends a dose of 80 - 90
micrograms daily, the FSRH suggest a maximum of 70 micrograms daily and NICE guidance states it
can be increased to 75 or 100 micrograms per day (1;3;6). The dose should not be increased if
breakthrough bleeding occurs during the first month, as it may subside. If breakthrough bleeding
occurs during the third month, it may help to change to a two-cycle regimen (or two-pack regimen)
followed by a shortened pill free interval of four days (5).
Additional contraceptive methods
As already mentioned, the additional use of condoms can be considered (2), but if a higher dose of EE
is used, along with tricycling and a shortened pill-free interval, the most recent guidance states that
additional condom use is not essential (1).
Stopping the enzyme inducing drug
If an enzyme inducing drug is stopped, it can take up to 4 weeks for the liver enzymes to return to
normal functionality (1;4). Therefore higher doses of the COC, with or without additional contraceptive
protection, should be continued for 4 weeks after stopping the AED. The pill-free interval should be
omitted when switching back to a standard or low-dose COC (6).
Tricycling and dose doubling of COCs as described above are unlicensed uses. The manufacturer of
the chosen contraceptives will not accept liability if a problem should occur. It is important that the
patient is aware that the combination of two COCs, along with a shortened pill free interval, is
unlicensed and there is uncertainty about the effectiveness of this regimen (4).
Summary
Suitable oral contraception for a patient taking an enzyme-inducing drug such as carbamazepine or
phenytoin, is a combination of two COCs that contain the same progestogen and give a combined total
of at least 50 micrograms of ethinylestradiol. The tricycling regimen is recommended, taking three
cycles without a pill-free interval, then a shorter four-day pill-free break. The use of a COC in this way
is unlicensed. Some sources suggest using additional non hormonal methods. The preferred method
of contraception would be an IUD or injectable such as depot medroxyprogesterone acetate (DMPA).
Drugs which induce hepatic enzymes are unlikely to affect the pharmacokinetics of DMPA (2).
Limitations



The interaction between COCs and AEDs such as carbamazepine and phenytoin is widely
documented but published data are lacking to support the use of a higher dose COC.
Risk factors for the use of COCs must be taken into account for each patient before prescribing.
Note that this Q&A is focused on patients taking enzyme-inducing anti-epileptic drugs such as
carbamazepine or phenytoin. Though the answer may be suitable for patients taking other enzyme
inducing medication, this fact must be taken into account. Rifampicin and rifabutin are more potent
enzyme inducers than AEDs and women using these drugs long-term are advised to switch to a
method unaffected by enzyme-inducing drugs (1).
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
References
(1) Drug Interactions with hormonal contraception. January 2011 (updated January 2012). Faculty
of Sexual & Reproductive Healthcare, Clinical Effectiveness Unit.
http://www.fsrh.org/pdfs/CEUGuidanceDrugInteractionsHormonal.pdf
(2) CEU Statement (January 2010): Antiepileptic drugs and contraception. Faculty of Sexual &
Reproductive Healthcare, Clinical Effectiveness Unit
http://www.fsrh.org/pdfs/CEUStatementADC0110.pdf
(3) The epilepsies (CG 137). The diagnosis and management of the epilepsies in adults and
children in primary and secondary care. Phamacological update of Clincal Guideline 20.
January 2012. National Clinical Guidelines Centre for NICE http://www.nice.org.uk/
(4) British National Formulary 63rd edition. March 2012. Ryan, RSM. editor. British Medical
Association and Royal Pharmaceutical Society of Great Britain. http://www.bnf.org/bnf/
(5) O'Brien MD, Guillebaud J. Contraception for women with epilepsy. Epilepsia 2006; 47(9):14191422.
(6) Guillebaud J. Combined hormonal contraception. Contraception today. Sixth edition. London:
Informa UK Ltd, 2007: 11-67.
(7) Guillebaud J. Chapter 14: What else can make the pill less effective? The pill: the facts. Oxford:
Oxford University Press, 2009: 109-115.
Quality Assurance
Prepared by
Alexandra Denby, London Medicines Information Service.
Date Prepared
September 2012
Checked by
Varinder Rai, London Medicines Information Service
Date of check
September 2012
Search strategy
 Embase (1996-) (HORMONAL CONTRACEPTION/ OR ORAL CONTRACEPTION/) AND
ANTICONVULSIVE AGENT/drug interaction) [Limit to: Publication Year 2010-Current and Human
and English Language]
 Embase (1996-) (HORMONAL CONTRACEPTION/ OR ORAL CONTRACEPTION/) AND
PHENYTOIN OR CARBAMAZEPINE) [Limit to: Publication Year 2010-Current and Human and
English Language]
 Medline (1996-) (PHENYTOIN OR CARBAMAZEPINE.) AND (exp CONTRACEPTIVES, ORAL,
COMBINED/ OR exp CONTRACEPTIVES, ORAL, SYNTHETIC/)
 The Faculty of Sexual and Reproductive Health (Formally the Faculty of Family Planning and
Reproductive Health Care), date accessed 11/09/2012.
From the NHS Evidence website www.evidence.nhs.uk
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