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

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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 enzyme-inducing 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 combinationsof 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 / 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.
  • Mercilon® Marvelon®
  • Gedarel® 20/150 Gedarel® 30/150
/ Desogesterol
  • Femodette® Femodene®
  • Millinette®20/75 Millinette® 30/75
  • Sunya 20/75® Katya 30/75®
/ Gestodene
Note that this list is not exhaustive and that the latest edition of the BNF should be consulted for currently available COCs.

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 4cycles of monophasictabletsshould 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 dailyandNICE 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 occursduring the first month, as it may subside. If breakthrough bleeding occurs during the third month, it may help to change to a two-cycleregimen(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).

References

(1) Drug Interactions with hormonal contraception. January 2011 (updated January 2012). Faculty of Sexual & Reproductive Healthcare, Clinical Effectiveness Unit.

(2) CEU Statement (January 2010): Antiepileptic drugs and contraception. Faculty of Sexual & Reproductive Healthcare, Clinical Effectiveness Unit

(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

(4) British National Formulary 63rd edition. March 2012. Ryan, RSM. editor. British Medical Association and Royal Pharmaceutical Society of Great Britain.

(5) O'Brien MD, Guillebaud J. Contraception for women with epilepsy. Epilepsia 2006; 47(9):1419-1422.

(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/) ANDANTICONVULSIVE 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.

1

From the NHS Evidence website