- Medicines and Healthcare products Regulatory Agency
- 15 September 2016
- Therapeutic area:
- Obstetrics, gynaecology and fertility
Medicines or herbal remedies that induce CYP3A4 enzymes reduce blood levels of levonorgestrel, which may reduce emergency contraceptive efficacy.
Updated advice for healthcare professionals:
- women seeking emergency contraception who have used cytochrome P450 3A4 (CYP3A4) enzyme inducers (see below) within the last 4 weeks, should:
- preferably use a non-hormonal emergency contraceptive—ie, a copper intrauterine device
- if this is not an option, double the usual dose of levonorgestrel from 1.5 milligrams to 3 milligrams (ie, 2 packs)
- for these women:
- provide advice on highly effective ongoing contraception that is not affected by hepatic enzyme-inducing drugs (see guidance from the Faculty of Sexual and Reproductive Health)
- advise them to have a pregnancy test to exclude pregnancy after use of levonorgestrel-containing emergency contraception
- advise them to seek prompt medical advice if they do become pregnant
This updated advice is in line with existing guidance from UK experts in sexual and reproductive health, and applies to both prescription and non-prescription supply which will help ensure that women receive consistent advice.
Product information for healthcare professionals and women and the outer packaging for levonorgestrel emergency contraception are being updated with this advice.
Levonorgestrel emergency contraception
Indication and posology
Levonorgestrel-containing emergency contraception is used to prevent unintended pregnancy when taken within 72 hours (3 days) of unprotected intercourse or failure of a contraceptive method. The sooner it is taken after having unprotected sex, the more effective it will be.
Levonorgestrel-containing emergency contraception is available with or without a prescription as a single 1500 microgram tablet, or on prescription as two 750 microgram tablets taken as a single dose.
Effect of hepatic enzyme inducers on levonorgestrel metabolism
Concomitant use of liver enzyme inducers—mainly inducers of CYP3A4 enzymes—increases the metabolism of levonorgestrel.
Concomitant administration of the antiretroviral efavirenz (used to treat HIV) reduces plasma levels (AUC) of levonorgestrel by around 50%1. Data are not available for all CYP3A4 enzyme inducers; however, studies of levonorgestrel-containing combined hormonal contraceptives show that other hepatic enzyme-inducing medicines or herbal medicines may produce similar reductions in plasma levels. These contraceptive products already contain advice on additional or alternative methods of contraception.
Elevated levels of CYP3A4 enzymes can persist for up to 4 weeks after cessation of the enzyme-inducing medicine.
This decrease in plasma levonorgestrel may reduce contraceptive efficacy of levonorgestrel-containing emergency hormonal contraceptives.
Examples of enzyme inducers that reduce plasma levonorgestrel levels
Some medicines used to treat:
- epilepsy (eg, barbiturates, primidone, phenytoin, carbamazepine)
- tuberculosis (eg, rifampicin, rifabutin)
- HIV (eg, ritonavir, efavirenz)
- fungal infections (eg, griseofulvin)
Herbal remedies that contain St John’s wort (Hypericum perforatum) also reduce levonorgestrel levels.
See the British National Formulary for further examples of relevant interactions. The University of Liverpool HIV Drug Interaction Checker also provides useful drug interaction charts.
Levonorgestrel dose as emergency contraception in current or recent users of hepatic enzyme inducers
For women unable or unwilling to use a copper intrauterine device, a woman seeking emergency contraception who has used a hepatic enzyme inducer in the past 4 weeks, should double the usual dose of levonorgestrel (from 1.5 milligrams to 3 milligrams, 2 packs) to compensate for the reduced plasma levonorgestrel levels. Other instructions for use are the same as for the usual dose.
No increased risk of side effects is expected from the higher dose in these circumstances. Users and healthcare professionals are reminded to report any suspected side effects occurring with levonorgestrel, including any thought to be associated with a double dose of emergency contraception, on a Yellow Card.
Enzyme-inducing medicines: exposure during pregnancy
Exposure during pregnancy to some of the enzyme-inducing medicines listed above has been associated with an increased risk of birth defects (see the summary of product characteristics for the specific medicine for more information). It is therefore important to provide advice on highly effective forms of regular contraception for women who take these medicines, and to exclude pregnancy after use of levonorgestrel-containing emergency contraception.
Information sheet for women
The key elements of this advice are included in an information sheet for women, which you may find useful when advising them.
Copper intrauterine devices
These devices are effective as non-hormonal emergency contraception as well as providing reliable long-term contraception and are not affected by enzyme-inducing medicines. A copper intrauterine device may be fitted up to 5 days after unprotected intercourse and, if available, may be an appropriate method of emergency contraception for some women.
Names of levonorgestrel-containing emergency contraception
- Levonelle One Step 1500 microgram tablet
- Levonelle-2 750 microgram tablet (ie, for a double dose this is 4 tablets, 2 packs)
- Levonelle 1500 microgram tablet
- Levonorgestrel 1.5 mg tablet(s)
- Boots Emergency Contraceptive 1.5 mg tablet
- Emerres Una 1.5 mg tablet
- Emerres 1.5 mg tablet
- Ezinelle 1.5 mg tablet
- Isteranda 1.5 mg tablets
- Melkine 1.5 mg tablet
- Toomee 1.5 mg tablets
- Upostelle 1500 microgram tablets
- Emergency Contraceptive Consilient 1500 microgram tablet
Ulipristal acetate emergency contraception (EllaOne) is not recommended in women who are using enzyme-inducing drugs or who have stopped them in the last 4 weeks.
European Medicines Agency statement, May 2016
Faculty of Sexual and Reproductive Health guidance on drug interactions with hormonal contraceptives: advice on highly effective methods of contraception not affected by enzyme inducers
Faculty of Sexual and Reproductive Health guidance on emergency contraception
Article citation: Drug Safety Update Volume 10 Issue 2, September 2016: 1.
Carten ML et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz. Infect Dis Obstet Gynecol 2012; article ID: 137192. ↩
Published: 15 September 2016
Therapeutic area: Obstetrics, gynaecology and fertility