There are several classes/types of drugs that interact with hormonal contraception, which can increase or reduce the effectiveness of the contraception. Often, there are no studies that directly inform how a drug may be affected by exposure to hormonal contraception. Information is usually extrapolated from studies of interactions between other drugs, which are then applied to hormonal contraception. Sometimes, individual case studies are also used. Faculty of Sexual and Reproductive Health (FSRH) guidance (2022) errs on the side of caution where there is potential to reduce the effectiveness of a hormonal contraception, and this is even more important when a teratogenic drug is in use.
The types of drug interactions that affect hormonal contraception are related to the induction or inhibition of hepatic cytochrome P450 enzymes (CYP450), so a basic understanding of the enzymes is necessary. Drug interactions occur when a drug changes the bioavailability of another drug by altering the absorption, distribution, metabolism or excretion. Cytochrome P450 (CYP450) is a haemoprotein that plays a key role in the metabolism of drugs and other synthetic chemicals (McDonnell and Dang, 2013).
Drugs that affect the CYP pathway could be inhibitors, inducers, or substrates for a specific CYP pathway. The metabolism of these drugs may alter the metabolism of concurrently administered agents.
Drugs that induce an enzymatic pathway of CYP might reduce the concentrations of a drug metabolised by the same pathway. This could lead to sub-therapeutic drug levels or treatment failure. Drugs that inhibit an enzymatic pathway of CYP may cause increased concentrations of other drugs metabolised by the same pathway. This may result in drug toxicity.
Drug interactions and hormonal contraceptives
CYP450 enzymes increase clearance of contraceptive hormones, making them less effective. This includes all combined hormonal contraceptives, all progestogen-only pills (POP), the etonogestrel implant and oral emergency contraception (EC). Progestogen-only injections and levonorgestrel releasing intrauterine systems are not affected by enzyme inducing drugs (FSRH, 2022).
It is important to consider that concurrent use of drugs that inhibit CYP450 could result in increased exposure to contraceptive hormones. This could potentially increase side-effects and, theoretically, elevate serum levels of ethinylestradiol, which could result in increased risk of thrombosis.
Antibiotics
In the past, there has been concern that broad spectrum antibiotics could alter the effectiveness of the combined oral contraceptive pill (COCP). However, guidance from the FSRH (2022) states that no additional contraceptive precaution is required during the use of antibiotics unless the antibiotic is an enzyme inducer or the antibiotic (or illness) causes vomiting or diarrhoea.
Patients with epilepsy
Women of childbearing age with epilepsy need special consideration when discussing suitable contraception. Steroid hormones such as oestrogen and progestogen are metabolised by CYP450 enzymes, and use of enzyme-inducing anti-seizure medications can decrease effectiveness of some systemic hormonal contraception, including pills, patches, or the vaginal ring. Although, theoretically, weak enzyme-inducing anti-seizure medications also decrease steroid hormones, the clinical effect in the context of hormonal contraception is unclear (Kennedy and Chen, 2019). Enzyme inducers, such as carbamazepine, phenytoin and topiramate, are commonly used drugs in epilepsy management.
Combined oral contraceptives and other oestrogen-containing methods can increase lamotrigine metabolism through glucuronidation, reducing lamotrigine levels. This could lead to decreased seizure control (FSRH, 2022). The dose of lamotrigine may need to be increased to counterbalance this (Kennedy and Chen, 2019). Desogestrol may lead to increased exposure to lamotrigine but there is limited evidence on the effect of other progestogen-only contraceptives. Overall, it is possible lamotrigine could reduce the effectiveness of hormonal contraception.
The FSRH (2022) has suggested good practice points for use of hormonal contraception in people taking lamotrigine:
- If the use of combined hormonal contraceptive is unavoidable, lamotrigine dose should be increased and serum lamotrigine levels may be required to avoid a reduction in the effectiveness of lamotrigine
- Individuals using a progestogen-only contraceptive should be aware of the signs of lamotrigine toxicity (dizziness, ataxia, diplopia). Consider monitoring serum lamotrigine levels when the progestogen is stopped
- When initiating or discontinuing hormonal contraception this should be done in consultation with the individual's GP, neurologist or psychiatrist
- Although there is no study data to inform this, condoms should be used in addition to combined hormonal contraception, the etonogestrel implant and all progestogen-only pills
- Depot medroxyprogesterone acetate, levonorgestrel-releasing intrauterine systems and copper intrauterine devices do not appear to be affected by lamotrigine.
The BNF app (https://www.pharmaceuticalpress.com/bnf-publications/bnf-bnfc-app) is a useful resource on appropriate measures to take for the different contraceptives, which can be helpful during a contraceptive consultation, particularly when initiating or reviewing hormonal contraception or requesting emergency contraception (Aref et al, 2019). In a retrospective observational study, Sunaga et al (2021) examined the rate of contraception failure in women using CYP3A4 enzyme inducer anti-seizure medications. The drugs observed in the study were topiramate, carbamazepine and phenytoin. Their main observations found a disproportionate number of case reports of unintended pregnancies among patients treated with oral and implant contraceptives when exposed to CYP3A4-inducing drugs. Intrauterine and vaginal ring devices were not affected by this drug–drug interaction. Therefore, they suggest that intrauterine and vaginal ring contraceptive products may be preferred among women concomitantly using CYP3A4-inducing medications compared to oral or implant contraceptive products.
Table 1. Definition of terms
| Pharmacological term | Definition |
|---|---|
| Enzyme inducer | A type of drug that increases the metabolic activity of an enzyme |
| Enzyme inhibitor | A type of drug that reduces or suppresses the activity of an enzyme |
| Glucuronidation | A metabolic process by which drugs or other substances are combined with glucuronic acid to form more water-soluble compounds, which are more readily excreted by the kidneys or in bile |
| Pharmacokinetics | Aspect of pharmacology dealing with how drugs reach their site of action and are removed from the body |
| Pharmacodynamics | The effect drugs have on the body |
| Substrate | A drug or other substances which are metabolised by cytochrome enzymes |
| Teratogen | Any agent that causes an abnormality following fetal exposure during pregnancy |
Despite these important drug interactions, several studies show that many women are not adequately counselled about possible drug interactions between anti-seizure medications and contraception (Kennedy and Chen, 2019).
Sugammadex
Sugammadex is used in general anaesthesia to reverse the neuromuscular blockade induced in surgery. It is usually given for rapid reversal in an emergency (BNF, 2023a). It is likely to bind some serum contraceptive progestogen and, to a lesser extent, serum oestrogen. The effect is short lived and a bolus dose of sugammadex may be equivalent to one missed dose of oral contraception. Therefore, advice post-administration of sugammadex is to follow standard guidance for one missed pill, and users of non-oral contraceptive should use condoms for 7 days (FSRH, 2022). Risk of pregnancy is thought to be low, particularly for the levonorgestrol intra-uterine system (LNG-IUS) and depot medroxyprogesterone acetate (DMPA).
Thyroxine
Oral HRT can increase thyroid binding globulin in women with hypothyroidism. This can require an increase in dose of thyroxine (FSRH, 2022). This effect may be expected with combined oral contraception. The FSRH suggests good practice for individuals taking thyroxine would be to consider checking thyroid function 6 weeks after the initiation of combined oral contraception (FSRH, 2022).
Griseofulvin
Griseofulvin is a drug used to treat dermatophyte infections of the skin, scalp nails and hair when topical treatment is inappropriate or has failed (BNF, 2023b). It does not appear to be an enzyme inducer but the FSRH (2022) discusses some case reports where pregnancy or a change in bleeding pattern has occurred in users of oral contraception and griseofulvin. Caution is recommended for users of combined oral contraceptives, progestogen only pills and the etonorgestrol implant particularly as griseofulvin is a potential teratogen. Condoms should be used reliably in addition to these forms of contraception. It is thought DMPA, LNG-IUSs and copper IUDs are not affected.
Ulipristal acetate
One small study found that a single 10 mg dose of ulipristal acetate administered during use of esomeprazole reduced exposure to ulipristal acetate. The effect of esomeprazole and other drugs that can increase gastric pH on the standard 30 mg dose of ulipristal acetate have not been studied. The FSRH suggests the use of a copper IUD for emergency contraception but if not appropriate or acceptable to the individual, LNG emergency contraception can be offered within 96 hours of unprotected intercourse. Ulipristal acetate can be offered but it is possible the effectiveness could be reduced.
Teratogens (and potential teratogens)
In a patient who is using teratogenic drugs, or drugs with potential teratogenic effects, is it essential for highly effective contraception to be used. Some teratogenic drugs are also enzyme inducers and this must be taken into consideration.
Conclusion
There are several commonly used drugs that can interact with hormonal contraception. When undertaking a contraceptive consultation, it is vital that a full drug history is taken and the appropriate contraceptive methods are discussed with the individual.
Box 1.Useful websites for checking drug interactions and teratogens
- BNF Drug interactions checker https://bnf.nice.org.uk/interactions
- University of Liverpool HIV drug interaction checker https://www.hiv-druginteractions.org
- UK Teratology Information Service https://www.uktis.org
Key points
- Several commonly used drugs can interact with hormonal contraceptives, reducing their safety and effectiveness
- A through consultation, including a drug history, should be given before prescribing or administering hormonal contraception
- In general, antibiotics do not affect hormonal contraception
- Women of childbearing age with epilepsy need special consideration when discussing suitable contraception, as many anti-seizure drugs can interact with hormonal contraception
CPD reflective questions
- Reflect on a patient you have advised regarding contraception who was prescribed a drug with potential interactions
- How will this article change your practice?
- Reflect on your contraception knowledge – are you competent to advise on or prescribe lesser used contraception such as the vaginal ring?