Implants and Enzyme Inducers

Etonogestrel and levonorgestrel are metabolised by hepatic cytochrome P450 3A4. Medicines that induce this enzyme lower serum progestin concentrations and reduce implant effectiveness, and pregnancies have occurred in implant users taking efavirenz, rifampicin and enzyme-inducing antiseizure medicines. This is the main reason an implant may fail despite correct insertion.

Mechanism of interaction. Enzyme induction increases progestin clearance. Induction begins within days, is maximal at about 2 weeks, and persists for about 28 days after the inducer is stopped.

Size of effect. Efavirenz reduces etonogestrel exposure by more than half and levonorgestrel exposure by about half. Rifampicin causes a similar or greater fall. The effect on pregnancy risk rises after the first year of implant use as baseline release falls.

Medicines that lower implant effect.

Medicines without important interaction. Dolutegravir, raltegravir, tenofovir, lamivudine, emtricitabine, abacavir, zidovudine, etravirine, rilpivirine, valproate, levetiracetam, lamotrigine, isoniazid alone, most antibiotics, antifungals other than griseofulvin, and antimalarials.

Effectiveness without interaction. About 0.05 pregnancies per 100 women in the first year.

Eligibility categories. Implants are category 2 with efavirenz, nevirapine, ritonavir-boosted protease inhibitors, rifampicin, rifabutin and enzyme-inducing antiseizure medicines. Category 1 with dolutegravir, raltegravir, nucleoside reverse transcriptase inhibitors, etravirine and rilpivirine.

Assessment. Take a full medicine history at insertion and at every contact, including tuberculosis treatment, antiretroviral regimen changes, antiseizure medicines and herbal products. Ask about planned treatment duration.

Method comparison when an inducer is needed.

• Copper IUD and levonorgestrel IUD: effect not reduced; preferred for long-term inducer use.

• DMPA: effect not reduced to a clinically important degree.

• Implant: usable with consistent condoms during and for 28 days after the inducer.

• Combined pill and progestin-only pill: reduced effect; generally avoided.

Counselling points. Explain that the implant may not protect fully while the inducer is taken and for 4 weeks after, that condoms are needed for this time, and that a switch to an IUD or DMPA removes the need. Respect the patient's choice to keep the implant with condoms.

Special groups. Women living with HIV: antiretroviral regimens based on dolutegravir avoid the interaction. Tuberculosis: the course of rifampicin is time-limited, so implant plus condoms is practical. Epilepsy: long-term enzyme inducers favour an IUD or DMPA, and the risks of unplanned pregnancy with teratogenic antiseizure medicines make highly reliable contraception essential.

Regimen lines with an enzyme inducer.

• Etonogestrel 68 mg rod: subdermal; insert by the usual start rules; replace at 3 years; add male or female condoms at every act of intercourse for the whole period of inducer use and for 28 days after stopping.

• Levonorgestrel two 75 mg rods: subdermal; insert by the usual start rules; replace at 5 years or 3 years by system; add condoms throughout and for 28 days after stopping.

• Do not shorten the replacement interval as a substitute for condoms; this has not been shown to restore protection.

Starting an inducer in an established implant user. Advise condoms from the first dose, or offer a switch. If an IUD is chosen, insert it and remove the implant at the same visit if the patient is reasonably not pregnant.

Starting an implant in a patient already on an inducer. Insert with condoms throughout, or offer a nonaffected method.

Switching to DMPA. DMPA intramuscular 150 mg every 13 weeks, with repeat allowed up to 4 weeks late, or DMPA subcutaneous 104 mg every 13 weeks. Give the first injection before removing the implant or on the day of removal; no backup is needed.

Emergency contraception. For unprotected intercourse during inducer use, the copper IUD is the preferred emergency method. If oral levonorgestrel is used, a 3 mg single dose (double the usual 1.5 mg dose) is given within 120 hours.

Monitoring. Review medicines at each contact. Offer a pregnancy test if there is missed bleeding in a patient who previously had regular bleeding, or symptoms of pregnancy.

Antiretroviral review. Where the HIV service allows, a change from efavirenz to dolutegravir removes the interaction; coordinate with the HIV clinician.

Contraceptive failure. The main complication. Pregnancy in a patient on an inducer must be assessed for ectopic location. If the pregnancy continues, remove the implant; no foetal harm is known from the implant.

Bleeding changes. A change in bleeding pattern after starting an inducer may reflect lower progestin levels. Exclude pregnancy before treating.

Teratogenic medicines. In patients on valproate, carbamazepine, phenytoin, topiramate, or other teratogens, contraceptive failure carries additional foetal risk. Prefer an IUD and document counselling.

Prescribing errors. Failing to record inducer use at insertion, failing to advise condoms after a tuberculosis diagnosis, and assuming all antiretrovirals interact.

Red flags. Positive pregnancy test, pelvic pain with missed bleeding, heavy bleeding.

Referral and escalation. Refer suspected ectopic pregnancy urgently. Coordinate with HIV, tuberculosis and neurology clinicians on regimen changes.