Doubling the dose of emergency contraception is a safe and effective way of overcoming efavirenz interaction

Dr Kimberly Scarsi presenting to CROI 2021.
Dr Kimberly Scarsi (left) presenting to CROI 2021.

Doubling the dose of the emergency contraception drug levonorgestrel can overcome an interaction between the medication and efavirenz, according to research presented to the 2021 virtual Conference on Retroviruses and Opportunistic Infections. The 3.0mg levonorgestrel dose achieved increases in blood concentrations of the drug of between 51 and 133% compared to the standard 1.5mg dose, therefore compensating for efavirenz-associated interactions. Doubling the dose was safe with no reported side effects.

Standard treatment is a 1.5mg levonorgestrel dose. This can reduce the risk of pregnancy by at least 50%.

The drug is metabolised by the liver using the P450 3A4 cytochrome, the same pathway used by the anti-HIV drug efavirenz, a key component of antiretroviral therapy (ART) regimens in many global settings.


body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

drug interaction

A risky combination of drugs, when drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.


Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.

This can lead to a drug-drug interaction, potentially reducing levonorgestrel concentrations by 56%, severely compromising its effectiveness to prevent unwanted pregnancy.

Doubling the dose of levonorgestrel to 3.0mg has been suggested as a way of overcoming this interaction, by both the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency. However, there is little information on the safety and effectiveness of this strategy.

The ACTG 5375 study was therefore designed to overcome this gap in knowledge. This open-label pharmacokinetic study involved sites in North and South America, sub-Saharan Africa and Thailand. Dr Kimberly Scarsi of the University of Nebraska presented interim results involving 50 women living with HIV who were taking efavirenz-based ART. Eligible participants did not require emergency contraception and  were not taking any other form of hormonal contraception. They were randomised on a two-to-one basis to receive the standard 1.5mg dose or the 3.0mg double dose.

Pharmacokinetics were intensively monitored in the 48 hours after administration of levonorgestrel, and safety analysis continued for 28 days after the treatment was taken.

A total of 17 women received the standard dose, 33 the double dose. There were some differences in the characteristics of the two groups. Those randomised to receive the 1.5mg dose were older than the double dose group (average age 42 vs 36 years), more likely to be Black (41% vs 34%) and less likely to have an undetectable viral load (82% vs 100%). Body weight was broadly comparable (average body mass index (BMI) 20 kg/m2 vs 24kg/m2), so too the proportion of women falling into the obese BMI category (BMI of 30 kg/m2; 18% vs 15%). Of note, the effectiveness of levonorgestrel is potentially reduced in obese individuals, a potential exclusion criterion for its use.

All key pharmacokinetic measures over 48 hours favoured the double dose: concentrations of levonorgestrel increased between 51% (peak concentratin or Cmax 25ng/ml vs 15 ng/ml – GMR = 1.51; 90% CI 1.17-1.95) and 133% (48 hour post administration concentration or C48 0.6ng/ml vs 0.3ng/ml – GMR = 2.33; 90% CI 1.49-3.64). Elimination of the drug over 48 hours (AUC, or area under the curve) also favoured the double dose, its levels increased by 66% (up to eight hours after administration) to 77% (48 hours after dosing).

Doubling the dose did not lead to potential side effects such as diarrhoea, nausea, heavy bleeding during periods or bleeding between periods.

Despite the pharmacokinetic improvements seen with the 3.0mg dose, Dr Scarsi noted that this was still generally inferior to that observed in HIV-negative women given a standard single dose who, by most parameters, had higher concentrations of levonorgestrel over 48 hours than those recorded among HIV-positive women receiving a double dose.

Further research is now planned to determine the impact of BMI and body composition on drug levels and the potential role of adherence to ART.

Dr Scarsi concluded that when taken alongside efavirenz, the double dose increased pharmacokinetic levels of levonorgestrel by between 51 and 133% with no increased risk of side effects.


Scarsi KK PK of dose-adjusted emergency contraception with EFV-based ART in ACTG 5375. Conference on Retroviruses and Opportunistic Infections, abstract 91, 2021.

Download the abstract eBook from the conference website.