Efavirenz significantly reduces levels of some oral contraceptives

Polly Clayden, HIV i-Base

A PK study evaluated the effect of co-administration of EFV 600 mg on an ethinylestradiol (EE) and norgestimate (NGM)-containing oral contraceptive (OC).

This was an open-label, 3-period, single-sequence study conducted in healthy female volunteers. Women received Ortho Tri-Cyclen┬« LO once nightly (QHS) on Days 1 – 28 (period 1, n=28), Ortho Cyclen┬« QHS on Days 29 – 56 (period 2, n=23) and Ortho Cyclen with EFV 600 mg QHS on Days 57 – 70 (period 3, n=21).

The investigators determined noncompartmental PK. Adjusted geometric mean ratios (GMR) and 90% confidence intervals (CI) for the PK of EE and the major active metabolite of NGM, norelgestromin (NGMN), were estimated. They also conducted a similar evaluation of the secondary active metabolite levonorgestrel (LNG) PK in a small group of women (n=6). Serum progesterone (PG) levels were determined on Days 18, 46 and 74.

Comparing, period 3 to period 2, the investigators found that EFV had no effect on EE Cmax or AUC with GMRs (90% CI) of 1.06 (0.95 – 1.19) and 0.90 (0.80 – 1.01), respectively. EFV significantly decreased NGMN Cmax and AUC with GMRs (90% CI) of 0.54 (0.48-0.61) and 0.36 (0.33-0.38), respectively; LNG exposures (N=6) were also significantly decreased, with AUC GMR (90% CI) of 0.17 (0.13-0.21). PG levels were similar across periods.

The investigators concluded that these results reinforce the need for additional methods of barrier contraception when taking OC and EFV together.


The decreases in plasma estradiol levels related to ARVs have not lead to reports where this has resulted in contraceptive failures (i.e. unintended pregnancy). However, it is highly likely that women on EFV may experience break-through bleeding, i.e. irregular spotting or bleeding. There is nothing bad about this except for personal inconvenience and annoyance.

What is of concern though, is that women may mistakenly assume that abnormal bleeding while on the pill, means that the contraceptive is not working, and because of this they decide to stop taking it, and subsequently become pregnant.

The take home messages are:

  1. patients on hormonal contraceptives should be counseled about the possibility of breakthrough spotting/bleeding and advised that this is common; and
  2. if they are concerned that the contraceptives aren’t working or that they might be pregnant or want reassurance, they should talk to their doctor or healthcare worker and/or get a pregnancy test, but they should NOT stop using the contraceptive simply because they’re worried about irregular bleeding.


Sevinsky H, Eley T, He B et al. Effect of efavirenz on the pharmacokinetics of ethinyl estradiol and norgestimate in healthy female subjects. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-958.

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