In a 3-month drug interaction study, no significant differences in MPA pharmacokinetic parameters were found between subjects receiving efavirenz-containing antiretroviral therapy and subjects receiving no antiretroviral therapy. Similar results were found by other investigators, although the MPA plasma levels were more variable in the second study. In both studies, plasma progesterone levels for subjects receiving efavirenz and DMPA remained low consistent with suppression of ovulation. Because of the limited information available, a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness. Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz.

A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations (i.e., <0.1 ng/mL). Medroxyprogesterone acetate clearance was increased by 24.7% and 52.4% with efavirenz and efavirenz plus rifampicin, respectively. An increased risk of subtherapeutic medroxyprogesterone acetate concentrations at week 12 was predicted for a typical 60 kg women on efavirenz (4.99%) and efavirenz with rifampicin (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that dosing medroxyprogesterone acetate every 8-10 weeks overcomes the risk of subtherapeutic medroxyprogesterone acetate exposure with these drugs.

The concurrent use of rifampicin and efavirenz (both inducers of drug metabolizing enzymes) on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) was investigated. Plasma DMPA concentrations were determined pre-dose, 2, 4, 6, 8, 10 and 12 weeks after DMPA 150 mg injection in presence of both efavirenz and rifampicin treatments. Progesterone levels were measured from week 2 onwards. The primary outcome measure was the proportion of women with sub-therapeutic MPA <0.1 ng/mL (i.e. levels associated with escape ovulation) prior to 12 weeks post-DMPA dose. MPA pharmacokinetics was compared with historical antiretroviral naïve controls without TB who received DMPA. 5/42 women had MPA <0.1 ng/mL at week 12 with 1 having MPA <0.1 ng/mL at week 10 compared to 1/16 at week 12 among historical controls. No participant had progesterone levels >5 ng/mL (suggesting ovulation) throughout the study. Compared to controls, the median AUC over 12 weeks was lower (7.63 vs 12.38 ng.week/mL, p=0.004) and apparent clearance was higher (19,681 vs 12,117 L/week, p=0.004). The concomitant use of DMPA with efavirenz together with rifampicin resulted in a higher MPA clearance compared to controls, leading to sub-therapeutic concentrations of MPA in some women at 10 and 12 weeks post-dose, although progesterone levels associated with ovulation were not observed. The authors suggest that a more frequent dosing of DMPA might be needed in women on efavirenz with HIV-associated TB treated with rifampicin.

The pharmacokinetics of medroxyprogesterone (IM depot injection) were studied in 15 HIV+ women receiving zidovudine, lamivudine and efavirenz. When compared to data obtained from 15 HIV+ women not receiving antiretroviral therapy, there were no differences in medroxyprogesterone AUC, Cmin, half life or clearance. Side effects related to medroxyprogesterone were not increased. Thus, it is likely that this combination regimen would not decrease medroxyprogesterone’s contraceptive effectiveness. The effect on medroxyprogesterone on the pharmacokinetics of zidovudine, lamivudine or efavirenz was not assessed.

The interaction between efavirenz and MPA (given intramuscularly as DMPA) was evaluated in 17 HIV+ women. When compared to a control group of subjects (n=16), there were no significant changes in the Cmin or AUC of MPA when given with efavirenz, with suppression of ovulation being maintained. The pharmacokinetics of efavirenz were determined prior to and 4 weeks after DMPA administration. There were no significant changes in efavirenz exposure (4% decrease in AUC, 12% decrease in Cmax, 6% increase in Cmin).