PPMDB.org logo

The Precautionary and Prohibited Medications Database

Maintained by a collaboration of the University at Buffalo Pharmacology Specialty Laboratory and Frontier Science & Technology Research Foundation

Efavirenz and Ethinylestradiol

 
Medications Efavirenz and Ethinylestradiol
Designation Precautionary
Last updated 24-Apr-2019
Interaction History
Effect on concentration Efavirenz: Unknown

Ethinylestradiol: Decrease
Pharmacologic effect Efavirenz: N/A

Ethinylestradiol: N/A
Pharmacologic effect applies to drugs in the same class Efavirenz:

Ethinylestradiol:
Pharmacologic effect description Efavirenz:

Ethinylestradiol:
Potential pharmacokinetic effect Efavirenz: N/A

Ethinylestradiol: N/A
Potential pharmacokinetic effect applies to drugs in the same class Efavirenz:

Ethinylestradiol:
Potential pharmacokinetic mechanism Efavirenz:

Ethinylestradiol:

Summary

While the study by Sevinsky showed no significant effect on Ethinyl Estradiol in tricyclic oral contraceptive, the study by Scarsi found that Efavirenz induction of CYP3A4 causes a decrease in concentration of Ethinyl Estradiol in vaginal hormonal contraceptive. Moreover, the study by Hass showed a greater decrease in Ethinyl Estradiol concentrations by EFV in patients who are slow metabolizers of CYP2B6. All studies agree that caution is warranted when administering these contraceptives with Efavirenz. Alternative contraceptive methods should be considered.

Sources

Efavirenz versus Ethinyl Estradiol / Norgestimate

Study Design
The effect of efavirenz (600 mg once daily) on the pharmacokinetics of a tricyclic oral contraceptive containing ethinyestradiol and norgestimate was studied in 21 female HIV- subjects.  
Study Results
Efavirenz had no effect on ethinylestradiol Cmax (6% increase) or AUC (10% decrease). Exposure to the active metabolites of norgestimate - norgestromin and levonorgestrel - were significantly decreased. The Cmax and AUC of norgestromin decreased by 46% and 74%, respectively, while the AUC of levonorgestrel decreased by 83% (n=6). Efavirenz pharmacokinetics were similar to historical data.  
Study Conclusions
Barrier methods of contraception are recommended when efavirenz is co-administered with oral contraceptives. Although there was no significant effect on the estrogen component, the significant decrease in the progestogen component reinforces the need for additional barrier contraception when taking oral contraceptives with efavirenz 
References
Sevinsky H, Eley T, Persson A, Garner D, Yones C, Nettles R, Zhang J. The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy hiv-negative women. Antiviral Therapy. 2011; 2: 149.  

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol

Study Design
A vaginal ring releasing Etonogestrel/Ethinyl Estradiol (ENG/EE 120/15 mcg/day) was inserted at entry in three groups of participants: (1) not yet receiving ART (control group; n=25); (2) ART containing efavirenz (EFV) 600mg daily (EFV group; n=25); (3) ART containing Atazanavir/Ritonavir (ATV/r) 300/100mg daily (ATV/r group; n=24). Participants returned on days 7, 14, and 21 for single measurements of ENG and EE PK, assessed by a validated LC/MS/MS method. Plasma hormone PK exposure was compared between each ART group and the control group at each visit by geometric mean ratio (GMR) with 90% CI, and by Wilcoxon-rank sum at the primary endpoint (day 21). 
Study Results
Compared to the control group, participants in the EFV group had 76-79% lower ENG and 53-57% lower EE over 21 days (all p<0.001). In contrast, participants in the ATV/r group had 71-79% higher ENG (all p<0.001), yet 29-35% lower EE (p=0.066, 0.032 and 0.004 for days 7, 14 and 21, respectively) over 21 days compared to the control group. The GMR (90% CI) for ENG and EE concentrations for EFV: Control at Day 21 were 0.24 (0.18-0.32) and 0.43 (0.33-0.57) respectively.  
Study Conclusions
Women on EFV- based ART should consider an alternative contraception method or barrier contraception in addition to the vaginal ring until the clinical relevance of these PK changes is better understood. 
References
Scarsi, K, Cramer, S, Gingrich, D. Vaginal contraceptive hormone exposure profoundly altered by efv- and atv/r-based art. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol / Norgestimate

Study Design
The effect of efavirenz (600 mg once daily) on the pharmacokinetics of a tricyclic oral contraceptive containing ethinyestradiol and norgestimate was studied in 21 female HIV- subjects.  
Study Results
Efavirenz had no effect on ethinylestradiol Cmax (6% increase) or AUC (10% decrease). Exposure to the active metabolites of norgestimate - norgestromin and levonorgestrel - were significantly decreased. The Cmax and AUC of norgestromin decreased by 46% and 74%, respectively, while the AUC of levonorgestrel decreased by 83% (n=6). Efavirenz pharmacokinetics were similar to historical data.  
Study Conclusions
Barrier methods of contraception are recommended when efavirenz is co-administered with oral contraceptives. Although there was no significant effect on the estrogen component, the significant decrease in the progestogen component reinforces the need for additional barrier contraception when taking oral contraceptives with efavirenz 
References
Scarsi, K, Cramer, S, Gingrich, D. Vaginal contraceptive hormone exposure profoundly altered by efv- and atv/r-based art. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol

Study Design
A vaginal ring releasing Etonogestrel/Ethinyl Estradiol (ENG/EE 120/15 mcg/day) was inserted at entry in three groups of participants: (1) not yet receiving ART (control group; n=25); (2) ART containing efavirenz (EFV) 600mg daily (EFV group; n=25); (3) ART containing Atazanavir/Ritonavir (ATV/r) 300/100mg daily (ATV/r group; n=24). Participants returned on days 7, 14, and 21 for single measurements of ENG and EE PK, assessed by a validated LC/MS/MS method. Plasma hormone PK exposure was compared between each ART group and the control group at each visit by geometric mean ratio (GMR) with 90% CI, and by Wilcoxon-rank sum at the primary endpoint (day 21). 
Study Results
Compared to the control group, participants in the EFV group had 76-79% lower ENG and 53-57% lower EE over 21 days (all p<0.001). In contrast, participants in the ATV/r group had 71-79% higher ENG (all p<0.001), yet 29-35% lower EE (p=0.066, 0.032 and 0.004 for days 7, 14 and 21, respectively) over 21 days compared to the control group. The GMR (90% CI) for ENG and EE concentrations for EFV: Control at Day 21 were 0.24 (0.18-0.32) and 0.43 (0.33-0.57) respectively.  
Study Conclusions
Women on EFV- based ART should consider an alternative contraception method or barrier contraception in addition to the vaginal ring until the clinical relevance of these PK changes is better understood. 
References
Scarsi, K, Cramer, S, Gingrich, D. Vaginal contraceptive hormone exposure profoundly altered by efv- and atv/r-based art. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol

Study Design
A vaginal ring releasing Etonogestrel/Ethinyl Estradiol (ENG/EE 120/15 mcg/day) was inserted at entry in three groups of participants: (1) not yet receiving ART (control group; n=25); (2) ART containing efavirenz (EFV) 600mg daily (EFV group; n=25); (3) ART containing Atazanavir/Ritonavir (ATV/r) 300/100mg daily (ATV/r group; n=24). Participants returned on days 7, 14, and 21 for single measurements of ENG and EE PK, assessed by a validated LC/MS/MS method. Plasma hormone PK exposure was compared between each ART group and the control group at each visit by geometric mean ratio (GMR) with 90% CI, and by Wilcoxon-rank sum at the primary endpoint (day 21). 
Study Results
Compared to the control group, participants in the EFV group had 76-79% lower ENG and 53-57% lower EE over 21 days (all p<0.001). In contrast, participants in the ATV/r group had 71-79% higher ENG (all p<0.001), yet 29-35% lower EE (p=0.066, 0.032 and 0.004 for days 7, 14 and 21, respectively) over 21 days compared to the control group. The GMR (90% CI) for ENG and EE concentrations for EFV: Control at Day 21 were 0.24 (0.18-0.32) and 0.43 (0.33-0.57) respectively.  
Study Conclusions
Women on EFV- based ART should consider an alternative contraception method or barrier contraception in addition to the vaginal ring until the clinical relevance of these PK changes is better understood. 
References
Hass, D, Cramer, YS, Godfrey, C, et al.. Pharmacogenetics worsens an adverse antiretroviral hormonal contraceptive interaction. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol / Norgestimate

Study Design
The effect of efavirenz (600 mg once daily) on the pharmacokinetics of a tricyclic oral contraceptive containing ethinyestradiol and norgestimate was studied in 21 female HIV- subjects.  
Study Results
Efavirenz had no effect on ethinylestradiol Cmax (6% increase) or AUC (10% decrease). Exposure to the active metabolites of norgestimate - norgestromin and levonorgestrel - were significantly decreased. The Cmax and AUC of norgestromin decreased by 46% and 74%, respectively, while the AUC of levonorgestrel decreased by 83% (n=6). Efavirenz pharmacokinetics were similar to historical data.  
Study Conclusions
Barrier methods of contraception are recommended when efavirenz is co-administered with oral contraceptives. Although there was no significant effect on the estrogen component, the significant decrease in the progestogen component reinforces the need for additional barrier contraception when taking oral contraceptives with efavirenz 
References
Hass, D, Cramer, YS, Godfrey, C, et al.. Pharmacogenetics worsens an adverse antiretroviral hormonal contraceptive interaction. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol / Norgestimate

Study Design
The effect of efavirenz (600 mg once daily) on the pharmacokinetics of a tricyclic oral contraceptive containing ethinyestradiol and norgestimate was studied in 21 female HIV- subjects.  
Study Results
Efavirenz had no effect on ethinylestradiol Cmax (6% increase) or AUC (10% decrease). Exposure to the active metabolites of norgestimate - norgestromin and levonorgestrel - were significantly decreased. The Cmax and AUC of norgestromin decreased by 46% and 74%, respectively, while the AUC of levonorgestrel decreased by 83% (n=6). Efavirenz pharmacokinetics were similar to historical data.  
Study Conclusions
Barrier methods of contraception are recommended when efavirenz is co-administered with oral contraceptives. Although there was no significant effect on the estrogen component, the significant decrease in the progestogen component reinforces the need for additional barrier contraception when taking oral contraceptives with efavirenz 
References
Hass, D, Cramer, YS, Godfrey, C, et al.. Pharmacogenetics worsens an adverse antiretroviral hormonal contraceptive interaction. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol

Study Design
This study enrolled women living with HIV in Africa, Asia, South America and the US into one of three groups: controls (not on anti-retroviral therapy), Efavirenz (EFV) group (600mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and Atazanavir (ATV)/Ritonavir (RTV) group (300/100mg daily with NRTIs). On day 0, a vaginal ring (VR) was inserted, releasing Etonogestrel (ENG)/Ethinyl Estradiol (EE) 120/15 mcg/day. On days 0 (pre-VR) and 21 (during VR), Pharmacokinetic sampling for EFV, ATV and RTV was done. On days 7, 14 and 21, single plasma samples for ENG and EE analysis were obtained. 27 single nucleotide polymorphisms (SNPs) were genotyped, including 3 that define CYP2B6 normal, intermediate and slow metabolizers, CYP3A4/5, UGT1A1 and CYP1A1/2 SNPs, and estrogen trait-associated SNPs. 
Study Results
In the EFV group, CYP2B6 genotype predicted lower day 21 EE (p=6.7E-4) concentrations. Compared to controls, EFV reduced median day 21 EE concentrations by 41% in CYP2B6 normal and intermediate metabolizers, but by 75% in slow metabolizers.  
Study Conclusions
CYP2B6 slow metabolizer genotype worsens the PK interaction of EFV with EE administered by VR, likely due to higher EFV concentrations given that CYP2B6 is the main metabolizing pathway for EFV. Altering EFV dosing based on CYP2B6 genotype may reduce, but likely not eliminate, the impact of EFV on EE.  
References
Hass, D, Cramer, YS, Godfrey, C, et al.. Pharmacogenetics worsens an adverse antiretroviral hormonal contraceptive interaction. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019. 

Study information updated: 24-Apr-2019

Efavirenz versus Ethinyl Estradiol

Study Design
A vaginal ring releasing Etonogestrel/Ethinyl Estradiol (ENG/EE 120/15 mcg/day) was inserted at entry in three groups of participants: (1) not yet receiving ART (control group; n=25); (2) ART containing efavirenz (EFV) 600mg daily (EFV group; n=25); (3) ART containing Atazanavir/Ritonavir (ATV/r) 300/100mg daily (ATV/r group; n=24). Participants returned on days 7, 14, and 21 for single measurements of ENG and EE PK, assessed by a validated LC/MS/MS method. Plasma hormone PK exposure was compared between each ART group and the control group at each visit by geometric mean ratio (GMR) with 90% CI, and by Wilcoxon-rank sum at the primary endpoint (day 21). 
Study Results
Compared to the control group, participants in the EFV group had 76-79% lower ENG and 53-57% lower EE over 21 days (all p<0.001). In contrast, participants in the ATV/r group had 71-79% higher ENG (all p<0.001), yet 29-35% lower EE (p=0.066, 0.032 and 0.004 for days 7, 14 and 21, respectively) over 21 days compared to the control group. The GMR (90% CI) for ENG and EE concentrations for EFV: Control at Day 21 were 0.24 (0.18-0.32) and 0.43 (0.33-0.57) respectively.  
Study Conclusions
Women on EFV- based ART should consider an alternative contraception method or barrier contraception in addition to the vaginal ring until the clinical relevance of these PK changes is better understood. 
References
Hass, D, Cramer, YS, Godfrey, C, et al.. Pharmacogenetics worsens an adverse antiretroviral hormonal contraceptive interaction. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019. 

Study information updated: 24-Apr-2019