Clinical Guide > ARV Effects > Contraceptives
Antiretroviral Medications and Hormonal Contraceptive Agents
January 2011
Background
Few pharmacokinetic or clinical studies have examined interactions between antiretroviral (ARV) medications and hormonal contraceptives, but it is known that certain protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) do interact with hormonal contraceptives. These interactions may increase the risk of medication failure or medication adverse effects--of either the ARV or the contraceptive. There are no known interactions between hormonal contraceptives and nucleoside analogues, integrase inhibitors, or CCR5 antagonists.
Oral Contraceptives
All oral contraceptives currently marketed in the United States, with the exception of progestin-only pills (which contain norethindrone), contain both ethinyl estradiol and a progestin (desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, or norgestrel). The oral contraceptives ethinyl estradiol and norethindrone may interact in complex ways with PIs and NNRTIs. The mechanism of these interactions may be multifactorial and includes the activity of these agents on cytochrome P450 enzymes. Pharmacokinetic studies have shown changes (either increases or decreases) in levels of ethinyl estradiol and norethindrone in women who are taking certain PIs or NNRTIs. Other studies have shown decreases in levels of amprenavir in women taking oral contraceptives.
The clinical significance of these drug interactions has not been evaluated thoroughly, but may cause oral contraceptive failure, ARV failure, or medication toxicity, depending on whether drug levels are lowered or raised by the interacting drug. The consequences of decreased hormone levels may include an increased risk of pregnancy, so an alternative or additional method of contraception commonly is recommended. The consequences of decreased ARV levels may include virologic failure and development of resistance mutations. The consequences of a higher level of hormones may include risk of thromboembolism, breast tenderness, headache, nausea, and acne.
The available pharmacokinetic data are summarized in Table 1. For further discussion of oral and non-oral contraceptives for HIV-infected women, see chapter Health Care of HIV-Infected Women Through the Life Cycle.
Table 1. Interactions Between Antiretroviral Agents and Oral Contraceptives
Antiretroviral Agent | Pharmacokinetic Changes with Oral Contraceptives | Comments |
---|
|
Key to symbols: = Use alternative/additional method or do not administer together = Use with caution = Safe to use in combination or no dosage adjustment necessary |
Protease Inhibitors |
---|
Atazanavir (ATV, Reyataz) | - EE AUC ↑ 48%
- NE AUC ↑ 110%
| | - OC should contain ≤30 mcg EE. Monitor for side effects, or use alternative method.
- OCs containing <25 mcg EE or progestins other than norethindrone or norgestimate have not been studied.
|
ATV/r | - EE AUC ↓ 19%
- 17-deacetyl norgestimate (active metabolite of NG) AUC ↑ 85%
| | - OC should contain ≥35 mcg EE.
- OCs containing progestins other than norethindrone or norgestimate have not been studied.
|
Darunavir (DRV, Prezista) DRV/r | | | - Use alternative or additional method of contraception.
|
Fosamprenavir (FPV, Lexiva) | - EE Cmin ↑ 32%
- NE Cmin ↑ 45%; AUC ↑ 18%
- Amprenavir AUC ↓ 22%
- Amprenavir Cmin ↓ 20%
| | - Data are derived from studies with amprenavir (the active metabolite of FPV).
- Risk of ARV failure and of EE or NE adverse effects: do not coadminister fosamprenavir with OCs.
- Use alternative method of contraception.
|
FPV/r | | | - Risk of contraceptive failure and of ritonavir adverse effects.
- Use alternative method of contraception.
|
Indinavir (IDV, Crixivan) | | | - No dosage adjustment is recommended.
- Monitor for EE or NE adverse effects.
|
IDV/r | | | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
Lopinavir/r (LPV/r, Kaletra) | | | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
Nelfinavir (NFV, Viracept) | | | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
Ritonavir (RTV, Norvir) | | | - Risk of contraceptive failure; use alternative method of contraception.
|
Saquinavir (SQV, Invirase)/r | - No data; theoretic EE ↓
- SQV kinetics not affected by OC
| | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
Tipranavir (TPV, Aptivus)/r | - EE AUC ↓ 48%
- NE no significant change
| | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
Nonnucleoside Reverse Transcriptase Inhibitors |
---|
Efavirenz (EFV, Sustiva) | - EE AUC ↑ 37%
- No data available on NE component
- NG AUC ↓ 64%
- LN AUC ↓ 58-83%
| | - Decrease in progestin levels: risk of contraceptive failure [including failure of emergency contraception (Plan B)]; use alternative or additional method of contraception.
|
Etravirine (ETR, Intelence) | | | - No dosage adjustment is necessary.
|
Nevirapine (NVP, Viramune) | | | - Risk of contraceptive failure; use alternative or additional method of contraception.
|
CCR5 Antagonist |
---|
Maraviroc (MVC, Selzentry) | - No significant effect on EE or LN
| | - Safe to use in combination.
|
Integrase Inhibitor |
---|
Raltegravir (RAL, Isentress) | - No significant change in EE AUC or NG AUC
| | - Safe to use in combination.
|
Non-Oral Hormonal Contraceptives
Hormonal contraceptives using delivery methods other than oral include the following:
- Products containing both progestin and estrogen components: transdermal patch, vaginal ring
- Products containing a progestin alone (medroxyprogesterone acetate, levonorgestrel, norelgestromin, or etonogestrel): subcutaneous or IM injection, intrauterine system, implantable device
There has been little research on the interactions between ARVs and most of these agents. Theoretically, interactions with ARVs would be less likely with contraceptive methods that have primarily local action and minimal systemic absorption, and for injection or transdermal delivery systems, since first-pass metabolism is avoided. However, caution is still warranted, as this assumption has not been proven.
Because the transdermal patch and vaginal ring contain ethinyl estradiol, women who take ARVs that increase or decrease serum estradiol levels (see Table 1) are advised to use an alternative (or additional) contraceptive method. Small studies of depo-medroxyprogesterone acetate (DMPA, or Depo-Provera) have shown no significant interactions between DMPA and nelfinavir, efavirenz, or nevirapine. Interactions between DMPA and other ARVs have not been studied, but DMPA's interactions with PIs and NNRTIs would be expected to be similar to those of norethindrone (see Table 1). For other non-oral hormones, pending further study, an alternative (or additional) method of contraception should be considered.
References
- Abel S, Russell D, Ridgway C, et al. Overview of the drug-drug interaction data for maraviroc (UK-427, 857). In: Program and abstracts of the 6th International Workshop on Clinical Pharmacology of HIV Therapy; April 28-30, 2005; Quebec. Abstract 76.
- Anderson MS, Wenning L, Moreau A, et al. Effect of raltegravir on the pharmacokinetics of oral contraceptives. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago. Abstract A-1425.
- Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs. J Fam Plann Reprod Health Care. 2002 Apr;28(2):78-80.
- Carten M, Kiser J, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel, and efavirenz. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010; San Francisco. Abstract 934.
- Chu JH, Gange SJ, Anastos K et al. Hormonal contraceptive use and the effectiveness of highly active antiretroviral therapy. Am J Epidemiol. 2005 May 1;161(9):881-90.
- Cohn SE, Park JG, Watts DH, et al.; ACTG A5093 Protocol Team. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. 2007 Feb;81(2):222-7.
- Gupta S. Non-oral hormonal contraception. Curr Ob Gyn. 2006 Feb;16(1):30-8.
- Heikinheimo O, Lehtovirta P, Suni J, et al. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women--effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod. 2006 Nov;21(11):2857-61.
- Implanon [package insert]. Kenilworth, NJ: Schering-Plough; 2009.
- Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinylestradiol in healthy female volunteers. In: Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; February 1-5, 1998; Chicago. Abstract 348.
- Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy. 2009 Aug;29(8):924-9.
- Liverpool HIV Pharmacology Group. Drug Interactions Charts. Accessed June 30, 2010.
- Mayer K, Poblete R, Hathaway B, et al. Efficacy, effect of oral contraceptive, and adherence in HIV infected women receiving Fortovase (saquinavir) soft gel capsule thrice and twice daily regimens. In: Program and abstracts of the XIII International AIDS Conference; July 9-14, 2000; Durban, South Africa. Abstract TuPeB3226.
- McNicholl I. Database of Antiretroviral Drug Interactions. HIV InSite. San Francisco: UCSF Center for HIV Information. Accessed June 30, 2010.
- Mitchell HS, Stephens E. Contraception choice for HIV positive women. Sex Transm Infect. 2004 Jun;80(3):167-73.
- Nanda K, Amaral E, Hays M, et al. Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril. 2008 Oct;90(4):965-71.
- Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinyloestradiol in healthy female volunteers. Br J Clin Pharmacol. 1998 Aug;46(2):111-6.
- Scholler-Gyure M, Debroye C, Aharchi F, et al. No effect of TMC125 on the pharmacokinetics of oral contraceptives. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow. Abstract P277.
- Sekar VJ, Lefebvre E, Guzman SS, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther. 2008;13(4):563-9.
- Sevinsky H, Eley T, He B, et al. Effect of efavirenz on the pharmacokinetics of ethinylestradiol and norgestimate in healthy female subjects. In: Program and abstracts of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington. Abstract A-958.
- Tackett D, Child M, Agarwala S, et al. Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-13, 2003; Boston. Abstract 543.
- Toronto General Hospital, Immunodeficiency Clinic. Drug Interaction Tables. Accessed June 30, 2010.
- U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 10, 2011.
- Watts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008 Feb;77(2):84-90.
- Zieman M. Overview of contraception. Up to Date Online. June 1, 2009. Accessed June 30, 2010.