Clinical Guide > ARV Effects > Contraceptives

# Antiretroviral Medications and Hormonal Contraceptive Agents

January 2011

### Chapter Contents

      - Background
      - Oral Contraceptives
      - Non-Oral Hormonal Contraceptives
      - ReferencesTable 1. Interactions Between Antiretroviral Agents and Oral ContraceptivesBackground
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 ContraceptivesAntiretroviral AgentPharmacokinetic Changes with Oral ContraceptivesComments
Adapted from U.S. Department of Health and Human Services. *Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents*, Table 15a. January 10, 2011. 

Abbreviations: AUC = area under the time-concentration curve (drug exposure); C max = maximum concentration; C min = minimum concentration; EE = ethinyl estradiol; LN = levonorgestrel; NE = norethindrone; NG = norgestimate; OC = oral contraceptive; RTV = ritonavir; /r = low-dose ritonavir
*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 InhibitorsAtazanavir (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- EE AUC ↓ 44%
- NE AUC ↓ 14%
- Use alternative or additional method of contraception.
Fosamprenavir (FPV, Lexiva)- EE C min  ↑ 32%
- NE C min  ↑ 45%; AUC ↑ 18%
- Amprenavir AUC ↓ 22%
- Amprenavir C min  ↓ 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- EE AUC ↓ 37%
- NE AUC ↓ 34%
- Risk of contraceptive failure and of ritonavir adverse effects.
- Use alternative method of contraception.
Indinavir (IDV, Crixivan)- EE AUC ↑ 24%
- NE AUC ↑ 26%
- No dosage adjustment is recommended.
- Monitor for EE or NE adverse effects.
IDV/r- No data
- Risk of contraceptive failure; use alternative or additional method of contraception.
Lopinavir/r (LPV/r, Kaletra)- EE AUC ↓ 42%
- NE AUC ↓ 17%
- Risk of contraceptive failure; use alternative or additional method of contraception.
Nelfinavir (NFV, Viracept)- EE AUC ↓ 47%
- NE AUC ↓ 18%
- Risk of contraceptive failure; use alternative or additional method of contraception.
Ritonavir (RTV, Norvir)- EE AUC ↓ 40%
- 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 InhibitorsEfavirenz (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)- EE AUC ↑ 22%
- NE AUC ↓ 5%
- No dosage adjustment is necessary.
Nevirapine (NVP, Viramune)- EE AUC ↓ 20%
- NE AUC ↓ 19%
- Risk of contraceptive failure; use alternative or additional method of contraception.
CCR5 AntagonistMaraviroc (MVC, Selzentry)- No significant effect on EE or LN
- Safe to use in combination.
Integrase InhibitorRaltegravir (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.
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