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Appendix M

Summary of Evidence Regarding Potential Drug Interactions between Hormonal Contraception and Antiretroviral Therapies

Limited data from small, mostly unpublished studies suggest that some antiretroviral (ARV) therapies might alter the pharmacokinetics of combined oral contraceptives (COCs). Few studies have measured clinical outcomes. However, contraceptive steroid levels in the blood decrease substantially with ritonavir-boosted protease inhibitors. Such decreases have the potential to compromise contraceptive effectiveness. Some of the interactions between contraceptives and ARVs also have led to increased ARV toxicity. For smaller effects that occur with non-nucleoside reverse transcriptase inhibitors, clinical significance is unknown, especially because studies have not examined steady-state levels of contraceptive hormones. No clinically significant interactions have been reported between contraceptive hormones and nucleoside reverse transcriptase inhibitors.

Tables 1 and 2 summarize the evidence available about drug interactions between ARV therapies and hormonal contraceptives. For up-to-date, detailed information about human immunodeficiency virus (HIV) drug interactions, the following resources might be helpful:

  • Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
  • HIV Drug Interactions website, University of Liverpool, UK. Available at www.hiv-druginteractions.org.

References

  1. Kearney BP, Isaacson E, Sayre J, Cheng AK. Tenofovir DF and oral contraceptives: lack of a pharmacokinetic drug interaction [Abstract A-1618]. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 14--17, 2003. Washington, DC: American Society for Microbiology; 2003.
  2. Aweeka FT, Rosenkranz SL, Segal Y, et al. The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine. AIDS 2006;20:1833--41.
  3. Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinyl estradiol in healthy female volunteers [Abstract 348]. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, February 1--5, 1998.
  4. Sevinsky H, Eley T, He B, et al. Effect of efavirenz on the pharacokinetics of ethinyl estradiol and norgestimate in healthy female subjects [Abstract A958]. In: Program and abstracts of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, October 25--28, 2008. Washington, DC: American Society for Microbiology; 2008.
  5. Danel C, Moh R, Anzian A, et al. Tolerance and acceptability of an efavirenz-based regimen in 740 adults (predominantly women) in West Africa. J Acquir Immune Defic Syndr 2006;42:29--35.
  6. Scholler-Gyure M, Debroye C, Aharchi F, et al. No clinically relevant effect of TMC125 on the pharmacokinetics of oral contraceptives. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, November 12--16, 2006..
  7. Mildvan D, Yarrish R, Marshak A, et al. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr 2002;29:471--7.
  8. Zhang J, Chung E, Eley T et al. Effect of atazanavir/ritonavir on the pharmacokinetics of ethinyl estradiol and 17-deactyl-norgestimate in healthy female subjects [Abstract A-1415]. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 17--20, 2007. Washington, DC: American Society for Microbiology; 2009.
  9. Sekar V, Lefebvre E S-GSeal. Pharacokinetic interaction between nevirapine and ethinyl estradiol, norethindrone, and TMC114, a new protease inhibitor [Abstract A-368]. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 27--30, 2006. Washington, DC: American Society for Microbiology; 2009.
  10. Glaxo Smith Kline. Prescription medicines. Lexiva (fosamprenavir calcium). Glaxo Smith Kline 2009. Available from http://us.gsk.com/products/assets/us_lexiva.pdf. Accessed March 15, 2010.
  11. Glaxo Smith Kline. Study APV10020. A phase I, open label, two period, single-sequence, drug-drug interaction study comparing steady-state plasma ethinyl estradiol and norethisterone pharmacokinetics following administration of brevinor for 21 days with and without fosamprenavir 700 mg twice daily (BID) and ritonavir 100 mg (BID) for 21 days in healthy adult female subjects. Glaxo Smith Kline 2009. Available from http://www.gsk-clinicalstudyregister.com/files/pdf/23138.pdf. Accessed March 15, 2010.
  12. Merck & Company. Indinavir patient prescribing information. Merck & Company 2009. Available from http://www.merck.com/product/usa/pi_circulars/c/crixivan/crixivan_pi.pdf. Accessed March 15, 2010.
  13. Abbott Laboratories. Lopinavir and ritonavir prescribing information, 2009. Abbott Laboratories 2009. Available from http://www.rxabbott.com/pdf/kaletratabpi.pdf. Accessed March 15, 2010.
  14. Agouron Pharmaceuticals. Viracept (Nelfinavir mesylate) prescribing information, 2008. Agouron Pharmaceuticals 2009. Available from http://us.gsk.com/products/assets/us_viracept.pdf. Accessed March 15, 2010.
  15. Mayer K, Poblete R, Hathaway B et al. Efficacy, effect of oral contraceptives, and adherence in HIV infected women receiving Fortovase (Saquinavir) soft gel capsule (SQV-SGC; FTV) thrice (TID) and twice (BID) daily regimens. XIII International AIDS Conference, 2000, Durban, South Africa 2009.
  16. Frohlich M, Burhenne J, Martin-Facklam M, et al. Oral contraception does not alter single dose saquinavir pharmacokinetics in women. Br J Clin Pharmacol 2004;57:244--52.
  17. Food and Drug Administration. Highlights of prescribing information. Aptivus (Tipranavir) Capsules. USFDA 2009. Available from http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf.
  18. Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther 2007;81:222--7.
  19. Nanda K, Amaral E, Hays M, et al. Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril 2008;90:965--71.
  20. 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;77:84--90.

TABLE 1. Drug interactions between COCs and ARV drugs*

ARV

Contraceptive effects

ARV effects

Nucleoside reverse transcriptase inhibitors (NRTIs)

Tenofovir disaproxil fumarate

EE ↔, NGM ↔ (1)

Tenofovir ↔ (1)

Zidovudine

No data

Zidovudine ↔ (2)No change in viral load or CD4+ (2)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz

EE ↑ (3), EE ↔ (4), NGM ↓ (4), LNG ↓ (4) Pregnancy rate 2.6/100 woman-years in 1 study in which up to 80% used hormonal contraceptives (35% used COC) (5)

Efavirenz ↔ (3,4)

Etravirine

EE ↔, NET ↔ (6)

Etravirine ↑ (6)

Concurrent administration, generally safe and well tolerated (6)

Nevirapine

EE ↔, NET ↔ (7)

Nevirapine ↔ (7)

Protease inhibitors and ritonavir-boosted protease inhibitors

Atazanavir/ritonavir

EE ↑, NET ↑ (8)

No data

Darunavir/ritonavir

EE ↓, NET ↔ (9)

Darunavir ↔ (9)

Fos-amprenavir/ritonavir

EE ↓ (10,11), NET ↓ (11)

Amprenavir ↔, ritonavir ↑, Elevated liver transaminases (10)

Indinavir§

EE ↔, NET ↔ (12)

No data

Lopinavir/ritonavir

EE ↓, NET ↔ (13)

No data

Nelfinavir

EE ↓, NET ↔ (14)

No data

Saquinavir§

No data

Saquinavir ↔ (15,16)

Tipranavir/ritonavir

EE↓ (17)

↑ Skin and musculoskeletal adverse events; possible drug hypersensitivity reaction (17)

* Abbreviations: COC = combined oral contraceptive; ARV = antiretroviral; EE = ethinyl estradiol; NGM = norgestimate; NNRTI = non-nucleoside reverse transcriptase inhibitor; LNG = levonorgestrel; NET = norethindrone.

↔, no change or change ≤30%; ↑, increase >30%; ↓, decrease >30%.

§ Saquinavir and indinavir are commonly given boosted by ritonavir, but there are no data on contraceptive interactions with the boosted regimens.


TABLE 2. Drug interactions between DMPA and ARV drugs*

ARV

Contraceptive effects

ARV effects

Nucleoside reverse transcriptase inhibitors (NRTIs)

Zidovudine

No data

Zidovudine ↔ (2)No change in viral load

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz

MPA ↔ (18,19) No ovulations during 3 cycles(18,19)Pregnancy rate 2.6/100 woman-years in 1 study where up to 80% used hormonal contraceptives (65% used POIs) (5)

Efavirenz ↔ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)

Nevirapine

MPA ↔ (18)No ovulations during 3 cycles(18)

Nevirapine ↑ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)

Protease inhibitors and ritonavir-boosted protease inhibitors

Nelfinavir

MPA ↔ (18)

Nelfinavir ↔ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)

* Abbreviations: DMPA = depot medroxyprogesterone acetate; ARV = antiretroviral; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase; MPA = medroxyprogesterone acetate; POI = progestin-only injectables.

↔, no change or change ≤30%; ↑, increase > 30%.

§ The trial applied the standardized National Institutes of Health Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, 2004 (http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GradingTable_Clarification_August2009_Final.pdf). Grade 3 events are classified as severe. Severe events are defined as symptoms that limit activity or might require some assistance; require medical intervention or therapy; and might require hospitalization. Grade 4 events are classified as life threatening. Life-threatening events include symptoms that result in extreme limitation of activity and require substantial assistance; require substantial medical intervention and therapy; and probably require hospitalization or hospice.


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