Antiretroviral Drug Interactions & Polypharmacy

1. Antiretroviral Drug Interactions & Polypharmacy Elizabeth Sherman, PharmD, AAHIVE HIV/AIDS Clinical Pharmacy Specialist, Memorial Healthcare System Assistant Professor, Nova Southeastern University Faculty, Florida/Caribbean AETC

2. Disclosure of Financial Relationships This speaker has no financial relationships with commercial entities to disclose. This speaker will not discuss any off-label use or investigational product during the program. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

3. What is your profession? • Physician • Nurse • Pharmacist • Medical assistant • Case manager • Student • Other

4. Which best describes your patient setting? • Outpatient clinic • Hospital/Inpatient • Other

5. How comfortable are you in managing drug interactions in HIV-infected patients? • Extremely comfortable: I wrote the book on drug interactions. • Somewhat comfortable: I keep up on the topic and/or have access to a pharmacist. • Uncomfortable: I know they exist but have a difficult time recognizing them. • Drug interactions? Isn’t this clinical trials/adherence?

6. Objectives • Avoid pitfalls of unintentional polypharmacy in HIV-infected patients • Review clinically significant drug interactions in patients with multiple diagnoses

7. Objectives • Recognize pitfalls of unintentional polypharmacy in HIV-infected patients • Review clinically significant drug interactions in patients with multiple diagnoses

8. Polypharmacy & HIV Infection • Polypharmacy is “many drugs” • Typically refers to 5+ medications1 • Polypharmacy occurs in 20-50% of HIV-infected patients2 • Adverse drug reactions more common and serious in older patients • Regular drug interaction screening is essential 1. Wick JY. Pharmacy Times 2006. 2. The HIV and Aging Consensus Project. www.aahivm.org/hivandagingforum

9. AAHIVM Recommendations to Reduce Unintentional Polypharmacy • Medication reconciliation at every visit • Ask patients to bring in all medications • Obtain dispensing history from pharmacy • Assess continued need for each medication • Encourage use of one pharmacy • HIV specialty pharmacy preferred • Consult a clinical pharmacist • AETC Consultation (www.fcaetc.org/consultation) • UCSF HIV Warmline (800-933-3413) The HIV and Aging Consensus Project, www.aahivm.org/hivandagingforum

10. Polypharmacy & Aging HIV-Infected Patients Antiretroviral therapy (ART) transformed HIV into complex chronic disease with multimorbidity

11. ART Undergoes Pharmacokinetic Transformation • Absorption • Distribution • Metabolism • Elimination • Setting for most ARV drug interactions • Cytochrome P450 drug metabolizing enzyme influences/influenced by, many ARVs and many other drugs • PIs, NNRTIs, maraviroc, and elvitegravir/cobicistat can be P450 substrates, inducers, or inhibitors

12. Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes Drug alone Drug alone Concentration P450 Time

13. Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes Drug + Inhibitor Drug + Inhibitor Too much drug! Concentration P450 Drug alone Time Inhibitor blocks P450 enzyme

14. Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes Drug + Inducer Not enough drug! Drug alone Concentration P450 Drug + Inducer Time Inducer increases P450 enzyme production

15. ARV Metabolism and Drug Interaction Potential

16. Objectives • Recognize pitfalls of unintentional polypharmacy in HIV-infected patients • Review clinically significant drug interactions in patients with multiple diagnoses

17. Antiretrovirals Have Drug Interactions With Multiple Medications • Statins (HMG Co-A reductase inhibitors) • Anti-acid therapy • Antiepileptics • Phosphodiesterase inhibitors • Antiplatelets & anticoagulants • Hepatitis C protease inhibitors • Antimycobacterials • Antifungals • Benzodiazepines • Hormonal contraceptives • Asthma medications and corticosteroids • Antiarrhythmics, calcium channel blockers • Antipsychotics and antidepressants • Herbal and dietary supplements • Other antiretrovirals

18. ARV Interactions with Statins • Statins (HMG Co-A reductase inhibitors) • P450 substrates • May be affected by NNRTIs, PIs, & cobicistat • March 2012: FDA updates statin dosing recommendations with ARVs

19. Managing ARV Interactions with Statins FDA Drug Safety Communication. March 1,2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Gilead Sciences, Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

20. ARV Interactions with Anti-Acid Therapy • Medications decreasing stomach acidity can interfere with ARVs requiring an acidic environment for absorption (PI, NNRTI) • Elvitegravir absorption is decreased by binding with di/trivalent cations • Indicated for GERD/peptic ulcer disease to decrease gastric acidity • Antacids: Aluminum, magnesium hydroxide, or calcium carbonate • H2 receptor antagonists: cimetidine, famotidine, ranitidine • Proton pump inhibitors: esomeprazole, lansoprazole, omeprazole, pantoprazole

21. Managing ARV Interactions with Anti-Acid Therapy Bristol-Myers Squibb. Reyataz (atazanavir) package insert. Princeton, NJ; 2012.Tibotec Therapeutics. Edurant (rilpivirine) package insert. Raritan, NJ; 2012. Gilead Sciences, Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

22. ARV Interactions with Antiepileptics • Antiepileptic drugs: Carbemazepine, phenytoin, phenobarbital have two-way drug interactions • They are P450 inducers: may decrease levels of ARVs that are P450 substrates (PI, NNRTI, maraviroc, elvitegravir) • They are P450 substrates: ARVs that are P450 inducers/inhibitors (PI, NNRTI, cobicistat) may affect antiepileptic efficacy/toxicity • Levetiracetam not metabolized by P450, recommend as alternative

23. Managing ARV Interactions with Antiepileptics:Carbemazepine, Phenytoin, & Phenobarbital DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

24. ARV Interactions with Phosphodiesterase (PDE) Inhibitors • Sildenafil, tadalafil & vardenafil • Metabolized by P450 (are P450 substrates) • NNRTIs induce P450, decreasing PDE inhibitor; may need to increase PDE based on clinical effect • PIs & elvitegravir/cobicistat inhibit P450, increasing PDE inhibitor, increasing risk of adverse events • Used to treat erectile dysfunction (ED), pulmonary arterial hypertension (PAH) and benign prostatic hyperplasia (BPH)

25. Managing ARV Interactions with Phosphodiesterase (PDE) Inhibitors DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

26. ARV Interactions with Antiplatelets/Anticoagulants • Clopidogrel • Prodrug activated by P450; active metabolite decreased by NNRTI etravirine • Warfarin • Metabolized by P450; levels affected by NNRTIs & PIs; elvitegravir/cobicistat unknown • Requires cautious dosing and frequent INR monitoring with ART change • Rivaroxaban • Metabolized by P450; May be affected by PIs

27. Managing ARV Interactions with Antiplatelets/Anticoagulants DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

28. Summary • ART presents higher potential for drug interactions • Aging patients may present more comorbidities and therefore greater potential for drug interactions • Review medications at every patient visit • Check for drug interactions • Ask about over the counter medications

29. ARV Drug Interaction Resources • F/C AETC or HIV Warmline Consultation [fcaetc.org/Consultation] • DHHS HIV Guidelines (Tables 14-16) [www.aidsinfo.nih.gov] • University of Liverpool HIV iChart app for iPhone and Android [www.hiv-druginteractions.org]

30. Case from the Clinic • 50 yo female, HIV/AIDS diagnosed this month on hospital admission • Creole-speaking, recently immigrated from Bahamas • CD4 155 (7%), HIV RNA 1,000,000 • Baseline genotype: K103N (resistance to EFV and NVP) • HBV co-infection, toxoplasmosis, oral thrush, pulmonary arterial hypertension and GERD

31. Case from the Clinic • Presents to HIV clinic with her daughter (caretaker) following hospital discharge • Daughter has limited time to assist in care • Daughter suggests patient has difficulty with complex instructions • Requests simplest ART regimen • PI-based regimen is started: tenofovir/emtricitabine + atazanavir + ritonavir

32. Case from the Clinic • Inpatient notes reviewed • Discharge medication list from hospital: • Phenytoin • Leucovorin • Sulfadiazine • Pyrimethamine • Pantoprazole • Sildenafil • Fluconazole

33. Which medication combination are you concerned about? • ATV/r + pantoprazole • ATV/r + sildenafil • ATV/r + phenytoin • All of the above

34. Antiretroviral Drug Interactions & Polypharmacy Elizabeth Sherman, PharmD, AAHIVE HIV/AIDS Clinical Pharmacy Specialist, Memorial Healthcare System Assistant Professor, Nova Southeastern University Faculty, Florida/Caribbean AETC