antiretroviral drug interactions & polypharmacy

Antiretroviral Drug Interactions & Polypharmacy

Elizabeth Sherman, PharmD, AAHIVEHIV/AIDS Clinical Pharmacy Specialist,

Memorial Healthcare SystemAssistant Professor,

Nova Southeastern UniversityFaculty, Florida/Caribbean AETC

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.

What is your profession?

A. PhysicianB. NurseC. PharmacistD. Medical assistantE. Case managerF. StudentG. Other

A. B. C. D. E. F. G.

0% 0% 0% 0%0%0%0%

Which best describes your patient setting?

A. Outpatient clinicB. Hospital/InpatientC. Other

Outpati

ent clin

ic

Hospita

l/Inpatient

Other

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How comfortable are you in managing drug interactions in HIV-infected patients?

A. Extremely comfortable: I wrote the book on drug interactions.

B. Somewhat comfortable: I keep up on the topic and/or have access to a pharmacist.

C. Uncomfortable: I know they exist but have a difficult time recognizing them.

D. Drug interactions? Isn’t this clinical trials/adherence? A. B. C. D.

0% 0%0%0%

Objectives

• Avoid pitfalls of unintentional polypharmacy in HIV-infected patients

• Review clinically significant drug interactions in patients with multiple diagnoses

Objectives

• Recognize pitfalls of unintentional polypharmacy in HIV-infected patients

• Review clinically significant drug interactions in patients with multiple diagnoses

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

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

Polypharmacy & Aging HIV-Infected Patients

Antiretroviral therapy (ART) transformed HIV into complex chronic disease with multimorbidity

Longer lifespan

Additional disease states

Additional medications

Increased risk of drug-drug interactions (and side effects)

ART Undergoes Pharmacokinetic Transformation

1. Absorption

2. Distribution

3. Metabolism

4. 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

Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes

Drug alone

P450

Con

cent

ratio

nTime

Drug alone

Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes

Drug + Inhibitor

P450

Con

cent

ratio

nTime

Drug alone

Inhibitor blocksP450 enzyme

Drug + InhibitorToo

much drug!

Drug + Inducer

P450

Con

cent

ratio

nTime

Drug alone

Inducer increasesP450 enzyme production

Drug + Inducer

Not enough drug!

Drug Metabolism Occurs via HepaticCytochrome P450 Enzymes

ARV Metabolism and Drug Interaction PotentialARV Drug Class Route of Metabolism Drug Intxn Potential

NRTI Mostly renal MediumNNRTI Liver metabolism: P450 substrates, some are

P450 inducers/inhibitorsHigh

PI Liver metabolism: P450 substrates, most are P450 inhibitors

High

Integrase Inhibitors

Liver metabolism •Raltegravir: UGT1A1 enzyme (not P450)•Elvitegravir: P450 substrate/inducer (Cobicistat: P450 inhibitor)

Medium-High

Entry Inhibitor: CCR5

Liver metabolism: P450 substrate Medium

Entry Inhibitor:Fusion

Peptide undergoes catabolism to amino acids: No known drug interactions

Low

Objectives

• Recognize pitfalls of unintentional polypharmacy in HIV-infected patients

• Review clinically significant drug interactions in patients with multiple diagnoses

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

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

Managing ARV Interactions with StatinsStatin Interacting Antiretroviral(s) Prescribing RecommendationAtorvastatin •Tipranavir + ritonavir Avoid atorvastatin

•Lopinavir + ritonavir Use with caution: lowest necessary atorvastatin dose

•Darunavir + ritonavir•Fosamprenavir ± ritonavir•Saquinavir + ritonavir

Do not exceed 20mg atorvastatin daily

•Nelfinavir Do not exceed 40mg atorvastatin daily

Lovastatin •HIV protease inhibitors•Cobicistat

CONTRAINDICATED

Pitavastatin •Atazanavir ± ritonavir•Darunavir + ritonavir•Lopinavir + ritonavir

No dose limitations

Pravastatin •Darunavir + ritonavir•Lopinavir + ritonavir

No dose limitations

Rosuvastatin •Atazanavir ± ritonavir•Lopinavir + ritonavir

Limit rosuvastatin dose to 10mg once daily

Simvastatin •HIV protease inhibitors•Cobicistat

CONTRAINDICATED

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.

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

Managing ARV Interactions with Anti-Acid Therapy

Anti-acid Atazanavir (ATV) Intxns Rilpivirine (RPV) Intxns Elvitegravir (EVG) Intxns

Al, Mg, Ca Antacids

ATV 2 hrs before or 1 hour after antacids

Antacids 2 hours before or 4 hours after RPV

Separate EVG and antacids by at least 2 hours

H2 Receptor Antagonists (H2RA)

•Atazanavir with ritonavir: ATV/r with or 10 hours after H2RA (max famotidine 40mg BID for treatment naïve; 20mg BID for treatment experienced)•Atazanavir alone: ATV 2 hours before or 10 hours after H2RA (max famotidine 20mg BID for treatment naïve; CONTRAINDICATED for treatment experienced)

H2RA 12 hours before or 4 hours after RPV

No dose adjustment

Proton Pump Inhibitors (PPI)

Atazanavir must be boosted with ritonavir: PPI 12 hours prior to ATV/r (max omeprazole 20mg for treatment naïve; CONTRAINDICATED for treatment experienced)

CONTRAINDICATED No dose adjustment

Bristol-Myers Squibb. Reyataz (atazanavir) package insert. Princeton, NJ; 2012.Tibotec Therapeutics. Edurant (rilpivirine) packageinsert. Raritan, NJ; 2012. Gilead Sciences, Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.

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

Managing ARV Interactions with Antiepileptics:Carbemazepine, Phenytoin, & Phenobarbital

Antiretroviral Effect on ARV/Antiepileptic Drug Clinical Management

PI •PIs inhibit P450, causing increased antiepileptic levels•Antiepileptics induce P450, causing lower PI levels

Avoid; or monitor PI efficacy (viral load) & antiepileptic toxicity (drug levels)

NNRTI •NNRTIs induce P450, causing lower antiepileptic levels•Antiepileptics induce P450, causing lower NNRTI levels

EFV and NVP require close monitoring of ARV levels/efficacy; ETR and RPV CONTRAINDICATED

Maraviroc •Antiepiletics induce P450, causing lower maraviroc levels

Increase maraviroc dose to 600mg BID

Elvitegravir/cobicistat

•Cobicistat inhibits P450, causing increased antiepileptic levels•Antiepileptics induce P450, causing lower elvitegravir & cobicistat levels

Consider alternative anticonvulsant

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.

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)

Managing ARV Interactions with Phosphodiesterase (PDE) Inhibitors

PDE Inhibitor + ARV PDE Inhibitor Dosing Recommendation Based on Indication

Sildenafil + PI •ED: Start 25mg q48H•PAH: CONTRAINDICATED

Sildenafil + elvitegravir/cobicistat

•ED: Max 25mg q48H•PAH: CONTRAINDICATED

Tadalafil + PI •ED: Start 5mg, max 10mg q72H•PAH: Increase dose to max 40mg daily based on tolerability, may require tadalafil discontinuation prior to PI start•BPH: Max dose 2.5mg daily

Tadalafil + elvitegravir/cobicistat

•ED: Max 10mg q72H•PAH: Increase dose to max 40mg daily based on tolerability, may require tadalafil discontinuation prior to EVG/COBI start

Verdenafil + PI •ED: Start 2.5mg q72H

Verdenafil + elvitegravir/cobicistat

•ED: Max 2.5mg q72H

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.

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

Managing ARV Interactions with Antiplatelets/Anticoagulants

Antiplatelet/Anticoagulant Clinical ManagementClopidogrel Avoid coadministration with

etravirine, if possibleWarfarin Monitor INR closely when starting or

stopping NNRTI, PI, or elvitegravir/ cobicistat & adjust warfarin accordingly

Rivaroxaban Avoid use with ritonavir boosted PIs

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.

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

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]

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

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

Case from the Clinic• Inpatient notes reviewed• Discharge medication list from hospital:

– Phenytoin– Leucovorin– Sulfadiazine– Pyrimethamine– Pantoprazole– Sildenafil– Fluconazole

Which medication combination are you concerned about?

A. ATV/r + pantoprazoleB. ATV/r + sildenafilC. ATV/r + phenytoinD. All of the above

A. B. C. D.

3%

89%

8%1%

Antiretroviral Drug Interactions & Polypharmacy

Elizabeth Sherman, PharmD, AAHIVEHIV/AIDS Clinical Pharmacy Specialist,

Memorial Healthcare System

Assistant Professor, Nova Southeastern University

Faculty, Florida/Caribbean AETC