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
0% 0%0%
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
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