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LANA GERZENSHTEIN, PHARMD, BCPSNORTHWESTERN MEMORIAL HOSPITAL

The Antiretroviral Order/Prescription:

Components to Check

NORTHWESTERN MEMORIAL HOSPITALMARCH 2012

Conflict of Interest Declaration

I have no actual or potential conflict of interest in relation to this activity.

Learning Objectives

Recognize common components of an antiretroviral (ARV) regimen

Identify potential errors associated with an ARV y porder/prescription

Ugh!

Orders for HIV meds!!! ??????HELP!

Highly Active Antiretroviral Therapy (HAART)

Combination therapy consisting of at least 3 antiretroviral (ARV) agents with at least 2 different mechanisms of action

www.cdc.gov. Accessed March 3,2012

Classes of antiretrovirals (ARVs)

Nucleoside reverse transcriptase inhibitors (NRTIs)Nonnucleoside reverse transcriptase inhibitors (NNRTIs)Protease inhibitors (PIs)Integrase inhibitors (IIs)Fusion inhibitorsChemokine receptor antagonists

Entry Inhibitors

> 20 FDA approved agents

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ARV Agents Approved by the FDA Nucleoside Reverse

Transcriptase Inhibitors (NRTIs)

Non-nucleoside Reverse Transcriptase

Inhibitors (NNRTs)Protease Inhibitors

(PIs)Entry Inhibitors Integrase Inhibitors

Abacavir (Ziagen®, ABC)

Delavirdine(Rescriptor®, DLV)

Atazanavir(Reyataz®, ATV)

Chemokine Receptor Antagonist

Raltegravir (Isentress®, RAL)

Didanosine (Videx®, ddI) Efavirenz (Sustiva®, EFV)

Darunavir (Prezista®, DRV)

Maraviroc (Selzentry®)

Emtricitabine(Emtriva®, FTC)

Etravirine(Intelence®, ETV)

Fosamprenavir(Lexiva®, fosAPV)(Emtriva , FTC) (Intelence , ETV) (Lexiva , fosAPV)

Lamivudine(Epivir®, 3TC)

Nevirapine(Viramune®, NVP)

Indinavir(Crixivan®, IDV)

Fusion Inhibitor

Stavudine(Zerit®, d4T)

Rilpivirine(Edurant®, RLV)

Lopinavir/ritonavir(Kaletra®, LPV/r)

Enfuvirtide(Fuzeon®, T-20)

Tenofovir (Viread®, TDF)

Nelfinavir (Viracept®, NFV)

Zidovudine(Retrovir®, AZT)

Ritonavir(Norvir®, RTV)

Saquinavir(Invirase®, SQV)

Tipranavir(Aptivus®, TPV)

FDA Approved ARV Co-formulations

Generic BrandAbacavir/Lamivudine Epzicom®

Abacavir/Lamivudine/Zidovudine Trizivir®

Emtricitabine/Tenofovir Truvada®

Efavirenz/Emtricitabine/Tenofovir Atripla®

Rilpivirine/Emtricitabine/Tenofovir Complera®

Lamivudine/Zidovudine Combivir®

Lopinavir/Ritonavir Kaletra®

Antiretroviral Therapy (ART)-Related Errors

Carcelero et al: 189 patients with 247 admissions21.7% (41/189) patients with 60 errors identified

Merchen et al:248 patients with 381 admissions Significant percentage of 248 patients with 381 admissions551 errors identified

Pastakia et al:72% (49/68) had at least one error56% with potential to cause harm

Snyder et al:77% (20/26) with 69 errors

g p gerrors occur within 24 hours after admission

Types Of Errors

Dosing ErrorsAdministration Errors (timing, food requirements)Drug InteractionsIncorrect Regimens (omission, substitution)g ( , )

Potential results: HIV drug resistance, treatment failure or medication related toxicity

Case Study 1

CJ is a 35 y/o HIV-infected female admitted for treatment of community-acquired pneumonia. In addition to verifying orders for the appropriate antibiotics, you receive the following order. CJ has NKDA and no other maintenance medicationsNKDA and no other maintenance medications.

tenofovir/emtricitabine (Truvada®) 300/200mg, 1 tablet po daily

darunavir (Prezista®) 400mg, 2 tablets po daily

Should we verify these orders or do we need to obtain some more information?

RX Check List

Does the combination seem appropriate?

Is the dosage correct?

Are there administration requirements to address?

Any potential drug interactions?

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RX Check List

Does the combination seem i t ?appropriate?

HAART: Treatment Naïve Patients*

Tenofovir/Emtricitabine

Efavirenz

1 Non-nucleoside Reverse Transcriptase Inhibitor

2 Nucleoside Reverse Transcriptase Inhibitors OR

1 Boosted Protease InhibitorTenofovir/EmtricitabineAtazanavir + ritonavirDarunavir + ritonavir

1 Boosted Protease Inhibitor

Raltegravir

OR1 Integrase Inhibitor

DHHS Guidelines. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 5, 2012

*Preferred Agents: efficacy, side effect profile, ease of administration

Ritonavir: Pharmacokinetic (PK) “Boosting”

Rationale: improve PK of concurrent PIPotent inhibitor of CYP-450 isoenzymesCYP3A4 – primary enzyme involved in metabolism of most PIsPresent in the intestinal tract & liver role in PI first-pass metabolismmetabolismInhibitor of efflux channel P-glycoprotein

Result:Bioavailability of concurrent PI increasesDecreases metabolism of concurrent PI increase in AUC, Cmax, Cmin and t1/2

Zeldin et al. JAC (2004) 53, 4–9.

Ritonavir: Pharmacokinetic (PK) “Boosting”

Clinical advantagesLess frequent dosing of concurrent PI improve adherenceAchieve higher sustained levels high levels of viral suppression in both ARV naïve and PI-experienced population

Ritonavir must be administered at the same time as other PIs in the regimen

Typical “boosting” dose ranges from 100mg daily to a maximum of 200mg twice daily

Full dose (600mg BID) ritonavir is not commonly given and should be a RED FLAG

Zeldin et al. JAC (2004) 53, 4–9.

Ritonavir: Pharmacokinetic (PK) “Boosting”

PIs REQUIRING boosting:DarunavirLopinavir/ritonavir (combined product)SaquinavirqTipranavir

All others: boosting recommended exceptNelfinavir (no PK benefit shown)

• Monographs available for all the classes of antiretrovirals

http://hivinsite.ucsf.edu. Accessed March 7, 2012.

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http://depts.washington.edu/nwaetc. Accessed March 7, 2012. http://www.aidsmeds.com. Accessed March 7, 2012.

RX Check List

Is the dosage correct?

Metabolism/Elimination

NRTIs:Renally excreted, all require dose adjustment with changes in CrCl (usually starting at a CrCl≤50ml/min)E ti b i dj t t f h tiException: abacavir, adjustment for hepatic dysfunction

NNRTs, PIs, maraviroc:Substrates of CYP450 enzymesDose adjustment based on concurrent medications

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 3/5/2012http://hivinsite.ucsf.edu. Accessed March 3. 2012.

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http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 3/5/2012

RX Check List

Are there administration i t t dd ?requirements to address?

Administration Requirements (food)

Empty stomachEfavirenz: increased absorption with high fat meals, can lead to increased CNS adverse effectsDidanosine

With food: enhance absorptionWith food: enhance absorptionAtazanavirRilpivirineEtravirineDarunavirNelfinavirSaquinavirTipranavir

Food administration recommended for all PI-based regimens to improve tolerability

Administration: solutions, food requirements

Nyberg et al, Top Antivir Med, 2011;19:126-131.

Case Study 1

tenofovir/emtricitabine (Truvada®) 300/200mg, 1 tablet po daily

darunavir (Prezista®) 400mg, 2 tablets po daily

Scr: 0.8mg/dl, CrCl: >60ml/min

Combination seem appropriate?Need to add ritonavir 100mg po daily administered at the same time

as darunavir

Dosage correct?

Administration requirements addressed?Instructions should include with food

Drug interactions assessed?

Case Study 2

DM is a 38 y/o HIV-infected male, admitted with a diagnosis of PE, on IV heparin, now starting warfarin. His HAART includes:Tenofovir/emtricitabine (Truvada®) 300/200mg po dailyAtazanavir (Reyataz®) 300mg po dailyAtazanavir (Reyataz®) 300mg po dailyRitonavir (Norvir®) 100mg po dailyYour receive orders for the following:

Omeprazole 20mg po dailyWarfarin 5mg po daily

What are the drug interaction considerations?

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RX Check List

Any potential drug i t ti ?interactions?

ARV: drug-drug interaction potential

NNRTIs, PIs Substrates of CYP450 isoenzyme systemEffects on CYP450 enzymes: Inhibit, induce or mixed properties

MaravirocSubstrate of CYP3A4D i b d t di tiDosing based on concurrent medications

With CYP3A4 inhibitor: 150mg po bid (ritonavir)With CYP3A4 inducer: 600mg po bid (rifampin, efavirenz)

RaltegravirUGT-1A1-mediated glucuronidation

Case Study 2

Warfarin metabolism S-isomer: CYP2C9R-isomer: CYP3A4, 1A2

RitonavirPotent inhibitor of CYP3A4Potent inhibitor of CYP3A4Inducer of CYP2C9!Clinically: higher warfarin dose requirement anticipated

Efavirenz/EtravirineInducers of CYP3A4Inhibitors of CYP2C9,2C19Clinically: Unclear direction

Case Study 2

Requires acidic environment for absorption:Atazanavir:

Treatment experienced patients: PPI is not recommended, H2-blockers may be used with appropriate separation of administration timesTreatment naïve patients: PPIs or H2-blockers are OK with appropriate separation of administration times

Rilpivirine:PPI contraindicated for both treatment naïve and experienced patientsH2-blockers are ok for both treatment naïve and experienced patients with appropriate separation of administration times

http://www.hiv-druginteractions.org/. Accessed March 3, 2012. http://www.hiv-druginteractions.org/. Accessed March 3, 2012.

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Case Study 2

Tenofovir/emtricitabine (Truvada®) 300/200mg po dailyAtazanavir (Reyataz®) 300mg po dailyRitonavir (Norvir®) 100mg po daily

Omeprazole 20mg po dailyp g p yWarfarin 5mg po daily

Combination seem appropriate?Dosage correct? Administration requirements addressed?

Instructions should include with food

Drug interactions assessed? Does pt need acid suppression? If yes, consider H2-blocker. Monitor INR closely and expect need for higher warfarin doses.

Resources: HIV Websites

Guidelines, Educational:www.aidsinfo.nih.govwww.iasusa.org/guidelines/index.htmlwww.aids.ed.orgHivinsite ucsf edu/Hivinsite.ucsf.edu/www.medscape.com/hivwww.hiv-druginteractions.org/

Armstrong, et al. HIV-Associated Resources on the Internet. Top Antivir Med, 2011;19:126-131.

Summary

The approach to the ARV order should include careful consideration of the drug combination, dosing and administration requirements and assessment for drug-drug interactions.M lti l HIV b it il bl fMultiple HIV resource websites are available for reference.Pharmacists familiar with HIV pharmacotherapy can play an important role in reducing order-related errors.TALK TO YOUR PATIENT!

I GOT THIS!

Orders for HIV meds…NO PROBLEM!!!!!

Learning Assessment Question 1:

Which of the following is an ARV combination recommended for treatment naïve patients based on the October, 2011 DHHS guidelines?

A. Tenofovir/Emtricitabine (Truvada®) B. Tenofovir/Emtricitaine (Truvada®)+ Atazanavir

(Reyataz®)C. Efavirenz/Emtricitabine/Tenofovir (Atripla®)D. Ritonavir (Norvir®) + Raltegravir (Isentress®)

Learning Assessment Question 2:

Which of the following ARV(s) require dose adjustment with renal insufficiency?

A. Efavirenz/Emtricitabine/Tenofovir (Atripla®)B. Darunavir (Prezista®)C. Raltegravir (Isentress®)D. Efavirenz (Sustiva®)

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Learning Assessment Question 3:

You receive an order for omeprazole on a patient who’s current medication list includes tenofovir/emtricitabine(Truvada®), and rilpivirine (Edurant®). You decide to?

A. Do nothing, order looks good to you, verify.R d th h i i h th d t H2B. Recommend the physician change the order to an H2-blocker (with appropriate administration separation) due to an interaction between omeprazole and the rilpivirine.

C. Recommend the physician change the order to an H2-blocker (with appropriate administration separation) due to an interaction between omeprazole and the NRTIs.

D. Recommend the physician change the ARV regimen as this combination is not recommended.

References1. Centers for Disease Control and Prevention. Available at

http://www.cdc.gov/hiv/topics/perinatal/resources/meetings/2007/pdf/Lampe_Guidelines_Q&A.pdf. Accessed March 3, 2012.2. FDA-Approved Anti-HIV Medications. Available at http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf.

Accessed March 3, 2012.3. Carcelero E, Tuset M, Martin M, De Lazzari E, Codina C, et al. Evaluation of antiretroviral-related errors and interventions by

the clinical pharmacist in hospitalized HIV-infected patients. HIV Med. 2011; 12(8):494-499.4. Merchen BA, Gerzenshtein L, Scarsi KK, Achenbach C, et al. HIV-Specialized Pharmacists’ Impact on Prescribing Errors in

Hospitalized Patients on Antiretroviral Therapy. Presented at: the 51st Interscience Conference on Antimicrobial Agent and Chemotherapy, September 2011, Chicago, IL.

5. Pastakia SD, Corbett AH, Raasch RH, Napravnik S, et al. Frequency of HIV-Related Medication Errors and Associated Risk Factors in Hospitalized Patients. Ann Pharmacother. 2008;42:491-7.

6. Snyder AM, Klinker K, Orrick JJ, Janelle J, et al. An In-Depth Analysis of Medication Errors in Hospitalized Patients with HIV. Ann Pharmacother. 2011;45:459-68.

7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infectedadults and adolescents. Department of Health and Human Services. October 14, 2011. 1-166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 3, 2012.

8. Zeldin RK, Petruschke, RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53(1):4-9.

9. HIV INSITE. Antiretroviral Drug Profiles. Available at http://hivinsite.ucsf.edu/InSite?page=ar-drugs. Accessed March 7, 2012.

10. The Northwest AIDS Education and Training Center at the University of Washington. Pill Chart. Available at http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf. Accessed March 7, 2012.

11. AIDMEDS Drug Chart. Available at http://aidsmeds.com/articles/DrugChart_10632.shtml. Accessed March 7, 2012.12. Nyberg R, Patterson B, Williams, MM. When Patients Cannot Take Pills: Antiretroviral Drug Formulations for Managing Adult

HIV Infection. Top Antivir Med. 2011;19:126-131.13. University of Liverpool. Interaction Charts. Available at http://www.hiv-druginteractions.org/. Accessed March 3, 2012.14. Armstrong WS, del Rio C. HIV–Associated Resources on the Internet. Top Antivir Med. 2009;17(5): 151-162.