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Managing the Treatment-Experienced Patient

Eric S. Daar, MDProfessor of Medicine, David Geffen School of Medicine at

UCLAChief, Division of HIV Medicine, Harbor-UCLA Medical Center

Los Angeles, CA

Funded by Merck & Co., Inc.

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Causes of Drug Resistance

• Resistance may be due to:– Presence of resistant virus before treatment– Long duration of nonsuppressive therapy– Treatment early in the ARV era– Patient noncompliance with regimen

• Psychological, psychosocial factors• Substance abuse• Inadequate knowledge about dosing, adverse effects

– Patient intolerance to regimen• Drug-drug or drug-food interactions

• PREVENTION is the best way to avoid resistance

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Evaluation of Patient with Drug-Resistant HIV

• Ensure patient compliance, tolerance• Review treatment and resistance history• Determine level of resistant virus

– Genotypic, phenotypic susceptibility testing

• Set goals– HIV RNA below limit of detection– Delay CD4 decline and clinical deterioration

• Select new regimen carefully– Ideally 2 to 3 fully active agents

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Predicting Mutations by Drug Class

Class Findings

NRTIs • Depends on drug and whether there are preexisting mutations• TAMs may confer resistance to whole class• Rapid selection of single mutations for nonthymidines

First-generation NNRTIs

• Resistance to class emerges rapidly with a single mutation• Low barrier to resistance; “fragile” part of any ARV regimen

PIs • Depends on drug and whether there are preexisting mutations• Early PIs: mutations conferred resistance to whole class• RTV boosting decreases risk of emerging PI and NRTI resistance

Fusion inhibitor • Mutations occur at virologic failure of ENF• Rapid resistance

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Time to Development of Resistance

NRTIs (3TC, FTC) NNRTIs*

Days‒Weeks

NRTIs (ddI, TDF, ABC, AZT, d4T),

entry inhibitor (ENF), PIs†

Weeks‒Months

PIs + RTV‡

Months‒Years

3TC = lamivudine; ABC = abacavir; AZT = zidovudine; d4T = stavudine; ddI = didanosine; ENF = enfuvirtide; FTC = emtricitabine; RTV = ritonavir; TDF = tenofovir. * First-generation NNRTIs (efavirenz, nevirapine, delavirdine).† Non–RTV-boosted PI (saquinavir, indinavir, nelfinavir, fosamprenavir, atazanavir). ‡ RTV-boosted PI (saquinavir, fosamprenavir, lopinavir, atazanavir, darunavir).

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Methods of Resistance Testing

Test Advantages Disadvantages

Genotypic Readily available; inexpensive; improves virologic responses

Complex results with multiple mutations; may miss less common mutations

Phenotypic Commercially available; effective with more advanced failure and complex mutation patterns

May miss less common mutations; may underestimate resistance; must specify clinical cutoffs for each drug

“Virtual” phenotypic

Estimate of phenotypic data with no expense of an actual phenotypic test

All those for genotypic, phenotypic tests; less effective for new drugs not represented in the database

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Resistance Testing in Clinical Practice

Clinical setting Recommendations

Acute infection Test at the time of diagnosis, regardless of whether treatment is to be started. Use genotypic testing.

Chronic infection; treatment naive

Test at the time of diagnosis, regardless of whether treatment is to be started. Use genotypic testing.

Virologic failure Test while on therapy. Use genotypic, phenotypic, or both.

Suboptimal virologic response

Test while on therapy. Use genotypic, phenotypic, or both.

Pregnancy Test before initiation of therapy, or during therapy with detectable plasma HIV RNA. Use genotypic testing if not on therapy, otherwise genotypic, phenotypic, or both.

Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at www.aidsinfo.nih.gov.

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Choosing a New Regimen

• Identify active agents – Drug susceptibility testing– Patient’s treatment history– New agents in existing and novel classes

• Benefits shown in recent clinical trials • Potential adverse effects, mutations, cross-resistance

• If several are available:– Convenience of dosing– Adverse effects– Drug-drug interactions

• Select 2 to 3 “fully active” agents• Perform careful patient follow-up

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New Agents for Consideration in Treatment-Experienced Patient

Drug Class Mechanism

Tipranavir PI Nonpeptidic PI; inhibits viral enzyme

Darunavir PI Nonpeptidic PI; inhibits viral enzyme

Etravirine NNRTI Second-generation NNRTI; inhibits viral enzyme

Maraviroc Entry inhibitor CCR5 coreceptor antagonist prevents virus from entering CD4 cell

Raltegravir Integrase inhibitor Inhibits enzyme that allows viral DNA integration into host DNA

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Trials of Tipranavir: RESIST 1 and 2

CPI = comparator PI; ENF = enfuvirtide; OBR = optimized background regimen; r = ritonavir; TPV = tipranavir. *Reduction in viral load of ≥ 1 log10 copies/mL from baseline.

Hicks CB, et al. Lancet 2006;368:466–75.

Results, 48 wkTPV/r

(n = 746)CPI/r

(n = 737) PTreatment response* 251 (33.6%) 113 (15.3%) < 0.001

With ENF in OBR 72/123 (58.5%) 21/97 (21.6%) < 0.001

HIV RNA < 400 copies/mL 227 (30.4%) 102 (13.8%) < 0.001

HIV RNA < 50 copies/mL 170 (22.8%) 75 (10.2%) < 0.001

Time to treatment failure, median 113 days 0 days < 0.001

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Trials of Darunavir: POWER 1 and 2

Results, 48 wkDRV/r

(n = 131)CPI/r

(n = 124) P

Treatment response* 67/110 (61%) 18/120 (15%) < 0.001

With ENF in OBR 29/36 (81%) 8/35 (23%) < 0.001

HIV RNA < 50 copies/mL 50 (45%) 12 (10%) < 0.001

CPI = comparator PI; DRV = darunavir; ENF = enfuvirtide; OBR = optimized background regimen; r = ritonavir.*Reduction in viral load of ≥ 1 log10 copies/mL from baseline.

Clotet B, et al. Lancet 2007;369:1169–78.

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Trials of Darunavir: TITAN

Results, 48 wkDRV/r

(n = 298)LPV/r

(n = 297) P

HIV RNA < 400 copies/mL 220/286 (77%) 199/293 (68%) < 0.001

HIV RNA < 50 copies/mL 211 (71%) 179 (60%) 0.005

Virologic failures* 28 56

Primary PI mutations 6/28 (21%) 20/56 (36%) ―

NRTI mutations 4/28 (14%) 15/56 (27%) ―

DRV = darunavir; LPV = lopinavir; r = ritonavir. * With available data.

Madruga JV, et al. Lancet 2007;370:49–58.

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Trials of Etravirine: DUET-1 and -2

DUET-1Results, 24 wk1

ETR(n = 304)

OBR(n = 308) P

HIV RNA < 50 copies/mL 170 (56%) 119 (39%) 0.005

Change in CD4 count, mean + 89 + 64 0.002

ETR = etravirine + optimized background regimen; NS = not significant; OBR = optimized background regimen alone.

1. Madruga JV, et al. Lancet 2007;370:29–38.2. Lazzarin A, et al. Lancet 2007;370:39–48.

DUET-2Results, 24 wk2

ETR(n = 295)

OBR(n = 296) P

HIV RNA < 50 copies/mL 183 (62%) 124 (44%) 0.003

Change in CD4 count, mean + 78 + 66 NS

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Entry and Tropism Assays

• 2 co-receptors: CXCR4 and CCR5– R5 virus in ~80% of patients early in disease– X4 or dual/mixed virus in 40% to 50% with longer

treatment history; advanced disease

• Entry assay– Susceptibility to fusion inhibitors (eg, enfuvirtide)

• Tropism assay– Susceptibility to CCR5 antagonists (eg, maraviroc)

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Trials of Enfuvirtide: TORO 1 and 2

TORO 1Results, 24 wk1

ENF(n = 326)

OBR(n = 165) P

Change in HIV RNA* ‒ 1.696 ‒ 0.764 < 0.001

Change in CD4 count, mean + 76.2 + 32.1 < 0.001

HIV RNA < 50 copies/mL 19.6% 7.3% < 0.001

TORO 2Results, 24 wk2

ENF(n = 335)

OBR(n = 169) P

Change in HIV RNA* ‒ 1.429 ‒ 0.648 < 0.001

Change in CD4 count, mean + 65.5 + 38.0 0.02

HIV RNA < 50 copies/mL 41% 9% 0.01

ENF = enfuvirtide + optimized background regimen; OBR = optimized background regimen alone.*Mean change from baseline in log10 copies/mL.

1. Lalezari JP, et al. N Engl J Med 2003;348:2175–85.2. Lazzarin A, et al. N Engl J Med 2003;348:2186–95.

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Trials of Maraviroc: MOTIVATE 1 and 2

MOTIVATE 1Results, 24 wk1

MVC QD(n = 232)

MVC BID(n = 235)

OBR(n = 118) P*

Change in HIV RNA† ‒ 1.82 ‒ 1.95 ‒ 1.03 < 0.05

HIV RNA < 50 copies/mL 42.2% 48.5% 24.6% < 0.001

Change in CD4 count, mean + 107 + 111 + 52 < 0.001

MOTIVATE 2Results, 24 wk2

MVC QD(n = 182)

MVC BID(n = 191)

OBR(n = 91) P*

Change in HIV RNA† ‒ 1.95 ‒ 1.97 ‒ 0.93 < 0.05

HIV RNA < 50 copies/mL 45.6% 40.8% 20.9% < 0.001

Change in CD4 count, mean + 112 + 102 + 64 NR

MVC = maraviroc + optimized background regimen; NR = not reported; OBR = optimized background regimen alone. *Both MVC groups separately vs placebo. †Mean change from baseline in log10 copies/mL.

1. Lalezari J, et al. Available at www.retroconference.org/2007/abstracts/30635.htm.2. Nelson M, et al. Available at www. retroconference.org/2007/abstracts/30636.htm.

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Trials of Raltegravir:BENCHMRK-1 and -2

BENCHMRK-1 and -2Pooled results

RAL (n = 462)

OBR (n = 237)

Subjects with week 24 data n = 286 n = 150

HIV RNA < 400 copies/mL 216 (75.5%) 59 (39.3%)

HIV RNA < 50 copies/mL 179 (62.6%) 50 (33.3%)

Change in CD4 count, mean +89 +35

RAL = raltegravir + optimized background regimen; OBR = optimized background regimen alone.

Isentress™ (raltegravir) tablets [prescribing information].

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New Drugs: Theoretical Concerns

• Cross-class resistance– New drugs in existing classes (eg, tipranavir,

darunavir, etravirine)– Not an issue for first-in-class agents

• New mutations– Drugs in novel classes (eg, enfuvirtide,

maraviroc, raltegravir)– Possible emergence of dual/mixed or X4 virus

(maraviroc)

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If Virologic Suppression Is Not Possible

• Goal is to delay CD4 decline• Treatment cessation not recommended

– 4-month interruption increased morbidity/mortality1

• Option: continue a partially suppressive regimen – NRTIs may have continued antiviral activity2

– Weigh against risk of further resistance– 30% loss of susceptibility to 1 drug in 1 year3

1. Lawrence J, et al. N Engl J Med 2003;349:837–46. 2. Deeks SG, et al. J Infect Dis 2005;192:1537–44.3. Hatano H, et al. Clin Infect Dis 2006;43:1329–36.

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Summary: Treatment Resistance

• Causes– Treatment-related factors– Patient-related factors

• Evaluation– Patient compliance– Treatment history– Drug susceptibility

• Management – Set goal: priority is full virologic suppression– Consider new agents; be aware of risk/benefit

• Follow-up

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Summary: Management Goals

Prevention of resistance1

2

3

Full virologic suppression

If no options for fully active regimen, continue partially suppressive regimen

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Case Example: History

• 43-year-old man with HIV diagnosis in 1992

– Presented with cryptococcal meningitis

– CD4 count 18 cells/mm3

• Initial ARV treatment

– AZT 2 yr

– AZT+3TC 1 yr

– AZT+3TC with IDV through 1998

• Since then

– Therapy modifications (eg, NFV, SQV/r, LPV/r, EFV)

– Multiple reverse transcriptase and protease mutations

– Persistently detectable HIV RNA

– CD4 counts remaining at 50‒200 cells/mm3

– Clinically stable

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Case Example: Current Status

• Treatment: AZT/3TC/ABC + TDF and LPV/r, past 6 mos• Clinically stable, only mild onychomycosis• No hepatitis, diabetes, hypertension• No other medications• No adherence issues

– No drug/alcohol use– No adverse effects

• Current testing– CD4 count 134 cells/mm3

– HIV RNA 33,400 copies/mL

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Case Example: Resistance Testing

ClassGenotypic results

(mutations)Phenotypic results

(fully resistant)*NRTI D67N, T69D, K70K/R, V118I,

M184V, K219QFTC, 3TC, D4T, AZT

PI L33L/F, F53L, I54I/V, A71V, 73S, I84V, L90M

ATV, NFV, RTV

NNRTI K103N DLV, EFV, NVP

ATV = atazanavir; DLV = delavirdine; NFV = nelfinavir; NVP = nevirapine.*Virus is fully resistant to those drugs listed.

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Case Example: New Regimen

• Background regimen – TDF and FTC along with DRV/r– DRV instead of TPV because TPV reduces ETR

levels

• Fully active drugs– ETR, RAL, and MVC – MVC added after negative tropism test

• Outcome– HIV RNA undetectable by 8 wk– Good tolerability

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ISENTRESS® (raltegravir) tablets

• Indications and Usage– ISENTRESS in combination with other antiretroviral agents is indicated for

the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

– This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in 2 controlled studies of ISENTRESS. These studies were conducted in clinically advanced 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults.

– The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

– The safety and efficacy of ISENTRESS have not been established in treatment-naive adult patients or pediatric patients.

– There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.

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ISENTRESS® (raltegravir) tablets

• Warnings and Precautions– Immune Reconstitution Syndrome

• During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.

– Drug Interactions• Caution should be used when co-administering ISENTRESS with

strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir.

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ISENTRESS® (raltegravir tablets)

• Adverse Reactions– The most common adverse reactions (>10%) of all

intensities*, reported in subjects in either the ISENTRESS or the placebo treatment group, regardless of causality were: diarrhea (16.6%, 19.5%), nausea (9.9%, 14.2%), headache (9.7%, 11.7%), and pyrexia (4.9%, 10.3%) respectively.

– The drug-related+ adverse reactions (≥2%) of moderate to severe intensity* reported in subjects in either the ISENTRESS or placebo treatment group were diarrhea (3.7%, 4.6%), nausea (2.2%, 3.2%), and headache (2.4%, 1.4%) respectively.

*Intensities are defined as follows: Mild (awareness of sign or symptom, but easily tolerated); Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).

+Includes adverse reactions at least possibly, probably, or very likely related to the drug.

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ISENTRESS® (raltegravir tablets)Adverse Reactions (cont)

• Adverse Reactions (cont)– Creatine kinase elevations were observed in subjects who

received ISENTRESS. Myopathy and rhabdomyolysis were reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

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CRIXIVAN® (indinavir sulfate)• Indication

– CRIXIVAN in combination with other antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on 2 clinical trials of approximately 1 year’s duration that demonstrated

1) a reduction in the risk of AIDS-defining illnesses or death2) a prolonged suppression of HIV RNA

• Contraindication– CRIXIVAN is contraindicated in patients with clinically significant

hypersensitivity to any of its components.– Inhibition of CYP3A4 by CRIXIVAN can result in elevated plasma

concentrations of the following drugs, potentially causing serious or life-threatening reactions:

Drug Class Drugs within Class that are Contraindicated with CRIXIVAN

Antiarrhythmics Amiodarone

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Sedative/hypnotics Alprazolam, oral midazolam, triazolam

GI motility agents Cisapride

Neuroleptics Pimozide

Drug Interactions With CRIXIVAN: Contraindicated Drugs

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CRIXIVAN® (indinavir sulfate)

• ALERT: Find out about medicines that should NOT be taken with CRIXIVAN.• Nephrolithiasis/urolithiasis has occurred with CRIXIVAN therapy. The cumulative

frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with CRIXIVAN.

• Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of CRIXIVAN.

Selected Warnings

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CRIXIVAN® (indinavir sulfate)

• New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

• Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway (eg, atorvastatin or rosuvastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including CRIXIVAN, are used in combination with these drugs

• Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse reactions, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.

Selected Warnings (cont)

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Selected Drug Interactions

CRIXIVAN® (indinavir sulfate)

Drugs That Should Not Be Coadministered with CRIXIVAN

Drug Class: Drug Name Clinical Comment Antiarrhythmics: amiodarone CONTRAINDICATED due to potential for serious and/or life-threatening

reactions such as cardiac arrhythmias. Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

Sedative/hypnotics: oral midazolam, triazolam, alprazolam

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

GI motility agents: cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Neuroleptic: pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Herbal products: St. John’s wort (Hypericum perforatum)

May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.

Antimycobacterial: rifampin May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors or other coadministered antiretroviral agents.

HMG-CoA Reductase inhibitors: lovastatin, simvastatin

Potential for serious reactions such as risk of myopathy including rhabdomyolysis.

Protease inhibitor: atazanavir Both CRIXIVAN and atazanavir are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of these drugs have not been studied and coadministration of CRIXIVAN and atazanavir is not recommended.

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CRIXIVAN® (indinavir sulfate)

• Indirect hyperbilirubinemia has occurred frequently during treatment with CRIXIVAN and has infrequently been associated with increases in serum transaminases. It is not known whether CRIXIVAN will exacerbate the physiologic hyperbilirubinemia seen in neonates.

• Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/high-power field).

• There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

• In patients with hepatic insufficiency due to cirrhosis, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN. Patients with renal insufficiency have not been studied.

• Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Selected Precautions

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CRIXIVAN® (indinavir sulfate)

• Indinavir is an inhibitor of the cytochrome P-450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects.

• Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.

• There are no adequate and well-controlled studies in pregnant patients. CRIXIVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Selected Precautions (cont)

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Established and Other Potentially Significant Drug InteractionsAlteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction

HIV Antiviral Agents

CRIXIVAN® (indinavir sulfate)

Drug Name Effect Clinical Comment Delavirdine ↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be

considered when taking delavirdine 400 mg three times a day. Didanosine Indinavir and didanosine formulations containing buffer should be

administered at least one hour apart on an empty stomach. Efavirenz ↓ indinavir concentration The optimal dose of indinavir, when given in combination with

efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.

Nelfinavir ↑ indinavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Nevirapine ↓ indinavir concentration Indinavir concentrations may be decreased in the presence of nevirapine. The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Ritonavir ↑ indinavir concentration ↑ ritonavir concentration

The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that the incidence of nephrolithiasis is higher in patients receiving indinavir in combination with ritonavir than those receiving CRIXIVAN 800 mg q8h.

Saquinavir ↑ saquinavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Note: ↑ = increase;↓ = decrease

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Established and Other Potentially Significant Drug Interactions (cont)

CRIXIVAN® (indinavir sulfate)

Drug Name Effect Clinical Comment Antiarrhythmics: bepridil, lidocaine (systemic) and

quinidine

↑ antiarrhythmic agents concentration

Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with CRIXIVAN.

Anticonvulsants: carbamazepine,

phenobarbital, phenytoin

↓ indinavir concentration Use with caution. CRIXIVAN may not be effective due to decreased indinavir concentrations in patients taking these agents concomitantly.

Calcium Channel Blockers, Dihydropyridine: e.g., felodipine, nifedipine,

nicardipine

↑ dihydropyridine calcium channel blockers

concentration

Caution is warranted and clinical monitoring of patients is recommended.

Clarithromycin ↑ clarithromycin concentration

↑ indinavir concentration

The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Inhaled/nasal steroid: Fluticasone

↑ fluticasone concentration Concomitant use of fluticasone propionate and CRIXIVAN may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Fluticasone use is not recommended in situations where CRIXIVAN is coadministered with a potent CYP3A4 inhibitor such as ritonavir unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

HMG-CoA Reductase Inhibitors: atorvastatin,

rosuvastatin

↑ atorvastatin concentration ↑ rosuvastatin concentration

Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors that are not primarily metabolized by CYP3A4, such as pravastatin, or fluvastatin in combination with CRIXIVAN.

Note: ↑ = increase;↓ = decrease

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Established and Other Potentially Significant Drug Interactions (cont)

CRIXIVAN® (indinavir sulfate)Drug Name Effect Clinical Comment

Immunosuppressants: cyclosporine,

tacrolimus, sirolimus

↑ immunosuppressant agents concentration

Plasma concentrations may be increased by CRIXIVAN.

Itraconazole ↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering itraconazole concurrently.

Midazolam (parenteral administration)

↑ midazolam concentration

Concomitant use of parenteral midazolam with CRIXIVAN may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with CRIXIVAN is CONTRAINDICATED.

Ketoconazole ↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered. Rifabutin ↓ indinavir concentration

↑ rifabutin concentration Dose reduction of rifabutin to half the standard dose and a dose increase of CRIXIVAN to 1000 mg (three 333-mg capsules) every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered.

Sildenafil ↑ sildenafil concentration Sildenafil dose should not exceed a maximum of 25 mg in a 48-hour period in patients receiving concomitant indinavir therapy.

Tadalafil ↑ tadalafil concentration Tadalafil dose should not exceed a maximum of 10 mg in a 72-hour period in patients receiving concomitant indinavir therapy.

Antidepressant: Trazodone

↑ trazodone concentration Concomitant use of trazodone and CRIXIVAN may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as CRIXIVAN, the combination should be used with caution and a lower dose of trazodone should be considered.

Vardenafil ↑ vardenafil concentration Vardenafil dose should not exceed a maximum of 2.5 mg in a 24-hour period in patients receiving concomitant indinavir therapy.

Note: ↑ = increase;↓ = decrease

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CRIXIVAN® (indinavir sulfate)Selected Adverse Reactions

• Clinical adverse experiences reported in ≥2% of patients in study ACTG 320 of unknown drug relationship and of severe or life-threatening intensity for CRIXIVAN plus zidovudine plus lamivudine (n=571) – Abdominal pain, 1.9%; asthenia/fatigue, 2.4%; fever, 3.8%;

nausea, 2.8%; diarrhea, 0.9%; vomiting, 1.4%; acid regurgitation, 0.4%; anorexia, 0.5%; anemia, 2.4%; back pain, 0.9%; headache, 2.4%; dizziness, 0.5%; pruritus, 0.5%; rash, 1.1%; cough, 1.6%; difficulty breathing/dyspnea/shortness of breath, 1.8%; nephrolithiasis/urolithiasis (including renal colic, and flank pain with and without hematuria), 2.6%; dysuria, 0.4%; taste perversion, 0.2%.

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Before prescribing ISENTRESS (raltegravir) tablets or

CRIXIVAN (indinavir sulfate), please read the accompanying Prescribing

Information.

CRIXIVAN and ISENTRESS are registered trademarks of Merck & Co., Inc.

20804674(2)-ISN