Transcript Managing the Treatment

Managing the
Treatment-Experienced Patient
Eric S. Daar, MD
Professor of Medicine, David Geffen School of Medicine at
UCLA
Chief, Division of HIV Medicine, Harbor-UCLA Medical Center
Los Angeles, CA
Funded by Merck & Co., Inc.
1
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
2
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
3
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
4
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).
5
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
6
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.
7
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
8
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
9
Trials of Tipranavir: RESIST 1 and 2
Results, 48 wk
Treatment response*
TPV/r
(n = 746)
CPI/r
(n = 737)
P
251 (33.6%)
113 (15.3%)
< 0.001
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
With ENF in OBR
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.
10
Trials of Darunavir: POWER 1 and 2
DRV/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
Results, 48 wk
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.
11
Trials of Darunavir: TITAN
DRV/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
28
56
Primary PI mutations
6/28 (21%)
20/56 (36%)
―
NRTI mutations
4/28 (14%)
15/56 (27%)
―
Results, 48 wk
Virologic failures*
DRV = darunavir; LPV = lopinavir; r = ritonavir.
* With available data.
Madruga JV, et al. Lancet 2007;370:49–58.
12
Trials of Etravirine: DUET-1 and -2
DUET-1
Results, 24 wk1
ETR
(n = 304)
OBR
(n = 308)
P
HIV RNA < 50 copies/mL
170 (56%)
119 (39%)
0.005
+ 89
+ 64
0.002
DUET-2
Results, 24 wk2
ETR
(n = 295)
OBR
(n = 296)
P
HIV RNA < 50 copies/mL
183 (62%)
124 (44%)
0.003
+ 78
+ 66
NS
Change in CD4 count, mean
Change in CD4 count, mean
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.
13
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 1
Results, 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
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
41%
9%
0.01
TORO 2
Results, 24 wk2
HIV RNA < 50 copies/mL
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 1
Results, 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 2
Results, 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 -2
Pooled results
RAL
(n = 462)
OBR
(n = 237)
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%)
+89
+35
Subjects with week 24 data
Change in CD4 count, mean
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
1
2
3
Prevention of resistance
Full virologic suppression
If no options for fully active regimen, continue
partially suppressive regimen
21
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
Class
Genotypic results
(mutations)
Phenotypic results
(fully resistant)*
NRTI
D67N, T69D, K70K/R, V118I,
M184V, K219Q
FTC, 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
25
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.
26
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.
27
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.
29
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)
2)
•
a reduction in the risk of AIDS-defining illnesses or death
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 lifethreatening reactions:
Drug Interactions With CRIXIVAN: Contraindicated Drugs
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
30
CRIXIVAN® (indinavir sulfate)
Selected Warnings
•
•
•
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.
31
CRIXIVAN® (indinavir sulfate)
Selected Warnings (cont)
•
•
•
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and
hyperglycemia have been reported during post-marketing surveillance in HIVinfected 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.
32
CRIXIVAN® (indinavir sulfate)
Selected Drug Interactions
Drugs That Should Not Be Coadministered with CRIXIVAN
Drug Class: Drug Name
Antiarrhythmics: amiodarone
Ergot derivatives: dihydroergotamine,
ergonovine, ergotamine,
methylergonovine
Sedative/hypnotics: oral midazolam,
triazolam, alprazolam
GI motility agents: cisapride
Neuroleptic: pimozide
Herbal products: St. John’s wort
(Hypericum perforatum)
Antimycobacterial: rifampin
HMG-CoA Reductase inhibitors:
lovastatin, simvastatin
Protease inhibitor: atazanavir
Clinical Comment
CONTRAINDICATED due to potential for serious and/or life-threatening
reactions such as cardiac arrhythmias.
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.
CONTRAINDICATED due to potential for serious and/or life-threatening
reactions such as prolonged or increased sedation or respiratory
depression.
CONTRAINDICATED due to potential for serious and/or life-threatening
reactions such as cardiac arrhythmias.
CONTRAINDICATED due to potential for serious and/or life-threatening
reactions such as cardiac arrhythmias.
May lead to loss of virologic response and possible resistance to
CRIXIVAN or to the class of protease inhibitors.
May lead to loss of virologic response and possible resistance to
CRIXIVAN or to the class of protease inhibitors or other
coadministered antiretroviral agents.
Potential for serious reactions such as risk of myopathy including
rhabdomyolysis.
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.
33
CRIXIVAN® (indinavir sulfate)
Selected Precautions
• 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.
34
CRIXIVAN® (indinavir sulfate)
Selected Precautions (cont)
• 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.
35
CRIXIVAN® (indinavir sulfate)
Established and Other Potentially Significant Drug Interactions
Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction
HIV Antiviral Agents
Drug Name
Delavirdine
Didanosine
Efavirenz
Nelfinavir
Nevirapine
Ritonavir
Saquinavir
Effect
Clinical Comment
↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be
considered when taking delavirdine 400 mg three times a day.
Indinavir and didanosine formulations containing buffer should be
administered at least one hour apart on an empty stomach.
↓ 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.
↑ indinavir concentration The appropriate doses for this combination, with respect to
efficacy and safety, have not been established.
↓ 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.
↑ indinavir concentration The appropriate doses for this combination, with respect to
↑ ritonavir concentration 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 concentration The appropriate doses for this combination, with respect to
efficacy and safety, have not been established.
Note: ↑ = increase;↓ = decrease
36
CRIXIVAN® (indinavir sulfate)
Established and Other Potentially Significant Drug Interactions (cont)
Drug Name
Antiarrhythmics: bepridil,
lidocaine (systemic) and
quinidine
Anticonvulsants:
carbamazepine,
phenobarbital, phenytoin
Calcium Channel Blockers,
Dihydropyridine: e.g.,
felodipine, nifedipine,
nicardipine
Clarithromycin
Inhaled/nasal steroid:
Fluticasone
HMG-CoA Reductase
Inhibitors: atorvastatin,
rosuvastatin
Effect
↑ antiarrhythmic agents
concentration
Clinical Comment
Caution is warranted and therapeutic concentration monitoring is recommended for
antiarrhythmics when coadministered with CRIXIVAN.
↓ indinavir concentration
Use with caution. CRIXIVAN may not be effective due to decreased indinavir
concentrations in patients taking these agents concomitantly.
↑ dihydropyridine calcium
channel blockers
concentration
↑ clarithromycin
concentration
↑ indinavir concentration
↑ fluticasone concentration
Caution is warranted and clinical monitoring of patients is recommended.
The appropriate doses for this combination, with respect to efficacy and safety,
have not been established.
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.
↑ atorvastatin concentration Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring,
↑ rosuvastatin concentration 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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CRIXIVAN® (indinavir sulfate)
Established and Other Potentially Significant Drug Interactions (cont)
Drug Name
Immunosuppressants:
cyclosporine,
tacrolimus, sirolimus
Itraconazole
Midazolam (parenteral
administration)
Ketoconazole
Rifabutin
Effect
↑ immunosuppressant
agents concentration
Clinical Comment
Plasma concentrations may be increased by CRIXIVAN.
↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended
when administering itraconazole concurrently.
↑ midazolam
Concomitant use of parenteral midazolam with CRIXIVAN may increase
concentration
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.
↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be
↓ indinavir concentration considered.
Dose reduction of rifabutin to half the standard dose and a dose increase
↑ rifabutin concentration 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 concentration Concomitant use of trazodone and CRIXIVAN may increase plasma
Trazodone
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.
38
Note: ↑ = increase;↓ = decrease
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%.
39
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
40