Download Complications of Antiretroviral Therapy

Complications of
Antiretroviral Therapy
Paul E. Sax, MD
Associate Professor of Medicine, Harvard Medical School
Clinical Director, Division of Infectious Diseases and HIV Program
Brigham and Women’s Hospital
Boston, MA
Brian A. Boyle, MD, JD
Associate Professor of Medicine, Weill Medical College of Cornell University (courtesy)
New York, NY
Associate Director, ViralED, LLC
Medical Editor, HIVandHepatitis.com
Calvin J. Cohen, MD
Clinical Instructor, Harvard Medical School
Research Director, Harvard Vanguard Medical Associates and Community Research Initiative of
New England
Boston, MA
ART Toxicity: Management Principles
• Mild adverse effects
– Continue therapy
– Patient education, reassurance
• Severe or intolerable adverse effects
– Single drug substitution, same class
– Simultaneous discontinuation of all drugs
– Staggered discontinuation
• First NNRTIs
• NRTIs 5‒7 days later
Potential Toxicities of NRTIs
• Common
–
–
–
–
Lipoatrophy (especially stavudine and zidovudine)
Peripheral neuropathy (didanosine and stavudine)
Bone marrow suppression (zidovudine)
Hypersensitivity reaction (abacavir)
• Uncommon/Rare
– Mitochondrial toxicity (especially stavudine)
– Hepatic steatosis, lactic acidosis (especially
stavudine)
– Myopathy, myositis (zidovudine)
– Pancreatitis (didanosine)
– Renal impairment (tenofovir)
Potential Toxicities of PIs
• Common
– Fat accumulation
– Dyslipidemia
– Hyperbilirubinemia (atazanavir,
indinavir)
– Nephrolithiasis/urolithiasis (indinavir)
– Skin changes (indinavir)
• Uncommon/Rare
–
–
–
–
–
Hepatotoxicity
Hyperglycemia
Increased bleeding in hemophilia
Nephrolithiasis/urolithiasis (atazanavir)
ECG changes (atazanavir)
Potential Toxicities of NNRTIs
• Hepatotoxicity (especially nevirapine)
– Use nevirapine cautiously (CD4 counts <250
cells/mm3 in women or <400 cells/mm3 in men;
regular liver function monitoring)
• Rash (especially nevirapine)
– May induce severe morbidity and mortality
• CNS effects (efavirenz)
– Usually resolve within 4 weeks of starting therapy
• Teratogenicity (efavirenz)
– Pregnancy category D (neural tube defects)
Potential Toxicities of Enfuvirtide (Fusion
Inhibitor)
• Enfuvirtide is the only approved agent in this
class
– No known systemic toxicity
– Injection site reactions in nearly 100%
•
•
•
•
•
Redness
Itching
Swelling
Pain
Hard skin or lumps
Long-term Complications of ART:
Body Fat Alterations
• Lipoatrophy
– Most common morphologic abnormality
– Likely due to mitochondrial toxicity of NRTIs
– Less likely with non-thymidine containing
regimens
• Fat accumulation
– Less common than lipoatrophy
– Thought to be due to PI therapy
Change from baseline,%
Changes in Body Fat Indices with ART
n
Adapted with permission from Dubé MP, et al. J Acquir Immune Defic Syndr
2007;45:508-14.
Lipoatrophy by ART Regimen:
Changes at 144 Weeks
Change in limb fat, %
Change in trunk fat, %
Dubé MP, et al. J Acquir Immune Defic Syndr 2007;45:508-14.
Lipoatrophy by Regimen:
NRTIs vs NRTI-Sparing Regimen
P values at week 96
LPV/EFV vs LPV: 0.023
LPV/EFV vs EFV: <0.001
LPV vs EFV:
0.003
Haubrich RH, et al. 14th Conference on Retroviruses and Opportunistic Infections, 2007.
ACTG 5142
Lipoatrophy by NRTI
Patients with lipoatrophy, %
d4T
ZDV
TDF
50
40
30
20
10
0
Week 48
Week 96
P values at week 96
ZDV vs TDF: <0.001
d4T vs TDF: <0.001
d4T vs ZDV: 0.038
Haubrich RH, et al. 14th Conference on Retroviruses and Opportunistic Infections, 2007.
Lipoatrophy by Regimen:
Effect of Switching Stavudine
Moyle et al
Moyle GJ, et al. AIDS 2006;20:2043-50.
Martin A, et al. AIDS 2004;18:1029-36.
Martin et al
Mitochondrial Toxicity by Regimen:
Effect of Switching Stavudine
mtDNA copies per cell type
Muscle
Apoptosis score
Fat
HIV‒
PBMC
HIV‒
HIV‒
HIV‒
Wk 0 Wk 48
Wk 0 Wk 48
Adapted with permission from McComsey GA, et al. AIDS 2005;19:15-23.
Wk 0 Wk 48
Long-term Complications of ART:
Lipid Effects
Lipid effects include elevated TC, LDL-C, TGs
• PIs
– Highest risk among antiretroviral classes
– Risk is highest with ritonavir (dose-dependent)
• NRTIs
– Highest risk with stavudine, then zidovudine
• NNRTIs
– Efavirenz may increase lipids more than
nevirapine
– Improvement in HDL-C seen with both drugs,
especially nevirapine
Dyslipidemia Due to HIV and ART
Seroconversion
ART begun
Riddler SA, et al. JAMA 2003;289:2978-82.
Lipid Effects of PIs
Drug
TG / VLDL-C
LDL-C
HDL-C
Ritonavir



Lopinavir / ritonavir


/
Tipranavir / ritonavir



Saquinavir / ritonavir



Fosamprenavir / ritonavir



Indinavir / ritonavir



Darunavir / ritonavir

/
?
Atazanavir / ritonavir

/

Nelfinavir
?


Atazanavir


/?
Indinavir



Table created by Stefan Mauss, MD (Center for HIV and Hepatogastroenterology, Düsseldorf,
Germany), using the author’s best judgment about the relative lipid effects of the agents listed,
based on accumulated studies to date. Used with permission of the author.
Management of Dyslipidemia
Apply NCEP guidelines
Lifestyle
changes
Lifestyle + lipid-lowering
therapy (statin);
Consider fibrates if TGs
are main concern
ART
substitution
Challenges of lipid-lowering therapy
Multiple
medications
Drug-drug interactions
(statins, PIs)
NCEP = National Cholesterol Education Program.
Difficulty reaching NCEP
goals despite therapy
Lipid-Lowering Therapy:
Drug-Drug Interactions with ART
Low potential for interaction
Fibrates
Pravastatin
Fluvastatin
Fish oil
Niacin*
Start lowest dose; use cautiously
Atorvastatin
Rosuvastatin
Contraindicated with PIs
Lovastatin
Simvastatin
* In rare cases, can induce insulin resistance.
Long-term Complications of ART:
Insulin Resistance and Diabetes
• Risk factors
–
–
–
–
Reduction in insulin sensitivity with PIs
Long-term exposure to NRTIs
HCV coinfection
Traditional risk factors
• Management
– Fasting glucose level before ART
– Routine glucose monitoring, possible 2-hr GTT
– IGT or diabetes: consider switch from PIs to
NNRTIs
Insulin Resistance by ART Regimen
Difference in
QUICKI
Subgroup
HIV‒
0
OR, insulin
>15 μU/mL
1
Per 1-yr increase in ART:
‒0.27 (‒0.49 to ‒0.05)*
1.59 (1.07‒2.35)*
0.00 (‒0.04 to 0.04)
1.06 (0.99‒1.14)
Indinavir
‒0.05 (‒0.12 to 0.02)
1.14 (1.02‒1.26)*
NNRTIs overall
0.01 (‒0.05 to 0.07)
0.95 (0.84‒1.06)
NRTIs overall
‒0.04 (‒0.07 to ‒0.01)*
1.08 (1.02‒1.13)*
Stavudine
‒0.11 (‒0.17 to ‒0.05)*
1.22 (1.11‒1.35)*
Lamivudine
‒0.06 (‒0.12 to 0.00)*
1.12 (1.02‒1.24)*
HIV+
PIs overall
OR = odds ratio; QUICKI = quantitative insulin sensitivity check index.
* P < 0.05.
Brown TT, et al. AIDS 2005;19:1375-83.
Diabetes by ART Regimen
Group
Prevalence *
Incidence †
Adjusted RR
HIV‒
1
1.4 (0.8‒2.6)
1
HIV+, no Tx
2.21 (1.12‒4.38)
1.7 (0.6‒4.5)
NA
HIV+, HAART
4.64 (3.03‒7.10)
4.7 (3.2‒7.1)
4.11 (1.85‒9.16)
NA = not applicable; RR = rate ratio adjusted for age and body mass index.
* Prevalence based on 1278 men; adjusted for age and body mass index.
† Incidence per 100 person-years, based on 680 men.
Brown TT, et al. Arch Intern Med 2005;165:1179-84.
Long-term Complications of ART:
Cardiovascular Risk
• Risk factors
–
–
–
–
–
–
–
Dyslipidemia
Insulin resistance
Body fat changes
Endothelial dysfunction
Smoking
Duration of ART
Possible increased risk with PIs
• Management
– Continue ART
– Treat/manage cardiovascular risk factors
Myocardial Infarction by ART Regimen
Group
Adjusted RR*
95% CI
All ART
1.16
1.09‒1.23
PIs
1.16
1.10‒1.23
NNRTIs
1.05
0.98‒1.13
p-yr = person-years.
* Relative rate per year of exposure.
Friis-Moller N, et al. N Engl J Med 2007;356:1723-35.
Long-term Complications of ART:
Lactic Acidosis
• Asymptomatic hyperlactatemia
– Mildly elevated blood lactate
– Does not predict lactic acidosis
– May be due to artifacts of sampling
• Symptomatic hyperlactatemia
– Nonspecific symptoms: fatigue, anorexia, weight loss
• Lactic acidosis syndrome
–
–
–
–
Severe symptomatic hyperlactatemia
Metabolic acidosis, hepatomegaly, steatosis
Rare but may be fatal
Stop NRTI treatment
Hyperlactatemia Risk Factors
Significant Risk Factor
OR
95% CI
P
ALT (per 10 U/L) *
1.13
1.001‒1.3
0.03
NRTI treatment *
3.0
1.0‒9.27
0.05
Stavudine (n = 56) †
2.8
1.4‒5.7
0.004
Stavudine/lamivudine (n = 40) †
2.2
1.0‒4.8
0.05
ALT = alanine aminotransferase, OR = odds ratio.
* Multiple logistic regression analysis.
† Unadjusted univariate analysis.
Vrouenraets SM, et al. Antivir Ther 2002;7:239-44.
Long-term Complications of ART:
Distal Sensory Peripheral Neuropathy
• Etiology
–
–
–
–
–
HIV itself
Secondary infections (CMV, syphilis)
Nutritional deficiency
Alcohol abuse
NRTIs (especially stavudine + didanosine)
• Characteristics
– Pain, numbness, loss of sensation
– Tends to involve longest nerves first, hence first evident in
feet
• Management
– Discontinue offending NRTIs
– Adjunctive treatments for persistent pain
Peripheral Neuropathy by ART
Regimen
Regimen
HR
95% CI
P
d4T
1.39
0.84‒2.32
0.20
ddI+HU
2.35
0.69‒8.07
0.18
ddI+d4T
3.50
1.81‒6.77
0.001
ddI+d4T+HU
7.80
3.92‒15.5
0.0001
HR = hazard ratio; HU = hydroxyurea.
Moore RD, et al. AIDS 2000;14:273-8.
Summary: Potential Adverse Effects
NRTIs
Lipoatrophy
Hepatic steatosis
Lactic acidosis
Peripheral neuropathy
Bone marrow suppression
Myopathy
Pancreatitis
Renal impairment
Hypersensitivity
PIs
Fat accumulation
Dyslipidemia
Hepatotoxicity
Hyperglycemia
Hemophilia bleeding
ECG changes
Hyperbilirubinemia
Urologic stones
Skin changes
NNRTIs
Hepatotoxicity
Rash
CNS effects
Teratogenicity
Fusion
inhibitor
(enfuvirtide)
Injection site
reactions
Summary:
Management of Adverse Effects
• Adjunctive strategies:
– Choose agents carefully
– Optimize lifestyle
• Pharmacologic strategies:
– Mild effects: continue therapy
– Moderate effects: single-drug substitution
– Severe effects: discontinuation
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
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.
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.
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.
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.
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.
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
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
CRIXIVAN® (indinavir sulfate)
Established and Other Potentially Significant Drug Interactions (cont)
Drug Name
Immunosuppressants:
cyclosporine,
tacrolimus, sirolimus
Itraconazole
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 (parenteral
↑ midazolam
Concomitant use of parenteral midazolam with CRIXIVAN may increase
administration)
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.
Ketoconazole
↑ indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be
considered.
Rifabutin
↓ indinavir concentration 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.
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%.
Before prescribing
CRIXIVAN (indinavir sulfate), please
read the accompanying Prescribing
Information.
CRIXIVAN is a registered trademark of Merck & Co., Inc.
20707440(2)-CRX