DIRA 1.0: Atlas of Drug-induced Rhabdomyolysis

ATAZANAVIR

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIR concern

Severity Score:3

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

WARNINGS AND PRECAUTIONS
Cardiac Conduction Abnormalities
Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions ( 6.2) and Overdosage ( 10) ]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). ECG monitoring should be considered in these patients. [See Clinical Pharmacology ( 12.2) .]
DRUG INTERACTIONS
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ADVERSE REACTIONS
Postmarketing Experience
Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions ( 5.1) ]
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. [See Warnings and Precautions ( 5.1) .]
Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia's correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec. [See Warnings and Precautions ( 5.1) .]

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

Rhabdomyolysis

42868

Other ADRs

5145

14112134

Odds Ratio = 2.816

Drug Property Information

ATC Code(s):

J05AE08 - atazanavir

J05AE - Protease inhibitors
J05A - DIRECT ACTING ANTIVIRALS
J05 - ANTIVIRALS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

J05AR15 - atazanavir

J05AR - "Antivirals for treatment of HIV infections, combinations"
J05A - DIRECT ACTING ANTIVIRALS
J05 - ANTIVIRALS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

Active Ingredient:atazanavir sulfate

Active Ingredient UNII:4MT4VIE29P

Drugbank ID:DB01072

PubChem Compound:148192

CAS Number:198904-31-3

Dosage Form(s):capsule, gelatin coated; powder

Route(s) Of Administrator:oral

Daily Dose:

300.0 mg/day J05AE08

Chemical Structure:

SMILE Code:
CC(C)(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)[C@H](CN(CC2=CC=C(C=C2)C3=CC=CC=N3)NC(=O)[C@H](C(C)(C)C)NC(=O)OC)O)NC(=O)OC

Reference

COHORT STUDY:

N/A

OTHER REFERENCE(S):

1: Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: Results from the SCOLTA project long-term surveillance.

[Madeddu Giordano,De Socio Giuseppe V L,Ricci Elena,Quirino Tiziana,Orofino Giancarlo,Carenzi Laura,Franzetti Marco,Parruti Giustino,Martinelli Canio,Vichi Francesca,Penco Giovanni,Dentone Chiara,Celesia Benedetto Maurizio,Maggi Paolo,Libertone Raffaella,Bagella Paola,Di Biagio Antonio,Bonfanti Paolo,C.I.S.A.I. Group, Italy]
Int J Antimicrob Agents.2015 Mar;45(3):289-94. doi: 10.1016/j.ijantimicag.2014.10.013. Epub 2014 Nov 13. PMID: 25476452

2: No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database.

[Napoli Andrew A,Wood Jennifer J,Coumbis John J,Soitkar Amit M,Seekins Daniel W,Tilson Hugh H]
J Int AIDS Soc.2014 Sep 4;17:19214. doi: 10.7448/IAS.17.1.19214. eCollection 2014. PMID: 25192857

3: Tolerability of HIV postexposure prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation.

[Tosini William,Muller Philippe,Prazuck Thierry,Benabdelmoumen Ghania,Peyrouse Eric,Christian Bernard,Quertainmont Yann,Bouvet Elisabeth,Rabaud Christian]
AIDS.2010 Sep 24;24(15):2375-80. doi: 10.1097/QAD.0b013e32833dfad1. PMID: 20729709

4: Rhabdomyolysis in an HIV-infected patient on anti-retroviral therapy precipitated by high-dose pravastatin.

[Mikhail Nasser,Iskander Elizabeth,Cope Dennis]
Curr Drug Saf.2009 May;4(2):121-2. PMID: 19442105

5: Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir.

[Schmidt Ginelle A,Hoehns James D,Purcell Jessica L,Friedman Robert L,Elhawi Yasir]
J Am Board Fam Med.2007 Jul-Aug;20(4):411-6. PMID: 17615423

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