DIRA 1.0: Atlas of Drug-induced Rhabdomyolysis

POSACONAZOLE

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
Arrhythmias and QT Prolongation
Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.
Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].
DRUG INTERACTIONS
CYP3A4 Substrates
Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].
CONTRAINDICATIONS
QT Prolongation with Concomitant Use with CYP3A4 Substrates
Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].
ADVERSE REACTIONS
The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:
Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]
[CYP3A4 Substrates]
Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].
PATIENT COUNSELING INFORMATION
Drug Interactions
Advise patients to inform their physician immediately if they:
develop severe diarrhea or vomiting.
are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
Posaconazole delayed-release tablets may cause serious side effects, including:
problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

Rhabdomyolysis

42905

Other ADRs

1590

14115689

Odds Ratio = 1.449

Drug Property Information

ATC Code(s):

J02AC04 - posaconazole

J02AC - Triazole derivatives
J02A - ANTIMYCOTICS FOR SYSTEMIC USE
J02 - ANTIMYCOTICS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

Active Ingredient:posaconazole

Active Ingredient UNII:6TK1G07BHZ

Drugbank ID:DB01263

PubChem Compound:468595

CAS Number:171228-49-2

Dosage Form(s):solution; suspension; tablet, coated

Route(s) Of Administrator:intravenous; oral

Daily Dose:

300.0 mg/day J02AC04

Chemical Structure:

SMILE Code:
CC[C@@H]([C@H](C)O)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5C[C@](OC5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F

Reference

COHORT STUDY:

N/A

OTHER REFERENCE(S):

1: Rhabdomyolysis Following Initiation of Posaconazole Use for Antifungal Prophylaxis in a Patient With Relapsed Acute Myeloid Leukemia: A Case Report.

[Mody Mayur D,Ravindranathan Deepak,Gill Harpaul S,Kota Vamsi K]
J Investig Med High Impact Case Rep.2017 Feb 1;5(1):2324709617690747. doi: 10.1177/2324709617690747. eCollection 2017 Jan-Mar. PMID: 28203579

2: Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole.

[Dybro Anne Mette,Damkier Per,Rasmussen Torsten Bloch,Hellfritzsch Maja]
BMJ Case Rep.2016 Sep 7;2016. pii: bcr2016216457. doi: 10.1136/bcr-2016-216457. PMID: 27605198

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