DIQTA 1.0: Drug-Induced QT Prolongation Atlas

PONATINIB HYDROCHLORIDE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIQT concern

Severity Score:2.0

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

WARNINGS AND PRECAUTIONS
Cardiac Arrhythmias
Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were Grade 3 or 4. Other Grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%). For 27 patients, the event led to hospitalization.
OVERDOSAGE
Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 ms and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on Cycle 1 Day 2. The patient experienced fatigue and non-cardiac chest pain on Day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
A QT assessment was performed in 39 patients with cancer who received 30 mg, 45 mg, or 60 mg Iclusig once daily. No large changes in the mean QTc interval (i.e., >20 msec) from baseline were detected in the study. However, a small increase in the mean QTc interval (i.e., <10 msec) cannot be excluded because of study design limitations. In a Phase 3 trial comparing ponatinib with imatinib, the mean change from baseline to worst QTcF value in ponatinib-treated patients (n=124) was <10 msec.
MEDICATION GUIDE
Before you take Iclusig, tell your healthcare provider about all of your medical conditions, including if you:
have a history of blood clots in your blood vessels (arteries or veins)
have heart problems, including heart failure, irregular heartbeats, and QT prolongation

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24081

Other ADRs

26645

38354942

Odds Ratio = 0.658

Drug Property Information

ATC Code(s):

L01EA05 - ponatinib hydrochloride

L01EA -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:ponatinib hydrochloride

Active Ingredient UNII:96R6PU3D8J

Drugbank ID:DB08901

PubChem Compound:24826799

CTD ID:C545373

PharmGKB:PA165980594

CAS Number:943319-70-8

Dosage Form(s):tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
CN1CCN(CC2=CC=C(NC(=O)C3=CC(C#CC4=CN=C5C=CC=NN45)=C(C)C=C3)C=C2C(F)(F)F)CC1

Reference

1: Cardiovascular Toxicity of Tyrosine Kinase Inhibitors Used in Chronic Myeloid Leukemia: An Analysis of the FDA Adverse Event Reporting System Database (FAERS).

[Cirmi Santa,El Abd Asmae,Letinier Louis,Navarra Michele,Salvo Francesco]
Cancers (Basel),2020 Mar 30;12(4):826. PMID: 32235443

2: Cardiovascular Complications of Targeted Therapies for Chronic Myeloid Leukemia.

[Damrongwatanasuk Rongras,Fradley Michael G]
Curr Treat Options Cardiovasc Med,2017 Apr;19(4):24. PMID: 28316033

3: Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit.

[Shah Rashmi R,Morganroth Joel]
Drug Saf,2015 Aug;38(8):693-710. PMID: 26008987

4: QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors.

[Ghatalia P,Je Y,Kaymakcalan M D,Sonpavde G,Choueiri T K]
Br J Cancer,2015 Jan 20;112(2):296-305. PMID: 25349964

5: Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.

[Sonnichsen Daryl,Dorer David J,Cortes Jorge,Talpaz Moshe,Deininger Michael W,Shah Neil P,Kantarjian Hagop M,Bixby Dale,Mauro Michael J,Flinn Ian W,Litwin Jeffrey,Turner Christopher D,Haluska Frank G]
Cancer Chemother Pharmacol,2013 Jun;71(6):1599-607. PMID: 23609479

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