DIQTA 1.0: Drug-Induced QT Prolongation Atlas

CERITINIB

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:4.0

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

WARNINGS AND PRECAUTIONS
QT Interval Prolongation
QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmia (e.g., torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, 6% of 919 patients with at least one post-baseline electrocardiogram (ECG) assessment had an increase from baseline of QTc > 60 msec. Approximately 1.3% of patients taking ZYKADIA 750 mg under fasted conditions were found to have a QTc > 500 msec. ZYKADIA causes concentration-dependent increases in the QTc interval [see Clinical Pharmacology (12.2)]. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc prolongation.
When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Based on the severity of the adverse reaction, withhold ZYKADIA, with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage and Administration (2.3)].
DRUG INTERACTIONS
Drugs that Prolong QT Interval
ZYKADIA causes concentration-dependent increases in the QTc interval. When possible, avoid coadministration of ZYKADIA with other products with a known potential to prolong the QTc interval [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)].
DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
Clinical Trials Experience
Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included neuropathy (17% comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9% comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
Twelve of 919 patients (1.3%) treated with ZYKADIA 750 mg once daily under fasted conditions with at least one post-baseline ECG assessment were found to have a QTc > 500 msec and 58 patients (6%) had an increase from baseline QTc > 60 msec. In ASCEND-4, a central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 15.3 msec at ZYKADIA 750 mg once daily under fasted conditions. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc interval prolongation [see Warnings and Precautions (5.4)].
Ten of 925 patients (1.1%) had bradycardia defined as < 50 beats/minute [see Warnings and Precautions (5.6)].
PATIENT COUNSELING INFORMATION
Arrhythmias
Inform patients of the risks of QTc interval prolongation and bradycardia. Advise patients to contact their healthcare provider immediately to report new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications [see Warnings and Precautions (5.4, 5.6)].

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24071

Other ADRs

7398

38374189

Odds Ratio = 4.526

Drug Property Information

ATC Code(s):

L01ED02 - ceritinib

L01ED -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:CERITINIB

Active Ingredient UNII:K418KG2GET

Drugbank ID:DB09063

PubChem Compound:57379345

CTD ID:C586847

PharmGKB:

CAS Number:1032900-25-6

Dosage Form(s):capsule; tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
CC(C)OC1=C(NC2=NC=C(Cl)C(N2)=NC2=CC=CC=C2S(=O)(=O)C(C)C)C=C(C)C(=C1)C1CCNCC1

Reference

1: Current perspective: Osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring.

[Schiefer Mart,Hendriks Lizza E L,Dinh Trang,Lalji Ulrich,Dingemans Anne-Marie C]
Eur J Cancer,2018 Mar;91:92-98. PMID: 29413968

2: 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

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