DIQTA 1.0: Drug-Induced QT Prolongation Atlas

NILOTINIB

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:5.0

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

BOXED WARNING
WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies [see Warnings and Precautions (5.2)]. Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [see Warnings and Precautions (5.2, 5.3, 5.7, 5.12)].
Sudden deaths have been reported in patients receiving Tasigna [see Warnings and Precautions (5.3)]. Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Contraindications (4), Warnings and Precautions (5.2)].
Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [see Drug Interactions (7.1, 7.2)].
Avoid food 2 hours before and 1 hour after taking the dose [see Dosage and Administration (2.1)].
WARNINGS AND PRECAUTIONS
QT Prolongation
Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Electrocardiograms should be performed at baseline, 7 days after initiation of Tasigna, and periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)].
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating Tasigna and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].
Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Dosage and Administration (2.1), Drug Interactions (7.1, 7.2)]. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval [see Warnings and Precautions (5.7, 5.12)].
DOSAGE AND ADMINISTRATION
[Dosage Modification With Concomitant Strong CYP3A4 Inhibitors]
Avoid the concomitant use of strong CYP3A4 inhibitors. Should treatment with any of these agents be required, interrupt therapy with Tasigna. If patients must be coadministered a strong CYP3A4 inhibitor, reduce dosage to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, allow a washout period before adjusting Tasigna dose upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2), Clinical Pharmacology (12.3)].
ADVERSE REACTIONS
Clinical Trials Experience
Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of greater than 500 msec while on study drug.
Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.2)].
The following adverse drug reactions were reported in adult patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (greater than or equal to 1% and less than 10%), uncommon (greater than or equal to 0.1% and less than 1%), and unknown frequency (single events). For laboratory abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 7 and 8, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies:
Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease.
[Drugs That Prolong the QT Interval]
Avoid coadministration of Tasigna with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2), Drug Interactions (7.1), Clinical Pharmacology (12.2)].
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
Tasigna is associated with concentration-dependent QT prolongation. At a dose of Tasigna 400 mg twice daily given without food in healthy subjects, the maximum mean placebo-adjusted QTcF changes were 10.4 msec (90% CI: 2.85, 18.0). After a single dose of Tasigna 800 mg (two times the maximum approved recommended dosage) given with a high fat meal to healthy subjects, the maximum mean placebo-adjusted QTcF changes were) 18.0 msec (90% CI: 9.65, 25.8). Peak plasma concentrations in the QT study were 26% lower than or comparable with those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings and Precautions (5.2), Adverse Reactions (6.1)].
PATIENT COUNSELING INFORMATION
QT Prolongation
Advise patients that Tasigna can cause possibly life-threatening, abnormal heart beat. Advise patients to seek immediate medical attention if symptoms of abnormal heart beat occur, such as feeling light-headed, faint or experiencing an irregular heartbeat [see Warnings and Precautions (5.2)].
MEDICATION GUIDE
Tasigna can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heartbeat, which may lead to sudden death.
You may lower your chances for having QTc prolongation with Tasigna if you:
Take Tasigna on an empty stomach:
Avoid eating food for at least 2 hours before the dose is taken, and
Avoid eating food for at least 1 hour after the dose is taken.
Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract during treatment with Tasigna. Food and grapefruit products increase the amount of Tasigna in your body.
Avoid taking other medicines or supplements with Tasigna that can also cause QTc prolongation.
Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
Do not take any other medicine during treatment with Tasigna unless your healthcare provider tells you it is okay to do so.
If you cannot swallow Tasigna capsules whole, you may open the Tasigna capsule and sprinkle the contents of each capsule in 1 teaspoon of applesauce (puréed apple). Swallow the mixture right away (within 15 minutes). For more information, see “How should I take Tasigna?
USE IN SPECIFIC POPULATIONS
Hepatic Impairment
Reduce the Tasigna dosage in patients with hepatic impairment and monitor the QT interval closely in these patients [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

640

23452

Other ADRs

70914

38310673

Odds Ratio = 14.744

Drug Property Information

ATC Code(s):

L01EA03 - nilotinib

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

Active Ingredient:NILOTINIB

Active Ingredient UNII:F41401512X

Drugbank ID:DB04868

PubChem Compound:644241

CTD ID:C498826

PharmGKB:PA165958345

CAS Number:641571-10-0

Dosage Form(s):capsule

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
CC1=CN(C=N1)C1=CC(NC(=O)C2=CC=C(C)C(NC3=NC=CC(=N3)C3=CN=CC=C3)=C2)=CC(=C1)C(F)(F)F

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