DIQTA 1.0: Drug-Induced QT Prolongation Atlas

RIBOCICLIB

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
KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2) and Drug Interactions (7.4)].
Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of KISQALI plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had a > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.
These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
In MONALEESA-2, on the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3 [see Adverse Reactions (6)].
Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.
Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI therapy [see Dosage and Administration (2.2)].
Avoid the use of KISQALI in patients who already have or who are at significant risk of developing QT prolongation, including patients with:long QT syndrome
uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
electrolyte abnormalities
Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.
[Increased QT Prolongation With Concomitant Use of Tamoxifen]
KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAIs) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI [see Clinical Pharmacology (12.2)].
DRUG INTERACTIONS
Drugs That Prolong the QT Interval
Avoid coadministration of KISQALI with medicinal products with a known potential to prolong QT, such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, and ondansetron) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
QT Interval Prolongation [see Warnings and Precautions (5.3, 5.4)]
Hepatobiliary Toxicity [see Warnings and Precautions (5.5)]
Neutropenia [see Warnings and Precautions (5.6)]
[Clinical Trials Experience]
On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of KISQALI plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on KISQALI plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for KISQALI 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean Cmax at steady-state [see Warnings and Precautions (5.2, 5.3)].
PATIENT COUNSELING INFORMATION
QT Prolongation
Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation [see Warnings and Precautions (5.3, 5.4)].
[Drug Interactions]
Inform patients to avoid grapefruit or grapefruit juice while taking KISQALI [see Drug Interactions (7.1)].
Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs known to prolong the QT interval [see Drug Interactions (7.1, 7.2, 7.4)].
PATIENT PACKAGE INSERT
KISQALI may cause serious side effects, including:
Heart rhythm problems (QT prolongation). KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Your healthcare provider should check your heart and do blood tests before and during treatment with KISQALI. Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you feel dizzy or faint.
NONCLINICAL TOXICOLOGY
Animal Toxicology and/or Pharmacology
In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax).

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

188

23904

Other ADRs

19936

38361651

Odds Ratio = 15.134

Drug Property Information

ATC Code(s):

L01EF02 - ribociclib

L01EF -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:RIBOCICLIB

Active Ingredient UNII:TK8ERE8P56

Drugbank ID:DB11730

PubChem Compound:44631912

CTD ID:C000589651

PharmGKB:PA166153470

CAS Number:1211441-98-3

Dosage Form(s):tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
CN(C)C(=O)C1=CC2=CN=C(NC3=CC=C(C=N3)N3CCNCC3)N=C2N1C1CCCC1

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