DIQTA 1.0: Drug-Induced QT Prolongation Atlas

ENCORAFENIB

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 Prolongation
BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see CLINICAL PHARMACOLOGY (12.2)]. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib.
Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms [see DOSAGE AND ADMINISTRATION (2.5), ADVERSE REACTIONS (6.1)].
DRUG INTERACTIONS
Drugs That Prolong the QT Interval
BRAFTOVI is associated with dose-dependent QTc interval prolongation [see WARNINGS AND PRECAUTIONS (5.5), CLINICAL PHARMACOLOGY (12.2)]. Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.
DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
New Primary Malignancies [see WARNINGS AND PRECAUTIONS (5.1)]
Hemorrhage [see WARNINGS AND PRECAUTIONS (5.3)]
Uveitis [see WARNINGS AND PRECAUTIONS (5.4)]
QT Prolongation [see WARNINGS AND PRECAUTIONS (5.5)]
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
A dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation. Based on a central tendency analysis of QTc in a study of adult patients with melanoma who received the recommended dose of BRAFTOVI in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms [see WARNINGS AND PRECAUTIONS (5.5)].
PATIENT COUNSELING INFORMATION
QT Prolongation
Advise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope [see WARNINGS AND PRECAUTIONS (5.5)].
What are the possible side effects of BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider should do tests before you start taking BRAFTOVI with binimetinib or cetuximab and during your treatment to check your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or if you feel your heart beating irregularly or fast while taking BRAFTOVI with binimetinib or cetuximab. These symptoms may be related to QT prolongation.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24088

Other ADRs

1664

38379923

Odds Ratio = 3.831

Drug Property Information

ATC Code(s):

L01EC03 - encorafenib

L01EC -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:ENCORAFENIB

Active Ingredient UNII:8L7891MRB6

Drugbank ID:DB11718

PubChem Compound:50922675

CTD ID:C000601108

PharmGKB:PA166179872

CAS Number:1269440-17-6

Dosage Form(s):capsule

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
COC(=O)N[C@@H](C)CNC1=NC=CC(=N1)C1=CN(N=C1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F)C(C)C

Reference

1: Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors: A Systematic Review and Meta-analysis.

[Mincu Raluca I,Mahabadi Amir A,Michel Lars,Mrotzek Simone M,Schadendorf Dirk,Rassaf Tienush,Totzeck Matthias]
JAMA Netw Open,2019 Aug 2;2(8):e198890. PMID: 31397860

2: Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management.

[Heinzerling Lucie,Eigentler Thomas K,Fluck Michael,Hassel Jessica C,Heller-Schenck Daniela,Leipe Jan,Pauschinger Matthias,Vogel Arndt,Zimmer Lisa,Gutzmer Ralf]
ESMO Open,2019 May 23;4(3):e000491. PMID: 31231568

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