DIQTA 1.0: Drug-Induced QT Prolongation Atlas

BEDAQUILINE FUMARATE

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: INCREASED MORTALITY AND QT PROLONGATION
QT Prolongation
QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops [see WARNINGS AND PRECAUTIONS (5.2)].
WARNINGS AND PRECAUTIONS
QT Prolongation
SIRTURO prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected [see ADVERSE REACTIONS (6.1) and DRUG INTERACTIONS (7.4)]. SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
The following may increase the risk for QT prolongation when patients are receiving SIRTURO:
use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine
a history of Torsade de Pointes
a history of congenital long QT syndrome
a history of or ongoing hypothyroidism
a history of or ongoing bradyarrhythmias
a history of uncompensated heart failure
serum calcium, magnesium, or potassium levels below the lower limits of normal
If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.
Discontinue SIRTURO and all other QT prolonging drugs if the patient develops:
Clinically significant ventricular arrhythmia
A QTcF interval of greater than 500 ms (confirmed by repeat ECG)
If syncope occurs, obtain an ECG to detect QT prolongation.
OVERDOSAGE
There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
Increased mortality [see WARNINGS AND PRECAUTIONS (5.1)]
QT Prolongation [see WARNINGS AND PRECAUTIONS (5.2) and CLINICAL PHARMACOLOGY (12.2)]
Hepatotoxicity [see WARNINGS AND PRECAUTIONS (5.4)]
Drug Interactions [see WARNINGS AND PRECAUTIONS (5.5)]
[QT Interval Prolonging Drugs]
In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval.
In Study 3, mean increases in QTc were larger in the 17 adult patients who were taking clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. [see WARNINGS AND PRECAUTIONS (5.2) and CLINICAL PHARMACOLOGY (12.2)].
CLINICAL PHARMACOLOGY
Pharmacodynamics
Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) compared to the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation.
Cardiac Electrophysiology
In Study 1, in adults, the mean increases in QTcF, corrected using the Fridericia method, were greater in the SIRTURO treatment group compared to the placebo treatment group from the first week of treatment (9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTcF during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study week 60.
In Study 3, where adult patients with no treatment options received other QT-prolonging drugs used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QTcF prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients taking SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QTcF segment duration in excess of 480 ms, whereas patients taking at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, and resulted in QTcF segment duration in excess of 500 ms in one patient [see WARNINGS AND PRECAUTIONS (5.2)].
MEDICATION GUIDE
What is the most important information I should know about SIRTURO?
SIRTURO can cause serious side effects, including:
Increased risk of death. Some people who had pulmonary tuberculosis resistant to other antibiotics (multi-drug resistant tuberculosis) and were treated with SIRTURO, had an increased risk in death.
A serious heart rhythm problem called QT prolongation. This condition can cause an abnormal heartbeat in people who take SIRTURO and may lead to death. Your healthcare provider should check your heart and do blood tests before and during treament with SIRTURO. 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.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

274

23818

Other ADRs

4539

38377048

Odds Ratio = 97.266

Drug Property Information

ATC Code(s):

J04AK05 - bedaquiline fumarate

J04AK - Other drugs for treatment of tuberculosis
J04A - DRUGS FOR TREATMENT OF TUBERCULOSIS
J04 - ANTIMYCOBACTERIALS
J - ANTIINFECTIVES FOR SYSTEMIC USE

Active Ingredient:Bedaquiline Fumarate

Active Ingredient UNII:P04QX2C1A5

Drugbank ID:DB08903

PubChem Compound:5388906

CTD ID:C493870

PharmGKB:

CAS Number:843663-66-1

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

86.0 mg/day J04AK05

Chemical Structure:

SMILE Code:
COC1=NC2=C(C=C(Br)C=C2)C=C1[C@@H](C1=CC=CC=C1)[C@@](O)(CCN(C)C)C1=CC=CC2=C1C=CC=C2

Reference

1: Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States.

[Mase Sundari,Chorba Terence,Parks Samuel,Belanger Ann,Dworkin Felicia,Seaworth Barbara,Warkentin Jon,Barry Pennan,Shah Neha]
Clin Infect Dis,2020 Aug 14;71(4):1010-1016. PMID: 31556947

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