What are the contraindications for using Bedaquiline (Sirturo) in patients with a history of QT interval prolongation, arrhythmias, or impaired liver or kidney function?

Contraindications for Bedaquiline Use

Bedaquiline has only one absolute contraindication: known hypersensitivity to bedaquiline or any of its components. 1

Absolute Contraindication

• Hypersensitivity to bedaquiline is the sole absolute contraindication listed in clinical guidelines 1

Relative Contraindications and High-Risk Situations Requiring Extreme Caution

Pregnancy and Breastfeeding

• Pregnancy and breastfeeding are contraindicated due to lack of adequate or well-controlled studies in pregnant women 1
• It is unknown whether bedaquiline or its metabolites are excreted in human milk 1

Pediatric Population

• Children aged <18 years should not receive bedaquiline as safety and effectiveness have not been established in this population 1
• However, CDC guidelines note bedaquiline may be used on a case-by-case basis in children when no effective alternative exists 1

Severe Hepatic Impairment

• Bedaquiline should be avoided in patients with severe hepatic impairment (Child-Pugh C) 1
• No dose adjustment is required for mild to moderate hepatic impairment (Child-Pugh A or B) 1

Severe Renal Impairment

• Use with caution in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis 1
• No dose adjustment is required for mild to moderate renal impairment 1
• Consider obtaining serum drug levels in patients with renal impairment 1

Critical Cardiac Risk Factors Requiring Intensive Monitoring (Not Absolute Contraindications)

While not absolute contraindications, the following cardiac conditions require weekly ECG monitoring rather than standard monthly monitoring 1:

High-Risk Cardiac Conditions

• History of Torsade de Pointes 1
• Congenital long QT syndrome 1
• Hypothyroidism and bradyarrhythmias 1
• Uncompensated heart failure 1

Electrolyte Abnormalities

• Serum calcium, magnesium, or potassium levels below the lower limits of normal require correction before initiating bedaquiline and weekly ECG monitoring during treatment 1
• Maintain potassium >4.0-4.5 mEq/L and magnesium >2.0 mg/dL during therapy 2

Concurrent QT-Prolonging Medications

• Patients taking other QT-prolonging drugs require weekly ECG monitoring, including: 1
  • Fluoroquinolones (levofloxacin, moxifloxacin) 1
  • Macrolide antibiotics (azithromycin, clarithromycin) 1
  • Clofazimine 1
  • Antiemetics (metoclopramide, domperidone, 5HT3 antagonists) 1, 3

Drug Interactions Requiring Avoidance

CYP3A4 Inducers

• Avoid coadministration with CYP3A4 inducers (rifampin, rifabutin, carbamazepine, phenytoin) as they accelerate bedaquiline metabolism, resulting in reduced efficacy 1

Strong CYP3A4 Inhibitors

• Avoid prolonged coadministration with strong CYP3A4 inhibitors for more than 14 days (ketoconazole, itraconazole, ritonavir) as they reduce metabolism and increase serum concentrations of bedaquiline 1

Mandatory Discontinuation Criteria

Bedaquiline and all other QT-prolonging drugs must be discontinued if: 1

• Clinically significant ventricular arrhythmia develops 1
• QTcF interval >500 ms (confirmed by repeat ECG) 1
• Aminotransferase elevations accompanied by total bilirubin elevation >2 times upper limit of normal 1
• Aminotransferase elevations >8 times upper limit of normal 1

Special Populations Requiring Caution

Elderly Patients

• Limited data exist for patients ≥65 years, though age >65 is an independent risk factor for drug-induced QT prolongation 1, 2

HIV/TB Co-infection

• Limited or no information exists on bedaquiline use in HIV/TB co-infection, though one study showed an inverse association between HIV-positive status and QT prolongation 1, 4

Alcohol or Substance Use

• Manufacturer recommends avoiding alcohol while taking bedaquiline due to limited safety data 1

Clinical Context: Risk-Benefit Assessment

The CDC emphasizes that bedaquiline should only be used when an effective treatment regimen cannot otherwise be provided, given the black box warning regarding increased mortality risk (11.4% vs 2.5% in placebo-controlled trials) 1. However, recent real-world data from California and South Africa show bedaquiline was generally well-tolerated with no cardiac deaths or arrhythmias, despite QTc prolongation occurring in 11-26% of patients 5, 4. The combination of bedaquiline with fluoroquinolones and/or clofazimine increases the risk of QT prolongation 4.82-fold but remains manageable with appropriate monitoring 6.