SIRTURO

SIRTURO- bedaquiline fumarate tablet
Janssen Products, LP

WARNING: INCREASED MORTALITY and QT PROLONGATION

Increased Mortality

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)].

1 INDICATIONS AND USAGE

SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided.

This indication is approved under accelerated approval based on time to sputum culture conversion [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use:

  • Do not use SIRTURO for the treatment of:
    • Latent infection due to Mycobacterium tuberculosis
    • Drug-sensitive tuberculosis
    • Extra-pulmonary tuberculosis
    • Infections caused by non-tuberculous mycobacteria
  • The safety and efficacy of SIRTURO in the treatment of HIV infected patients with MDR-TB have not been established as clinical data are limited [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

  • Administer SIRTURO by directly observed therapy (DOT).
  • Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)].
  • Emphasize the need for compliance with full course of therapy.

2.2 Required Testing Prior to Administration

Prior to treatment with SIRTURO, obtain the following:

2.3 Recommended Dosage in Combination Therapy

Only use SIRTURO in combination with at least 3 other drugs to which the patient’s MDR-TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, SIRTURO treatment may be initiated in combination with at least 4 other drugs to which the patient’s MDR-TB isolate is likely to be susceptible. Refer to the prescribing information of the drugs used in combination with SIRTURO.

See Table 1 for the recommended dosage of SIRTURO in adult and pediatric patients (12 to less than 18 years of age).

Table 1: Recommended Dosage of SIRTURO
Population Dosage
Adult patients (18 years of age and older) 400 mg orally once daily for the first two weeks, followed by 200 mg orally three times per week (with at least 48 hours between doses) for 22 weeks (total duration of 24 weeks)
Pediatric patients (12 to less than 18 years of age) and weighing at least 30 kg

The SIRTURO tablet should be swallowed whole with water and taken with food.

If a dose is missed during the first 2 weeks of treatment, do not administer the missed dose (skip the dose and then continue the daily dosing regimen). From Week 3 onwards, if a 200 mg dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen.

3 DOSAGE FORMS AND STRENGTHS

SIRTURO tablets, 100 mg are uncoated white to almost white round biconvex with debossing of “T” over “207″ on one side and “100″ on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality

An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults (based on the 120-week visit window). One death occurred during the 24 weeks of administration of SIRTURO. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. Only use SIRTURO in patients 12 years of age and older when an effective treatment regimen cannot otherwise be provided [see Adverse Reactions (6)].

5.2 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.

5.3 Risk of Development of Resistance to Bedaquiline

A potential for development of resistance to bedaquiline in M. tuberculosis exists [see Microbiology (12.4)]. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary MDR-TB to reduce the risk of development of resistance to bedaquiline [see Indications and Usage (1)].

5.4 Hepatotoxicity

In clinical trials, more hepatic-related adverse reactions were reported in adults with the use of SIRTURO plus other drugs used to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function. Hepatic-related adverse reactions have also been reported in pediatric patients 14 to less than 18 years of age [see Adverse Reactions (6.1)].

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO if:

  • aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
  • aminotransferase elevations are greater than eight times the upper limit of normal
  • aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks

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