Sirturo Drug Information

SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (2 years and older and weighing at least 8 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid. Limitations of Use: Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive TB or for the treatment of infections caused by non-tuberculous mycobacteria.

Important Administration Instructions Administer SIRTURO by directly observed therapy (DOT). Only use SIRTURO in combination with at least three other drugs to which the patient's 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 four other drugs to which the patient's TB isolate is likely to be susceptible.

Refer to the prescribing information of the drugs used in combination with SIRTURO for further information. SIRTURO (20 mg and 100 mg) must be taken with food. SIRTURO 20 mg are functionally scored tablets which can be split at the scored lines into two equal halves of 10 mg each to provide doses less than 20 mg.

As an alternative method of administration, SIRTURO 20 mg tablets can be dispersed in water and administered or dispersed in water and further mixed with a beverage or soft food, or crushed and mixed with soft food, or administered through a feeding tube. Administer SIRTURO tablets with food. The total duration of treatment with SIRTURO in adults is 24 weeks.

When treatment with SIRTURO is considered necessary beyond 24 weeks, treatment may be continued at a dose of 200 mg three times per week.

Recommended Dosage in Pediatric Patients (2 years and older and weighing at least 8 kg) The recommended dosage of SIRTURO in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight and shown in Table 2: Table 2: Recommended Dosage of SIRTURO in Pediatric Patients (2 years and older and weighing at least 8 kg) Administer SIRTURO tablets with food.

Missed Dose 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 dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen. The total dose of SIRTURO during a 7-day period should not exceed the recommended weekly dose (with at least 24 hours between each intake).

Take with food. For SIRTURO 20 mg tablet, the four different methods of administration are outlined below. Each administration method requires SIRTURO to be taken with food in addition to any soft food or beverage used to administer SIRTURO by the different methods for patients who cannot swallow intact SIRTURO 20 mg tablets.

Methods of Administration of SIRTURO 20 mg Tablet Administration of 20 mg Tablets to Patients Who Can Swallow Intact Tablets: Administer SIRTURO 20 mg tablet whole or split in half along the functional score line into two equal halves of 10 mg each. Administer SIRTURO 20 mg tablet with water. Take with food.

Administration of 20 mg Tablets to Patients Who Cannot Swallow Intact Tablets: Dispersed in Water and Mixed with Beverage or Soft Food For patients who have difficulty swallowing intact tablets, SIRTURO 20 mg tablet can be dispersed in water prior to administration with food. If needed to aid with administration, the dispersed mixture in water can be further mixed with a beverage (e.g., water, milk products, apple juice, orange juice, cranberry juice or carbonated beverage) or soft food (e.g., yogurt, apple sauce, mashed banana or porridge) as follows: Disperse tablets in water (maximum of 5 tablets in 5 mL of water) in a drinking cup. Mix the contents of the cup well until the tablets are completely dispersed and then orally administer the contents of the cup immediately with food.

If needed to aid with oral administration, the dispersed mixture in water can be further mixed with at least 5 mL of beverage or 1 teaspoonful of soft food and then orally administer the contents of the cup immediately. If the total dose requires more than 5 tablets, repeat the above preparation steps with the appropriate number of additional tablets until the desired dose is reached. Ensure no tablet residue is left in the cup, rinse with beverage or add more soft food and orally administer the contents of the cup immediately.

Take with food in addition to any beverage or soft food used to aid in administration. Crushed and Mixed with Soft Food SIRTURO 20 mg tablet can be crushed and mixed with soft food (e.g., yogurt, apple sauce, mashed banana or porridge) immediately prior to use and administered orally. To ensure no tablet residue is left in the container, add more soft food and administer the contents immediately.

Administration Through a Feeding Tube SIRTURO 20 mg tablet can be administered through a feeding tube (8 French or greater) as follows: Disperse 5 tablets or less in 50 mL of non-carbonated water and mix well. Mixture should be white to almost white with visible particles expected. Administer through the feeding tube immediately.

Rinse and flush with 25 mL of additional water to ensure no tablet residue is left in materials used for preparation or the feeding tube. Administer with food.

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Refer to the prescribing information of the drugs used in combination with SIRTURO for their respective adverse reactions. In these studies, patients received SIRTURO in combination with other antimycobacterial drugs.

Studies 1 and 2 were randomized, double-blind, placebo-controlled trials in newly diagnosed patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid. Study 3 was an open-label, noncomparative study with SIRTURO administered as part of an individualized treatment regimen in previously treated patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid, including patients resistant to second-line injectables and/or fluroquinolones. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse reaction.

Study 4 was an open-label, randomized, active-controlled trial in patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin that evaluated a 40-week arm of SIRTURO in combination with other oral antimycobacterial drugs compared with a 40-week active control arm that included an injectable antimycobacterial drug in combination with other oral antimycobacterial drugs. A 28-week arm including SIRTURO, an injectable and other antimycobacterial drugs, was also evaluated in the trial, but recruitment was stopped early due to changes in the standard of care. Common Adverse Reactions Table 3 presents select adverse reactions that occurred more frequently in the SIRTURO arm than the placebo arm in Study 1.

The most common adverse reactions reported in 10% or more patients treated with SIRTURO and occurred more frequently than the placebo arm were nausea, arthralgia, headache, hemoptysis and chest pain. Table 4 presents select adverse reactions occurring in 5% or greater of patients receiving SIRTURO in combination with other antimycobacterial drugs in the 40-week SIRTURO arm in Study 4. The most common adverse reactions reported in 10% or more patients in the 40-week SIRTURO arm were QTc prolongation, nausea, vomiting, arthralgia, transaminases increased, abdominal pain, pruritus, dizziness, headache, chest pain, rash, insomnia, dry skin, and palpitations.

Five of the 9 SIRTURO deaths and the 2 placebo deaths were TB-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight patients in the SIRTURO treatment group was 329 days after last intake of SIRTURO.

The imbalance in deaths is unexplained; no discernible pattern between death and sputum conversion, relapse, sensitivity to other drugs used to treat TB, HIV status, and severity of disease was observed. In the open-label Study 3, 16/233 (6.9%) patients died. The most common cause of death as reported by the investigator was TB (nine patients).

In Study 4, patients originally assigned to non-SIRTURO containing regimens could receive SIRTURO as salvage when the original therapy was not tolerated or ineffective. For the 40-week SIRTURO arm, the most common cause of death was related to TB (five patients). In the 40-week active control arm, which included four of 29 patients who received SIRTURO as part of a salvage treatment, the most common cause of death was related to respiratory disease (e.g., TB, lobar pneumonia, respiratory distress in an HIV-positive patient).

The adjusted difference in proportion of fatal adverse reactions between the 40-week SIRTURO arm and the 40-week active control arm was 1.2%. In the 28-week SIRTURO arm at Week 132, 2/143 (1.4%) patients died; one of the two deaths was also related to TB. The overall mortality for patients treated with SIRTURO was 17/383 (4.4%).

Clinical Studies Experience in Pediatric Patients The safety assessment of SIRTURO in pediatric patients is based on data from 45 pediatric patients in an ongoing, single-arm, open-label, multi-cohort trial. Among the 15 patients, no deaths were reported during the study (Week 120 analysis). Observed laboratory abnormalities were comparable to those in adults.

The most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), and led to discontinuation of SIRTURO in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO and some of the background regimen drugs. The most common adverse reaction was vomiting in 3/15 (20%) patients.

Among these 15 pediatric patients, no deaths were reported during treatment with SIRTURO (Week 24 analysis).

Effect of Other Drugs on SIRTURO Strong and Moderate CYP3A4 Inducers Coadministration of SIRTURO with moderate or strong CYP3A4 inducers may decrease systemic exposure of bedaquiline. CYP3A4 Inhibitors Coadministration of SIRTURO with CYP3A4 inhibitors increases the systemic exposure of bedaquiline which may increase the risk of adverse reactions. Closely monitor patient safety (e.g., liver function) when SIRTURO is coadministered with CYP3A4 inhibitors.

No dose adjustment of SIRTURO is needed when coadministered with CYP3A4 inhibitors.

Other Antimicrobial Medications

No dose adjustment of isoniazid or pyrazinamide is required during coadministration with SIRTURO. In a placebo-controlled clinical trial in adult patients, no major impact of coadministration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

QTc Interval Prolonging Drugs

In clinical trials of adult patients, additional QTc interval prolongation was observed during combination treatment with SIRTURO and other QTc prolonging drugs. In Study 3, concurrent use of clofazimine with SIRTURO resulted in QTc prolongation: mean increases in QTc were larger in the 17 adult patients who were taking clofazimine with bedaquiline at Week 24 (mean change from Day-1 of 32 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean change from Day-1 of 12 ms). Monitor ECGs if SIRTURO is coadministered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if there is evidence of serious ventricular arrhythmia or QTc interval greater than 500 ms.

ECG monitoring should be performed prior to initiation and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs.

Pregnancy Risk Summary Available data from published literature of SIRTURO use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with active TB during pregnancy (see Clinical Considerations ). Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oral administration of bedaquiline to pregnant rats and rabbits during organogenesis at exposures up to 6 times the clinical dose based on AUC comparisons (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Active TB in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death. No embryotoxic effects were found in rats or rabbits at dose exposures up to 6 times the clinical dose exposures based on AUC comparisons.

Pediatric Use The safety and effectiveness of SIRTURO have been established in pediatric patients 2 years and older weighing at least 8 kg. The use of SIRTURO in this pediatric population is supported by evidence from the study of SIRTURO in adults together with additional pharmacokinetic and safety data from the single-arm, open-label, multi-cohort trial that enrolled 45 pediatric patients 2 years to less than 18 years of age with confirmed or probable pulmonary TB caused by M. tuberculosis resistant to at least rifampin who were treated with SIRTURO for 24 weeks in combination with a background regimen. The safety, effectiveness and dosage of SIRTURO in pediatric patients less than 2 years of age and/or weighing less than 8 kg have not been established.

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 (QTc 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.