bedaquiline 20 MG Oral Tablet

INDICATIONS AND USAGE 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. SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in 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. ( 1 ) 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. ( 1 ) Limitations of Use Do not use SIRTURO for the treatment of: Latent infection due to Mycobacterium tuberculosis ( M. tuberculosis ) Drug-sensitive pulmonary TB Extra-pulmonary TB Infections caused by non-tuberculous mycobacteria

DOSAGE AND ADMINISTRATION Administer SIRTURO by directly observed therapy (DOT). ( 2.1 ) Emphasize need for compliance with full course of therapy. ( 2.1 ) Prior to administration, obtain ECG, liver enzymes and electrolytes. Obtain susceptibility information for the background regimen against Mycobacterium tuberculosis isolate if possible. ( 2.2 ) Only use SIRTURO in combination with at least 3 other drugs to which the patient's TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, may initiate SIRTURO in combination with at least 4 other drugs to which patient's TB isolate is likely to be susceptible. ( 2.1 ) Recommended dosage in adult patients: 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) once daily for 2 weeks followed by 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) 3 times per week (with at least 48 hours between doses) for 22 weeks. ( 2.3 ) Recommended dosage in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight. ( 2.4 ) Take SIRTURO tablets with food. ( 2.6 ) See full prescribing information for the different methods of administration of SIRTURO 20 mg tablet and administration of the 100 mg tablet. 2.1 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 [see Dosage and Administration (2.6) ]. 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 [see Dosage and Administration (2.6) ]. Emphasize the need for compliance with the full course of therapy. 2.2 Required Testing Prior to Administration Prior to treatment with SIRTURO, obtain the following: Susceptibility information for the background regimen against M. tuberculosis isolate if possible [see Dosage and Administration (2.1) ] ECG [see Warnings and Precautions (5.1) ] Serum potassium, calcium, and magnesium concentrations [see Warnings and Precautions (5.1) ] Liver enzymes [see Warnings and Precautions (5.4) ] 2.3 Recommended Dosage in Adult Patients The recommended dosage of SIRTURO in adult patients is: Table 1: Recommended Dosage of SIRTURO in Adult Patients Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Recommended dosage in pediatric patients is described in Table 2 below [see Dosage and Administration (2.4) ]. 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 [see Clinical Studies (14.1) ] . 2.4 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) Body Weight Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 8 kg to less than 10 kg 80 mg (4 of the 20 mg tablets) orally once daily 40 mg (2 of the 20 mg tablets) orally three times per week 10 kg to less than 15 kg 120 mg (6 of the 20 mg tablets) orally once daily 60 mg (3 of the 20 mg tablets) orally three times per week 15 kg to less than 30 kg 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally once daily 100 mg (1 of the 100 mg tablets OR 5 of the 20 mg tablets) orally three times per week Greater than or equal to 30 kg 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Administer SIRTURO tablets with food. The total duration of treatment with SIRTURO is 24 weeks. When treatment with SIRTURO is considered necessary beyond 24 weeks in patients 16 years and older, and weighing at least 30 kg, treatment may be continued at a dose of 200 mg three times per week [see Clinical Studies (14.1) ] . 2.5 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). 2.6 Method of Administration There is one method of administration of SIRTURO 100 mg tablet and four different methods of administration of SIRTURO 20 mg tablet as follows, each of which must be taken with food: For SIRTURO 100 mg tablet, administer the tablet whole with water. 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 e

WARNINGS AND PRECAUTIONS A mortality imbalance was seen in clinical trials in SIRTURO-treated patients with pulmonary TB due to Mycobacterium tuberculosis resistant to at least rifampin. ( 5.2 ) Hepatotoxicity may occur with use of SIRTURO. Monitor liver-related laboratory tests. Discontinue SIRTURO if evidence of liver injury occurs. ( 5.4 ) 5.1 QTc Prolongation SIRTURO prolongs the QTc interval [see Clinical Pharmacology (12.2) ] . Use with drugs that prolong the QTc interval may cause additive QTc prolongation [see Adverse Reactions (6) ] . In Study 4, where SIRTURO was administered with the QTc prolonging drugs clofazimine and levofloxacin, 5% of patients in the 40-week SIRTURO treatment group experienced a QTc ≥500 ms and 43% of patients experienced an increase in QTc ≥60 ms over baseline. Of the clofazimine- and levofloxacin-treated patients in the 40-week control arm, 7% of patients experienced a QTc ≥500 ms and 39% experienced an increase in QTc ≥60 ms over baseline. Obtain an ECG before initiation of treatment, 2 weeks after initiation, during treatment, as clinically indicated and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable). Obtain electrolytes at baseline and during treatment and correct electrolytes as clinically indicated. The following may increase the risk for QTc prolongation when patients are taking SIRTURO: use with other QTc prolonging drugs a history of Torsade de Pointes a history of congenital long QTc 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 Discontinue SIRTURO if the patient develops: Clinically significant ventricular arrhythmia A QTc interval of greater than 500 ms (confirmed by repeat ECG) If syncope occurs, obtain an ECG to detect QTc prolongation. 5.2 Mortality Imbalance in Clinical Trials 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 (Study 1; 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. In a subsequent active-controlled trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%) patients in the 40-week SIRTURO treatment group, 8/202 (4%) patients in the active-control treatment group including four of 29 patients who received SIRTURO as part of a salvage treatment, and 2/143 (1.4%) patients in the 28-week SIRTURO treatment group [see Adverse Reactions (6.1) ] . 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 TB due to M. tuberculosis resistant to at least rifampin and isoniazid, 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 TB compared to other drugs used to treat TB 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 5 years of age and older [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: transaminase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal transaminase elevations are greater than eight times the upper limit of normal transaminase elevations are greater than five times the upper limit of normal and persist beyond two weeks 5.5 Drug Interactions CYP3A4 Inducers Coadministration of SIRTURO with a moderate or strong CYP3A4 inducer decreases the systemic exposure of bedaquiline and may reduce the therapeutic effect of SIRTURO. Avoid coadministration of SIRTURO with moderate or strong CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin, rifapentine and rifabutin) [see Drug Interactions (7.1) ] . 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 [see Drug Interactions (7.1) ] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4) ] .