IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Increased Mortality: An increased risk of death was seen in the SIRTURO^™ treatment group. The imbalance in deaths is unexplained.

QT Prolongation: SIRTURO^™ prolongs the QT interval. An electrocardiogram (ECG) should be obtained before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO^™. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Discontinue SIRTURO^™ and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of >500 ms (confirmed by repeat ECG).

The following may increase the risk for QT prolongation when patients are receiving SIRTURO^™, and therefore ECGs should be monitored closely: 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 hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal.

SIRTURO^™ has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were reported with the use of SIRTURO^™ plus other drugs 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 diminished hepatic reserve. Monitor symptoms and liver-related laboratory tests. Discontinue SIRTURO^™ if aminotransferase elevations are accompanied by total bilirubin elevation >2X ULN; aminotransferase elevations are >8x ULN; or aminotransferase elevations persist beyond 2 weeks.

Drug Interactions: Co-administration of strong systemic CYP3A4 inducers (e.g., rifamycins such as rifampin, rifapentine, and rifabutin) should be avoided. Co-administration with strong systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate clinical monitoring for SIRTURO^™-related adverse reactions is recommended.

HIV-TB Co-infected Patients: There are no clinical data on the combined use of antiretroviral agents and SIRTURO^™ in HIV/MDR-TB co-infected patients, and only limited clinical data on the use in HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy.

Treatment Failure: SIRTURO^™ should be administered by directly observed therapy. SIRTURO^™ should only be administered in combination with at least 3 drugs active against the patient’s TB isolate. Nonadherence to the treatment regimen could result in failure or resistance.

Adverse Reactions

The most common adverse drug reactions reported in greater than or equal to 10.0% of patients treated with SIRTURO^™ compared to the placebo treatment group were nausea (38.0% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%), and additional adverse events reported in greater than or equal to 10.0% of patients and with a higher frequency than the placebo treatment group were hemoptysis (17.7% vs. 11.1%) and chest pain (11.4% vs. 7.4%).

SIRTURO(bedaquiline)-贝达喹啉临床应用指导
贝达喹啉（bedaquiline），曾称TMC207、R207910，商品名：斯耐瑞（SIRTURO），是近四十余年来问世的唯一抗结核新药。该药属是新型二芳基喹啉类抗分枝杆菌药物，通过抑制结核分枝杆菌ATP合成酶质子泵的活性影响结核分枝杆菌的ATP合成，发挥抗菌及杀菌作用。体外研究表明，贝达喹啉对结核分枝杆菌敏感菌株和耐药菌株均具有同等的杀菌活性，对休眠菌也具有良好的灭菌作用，与传统的抗结核药物之间无交叉耐药性。

Ⅰ期临床试验显示，贝达喹啉对人体的安全性和耐受性良好。贝达喹啉联合背景方案治疗耐多药结核病的II期多中心、分层、随机双盲、安慰剂对照研究显示，贝达喹啉可加速痰结核分枝杆菌培养阴转速度，提高耐多药结核病的治疗效果。美国食品药品管理局（US-FDA）于2012年12月批准了该药上市，用于治疗耐多药肺结核。

 Generic Name and Formulations:
Bedaquiline 100mg; tabs.

Company:
Janssen Therapeutics

Indications for SIRTURO:
As part of combination therapy in pulmonary multi-drug resistant tuberculosis (MDR-TB) only when an effective treatment regimen cannot otherwise be provided. Limitations of use: the safety and efficacy for treatment of latent infection, drug-sensitive, or extra-pulmonary tuberculosis (eg, CNS) has not been established.

Adult Dose for SIRTURO:
Administer by directly observed therapy and in combination with ≥3 other drugs to which the isolate is susceptible. Swallow whole with water. Take with food. ≥18yrs: 400mg once daily for 2 weeks followed by 200mg three times weekly (≥48hrs between doses) for 22 weeks.

Children's Dose for SIRTURO:
<18yrs: not established.

Pharmacological Class:
Diarylquinoline.

Warnings/Precautions:
Increased risk of mortality. Increased risk of QT prolongation in patients with history of Torsade de Pointes, congenital long QT syndrome, hypothyroidism, bradyarrhythmias, uncompensated heart failure, electrolyte abnormalities; monitor closely. Obtain ECG prior to therapy, and at least 2, 12, and 24 weeks after starting. Correct any electrolyte abnormalities at baseline and monitor if QT prolongation is detected. Discontinue Sirturo and all other QT prolonging drugs if ventricular arrhythmia or QTcF interval >500ms develops. Monitor ALT/AST, phosphatase, bilirubin at baseline, monthly during treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic drugs if serum aminotransferases >3XULN (repeat testing within 48 hours). Discontinue if aminotransferase elevation with total bilirubin >2XULN, aminotransferase elevation >8XULN, or aminotransferase elevations persist >2 weeks. Severe hepatic or severe renal impairment/ESRD. Pregnancy (Cat.B). Nursing mothers: not recommended.

Interactions:
Avoid concomitant use with strong CYP3A4 inducers (eg, rifampin, rifapentine, rifabutin). Avoid concomitant use with strong CYP3A4 inhibitors (eg, ketoconazole) for >14 days; monitor. Additive QT prolongation with other drugs that prolong the QT interval (eg, fluoroquinolones, macrolides, clofazimine). Avoid alcohol and other hepatotoxic drugs. Sirturo exposure increased with Kaletra (caution).

Adverse Reactions:
Nausea, arthralgia, headache, hemoptysis, chest pain; arrhythmias, syncope (obtain ECG), hepatic dysfunction, QT prolongation.

How Supplied:
Tabs—188