SIRTURO(BEDAQUILINE FUMARATE Tablets)

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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), or non-tuberculous mycobacterial infections have 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 48hrs). 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
FDA批准新药Sirturo用于治疗多重耐药的成人结核
FDA刚通过了一种新的抗结核药物Sirturo（bedaquiline），它可用于多重耐药的成人结核当其他治疗手段无效时的联合疗法。这是近四十年来FDA首次批准的抗结核药物。

    多重耐药性肺结核是结核病之一，它是指对四种主要的抗结核药物——异烟肼和利福平无应答反应的一种结核病。结核杆菌通过空气传播，它通常累及肺部，但有时也累及脑、肾和其他脏器。根据美国疾病预防与控制中心（CDC）的数据，，2011年有近900万人患上结核病，其中美国有10528例。

    2012年12月28日，美国食品与药物管理局（FDA）通过加速审批程序批准了Sirturo（bedaquiline，双芳基喹啉类抗结核药）在无其它替代药物可用时作为成人多重耐药的结核（TB）联合治疗的组成部分。Sirturo是首个获准治疗多重耐药TB的药物，且应与其他药物联合治疗TB。该药通过抑制人体内结核杆菌复制和播散所需的酶而发挥作用。

    FDA抗菌药物评估和研究中心办公室主任Edward说：“多重耐药的结核杆菌对全世界造成严重的健康威胁，Sirturo（bedaquiline）为没有其他治疗选择的患者带来了希望。但是，这个药物也有一些严重的危险，医生应确保合理应用该药物，只适用于对其他抗结核治疗无效的患者。”

    尽管在一项临床实验中，Sirturo（bedaquiline）组有9名患者死亡，而安慰剂组只有2名，FDA还是加速通过Sirturo（bedaquiline）临床应用的计划。代理商可向Sirturo（bedaquiline）的制造公司求证该药物的前期实验数据集临床有效性和安全性。

    纳入440例患者的两项2期临床试验确定了Sirturo的安全性和有效性。第一项试验的患者被随机分为接受其他抗结核药物加Sirturo或其他抗结核药物加安慰剂治疗。正在进行的第二项试验中的患者接受其他抗结核药物加Sirturo治疗。

    两项试验中均评估患者痰培养结核菌转阴时间长度（SCC）。第一项试验显示，Sirturo联合治疗组实现SCC的中位时间为83天，而安慰剂联合治疗组为125天。第二项试验显示，SCC的中位时间为57天，支持了第一项试验的结果。临床试验中出现的最常见不良反应包括恶心，关节疼痛和头痛。

    Sirturo的说明书和标签中带有加框警示语，他可影响患者的心电活动（QT间期延长），可能会导致心脏节律异常和并可能致命。试验中接受安慰剂治疗的患者中有2例死亡，接受Sirturo治疗的患者中有9例死亡。接受Sirturo治疗的5例死亡患者和接受安慰剂治疗的2例死亡患者似乎与结核相关，但其余接受Sirturo治疗的患者死亡原因与上述原因不一致。

Pharmacological Class:
Diarylquinoline.

Active Ingredient(s):
Bedaquiline 100mg; tabs.

Company
Janssen Therapeutics
Indication(s):
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.

Pharmacology:
Bedaquiline inhibits mycobacterial ATP (adenosine 5’-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.

Clinical Trials:
Study 1 was a placebo-controlled trial conducted in newly diagnosed patients with MDR pulmonary Mycobacterium tuberculosis. Patients were randomized to either Sirturo plus other drugs used to treat MDR-TB or placebo plus other drugs used to treat MDR-TB. The other drugs consisted of a combination of 5 other antimycobacterials. The Sirturo dose was given as 400mg once daily for the first 2 weeks and then 200mg was given three times weekly for the following 22 weeks.

Time to sputum culture conversion was: the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during therapy. In this ongoing trial, the Sirturo group had a decreased time to culture conversion and improved culture conversion rates vs. placebo at Week 24. Median time to culture conversion was 83 days for Sirturo vs. 125 days for placebo.

Study 2 was similarly designed to Study 1 except that Sirturo or placebo was given for 8 weeks vs. 24 weeks. The Sirturo group had a decreased time to culture conversion and improved culture conversion rates vs. placebo at Week 8. At Weeks 8 and 24, the differences in culture conversion proportions were 38.9% (95% CI: [12.3%, 63.1%] and P=0.004), 15.7% (95% CI: [-11.9%, 41.9%] and P= 0.32), respectively.

Legal Classification:
Rx

Adults:
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. ≥18 years: 400mg once daily for 2 weeks followed by 200mg three times weekly for 22 weeks.

Children:
<18 years: not established.

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 (Category B). Nursing mothers: not recommended.

Interaction(s)
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 Reaction(s)
Nausea, arthralgia, headache, hemoptysis, chest pain; arrhythmias, syncope (obtain ECG), hepatic dysfunction, QT prolongation.

How Supplied:
Tabs—188

LAST UPDATED:
6/28/2013