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贝达喹啉片|SIRTURO(bedaquiline)tablets
2015-05-16 19:19:12 来源: 作者: 【 】 浏览:1922次 评论:0
肺结核新药Sirturo(Bedaquiline)120周跟踪结果发表,显著提高治愈率
2012年12月28日,美国食品药品管理局(FDA)宣布,已加速批准Sirturo(bedaquiline)作为其他治疗无效的成人多耐药肺结核的联合治疗组成部分。Sirturo是首个获准用于治疗多耐药结核的药物,而且应与其他抗结核药物联用。该药通过抑制结核分枝杆菌复制和扩散所必需的酶而发挥疗效。
Sirturo(Bedaquiline)治疗多耐药肺结核的长期跟踪结果。这是一个二期临床,共有160人参加。用药组和对照组都以标准疗法作为背景治疗。用药组前两周使用每日一次400mg Sirturo,然后使用22周每周3次200mg的维持剂量。结果在第120周用药组治愈率为58%,而对照组为32%,但用药组有10人死亡而对照组只有2人死亡。
肺结核是世界第二传染病杀手,2012年有860万病人,其中130万人死于这个疾病。这是比ALS和Ebola严重得多的疾病,但没有人为肺结核药物研发泼冰水,因为肺结核的发病区使不起冰水,甚至连干净的饮用水都是奢侈品。正所谓“石壕村里夫妻别,泪比长生殿上多”。这样严重的大病种40年来只有Sirturo一个全新机理药物上市。肺结核一般需联合多种药物长期治疗,可达2年用药时间,所以Sirturo的半年用药时间算短的。
美国约有1万患者,Sirturo因此在FDA获得孤儿病药权利。Sirturo抑制ATP合成酶,适用人群为对多种药物耐药肺结核病人。这种病人死亡率高达15%,2008年共有15万人死于该病。2012年9月FDA给予Sirturo优先审批,11月FDA专家组以18-0支持其疗效,以11-7支持其安全性。Sirturo有延长QT的副作用,可以导致严重的心脏副作用甚至死亡。在这个实验的79名用药组中有10例死亡,其中1人死于车祸,不算数,但仍有5例和结核病失控有关。另外4例死亡发生在停药较长时间以后,所以难以推断是否是药物造成。据FDA讲Sirturo的超长半衰期(5个月)也无法解释滞后死亡。FDA称多耐药肺结核死亡率高,病人没有其它选择,并如果不及时治愈可能继续传播给他人,所以权衡利弊值得使用,但有黑框警告。

 
HIGHLIGHTS OF PRESCRIBING INFORMATION

 These highlights do not include all the information needed to use SIRTURO ® safely and effectively. See full prescribing information for SIRTURO.
SIRTURO ® (bedaquiline) Tablets

Initial U.S. Approval – 2012
WARNINGS:
See full prescribing information for complete boxed warning.

  • 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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided.
  • QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation.
INDICATIONS AND USAGE

SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. SIRTURO is not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria. (1)

DOSAGE AND ADMINISTRATION

400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food. Swallow SIRTURO tablets whole with water. (2)

DOSAGE FORMS AND STRENGTHS

100 mg tablet. (3)
CONTRAINDICATIONS

None. (4)
WARNINGS AND PRECAUTIONS

  • QT prolongation can occur with SIRTURO. Monitor ECGs frequently. (5.2)
  • Discontinue SIRTURO if significant ventricular arrhythmia or a QTcF interval > 500 ms develops. (5.2)
  • Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs more frequently. (5.2)
  • Hepatic-related adverse drug reactions have been reported with use of SIRTURO. Monitor liver-related laboratory tests. (5.3)
  • Non-adherence to the treatment regimen could result in failure or resistance. (5.6)
ADVERSE REACTIONS
  • The most common adverse reactions reported in ≥10% of patients treated with SIRTURO are nausea, arthralgia, and headache.
  • Additional adverse events reported in ≥10% of patients treated with SIRTURO and with a higher frequency than the placebo treatment group are hemoptysis and chest pain. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Therapeutics, Division of Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
  • Avoid use of systemic potent CYP3A4 inducers with SIRTURO. (7.1)
  • Avoid use for more than 14 consecutive days of systemic strong CYP3A4 inhibitors with SIRTURO unless the benefit outweighs the risk. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended. (7.1)
 USE IN SPECIFIC POPULATIONS
  • No dosage adjustment is required in patients with mild to moderate renal impairment or in patients with mild to moderate hepatic impairment. (8.6, 8.7)
  • Use with caution in patients with severe renal impairment. (8.7)
  • Use with caution in patients with severe hepatic impairment and only when the benefits outweigh the risks; clinical monitoring for SIRTURO-related adverse reactions is recommended. (8.6)
 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 10/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNINGS:

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality

5.2 QT Prolongation

5.3 Hepatic-Related Adverse Drug Reactions (ADRs)

5.4 Drug Interactions

5.5 HIV-TB Co-Infected patients

5.6 Treatment Failure

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

7 DRUG INTERACTIONS

7.1 CYP3A4 Inducers/Inhibitors

7.2 Other Antimicrobial Medications

7.3 Antiretroviral Medications

7.4 QT Interval Prolonging Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamic Effects

12.3 Pharmacokinetics

12.4 Microbiology

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. SIRTURO should be administered by directly observed therapy (DOT).

This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB.

Limitations of Use:

The safety and efficacy of SIRTURO for the treatment of latent infection due to Mycobacterium tuberculosis have not been established. The safety and efficacy of SIRTURO for the treatment of drug-sensitive TB have not been established. In addition, there are no data on the treatment with SIRTURO of extra-pulmonary TB (e.g., central nervous system). The safety and efficacy of SIRTURO for the treatment of infections caused by non-tuberculous mycobacteria (NTM) have not been established. Therefore, use of SIRTURO in these settings is not recommended.

2 DOSAGE AND ADMINISTRATION

SIRTURO should only be used 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, treatment may be initiated with SIRTURO in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible.

Throughout treatment with, and following the last intake of SIRTURO, patients should continue to take their companion drugs as directed.

The recommended dosage of SIRTURO is:

  • Weeks 1–2: 400 mg (4 tablets of 100 mg) once daily with food
  • Weeks 3–24: 200 mg (2 tablets of 100 mg) 3 times per week with food (with at least 48 hours between doses) for a total dose of 600 mg per week.

The total duration of treatment with SIRTURO is 24 weeks. The SIRTURO tablet should be swallowed whole with water. Patients should avoid alcohol use while on treatment.

Missed doses

Patients should be advised of the need to take SIRTURO as prescribed. Compliance with the full course of therapy must be emphasized.

If a dose is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. From Week 3 onwards, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the 3 times a week regimen.

3 DOSAGE FORMS AND STRENGTHS

100 mg Tablet

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 (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 TB, HIV status, or severity of disease could be observed. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see Adverse Reactions (6)].

5.2 QT Prolongation

SIRTURO prolongs the QT interval. An 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. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected [see Adverse Reactions (6.1) and Drug Interactions (7.4)].

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

Discontinue SIRTURO and all other QT prolonging drugs if the patient develops:

    • Clinically significant ventricular arrhythmia
    • A QTcF interval of > 500 ms (confirmed by repeat ECG)
  • Monitor ECGs frequently to confirm that the QTc interval has returned to baseline.
  • If syncope occurs, obtain an ECG to detect QT prolongation.

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

5.3 Hepatic-Related Adverse Drug Reactions (ADRs)

More hepatic-related adverse drug reactions were reported 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 diminished hepatic reserve.

  • Monitor symptoms and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed.
  • An increase of serum aminotransferases to > 3×ULN should be followed by repeat testing within 48 hours. Testing for viral hepatitis should be performed and other hepatotoxic medications discontinued.
  • Evidence of new or worsening liver dysfunction (including clinically significant elevation of aminotransferases and/or bilirubin and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on SIRTURO should prompt additional eva luation by the prescriber.
  • Discontinue SIRTURO if:
    • aminotransferase elevations are accompanied by total bilirubin elevation > 2×ULN
    • aminotransferase elevations are > 8×ULN
    • aminotransferase elevations persist beyond 2 weeks

5.4 Drug Interactions

CYP3A4 inducers/inhibitors

Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Co-administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers used systemically should therefore be avoided while on treatment with SIRTURO [see Drug Interactions (7.1)].

Co-administration of SIRTURO with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, the use of strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided while on SIRTURO, unless the benefit of treatment with the drug combination outweighs the risk [see Drug Interactions (7.1)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.

5.5 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 of SIRTURO in HIV/MDR-TB co-infected patients (n=22) who were not receiving antiretroviral (ARV) therapy [see Drug Interactions (7.3)].

5.6 Treatment Failure

SIRTURO should be administered by directly observed therapy (DOT). SIRTURO should only be administered in combination with at least 3 drugs active against the patient's TB isolate. Isolates from patients who fail to convert or relapse following treatment should be tested for bedaquiline minimum inhibitory concentrations.

6 ADVERSE REACTIONS

The most frequent adverse drug reactions (> 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea, arthralgia, and headache. Additional adverse events reported in ≥10% of patients treated with SIRTURO and with a higher frequency than the placebo treatment group were hemoptysis and chest pain.

6.1 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.

Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 bedaquiline-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 are randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 is an ongoing, open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.

In Study 1 overall, 35.0% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) patients in the placebo treatment group were HIV-infected. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse event.

Table 1: Select Adverse Drug Reactions from Study 1 That Occurred More Frequently Than Placebo During Treatment with SIRTURO
Adverse Drug Reactions SIRTURO Treatment Group
N=79
n (%)
Placebo Treatment Group
N=81
n (%)
*
Terms represented by 'transaminases increased' included transaminases increased, AST increased, ALT increased, hepatic enzyme increased, and hepatic function abnormal.
Reported Adverse Events with a greater incidence in the SIRTURO treatment group but which were not identified as adverse drug reactions.
Nausea 30 (38.0) 26 (32.1)
Arthralgia 26 (32.9) 18 (22.2)
Headache 22 (27.8) 10 (12.3)
Transaminases Increased* 7 (8.9) 1 (1.2)
Blood Amylase Increased 2 (2.5) 1 (1.2)
Hemoptysis 14 (17.7) 9 (11.1)
Chest Pain 9 (11.4) 6 (7.4)
Anorexia 7 (8.9) 3 (3.7)
Rash 6 (7.6) 3 (3.7)

No additional unique ADRs were identified from the uncontrolled Study 3.

Deaths:

In Study 1, there was a statistically significant increased mortality risk by Week 120 in the SIRTURO treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value=0.03, an exact 95% confidence interval of the difference [1.1%, 18.2%]). 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 subjects 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.

QT Prolongation:

In Study 1, the mean increases in QTc, corrected using the Fridericia method, were greater in the SIRTURO treatment group compared to the placebo treatment group from the first week of treatment (9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTc during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). QT increases from baseline in the SIRTURO group persisted even after SIRTURO treatment was stopped. During the trial, there was no clear correlation of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the subjects that died.

In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat TB, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients receiving SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QT segment duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, resulting in QTcF segment durations in excess of 500 ms in one patient.

There were no documented cases of Torsade de Pointes in the safety database [see Warnings and Precautions (5.2)].

Hepatic-Related ADRs (including abnormalities in serum transaminases):

Hepatic ADRs developed in more SIRTURO-treated patients than those treated with other drugs used to treat TB.

Laboratory tests: In both Studies 1 and 2, reversible aminotransferase elevations of at least 3×ULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%] in the placebo treatment group.

Reported adverse reactions: In Study 1, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) patients in the placebo treatment group.

7 DRUG INTERACTIONS

CYP3A4 is the major CYP isoenzyme involved in the metabolism of bedaquiline and the formation of the major N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency.

In vitro, bedaquiline does not significantly inhibit the activity of the following CYP450 enzymes that were tested: CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5 and CYP4A, and it does not induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 activities.

7.1 CYP3A4 Inducers/Inhibitors

Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4.

Rifampin (strong CYP3A4 inducer)

In a drug interaction study of 300 mg bedaquiline and rifampin 600 mg once daily for 21 days in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52%. Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of bedaquiline and rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers used systemically should be avoided [see Pharmacokinetics (12.3)].

Ketoconazole (strong CYP3A4 inhibitor)

Co-administration of 400 mg bedaquiline once daily for 14 days and ketoconazole 400 mg once daily for 4 days in healthy subjects increased the exposure (AUC) to bedaquiline by 22%. Due to the potential risk of adverse reactions to bedaquiline because of the increase in systemic exposure, prolonged co-administration of bedaquiline and strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Pharmacokinetics (12.3)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.

7.2 Other Antimicrobial Medications

The combination of 400 mg bedaquiline once daily for 14 days with isoniazid (300 mg once daily for 5 days)/pyrazinamide (1000 mg once daily for 5 days) in healthy subjects did not result in clinically relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide. No dose-adjustment of isoniazid or pyrazinamide is required during co-administration with SIRTURO. In a placebo-controlled clinical trial in patients with MDR-TB, no major impact of co-administration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

7.3 Antiretroviral Medications

Clinical data in HIV/MDR-TB co-infected patients on the combined use of Kaletra or nevirapine, as well as other antiretroviral agents, with SIRTURO are not available [see Warnings and Precautions (5)].

Kaletra (400 mg lopinavir/100 mg ritonavir)

In a healthy volunteer drug interaction study of 400 mg single dose bedaquiline and Kaletra twice daily for 24 days, exposure (AUC) to bedaquiline was increased by 22%. SIRTURO must be used with caution when co-administered with Kaletra and only if the benefit outweighs the risk [see Warnings and Precaution (5.5) and Pharmacokinetics (12.3)].

Nevirapine

Co-administration of bedaquiline 400 mg single dose and nevirapine 200 mg twice daily for 4 weeks with bedaquiline did not result in clinically relevant changes in the exposure to bedaquiline in HIV-infected patients. No dosage adjustment of bedaquiline is required when co-administered with nevirapine [see Pharmacokinetics (12.3)].

7.4 QT Interval Prolonging Drugs

In a drug interaction study of bedaquiline and ketoconazole, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval.

In Study 3, mean increases in QTc were larger in the 17 subjects who were using clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in subjects who were not using clofazimine with bedaquiline at Week 24 (mean change from reference of 12.3 ms) [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS




8USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to bedaquiline. In these studies, the corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. There are, however, no adequate and well-controlled studies of SIRTURO in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that drug is concentrated in breast milk.

In rats, treated with bedaquiline at doses 1 to 2 times the clinical dose (based on AUC comparisons), concentrations in milk were 6- to 12-fold higher than the maximum concentration observed in maternal plasma. Pups from these dams showed reduced body weights compared to control animals throughout the lactation period.

Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of SIRTURO in children and adolescents less than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies of SIRTURO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) [see Pharmacokinetics (12.3)]. Based on these results, no dose adjustment is necessary for SIRTURO in patients with mild or moderate hepatic impairment. SIRTURO has not been studied in patients with severe hepatic impairment and should be used with caution in these patients only when the benefits outweigh the risks. Clinical monitoring for SIRTURO-related adverse reactions is recommended [see

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