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ATP adenosine 5'-triphosphate 5'- HIV-1 human immunodeficiency virus type 1 1 MDR-TB multidrug resistant-tuberculosis TMC207 bedaquiline

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TMC207 Tibotec

Janssen Research & Development

TMC207 Mycobacterium tuberculosis M. tuberculosis 5'-

ATP ATP

TMC207

TMC207 TMC207-TiDP13-C208 TMC207-TiDP13-C209

MDR-TB

Fast Track 2012 12

2014 3

TMC207 MDR-TB 1 40

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TMC207 2005 1 2005 8

2015 9

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1.5-1 CTD Module 1.5

CTD Module 1.5 CTD Module 2 2.5.1.1.1 2.5.1.2.1

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2.5.1.2.3 TMC207

2.5.1.3

2.5.1.3.2 2.4

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1.5-2 1.5-3 1.5-4

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R207910BAC1003

TMC207

TMC207-C108

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TMC207-C104 TMC207

TMC207-C109 TMC207

TMC207-TiDP13-C110 / TMC207

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Stage 1MDR-TB

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Stage 2MDR-TB

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CCDS

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Janssen Research & Development, LLC

COMPANY CORE DATA SHEET

Bedaquiline Tablets

Version

以下、非公表のため2頁～25頁を省略

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, for oral use Initial U.S. Approval 2012

WARNINGS: INCREASED MORTALITY; QT PROLONGATION See full prescribing information for complete boxed warning.

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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided. (5.1)

QT Prolongation QT prolongation can occur with SIRTURO. Use with drugs that

prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval >500 ms develops. (5.2)

---------------------------RECENT MAJOR CHANGES---------------------------Indications and Usage (1) 05/2015

----------------------------INDICATIONS AND USAGE----------------------------SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (18 years and older) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO by directly observed therapy (DOT). (1, 2.1)

This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1, 14)

Limitations of Use: Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria (1). Safety and efficacy of SIRTURO in HIV-infected patients with MDR-TB have not been established, as clinical data are limited (14).

-----------------------DOSAGE AND ADMINISTRATION----------------------- 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)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNINGS: INCREASED MORTALITY; QT PROLONGATION 1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions 2.2 Required Testing Prior to Administration 2.3 Recommended Dosage in Combination Therapy

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality 5.2 QT Prolongation 5.3 Hepatotoxicity 5.4 Drug Interactions

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

Only use SIRTURO 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, may initiate SIRTURO in combination with at least 4 other drugs to which patient’s MDR-TB isolate is likely to be susceptible (2.3)

Recommended dosage: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week (with at least 48 hours between doses) for 22 weeks (2.3)

Swallow SIRTURO tablets whole with water and take with food. (2.3)

--------------------DOSAGE FORMS AND STRENGTHS----------------------Tablets: 100 mg (3)

-------------------------------CONTRAINDICATIONS-------------------------------None. (4)

--------------------------WARNINGS AND PRECAUTIONS-------------------- QT prolongation can occur with SIRTURO. Monitor ECGs and

discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval > 500 ms develops. (5.2)

Hepatotoxicity may occur with use of SIRTURO. Monitor liver-related laboratory tests. Discontinue if evidence of liver injury. (5.3)

------------------------------ADVERSE REACTIONS------------------------------ The most common adverse reactions reported in 10% or more of

patients treated with SIRTURO were nausea, arthralgia, headache,hemoptysis and chest pain. (6.1)

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 strong and moderate CYP3A4 inducers with SIRTURO.

(7.1, 7.3) Avoid use for more than 14 consecutive days of systemic strong

CYP3A4 inhibitors with SIRTURO unless the benefit outweighs the risk. Monitor for SIRTURO-related adverse reactions. (7.1)

-----------------------USE IN SPECIFIC POPULATIONS----------------------- Use with caution in patients with severe hepatic impairment and only

when the benefits outweigh the risks. Monitor for SIRTURO-related adverse reactions. (8.6)

Use with caution in patients with severe renal impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised: 12/2015

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 Pharmacodynamics 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

Reference ID: 3857988

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FULL PRESCRIBING INFORMATION

WARNINGS: INCREASED MORTALITY; QT PROLONGATION 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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see Indications and Usage (1) and Warnings and Precautions (5.1)].

QT Prolongation QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT

interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGESIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adults (18 years and older) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO by directly observed therapy (DOT).

This indication is approved under accelerated approval based on time to sputum culture conversion [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use:

Do not use SIRTURO for the treatment of:

o Latent infection due to Mycobacterium tuberculosis o Drug-sensitive tuberculosis o Extra-pulmonary tuberculosis o Infections caused by non-tuberculous mycobacteria

The safety and efficacy of SIRTURO in the treatment of HIV infected patients with MDR-TB have not been established as clinical data are limited [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions

Administer SIRTURO by directly observed therapy (DOT).


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Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)].

Emphasize the need for compliance with 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 (2.3)]

ECG [see Warnings and Precautions (5.2)] Serum potassium, calcium, and magnesium concentrations [see Warnings and

Precautions (5.2)] Liver enzymes [see Warnings and Precautions (5.3)]

2.3 Recommended Dosage in Combination Therapy Only use SIRTURO 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, SIRTURO treatment may be initiated in combination with at least 4 other drugs to which the patient’s MDR-TB isolate is likely to be susceptible. Refer to the prescribing information of the drugs used in combination with SIRTURO.

The recommended dosage of SIRTURO is 400 mg orally once daily for the first two weeks, followed by 200 mg orally three times per week (with at least 48 hours between doses) for 22 weeks (total duration of 24 weeks).

The SIRTURO tablet should be swallowed whole with water and taken with food.

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 200 mg dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen.

3 DOSAGE FORMS AND STRENGTHS SIRTURO tablets, 100 mg are uncoated white to almost white round biconvex with debossing of “T” over “207” on one side and “100” on the other side.

4 CONTRAINDICATIONS None.


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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 tuberculosis, 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. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected [see Adverse Reactions (6.1) and Drug Interactions (7.4)].SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

The following may increase the risk for QT prolongation when patients are receiving SIRTURO:

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 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

If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.

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

o Clinically significant ventricular arrhythmia

o A QTcF interval of greater than 500 ms (confirmed by repeat ECG)

If syncope occurs, obtain an ECG to detect QT prolongation.


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5.3 Hepatotoxicity More hepatic-related adverse reactions were reported with the use of SIRTURO plus other drugs used to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function.

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) atbaseline, 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:

aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal

aminotransferase elevations are greater than eight times the upper limit of normal

aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two 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. Avoid co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers, such as efavirenz, during 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, avoid the use of strong CYP3A4 inhibitors for more than 14 consecutive days 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

Increased mortality [see Warnings and Precautions (5.1)]


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QT Prolongation [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]

Hepatotoxicity [see Warnings and Precautions (5.3)] Drug Interactions [see Warnings and Precautions (5.4)]

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.

Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)]. Refer to the prescribing information of the drugs used in combination with SIRTURO for their respective adverse reactions.

Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 SIRTURO-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1and 3) at the proposed dose. Studies 1 and 2 were 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 was an open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.

In Study 1, 35% 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 1because of an adverse reaction.


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Table 1: Select Adverse Reactions from Study 1 That Occurred More Frequently Than Placebo During Treatment with SIRTURO

Adverse Reactions SIRTURO Treatment Group Placebo Treatment Group N=79 N=81 n (%) n (%)

Nausea 30 (38) 26 (32) Arthralgia 26 (33) 18 (22) Headache 22 (28) 10 (12) Hemoptysis 14 (18) 9 (11) Chest Pain 9 (11) 6 (7) Anorexia Transaminases Increased*

7 (9) 7 (9)

3 (4)1 (1)

Rash 6 (8) 3 (4)Blood Amylase Increased 2 (3) 1 (1) * Terms represented by ‘transaminases increased’ included transaminases increased, AST increased, ALT increased, hepatic enzyme increased, and hepatic function abnormal.

No additional unique Adverse Reactions were identified from the uncontrolled Study 3.

In both Studies 1 and 2, aminotransferase elevations of at least 3 times the upper limit of normal developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%]) than in the placebo treatment group. In Study 3, 22/230 (9.6%) patients had alanine aminotransferase or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal during the overall treatment period.

Increased Mortality

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 tuberculosis-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 tuberculosis, HIV status, and severity of disease was observed.

In the open-label Study 3, 6.9% (16/233) subjects died. The most common cause of death as reported by the investigator was TB (9 subjects). All but one subject who died of TB had not converted or had relapsed. The causes of death in the remaining subjects varied.


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7 DRUG INTERACTIONS 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.

CYP3A4 Inducers

Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers should be avoided during treatment with SIRTURO [see Clinical Pharmacology (12.3)].

CYP3A4 inhibitors

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, such as ketoconazole or itraconazole, for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Clinical Pharmacology (12.3)].Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.

7.2 Other Antimicrobial Medications 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 Lopinavir/ritonavir

Although clinical data in HIV/MDR-TB co-infected patients on the combined use of lopinavir (400 mg)/ritonavir (100 mg) with SIRTURO are not available, use SIRTURO with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk [see Clinical Pharmacology (12.3)].

Nevirapine

No dosage adjustment of bedaquiline is required when co-administered with nevirapine [see Clinical Pharmacology (12.3)].


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Efavirenz

Concomitant administration of bedaquiline and efavirenz, or other moderate CYP3A inducers, should be avoided [see Warnings and Precautions (5.4)].

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 taking clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in subjects who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

8 USE 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 time to 2 times the clinical dose (based on AUC comparisons), concentrations in milk were 6-fold 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.


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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 pediatric patients have not been established.

8.5 Geriatric Use Because of limited data, differences in outcomes or specific risks with SIRTURO cannot be ruled out for patients 65 years of age and older.

8.6 Hepatic Impairment The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) [see Clinical Pharmacology (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 Warnings and Precautions (5.3)].

8.7 Renal Impairment SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%). No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, SIRTURO should be used with caution [see Clinical Pharmacology (12.3)].Monitor for adverse reactions of SIRTURO when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.

10 OVERDOSAGE 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 (QT interval) in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be achieved by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.


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Br

NHO

NMe2

OMe

HOOC COOH

(R) (S)

11 DESCRIPTION SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.

Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32 H31 BrN 2O2•C4H4O4

and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:

SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).

12 CLINICAL PHARMACOLOGY

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

12.2 PharmacodynamicsBedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) compared to the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation.

Cardiac Electrophysiology

In Study 1, the mean increases in QTcF, 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


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mean increase in QTcF during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study week 60.

In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QTcF prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients taking SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QTcF segment duration in excess of 480 ms, whereas patients taking at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, and resulted in QTcF segment duration in excess of 500 ms in one patient. [See Warnings and Precautions (5.3)]


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12.3 Pharmacokinetics Absorption After oral administration of SIRTURO maximum plasma concentrations (C max ) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied [700 mg single-dose (1.75 times the 400 mg loading dose)] [see Dosage and Administration (2.3)]. Administration of SIRTURO with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, SIRTURO should be taken with food to enhance its oral bioavailability.

Distribution The plasma protein binding of bedaquiline is greater than 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 Liters.

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

Elimination After reaching Cmax , bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.

Excretion Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant.

Specific Populations

Hepatic Impairment: After single-dose administration of 400 mg SIRTURO to 8 patients with moderate hepatic impairment (Child-Pugh B), mean exposure to bedaquiline and M2 (AUC672h ) was approximately 20% lower compared to healthy subjects. SIRTURO has not been studied in patients with severe hepatic impairment. [See Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].


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Renal Impairment: SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%).

In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO 200 mg three times per week, creatinine clearance was not found to influence the pharmacokinetic parameters of bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis bedaquiline concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly removed from plasma by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)].

Sex: In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO no clinically relevant difference in exposure between men and women were observed.

Race/Ethnicity: In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO, systemic exposure (AUC) to bedaquiline was found to be 34% lower in Black patients than in patients from other race categories. This lower exposure was not considered to be clinically relevant as no clear relationship between exposure to bedaquiline and response has been observed in clinical trials of MDR-TB. Furthermore, response rates were comparable in patients of different race categories that completed 24 weeks of bedaquiline treatment.

HIV Co-infection: There are limited data on the use of SIRTURO in HIV co-infected patients [see Drug Interactions (7)].

Geriatric Population: There are limited data on the use of SIRTURO in tuberculosis patients 65 years and older.

In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO, age was not found to influence the pharmacokinetics of bedaquiline.

Pediatric Population: The pharmacokinetics of SIRTURO in pediatric patients have not been evaluated.

Drug-Drug Interactions

In vitro, bedaquiline does not significantly inhibit the activity of the following CYP450


14

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.

Bedaquiline is an in vitro substrate of CYP3A4, and because of this, the following clinical drug interaction studies were performed.

Ketoconazole: Co-administration of multiple-dose bedaquiline (400 mg once daily for 14 days) and multiple-dose ketoconazole (once daily 400 mg for 4 days) in healthy subjects increased the AUC 24h , Cmax and Cmin of bedaquiline by 22% [90% CI (12; 32)], 9% [90% CI (-2, 21)] and 33% [90% CI (24, 43)] respectively [see Drug Interactions (7.1) and (7.4)].

Rifampin: In a drug interaction study of single-dose 300 mg bedaquiline and multiple-dose rifampin (once daily 600 mg for 21 days) in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52% [90% CI (-57; -46)] [see Drug Interactions (7.1)].

Antimicrobial agents: The combination of multiple-dose bedaquiline 400 mg once daily with multiple-dose isoniazid/pyrazinamide (300 mg/2000 mg once daily) in healthy subjects did not result in clinically relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide [see Drug Interactions (7.2)].

In a placebo-controlled study in patients with MDR-TB, no major impact of co-administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

Lopinavir/ritonavir: In a drug interaction study in healthy volunteers of single-dose bedaquiline (400 mg) and multiple-dose lopinavir (400 mg)/ritonavir (100 mg) given twice daily for 24 days, the mean AUC of bedaquiline was increased by 22% [90% CI (11; 34)] while the mean C max was not substantially affected [see Drug Interactions (7.3)].

Nevirapine: Co-administration of multiple-dose nevirapine 200 mg twice daily for 4 weeks in HIV-infected patients with a single 400 mg dose of bedaquiline did not result in clinically relevant changes in the exposure to bedaquiline [see Drug Interactions (7.3)].

Efavirenz: Co-administration of a single dose of bedaquiline 400 mg and efavirenz 600 mg daily for 27 days to healthy volunteers resulted in approximately a 20% decrease in the AUCinf of bedaquiline; the Cmax of bedaquiline was not altered. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively. The effect of efavirenz on the pharmacokinetics of bedaquiline and M2 following steady-state administration of bedaquiline has not been evaluated [see Drug Interactions (7.3)].


15

12.4 Microbiology Mechanism of Action

SIRTURO is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis.

Drug Resistance

A potential for development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump have been associated with increased bedaquiline MIC values in isolates of M.tuberculosis. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4.0 micrograms per mL. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.50 micrograms per mL.

Cross-Resistance

M. tuberculosis isolates from a clinical study in patients with MDR-TB that developed at least 4-fold increase in bedaquiline MIC were associated with mutations in Rv0678 gene that lead to upregulation of the MmpS5-MmpL5 efflux pump. Isolates with these efflux-based mutations are less susceptible to clofazimine.

Activity In Vitro and in Clinical Infections

SIRTURO has been shown to be active in vitro and in clinical infections against most isolates of M. tuberculosis [see Indications and Usage (1) and Clinical Studies (14)].

Susceptibility Test Methods

In vitro susceptibility tests should be performed according to published methods1,2,3, and a MIC value should be reported. However, no correlation was seen between the culture conversion rates at Week 24 and baseline MICs in clinical studies (Table 2) and susceptibility test interpretive criteria for bedaquiline cannot be established at this time. Aspecialist in drug-resistant TB should be consulted in evaluating therapeutic options.

When susceptibility testing is performed by 7H9 broth microdilution or agar methods, a range of concentrations from 0.008 microgram per mL to 2.0 micrograms per mL should be assessed. The minimum inhibitory concentration (MIC) should be determined as the lowest


16

concentration of bedaquiline that results in complete inhibition of growth by either agar orbroth methods. All assays should be performed in polystyrene plates or tubes. Löwenstein-Jensen (LJ) medium should not be used for the susceptibility testing. Bedaquiline working solution should be prepared in dimethylsulfoxide (DMSO). An inoculum of approximately 105 colony forming units/mL should be used for both liquid and solid media.

The bedaquiline agar (left) and resazurin microtiter assay (REMA; a 7H9 broth microdilution to which resazurin, a bacterial growth indicator, was added) (right) MIC distributions against clinical isolates resistant to isoniazid and rifampin from Studies 1, 2, and 3 are provided below.

Figure 1: Bedaquiline MIC Distribution against Baseline MDR H&R -TB Isolates from Studies 1, 2, and 3mITT Subjects: Agar Method (left) and Broth (REMA) Method (right)

MICs for baseline M. tuberculosis isolates from subjects in Studies 1 and 3 and their sputum culture conversion rates at Week 24 are shown in Table 2 below. Based on the available data, there was no trend for poor microbiologic outcomes related to baseline bedaquiline MIC.

Table 2: Culture Conversion Rates (Week 24 Data Selection, No Overruling for Discontinuation) at Week 24 By Baseline Bedaquiline MIC for mITT Subjects from Study 1 and Study 3

SIRTURO (Bedaquiline) Treatment Group Baseline Bedaquiline 24-Week Culture Conversion Rate MIC

n/N (%) (micrograms/mL) 7H11 Agar 7H9 Broth (REMA)


17

0.008 2/2 (100) 21/25 (84.0)

0.015 13/15 (86.7) 33/39 (84.6)

0.03 36/46 (78.3) 70/92 (76.1)

0.06 82/107 (76.6) 45/56 (80.4)

0.12 36/42 (85.7) 6/7 (85.7)

0.25 3/4 (75.0) 3/4 (75.0)

0.5 5/6 (83.3) 0/1 (0)

1 0/1 (0) N=number of subjects with data; n=number of subjects with that result; MIC=minimum inhibitory concentration; BR=background regimen

Nineteen patients in the efficacy population of study 3 had bedaquiline susceptibility testing results of paired (baseline and post-baseline, all of which were at Week 24 or later) genotypically identical isolates. Twelve of the 19 had a post- -fold increase in bedaquiline MIC. Whole genome sequencing of 9 of these 12 post-baseline isolates was done and no mutations were found in the ATP synthase operon. All 9 were found to have a mutation in Rv0678. Eleven of the twelve (11/12) increases in bedaquiline MIC were seen in patients with pre-XDR-TB or with XDR-TB. Pre-XDR-TB is defined as MDR-TB isolates resistant to either a fluoroquinolone or a second line injectable drug, and XDR-TB as MDR-TB isolates resistant to both a fluoroquinolone and a second line injectable drug. Based on available data, response rate (culture conversion at week 120 endpoint) was similar in

-fold increases in bedaquiline MIC (5/12) and subjects with < 4-fold increases (3/7).

Quality Control

Susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of testing. Assays using standard bedaquiline powder should provide the following range of MIC values shown in Table 3.

Table 3: Quality Control Ranges using Agar and Broth Dilution Methods and M. tuberculosis H37Rv

Bedaquiline MIC (micrograms/mL)

Organism 7H9 Broth 7H10 Agar 7H11 Agar

M. tuberculosis H37Rv 0.015 – 0.06 0.015 – 0.12 0.015 – 0.12


18

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in subjects in the Phase 2 clinical trials.

No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay.

SIRTURO had no effects on fertility when evaluated in male and female rats. No relevantdrug-related effects on developmental toxicity parameters were observed in rats and rabbits.The corresponding plasma exposure (AUC) was 2-fold higher in rats and lower for rabbits compared to humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioral development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6-fold to 12-fold higher that the maximum concentration observed in maternal plasma.

13.2 Animal Toxicology and/or Pharmacology Bedaquiline is a cationic, amphiphilic drug that induced phospholipidosis (at almost all doses, even after very short exposures) in drug-treated animals, mainly in cells of the monocytic phagocytic system (MPS). All species tested showed drug-related increases in pigment-laden and/or foamy macrophages, mostly in the lymph nodes, spleen, lungs, liver, stomach, skeletal muscle, pancreas and/or uterus. After treatment ended, these findings were slowly reversible. Muscle degeneration was observed in several species at the highest doses tested. For example the diaphragm, esophagus, quadriceps and tongue of rats were affected after 26 weeks of treatment at doses similar to clinical exposures based on AUC comparisons. These findings were not seen after a 12-week, treatment-free, recovery period and were not present in rats given the same dose biweekly. Degeneration of the fundic mucosa of the stomach, hepatocellular hypertrophy and pancreatitis were also seen.

14 CLINICAL STUDIES A placebo-controlled, double-blind, randomized trial (Study 1) was conducted in patients with newly diagnosed sputum smear-positive MDR pulmonary M. tuberculosis. All patients received a combination of five other antimycobacterial drugs used to treat MDR-TB (i.e., ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative) for a total duration of 18-24 months or at least 12 months after the first


19

confirmed negative culture. In addition to this regimen, patients were randomized to receive 24 weeks of treatment with SIRTURO 400 mg once daily for the first 2 weeks followed by 200 mg 3 times per week for 22 weeks or matching placebo for the same duration. Overall, 79 patients were randomized to the SIRTURO arm and 81 to the placebo arm. A final evaluation was conducted at Week 120.

Sixty-seven patients randomized to SIRTURO and 66 patients randomized to placebo had confirmed MDR-TB, based on susceptibility tests (taken prior to randomization) or medical history if no susceptibility results were available, and were included in the efficacy analyses. Demographics were as follows: 63% of the study population was male, with a median age of 34 years, 35% were Black, and 15% were HIV-positive (median CD4 cell count 468 cells/μL). Most patients had cavitation in one lung (62%); and 18% of patients had cavitation in both lungs.

Time to sputum culture conversion was defined as 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 treatment. In this trial, the SIRTURO treatment group had adecreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 24. Median time to culture conversion was 83 days for the SIRTURO treatment group compared to 125 days for the placebo treatment group. Table 4shows the proportion of patients with sputum culture conversion at Week 24 and Week 120.


20

Table 4: Culture Conversion Status in Patients with MDR-TB at Week 24 and Week 120 in Study 1

Microbiologic Status SIRTURO (24 weeks) +

combination of other antimycobacterial

drugs N=67

Placebo (24 weeks) + combination of other

antimycobacterial drugs N=66

Difference [95% CI] p-value

Week 24Sputum Culture Conversion

78% 58% 20.0% [4.5%, 35.6%] 0.014

Treatment failure* 22% 42%Died 1% 0%Lack of conversion 21% 35%Discontinuation 0% 8%

Week 120**

Sputum Culture Conversion

61% 44% 17.3% [0.5%, 34.0%] 0.046

Treatment failure* 39% 56%Died 12% 3%Lack of conversion/relapse

16% 35%

Discontinuation 10% 18%*A patient’s reason for treatment failure was counted only in the first row for which a patient qualifies.**Patients received 24 weeks of SIRTURO or placebo for the first 24 weeks and received a combination of other antimycobacterial drugs for up to 96 weeks.

Study 2 was a smaller placebo controlled study designed similarly to Study 1 except that SIRTURO or placebo was given for only 8 weeks instead of 24 weeks. Patients were randomized to either SIRTURO and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=23) or placebo and other drugs used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed MDR-TB based on subjects’ baseline M. tuberculosis isolate obtained prior to randomization. The SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group 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-value: 0.004), 15.7% (95% CI: [-11.9%, 41.9%] and p-value: 0.32), respectively.

Study 3 was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of SIRTURO as part of an individualized MDR-TB treatment regimen in 233 patients with sputum smear positive (within 6 months prior to screening) pulmonary MDR-TB. Patients received SIRTURO for 24 weeks in combination with antibacterial drugs. Upon completion of the 24 week treatment with SIRTURO, all patients continued to receive their background regimen in accordance with national TB program (NTP) treatment guidelines. A final


21

evaluation was conducted at Week 120. Treatment responses to SIRTURO at week 120 were generally consistent with those from Study 1.

15 REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of

Mycobacteria, Nocardiaceae, and other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute,950 West Valley Rd., Suite 2500, Wayne, PA, 19087, 2011.

2. Martin A, Portaels F, Palomino JC. Colorimetric redox-indicator methods for the rapid detection of multidrug resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2007; 59 (2): 175-83.

3. Clinical and Laboratory Institute Standards (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard — Nineth Edition. CLSI Document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087, 2012.

16 HOW SUPPLIED/STORAGE AND HANDLING How supplied

SIRTURO is supplied as uncoated white to almost white round biconvex 100 mg tablets

with debossing of “T” over “207” on one side and “100” on the other side. The tablets are

packaged in white high density polyethylene (HDPE) bottles with child-resistant

polypropylene (PP) closure with induction seal liner. Each bottle contains 188 tablets.

NDC 59676-701-01

Storage and handling

Keep out of reach of children.

Dispense in original container. Store tablets dispensed outside the original container in a tight light-resistant container with an expiration date not to exceed 3 months.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Adverse Reactions


22

Advise patients that the following serious side effects can occur with SIRTURO: death, heart rhythm abnormalities, and/or hepatitis. In addition, advise patients about other potential side effects: nausea, joint pain, headache, increased blood amylase, hemoptysis, chest pain, anorexia, and/or rash. Additional testing may be needed to monitor or reduce the likelihood of adverse effects.

Compliance with Treatment Advise patients to take SIRTURO in combination with other antimycobacterial drugs asprescribed. Emphasize compliance with the full course of therapy. Advise patients that skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the treatment and (2) increase the likelihood that their mycobacterium may develop resistance and the disease will not be treatable by SIRTURO or other antibacterial drugs in the future.

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

Administration Instructions Inform patients to take SIRTURO with food.

Use with Alcohol and other Medications Advise patients to abstain from alcohol, hepatotoxic medications or herbal products.

Advise patients to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with SIRTURO.

Product of India

Finished Product Manufactured by: Kemwell Biopharma Pvt. Ltd., Bangalore, India

Manufactured for:

Janssen Therapeutics, Division of Janssen Products, LP Titusville, NJ 08560

Janssen Products, LP 2012


23

MEDICATION GUIDE SIRTURO® (ser toor’ oh)

(bedaquiline)Tablets, for oral use

Read this Medication Guide before you start taking SIRTURO® and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about SIRTURO®?SIRTURO® is an antibiotic prescription medicine used to treat multi-drug resistant tuberculosis (TB) of the lungs in people with limited treatment options. Multi-drug resistant tuberculosis is a serious disease that can result in death and for which there are few treatment choices. More people treated with SIRTURO® cleared TB from their sputum compared to people who did not receive SIRTURO®.

It is important to complete the full course of treatment with SIRTURO® and your other TB medicines and not skip doses. Skipping doses may decrease the effectiveness of the treatment and increase the likelihood that your TB disease will not be treatable by SIRTURO® or other medicines.

SIRTURO® can cause serious side effects, including:

In one clinical trial, more deaths were seen in people who were treated with SIRTURO®

compared to people who did not receive SIRTURO®.

Heart rhythm problems can happen with SIRTURO®.Talk with your healthcare provider about whether SIRTURO® is right for you.

What is SIRTURO®?SIRTURO® is an antibiotic prescription medicine used to treat resistant tuberculosis (TB) of the lungs.

It is not known if SIRTURO® is safe and effective in:

people who do not have active TB

people who have TB that is not resistant to antibiotics

people who have types of TB other than TB of the lungs

people who have an infection caused by a bacteria other than TB

children under 18 years of age


24

Before you take SIRTURO®, tell your healthcare provider if you:

have had an abnormal heart rhythm (ECG) or other heart problems.

anyone in your family has or has had a heart problem called “congenital long QT syndrome”.

have decreased thyroid gland function (this can be seen in a blood test).

have liver or kidney problems or any other medical conditions, including HIV infection.

are pregnant or plan to become pregnant. It is not known if SIRTURO® will harm your unborn baby.

are breastfeeding or plan to breastfeed. It is not known if SIRTURO® passes into breast milk. You and your healthcare provider should decide if you will take SIRTURO® or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take SIRTURO®?SIRTURO® must always be taken with other medicines to treat TB. Your healthcare provider will decide which other medicines you should take with SIRTURO®.

Take SIRTURO® with food. Swallow the tablets whole with water.

Take SIRTURO® exactly as your healthcare provider tells you to take it. Take SIRTURO®

for a total of 24 weeks. You may need to take your other TB medicines for longer than 24 weeks. Check with your healthcare provider.

Week 1 and Week 2: Take 400 mg (4 tablets) 1 time each day.

Week 3 to Week 24:

Take 200 mg (2 tablets) a day 3 times a week.

Take SIRTURO® doses at least 48 hours apart. For example, you may take SIRTURO® onMonday, Wednesday and Friday every week.

Do not skip SIRTURO® doses. If you skip doses, or do not complete the total 24 weeks of SIRTURO® your treatment may not work as well and your TB may be harder to treat.

If you take more SIRTURO® than you should, talk to a healthcare provider right away.

If you miss your SIRTURO® dose during Week 1 or Week 2:

Do not take a double dose to make up for the missed dose. Take the next dose as usual.

If you miss your SIRTURO® dose during Week 3 to Week 24:

Take the missed dose as soon as possible and resume the 3 times a week schedule.

If you miss a dose and you are not sure what to do, talk to your healthcare provider.


25

Do not stop taking SIRTURO® without first talking to your healthcare provider.

What should I avoid while taking SIRTURO®?

You should not drink alcohol while taking SIRTURO®.

What are the possible side effects of SIRTURO®?SIRTURO® may cause serious side effects, including:

See “What is the most important information I should know about SIRTURO®?”

serious heart rhythm changes (QT prolongation). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint.

liver problems (hepatotoxicity). Call your healthcare provider right away if you have unexplained symptoms such as nausea or vomiting, stomach pain, fever, weakness, itching,unusual tiredness, loss of appetite, light colored bowel movements, dark colored urine,yellowing of your skin or the white of your eyes.

The most common side effects of SIRTURO® include nausea, joint pain, headache, an abnormal lab test associated with damage to the pancreas, coughing up blood, chest pain, loss of appetite, or rash.

These are not all the possible side effects of SIRTURO®. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SIRTURO®?Store SIRTURO® at 59°F to 86°F (15°C to 30°C).

Keep SIRTURO® in the original container, and keep SIRTURO® out of light.

Keep SIRTURO® and all medicines out of reach of children.

General information about the safe and effective use of SIRTURO®:This Medication Guide summarizes the most important information about SIRTURO®. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SIRTURO® that is written for health professionals.


26

What are the ingredients in SIRTURO®?Active ingredient: bedaquiline

Inactive ingredients: colloidal anhydrous silica, corn starch, croscarmellose sodium, hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing)

Product of India

Finished Product Manufactured by: Kemwell Biopharma Pvt. Ltd., Bangalore, India

Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP Titusville, NJ 08560 Janssen Products, LP 2012

This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: 12/2015


27

1

These highlights do not include all the

information needed to use SIRTURO® safely

and effectively. See full prescribing information

for SIRTURO.

SIRTURO® (bedaquiline) tablets, for oral use

Initial U.S. Approval 2012

WARNINGS: INCREASED MORTALITY;

QT PROLONGATION

See full prescribing information for complete

boxed warning.

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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided. (5.1)

QT Prolongation QT prolongation can occur with

SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval >500 ms develops. (5.2)

-------------------- --------------------

Indications and Usage (1) 05/2015

------------------------ ------------------------

SIRTURO is a diarylquinoline antimycobacterial

drug indicated as part of combination therapy in

adults (18 years and older) with pulmonary

multi-drug resistant tuberculosis (MDR-TB).

Reserve SIRTURO for use when an effective

treatment regimen cannot otherwise be provided.

Administer SIRTURO by directly observed

therapy (DOT). (1, 2.1)

This indication is approved under accelerated

approval based on time to sputum culture

conversion. Continued approval for this indication

may be contingent upon verification and

description of clinical benefit in confirmatory trials.

(1, 13)

Limitations of Use: Do not use SIRTURO for the

treatment of latent, extra- pulmonary or

drug-sensitive tuberculosis or for the treatment of

infections caused by non-tuberculous mycobacteria

(1). Safety and efficacy of SIRTURO in

HIV-infected patients with MDR-TB have not

been established, as clinical data are limited (13).

------------------------ ------------------------

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 MDR-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 MDR-TB isolate is likely to be susceptible (2.3)

Recommended dosage: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week (with at least 48 hours between doses) for 22 weeks (2.3)

Swallow SIRTURO tablets whole with water and take with food. (2.3)

2

------------------------ ------------------------

Tablets: 100 mg (3)

--------------------------- ---------------------------

None. (4)

--------------- --------------- QT prolongation can occur with

SIRTURO. Monitor ECGs and discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval > 500 ms develops. (5.2)

Hepatotoxicity may occur with use of SIRTURO. Monitor liver- related laboratory tests. Discontinue if evidence of liver injury. (5.3)

-------------------------- --------------------------

The most common adverse reactions reported in 10% or more of patients treated with SIRTURO were nausea, arthralgia, headache, hemoptysis and chest pain. (6.1)

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.

--------------------- ---------------------

Avoid use of strong and moderate CYP3A4 inducers with SIRTURO. (7.1, 7.3)

Avoid use for more than 14 consecutive days of systemic strong CYP3A4 inhibitors with SIRTURO unless the benefit outweighs the risk. Monitor for SIRTURO-related adverse reactions. (7.1)

----------------- -----------------

Use with caution in patients with severe hepatic impairment and only when the benefits outweigh the risks. Monitor for SIRTURO-related adverse reactions. (8.6)

Use with caution in patients with severe renal impairment. (8.7)

See 17 for PATIENT COUNSELING

INFORMATION and Medication Guide

Revised: 12/2015

3

1. ............................................................................................................................................... 4 2. ............................................................................................................................................... 4

2.1 ................................................................................................................ 4 2.2 ........................................................................................................................ 5 2.3 ............................................................................................................ 5

3. ................................................................................................................................................. 5 4. ........................................................................................................................................................... 5 5. ........................................................................................................................... 5

5.1 ........................................................................................................................................ 5 5.2 QT ............................................................................................................................................. 6 5.3 ................................................................................................................................................ 6 5.4 .................................................................................................................................... 7

6. ....................................................................................................................................................... 7 6.1 .................................................................................................................................... 7

7. ........................................................................................................................................... 8 7.1 CYP3A4 ................................................................................................................ 8 7.2 .................................................................................................................................... 9 7.3 ........................................................................................................................ 9 7.4 QT .............................................................................................................. 9

8. ..................................................................................................................... 10 8.1 .................................................................................................................................. 10 8.3 .............................................................................................................................. 10 8.4 .............................................................................................................................. 10 8.5 .............................................................................................................................. 10 8.6 .............................................................................................................. 10 8.7 .............................................................................................................. 11

9. ................................................................................................................................................. 11 10. ............................................................................................................................................. 11 11. ................................................................................................................................................. 12

11.1 .......................................................................................................................................... 12 11.2 .............................................................................................................................................. 12 11.3 .......................................................................................................................................... 12 11.4 .......................................................................................................................................... 15

12. ............................................................................................................................................. 17 12.1 ...................................................................................... 17 12.2 .......................................................................................................... 18

13. ................................................................................................................................................. 18 14. ................................................................................................................................................. 20 15. ......................................................................................................... 20 16. ................................................................................................................................. 20

4

QT

2.5% 81 2

11.4% 79 9

1 5.1

QT

QT QT

QT

500 ms QTcF

5.2

1.

18

13

·

· HIV13

2.

2.1

·

5

· 2.3

·

2.2

·

2.2

· 5.2

· 5.2

· 5.3

2.3

in vitro

3 In vitro

4

2 1 1 400 mg 22

48 3 200 mg 24

2 1

1 1 3 200 mg

3

3.

100 mg T 207

2 “100”

4.

5.

5.1

1 120

2.5% 81 2 11.4% 79 9

1 24

6

HIV

6

5.2 QT

QT 2 12

24

QT

6.1 7.4

QT · QT

· Torsade de Pointes

· QT

·

·

·

·

QT

QTcF 500 ms

QT

5.3

1

ALT AST

· 2

· 8

7

· 5 2

5.4

CYP3A4

CYP3A4 CYP3A4

CYP3A4

CYP3A4

7.1

CYP3A4

CYP3A4 14

7.1

6.

· 5.1

· QT 5.2 11.2

· 5.3

· 5.4

6.1

2.3

8 2 24 1 3

335 1 2

2

3

1 35% 17.5% 12.5% 9.4%

25.6% 79 8 10.1% 81

16 19.8% HIV 7 8.9% 6 7.4%

8

1 1

N=79

n %

N=81

n % 30 (38) 26 (32)

26 (33) 18 (22) 22 (28) 10 (12) 14 (18) 9 (11) 9 (11) 6 (7)

7 (9) 3 (4) * 7 (9) 1 (1)

6 (8) 3 (4) 2 (3) 1 (1)

* AST ALT

3

1 2 3

102 11 10.8% 105 6 5.7%

3 230 22 9.6% 3

1 120 79 9 11.4%

81 2 2.5% p =0.03 95%

1.1% 18.2% 9 5 2

1 24

8 329

HIV

3 6.9% 233 16

9 1

7.

7.1 CYP3A4

CYP3A4 CYP3A4

9

CYP3A4

CYP3A4

CYP3A4 11.3

CYP3A4

CYP3A4

14 11.3

7.2

1

7.3

HIV 400 mg

100 mg

11.3

11.3

CYP3A

5.4

7.4 QT

QTc

QT QT

3 24 QTc

12.3 ms

17 31.9 ms

10

QTc

QTcF 500

ms 5.2

11.2

8.

8.1

B

AUC 2

8.3

1 2 AUC

6 12

8.4

8.5

65

8.6

Child-Pugh B

11.3

5.3

11

8.7

0.001%

11.2

9.

QT

10.

100 mg 100 mg

1 120.89 mg

100 mg

(1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol

compound with fumaric acid (1:1) C32H31BrN2O2•C4H4O4

671.58 555.50 + 116.07

colloidal silicon dioxide

2910 15 mPa.s

20

12

11.

11.1

11.4

11.2

N- M2 M2

23 31% 4 6

M2

QT

1 1 QTcF Fridericia QT

3.5 ms 9.9 ms 24

QTcF 15.7 ms 6.2 ms

18 QTcF

60

3 QT

QT

QTcF QT

23.7 ms QTcF

QTcF 480 ms QT 2

30.7 ms QTcF

1 QTcF 500 ms 5.3

11.3

5 Cmax

Cmax AUC 700 mg

400 mg 1.75 2.3

22 g 558 Kcal

2

99.9%

164 L

13

CYP3A4 in vitro N- M2

CYP M2

4 6

Cmax N-

M2 5.5

M2

0.001%

Child-Pugh B 8 400 mg

M2 AUC672h 20%

5.3 8.6

0.001%

200 mg 3

8.7

AUC

34%

24

HIV HIV

7

65

14

In vitro CYP450 CYP1A2 CYP2A6 CYP2C8/9/10

CYP2C19 CYP2D6 CYP2E1 CYP3A4 CYP3A4/5 CYP4A

CYP1A2 CYP2C9 CYP2C19 CYP3A4

in vitro CYP3A4

400 mg 1 1 14

400 mg 1 1 4 AUC24h Cmax

Cmin 22% 90% CI 12; 32 9% 90% CI -2, 21 33% 90% CI 24,

43 7.1 7.4

300 mg

600 mg 1 1 21 1

AUC 52% 90% CI -57; -46 7.1

400 mg 1 1

300 mg/2000 mg 1 1

AUC

7.2

1

400 mg

400 mg/100 mg 1 2 24 1

AUC 22% 90% CI 11; 34 Cmax

7.3

400 mg HIV

200 mg 1 2 4

7.3

400 mg

600 mg 27 AUCinf 20%

Cmax M2 AUC Cmax

70% 80% M2

7.3

15

11.4

c ATP 5'-

atpE

MmpS5-MmpL5

MIC atpE

MIC 8 133 0.25 4.0 g/mL

MIC 2 8

0.25 0.50 g/mL

MIC 4

MmpS5-MmpL5 Rv0678

In Vitro

in vitro

1 14

1 ,2 ,3 in vitro MIC

24 MIC

2

7H9 Broth

0.008 2.0 g/mL

MIC

Löwenstein- Jensen LJ

DMSO

105 CFU/mL

1 2 3

MIC

REMA; 7H9 Broth

16

1 3 MIC

24 2

MIC

2 MIC 24 24

1 3 mITT

MIC gs/mL

24

n/N(%) 7H11 7H9 Broth REMA

0.008 2/2 (100) 21/25 (84.0) 0.015 13/15 (86.7) 33/39 (84.6) 0.03 36/46 (78.3) 70/92 (76.1) 0.06 82/107 (76.6) 45/56 (80.4) 0.12 36/42 (85.7) 6/7 (85.7) 0.25 3/4 (75.0) 3/4 (75.0) 0.5 5/6 (83.3) 0/1 (0)

1 0/1 (0) N= n= MIC= BR=

3 19

24

19 12 MIC 4

17

12 9

ATP 9 Rv0678

pre-XDR-TB XDR-TB 12 11

MIC 2

Pre-XDR-TB 2

XDR-TB

MIC 4 12 5 4

7 3 120

3 MIC

3

MIC H37Rv MIC gs/mL

7H9 Broth 7H10 7H11 H37Rv 0.015 0.06 0.015 0.12 0.015 0.12

12.

12.1

10 mg/kg/

AUC II

1 2

in vitro Ames

in vitro in vivo

AUC 2

F1

6 12

18

12.2

MPS

AUC

26

12

13.

1 18 24

12 5

/terizidone

2 400 mg 1 1 22 200 mg 3

24 79

81 120

67 66

63% 35% 15% HIV CD4

468 cells/μL 34 62%

18%

25 2

1 24

83

125 24 120

4

19

4 24 120 1

24+

N=67

24+

N=66

95% CI p

24

78% 58% 20.0% 4.5%, 35.6%0.014

* 22% 42%

1% 0%

21% 35%

0% 8%

120 **

61% 44% 17.3% 0.5%, 34.0%0.046

* 39% 56%

12% 3%

16% 35%

10% 18% * ** 24 96

2 24 8 1

n=23

n=24

21 23

8

8 24

38.9% 95% CI 12.3%, 63.1% p 0.004 15.7% 95% CI -11.9%, 41.9% p 0.32

3 6 233

2b

24 24 NTP

120

120 1

20

14.

1 Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiaceae, and other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087, 2011.

2 Martin A, Portaels F, Palomino JC. Colorimetric redox-indicator methods for the rapid detection of multidrug resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2007; 59 (2): 175-83.

3 Clinical and Laboratory Institute Standards (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard — Nineth Edition. CLSI Document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087, 2012.

15.

100 mg T 207

2 100

PP

HDPE 1 188

NDC 59676-701-01

3

25°C 77°F 15 30°C 59 86°F USP

16.

FDA

(1) (2)

21

2

3 200 mg

3

Kemwell Biopharma Pvt. Ltd., Bangalore, India

Janssen Therapeutics, Division of Janssen Products, LP Titusville, NJ 08560

© Janssen Products, LP 2012

22

SIRTURO®

SIRTURO®

SIRTURO® SIRTURO®

SIRTURO®

SIRTURO® SIRTURO®

SIRTURO®

SIRTURO®

1 SIRTURO® SIRTURO®

SIRTURO®

SIRTURO®

SIRTURO® SIRTURO®

SIRTURO®

18

SIRTURO®

QT

23

HIV SIRTURO®

SIRTURO®

SIRTURO®

SIRTURO® SIRTURO® SIRTURO®

SIRTURO®

SIRTURO® SIRTURO®

24 24

1 2

400 mg 4 1 1

3 24 200 mg 2 1 1 3 SIRTURO® 48

SIRTURO®

SIRTURO® 24

SIRTURO®

1 2 SIRTURO® 2

3 24 SIRTURO®

3

SIRTURO® SIRTURO®

SIRTURO® SIRTURO® SIRTURO® QT

24

SIRTURO®

SIRTURO®

1-800-FDA-1088

SIRTURO® SIRTURO® 15 30°C 59 86°F SIRTURO®

SIRTURO®

SIRTURO® SIRTURO®

SIRTURO®

SIRTURO®

2910 20

Kemwell Biopharma Pvt. Ltd Bangalore, India

Janssen Therapeutics, Division of Janssen Products, LP Titusville, NJ, 08560 ©Janssen Products, LP 2012

2015 12

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

2

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

SIRTURO 100 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains bedaquiline fumarate equivalent to 100 mg of bedaquiline.

Excipient with known effect: Each tablet contains 145 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

Uncoated, white to almost white round biconvex tablet, 11 mm in diameter, with debossing of "T" over "207" on one side and "100" on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

SIRTURO is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. See sections 4.2, 4.4 and 5.1.Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Treatment with SIRTURO should be initiated and monitored by a physician experienced in the management of multi-drug resistant Mycobacterium tuberculosis.

SIRTURO should be used in combination with at least three medicinal products to which the patient’s isolate has been shown to be susceptible in vitro. Treatment with the other agents in the regimen should continue after completion of treatment with SIRTURO. If in vitro testing results are unavailable, treatment may be initiated with SIRTURO in combination with at least four medicinal products to which the patient's isolate is likely to be susceptible. Refer to the Summary of Product Characteristics of the medicinal products used in combination with SIRTURO for their specific dosing recommendations.

It is recommended that SIRTURO is administered by directly observed therapy (DOT).

PosologyThe recommended dosage is:! Weeks 1-2: 400 mg (4 tablets of 100 mg) once daily! Weeks 3-24: 200 mg (2 tablets of 100 mg) three times per week (with at least 48 hours

between doses).

3

The total duration of treatment with SIRTURO is 24 weeks. Data on longer treatment duration is very limited. In patients with extensive drug resistance, where SIRTURO is considered necessary beyond 24 weeks to obtain a curative treatment, a longer duration of therapy may be considered only on a case by case basis and under close safety surveillance (see sections 4.4 and 4.8).

Missed dosesPatients should be advised to take SIRTURO exactly as prescribed and to complete the full course of therapy.

If a dose is missed during the first two weeks of treatment, patients should not make up the missed dose, but should continue the usual dosing schedule.

If a dose is missed from week three onwards, patients should take the missed dose of 200 mg as soon as possible and then resume the three times a week regimen.

Elderly population (≥ 65 years of age)There is limited clinical data (n = 2) on the use of SIRTURO in elderly patients.

Hepatic impairmentNo dose adjustment is necessary for SIRTURO in patients with mild or moderate hepatic impairment(see section 5.2). SIRTURO should be used with caution in patients with moderate hepatic impairment (see section 5.2). SIRTURO has not been studied in patients with severe hepatic impairment and is not recommended in this population.

Renal impairmentNo dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis, SIRTURO should be used with caution (see section 5.2).

Paediatric populationThe safety and efficacy of SIRTURO in children aged < 18 years have not yet been established.No data are available.

Method of administrationSIRTURO should be taken orally with food, as administration with food increases oral bioavailability by about 2-fold (see section 5.2). SIRTURO tablets should be swallowed whole with water.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

There are no data on treatment with SIRTURO longer than 24 weeks within the clinical studies C208 and C209 (see section 5.1).

There are no clinical data on the use of SIRTURO to treat:! extra-pulmonary tuberculosis (e.g. central nervous system, bone)! infections due to mycobacterial species other than Mycobacterium tuberculosis! latent infection with Mycobacterium tuberculosis

There are no clinical data on the use of SIRTURO as part of combination regimens used to treat drug-susceptible Mycobacterium tuberculosis.

MortalityIn the 120-week C208 trial where SIRTURO was administered for 24 weeks in combination with a background regimen, more deaths occurred in the SIRTURO treatment group than in the placebo

4

group (see section 4.8). The imbalance in deaths is unexplained; no evidence has been found for a causal relationship with SIRTURO treatment. For additional information on deaths in the C209 trial, see section 4.8.

Cardiovascular safetyBedaquiline prolongs the QTc interval. An electrocardiogram should be obtained before initiation of treatment and at least monthly after starting treatment with bedaquiline. 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 sections 4.5 and 4.8).

When bedaquiline is co-administered with other medicinal products that prolong the QTc interval(including delamanid and levofloxacin), an additive or synergistic effect on QT prolongation cannot be excluded (see section 4.5). Caution is recommended when prescribing bedaquiline concomitantly with medicinal products with a known risk of QT prolongation. In the event that co-administration of such medicinal products with bedaquiline is necessary, clinical monitoring including frequent electrocardiogram assessment is recommended.

In the event that co-administration of clofazimine with bedaquiline is necessary, clinical monitoring including frequent electrocardiogram assessment is recommended (see section 4.5).

SIRTURO treatment initiation is not recommended in patients with the following, unless the benefits of bedaquiline are considered to outweigh the potential risks:! Heart failure;! QT interval as corrected by the Fridericia method (QTcF) > 450 ms (confirmed by repeat

electrocardiogram);! A personal or family history of congenital QT prolongation;! A history of or ongoing hypothyroidism;! A history of or ongoing bradyarrhythmia;! A history of Torsade de Pointes;! Concomitant administration of fluoroquinolone antibiotics that have a potential for significant

QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin).! Hypokalemia

SIRTURO treatment must be discontinued if the patient develops:! Clinically significant ventricular arrhythmia! A QTcF interval of > 500 ms (confirmed by repeat electrocardiogram).

If syncope occurs, an electrocardiogram should be obtained to detect any QT prolongation.

Hepatic safetyIncreases in transaminases or aminotransferase elevations accompanied by total bilirubin ≥ 2x ULNwere seen in clinical trials during administration of SIRTURO with the background regimen (see section 4.8). Patients should be monitored throughout the treatment course, since the increases in liver enzymes were slow to appear and increased gradually during the 24 weeks. Monitor symptoms and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. If AST or ALT exceeds 5 times the upper limit of normal then the regimen should be reviewed and SIRTURO and/or any hepatotoxic background medicinal product should be discontinued.Other hepatotoxic medicinal products and alcohol should be avoided while on SIRTURO, especially in patients with diminished hepatic reserve.

Interactions with other medicinal productsCYP3A4 inducersBedaquiline is metabolised by CYP3A4. Co-administration of bedaquiline and medicinal products that induce CYP3A4 may decrease bedaquiline plasma concentrations and reduce its therapeutic effect.

5

Co-administration of bedaquiline and moderate or strong CYP3A4 inducers used systemically should,therefore, be avoided (see section 4.5).

CYP3A4 inhibitorsCo-administration of bedaquiline and moderate or strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions (see section 4.5). Therefore, the combination of bedaquiline and moderate or strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided. If co-administration is required, more frequent electrocardiogram monitoring and monitoring of transaminases is recommended.

Patients infected with human immunodeficiency virus (HIV)There are no clinical data on the safety and efficacy of bedaquiline when co-administered with antiretroviral agents.

There are only limited clinical data on the efficacy of bedaquiline in HIV-infected patients not receiving antiretroviral (ARV) therapy. Those patients studied all had CD4+ cell counts greater than 250 x 106 cells/l (N = 22; see section 4.5).

Lactose intolerance and lactase deficiencySIRTURO contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The elimination of bedaquiline has not been fully characterised in vivo. CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2). Urinary excretion of bedaquiline is negligible. Bedaquiline and M2 are not substrates or inhibitors of P-glycoprotein.

CYP3A4 inducersBedaquiline exposure may be reduced during co-administration with inducers of CYP3A4.

In an interaction study of single-dose bedaquiline and once daily rifampicin (strong inducer) in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52% [90% CI (-57; -46)]. Due to the possibility of a reduction of the therapeutic effect of bedaquiline due to a decrease in systemic exposure, co-administration of bedaquiline and moderate or strong CYP3A4 inducers (e.g. efavirenz, etravirine, rifamycins including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)) used systemically should be avoided.

CYP3A4 inhibitorsBedaquiline exposure may be increased during co-administration with inhibitors of CYP3A4.

The short-term co-administration of bedaquiline and ketoconazole (potent CYP3A4 inhibitor) in healthy subjects increased the exposure (AUC) to bedaquiline by 22% [90% CI (12; 32)]. A more pronounced effect on bedaquiline may be observed during prolonged co-administration of ketoconazole or other inhibitors of CYP3A4.

There are no safety data from bedaquiline multiple dose trials which utilised a dose higher than the indicated dose. Due to the potential risk of adverse reactions due to an increase in systemic exposure, prolonged co-administration of bedaquiline and moderate or strong CYP3A4 inhibitors (e.g. ciprofloxacin, erythromycin, fluconazole, clarithromycin, ketoconazole, ritonavir) used systemically for more than 14 consecutive days should be avoided. If co-administration is required, more frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.4).

6

Other antituberculosis medicinal productsThe short-term co-administration of bedaquiline with isoniazid/pyrazinamide 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-administrationwith bedaquiline.In a placebo-controlled clinical study in patients with multi-drug resistant Mycobacterium tuberculosis, no major impact of co-administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

Antiretroviral medicinal productsIn an interaction study of single-dose bedaquiline and multiple-dose lopinavir/ritonavir, exposure (AUC) to bedaquiline was increased by 22% [90% CI (11; 34)]. A more pronounced effect on bedaquiline plasma exposures may be observed during prolonged co-administration withlopinavir/ritonavir. Published data on patients treated with bedaquiline as part of therapy for drug-resistant TB and lopinavir/ritonavir-based ART have shown that bedaquiline exposure (AUC) over 48 hours was increased approximately 2 fold. This increase is likely due to ritonavir. If the benefit outweighs the risk, SIRTURO may be used with caution when co-administered with lopinavir/ritonavir. Increases in plasma exposure to bedaquiline would be expected when it is co-administered with other ritonavir-boosted HIV protease inhibitors. Of note, no change in bedaquiline dosing is recommended in case of co-treatment with lopinavir/ritonavir or other ritonavir-boosted HIV protease inhibitors. There are no data to support a lowered bedaquiline dose in such circumstances.

Co-administration of single-dose bedaquiline and multiple-dose nevirapine did not result in clinically relevant changes in the exposure to bedaquiline. Clinical data on co-administration of bedaquiline andantiretroviral agents in patients co-infected with human immunodeficiency virus and multi-drug resistant Mycobacterium tuberculosis are not available (see section 4.4). Efavirenz is a moderate inducer of CYP3A4 activity and co-administration with bedaquiline may result in reduced bedaquilineexposure and loss of activity, and is, therefore, not recommended.

QT interval prolonging medicinal productsThere is limited information available on the potential for a pharmacodynamic interaction between bedaquiline and medicinal products that prolong the QT interval. In an 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 medicinal products. An additive or synergistic effect on QT prolongation of bedaquiline when co-administered with other medicinal products that prolong the QT interval cannot be excluded and frequent monitoring is recommended (see section 4.4).

QT interval and concomitant clofazimine useIn an open label Phase IIb trial, mean increases in QTcF were larger in the 17 subjects who were using concomitant clofazimine at week 24 (mean change from reference of 31.9 ms) than in subjects who were not using concomitant clofazimine at week 24 (mean change from reference of 12.3 ms) (see section 4.4).

Paediatric populationInteraction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

PregnancyThere are limited data on the use of SIRTURO in pregnant women. At clinically relevant exposures, animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).As a precautionary measure, it is recommended to avoid the use of SIRTURO during pregnancy unless the benefit of therapy is considered to outweigh the risks.

7

BreastfeedingIt is not known whether bedaquiline or its metabolites are excreted in human milk.

In rats, concentrations of bedaquiline in milk were 6- to 12-fold higher than the maximum concentration observed in maternal plasma. Body weight decreases in pups were noted in high dose groups during the lactation period (see section 5.3).

Because of the potential for adverse reactions in breastfed infants, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from SIRTURO therapy taking into account the benefit of breast-feeding for the infant and the benefit of therapy for the mother.

FertilityNo human data on the effect of bedaquiline on fertility are available. In female rats, there was no effect on mating or fertility with bedaquiline treatment, however some effects were observed in male rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Bedaquiline has minor influence on the ability to drive and use machines. Adverse reactions, such as dizziness, may affect the ability to drive or use machines. Patients should be advised not to drive or operate machinery if they experience dizziness while taking SIRTURO.

4.8 Undesirable effects

Summary of the safety profileAdverse drug reactions for SIRTURO were identified from pooled Phase IIb clinical trial data (both controlled and uncontrolled) containing 335 patients who received SIRTURO in combination with a background regimen of tuberculosis medicinal products. The basis of assessment of causality between the adverse drug reactions and SIRTURO was not restricted to these trials, but also on review of the pooled Phase I and Phase IIa safety data. The most frequent adverse drug reactions (> 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea (35.3% in the SIRTURO group vs 25.7% in the placebo group), arthralgia (29.4% vs 20.0%), headache (23.5% vs 11.4%), vomiting (20.6% vs 22.9%) and dizziness (12.7% vs 11.4%). Refer to the Summary of Product Characteristics of the medicinal products used in combination with SIRTURO for their respective adverse reactions.

Tabulated list of adverse reactionsAdverse drug reactions to SIRTURO reported from controlled trials in 102 patients treated with SIRTURO are presented in the table below.Adverse drug reactions are listed by system organ class (SOC) and frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

System Organ Class (SOC) Frequency Category ADRsNervous system disorders Very Common Headache, dizzinessCardiac disorders Common Electrocardiogram QT

prolongedGastrointestinal disorders Very Common Nausea, vomiting

Common DiarrhoeaHepatobiliary disorders Common Transaminases increased*Musculoskeletal and connective tissue disorders

Very Common ArthralgiaCommon Myalgia

* Terms represented by ‘transaminases increased’ included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, and transaminases increased (see section below).

8

Description of selected adverse eventsDeathsIn the randomised phase IIb study (C208, stage 2) a higher rate of deaths was seen in the SIRTURO treatment group (12.7%;10/79 patients) compared to the placebo treatment group (3.7%; 3/81 patients). One death in the SIRTURO group and one death in the placebo group were reported after the week 120 window. In the SIRTURO group, all of the five deaths due to tuberculosis occurred in patients whose sputum culture status at last visit was ‘not converted’. The causes of death in the remaining SIRTURO subjects were alcohol poisoning, hepatitis/hepatic cirrhosis, septic shock/peritonitis, cerebrovascular accident and motor vehicle accident. One of the ten deaths in the SIRTURO group (due to alcohol poisoning) occurred during the 24-week treatment period. The other nine deaths among those treated with SIRTURO occurred after completion of treatment with this agent (range 86-911 days post-SIRTURO; median 344 days). The observed imbalance in deaths between the two treatment groups is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other medicinal products used to treat tuberculosis, human immunodeficiency virus status, or severity of disease could be observed. During the trial, there was no evidence of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the patients that died.

In the Phase IIb, open-label study (C209), 6.9% (16/233) patients died. The most common cause of death as reported by the investigator was tuberculosis (9 patients). All but one patients who died of tuberculosis had not converted or had relapsed. The causes of death in the remaining patients varied.

Description of selected adverse reactions

CardiovascularIn the controlled Phase IIb study (C208), mean increases from baseline values in QTcF were observed from the first on-treatment assessment onwards (9.9 ms at week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase from baseline values in QTcF during the 24 weeks of SIRTUROtreatment was 15.7 ms (at week 18). After the end of SIRTURO treatment (i.e. after week 24), QTcF increases in the SIRTURO group gradually became less pronounced. The largest mean increase from baseline values in QTcF in the placebo group during the first 24 weeks was 6.2 ms (also at week 18) (see section 4.4).In the Phase IIb, open label study (C209), where patients with no treatment options received other QT-prolonging medicinal products used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging medicinal products in the treatment regimen.Patients receiving SIRTURO alone with no other QT prolonging medicinal product developed a maximal mean QTcF increase over baseline of 23.7 ms with no QT duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging medicinal products developed a maximal mean QTcF prolongation of 30.7 ms over baseline, resulting in a QTcF duration in excess of 500 ms in one patient.There were no documented cases of Torsade de Pointes in the safety database (see section 4.4). Seesection 4.5, QT interval and concomitant clofazimine use, for further information regarding patients using clofazimine concomitantly.

Increased transaminasesIn study C208 (stage 1 and 2), aminotransferase elevations of at least 3 x ULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] versus 6/105 [5.7%]) in the placebo treatment group. In the SIRTURO treatment group, the majority of these increases occurred throughout the 24 weeks of treatment and were reversible. During the investigational phase in Stage 2 of study C208, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) in the placebo treatment group.

Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

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professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Cases of intentional or accidental acute overdose with bedaquiline were not reported during clinical trials. In a study in 44 healthy subjects receiving a single 800 mg dose of SIRTURO, adverse reactions were consistent with those observed in clinical studies at the recommended dose (see section 4.8).

There is no experience with the treatment of acute overdose with SIRTURO. General measures to support basic vital functions including monitoring of vital signs and electrocardiogram (QT interval) monitoring should be taken in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be aided by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. Clinical monitoring should be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis, ATC code: J04AK05

Mechanism of actionBedaquiline is a diarylquinoline. Bedaquiline specifically inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an essential enzyme for the generation of energy in Mycobacterium tuberculosis. The inhibition of ATP synthase leads to bactericidal effects for both replicating and non-replicating tubercle bacilli.

Pharmacodynamic effectsBedaquiline has activity against Mycobacterium tuberculosis with a minimal inhibitory concentration (MIC) for drug-sensitive as well as drug-resistant strains (multi-drug resistant including pre-extensively drug resistant strains, extensively drug resistant strains) in the range of ≤ 0.008-0.12 mg/l. The N-monodesmethyl metabolite (M2) is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (3- to 6-fold lower) compared to the parent compound.

The intracellular bactericidal activity of bedaquiline in primary peritoneal macrophages and in a macrophage-like cell line was greater than its extracellular activity. Bedaquiline is also bactericidal against dormant (non-replicating) tubercle bacilli. In the mouse model for TB infection, bedaquilinehas demonstrated bactericidal and sterilizing activities.

Bedaquiline is bacteriostatic for many non-tuberculous mycobacterial species. Mycobacterium xenopi, Mycobacterium novocastrense, Mycobacterium shimoidei and non-mycobacterial species are considered inherently resistant to bedaquiline.

Pharmacokinetic/pharmacodynamic relationshipWithin the concentration range achieved with the therapeutic dose, no pharmacokinetic/pharmacodynamic relationship was observed in patients.

Mechanisms of resistanceAcquired resistance mechanisms that affect bedaquiline MICs include mutations in the atpE gene, which codes for the ATP synthase target, and in the Rv0678 gene, which regulates the expression of the MmpS5-MmpL5 efflux pump. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4.0 mg/l. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in

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bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.50 mg/l. Isolates with efflux-based mutations are also less susceptible to clofazimine.

However no clear relationship between increased post-baseline bedaquiline MICs and microbiologic outcomes was observed in the phase 2 trials where bedaquiline was given for 24 weeks, followed by continuation of the background regimen.

Susceptibility testing breakpointsWhen available, the clinical microbiology laboratory should provide the physician with the results ofin vitro susceptibility test results for antimicrobial medicinal products used in resident hospitals as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting a combination of antibacterial medicinalproducts for treatment.

BreakpointsMinimal inhibitory concentration (MIC) breakpoints are as follows:Epidemiological Cut-Off (ECOFF) 0.25 mg/lClinical Breakpoints S ≤ 0.25 mg/l; R > 0.25 mg/lS = susceptibleR = resistant

Commonly susceptible speciesMycobacterium tuberculosis

Inherently resistant organismsMycobacterium xenopiMycobacterium novocastrenseMycobacterium shimoideiNon-mycobacterial species

Clinical efficacy and safetyThe following definitions applies for resistance categories used:

Multi-drug resistant Mycobacterium tuberculosis (MDRH&R-TB): isolate resistant to at least isoniazid and rifampicin, but susceptible to fluoroquinolones and second line injectable agents.Pre-extensively drug resistant tuberculosis (pre-XDR-TB): isolate resistant to isoniazid, rifampicin, and either any fluoroquinolone or at least one second line injectable agent (but not to both a fluoroquinolone and a second line injectable agent).Extensively drug resistant tuberculosis (XDR-TB): isolate resistant to isoniazid, rifampicin, any fluoroquinolone, and at least one second line injectable agent.

A Phase IIb, placebo-controlled, double-blind, randomised trial (C208) evaluated the antibacterial activity, safety, and tolerability of SIRTURO in newly diagnosed patients with sputum smear-positive pulmonary MDRH&R- and pre-XDR-TB. Patients received SIRTURO (n = 79) or placebo (n = 81) for 24 weeks, both in combination with a preferred 5-drug background regimen (BR) consisting of ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone. After the 24-week investigational period, the background regimen was continued to complete 18 to 24 months of total multi-drug resistant Mycobacterium tuberculosis treatment. A final evaluation was conducted at Week 120. Main demographics were as follows: 63.1% were males, median age 34 years, 35% were Black, and 15% were HIV positive. Cavitation in one lung was seen in 58% of patients, and in both lungs in 16%. For patients with full characterisation of resistance status, 76% (84/111) were infected with an MDRH&R-TB strain and 24% (27/111) with a pre-XDR-TB strain.

SIRTURO was administered as 400 mg once daily for the first 2 weeks, and as 200 mg 3 times/week for the following 22 weeks.

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The primary outcome parameter was the time to sputum culture conversion (i.e. the interval between the first SIRTURO intake and the first of two consecutive negative liquid cultures from sputum collected at least 25 days apart) during treatment with SIRTURO or placebo (median time to conversion was 83 days for the SIRTURO group, 125 days for the placebo group (hazard ratio, 95% CI: 2.44 [1.57; 3.80]), p < 0.0001).

In the SIRTURO group, no or only minor differences in time to culture conversion and culture conversion rates were observed between patients with pre-XDR-TB and patients with MDRH&R-TB.

Response rates at week 24 and week 120 (i.e. around 6 months after stopping all therapy) arepresented in table 1.

Table 1: Culture conversion StatusCulture Conversion Status, n (%)

mITT populationN SIRTURO/BR N Placebo/BR

Overall responder at Week 24

66 52 (78.8%) 66 38 (57.6%)

Patients with MDRH&R-TB

39 32 (82.1%) 45 28 (62.2%)

Patients infectedwith a pre-XDR-TB

15 11 (73.3%) 12 4 (33.3%)

Overall non-responder* at Week 24

66 14 (21.2%) 66 28 (42.4%)

Overall responder at Week 120

66 41 (62.1%) 66 29 (43.9%)

Patients with MDRH&R-TB

39# 27 (69.2%) 46# § 20 (43.5%)

Patients infected with pre-XDR-TB

15# 9 (60.0%) 12# 5 (41.7%)

Overall non-responder* at Week 120

66 25 (37.9%) 66 37 (56.1%)

Failure to convert 66 8 (12.1%) 66 15 (22.7%)Relapse† 66 6 (9.1%) 66 10 (15.2%)Discontinued but converted

66 11 (16.7%) 66 12 (18.2%)

* Patients who died during the trial or discontinued the trial were considered as non-responders.† Relapse was defined in the trial as having a positive sputum culture after or during treatment following prior sputum

culture conversion.# Extent of resistance based on central laboratory drug susceptibility testing results was not available for 20 subjects in

the mITT population (12 in the SIRTURO group and 8 in the placebo group). These subjects were excluded from the subgroup analysis by extent of resistance of M tuberculosis strain.

§ Central laboratory drug susceptibility testing results became available for one additional placebo subject after the week 24 interim analysis.

Study C209 evaluated the safety, tolerability, and efficacy of 24 weeks treatment with open-labelSIRTURO as part of an individualized treatment regimen in 233 patients who were sputum smear positive within 6 months prior to screening. This study included patients of all three resistance categories (MDRH&R-, pre-XDR- and XDR-TB).

The primary efficacy endpoint was the time to sputum culture conversion during treatment with SIRTURO (median 57 days, for 205 patients with sufficient data). At week 24, sputum culture conversion was seen in 163/205 (79.5%) patients. Conversion rates at week 24 were highest (87.1%; 81/93) in patients with MDRH&R-TB, 77.3% (34/44) in pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. Extent of resistance based on central laboratory drug susceptibility testing

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results was not available for 32 subjects in the mITT population. These subjects were excluded from the subgroup analysis by extent of resistance of Mycobacterium tuberculosis strain.

At week 120, sputum culture conversion was seen in 148/205 (72.2%) patients. Conversion rates at week 120 were highest (73.1%; 68/93) in patients with MDRH&R-TB, 70.5% (31/44) in pre-XDR-TB patients and lowest (62.2%; 23/37) in XDR-TB patients.

At both week 24 and week 120, responder rates were higher for patients on 3 or more active substances (in vitro) in their background regimen.

Of the 163 patients who were responders at week 24, 139 patients (85.3%) were still responders at week 120. Twenty-four of these 24-week responders (14.7%) were considered non-responders at week 120, of which 19 patients had prematurely discontinued the trial while being culture converted and 5 patients had experienced relapse. Of the 42 patients who were non-responders at week 24, confirmed culture conversion after week 24 (i.e., after bedaquiline dosing ended but the background regimen was continued) occurred in 9 patients (21.4%) and was maintained at week 120.

Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with SIRTURO in one or more subsets of the paediatric population in the treatment of multi-drug resistant Mycobacterium tuberculosis (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme.This means that further evidence on this medicinal product is awaited.The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of bedaquiline have been evaluated in adult healthy subjects and in adult multi-drug resistant tuberculosis-infected patients. Exposure to bedaquiline was lower in multi-drug resistant tuberculosis-infected patients than in healthy subjects.

AbsorptionMaximum plasma concentrations (Cmax) are typically achieved at about 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied (700 mg single-dose and once daily 400 mg multiple doses). Administration of bedaquiline with food increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, bedaquiline should be taken with food to enhance its oral bioavailability.

DistributionThe plasma protein binding of bedaquiline is > 99.9% in all species tested, including human. The plasma protein binding of the N-monodesmethyl metabolite (M2) in humans is at least 99.8%. In animals, bedaquiline and its active N-monodesmethyl metabolite (M2) are extensively distributed to most tissues, however, brain uptake was low.

BiotransformationCYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2).

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

Bedaquiline and M2 were not substrates of P-gp in vitro. Bedaquiline was a weak OCT1, OATP1B1and OATP1B3 substrate in vitro, while M2 was not. Bedaquiline was not a substrate of MRP2 and

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BCRP in vitro. Bedaquiline and M2 did not inhibit the transporters P-gp, OATP1B1, OATP1B3, BCRP, OAT1, OAT3, OCT1, OCT2, MATE1 and MATE2 at clinically relevant concentrations in vitro. An in vitro study indicated a potential for bedaquiline to inhibit BCRP at the concentrations achieved in the intestine after oral administration. The clinical relevance is unknown.

EliminationBased on the preclinical studies, the bulk of the administered dose is eliminated in faeces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged active substance is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of both bedaquiline and the active N-monodesmethyl metabolite (M2) is about 5 months (ranging from 2 to 8 months). This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.

Special populations

Hepatic impairmentA single-dose study of SIRTURO in 8 subjects with moderate hepatic impairment (Child-Pugh B) demonstrated exposure to bedaquiline and M2 (AUC672h) was 19% lower compared to healthy subjects. No dose adjustment is deemed necessary in patients with mild or moderate hepatic impairment. Bedaquiline has not been studied in patients with severe hepatic impairment (see section 4.2).

Renal impairmentSIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is insignificant (< 0.001%).

In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO 200 mg three times a week, creatinine clearance (range: 40 to 227 ml/min) was not found to influence the pharmacokinetic parameters of bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment (creatinine clearance < 30 ml/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis, bedaquiline concentrations may be increased due to alteration of active substance absorption, distribution, and metabolism secondary to renal dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly removed from plasma by haemodialysis or peritoneal dialysis.

Paediatric patientsThe pharmacokinetics of SIRTURO in paediatric patients have not been evaluated.

Elderly patientsThere is limited clinical data (n = 2) on the use of SIRTURO in tuberculosis patients aged 65 years and older.

In a population pharmacokinetic analysis of tuberculosis patients (age range 18 years to 68 years)treated with SIRTURO age was not found to influence the pharmacokinetics of bedaquiline.

RaceIn a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, exposure to bedaquiline was found to be lower in Black patients than in patients from other race categories. This low exposure was not considered to be clinically relevant as no clear relationship between exposure to bedaquiline and response has been observed in clinical trials. Furthermore, response rates in patients that completed the bedaquiline treatment period were comparable between different race categories in the clinical trials.

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GenderIn a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO no clinically relevant difference in exposure between men and women were observed.

5.3 Preclinical safety data

Animal toxicology studies have been conducted with bedaquiline administration up to 3 months in mice, up to 6 months in rats, and up to 9 months in dogs. The plasma bedaquiline exposure (AUC) in rats and dogs was similar to that observed in humans. Bedaquiline was associated with effects in target organs which included monocytic phagocytic system (MPS), skeletal muscle, liver, stomach, pancreas and heart muscle. All of these toxicities except effects on MPS were monitored clinically. In the MPS of all species, pigment-laden and/or foamy macrophages were also seen in various tissues, consistent with phospholipidosis. The significance of phospholipidosis in humans is unknown. Most of the observed changes occurred after prolonged daily dosing and subsequent increases in plasma and tissue concentrations of the active substance. After treatment cessation, all indications of toxicity exhibited at least partial recovery to good recovery.

In a rat carcinogenicity study, bedaquiline, at the high doses of 20 mg/kg/day in males and 10 mg/kg/day in females, did not induce any treatment-related increases in tumour incidences.Compared to the exposures (AUC) observed in subjects with MDR-TB in the bedaquiline phase IItrials, the exposures (AUC) in rats at high doses were similar in males and 2-fold higher in females for bedaquiline, and 3-fold higher in males and 2-fold higher in females for M2.

In vitro and in vivo genotoxicity tests indicated that bedaquiline did not have any mutagenic or clastogenic effects.

Bedaquiline had no effects on fertility when evaluated in female rats. Three of 24 male rats treated with high bedaquiline doses failed to produce offspring in the fertility study. Normal spermatogenesis and a normal amount of spermatozoa in the epidydimides were noted in these animals. No structural abnormalities in the testes and epididymides were seen after up to 6-months of bedaquiline treatment. No relevant bedaquiline-related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. In the rat, no adverse effects were observed in a pre- and post-natal development study at maternal plasma exposure (AUC) similar to humans and exposure in the offspring 3-fold higher than in adult humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioural development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6- to12-fold higher that the maximum concentration observed in maternal plasma.

Environmental Risk Assessment (ERA)Environmental risk assessment studies have shown that bedaquiline has the potential to be persistent, bioaccumulative and toxic to the environment (see section 6.6).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrateMaize starchHypromellosePolysorbate 20Microcrystalline celluloseCroscarmellose sodiumSilica, colloidal anhydrous

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Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Tablets packaged in:- aluminium/aluminium foil blisters: 3 years- white high density polyethylene (HDPE) bottles: 3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original container or package in order to protect from light.

6.5 Nature and contents of container

188 tablets packaged in a white HDPE bottle with child-resistant polypropylene (PP) closure with aluminium induction seal liner.

Carton containing 4 push-through blister strips (containing 6 tablets per strip). Tablets are packaged in aluminium/aluminium foil blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product may pose a risk to the environment.Any unused product or waste material should be disposed of in accordance with local requirements(see section 5.3).

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NVTurnhoutseweg 30B-2340 BeerseBelgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/901/001EU/1/13/901/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 March 2014Date of latest renewal: 23 December 2016

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10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Janssen Pharmaceutica NVTurnhoutseweg 30B-2340 BeerseBelgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

! Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

! Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:! At the request of the European Medicines Agency;! Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures

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Description Due dateThe MAH will evaluate additional efficacy and safety data of bedaquiline in different treatment regimen compared to a regimen that does not include bedaquiline (confirmatory phase III study) following an agreed protocol.

! Annual updates on study progress in the frame of annual renewal submissions

! Interim IDMC analysis when half of the patients reach W76: 2Q 2018

! W76 primary analysis -Clinical Study Report 4Q 2020

! W132 final analysis -Clinical Study Report November 2021

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

22

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON


SIRTURO 100 mg tabletsBedaquiline

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains bedaquiline fumarate equivalent to 100 mg bedaquiline.

3. LIST OF EXCIPIENTS

Contains lactose.See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

188 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original container in order to protect from light.

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

This medicine may pose a risk to the environment. Any unused medicine should be disposed of in accordance with local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER



EU/1/13/901/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

sirturo 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:SN:NN:

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL






Contains lactose.


188 tablets






8. EXPIRY DATE

EXP


Store in the original container in order to protect from light.

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EU/1/13/901/001

13. BATCH NUMBER

Lot




26

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON






Contains lactose.See leaflet for further information.


24 tablets






8. EXPIRY DATE

EXP


Store in the original package in order to protect from light.

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EU/1/13/901/002

13. BATCH NUMBER

Lot




sirturo 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:SN:NN:

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER



2. NAME OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

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B. PACKAGE LEAFLET

30

Package leaflet: Information for the patient


This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.- Keep this leaflet. You may need to read it again.- If you have any further questions, ask your doctor, pharmacist or nurse.- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet1. What SIRTURO is and what it is used for2. What you need to know before you take SIRTURO3. How to take SIRTURO4. Possible side effects5. How to store SIRTURO6. Contents of the pack and other information

1. What SIRTURO is and what it is used for

SIRTURO contains the active substance bedaquiline.SIRTURO is a type of antibiotic. Antibiotics are medicines that kill bacteria that cause disease.SIRTURO is used to treat tuberculosis that affects the lungs when the disease has become resistant to other antibiotics. This is called multi-drug resistant pulmonary tuberculosis.SIRTURO must always be taken together with other medicines for treating tuberculosis.It is used in adults aged 18 years and over.

2. What you need to know before you take SIRTURO

Do not take SIRTURO if:! you are allergic to bedaquiline or any of the other ingredients of this medicine (listed in

section 6). Do not take SIRTURO if this applies to you. If you are not sure, talk to your doctor or pharmacist before taking SIRTURO.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking SIRTURO, if:! you have had an abnormal heart reading (ECG) or heart failure;! you have a personal or family history of a heart problem called “congenital long QT syndrome”;! you have a decreased thyroid gland function. This can be seen in a blood test;! you have liver disease or you drink alcohol on a regular basis;! you have human immunodeficiency virus (HIV) infection.

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If any of the above applies to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking SIRTURO.

Children and adolescentsDo not give this medicine to children and adolescents (under 18 years of age). This is because it has not been studied in this age group.

Other medicines and SIRTUROOther medicines may affect SIRTURO. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines without a prescription and herbal medicines.

The following are examples of medicines patients with multi-drug resistant tuberculosis may take and which may potentially interact with SIRTURO:

Medicine (name of the active substance)

Purpose of the medicine

rifampicin, rifapentine, rifabutin

to treat some infections like tuberculosis(antimycobacterial)

ketoconazole, fluconazole to treat fungal infections (antifungals)efavirenz, etravirine, lopinavir/ritonavir

to treat HIV infection (antiretroviral non-nucleoside reverse transcriptase inhibitors, antiretroviral protease inhibitors)

clofazimine to treat some infections like leprosy(antimycobacterial)

carbamazepine, phenytoin to treat epileptic fits (anticonvulsants)St. John’s wort (Hypericum perforatum)

an herbal product to relieve anxiety

ciprofloxacin, erythromycin, clarithromycin

to treat bacterial infections (antibacterials)

SIRTURO with alcoholYou should not drink alcohol while taking SIRTURO.

Pregnancy and breast-feedingIf you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machinesYou may feel dizzy after taking SIRTURO. If this happens do not drive or operate machinery.

SIRTURO contains lactose monohydrateSIRTURO contains “lactose” (a type of sugar). If you cannot tolerate or digest some sugars, talk to your doctor before taking this medicine.

3. How to take SIRTURO

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

SIRTURO must always be taken together with other medicines for treating tuberculosis. Your doctor will decide which other medicines you should take with SIRTURO.

How much to takeYou take SIRTURO for a 24 week course.

First 2 weeks:! Take 400 mg (4 tablets of 100 mg) once a day.

32

From week 3 to week 24:! Take 200 mg (2 tablets of 100 mg) once a day for 3 days of each week only.! There must be at least 48 hours in between each time you take SIRTURO. For example,

you may take SIRTURO on Monday, Wednesday and Friday every week from week 3 onwards.

You may need to keep taking your other medicines for tuberculosis for longer than 6 months. The use of SIRTURO for longer than 6 months has not been studied in clinical trials. Check with your doctoror pharmacist.

Taking this medicine! Take SIRTURO with food. The food is important to get the right levels of medicine in your

body.! Swallow the tablets whole with water.

If you take more SIRTURO than you shouldIf you take more SIRTURO than you should, talk to a doctor straight away. Take the medicine pack with you.

If you forget to take SIRTURODuring the first 2 weeks! Skip the missed dose and take the next dose as usual! Do not take a double dose to make up for a forgotten dose.

From week 3 onwards! Take the missed dose of 200 mg as soon as possible.! Resume the three times a week schedule.

If you have missed a dose and you are not sure what to do, talk to your doctor or pharmacist.

If you stop taking SIRTURODo not stop taking SIRTURO without first talking to your doctor.

Skipping doses or not completing the full course of therapy may:! make your treatment ineffective and your tuberculosis could get worse, and;! increase the chance that the bacteria will become resistant to the medicine. This means your

disease may not be treatable by SIRTURO or other medicines in the future.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common (may affect more than 1 in 10 people):! headache! joint pain! feeling dizzy! feeling or being sick (nausea or vomiting).

Common (may affect up to 1 in 10 people):! diarrhoea! increased liver enzymes (shown in blood tests)! aching or tender muscles, not caused by exercise

33

! abnormal reading on the electrocardiogram called “QT prolongation”. Tell your doctor right away if you faint.

Reporting of side effectsIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store SIRTURO

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the last day of that month.

Store SIRTURO in the original container or package in order to protect it from light.

This medicine may pose a risk to the environment. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What SIRTURO contains! The active substance is bedaquiline. Each tablet contains bedaquiline fumarate equivalent to

100 mg of bedaquiline.! The other ingredients are: colloidal anhydrous silica, croscarmellose sodium, hypromellose,

lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polysorbate 20.

What SIRTURO looks like and contents of the packUncoated, white to almost white round biconvex tablet, 11 mm in diameter, with debossing of "T" over "207" on one side and "100" on the other side.A plastic bottle containing 188 tablets.A carton containing 4 push-through blister strips (containing 6 tablets per strip).Not all pack sizes may be marketed.

Marketing Authorisation HolderJanssen-Cilag International NVTurnhoutseweg 30B-2340 BeerseBelgium

ManufacturerJanssen Pharmaceutica NVTurnhoutseweg 30B-2340 BeerseBelgium

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

34

België/Belgique/BelgienJanssen-Cilag NVAntwerpseweg 15-17B-2340 BeerseTel/Tél: +32 14 64 94 11

LietuvaUAB "JOHNSON & JOHNSON"Geležinio Vilko g. 18ALT-08104 VilniusTel: +370 5 278 68 88

България„Джонсън & Джонсън България” ЕООДж.к. Младост 4Бизнес Парк София, сграда 4София 1766Тел.: +359 2 489 94 00

Luxembourg/LuxemburgJanssen-Cilag NVAntwerpseweg 15-17B-2340 BeerseBelgique/BelgienTél/Tel: +32 14 64 94 11

Česká republikaJanssen-Cilag s.r.o.Karla Engliše 3201/06CZ-150 00 Praha 5 - SmíchovTel: +420 227 012 227

MagyarországJanssen-Cilag Kft.Nagyenyed u. 8-14H-Budapest, 1123Tel.: +36 1 884 2858

DanmarkJanssen-Cilag A/SBregnerødvej 133DK-3460 BirkerødTlf: +45 45 94 82 82

MaltaAM MANGION LTD.Mangion Building, Triq Ġdida fi Triq VallettaMT-Ħal-Luqa LQA 6000Tel: +356 2397 6000

DeutschlandJanssen-Cilag GmbHJohnson & Johnson Platz 1D-41470 NeussTel: +49 2137 955-955

NederlandJanssen-Cilag B.V.Graaf Engelbertlaan 75NL-4837 DS BredaTel: +31 76 711 1111

EestiUAB "JOHNSON & JOHNSON" Eesti filiaalLõõtsa 2EE-11415 TallinnTel: +372 617 7410

NorgeJanssen-Cilag ASPostboks 144NO-1325-LysakerTlf: +47 24 12 65 00

ΕλλάδαJanssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.Λεωφόρος Ειρήνης 56GR-151 21 Πεύκη, ΑθήναTηλ: +30 210 80 90 000

ÖsterreichJanssen-Cilag Pharma GmbHVorgartenstraße 206BA-1020 WienTel: +43 1 610 300

EspañaJanssen-Cilag, S.A.Paseo de las Doce Estrellas, 5-7E-28042 MadridTel: +34 91 722 81 00

PolskaJanssen-Cilag Polska Sp. z o.o.ul. Iłżecka 24PL-02-135 WarszawaTel.: +48 22 237 60 00

FranceJanssen-Cilag1, rue Camille Desmoulins, TSA 91003F-92787 Issy Les Moulineaux, Cedex 9Tél: 0 800 25 50 75 / +33 1 55 00 40 03

PortugalJanssen-Cilag Farmacêutica, Lda.Estrada Consiglieri Pedroso, 69 AQueluz de BaixoPT-2734-503 BarcarenaTel: +351 21 43 68 835

35

HrvatskaJohnson & Johnson S.E. d.o.o.Oreškovićeva 6h10010 ZagrebTel: +385 1 6610 700

RomâniaJohnson & Johnson România SRLStr. Tipografilor nr. 11-15Clădirea S-Park, Corp B3-B4, Etaj 3013714 Bucureşti, ROMÂNIATel: +40 21 207 1800

IrelandJanssen-Cilag Ltd.50-100 Holmers Farm WayHigh WycombeBuckinghamshire HP12 4EGUnited KingdomTel: +44 1 494 567 444

SlovenijaJohnson & Johnson d.o.o.Šmartinska cesta 53SI-1000 LjubljanaTel: +386 1 401 18 30

ÍslandJanssen-Cilag ABc/o Vistor hf.Hörgatúni 2IS-210 GarðabærSími: +354 535 7000

Slovenská republikaJohnson & Johnson s.r.o.CBC III, Karadžičova 12SK-821 08 BratislavaTel: +421 232 408 400

ItaliaJanssen-Cilag SpAVia M.Buonarroti, 23I-20093 Cologno Monzese MITel: +39 02 2510 1

Suomi/FinlandJanssen-Cilag OyVaisalantie/Vaisalavägen 2FI-02130 Espoo/EsboPuh/Tel: +358 207 531 300

ΚύπροςΒαρνάβας Χατζηπαναγής Λτδ,Λεωφόρος Γιάννου Κρανιδιώτη 226ΛατσιάCY-2234 ΛευκωσίαΤηλ: +357 22 207 700

SverigeJanssen-Cilag ABBox 4042SE-16904 SolnaTel: +46 8 626 50 00

LatvijaUAB "JOHNSON & JOHNSON" filiāle LatvijāMūkusalas iela 101Rīga, LV-1004Tel: +371 678 93561

United KingdomJanssen-Cilag Ltd.50-100 Holmers Farm WayHigh WycombeBuckinghamshire HP12 4EG - UKTel: +44 1 494 567 444

This leaflet was last revised in

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary.

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

2

4.8

1. 100 mg

2. 1 100 mg

1 145 mg

6.1

3.

11 mm T 207 2

100

4.

4.1

4.2 4.4 5.1

4.2

in vitro

3

In vitro

4

· 1 2 400 mg 100 mg 4 1 1

· 3 24 200 mg 100 mg 2 3 48

24 24

24

3

4.4 4.8

2

3 200 mg 3

65

n = 2

5.2

5.2

30 mL/

5.2

18

2

5.2

4.3 6.1

4.4 C208 C209 24

5.1

·

·

·

4

24 120

C208 4.8

C209 4.8

QTc

1

QT

4.5 4.8

QTc

QT 4.5

QT

4.5

·

· Fridericia QT QTcF 450 ms

· QT

·

·

·

· QT

·

·

· QTcF 500 ms

QT

5

2×ULN 4.8

24

1 ALT AST

5 AST ALT

CYP3A4

CYP3A4 CYP3A4

CYP3A4 4.5

CYP3A4

CYP3A4

4.5 14

CYP3A4

HIV

ARV HIV

N = 22 CD4

250 106 cells/L 4.5

Lapp

4.5 in vivo CYP3A4 in vitro

N- M2 CYP

M2 P

6

CYP3A4

CYP3A4

1 1

AUC 52% 90% CI

-57; -46

CYP3A4

Hypericum perforatum

CYP3A4

CYP3A4

CYP3A

AUC 22% 90% CI 12; 32

CYP3A

14

CYP3A4

4.4

AUC

AUC 22% 90% CI 11; 34

48

AUC 2

HIV

7

HIV

4.4 CYP3A

QT

QT

QTc

QT QT

4.4

QT

II 24 QTcF

12.3 ms

17

31.9 ms 4.4

4.6

5.3

6 12

5.3

8

5.3

4.7

4.8

335

II

I II

10.0% 35.3% vs 25.7% 29.4% vs

20.0% 23.5% vs 11.4% 20.6% vs 22.9% 12.7% vs 11.4%

102

SOC

very common 1/10 common 1/100 1/10 uncommon

1/1000 1/100

SOC

QT

*

* AST ALT

9

II C208 Stage 2 12.7% 79 10

3.7% 81 3 1

1 120 5

10 1 24

9

86 911 344

QT

II C209 6.9% 233 16

9 1

II C208

QTcF 1 QTcF 9.9 ms

3.5 ms 24 QTcF

15.7 ms 18 24

QTcF 24

QTcF 6.2 ms 18

4.4

QT

II C209

QT QTcF

QT

23.7 ms QTcF QTcF 480 ms

QT 2

30.7 ms QTcF 1 QTcF 500 ms

4.4

4.5

QT

C208 Stage 1 2 3

102 11 10.8% 105 6 5.7%

10

24

C208 Stage 2 24

79 7 8.9%

81 1 1.2%

5

4.9

44 800 mg

4.8

QT

5.

5.1 ATC J04AK05

ATP 5'-

ATP

0.008 0.12 mg/L

N- M2

23 31% 3 6

Mycobacterium

xenopi Mycobacterium novocastrense

11

Mycobacterium shimoidei

ATP atpE

MmpS5-MmpL5 Rv0678

atpE MIC 8 133 0.25

4.0 mg/L MmpS5-MmpL5

Rv0678 MIC 2 8

0.25 0.50 mg/L MmpS5-MmpL5 Rv0678

24

II MIC

in vitro

ECOFF 0.25 mg/L

S 0.25 mg/L R 0.25 mg/L

S =

R =

Mycobacterium tuberculosis

Mycobacterium xenopi

Mycobacterium novocastrense

Mycobacterium shimoidei

12

MDRH&R-TB

2

pre-XDR-TB :

2 1

2 1

XDR-TB

2 1

II C208

MDRH&R-TB

pre-XDR-TB

terizidone 5 BR 24

n = 79 n = 81 24

18 24

120

63.1% 35% 15% HIV 34

58% 16%

111 84 76% MDRH&R-TB

27 24% pre-XDR-TB

2 400 mg 1 1 22 200 mg 3

25 2

83

125 95% CI 2.44 1.57 3.80 p < 0.0001

pre-XDR-TB

MDRH&R-TB

24 120 6 1

13

1

, n %

mITT

N BR N BR

24 66 52 (78.8%) 66 38 (57.6%)

MDRH&R-TB

39 32 (82.1%) 45 28 (62.2%)

pre-XDR-TB

15 11 (73.3%) 12 4 (33.3%)

24 * 66 14 (21.2%) 66 28 (42.4%)

120 66 41 (62.1%) 66 29 (43.9%)

MDRH&R-TB

39# 27 (69.2%) 46# § 20 (43.5%)

pre-XDR-TB

15# 9 (60.0%) 12# 5 (41.7%)

120 * 66 25 (37.9%) 66 37 (56.1%)

66 8 (12.1%) 66 15 (22.7%) † 66 6 (9.1%) 66 10 (15.2%)

66 11 (16.7%) 66 12 (18.2%)

* †

# mITT 20 12 8

§ 24 1

C209 6 233

24

C209 3 MDRH&R-TB pre-XDR-TB

XDR-TB

C209

205 57

24 205 163 79.5% 24

MDRH&R-TB 87.1% 93 81 pre-XDR-TB

77.3% 44 34 XDR-TB 54.1% 37

20 mITT 32

14

120 205 148 72.2% 120

MDRH&R-TB 73.1% 93 68 pre-XDR-TB

70.5% 44 31 XDR-TB 62.2% 37

23

24 120 3

in vitro

24 163 139 85.3% 120

24 163 24 14.7% 120

19 5

24 42 9 21.4% 24

120

4.2

5.2

5 Cmax

Cmax AUC 700 mg

400 mg 1 1

2

99.9%

N- M2 99.8%

N-

M2

15

CYP3A4 in vitro N- M2

CYP

in vitro CYP450 CYP1A2 CYP2A6 CYP2C8/9/10 CYP2C19

CYP2D6 CYP2E1 CYP3A4 CYP3A4/5 CYP4A CYP1A2

CYP2C9 CYP2C19

M2 in vitro P-gp in vitro OCT1

OATP1B1 OATP1B3 M2 in vitro

MRP2 BCRP M2 in vitro

P-gp OATP1B1 OATP1B3 BCRP OAT1 OAT3 OCT1

OCT2 MATE1 MATE2 in vitro

BCRP

0.001%

Cmax

N- M2

5 2 8

M2

Child-Pugh B 8

M2 AUC672h 19%

4.2

0.001%

200 mg 3

40 227 mL/

30 mL/

16

65 n = 2

18 68

5.3 3 6 9

AUC

AUC Bedaquiline MPS

MPS

MPS

20 mg/kg/

10 mg/kg/

II AUC

AUC

2 M2 AUC 3

2

In vitro in vivo

24 3

6

17

AUC 2

AUC 3

F1

6 12

ERA

6.6

6.

6.1

20

Silica, colloidal anhdryous

6.2

6.3 :

· 2

· HDPE 3

6.4

PTP

6.5

PP HDPE 188

4 PTP 6

18

6.6

5.3

7. Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8. EU/1/13/901/001

EU/1/13/901/002

9. 2014 3 5

2016 12 23

10. European Medicines Agency EMA

http://www.ema.europa.eu

19

2

A.

B.

C.

D.

E.

20

A.

Janssen Pharmaceutica NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

B.

1 4.2

C.

·

2001/83/EC 107c 7

EURD

D.

· RMP

1.8.2 RMP

RMP

·

·

E.

EC 726/2004 14 7

3

1

21

2018 2

Week 76

2020 4 Week 76

2021 11 Week 132

23

A.

24

1.

100 mg

2.

1 100 mg

3.

4.

188

5.

6.

7.

8.

EXP

9.

10.

25

11.


Turnhoutseweg 30

B-2340 Beerse

Belgium

12.

EU/1/13/901/001

13.

14.

15.

16.

100 mg

26

1.

100 mg

2.

1 100 mg

3.

4.

188

5.

6.

7.

8.

EXP

9.

10.

27

11.


Turnhoutseweg 30

B-2340 Beerse

Belgium

12.

EU/1/13/901/001

13.

14.

15.

16.

28

1.

100 mg

2.

1 100 mg

3.

4.

24

5.

6.

7.

8.

EXP

9.

10.

29

11.


Turnhoutseweg 30

B-2340 Beerse

Belgium

12.

EU/1/13/901/002

13.

14.

15.

16.

100 mg

30

PTP PTP

PTP

1.

100 mg

2.


3.

EXP

4.

5.

31

B.

32

SIRTURO 100 mg

4

4

1.

2.

3.

4.

5.

6.

1.

18

33

2.

· 6

·

· QT

·

·

· HIV

18

HIV

34

3.

24

2

· 400 mg 100 mg 4 1 1

3 24

· 200 mg 100 mg 2 1 1 3

· 48 3

6 6

35

·

·

2

·

· 2

3

· 200 mg

· 3

·

·

4.

10 1

·

·

·

·

36

10 1

·

·

·

· QT

5

5.

EXP

6.

· 1 100 mg

· 20

11 mm T

207 100

1 188

1 PTP PTP 4 1 6

37


Turnhoutseweg 30

B-2340 Beerse

Belgium

Janssen Pharmaceutica NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

België/Belgique/Belgien

Janssen-Cilag NV

Antwerpseweg 15-17

B-2340 Beerse

Tel/Tél: +32 14 64 94 11

Lietuva

UAB "JOHNSON & JOHNSON"

Geležinio Vilko g. 18A

LT-08104 Vilnius

Tel: +370 5 278 68 88

„ & ”

. . 4

, 4

1766

.: +359 2 489 94 00

Luxembourg/Luxemburg

Janssen-Cilag NV

Antwerpseweg 15-17

B-2340 Beerse

Belgique/Belgien

Tél/Tel: +32 14 64 94 11

eská republika

Janssen-Cilag s.r.o.

Karla Engliše 3201/06

CZ-150 00 Praha 5 - Smíchov

Tel.: +420 227 012 227

Magyarország

Janssen-Cilag Kft.

Nagyenyed u. 8-14

H-Budapest, 1123

Tel.: +36 1 884 2858

Danmark

Janssen-Cilag A/S

Bregnerødvej 133

DK-3460 Birkerød

Tlf: +45 45 94 82 82

Malta

AM MANGION LTD.

Mangion Building, Triq dida fi Triq Valletta

MT- al-Luqa LQA 6000

Tel: +356 2397 6000

38

Deutschland

Janssen-Cilag GmbH

Johnson & Johnson Platz 1

D-41470 Neuss

Tel: +49 2137 955 955

Nederland

Graaf Engelbertlaan 75

NL-4837 DS Breda Tel: +31 76 711 1111

Eesti UAB "JOHNSON & JOHNSON" Eesti filiaal

Lõõtsa 2

EE-11415 Tallinn

Tel: +372 617 7410

Norge

Janssen-Cilag AS

Postboks 144

NO-1325-Lysaker

Tlf: +47 24 12 65 00

Janssen-Cilag . . . .

56

GR-151 21 ,

T : +30 210 80 90 000

Österreich

Janssen-Cilag Pharma GmbH

Vorgartenstraße 206B

A-1020 Wien

Tel: +43 1 610 300

España

Janssen-Cilag, S.A.

Paseo de las Doce Estrellas, 5-7

E-28042 Madrid

Tel: +34 91 722 81 00

Polska

Janssen-Cilag Polska Sp. z o.o.

ul. I ecka 24

PL-02-135 Warszawa

Tel.: +48 22 237 60 00

France

Janssen-Cilag

1, rue Camille Desmoulins, TSA 91003

F-92787 Issy Les Moulineaux, Cedex 9

Tél: 0 800 25 50 75 / +33 1 55 00 40 03

Portugal Janssen-Cilag Farmacêutica, Lda.

Estrada Consiglieri Pedroso, 69 A

Queluz de Baixo

PT-2734-503 Barcarena

Tel: +351 21 43 68 835

Hrvatska

Johnson & Johnson S.E. d.o.o.

Oreškovi eva 6h

10010 Zagreb

Tel: +385 1 6610 700

România

Johnson & Johnson România SRL

Str. Tipografilor nr. 11-15

Cl direa S-Park, Corp B3-B4, Etaj 3

013714 Bucure ti, ROMÂNIA

Tel: +40 21 207 1800

39

Ireland

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG

United Kingdom

Tel: +44 1 494 567 444

Slovenija

Johnson & Johnson d.o.o.

Šmartinska cesta 53

SI-1000 Ljubljana

Tel: +386 1 401 18 30

Ísland

Janssen-Cilag AB

c/o Vistor hf.

Hörgatúni 2

IS-210 Garðabær

Sími: +354 535 7000

Slovenská republika

Johnson & Johnson, s.r.o.

CBC III, Karadži ova 12

SK-821 08 Bratislava

Tel: +421 232 408 400

Italia

Janssen-Cilag SpA

Via M.Buonarroti, 23

I-20093 Cologno Monzese MI

Tel: +39 02 2510 1

Suomi/Finland

Janssen-Cilag Oy

Vaisalantie/Vaisalavägen 2

FI-02130 Espoo/Esbo

Puh/Tel: +358 207 531 300

226

CY-2234

: +357 22 207 700

Sverige

Janssen-Cilag AB

Box 7073

SE-192 07 Sollentuna

Tel: +46 8 626 50 00

Latvija

UAB "JOHNSON & JOHNSON" fili le Latvij

M kusalas iela 101

R ga, LV1004

Tel: +371 678 93561

United Kingdom

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG - UK

Tel: +44 1 494 567 444

40

1 1

http://www.ema.europa.eu

1.7

1

1.7 1.7-1

1.7-2

1.7

2

1.7-1

100mg

120.89mg 100mg 1

1.7

3

1.7

4

1.7

5

1.7

6

1.7-2

50mg

2014 7 4

50mg 1

1.7

7

1.7

8

1.7

9

2015 10

Ver.3.0

8 7 6 2 2 2

SIRTURO® Tablets

1.

RAPResponsible Access Program

2. QT

100mg

1 120.89mg

100mg

20

T 207

100

(mm) (mm) (mg) 11.0 4.1 460

T207

QT QTQT

2 1 1

400mg 31 200mg 3 48

1)

3

2) 6

1

1) QT QT QT

2) QT QT

(1) (2)

(3) QT (4) (5) (6) Torsade de Pointes

3) QTQT

2

1) QT

2)

3

CYP3A4

CYP3A4

CYP3A4

QT

QT QT

QT

4

6 3 50% 1 16.7 1

16.7 1 16.7

335 166 49.6%61 18.2% 57

17.0% 44 13.1% 41 12.2%

1 1 QT 2.7 QT

2 AST GOT ALT GPT

20 202012 12

最新の添付文書を参照すること

2 5 1 5

5

6

1)

1.7

2)

6 121

7

8

44

800mg

QT

9

PTP PTP

10

1 12012.7% 10/79 3.7% 3/81

2

2) 7) 3

2.62) 6) 7)

1 1

10 30 100 300 450 700 mg

1 1 8

10 mg 30 mg 100 mg 300 mg 450 mg 700 mg

6 6 6 6 6 6 tmax (h)

6.0 (6.0 8.0)

5.0 (5.0 5.0)

5.0 (2.0 6.0)

5.0 (2.0 6.0)

5.0 (2.0 5.0)

5.0 (5.0 6.0)

Cmax (ng/mL)

68.6 (14.8)

276 (64)

854 (283)

2547 (1305)

3755 (1165)

6747 (2210)

AUC (ng.h/mL)

1700 (291)

6052 (1861)

18134 (6577)

53113 (17911)

79179 (31794)

133125 (44913)

t1/2

(h) 162 (84)

143 (31)

135 (24)

169 (19)

117 (19)

172 (37)

( ) tmax ( )

1 1M2

1 14 2 39)

2 1 1

1 14 50 mg q.d. 150 mg q.d. 400 mg q.d.

Day 1 6 6 6

tmax (h) 5.0 (5.0 6.0) 5.0 (5.0 5.0) 4.0 (2.0 5.0) Cmax (ng/mL) 428 (112) 1132 (401) 3005 (493) C24h (ng/mL) 63.4 (10.0) 180 (53.0) 512 (114) AUC24h (ng.h/mL) 3989 (830) 9922 (3199) 27206 (5361) Day 14

6 5 6 tmax (h) 5.0 (5.0 6.0) 5.0 (5.0 5.1) 5.0 (3.0 6.0) Cmax (ng/mL) 590 (116) 1972 (559) 4298 (1315) C24h (ng/mL) 187 (44.0) 604 (147) 1280 (309) AUC24h (ng.h/mL) 7914 (2009) 24265 (5670) 51525 (10123) t1/2 (h) 169 (77) 167 (48) 173 (35)

( ) tmax ( )

3 1 1M2 1 14

M2 50 mg q.d. 150 mg q.d. 400 mg q.d.

Day 1 6 6 6

tmax (h) 8.0 (6.0 12.0) 12.0 (6.0 23.9) 8.0 (6.0 12.0) Cmax (ng/mL) 6.84 (1.56) 20.8 (7.9) 52.3 (18.5) C24h (ng/mL) 4.89 (1.33) 16.1 (4.1) 40.5 (13.7) AUC24h (ng.h/mL) 114 (30.6) 365 (142) 842 (211) Day 14

6 5 6 tmax (h) 10.0 (0.0 12.0) 5.1 (5.0 6.0) 8.0 (6.0 24.0) Cmax (ng/mL) 60.3 (19.1) 275 (62.0) 437 (126) C24h (ng/mL) 45.5 (12.7) 221 (56.0) 379 (119) AUC24h (ng.h/mL) 1204 (364) 5477 (1468) 8783 (2350) t1/2 (h) 258 (103) 204 (51) 299 (143)

( ) tmax ( )

2 1 II TBC2001 10)

2 400 mg 1 122 200 mg 3

M2 224 4 5

4 2 400

mg 1 1 22 200 mg 3

2 24

Week 2a 400 mg q.d.

Week 24b 200 mg t.i.w.

5 2 tmax (h) 4.10 (4.00 6.00) 6.12 4.07 Cmax (ng/mL) 6552 (1629) 3580 5460 C0h (ng/mL) 1775 (1012) 1250 2270 Css avg (ng/mL) 3223 (1029) 2438 3204 AUC24h (ng.h/mL) 77490 (24757) 58513 77148

a ( ) tmax ( ) b

5 2 400 mg 1 1 22 200 mg 3

M22 24

M2

Week 2 a

400 mg q.d. Week 24 b

200 mg t.i.w. 5 2

tmax (h) 5.00 (0.00 8.00) 8 8.03 Cmax (ng/mL) 443 (99.4) 451 450 C0h (ng/mL) 381 (85.7) 399 391 Css avg (ng/mL) 398 (89.6) 406 404 AUC24h (ng.h/mL) 9575 (2140) 9744 9735

a ( ) tmax ( ) b

2 II C208 Stage 2 11)

terizidone 2 400 mg 11 22 200 mg 3

M22 24

6 7

6 2 400 mg 1 1 22 200 mg 3

2 24

Week 2

400 mg q.d. Week 24

200 mg t.i.w. 26 a 17 b

tmax (h) 5.00 (2.33 6.17) 5.05 (3.07 6.77) Cmax (ng/mL) 2763 (1185) 1267 (434.5) C0h (ng/mL) 792.0 (263.9) 453.5 (295.2) Css avg (ng/mL) 1371 (528.8) 584.1 (196.5) AUC (ng.h/mL) 32960 (12720) 28010 (9408)

( ) tmax ( ) 24 Week 2 48 Week 24

a = 30 (C0h), = 29 (Cmax tmax) b = 18 (C0h), = 19 (Cmax tmax)

7 2 400 mg 1 1 22 200 mg 3

M22 24

M2

Week 2 400 mg q.d.

Week 24 200 mg t.i.w.

26 a 17 b tmax (h) 6.15 (1.10, 24.17) 12.08 (5.00, 48.08) Cmax (ng/mL) 466.9 (156.8) 177.9 (70.7) C0h (ng/mL) 426.5 (135.1) 162.4 (70.7) Css avg (ng/mL) 383.0 (129.9) 151.6 (52.81) AUC (ng.h/mL) 9217 (3151) 7270 (2532)

( ) tmax ( ) 24 Week 2 48 Week 24

a = 30 (C0h), = 29 (Cmax tmax) b = 18 (C0h), = 19 (Cmax tmax)

3 100mg

Cmax

AUClast 90% 2.632.23 3.09 1.95 1.67 2.26 12)

2

M299% in vitro

3 N-

M2 P450 CYP 3A450 400mg

14M2 20% 9

4

400 mg7

75 85 5

8 Child-PughB 8 400mg

Cmax

AUC72h AUClast 14%27% 19% PK

13)

6

108 mL/min 39.8~227mL/min1 200mg 3

14)

7

1) In vitro OATP1B OCT1 M2 P-gp

2)

8 M2

90Cmax AUC Cmin

a 15)

600mg 1 1

300mg 16

0.57 (0.48, 0.67)

0.48 (0.43, 0.54)

-

16 M2 1.31 (1.08, 1.59)

0.75 (0.65, 0.86)

-

16)

3002000mg

1 1

400mg 1 1

22

0.94 (0.89, 1.00)

0.87 (0.84, 0.91)

0.92 (0.88, 0.96)

M2 1.28 (1.21, 1.35)

1.30 (1.25, 1.34)

1.24 (1.20, 1.29)

17)

400mg 1 1

400mg 1 1

15

1.09 (0.98, 1.21)

1.22 (1.12, 1.32)

1.33 (1.24, 1.43)

M2 1.01 (0.95, 1.07)

1.01 (0.96, 1.07)

1.08 (1.03, 1.13)

18)

400100mg

1 1

400mg 13

0.99 (0.88, 1.12)

1.22 (1.11, 1.34)

-

13 M2 0.49 (0.43, 0.56)

0.59 (0.52, 0.67)

-

19)200mg

1 2400mg 16

0.80 (0.62, 1.04)

1.03 (0.87, 1.22)

-

M2 0.98 (0.88, 1.09)

1.05 (0.94, 1.17)

-

a

9

90

Cmax AUC Cmin

15)

600mg 1 1

300mg

16

0.73 (0.65, 0.81)

0.57 (0.53, 0.62)

-

16 25-

0.71 (0.64, 0.78)

0.45 (0.40, 0.51)

-

16)

300mg 1 1

400mg 1 1

22 1.20 (1.09, 1.33)

1.07 (1.02, 1.11)

1.20 a

(1.08, 1.32)

16)

2000mg1 1

22 1.10 (1.07, 1.14)

1.08 (1.06, 1.11)

1.18 (1.12, 1.25)

17)

400mg 1 1

400mg 1 1

15 0.93 (0.87, 0.98)

0.89 (0.84, 0.94)

0.55 (0.44, 0.70)

18)

400mg 1 1

400mg

13

- - 0.79 a

(0.72, 0.87)

100mg 1 1

13

- - 0.86 a

(0.78, 0.94)

19)200mg

1 2400mg

16 - - 0.99 a

(0.91, 1.08)

a 8 QT/QTc

44 400 mg

QT/QTc 800 mg QTcF

90%1.5 8.9 10 ms 20)

1. II TBC2001 10)

62 400 mg 1 1

22 200 mg 34 14 15

MGIT 24100 4/4 MGIT

2. II C208 Stage 2 21)

terizidone 400 mg 1 12 22

200 mg 3 6666

83 125

Cox 95% CI 2.44 1.57; 3.80 p < 0.0001 24

78.8% 52/66 57.6% 38/66

QTcF 19.9ms 3.5ms 24

QTcF 15.7ms 18QTcF

6.2ms 18 3. II C209 22)

2 400 mg 1 122 200 mg 3

20557 24 79.5%

163/205

10 C208 Stage2 C209 TBC2001

66

66

205

4

83 125 57 14 15a

24

%

78.852/66

57.638/66

79.5163/205

100 4/4

a

1 23)

ATP 2

1) In vitro 24) 25)

2) In vivo 25)

3 26) 27) ATP atpE

MmpS5-MmpL5 Rv0678

JAN

Bedaquiline Fumarate JAN (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol monofumarate C32H31BrN2O2•C4H4O4 671.58

0.007 (g/100 mL) 2.4 (g/100 mL)

2- 0.64 (g/100 mL) 14 (g/100 mL)

0.38 (g/100 mL) 210

PTP

1. 2.

6 6 1

1TMC207-TOX9296

2 13TMC207-TOX7419

3 1TMC207-TOX6017

4 26TMC207-TOX7421

5 1TMC207-TOX6018

6 26TMC207-TOX6612

7 39TMC207-TOX9239

8 TMC207R207910-CDE-101

9 TMC207R207910-CDE-102

10 TMC207TMC207-TBC2001

11 TMC207TMC207-C208 stage 2

12 TMC207TMC207-C108

13 TMC207TMC207-C112

14 TMC207TMC207-201105

15) TMC207TMC207-BAC1003

16 TMC207TMC207-C104

17) TMC207TMC207-C109

18 TMC207TMC207-C110

19 TMC207TMC207-C117

20 TMC207 QTTMC207-TBC1003

21 Diacon A.H. et al.: N EnglJ Med., 371(8), 723-32, 2014 22 Pym A. S. et al.: Eur Respir J., 47(2):564-74, 2016

23 Koul A., et al. : Nat Commun., 5. 3369. 2014 24 TMC207 TMC207-TiDP13-C209 25 Andries K., et al. : Science., 307(5707). 223. 2005 26 Huitric E., et al. : Antimicrob Agents Chemother., 54(3). 1022. 2010 27 TMC207 TMC207-Resistance

Mechanisms-ABMR

101-0065 3-5-2 0120-183-275

FAX 0120 275 831 9:00 17:40

1.8

1

1.8 ................................................................................................................................ 2

1.8.1 ................................................ 2

1.8.1.1 ............................................................................ 2

1.8.1.2 ............................................................................ 4

1.8.2 ................................................................................ 7

1.8

2

1.8

1.8.1

1.8.1.1

(1)

(2)

MDR-TB TMC207 IIb

TMC207-TiDP13-C208 C208 Stage 2 TMC207-TiDP13-C209

C209 II TMC207TBC2001 TBC2001

MDR-TB

C208 Stage 2 TMC207 background regimen BR

24 400 mg 1 1 q.d. 2 200 mg

3 t.i.w. 48 22 TMC207

modified intent-to-treat mITT 66 MGIT

mITT 66 missing=failure

p<0.0001 missing=failure

p=0.008 Week 24 TMC207 73

125 TMC207 78.8% 57.6%

MDR-TB

C209 mITT 205 MGIT

57 Week 24 79.5%

missing=failure C208 Stage 2 C209

XDR-TB XDR-TB 36

20 55.6% Week 24 TMC207 BR XDR-

TB

missing=failure C208 Stage 2

TMC207 62.1% 43.9%

p=0.035 C209

missing=failure 72.2%

International expert consensus group 1 C208 Stage 2 TMC207

C209 57.6% 61.0% C208 Stage 2

31.8%

1.8

3

MDR-TB TBC2001 IIb

MGIT FAS 4

MGIT

14 15

2.5.4.6

IIb TBC2001 TMC207 BR

TMC207

QT

IIb

TMC207 C208 TMC207 3.9% 0%

2.5.5.4.1 TMC207 TMC207 AST

Week 24 TMC207

TBC2001

AST 3 50.0% ALT 2 33.3% ALT 1

Grade 3

QTcF TMC207 IIb

TBC2001 QT C209 1

QT

2.5.5.4.4

CPK I TMC207

IIb CPK-MB I

TMC207 TMC207

2.5.5.12

QT

TMC207

WHO 2013

MDR-TB

1.8

4

1.8.1.2

(1)

2 1 1 400 mg

3 1 200 mg 3 48

(2)

IIb TMC207

TMC207

600 ng/mL AUC24h 14.4 g h/mL

I R207910-CDE-102 CDE-102 TMC207-C104

C104

M2

M2 AUC24h 100 g

h/mL

600 ng/mL AUC24h

14.4 g h/mL

C208 TMC207 400 mg q.d. 2

I CDE-102 C104

TMC207-C109 TMC207

DS-TB IIa

TMC207-C202 TMC207 25 mg 100 mg 400 mg

q.d. 7 400 mg log10CFU

Day 3 5 6 7

C208 TMC207 400 mg q.d.

C208 Stage 1 TMC207 400 mg q.d. 2

200 mg t.i.w. 6 TMC207 200 mg t.i.w.6

600 ng/mL

20 mg/kg/ 2 5 mg/kg/

2.6.6.3.8

t.i.w.

C208 Stage 1 MGIT

Cox TMC207

missing=failure p=0.0034

1.8

5

8

AUC24h 23 g h/mL 8 AUC24h

40 g h/mL TMC207 400 mg q.d. 2

M2 20% M2 AUC24h

100 g h/mL

24 C208 Stage 2 C209 TMC207

400 mg q.d. 2 200 mg t.i.w. 48 22

MDR-TB TMC207 BR

TMC207

1.8.1.1(2)

TMC207

400 mg q.d. 2 200 mg t.i.w. 48 22

WHO

TBC2001 TMC207 IIb

TMC207 400 mg q.d. 2 200 mg t.i.w. 48

22 TMC207 24 BR

TBC2001 MGIT TMC207

6 Week 24

TMC207

MDR-TB

TMC207 24

1.8.1.1(2)

TBC2001 PK 6

MDR-TB MDR-TB

2.7.2.5

TMC207-C108 C108 TMC207-

TiDP13-C111 C111 TMC207 100 mg

Cmax AUC

C108 2.6 2.0 C111 3.8 2.4 M2

Cmax AUC C108

C111 Cmax AUC672h 1.5

2.7.1.2.1.2

TMC207

1.8

6

2 1 1 400 mg

3 1 200 mg 3 48

1.8

7

1.8.2 1.8.2-1

1.8

8

1.8.2-1

1)

RAP Responsible Access

Program

2) QT

1)

2) QT

CCDS

QT QT QT

QT

CCDS

1)

3

2) 6

1) CCDS

2)

24

24

CCDS

1

1) QT QT QT

1) 2) 3)

1.8

9

2) QT QT

(1)

(2)

(3) QT

(4)

(5)

(6) Torsade de Pointes

3) QT QT

QT

CCDS

2

1) QT

2)

1)

QT

CCDS

2)

CCDS

3

CYP3A4

CCDS

1.8

10

CYP3A4

CYP3A4

QT

QT QT

QT

4.

6 3

50% 1 16.7 1 16.7 1

16.7

335

166 49.6% 61 18.2% 57 17.0% 44

13.1% 41 12.2%

1

(1) QT 2.7 QT

(2) AST GOT ALT GPT

C208

C209

1) 2)

C208 C209

C208

C209

1.8

11

2 5 1 5

5.

CCDS

6.

1)

1.7

2)

6 12

1) CCDS

1 1 400mg 2

2) CCDS

7.

9 4 25 607

8.

44 800mg

CCDS

1.8

12

QT

9

PTP PTP

8 3 27 240

PTP

10.

1 120 12.7% 10/79

3.7% 3/81

2

3 2.6

1)

CCDS

2)

CCDS

3) 1

1 400mg 2

1.8

13

1 Laserson KF, et al. Speaking the same language: treatment outcome definitions for multidrug-

resistant tuberculosis. Int J Tuberc Lung Dis. 2005;9(6):640-5.

1.9

1

1.9

1.9.1 JAN 27 2 24

0224 1

JAN

Bedaquiline Fumarate

(1R,2S)-1-(6- -2- -3- )-4-( )-2-( -1- )-

1- -2-

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-

phenylbutan-2-ol monofumarate

1.9.2 INN

bedaquiline

r-INN List 65, WHO Drug Information, Vol.25, No.1, 2011

1.9.3

0224 1

2 7 2 2 4

18 3 310331001

JAN

URL http://jpdb.nihs.go.jp/jan/Default.aspx

JAN

INN 18 3 31 0331001

25-1-B24 JAN JAN Roxadustat

C19H16N2O5 N-[(4- -1- -7- -3- ) ] N-[(4-Hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine

25-1-B26

JAN JAN Linaclotide

C59H79N15O21S6

C 14

L- -L- -L- - -L- -L- -L- -L--L- -L- -L- -L- -L- -L-

(1 6),(2 10),(5 13)- ( ) Linaclotide is a guanylate cyclase C receptor agonist. Linaclotide is a synthetic peptide consisting of 14 amino acid residues. Chemical name is as follows: L-Cysteinyl-L-cysteinyl-L- -glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl- L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclic (1 6),(2 10),(5 13)-tris(disulfide)

25-1-B28

JAN JAN Rovatirelin Hydrate

C16H22N4O4S 3H2O (4S,5S)-5- -N-{(2S)-1-[(2R)-2- -1- ]-1- -3-(1,3- -4- )

-2- }-2- -1,3- -4- (4S,5S)-5-Methyl-N-{(2S)-1-[(2R)-2-methylpyrrolidin-1-yl]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl}-2- oxo-1,3-oxazolidine-4-carboxamide trihydrate

25-1-B29

JAN JAN Bedaquiline Fumarate

N

H

N

HO

CH3

CH3

O

Br

CH3

HO2CCO2H•

C32H31BrN2O2 C4H4O4 (1R,2S)-1-(6- -2- -3- )-4-( )-2-( -1- )-1-

-2- (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)- 1-phenylbutan-2-ol monofumarate

25-1-B31

JAN JAN Ixekizumab (Genetical Recombination)

L DIVMTQTPLS LSVTPGQPAS ISCRSSRSLV HSRGNTYLHW YLQKPGQSPQ

LLIYKVSNRF IGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHLP

FTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK

VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE

VTHQGLSSPV TKSFNRGEC H QVQLVQSGAE VKKPGSSVKV SCKASGYSFT DYHIHWVRQA PGQGLEWMGV

INPMYGTTDY NQRFKGRVTI TADESTSTAY MELSSLRSED TAVYYCARYD

YFTGTGVYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD

YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY

TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL

MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR

VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL

PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD

GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG H Q1 H N296 H G445 L C219 H C133 H C225 H C225 H C228 H C228

Man-GlcNAc-GlcNAcGal0-2

GlcNAc-Man

GlcNAc-Man

Fuc

C6492H10012N1728O2028S46

H C2182H3349N573O678S17

L C1064H1661N291O336S6

-17IgG4 H 227 Ser

Pro C Lys445 H 4 2 219

L 2 149,000 Ixekizumab is a recombinant humanized monoclonal antibody composed of complementarity-determining regions derived from mouse anti-human interleukin-17 monoclonal antibody and framework regions and constant regions derived from human IgG4, and Ser residue at position 227 is substituted by Pro residue and C-terminus Lys residue is deleted in the H-chains. Ixekizumab is produced in Chinese hamster ovary cells. Ixekizumab is a glycoprotein (molecular weight: ca.149,000) composed of 2 H-chains ( 4-chains) consisting of 445 amino acid residues each and 2 L-chains ( -chains) consisting of 219 amino acid residues each.

25-1-B32

JAN JAN Asfotase Alfa (Genetical Recombination)

LVPEKEKDPK YWRDQAQETL KYALELQKLN TNVAKNVIMF LGDGMGVSTV

TAARILKGQL HHNPGEETRL EMDKFPFVAL SKTYNTNAQV PDSAGTATAY

LCGVKANEGT VGVSAATERS RCNTTQGNEV TSILRWAKDA GKSVGIVTTT

RVNHATPSAA YAHSADRDWY SDNEMPPEAL SQGCKDIAYQ LMHNIRDIDV

IMGGGRKYMY PKNKTDVEYE SDEKARGTRL DGLDLVDTWK SFKPRYKHSH

FIWNRTELLT LDPHNVDYLL GLFEPGDMQY ELNRNNVTDP SLSEMVVVAI

QILRKNPKGF FLLVEGGRID HGHHEGKAKQ ALHEAVEMDR AIGQAGSLTS

SEDTLTVVTA DHSHVFTFGG YTPRGNSIFG LAPMLSDTDK KPFTAILYGN

GPGYKVVGGE RENVSMVDYA HNNYQAQSAV PLRHETHGGE DVAVFSKGPM

AHLLHGVHEQ NYVPHVMAYA ACIGANLGHC APASSLKDKT HTCPPCPAPE

LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE

VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE

KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES

NGQPENNYKT TTPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH

NHYTQKSLSL SPGKDIDDDD DDDDDD

2

C493 – C493 C496 – C496 N123 N213 N254 N286 N413 N564

C7108H11008N1968O2206S56 2

C3554H5506N984O1103S28

1 485488 714 IgG1 Fc C 10

. 726 2180,000

Asfotase alfa is a recombinant fusion glycoprotein corresponding to a catalytic domain of human tissue non-specific alkaline phosphatase at positions 1 485, Fc domain of human Ig G1 at positions 488 714, and 10 residues of Asp are attached to the C-terminus. Asfotase alfa is produced in Chinese hamster ovary cells. Asfotase alfa is a glycoprotein (molecular weight: ca. 180,000) composed of 2 subunits consisting of 726 amino acid residues each.

25-2-B2

JAN JAN Ocriplasmin (Genetical Recombination)

A

APSFDCGKPQ VEPKKCPGR

B

VVGGCVAHPH SWPWQVSLRT RFGMHFCGGT LISPEWVLTA AHCLEKSPRP

SSYKVILGAH QEVNLEPHVQ EIEVSRLFLE PTRKDIALLK LSSPAVITDK

VIPACLPSPN YVVADRTECF ITGWGETQGT FGAGLLKEAQ LPVIENKVCN

RYEFLNGRVQ STELCAGHLA GGTDSCQGDS GGPLVCGEKD KYILQGVTSW

GLGCARPNKP GVYVRVSRFV TWIEGVMRNN

A C6 – B C105 A C16 – B C5

C1214H1890N338O348S14 A C88H142N26O26S2

B C1126H1752N312O322S12

543 79119 A 230

B Ocriplasmin is a recombinant human plasmin analog corresponding to amino acid sequence 543 791 of human plasmin. Ocriplasmin is a protein composed of an A-chain consisting of 19 amino acid residues and a B-chain consisting of 230 amino acid residues.

25-2-B4

JAN JAN Volasertib Hydrochloride

C34H50N8O3 3HCl N-{trans-4-[4-( ) -1- ] }-4-{[(7R)-7- -5- -8-(1- )-6- -5,6,7,8- -2- ] }-3-

N-{trans-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8- (1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide trihydrochloride

26-1-B1

JAN JAN Ledipasvir Acetonate

C49H54F2N8O6 C3H6O {(1S)-1-[(1R,3S,4S)-3-(5-{9,9- -7-[2-((6S)-5-{(2S)-2-[( ) ]-3-

}-5- [2.4] -6- )-1H- -4- ]-9H- -2- }-1H--2- )-2- [2.2.1] -2- ]-2- }

Methyl{(1S)-1-[(1R,3S,4S)-3-(5-{9,9-difluoro-7-[2-((6S)-5-{(2S)-2-[(methoxycarbonyl)amino]-3- methylbutanoyl}-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl]-9H-fluoren-2-yl}-1H-benzimidazol-2- yl)-2-azabicyclo[2.2.1]heptane-2-carbonyl]-2-methylpropyl}carbamate monoacetonate

26-1-B7 26-1-B19

JAN JAN Pemetrexed Sodium Hemipentahydrate

NH

CO2Na

HO

N

N

HN

O

H2N

CO2Na

H

• 2½H2O

C20H19N5Na2O6 2½H2O N-{4-[2-(2- -4- -4,7- -1H- [2,3-d] -5- ) ] }-L-

Disodium N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl}-L-glutamate hemipentahydrate

26-1-B16

JAN JAN Ombitasvir Hydrate

NCH3

O

H3C

N

O

NH

CH3

O

CH3

N

O

NH

NH

O O

HN

OOCH3 H3C

H H

HH

HH

H3CCH3

CH3

4½H2O•

C50H67N7O8 4½H2O N,N'-{(2S,5S)-1-[4-(1,1- ) ] -2,5- } {[(4,1-

) ][(2S)- -2,1- ][(2S)-3- -1- - 1,2- ]} Dimethyl N,N'-{(2S,5S)-1-[4-(1,1-dimethylethyl)phenyl]pyrrolidine-2,5-diyl}bis{[(4,1- phenyleneazanediyl)carbonyl][(2S)-pyrrolidine-2,1-diyl][(2S)-3-methyl-1-oxobutane- 1,2-diyl]}biscarbamate heminonahydrate

26-1-B20

JAN JAN Paritaprevir Hydrate

NN O

HNHO

ONH

SO

O

O

H

H

HNH O

NN

CH3

2H2O•

C40H43N7O7 2O (2R,6S,12Z,13aS,14aR,16aS)-N-( )-6-(5- -2- )-5,16- -2-( -6- )-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-

[e] [1,2-a][1,4] -14a(5H)- (2R,6S,12Z,13aS,14aR,16aS)-N-(Cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16- dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a- tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide dihydrate

JAN

Recommended INN: List 65 WHO Drug Information, Vol. 25, No. 1, 2011

52

bedaquilinum bedaquiline (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-

2-(naphthalen-1-yl)-1-phenylbutan-2-ol

bédaquiline (1R,2S)-1-(6-bromo-2-méthoxyquinoléin-3-yl)-4-(diméthylamino)- 2-(naphtalén-1-yl)-1-phénylbutan-2-ol

bedaquilina (1R,2S)-1-(6-bromo-2-metoxiquinolein-3-il)-4-(dimetilamino)- 2-(naftalen-1-il)-1-fenilbutan-2-ol

C32H31BrN2O2

N OCH3

H

HO

N

Br

CH3

CH3

brentuximabum vedotinum # brentuximab vedotin immunoglobulin G1-kappa auristatin E conjugate, anti-[Homo

sapiens TNFRSF8 (tumor necrosis factor receptor superfamily member 8, KI-1, CD30)], chimeric monoclonal antibody conjugated to auristatin E; gamma1 heavy chain (1-446) [Mus musculus VH (IGHV1-84*02 -(IGHD)-IGHJ3*01) [8.8.10] (1-117) -Homo sapiens IGHG1*01 CH3 K130>del (118-446)], (220-218')-disulfide (if not conjugated) with kappa light chain (1'-218') [Mus musculus V-KAPPA (IGKV3-4*01 -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (226-226'')-disulfide dimer; conjugated, on an average of 3 to 5 cysteinyl, to monomethylauristatin E (MMAE), via a maleimidecaproyl-valyl-citrullinyl-p-aminobenzylcarbamate (mc-val-cit-PABC) linker For the vedotin part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups and others"*.

brentuximab védotine immunoglobuline G1-kappa conjuguée à l'auristatine E, anti-[Homo sapiens TNFRSF8 (membre 8 de la superfamille des récepteurs du facteur de nécrose tumorale, KI-1, CD30)], anticorps monoclonal chimérique conjugué à l'auristatine E; chaîne lourde gamma1 (1-446) [Mus musculus VH (IGHV1-84*02 -(IGHD)-IGHJ3*01) [8.8.10] (1-117) -Homo sapiens IGHG1*01 CH3 K130>del (118-446)], (220-218')-disulfure (si non conjugué) avec la chaîne légère kappa (1'-218') [Mus musculus V-KAPPA (IGKV3-4*01 -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (226-226'')-disulfure; conjugué, sur 3 à 5 cystéinyl en moyenne, au monométhylauristatine E (MMAE), via un linker maléimidécaproyl-valyl-citrullinyl-p-aminobenzylcarbamate (mc-val-cit-PABC) Pour la partie védotine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups and others"*.

1.10

1

1.10

1.10

2

Bedaquiline Fumarate

2 1 1 400mg3 1

200mg 3 48

100 1 100

(mg/kg)a 200 800 >50

800

>800 >25

>300 a :

a (mg/kg/ )

a

(mg/kg/ )a

3

0, 5, 10, 20, 30

10 10 MCV MPS 20

HDW

/ 30

RDWAST ALT

CPKP

/

/

1.10

3

X

3

0, 1.5, 6, 24

6 24

AST ALT

6

0, 5, 10,

20 <5 5 Ca /

/

10

/

20

AST CPKA/G

/

/

1

0, 10, 40, 160

10 10 40

ALP

/

160

ALT ASTCa

13/26

0, 2.5, 10, 40/20 (

2.5 2.5

1.10

4

17)

10

/

/

40/20

/

40

ALP ALT AST CPK/

2/6

0, 10,

40/20 (57

)

<10 10/ /

/

/

40/20

/

40

QT/QTc

ALT ASTALP GGT CPK

cTnI

Ca K

/

/ / /

9

0, 2, 6, 18 2 2b

6

1.10

5

/

18

cTnI

//

/ /

a b

II 49.6% 166/335

61

12

57 8 44 8 41

7

II 50.0% 3/6

1

1 1

§ ³ × ß6 100mg - 医薬品医療機器総合機構 · 2018-04-05 · sirturo is a...

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