4.1. Therapeutic indications

SIRTURO is indicated for use as part of an appropriate combination regimen in adult and paediatric patients (2 years to less than 18 years of age and weighing at least 7 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampicin and isoniazid.

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 TB due to M. tuberculosis resistant to at least rifampicin and isoniazid..

Consideration should be given to WHO guidelines when selecting the appropriate combination regimen.

Only use SIRTURO in combination with other medicinal products to which the patient's isolate has been shown to be susceptible in vitro, or 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).

Posology

Adult Patients

The recommended dosage of SIRTURO in adult (18 years and older) patients is shown in Table 1.

Table 1: Recommended Dosage of SIRTURO in Adult Patients

Population

Dosing Recommendation

Weeks 1 to 2

Weeks 3 to 24

Adults (18 years and older)

400 mg orally once daily

200 mg orally three times per weeka

a At least 48 hours between doses

The total duration of treatment with SIRTURO is 24 weeks. SIRTURO should be taken with food.

Paediatric Patients

The recommended dosage for SIRTURO in paediatric patients (2 years to less than 18 years of age) is based on body weight and shown in Table 2.

Table 2: Recommended Dosage of SIRTURO in Paediatric Patients (2 years to less than 18 years of age)

Body Weight

Dosage Recommendation

Weeks 1 to 2

Weeks 3 to 24

Greater than or equal to 7 kg to less than 10 kg

80 mg orally once daily

40 mg orally three times per week a

Greater than or equal to 10 kg to less than 15 kg

120 mg orally once daily

60 mg orally three times per week a

Greater than or equal to 15 kg to less than 20 kg

160 mg orally once daily

80 mg orally three times per weeka

Greater than or equal to 20 kg to less than 30 kg

200 mg orally once daily

100 mg orally three times per weeka

Greater than or equal to 30 kg

400 mg orally once daily

200 mg orally three times per weeka

a At least 48 hours between doses

The total duration of treatment with SIRTURO is 24 weeks. SIRTURO should be taken with food.

Treatment duration

The total duration of treatment with SIRTURO is 24 weeks. When treatment with SIRTURO is considered necessary beyond 24 weekstreatment may be continued up to 40 weeks in adults, at a dose of 200 mg three times per week (see sections 4.8 and 5.1).

Missed doses

Patients 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 as soon as possible and then resume the three times a week regimen. The total dose of SIRTURO during a 7-day period should not exceed the recommended weekly dose (with at least 24 hours between each intake).

Elderly population

There are limited clinical data on the use of SIRTURO in elderly patients (see section 5.2).

Hepatic impairment

No 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 impairment

No 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 population

The safety and efficacy of SIRTURO in children less than 2 years of age or weighing less than 7 kg have not yet been established.

No data are available.

SIRTURO may be included in the treatment regimen for children greater than or equal to 2 years of age and weighing at least 7 kg with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid that is diagnosed based on clinical signs and symptoms of pulmonary TB, appropriate epidemiological context, and in line with international/local guidelines (see section 4.1).

Method of administration

SIRTURO should be taken orally with food, as administration with food increases oral bioavailability by about 2-fold (see section 5.2).

SIRTURO 100 mg tablets should be swallowed whole with water and taken with food.

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 clinical data on the use of SIRTURO to treat:

• extra-pulmonary TB (e.g., central nervous system, bone)

• infections due to mycobacterial species other than M. tuberculosis

• latent infection with M. tuberculosis

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

Resistance to bedaquiline

Bedaquiline should only be used in an appropriate combination regimen for treatment of pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid as recommended by official guidelines, such as from the WHO, to prevent development of resistance to bedaquiline (see section 4.2).

QT prolongation

SIRTURO may prolong the QT interval. An electrocardiogram should be obtained before initiation of treatment with SIRTURO and at least monthly after starting treatment to monitor the QTc interval. 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).

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

• Hypokalaemia

When bedaquiline is co-administered with other medicinal products that prolong the QTc interval (including clofazimine, delamanid or fluoroquinolones), an additive effect on QT prolongation is expected (see section 4.5). Treatment with SIRTURO may be considered after a favourable benefit-risk assessment and with ECG monitoring.

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 safety

Increases in transaminases accompanied by total bilirubin ≥ 2x ULN were seen in clinical trials in adult and paediatric patients 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.

Paediatric patients

In adolescents weighing between 30 and 40 kg, average exposure is predicted to be higher compared to adult patients (see section 5.2). This may be associated with an increased risk of QT prolongation or hepatotoxicity.

Interactions with other medicinal products

CYP3A4 inducers

Bedaquiline is metabolised by CYP3A4. Co-administration of SIRTURO with moderate or strong CYP3A4 inducers decreases bedaquiline plasma concentrations and may reduce the therapeutic effect of SIRTURO. Co-administration of SIRTURO and moderate or strong CYP3A4 inducers used systemically, such as efavirenz and rifamycins (i.e., rifampicin, rifapentine and rifabutin) should, therefore, be avoided (see section 4.5).

Lactose intolerance and lactase deficiency

SIRTURO 100 mg tablets

SIRTURO 100 mg tablet contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take SIRTURO 100 mg tablet.

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 inducers

In an interaction study of single-dose bedaquiline and once daily rifampicin (strong inducer) in healthy adults, the bedaquiline exposure (AUC) 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.

In the Phase III study, co-administration of the weak CYP3A4 inducer nevirapine and SIRTURO as part of combination therapy for up to 40 weeks in patients co-infected with HIV resulted in a mild decrease in average bedaquiline exposure (AUC) compared to a subgroup without HIV co-infection. This exposure difference was however not associated with a reduction in therapeutic effect. Therefore, no dose adjustment is needed when co-administering SIRTURO with weak CYP3A4 inducers.

CYP3A4 inhibitors

Co-administration of SIRTURO and CYP3A4 inhibitors does not have a clinically relevant effect on bedaquiline exposure. Therefore, the co-administration of SIRTURO and CYP3A4 inhibitors is allowed, and no dose adjustment is needed.

The short‑term co‑administration of bedaquiline and ketoconazole (strong CYP3A4 inhibitor) in healthy adults increased the mean bedaquiline exposure (AUC) by 22% [90% CI (12; 32)]. In healthy adults, 10 days of co-administration of another strong CYP3A4 inhibitor, clarithromycin, with single‑dose bedaquiline increased the mean bedaquiline exposure (AUC) by 14% [90% CI (9; 19)]. A more pronounced effect on bedaquiline may be observed during prolonged co‑administration of CYP3A4 inhibitors.

In the Phase III trial, long-term co-administration of SIRTURO as part of a combination therapy and lopinavir/ritonavir in patients co-infected with HIV resulted in a mild increase in mean bedaquiline exposure at Week 24 compared to a subgroup without HIV co-infection..No dose adjustment is required.

In the open-label Phase IIb trial, long-term co-administration of clofazimine and SIRTURO, as part of a combination therapy for up to 24 weeks, did not affect bedaquiline exposure.

Other antituberculosis medicinal products

The short-term co-administration of SIRTURO with isoniazid/pyrazinamide in healthy adults did not result in clinically relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide. No dose-adjustment of isoniazid or pyrazinamide is required during co-administration with SIRTURO.

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

QT interval prolonging medicinal products

In an open-label Phase IIb trial in adults, additive increases in QTcF were observed in the 17 patients who were using concomitant clofazimine at Week 24 (mean change from reference QTcF 31.9 ms compared to 12.3 ms) in patients who were not using concomitant clofazimine.

In the Phase III trial, additive increases in QTcF were observed when combining clofazimine and levofloxacin with SIRTURO (see sections 4.4 and 4.8).

In an interaction study of bedaquiline and ketoconazole in healthy adults, a greater effect on QTcF was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs (see sections 4.4 and 4.8).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data on the use of SIRTURO in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, avoid the use of SIRTURO during pregnancy unless the benefit of therapy is considered to outweigh the risks.

Breast-feeding

Bedaquiline is excreted in human milk. Limited published literature reports higher bedaquiline concentrations in human milk than in maternal plasma. In one breastfed infant, a single random plasma bedaquiline concentration was similar to maternal plasma concentration; the mother had a high concentration of bedaquiline in breast milk, with a milk to plasma ratio of 14:1. This is consistent with data from animal studies (see section 5.3). Available information indicates that systemic exposure in breastfed infants may reach levels similar to those observed in the breastfeeding mothers treated with bedaquiline. The clinical consequence of this exposure is unknown. Women who are treated with bedaquiline should not breastfeed.

Fertility

No 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 may have a minor influence on the ability to drive and use machines. Dizziness has been reported in some patients taking bedaquiline and should be considered when assessing a patient's ability to drive or operate machinery (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Adverse reactions for SIRTURO were identified from Phase IIb clinical trial data (both controlled and uncontrolled, C208 and C209) in 335 adult patients who received SIRTURO for 8 weeks or 24 weeks.No new adverse reactions were identified in the Phase III active-controlled trial including 354 patients who received SIRTURO for 40 weeks or 28 weeks. In these studies, patients received SIRTURO in combination with other antimycobacterial drugs.

The most frequent adverse reactions (>10.0% of patients) reported during treatment with SIRTURO in the open-labelPhase III trial were QT prolongation (61% in the SIRTURO group vs 56% in the control group), nausea (54% vs 63%), vomiting (54% vs 62%), arthralgia (45% vs 33%), transaminases increased (30% vs 29%), dizziness (18% vs 21%) and headache (17% vs 18%). 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 reactions

Adverse reactions to SIRTURO based on reported safety data from Phase II and Phase III trials in adult patients treated with SIRTURO are presented in the Table below.

Adverse 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 Categorya

ARs

Nervous system disorders

Very Common

Headache, dizziness

Gastrointestinal disorders

Very Common

Nausea, vomiting

Common

Diarrhoea

Hepatobiliary disorders

Very Common

Transaminases increasedb,c

Musculoskeletal and connective tissue disorders

Very Common

Arthralgia

Common

Myalgia

Investigations

Very Common

Electrocardiogram QT prolongedd

a Frequencies derived from Phase III trial STREAM Stage 2 40-week, all-oral treatment of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase).

b Terms represented by 'transaminases increased' included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, hypertransaminasaemia, and transaminases increased (see section below).

c Incidence of transaminases increased in the controlled Phase IIb study was Common (6.9% in the SIRTURO group and 1% in placebo control).

d Incidence of QT prolonged in Phase IIb study was Common (2.9% in the SIRTURO group and 3.8% in placebo control).

Description of selected adverse reactions

QT prolongation

Clinical trials of SIRTURO in adult TB patients collectively show a mild (<10 ms) QTcF increase throughout treatment attributable to M2, the major bedaquiline metabolite. In combination with other QT-prolonging drugs (e.g., clofazimine, delamanid, or fluoroquinolones), a prolongation of the QTc interval not more than additive was observed (see section 4.5).

In 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 (at Week 18) in QTcF during the 24 weeks of treatment with SIRTURO was 15.7 ms, compared to 6.2 ms in the placebo group. After treatment with SIRTURO ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study Week 60 (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 pulmonary TB, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation. In patients taking SIRTURO with no other QT-prolonging drugs, there were no patients with QTcF interval durations above 480 ms, and in patients who were taking at least two other QT-prolonging drugs, there was one patient with a QTcF interval duration above 500 ms.

In the controlled Phase III study, in which the 40-week SIRTURO and active control treatment groups included both clofazimine and a fluoroquinolone, the mean QTcF gradually increased from baseline over the first 10 to 14 weeks, when a plateau was reached and additive QT prolongation was observed. The highest mean QTcF increase from baseline was 34.5 ms for the SIRTURO-containing group and 29.9 ms for the non-SIRTURO-containing control. Throughout treatment, mean QTcF increase was less than 10 ms higher in the SIRTURO-containing group compared to the control. Upon treatment completion mean QTcF decreased steadily. QTcF values ≥500 ms were observed in 5.2% of patients in the SIRTURO-containing group compared to 7.4% in the non-SIRTURO-containing control group (see sections 4.4 and 4.5).

Increased transaminases

In Study C208 (Stage 1 and 2), transaminase elevations of at least 3 x ULN developed more frequently in the SIRTURO treatment group (11/101 [10.9%] versus 6/104 [5.8%]) 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 treatment phase in Stage 2 of Study C208, increased transaminases were reported in 7/78 (9.0%) patients in the SIRTURO treatment group compared to 1/80 (1.3%) in the placebo treatment group.

In the STREAM Stage 2 study, increased transaminases were reported in 63/211 (29.9%) patients in the 40-week SIRTURO treatment group versus 59/202 (29.2%) patients in the 40-week active control group.

Paediatric population

The safety assessment of bedaquiline is based on the Week 120 analyses for patients 12 years to less than 18 years of age and 5 years to less than 12 years of age, and the Week 24 analysis for patients 2 years to less than 5 years of age, from 45 paediatric patients greater than or equal to 2 years of age with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampicin and in an ongoing, single-arm, open-label, multi-cohort trial (see section 5.1). Overall, there was no indication of any differences in the safety profile in adolescents aged 14 years to less than 18 years (N=15) compared to that observed in the adult population. No deaths were reported during the study.

In paediatric patients aged 5 years to less than 11 years (N=15), the most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), reported as ALT/AST increased and hepatotoxicity; hepatotoxicity led to discontinuation of SIRTURO in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO and background regimen. No deaths were reported during the study.

In paediatric patients aged 2 years to less than 5 years (N=15), the most common adverse reaction was vomiting in 3/15 (20%) patients. QT prolongation and arthralgia were reported in one patient each. Among these 15 paediatric patients, no deaths were reported during treatment with SIRTURO (Week 24 analysis).

Reporting of suspected adverse reactions

Reporting 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 professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Cases of intentional or accidental acute overdose with SIRTURO were not reported during clinical trials. In a study in 44 healthy adults 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. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. Clinical monitoring should be considered.