SIRTURO 100mg tablets medication leaflet

SIRTURO 20 mg tablets

SIRTURO 100 mg tablets

SIRTURO 20 mg tablets

Each tablet contains bedaquiline fumarate equivalent to 20 mg of bedaquiline.

SIRTURO 100 mg tablets

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

Each 100 mg tablet contains 145 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

SIRTURO 20 mg tablets

Tablet.

Uncoated, white to almost white oblong tablet (12.0 mm long x 5.7 mm wide), with score line on bothsides, debossed with “2” and “0” on one side and plain on other side.

The tablet can be divided into equal doses.

SIRTURO 100 mg tablets

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.

SIRTURO is indicated for use as part of an appropriate combination regimen in adult and paediatricpatients (5 years to less than 18 years of age and weighing at least 15 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.

Treatment with SIRTURO should be initiated and monitored by a physician experienced in themanagement of TB due to M. tuberculosis resistant to at least rifampicin and isoniazid.

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

Only use SIRTURO in combination with other medicinal products to which the patient’s isolate hasbeen 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 dosingrecommendations.

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

The recommended dosage for 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 week aa At least 48 hours between doses

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

The recommended dosage for SIRTURO in paediatric patients (5 years to less than 18 years of age) isbased on body weight and shown in Table 2.

Table 2: Recommended Dosage of SIRTURO in Paediatric Patients (5 years to less than18 years of age)

Dosage Recommendation

Body Weight

Weeks 1 to 2 Weeks 3 to 24

Greater than or equal to 15 kg160 mg orally once daily 80 mg orally three times per week ato less than 20 kg

Greater than or equal to 20 kg200 mg orally once daily 100 mg orally three times per week ato less than 30 kg

Greater than or equal to 30 kg 400 mg orally once daily 200 mg orally three times per week aa At least 48 hours between doses

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

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

Patients should be advised to take SIRTURO exactly as prescribed and to complete the full course oftherapy.

If a dose is missed during the first two weeks of treatment, patients should not make up the misseddose, 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 possibleand then resume the three times a week regimen. The total dose of SIRTURO during a 7-day periodshould not exceed the recommended weekly dose (with at least 24 hours between each intake).

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

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 notrecommended in this population.

No dose adjustment is required in patients with mild or moderate renal impairment. In patients withsevere renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease requiringhaemodialysis or peritoneal dialysis, SIRTURO should be used with caution (see section 5.2).

The safety and efficacy of SIRTURO in children less than 5 years of age or weighing less than 15 kghave not yet been established. No data are available.

SIRTURO may be included in the treatment regimen for children greater than or equal to 5 years ofage and weighing at least 15 kg with confirmed or probable pulmonary TB due to M. tuberculosisresistant to at least rifampicin and isoniazid that is diagnosed based on clinical signs and symptoms ofpulmonary TB, appropriate epidemiological context, and in line with international/local guidelines(see section 4.1).

SIRTURO should be taken orally with food, as administration with food increases oral bioavailabilityby about 2-fold (see section 5.2). There is one method of administration of SIRTURO 100 mg tabletand four different options for administration of SIRTURO 20 mg tablet. Each administration methodrequires SIRTURO to be taken with food.

SIRTURO 100 mg tablets

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

SIRTURO 20 mg tablets

Administration of 20 mg Tablets to Patients Who Can Swallow Intact Tablets:

SIRTURO 20 mg tablet should be swallowed whole, or in two equal halves divided along thefunctional score line, with water and taken with food.

Administration of 20 mg Tablets to Patients Who Cannot Swallow Intact Tablets:

Dispersed in Water and Administered with Beverage or Soft Food

For patients who have difficulty swallowing intact tablets, SIRTURO 20 mg tablet can be dispersed inwater and administered. To aid with administration, the dispersed mixture in water can be furthermixed with a beverage (e.g., water, milk product, apple juice, orange juice, cranberry juice orcarbonated beverage) or soft food (e.g., yoghurt, apple sauce, mashed banana or porridge) as follows:

- Disperse tablets in water (maximum of 5 tablets in 5 mL of water) in a drinking cup.

- Mix the contents of the cup well until the tablets are completely dispersed and then orallyadminister the contents of the cup immediately with food. To aid with oral administration, thedispersed mixture in water can be further mixed with at least 5 mL of beverage or 1 teaspoonfulof soft food and then orally administer the contents of the cup immediately.

- If the total dose requires more than 5 tablets, repeat the above preparation steps with theappropriate number of additional tablets until the desired dose is reached.

- Ensure no tablet residue is left in the cup, rinse with beverage or add more soft food and orallyadminister the contents of the cup immediately.

Crushed and Mixed with Soft Food

SIRTURO 20 mg tablet can be crushed and mixed with soft food (e.g., yoghurt, apple sauce, mashedbanana or porridge) immediately prior to use and administered orally. To ensure no tablet residue isleft in the container, add more soft food and administer the contents immediately.

Refer to section 6.6 for information on administration through a feeding tube.

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

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 treatdrug-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 officialguidelines, such as from the WHO, to prevent development of resistance to bedaquiline (seesection 4.2).

SIRTURO may prolong the QT interval. An electrocardiogram should be obtained before initiation oftreatment 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 (seesections 4.5 and 4.8).

SIRTURO treatment initiation is not recommended in patients with the following, unless the benefitsof bedaquiline are considered to outweigh the potential risks:

- Heart failure

- QT interval as corrected by the Fridericia method (QTcF) >450 ms (confirmed by repeatelectrocardiogram)

- 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 isexpected (see section 4.5). Treatment with SIRTURO may be considered after a favourablebenefit-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 adultand paediatric patients during administration of SIRTURO with the background regimen (seesection 4.8). Patients should be monitored throughout the treatment course, since the increases in liverenzymes were slow to appear and increased gradually during the 24 weeks. Monitor symptoms andlaboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while ontreatment, and as needed. If AST or ALT exceeds 5 times the upper limit of normal then the regimenshould be reviewed and SIRTURO and/or any hepatotoxic background medicinal product should bediscontinued.

Other hepatotoxic medicinal products and alcohol should be avoided while on SIRTURO, especiallyin patients with diminished hepatic reserve.

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

Bedaquiline is metabolised by CYP3A4. Co-administration of SIRTURO with moderate or strong

CYP3A4 inducers decreases bedaquiline plasma concentrations and may reduce the therapeutic effectof SIRTURO. Co-administration of SIRTURO and moderate or strong CYP3A4 inducers usedsystemically, 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 ofgalactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take

SIRTURO 100 mg tablet.

The elimination of bedaquiline has not been fully characterised in vivo. CYP3A4 is the major CYPisoenzyme 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.

In an interaction study of single-dose bedaquiline and once daily rifampicin (strong inducer) in healthyadults, the bedaquiline exposure (AUC) was reduced by 52% [90% CI (-57; -46)]. Due to thepossibility of a reduction of the therapeutic effect of bedaquiline due to a decrease in systemicexposure, 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 aspart of combination therapy for up to 40 weeks in patients co-infected with HIV resulted in a milddecrease 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.

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

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

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

In the open-label Phase IIb trial, long-term co-administration of clofazimine and SIRTURO, as part ofa 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 notresult 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 cycloserinewas observed.

QT interval prolonging medicinal products

In an open-label Phase IIb trial in adults, additive increases in QTcF were observed in the 17 patientswho were using concomitant clofazimine at Week 24 (mean change from reference QTcF 31.9 mscompared 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 andlevofloxacin 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 wasobserved after repeated dosing with bedaquiline and ketoconazole in combination than after repeateddosing with the individual drugs (see sections 4.4 and 4.8).

Interaction studies have only been performed in adults.

There are limited data on the use of SIRTURO in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, avoid the use of SIRTURO during pregnancy unless the benefit of therapy isconsidered to outweigh the risks.

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

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

Bedaquiline may have a minor influence on the ability to drive and use machines. Dizziness has beenreported in some patients taking bedaquiline and should be considered when assessing a patient’sability to drive or operate machinery (see section 4.8).

Adverse reactions for SIRTURO were identified from Phase IIb clinical trial data (both controlled anduncontrolled, 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 patientswho received SIRTURO for 40 weeks or 28 weeks. In these studies, patients received SIRTURO incombination with other antimycobacterial drugs.

The most frequent adverse reactions (>10.0% of patients) reported during treatment with SIRTURO inthe open-label Phase III trial were QT prolongation (61% in the SIRTURO group vs 56% in thecontrol 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 tothe Summary of Product Characteristics of the medicinal products used in combination with

SIRTURO for their respective adverse reactions.

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

Adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories aredefined 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 Very Common Arthralgiaconnective tissue disorders Common Myalgia

Investigations Very Common Electrocardiogram QTprolongedda 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 first16 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 groupand 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 placebocontrol).

Clinical trials of SIRTURO in adult TB patients collectively show a mild (<10 ms) QTcF increasethroughout 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 QTcinterval 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 observedfrom the first on-treatment assessment onwards (9.9 ms at Week 1 for SIRTURO and 3.5 ms forplacebo). 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 SIRTUROended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group bystudy 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 usewith 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 inpatients who were taking at least two other QT-prolonging drugs, there was one patient with a QTcFinterval duration above 500 ms.

In the controlled Phase III study, in which the 40-week SIRTURO and active control treatment groupsincluded both clofazimine and a fluoroquinolone, the mean QTcF gradually increased from baselineover 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 and29.9 ms for the non-SIRTURO-containing control. Throughout treatment, mean QTcF increase wasless than 10 ms higher in the SIRTURO-containing group compared to the control. Upon treatmentcompletion mean QTcF decreased steadily. QTcF values ≥500 ms were observed in 5.2% of patientsin 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 frequentlyin the SIRTURO treatment group (11/101 [10.9%] versus 6/104 [5.8%]) in the placebo treatmentgroup. In the SIRTURO treatment group, the majority of these increases occurred throughout the24 weeks of treatment and were reversible. During the investigational phase in Stage 2 of Study C208,increased transaminases were reported in 7/78 (9.0%) patients in the SIRTURO treatment groupcompared 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 inthe 40-week SIRTURO treatment group versus 59/202 (29.2%) patients in the 40-week active controlgroup.

The safety assessment of bedaquiline is based on data from 30 paediatric patients greater than or equalto 5 years of age with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at leastrifampicin and isoniazid (see section 5.1).

Overall, there was no indication of any differences in the safety profile in adolescents aged 14 years toless than 18 years (N=15) compared to that observed in the adult population.

In paediatric patients aged 5 years to less than 11 years (N=15), the most common adverse reactionswere related to elevations in liver enzymes (5/15, 33%), reported as ALT/AST increased andhepatotoxicity; hepatotoxicity led to discontinuation of SIRTURO in three patients. Elevations in liverenzymes were reversible upon discontinuation of SIRTURO and background regimen. Among these15 paediatric patients, no deaths occurred during treatment with SIRTURO.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of intentional or accidental acute overdose with SIRTURO were not reported during clinicaltrials. In a study in 44 healthy adults receiving a single 800 mg dose of SIRTURO, adverse reactionswere 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 tosupport 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 shouldbe as clinically indicated or as recommended by the national poisons centre, where available. Sincebedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline fromplasma. Clinical monitoring should be considered.

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

J04AK05

Bedaquiline is a diarylquinoline. Bedaquiline specifically inhibits mycobacterial ATP (adenosine5'-triphosphate) synthase, an essential enzyme for the generation of energy in M. tuberculosis. Theinhibition of ATP synthase leads to bactericidal effects for both replicating and non-replicatingtubercle bacilli.

Bedaquiline has activity against M. tuberculosis complex strains with a minimal inhibitoryconcentration (MIC) in the range of ≤0.008 to 0.25 mg/L. The N-monodesmethyl metabolite (M2) isnot thought to contribute significantly to clinical efficacy given its lower average exposure (23% to31%) in humans and lower antimycobacterial activity (3- to 6-fold lower) compared to the parentcompound.

The intracellular bactericidal activity of bedaquiline in primary peritoneal macrophages and in amacrophage-like cell line was greater than its extracellular activity. Bedaquiline is also bactericidalagainst 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, Mycobacterium flavescens andnon-mycobacterial species are considered inherently resistant to bedaquiline.

Within the concentration range achieved with the therapeutic dose, no pharmacokinetic/pharmacodynamicrelationship was observed in patients.

Mechanisms of resistance

Acquired 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 ofthe MmpS5-MmpL5 efflux pump. Target-based mutations generated in preclinical studies lead to 8- to133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4 mg/L. Efflux-basedmutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases inbedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.5 mg/L. The majority ofisolates that are phenotypically resistant to bedaquiline are cross-resistant to clofazimine. Isolates thatare resistant to clofazimine can still be susceptible to bedaquiline.

The impact of high baseline bedaquiline MICs, the presence of Rv0678 based mutations at baseline,and/or increased post-baseline bedaquiline MICs on microbiological outcomes is unclear because ofthe low incidence of such cases in clinical trials.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forbedaquiline and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

Mycobacterium tuberculosis

Mycobacterium xenopi

Mycobacterium novocastrense

Mycobacterium shimoidei

Mycobacterium flavescens

Non-mycobacterial species

A Phase IIb, placebo-controlled, double-blind, randomised trial (C208) evaluated the antibacterialactivity, safety, and tolerability of SIRTURO in newly diagnosed adult patients with sputumsmear-positive pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid,including patients with resistance to second-line injectables or fluoroquinolones. Patients received

SIRTURO (N=79) or placebo (N=81) for 24 weeks, both in combination with a preferred 5-drugbackground regimen (BR) consisting of ethionamide, kanamycin, pyrazinamide, ofloxacin, andcycloserine/terizidone. SIRTURO was administered as 400 mg once daily for the first 2 weeks and as200 mg 3 times/week for the following 22 weeks. After the 24-week investigational period, thebackground regimen was continued to complete 18 to 24 months of total treatment. A final evaluationwas conducted at Week 120. Main demographics for the ITT population were as follows: 63.1% weremales, median age 34 years, 35% were Black, and 15% were HIV-positive. Cavitation in one lung wasseen in 58% of patients, and in both lungs in 16%. For patients in the mITT population with fullcharacterisation of resistance status, 76% (85/112) were infected with a M. tuberculosis strain resistantto rifampicin and isoniazid and 24% (27/112) with a M. tuberculosis strain also resistant to second-lineinjectables or fluoroquinolones.

The primary outcome parameter was the time to sputum culture conversion (i.e., the interval betweenthe first SIRTURO intake and the first of two consecutive negative MGIT cultures from sputumcollected at least 25 days apart) during treatment with SIRTURO or placebo (median time toconversion 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 cultureconversion rates were observed between patients with a M. tuberculosis strain resistant to rifampicinand isoniazid and patients with a M. tuberculosis strain also resistant to second-line injectables orfluoroquinolones.

Response rates at Week 24 and Week 120 (i.e., approximately 6 months after stopping all therapy) arepresented in Table 3.

Table 3: Culture Conversion Status in C208

Culture Conversion mITT Population

Status, n (%) N SIRTURO/BR N Placebo/BR

Overall responder at 66 52 (78.8%) 66 38 (57.6%)

Week 24

Patients with a 39 32 (82.1%) 45 28 (62.2%)

M. tuberculosisstrain resistant torifampicin andisoniazid

Patients with a 15 11 (73.3%) 12 4 (33.3%)

M. tuberculosisstrain resistant torifampicin andisoniazid, and alsoto second-lineinjectables orfluoroquinolones

Overall non-respondera 66 14 (21.2%) 66 28 (42.4%)at Week 24

Overall responder at 66 41 (62.1%) 66 29 (43.9%)

Week 120

Patients with a 39b 27 (69.2%) 46b,c 20 (43.5%)

M. tuberculosisstrain resistant torifampicin andisoniazid

Patients infected 15b 9 (60.0%) 12b 5 (41.7%)with a

M. tuberculosisstrain resistant torifampicin andisoniazid, and alsoto second-lineinjectables orfluoroquinolones

Overall non-respondera 66 25 (37.9%) 66 37 (56.1%)at Week 120

Failure to convert 66 8 (12.1%) 66 15 (22.7%)

Relapsed 66 6 (9.1%) 66 10 (15.2%)

Discontinued but 66 11 (16.7%) 66 12 (18.2%)converteda Patients who died during the trial or discontinued the trial were considered as non-responders.b Extent of resistance based on central laboratory drug susceptibility testing results was not available for 20 patients inthe mITT population (12 in the SIRTURO group and 8 in the placebo group). These patients were excluded from thesubgroup analysis by extent of resistance of M. tuberculosis strain.

c Central laboratory drug susceptibility testing results became available for one additional placebo patient after the

Week 24 interim analysis.

d Relapse was defined in the trial as having a positive sputum culture after or during treatment following prior sputumculture conversion.

During the trial, 12.7% (10/79) of the patients died in the SIRTURO treatment group (N=79)compared to 3.7% (3/81) of the patients in the placebo group (N=81). One death occurred duringadministration of SIRTURO. The median time to death for the remaining nine patients was 344 daysafter last intake of SIRTURO. In the SIRTURO treatment group, the most common cause of death asreported by the investigator was TB (5 patients). The causes of death in the remaining patients treatedwith SIRTURO varied. During the trial, there was no evidence of antecedent significant QTcFprolongation or clinically significant dysrhythmia in any of the patients who died.

Study C209 evaluated the safety, tolerability, and efficacy of 24 weeks treatment with open-label

SIRTURO as part of an individualised treatment regimen in 233 adult patients who were sputumsmear positive within 6 months prior to screening. This study included patients with M. tuberculosisstrains of all three resistance categories (resistant to rifampicin and isoniazid, also resistant tosecond-line injectables or fluoroquinolones, and also resistant to second-line injectables andfluoroquinolones).

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 cultureconversion was seen in 163/205 (79.5%) patients. Conversion rates at Week 24 were highest (87.1%;81/93) in patients with M. tuberculosis isolates resistant to only rifampicin and isoniazid, 77.3%(34/44) in patients with pulmonary TB due to M. tuberculosis resistant to rifampicin, isoniazid,second-line injectables or fluoroquinolones, and lowest (54.1%; 20/37) in patients with

M. tuberculosis isolates resistant to rifampicin, isoniazid, second-line injectables andfluoroquinolones. Extent of resistance based on central laboratory drug susceptibility testing resultswas not available for 31 patients in the mITT population. These patients were excluded from thesubgroup analysis by extent of resistance of M. 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 M. tuberculosis isolates resistant to onlyrifampicin and isoniazid, 70.5% (31/44) in patients with pulmonary TB due to M. tuberculosisresistant to rifampicin, isoniazid, second-line injectables or fluoroquinolones and lowest (62.2%;23/37) in patients with M. tuberculosis isolates resistant to rifampicin, isoniazid, second-lineinjectables and fluoroquinolones.

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

In the open-label C209 trial, 6.9% (16/233) of the patients died. The most common cause of death asreported by the investigator was TB (9 patients). Eight of nine patients who died of TB had notconverted or had relapsed. The causes of death in the remaining patients varied.

STREAM Stage 2 was a Phase III, open-label, multicentre, active-controlled, randomised trialconducted to evaluate the efficacy and safety of SIRTURO co-administered with other oral anti-TBdrugs for 40 weeks in patients with sputum smear-positive pulmonary TB caused by M. tuberculosisthat was resistant to at least rifampicin, with or without resistance additionally to isoniazid and/orsecond-line injectable agents or fluoroquinolones (but not both).

Patients were randomised to one of four treatment groups:

- Group A (N=32), the locally used treatment in accordance with 2011 WHO treatment guidelineswith a recommended 20-month duration

- Group B (N=202), a 40-week control treatment of moxifloxacin or levofloxacin, clofazimine,ethambutol, pyrazinamide, supplemented by injectable kanamycin, high-dose isoniazid, andprothionamide in the first 16 weeks (intensive phase)

- Group C (N=211), a 40-week, all-oral treatment of SIRTURO, levofloxacin, clofazimine,ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in thefirst 16 weeks (intensive phase)

- Group D (N=143), a 28-week treatment consisting of SIRTURO, levofloxacin, clofazimine, andpyrazinamide supplemented by kanamycin injectable and a higher isoniazid dose for the first8 weeks (intensive phase)

SIRTURO was administered as 400 mg once daily for the first 2 weeks and 200 mg 3 times/week forthe following 38 weeks (in Group C) or 26 weeks (in Group D). Changes in treatment regimen werepermitted at the discretion of the investigator in all groups. Enrolment in Groups A and D was stoppedprematurely due to changes in the standard of care for TB treatment.

The primary objective was to assess whether the proportion of patients with a favourable efficacyoutcome in Group C was noninferior to that in Group B at Week 76.

The primary efficacy outcome measure was the proportion of patients with a favourable outcome at

Week 76. A favourable outcome at Week 76 was defined as last 2 consecutive cultures negative andno unfavourable outcome. An unfavourable outcome at Week 76 encompassed clinically relevantchanges in treatment, all-cause mortality, at least 1 of the last 2 culture results positive, or no cultureresults within the Week 76 window.

In the overall study population (N=588), 59.9% were male, median age was 32.7 years, 47.3% were

Asian, 36.6% were Black, 16.2% were White and 16.5% were HIV-coinfected. Most patients hadcavitation (73.1%), with multiple cavities in 55.3% of patients. Of the 543 patients in the primaryefficacy population (mITT population, defined as patients with a positive culture for M. tuberculosis atscreening or randomisation), 12.5% of the patient’s M. tuberculosis isolates were resistant torifampicin while susceptible to isoniazid, 76.4% had resistance to at least rifampicin and isoniazid, and11% had resistance to rifampicin, isoniazid and either second-line injectables or fluoroquinolones.

Table 4 shows the proportion of patients with a favourable or unfavourable outcome at Week 76 in the

STREAM Stage 2 Phase III trial. The proportion of participants with a favourable outcome at

Week 76 was 82.7% in Group C compared to 71.1% in Group B. The main reason for an unfavourableoutcome in both groups was extension or modification of the assigned treatment regimen. Limitationsof the study included its open-label design; changes to the allocated treatment regimens werepermitted in case of treatment failure, recurrence or serious toxicity.

Table 4: Primary Analysis in STREAM Stage 2 (Phase III Trial)mITT Population

SIRTUROa Active Controlb(N=196) (N=187)

Favourable outcome at Week 76 162 (82.7) 133 (71.1)n (%)

Unfavourable outcome at Week 76 34 (17.3) 54 (28.9)n (%)

Reasons for unfavourable outcome through Week 76c

Treatment modified or extended 16 (8.2) 43 (23.0)

No culture results within Week 76 window 12 (6.1%) 7 (3.7)

Death through Week 76 5 (2.6) 2 (1.1)

At least one of last 2 cultures positive at Week 76 1 (0.5) 2 (1.1)mITT = modified intent-to-treata Group C 40-week, all-oral regimen of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide,supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase).b Group B 40-week control treatment of moxifloxacin or levofloxacin, clofazimine, ethambutol, pyrazinamide,supplemented by injectable kanamycin, high dose isoniazid and prothionamide in the first 16 weeks (intensive phase).c Patients were classified by the first event that made the patient unfavourable. Of the patients with an unfavourableoutcome at Week 76 in the control group, 29 patients had a treatment modification from their allocated treatment thatincluded SIRTURO as part of a salvage regimen.

The frequency of deaths was similar across treatment groups through Week 132. In the 40-week

SIRTURO group, 11/211 (5.2%) patients died; the most common cause of death was related to TB(5 patients). In the 40-week active control group, 8/202 (4.0%) patients died, including 4 of 29 patientswho received SIRTURO as part of a salvage treatment; the most common cause of death was relatedto respiratory pathology. The adjusted difference in proportion of fatal adverse events between the40-week SIRTURO group and the 40-week active control group was 1.2% [95% CI (-2.8%; 5.2%)].

The pharmacokinetics, safety and tolerability of SIRTURO in combination with a background regimenwere evaluated in trial C211, a single-arm, open-label, multi-cohort Phase II trial in 30 patients withconfirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampicin andisoniazid.

Paediatric patients (12 years to less than 18 years of age)

Fifteen patients had a median age of 16 years (range: 14 to 17 years), weighed 38 to 75 kg, and were80% female, 53% Black, 33% White and 13% Asian. The patients were to complete at least 24 weeksof treatment with SIRTURO administered as 400 mg once daily for the first 2 weeks and 200 mg3 times/week for the following 22 weeks using 100 mg tablets.

In the subset of patients with culture positive pulmonary TB at baseline, treatment with a regimenincluding bedaquiline resulted in conversion to a negative culture in 75.0% (6/8 microbiologicallyevaluable patients) at Week 24.

Paediatric patients (5 years to less than 12 years of age)

Fifteen patients had a median age of 7 years (range: 5 to 10 years), weighed 14 to 36 kg, and were60% female, 60% Black, 33% White and 7% Asian. The patients were to complete at least 24 weeksof treatment with SIRTURO administered as 200 mg once daily for the first 2 weeks and 100 mg3 times/week for the following 22 weeks using 20 mg tablets.

In the subset of patients with culture positive pulmonary TB at baseline, treatment with a regimenincluding bedaquiline resulted in conversion to a negative culture in 100% (3/3 microbiologicallyevaluable patients) at Week 24.

The 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 M. tuberculosisresistant to at least rifampicin and isoniazid (see section 4.2 for information on paediatric use).

The pharmacokinetic properties of bedaquiline have been evaluated in healthy adults and in patients5 years of age and older with active TB. Exposure to bedaquiline was lower in patients withpulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid than in healthyadults.

In adult patients with pulmonary TB, following 2 weeks of 400 mg bedaquiline once daily, mean (SD)

Cmax and AUC24h, ng∙h/mL were 3060 (1124) ng/mL and 41510 (15064) ng∙h/mL, respectively, forbedaquiline and 326 (135) ng/mL and 7267 (3029) ng∙h/mL, respectively, for the M2 metabolite.

Following 38 weeks of 200 mg bedaquiline three times weekly, mean (SD) Cmax and AUC168h,ng∙h/mL were 1787 (666) ng/mL and 168376 (74476) ng∙h/mL, respectively, for bedaquiline and246 (103) ng/mL and 39540 (17220) ng∙h/mL, respectively, for the M2 metabolite.

Maximum plasma concentrations (Cmax) are typically achieved at about 5 hours post-dose. Cmax and thearea under the plasma concentration-time curve (AUC) increased proportionally up to 700 mgsingle-dose and once daily 400 mg for 14 days. Administration of bedaquiline with food increased therelative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore,bedaquiline should be taken with food to enhance its oral bioavailability.

The plasma protein binding of bedaquiline is >99.9% in all species tested, including humans. Theplasma protein binding of its active metabolite, M2, in humans is at least 99.8%. In animals,bedaquiline and M2 are extensively distributed to most tissues, however, brain uptake is low.

CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and theformation and metabolism of 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

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 concentrationsin vitro. An in vitro study indicated a potential for bedaquiline to inhibit BCRP at the concentrationsachieved in the intestine after oral administration. The clinical relevance is unknown.

Based on the preclinical studies, the bulk of the administered dose is eliminated in faeces. The urinaryexcretion of unchanged bedaquiline was <0.001% of the dose in clinical studies, indicating that renalclearance of unchanged active substance is insignificant. After reaching Cmax, bedaquilineconcentrations decline tri-exponentially. The mean terminal elimination half-life of both bedaquilineand M2 is about 5 months (ranging from 2 to 8 months). This long terminal elimination phase likelyreflects slow release of bedaquiline and M2 from peripheral tissues.

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

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

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

In paediatric patients aged 5 years to less than 18 years and weighing 15 kg to less than 30 kg, theaverage plasma exposure of bedaquiline (AUC168h) at Week 24 is predicted to be 152 μg∙h/mL (90%prediction interval: 54.3 to 313 μg∙h/mL) when treated with the recommended weight-based dosingregimen. In paediatric patients weighing from 30 to 40 kg, the average plasma exposure of bedaquiline(AUC168h) at Week 24 is predicted to be higher (average: 229 µg∙h/mL; 90% prediction interval: 68.0to 484 μg∙h/mL) compared to adult patients. In paediatric patients aged 5 years to less than 18 yearsand weighing greater than 40 kg, the average plasma exposure of bedaquiline (AUC168h) at Week 24 ispredicted to be 165 μg∙h/mL (90% prediction interval: 51.2 to 350 μg∙h/mL) when treated with therecommended weight-based dosing regimen. The average plasma exposure of bedaquiline (AUC168h)at Week 24 in adults was predicted to be 127 µg∙h/mL (90% prediction interval: 39.7 to 249 μg∙h/mL).

The pharmacokinetics of SIRTURO in paediatric patients less than 5 years of age or weighing lessthan 15 kg have not been established.

In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, age was notfound to influence the pharmacokinetics of bedaquiline.

In five patients 65 to 69 years of age, the systemic bedaquiline exposure was similar to that of otheradults.

In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, exposure tobedaquiline was found to be lower in Black patients than in patients from other race categories. Thislower bedaquiline exposure in Black patients was not associated with lower efficacy in clinical trials,and no dose adjustment is needed.

In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, no clinicallyrelevant differences in exposure between men and women were observed.

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

In a rat carcinogenicity study, bedaquiline, at the high doses of 20 mg/kg/day in males and10 mg/kg/day in females, did not induce any treatment-related increases in tumour incidences.

Compared to the exposures (AUC) observed in patients with pulmonary TB in the bedaquiline

Phase II trials, the exposures (AUC) in rats at high doses were similar in males and 2-fold higher infemales 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 orclastogenic effects.

Bedaquiline had no effects on fertility when evaluated in female rats. Three of 24 male rats treatedwith high bedaquiline doses failed to produce offspring in the fertility study. Normal spermatogenesisand a normal amount of spermatozoa in the epidydimides were noted in these animals. No structuralabnormalities 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 ratsand rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats compared tohumans. In the rat, no adverse effects were observed in a pre- and post-natal development study atmaternal plasma exposure (AUC) similar to humans and exposure in the offspring 3-fold higher thanin adult humans. There was no effect of maternal treatment with bedaquiline at any dose level onsexual maturation, behavioural development, mating performance, fertility or reproductive capacity ofthe F1 generation animals. Body weight decreases in pups were noted in high dose groups during thelactation period after exposure to bedaquiline via milk and were not a consequence of in uteroexposure. Concentrations of bedaquiline in milk were 6- to12-fold higher than the maximumconcentration observed in maternal plasma.

In a juvenile rat toxicity study, the no observed adverse effect level (NOAEL) was 15 mg/kg/day(maximum dose 45 mg/kg/day) for observations of diffuse inflammation and/or degeneration inskeletal muscle (reversible), oesophagus (reversible) and tongue (reversible), liver hypertrophy(reversible) and corticomedullary renal mineralisation (partial recovery in males, and no recovery infemales within 8 weeks after end of exposure). The NOAEL corresponds to a plasma AUC24h of 13.1and 35.6 μg∙h/mL for bedaquiline (~0.7x clinical dose) and 10.5 and 16.3 μg∙h/mL for the

N-monodesmethyl metabolite of bedaquiline (M2) in males and females (~1.8x clinical dose),respectively.

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

SIRTURO 20 mg tablet

Microcrystalline cellulose

Crospovidone

Silica, colloidal anhydrous

Hypromellose

Polysorbate 20

Sodium stearyl fumarate

SIRTURO 100 mg tablet

Lactose monohydrate

Maize starch

Hypromellose

Polysorbate 20

Microcrystalline cellulose

Croscarmellose sodium

Silica, colloidal anhydrous

Magnesium stearate

Not applicable.

SIRTURO 20 mg tablets3 years

SIRTURO 100 mg tablets3 years

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

SIRTURO 20 mg tablets

Store in the original container and keep the container tightly closed in order to protect from light andmoisture. Do not remove desiccant.

SIRTURO 100 mg tablets

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

SIRTURO 20 mg tablets

White, opaque, high-density polyethylene (HDPE) bottle with child-resistant polypropylene (PP)closure with aluminium induction seal liner. Each bottle contains 60 tablets and silica gel desiccant.

SIRTURO 100 mg tablets

White HDPE bottle with child-resistant PP closure with aluminium induction seal liner containing188 tablets.

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

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused product or waste material should be disposed of in accordance with local requirements(see section 5.3).

SIRTURO 20 mg tablet can also be administered through a feeding tube (8 French or greater) asfollows:

- Disperse 5 tablets or less in 50 mL of non-carbonated water and mix well. Mixture should bewhite to almost white with visible particles expected.

- Administer through feeding tube immediately.

- Repeat with additional tablets until desired dose is reached.

- Rinse and flush with 25 mL of additional water to ensure no tablet residue is left in materialsused for preparation or the feeding tube.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/13/901/001

EU/1/13/901/002

EU/1/13/901/003

Date of first authorisation: 5 March 2014

Date of latest renewal: 20 December 2022

DD/MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.