Sirturo 20 Mg Tablets

SIRTURO is indicated in adult ( u2265 18 years) and paediatric patients (5 years to less than 18 years of age and weighing at least 15 kg), as part of combination therapy, for pulmonary tuberculosis (TB) due to multi-drug resistant Mycobacterium tuberculosis in HIV negative or HIV positive who are not taking antiretrovirals. Safety and efficacy of SIRTURO in HIV patients on treatment with antiretroviral (ARV) medicines have not been established. Safety and efficacy of SIRTURO beyond 120 weeks have not been established.

Posology SIRTURO should only be administered as part of a multi drug resistant tuberculosis (MDR-TB) regimen. It is recommended that SIRTURO is administered by directly observed therapy (DOT). MDR-TB is defined as in vitro resistance of the patientu2019s isolate to at least isoniazid and rifampicin.

Dosage u2013 Adults ( u2265 18 years) The recommended dosage of SIRTURO for MDR-TB in adult patients is:

• Weeks 1 u2013 2: 400 mg once daily
• Weeks 3 u2013 24: 200 mg 3 times per week (with at least 48 hours between doses)

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 section 4.8). SIRTURO should be taken with food.

Dosage u2013 Paediatric patients (5 years to less than 18 years of age) The recommended dosage of SIRTURO in paediatric patients (5 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 (5 years to less than 18 years of age)

a=At least 48 hours between doses

The total duration of treatment with SIRTURO is 24 weeks. SIRTURO should be taken with food. The prescribing medical practitioner should refer to international (e.g. WHO guidelines) and national/local TB treatment guidelines for direction on selection and duration of use of companion medicines with SIRTURO. SIRTURO should only be used in combination with at least 3 medicines to which the patientu2019s isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment may be initiated with SIRTURO in combination with at least 4 other medicines to which the patientu2019s isolate is likely to be susceptible. Throughout treatment with, and following the last intake of SIRTURO, patients should continue to take their companion medicines in accordance with international, national/local TB treatment guidelines and local MDR-TB treatment practice. Refer to the prescribing information of the medicines used in combination with SIRTURO for their specific dosing recommendations.

Missed doses Patients should be advised of the need to take SIRTURO as prescribed. Compliance with the full course of therapy must be emphasised. If a dose is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. From week 3 onwards, if a dose is missed, patients should take the missed dose, and adjust the dosing schedule to ensure that the total dose of SIRTURO during the 7 day period does not exceed the recommended weekly dose (with at least 24 hours between each intake). Do not exceed the recommended dosages.

Paediatric population (less than 5 years of age) The safety and efficacy of SIRTURO in children less than 5 years of age or weighing less than 15 kg have not been established.

Elderly populations There are limited data on the use of SIRTURO in elderly patients.

Hepatic impairment The pharmacokinetics of SIRTURO were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) (see section 5.2). 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 is not recommended in this population. (see section 4.3).

Renal impairment SIRTURO has been mainly studied in patients with normal renal function. Renal excretion of unchanged SIRTURO is insignificant (< 0,001 %). No dose adjustment is required in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease requiring haemodialysis or peritoneal dialysis, SIRTURO should be used with caution (see section 5.2).

Method of administration: SIRTURO should be taken orally with food, as administration with food increases oral bioavailability (see section 5.2). There are four different options for administration of SIRTURO 20 mg tablet and one method of administration of SIRTURO 100 mg tablet. Each administration method requires SIRTURO to be taken with food.

SIRTURO 20 mg tablet 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 the functional 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 in water and administered. To aid with administration, the dispersed mixture in water can be further mixed with a beverage (e.g., water, milk product, apple juice, orange juice, cranberry juice or carbonated 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 orally administer the contents of the cup immediately with food. To aid with administration, the dispersed mixture in water can be further mixed with at least 5 mL of beverage or 1 teaspoonful of 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 the appropriate number of additional tablets until desired dose is reached.
• Ensure no tablet residue is left in the cup, rinse with beverage or add more soft food and orally administer 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., yogurt, apple sauce, mashed banana or porridge) immediately prior to use and administered orally. Ensure no tablet residue is left in container, add more soft food and administer the contents immediately.

Administration Through a Feeding Tube SIRTURO 20 mg tablet can also be administered through a feeding tube (2,67 mm or greater) as follows:

• Disperse 5 tablets or less in 50 mL of non-carbonated water and mix well. Mixture should be white 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 materials used for preparation or the feeding tube.

SIRTURO 100 mg tablet SIRTURO 100 mg tablet should be swallowed whole with water.

• Hypersensitivity to the active substance (i.e. bedaquiline) or any of the excipients listed in section 6.1
• Congenital QT prolongation
• Patients with uncontrolled cardiac dysrhythmias
• Concomitant use with medicines known to prolong the QTc interval to time intervals known to induce serious dysrhythmias
• Patients with severe hepatic impairment (Child Pugh C)

HIV-TB co-infected patients There are no clinical data on safety and efficacy on the combined use of antiretroviral medicines and SIRTURO in HIV/MDR-TB co-infected patients and only limited clinical data on the use of SIRTURO in HIV/MDR-TB co-infected adult patients (n = 22) who were not receiving antiretroviral (ARV) therapy (see section 4.5)

There is limited information on interactions between SIRTURO (bedaquiline) and medicines that may increase or decrease bedaquiline concentrations. The use of systemic potent CYP3A4 inhibitors with SIRTURO should be avoided, as there may be an increased risk of SIRTURO associated toxicity (see section 4.5)

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

Cardiovascular safety During clinical trials in adults with SIRTURO a prolongation of QTc interval was observed (see section 4.8). An ECG should be obtained prior to and after initiation of therapy with SIRTURO 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 4.4 and 4.8).

SIRTURO treatment initiation is not recommended in patients with:

• Heart failure
• QT interval as corrected by the Fridericia method (QTcF) > 450 ms (confirmed by repeat ECG) (see section 4.3), or
• 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.

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

SIRTURO treatment must be discontinued if the patient develops:

• Clinically significant ventricular dysrhythmia.
• A QTcF interval of > 500 ms (confirmed by repeat ECG).

An additive or synergistic effect on QT prolongation of SIRTURO when co-administered with other medicines that prolong the QT interval (including delamanid) cannot be excluded (see section 4.5).

Caution is recommended when prescribing SIRTURO concomitantly with medications with a known risk of QT prolongation. In the event that co-administration of such medicinal products with SIRTURO is necessary, clinical monitoring including frequent ECG assessment is recommended.

Concomitant administration of SIRTURO with fluoroquinolone antibiotics that have a potential for significant QT prolongation (gatifloxacin and moxifloxacin) should be avoided. In case of concomitant administration of SIRTURO with fluoroquinolone antibiotics that have a lower potential for significant QT prolongation (ofloxacin and levofloxacin), caution should be used.

In an open label Phase IIb trial (C209) in adults, mean increases from baseline in QTcF were larger in subjects with concomitant clofazimine use than in subjects without concomitant clofazimine use (see section 4.5). In the event that co-administration of clofazimine with SIRTURO is necessary, clinical monitoring including frequent ECG assessment is recommended.

Warnings on interactions CYP3A4 inducers/inhibitors SIRTURO is metabolised by CY3A4 and its exposure may therefore be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4 (see section 4.5). Co-administration of SIRTURO and medicines that induce CYP3A4 may decrease SIRTURO plasma concentrations and reduce its therapeutic effect. Co-administration of strong CYP3A4 inducers, such as rifamycins (i.e, rifampicin; rifapentine and rifabutin) or moderate CYP3A4 inducers (i.e. efavirenz, St. Johnu2019s wort, carbamazepine, etc.) used systemically should therefore be avoided during treatment with SIRTURO.

Co-administration of SIRTURO and moderate or strong CYP3A4 inhibitors may increase the systemic exposure to SIRTURO, which could potentially increase the risk of adverse reactions. Therefore, the combination of SIRTURO and moderate or strong CYP3A4 inhibitors (such as ciprofloxacin, erythromycin, fluconazole, clarithromycin, ketoconazole, itraconazole, ritonavir) used systemically for more than 14 consecutive days should be avoided.

Resistance to bedaquiline Bedaquiline must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by official guidelines, such as from WHO, to reduce the risk of development of resistance to bedaquiline.

Mortality In 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 group (see section 4.8). The imbalance in deaths is unexplained; no evidence has been found for a causal relationship with SIRTURO treatment.

Hepatic safety Increases in transaminases or aminotransferase elevations accompanied by total bilirubin u2265 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 during treatment. 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 medicine should be discontinued.

Other hepatotoxic medicines 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.

Lactose intolerance and lactase deficiency SIRTURO 100 mg tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take SIRTURO 100 mg tablets. Lactose may have an effect on the glycaemic control of patients with diabetes mellitus.

CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of SIRTURO and the formation of the N -monodesmethyl metaboloite (M2). In vitro, SIRTURO 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, CYP2C19 or CYP3A4 activities.

CYP3A4 inducers/inhibitors SIRTURO exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4. In an interaction study of SIRTURO and rifampicin in healthy adult subjects, the exposure (AUC) to SIRTURO was reduced by 52 % [90 % CI (-57; -46)]. Due to the possibility of a reduction of the therapeutic effect of SIRTURO (bedaquiline) due to a decrease in systemic exposure, co-administration of strong CYP3A4 inducers such as rifamycins (i.e. rifampicin, rifapentine and rifabutin) or moderate CYP3A4 inducers used systemically, such as efavirenz, should be avoided during treatment with SIRTURO. (see section 4.4).

Co-administration of SIRTURO and ketoconazole for 4 days in healthy adult subjects increased the exposure (AUC) to SIRTURO (bedaquiline) by 22 % [90 % CI (12; 32)] and should be avoided. Other antimicrobial medications The combination of SIRTURO with isoniazid/pyrazinamide in healthy adult subjects did not result in clinically relevant changes in the exposure (AUC) to SIRTURO (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 adult patients with MDR-TB, no major impact of co-administration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cicloserin was observed.

Antiretroviral medications There is limited data on the interaction between SIRTURO and antiretroviral medicines. Lopinavir/ritonavir In an interaction study of a single dose of SIRTURO and repeated doses of lopinavir/ritonavir in adults, exposure (AUC) to SIRTURO (bedaquiline) was increased by 22 % [90 % CI (11; 34)]. Clinical data on the combined use of lopinavir/ritonavir and SIRTURO in HIV/MDR-TB co-infected patients are not available (see section 4.4). Nevirapine Co-administration of nevirapine in adults with a single dose of SIRTURO did not result in clinically relevant changes in the exposure to SIRTURO. Clinical data on the combined use of nevirapine and SIRTURO in HIV/MDR-TB co-infected patients are not available (see section 4.4).

QT interval prolonging medicines There is limited information available on the potential for a pharmacodynamic interaction between SIRTURO and medicines that prolong the QT interval. In a medicine interaction study of SIRTURO (bedaquiline) and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with SIRTURO and ketoconazole in combination than after repeated dosing with the individual medicines. An additive or synergistic effect on QT prolongation of SIRTURO when co-administered with other medicines that prolong the QT interval cannot be excluded (see section 4.4).

QT interval and concomitant clofazimine use In an open label Phase IIb trial in adults, mean increases in QTcF were larger in the 17 subjects who were using clofazimine at week 24 (mean change from reference of 31,9 ms) than in subjects who were not using clofazimine at week 24 (mean change from reference of 12,3 ms). (see section 4.4).

Paediatric population Medicine interaction studies have only been performed in adults. It is assumed that there would be similar medicine interactions in the paediatric population and similar cautions should apply for all medications stated above.

Safety in pregnancy and lactation has not been established. Breastfeeding It is not known whether bedaquiline or its metabolites are excreted in human milk. In rats, concentrations of SIRTURO 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. Women using SIRTURO should not breastfeed their infants.

Adverse reactions, such as dizziness, may affect the ability to drive or use machines, although no studies on this effect with SIRTURO have been performed. Patients should be advised not to drive or operate machinery if they experience dizziness while taking SIRTURO.

Summary of the safety profile Adverse reactions from clinical trials in adult patients Adverse drug reactions (ADRs) 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 TB medicines. The basis of assessment of causality between the ADRs 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 ADRs (> 10,0 % of patients) during treatment with SIRTURO in the controlled trials were nausea, arthralgia, headache, vomiting and dizziness. Refer to the prescribing information of the medicines used in combination with SIRTURO for their respective adverse reactions.

Tabulated list of adverse reactions Adverse drug reactions to SIRTURO reported from controlled trials in 102 patients treated with SIRTURO are presented in Table 2.

Adverse drug reactions are listed by system organ class (SOC) and frequency: Very common (u2265 1/10); Common (u2265 1/100 to < 1/10); and Uncommon (u2265 1 / 1000 to 1/100)

Table 2: Adverse drug reactions from controlled trials during treatment with SIRTURO

*Terms represented by u201cincreased transaminasesu201d included, AST increased, ALT increased, hepatic enzyme increased and abnormal hepatic function

No additional ADRs were identified in adult patients from the uncontrolled study (n=233) nor from the Phase I and II studies.

Adverse reactions from a clinical trial in paediatric patients (5 years to less than 18 years of age The safety assessment of bedaquiline is based on the Week 24 analysis of the single-arm, open label, multi-cohort, Phase 2 trial (C211) in 30 paediatric patients. Paediatric Patients (12 years to less than 18 years of age) The trial was designed to enrol patients from 12 years to less than 18 years of age (15 patients aged 14 years to less than 18 years were Enrolled) with confirmed or probable MDR-TB infection who received SIRTURO (400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks) in combination with a background regimen (see Pharmacological properties u2013 Clinical Studies). The most common adverse drug reactions were arthralgia in 6/15 (40%) patients and nausea in 2/15 (13%) patients. Among the 15 adolescent patients, no deaths occurred during treatment with SIRTURO. Observed laboratory abnormalities were comparable to those in adults. No new adverse drug reactions were identified compared to those seen in adults.

Paediatric Patients (5 years to less than 12 years of age) The trial was designed to enrol patients from 5 years to less than 12 years of age (15 patients aged 5 years to less than 11 years were Enrolled) with confirmed or probable MDR-TB infection who received SIRTURO (200 mg once daily for the first 2 weeks and 100 mg 3 times/week for the following 22 weeks) in combination with a background regimen (see Pharmacological properties u2013 Clinical Studies). The most common adverse drug reactions were related to elevations in liver enzymes (5/15, 33%), reported as ALT/AST increased and hepatotoxicity; hepatoxicity led to discontinuation of SIRTURO in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO and background regimen. Among these 15 paediatric patients, no deaths occurred during treatment with SIRTURO.

Deaths: In the randomised phase IIb C208 study in adult patients a higher rate of deaths was seen in the SIRTURO treatment group 12,7 % (10/79) compared to the placebo treatment group 3,7 % (3/81). 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 u2018not convertedu2019. 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 open-label C209 trial, 6,9 % (16/23) patients died. The most common cause of death as reported by the investigator was TB (9 patients). All but one patient who died of TB had not converted or had relapsed. The causes of death in the remaining patients varied.

Adverse events of special interest Cardiovascular In the controlled Phase IIb study (C208), mean increases 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 in QTcF during the 24 weeks of SIRTURO treatment 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 in QTcF in the placebo group during the first 24 weeks was 6,2 ms (at week 18) (see section 4.4).

Cases of intentional or accidental acute overdose with SIRTURO were not reported during clinical trials. In a study of 44 healthy adult 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 ECG (QT interval) should be taken in case of deliberate or accidental overdose. It is advisable to contact a poison information center to obtain the latest recommendations for the management of an overdose. Since SIRTURO is highly protein-bound, dialysis is not likely to significantly remove SIRTURO from plasma. Clinical monitoring should be considered.