SIRTURO 20 mg and 100 mg tablets

4.6 Fertility, pregnancy and lactation

Breast-feeding

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

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

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

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

Ireland

Janssen Sciences Ireland UC

Tel: +353 1 800 709 122

medinfo@its.jnj.com

Update of the Posology and method of administration (Section 4.2) – improved for clarity regarding use in combination regimens

Reupload due to technical issues regarding the inverted black triangle icon visibility

Update of the Posology and method of administration (Section 4.2) – improved for clarity regarding use in combination regimens

SIRTURO 20 mg tablets

• 30 months3 years

   

Update of renewal-09 January 2020

1.       What SIRTURO is and what it is used for

SIRTURO contains the active substance bedaquiline.

SIRTURO is a type of antibiotic. Antibiotics are medicines that kill bacteria that cause disease.

SIRTURO is used to treat tuberculosis that affects the lungs when the disease has become resistant to other antibiotics. This is called multi‑drug resistant pulmonary tuberculosis.

SIRTURO must always be taken together with other medicines for treating tuberculosis.

It is used in adults and adolescents (12 years to less than 18 years of age and weighing at least 30 kg)aged 18 years and over.

Children and adolescents

In adolescents weighing 30 to 40 kg, the levels of SIRTURO in the blood were predicted to be higher than in adults. Study information is too limited to be able to excludeThis might be associated with an increased risk of abnormal reading on the electrocardiogram (QT prolongation) or increased liver enzymes (shown in blood test).

Do not give this medicine to children and adolescents (under 1218 years of age) or weighing less than 30 kg. This is because it has not been studied in this age groupthese patients.

3.       How to take SIRTURO

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

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

Use in adults and in adolescents (12 years of age and older and weighing at least 30 kg)

4.1     Therapeutic indications

SIRTURO is indicated for use as part of an appropriate combination regimen for pulmonary multidrug‑resistant tuberculosis (MDR‑TB) in adults and adolescent patients (12 years to less than 18 years of age and weighing at least 30 kg) when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2     Posology and method of administration

Posology

The recommended dosage isof SIRTURO is shown in the table below.:

• Weeks 1‑2: 400 mg (4 tablets of 100 mg) once daily
• Weeks 3‑24: 200 mg (2 tablets of 100 mg) three times per week (with at least 48 hours between doses).
   

Paediatric population

The safety and efficacy of SIRTURO in children aged < 1218 years or weighing less than 30 kg have not yet been established.

No data are available.

SIRTURO may be included in the treatment regimen for adolescents greater than or equal to 12 years of age and weighing at least 30 kg with confirmed or with probable MDR-TB disease which is diagnosed based on clinical signs and symptoms of pulmonary MDR-TB, appropriate epidemiological context, and in line with international/local guidelines (see section 4.1).

4.3     Contraindications

Mortality

In the 120‑week C208 trial in adults 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 5.1). The imbalance in deaths is unexplained; no evidence has been found for a causal relationship with SIRTURO treatment. For additional information on deaths in the C209 trial, see section 5.1.

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.

Patients infected with human immunodeficiency virus (HIV)

There are no clinical data on the safety and efficacy of bedaquiline when co‑administered with antiretroviral agents.

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

SIRTURO contains lactose. Patients with rare hereditary problems of galactose intolerance, total the Lapp lactase deficiency or glucose‑galactose malabsorption should not take this medicine.

4.5     Interaction with other medicinal products and other forms of interaction

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

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

Other antituberculosis medicinal products

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

In a placebo‑controlled clinical study in patients with multi‑drug resistant Mycobacterium tuberculosis, no major impact of co‑administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

Antiretroviral medicinal products

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

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

QT interval prolonging medicinal products

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

QT interval and concomitant clofazimine use

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

4.8     Undesirable effects

Summary of the safety profile

Adverse drug reactions for SIRTURO were identified from pooled Phase IIb clinical trial data (both controlled and uncontrolled, C208 and C209) containing 335 adult patients who received SIRTURO in combination with a background regimen of tuberculosis medicinal products. The basis of assessment of causality between the adverse drug reactions and SIRTURO was not restricted to these trials, but also on review of the pooled Phase I and Phase IIa safety data in adults. The most frequent adverse drug reactions (> 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea (35.3% in the SIRTURO group vs 25.7% in the placebo group), arthralgia (29.4% vs 20.0%), headache (23.5% vs 11.4%), vomiting (20.6% vs 22.9%) and dizziness (12.7% vs 11.4%). Refer to the Summary of Product Characteristics of the medicinal products used in combination with SIRTURO for their respective adverse reactions.

Tabulated list of adverse reactions

Adverse drug reactions to SIRTURO reported from controlled trials in 102 adult patients treated with SIRTURO are presented in the table below.

Paediatric population

The safety assessment of bedaquiline is based on data from 15 adolescents greater than or equal to 14 years of age with confirmed or probable MDR-TB infection (see section 5.1). Overall, there was no indication of any differences in the safety profile in these adolescents compared to that observed in the adult population.

4.9     Overdose

Cases of intentional or accidental acute overdose with bedaquiline were not reported during clinical trials. In a study in 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 electrocardiogram (QT interval) monitoring should be taken in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be aided by the administration of activated charcoal. 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.

5.1     Pharmacodynamic properties

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

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

Mortality

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

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

Paediatric population

The pharmacokinetics, safety and tolerability of SIRTURO in combination with a background regimen were evaluated in trial C211, a single-arm, open-label Phase II trial, including 15 patients who had a median age of 16 years (range: 14-17 years), weighed 38 to 75 kg, and were 80% female, 53.3% Black and 13.3% Asian. The patients had confirmed or probable MDR-TB infection and were to complete at least 24 weeks of treatment. SIRTURO was administered as 400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks.

In the subset of patients with culture positive pulmonary MDR-TB at baseline, treatment with a regimen including bedaquiline resulted in conversion to a negative culture in 75.0% (6/8 microbiologically evaluable patients) at week 24.

5.2     Pharmacokinetic properties

The pharmacokinetic properties of bedaquiline have been evaluated in adult healthy subjects and in adult multi‑drug resistant tuberculosis‑infected patients 14 years of age and older. Exposure to bedaquiline was lower in multi‑drug resistant tuberculosis‑infected patients than in healthy subjects.

Biotransformation

CYP3A4 was the major CYP isoenzyme involved in  vitro in the metabolism of bedaquiline and the formation of the N‑monodesmethyl metabolite (M2).

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

Bedaquiline and M2 were not substrates of P-gp in  vitro. Bedaquiline was a weak OCT1, OATP1B1 and 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 concentrations in  vitro. An in  vitro study indicated a potential for bedaquiline to inhibit BCRP at the concentrations achieved in the intestine after oral administration. The clinical relevance is unknown.

Paediatric patients

The average plasma exposure of bedaquiline (AUC_168h) at week 24 was predicted to be 178 µg*h/mL (90% prediction interval: 55.8-383 µg*h/mL) in adolescents aged 12 to less than 18 years and weighing at least 30 kg receiving the adult dose regimen of SIRTURO (400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks). In adolescents weighing from 30 to  40 kg, the average plasma exposure of bedaquiline (AUC_168h) at week 24 was predicted to be higher (average: 224 µg*h/mL; 90% prediction interval: 77.4-474 µg*h/mL) compared to adult patients. The average plasma exposure of bedaquiline (AUC_168h) at week 24 in adults was predicted to be 127 µg*h/mL (90% prediction interval: 39.7-249 µg*h/mL).

The pharmacokinetics of SIRTURO in paediatric patients less than 14 years of age or weighing less than 38 kg have not been evaluated.

4.2     Posology and method of administration

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

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

.4       Special warnings and precautions for use

There are no clinical data on the use of SIRTURO to treat:

• extra‑pulmonary tuberculosis (e.g. central nervous system, bone)
• infections due to mycobacterial species other than Mycobacterium tuberculosis
• latent infection with Mycobacterium tuberculosis
   
  There are no clinical data on the use of SIRTURO as part of combination regimens used to treat drug‑susceptible Mycobacterium tuberculosis.
   
  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 prevent development of resistance to bedaquiline.

5.1     Pharmacodynamic properties

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 of the MmpS5-MmpL5 efflux pump. Target-based mutations generated in preclinical studies lead to 8- to 133‑fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4.0 mg/l. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8‑fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.50 mg/l. The majority of iIsolates with efflux-based mutations that are phenotypically resistant to bedaquiline are also less susceptible cross-resistant to clofazimine. Isolates that are 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 microbiologic outcomes is unclear because of the low incidence of such cases in the Phase II trials.However no clear relationship between increased post-baseline bedaquiline MICs and microbiologic outcomes was observed in the phase 2 trials where bedaquiline was given for 24 weeks, followed by continuation of the background regimen

4.4     Special warnings and precautions for use


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

4.5       Interaction with other medicinal products and other forms of interaction

Antiretroviral medicinal products

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

6.3     Shelf life

Tablets packaged in:

-                 aluminium/aluminium foil blisters: 2 3 years

-                 white high density polyethylene (HDPE) bottles: 3 years

Dosage and Administration and Adverse Reactions
Addition of statement referring to prescribing information of drugs used in combination with SIRTURO.

Pharmacodynamic Properties, Microbiology
Revision of data based on microbiology studies in the following subsections: “Mechanisms of resistance”, “Dilution Techniques”, and “Quality Control”.

Pharmacodynamic Properties, Clinical Studies
Addition of data based on microbiology studies.