SIRTURO 100 mg tablets

  • Name:

    SIRTURO 100 mg tablets

  • Company:
    info
  • Active Ingredients:

    Bedaquiline fumarate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 23/10/18

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Summary of Product Characteristics last updated on medicines.ie: 27/3/2019
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 27 March 2019 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 23 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Removal/change of distributor

Updated on 9 March 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 9 March 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

4.4     Special warnings and precautions for use

 

 

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

4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

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

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

 

4.7     Effects on ability to drive and use machines

 

Bedaquiline hasmay have a minor influence on the ability to drive and use machines. Adverse reactions, such as dizziness, may affect the ability to drive or use machines. Patients should be advised not to drive or operate machinery if they experience dizziness while taking SIRTURODizziness has been reported in some patients taking bedaquiline and should be considered when assessing a patient’s ability to drive or operate machinery (see section 4.8).

 

4.8     Undesirable effects

 

Description of selected adverse events

Deaths

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 subjects were alcohol poisoning, hepatitis/hepatic cirrhosis, septic shock/peritonitis, cerebrovascular accident and motor vehicle accident. One of the ten deaths in the SIRTURO group (due to alcohol poisoning) occurred during the 24‑week treatment period. The other nine deaths among those treated with SIRTURO occurred after completion of treatment with this agent (range 86‑911 days post‑SIRTURO; median 344 days). The observed imbalance in deaths between the two treatment groups is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other medicinal products used to treat tuberculosis, human immunodeficiency virus status, or severity of disease could be observed. During the trial, there was no evidence of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the patients that died.

 

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

5.1     Pharmacodynamic properties

 

 

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 subjects were alcohol poisoning, hepatitis/hepatic cirrhosis, septic shock/peritonitis, cerebrovascular accident and motor vehicle accident. One of the ten deaths in the SIRTURO group (due to alcohol poisoning) occurred during the 24 week treatment period. The other nine deaths among those treated with SIRTURO occurred after completion of treatment with this agent (range 86 911 days post SIRTURO; median 344 days). The observed imbalance in deaths between the two treatment groups is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other medicinal products used to treat tuberculosis, human immunodeficiency virus status, or severity of disease could be observed. During the trial, there was no evidence of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the patients that died.

 

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

 

 





Updated on 8 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 8 March 2018 PIL

Reasons for updating

  • Change to section 3 - duration of treatment
  • Change to section 6 - date of revision

Updated on 18 August 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 20 June 2017 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 15 November 2016 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

6.3     Shelf life

 

Tablets packaged in:

-                 aluminium/aluminium foil blisters: years

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

Updated on 25 February 2016 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 Shelf life of tablets packaged in HDPE bottle has changed from 24 to 36 months.

Updated on 12 January 2016 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Addition of statement 'Not all pack sizes may be marketed'

Updated on 11 January 2016 PIL

Reasons for updating

  • Change to dosage and administration

Updated on 19 November 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 19 November 2015 PIL

Reasons for updating

  • Change to storage instructions

Updated on 8 May 2015 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

In section 6.5,  addition of new pack size as follows:$0$0$0$0Carton containing 4 push-through blister strips (containing 6 tablets per strip). Tablets are packaged in aluminium/aluminium foil blisters.$0

Updated on 6 May 2015 PIL

Reasons for updating

  • Introduction of new pack/pack size

Updated on 22 January 2015 SmPC

Reasons for updating

  • Change to section 5.3 - Preclinical safety data

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Addition of results from rat carcinogenicity study to section 5.3 (pre-clinical safety) as follows:$0$0$0$0In a rat carcinogenicity study, bedaquiline, at the high doses of 20 mg/kg/day in males and 10 mg/kg/day in females, did not induce any treatment related increases in tumour incidences. Compared to the exposures (AUC) observed in subjects with MDR TB in the bedaquiline phase II trials, the exposures (AUC) in rats at high doses were similar in males and 2 fold higher in females for bedaquiline, and 3 fold higher in males and 2 fold higher in females for M2.$0

Updated on 17 December 2014 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update of sections 4.4, 4.8 and 5.1 further to the final study results of TMC207-C208 Stage 2 and Study TMC207-C209.Clarification in section 4.5 of the interaction of bedaquiline and lopinavir/ritonavir. Range of terminal elimination half-life of bedaquiline and its active metabolite added to section 5.2.

Updated on 2 May 2014 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 1 May 2014 PIL

Reasons for updating

  • New PIL for new product