Adverse reactions : תופעות לוואי

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 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. 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 patients treated with SIRTURO are presented in the table below.
Adverse drug reactions are listed by system organ class (SOC) and frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

System Organ Class (SOC)                Frequency Category                       ADRs Nervous system disorders                Very Common                              Headache, dizziness Cardiac disorders                       Common                                   Electrocardiogram QT prolonged
Gastrointestinal disorders              Very Common                              Nausea, vomiting Common                                   Diarrhoea
Hepatobiliary disorders                 Common                                   Transaminases increased* Musculoskeletal and                     Very Common                              Arthralgia connective tissue disorders             Common                                   Myalgia * Terms represented by ‘transaminases increased’ included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, and transaminases increased (see section below).

Description of selected adverse reactions

Cardiovascular
In the controlled Phase IIb study (C208), mean increases from baseline values in QTcF were observed from the first on-treatment assessment onwards (9.9 ms at week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase from baseline values 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 from baseline values in QTcF in the placebo group during the first 24 weeks was 6.2 ms (also at week 18) (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 tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging medicinal products in the treatment regimen.
Patients receiving SIRTURO alone with no other QT prolonging medicinal product developed a maximal mean QTcF increase over baseline of 23.7 ms with no QT duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging medicinal products developed a maximal mean QTcF prolongation of 30.7 ms over baseline, resulting in a QTcF duration in excess of 500 ms in one patient.
There were no documented cases of Torsade de Pointes in the safety database (see section 4.4). See section 4.5, QT interval and concomitant clofazimine use, for further information regarding patients using clofazimine concomitantly.

Increased transaminases
In study C208 (stage 1 and 2), aminotransferase elevations of at least 3 x ULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] versus 6/105 [5.7%]) in the placebo treatment group. In the SIRTURO treatment group, the majority of these increases occurred throughout the 24 weeks of treatment and were reversible. During the investigational phase in stage 2 of study C208, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) in the placebo treatment group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il