"Rotavirus can cause severe diarrhea in young children. They can get very dehydrated and need to be hospitalized. Rotavirus spreads easily. Parents can protect their children by making sure they are vaccinated with rotavirus vaccine.
The most frequent adverse drug reactions ( > 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea, arthralgia, and headache. Additional adverse events reported in ≥ 10% of patients treated with SIRTURO and with a higher frequency than the placebo treatment group were hemoptysis and chest pain.
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 bedaquiline-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 are randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 is an ongoing, open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.
In Study 1 overall, 35.0% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) patients in the placebo treatment group were HIV-infected. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse event.
Table 1: Select Adverse Drug Reactions from Study 1
That Occurred More Frequently Than Placebo During Treatment with SIRTURO
|Adverse Drug Reactions||SIRTURO Treatment Group
N = 79
|Placebo Treatment Group
N = 81
|Nausea||30 (38.0)||26 (32.1)|
|Arthralgia||26 (32.9)||18 (22.2)|
|Headache||22 (27.8)||10 (12.3)|
|Transaminases Increased*||7 (8.9)||1 (1.2)|
|Blood Amylase Increased||2 (2.5)||1 (1.2)|
|Hemoptysis†||14 (17.7)||9 (11.1)|
|Chest Pain†||9 (11.4)||6 (7.4)|
|Anorexia†||7 (8.9)||3 (3.7)|
|Rash†||6 (7.6)||3 (3.7)|
|* Terms represented by
'transaminases increased' included transaminases increased, AST increased, ALT increased,
hepatic enzyme increased, and hepatic function abnormal.
† Reported Adverse Events with a greater incidence in the SIRTURO treatment group but which were not identified as adverse drug reactions.
No additional unique ADRs were identified from the uncontrolled Study 3.
In Study 1, there was a statistically significant increased mortality risk by Week 120 in the SIRTURO treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value = 0.03, an exact 95% confidence interval of the difference [1.1%, 18.2%]). Five of the 9 SIRTURO deaths and the 2 placebo deaths were TB-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight subjects in the SIRTURO treatment group was 329 days after last intake of SIRTURO. The imbalance in deaths is unexplained; no discernible pattern between death and sputum conversion, relapse, sensitivity to other drugs used to treat TB, HIV status, and severity of disease was observed.
In Study 1, the mean increases in QTc, corrected using the Fridericia method, were greater in the SIRTURO treatment group compared to the placebo treatment group from the first week of treatment (9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTc during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). QT increases from baseline in the SIRTURO group persisted even after SIRTURO treatment was stopped. During the trial, there was no clear correlation of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the subjects that died.
In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat TB, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients receiving SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QT segment duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, resulting in QTcF segment durations in excess of 500 ms in one patient.
There were no documented cases of Torsade de Pointes in the safety database [see WARNINGS AND PRECAUTIONS].
Hepatic-Related ADRs (including abnormalities in serum transaminases)
Hepatic ADRs developed in more SIRTURO-treated patients than those treated with other drugs used to treat TB.
In both Studies 1 and 2, reversible aminotransferase elevations of at least 3xULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%] in the placebo treatment group.
Reported adverse reactions: In Study 1, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) patients in the placebo treatment group.
Read the Sirturo (bedaquiline tablets) Side Effects Center for a complete guide to possible side effects
CYP3A4 is the major CYP isoenzyme involved in the metabolism of bedaquiline and the formation of the major N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency.
In vitro, bedaquiline does not significantly inhibit the activity of the following CYP450 enzymes that were tested: CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5 and CYP4A, and it does not induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 activities.
Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4.
Rifampin (strong CYP3A4 inducer)
In a drug interaction study of 300 mg bedaquiline and rifampin 600 mg once daily for 21 days in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52%. Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of bedaquiline and rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers used systemically should be avoided [see Pharmacokinetics].
Ketoconazole (strong CYP3A4 inhibitor)
Co-administration of 400 mg bedaquiline once daily for 14 days and ketoconazole 400 mg once daily for 4 days in healthy subjects increased the exposure (AUC) to bedaquiline by 22%. Due to the potential risk of adverse reactions to bedaquiline because of the increase in systemic exposure, prolonged co-administration of bedaquiline and strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Pharmacokinetics]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.
Other Antimicrobial Medications
The combination of 400 mg bedaquiline once daily for 14 days with isoniazid (300 mg once daily for 5 days)/pyrazinamide (1000 mg once daily for 5 days) in healthy 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 coadministration with SIRTURO. In a placebo-controlled clinical trial in patients with MDR-TB, no major impact of co-administration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.
Kaletra (400 mg lopinavir/100 mg ritonavir)
In a healthy volunteer drug interaction study of 400 mg single dose bedaquiline and Kaletra twice daily for 24 days, exposure (AUC) to bedaquiline was increased by 22%. SIRTURO must be used with caution when co-administered with Kaletra and only if the benefit outweighs the risk [see WARNINGS AND PRECAUTIONS and Pharmacokinetics].
Co-administration of bedaquiline 400 mg single dose and nevirapine 200 mg twice daily for 4 weeks with bedaquiline did not result in clinically relevant changes in the exposure to bedaquiline in HIV-infected patients. No dosage adjustment of bedaquiline is required when co-administered with nevirapine [see Pharmacokinetics].
QT Interval Prolonging Drugs
In a drug interaction study of bedaquiline and ketoconazole, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval.
In Study 3, mean increases in QTc were larger in the 17 subjects who were using clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in subjects who were not using clofazimine with bedaquiline at Week 24 (mean change from reference of 12.3 ms) [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 9/11/2013
This monograph has been modified to include the generic and brand name in many instances.
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