"Alderman Farms Sales Corporation, Boynton Beach, Florida is recalling one pint containers of Certified Organic Cherry Tomatoes because they have the potential to be contaminated with Salmonella, an organism which can cause serious and some"...
An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial (based on the 120-week visit window). One death occurred during the 24 weeks of administration of SIRTURO. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see ADVERSE REACTIONS].
SIRTURO prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected [see ADVERSE REACTIONS and DRUG INTERACTIONS]. SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
The following may increase the risk for QT prolongation when patients are receiving SIRTURO:
- use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine
- a history of Torsade de Pointes
- a history of congenital long QT syndrome
- a history of or ongoing hypothyroidism
- a history of or ongoing bradyarrhythmias
- a history of uncompensated heart failure
- serum calcium, magnesium, or potassium levels below the lower limits of normal
If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.
Discontinue SIRTURO and all other QT prolonging drugs if the patient develops:
- Clinically significant ventricular arrhythmia
- A QTcF interval of greater than 500 ms (confirmed by repeat ECG)
If syncope occurs, obtain an ECG to detect QT prolongation.
More hepatic-related adverse reactions were reported with the use of SIRTURO plus other drugs used to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function.
Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO if:
- aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
- aminotransferase elevations are greater than eight times the upper limit of normal
- aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks
Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid coadministration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers, such as efavirenz, during treatment with SIRTURO [see DRUG INTERACTIONS].
Co-administration of SIRTURO with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors for more than 14 consecutive days while on SIRTURO, unless the benefit of treatment with the drug combination outweighs the risk [see DRUG INTERACTIONS]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Serious Adverse Reactions
Advise patients that the following serious side effects can occur with SIRTURO: death, heart rhythm abnormalities, and/or hepatitis. In addition, advise patients about other potential side effects: nausea, joint pain, headache, increased blood amylase, hemoptysis, chest pain, anorexia, and/or rash. Additional testing may be needed to monitor or reduce the likelihood of adverse effects.
Compliance with Treatment
Advise patients to take SIRTURO in combination with other antimycobacterial drugs as prescribed. Emphasize compliance with the full course of therapy. Advise patients that skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the treatment and (2) increase the likelihood that their mycobacterium may develop resistance and the disease will not be treatable by SIRTURO or other antibacterial drugs in the future.
If a dose is missed during the first 2 weeks of treatment, advise patients not to make up the missed dose but to continue the usual dosing schedule. From Week 3 onwards, if a 200 mg dose is missed, advise patients to take the missed dose as soon as possible, and then resume the 3 times a week regimen.
Inform patients to take SIRTURO with food.
Use with Alcohol and other Medications
Advise patients to abstain from alcohol, hepatotoxic medications or herbal products.
Advise patients to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with SIRTURO.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in subjects in the Phase 2 clinical trials.
No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay.
SIRTURO had no effects on fertility when evaluated in male and female rats. No relevant drug-related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats and lower for rabbits compared to humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioral development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6-fold to 12-fold higher that the maximum concentration observed in maternal plasma.
Use In Specific Populations
Pregnancy Category B
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to bedaquiline. In these studies, the corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. There are, however, no adequate and well-controlled studies of SIRTURO in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that drug is concentrated in breast milk.
In rats, treated with bedaquiline at doses 1 time to 2 times the clinical dose (based on AUC comparisons), concentrations in milk were 6-fold to 12-fold higher than the maximum concentration observed in maternal plasma. Pups from these dams showed reduced body weights compared to control animals throughout the lactation period.
Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of SIRTURO in pediatric patients have not been established.
Because of limited data, differences in outcomes or specific risks with SIRTURO cannot be ruled out for patients 65 years of age and older.
The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) [see CLINICAL PHARMACOLOGY]. 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 should be used with caution in these patients only when the benefits outweigh the risks. Clinical monitoring for SIRTURO-related adverse reactions is recommended [see WARNINGS AND PRECAUTIONS].
SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%). No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, SIRTURO should be used with caution [see CLINICAL PHARMACOLOGY]. Monitor for adverse reactions of SIRTURO when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/11/2015
Additional Sirturo Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.