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National Drug Monograph
June 2014
VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives
The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.
Executive Summary:
Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR-TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR-TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR-TB is difficult to cure, requiring 1824 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with side effects. CDC reports approximately 100 cases per year of MDR-TB in the United States.
In December 2012, on the basis of data from Phase IIb trials, the FDA approved use of bedaquiline under the provisions of the accelerated approval regulations for serious or life-threatening illnesses. Bedaquiline is indicated as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis (MDR-TB). It should be reserved for situations where an effective treatment regimen cannot otherwise be provided. Bedaquiline is not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria.
Bedaquiline should be used in combination with at least 3 other drugs to which the patients MDR-TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment with bedaquiline may be initiated in combination with at least 4 other drugs to which the patients MDR-TB isolate is likely to be susceptible. Directly observed therapy (DOT) is required for bedaquiline administration for total treatment duration of 24 weeks; patients need to continue to take other TB drugs as directed.
Bedaquiline has boxed warnings for 1) increased risk for death was observed in the bedaquiline treatment group (9/79; 11.4%) compared with the placebo treatment group (2/81; 2.5%) in the pivotal Phase IIb trial; 2) may cause QT prolongation; use with other QT prolonging medications may cause an additive effect. In addition, bedaquiline has warning/precautions pertaining to hepatic-related drug adverse reactions, drugs interactions, co-infection with HIV and treatment failures.
The CDC has published HYPERLINK "http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm" Provisional Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis. These provisional guidelines state that bedaquiline may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary MDR-TB (TB with an isolate showing genotypic or phenotypic resistance to both isoniazid and rifampin) when an effective treatment regimen cannot otherwise be provided.
In conclusion, bedaquiline is indicated as part of combination therapy in adults with pulmonary MDR-TB. Bedaquiline should only be used in situations where an effective treatment regimen cannot otherwise be provided. Bedaquiline has warning/precautions pertaining to increased mortality, QT prolongation, hepatic-related drug adverse reactions, drugs interactions, co-infection with HIV and treatment failures.
Introduction
The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating bedaquiline for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.
Pharmacology/Pharmacokinetics1,2
Bedaquiline is a diarylquinoline antimycobacterial with a novel mechanism of action. The drug inhibits mycobacterial ATP (adenosine 5-triphosphate) synthase, an enzyme that is essential for the generation of energy in M. tuberculosis.
Table 1. Pharmacology/Pharmacokinetics
ParameterBedaquilineMetabolismPrimarily hepatic by CYP3A4, metabolized to M2 (four to six times less active in terms of antimycobacterial potency compared to parent drug) and M3EliminationPrimarily excreted in the feces; renal elimination (<0.001%)Half-life5.5 monthsProtein Binding>99%Tmax~5 hoursBioavailabilityWhen taken with a standard meal (~22 grams of fat, 558 Kcal total), relative bioavailability increased by about 2-fold compared to administration under fasting conditionsMicrobiology1-5
Bedaquiline has shown in vitro activity against most isolates of M. tuberculosis including both replicating and non-replicating drug-sensitive (DS-TB) and drug-resistant M. tuberculosis (e.g., multi-drug resistant tuberculosis [MDR-TB] including some extensively drug-resistant tuberculosis (XDR-TB). No cross-resistance was found when tested against isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide, amikacin, and moxifloxacin.
FDA Approved Indication(s)1
B e d a q u i l i n e i s i n d i c a t e d a s p a r t o f c o m b i n a t i o n t h e r a p y i n a d u l t s ( e" 1 8 y e a r s ) w i t h p u l m o n a r y m u l t i - d r u g r e s i s t a n t t u b e r c u l o s i s ( M D R - T B ) .
I t s h o u l d b e r e s e r v e d f o r s i t u a t i o n s w h e r e a n e f f e c t i v e t r e a t m e n t r e g i m e n c a n n o t o t h e r w i s e b e p r o v i d e d .
B e d a q u i l i n e i s not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria.
Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis2
Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR-TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR-TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR-TB is difficult to cure, requiring 1824 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with side effects, and carries a mortality risk greater than that of drug-susceptible TB.
The purpose of these CDC guidelines are to provide provisional guidelines for FDA-approved and unapproved, or off-label uses in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR-TB who were not included in the clinical trials for the drug.
The CDC recommends the following:
Bedaquiline may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary MDR-TB (TB with an isolate showing genotypic or phenotypic resistance to both isoniazid and rifampin) when an effective treatment regimen cannot otherwise be provided.
Bedaquiline may be used on a case-by-case basis in children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR-TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. However, further study is required before recommending routine use in these populations.
Bedaquiline may be used on a case-by-case basis for durations longer than 24 weeks when an effective treatment regimen cannot be provided otherwise.
Potential Off-label Uses6
This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safetys HYPERLINK "http://vaww.national.cmop.va.gov/PBM/Directives%20Policies%20and%20Information%20Letters/Guidance%20on%20Off%20Label%20Prescribing.pdf" Guidance on Off-label Prescribing (available on the VA PBM Intranet site only).
There are no other trials with bedaquiline registered on Clinicaltrials.gov. Please refer to CDC recommendations for certain populations with MDR-TB that may be considered for use on a case-by-case basis.
Current VA National Formulary Alternatives7-8
First-line agents in drug-sensitive tuberculosis per the 2003 American Thoracic Society (ATS), CDC, and Infectious Diseases Society of America (IDSA) Treatment of Tuberculosis Guidelines: Ethambutol hydrochloride (Tablet); Isoniazid (Injection, Tablet); Isoniazid/Rifampin (Oral Capsule); Pyrazinamide (Tablet); Rifabutin (Tablet); Rifampin (Injection, Oral Capsule)
Second-line agents per the 2003ATS, CDC, and IDSA Treatment of Tuberculosis Guidelines: Amikacin sulfate (Injection solution); Capreomycin (Injection); Cycloserine (Oral Capsule); Ethionamide (Tablet); Kanamycin (Injection); Levofloxacin (Injection solution, Tablet); Moxifloxacin (Injection solution, Tablet); Streptomycin sulfate (Injection)
Other potential off-label agents for refractory cases: Amoxicillin/clavulanate potassium (Tablet, Oral Powder for Reconstitution); Clarithromycin (Tablet); Imipenem/cilastatin (Injection); Linezolid (Injection, Oral Powder for Reconstitution, Tablet)
Dosage and Administration1
Bedaquiline should be used in combination with at least 3 other drugs to which the patients MDR-TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment with bedaquiline may be initiated in combination with at least 4 other drugs to which the patients MDR-TB isolate is likely to be susceptible. Directly observed therapy (DOT) is required for bedaquiline administration for total treatment duration of 24 weeks; patients need to continue to take other TB drugs as directed. Bedaquiline should be swallowed whole with water; patients should avoid alcohol use while on treatment.
Table 2. The recommended dosage of bedaquiline
WeeksDoseRouteFrequencySpecificationsMissed dosesWeeks
1-2400 mg
(4 tablets of 100 mg)By mouthOnce dailyWith foodDo not make up dose, continue the usual dosing scheduleWeeks
3-24200 mg
(2 tablets of 100 mg)By mouth3 times per weekWith food (with at least 48 hours between doses) for a total dose of 600 mg per weekTake the missed 200 mg dose as soon as possible, then resume 3 times a week regimen
Dosing in Hepatic Impairment
Mild or moderate hepatic impairment: No dosage adjustment is necessary
Severe hepatic impairment: Not been studied; use with caution in these patients only when the benefits outweigh the risks.
Dosing in Renal Impairment
Mild or moderate renal impairment: No dosage adjustment is necessary.
Severe renal impairment or ESRD requiring hemodialysis or peritoneal dialysis: Use with caution.
Special Handling
Sirturo (bedaquiline) is dispensed in the private sector by Metro Medical Supply Specialty Pharmacy. VA pharmacies are not required to use Metro Medicals specialty pharmacy services to obtain Sirturo and can instead order the product as a wholesale transaction from the company. For more information, please use the link below for the Special Handling Webpage on the PBM Intranet: < HYPERLINK "https://vaww.cmopnational.va.gov/cmop/PBM/Special%20Handling%20Drugs/Forms/AllItems.aspx" https://vaww.cmopnational.va.gov/cmop/PBM/Special%20Handling%20Drugs/Forms/AllItems.aspx>
Efficacy1-3,9-10
Bedaquiline was approved as a priority review drug/orphan drug for the treatment of pulmonary-MDR-TB. Thus far, there have been 11 phase 1 studies and 4 phase 2 studies performed. The phase II studies include a phase IIa dose-ranging study (C202) and three phase IIb studies (C208 Stage 1, C208 Stage 2, and C209). This review will primarily be focusing on the phase IIb studies. The phase IIb study, C208 Stage 2, is considered the pivotal trial for the fast-track approved by the FDA; the trial provided a comparative evaluation between the efficacy of bedaquiline co-administered with a background regimen and the background regimen by itself, using the proposed bedaquiline dosing regimen. C208 Stage 1 and C209 are considered supportive trials. However, the only trial published to date is the C208 Stage 1 study. The FDA has required a phase III study to support the efficacy and safety data from the phase IIb trials.
Table 3. CDCs Summary of 3 bedaquiline efficacy and safety studies in Provisional Guidelines
Study StageDesignIntervention and control No. in each arm bdq/ placeboOutcome measuredKey resultDeficiencyPopulationC208 Stage 1Double-blind, randomized, placebo-controlled superiority trialBR for 1824 months +/- Bdq for 8 weeks23/24Primary: median time to SCC*
Secondary: SCC rate at weeks 8 and 24Bdq with BR was superior to BR alone in time to SCC (hazard ratio: 11.7).
Greater SCC rate noted for bdq with BR at week 8 (p = 0.004), but not at week 24.Surrogate marker for clinical benefit; small sample sizeNew onset MDR-TB; HIV with CD4<300 cells/mm3 and those on ARV excluded C208 Stage 2Double-blind, randomized, placebo-controlled superiority trialBR for 1824 months +/- Bdq for 24 weeks80/81Primary: median time to SCC
Secondary: SCC rate at weeks 24 and 72Bdq with BR was superior to BR alone in time to SCC (hazard ratio: 2.15).
Greater SCC rate noted for bdq with BR at week 24 (p = 0.014) but not at week 72.Surrogate marker for clinical benefit; small sample sizeNew onset MDR-TB; HIV with CD4<300 cells/mm3 and those on ARV excluded C209 Noncomparative,single-arm, open-label trialBR + Bdq294Primary: median time to SCCTime to SCC was 57 days.Surrogate marker for clinical benefit; observational studyPreviously treated pre-XDR and XDR TB; HIV with CD4<250 cells/mm3 excludedAbbreviations: ARV = antiretroviral treatment; Bdq = bedaquiline; BR = background regimen; MDR-TB = multidrug-resistant tuberculosis; XDR TB = extensively drug-resistant TB; CD4 = T-helper cell count; SCC = smear culture conversion; 95% CI = 95% confidence interval.
* Two consecutive cultures from sputum samples that were negative for Mycobacterium tuberculosis.
Background regimen (ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone).
Table 4. CDCs Summary of Study C208 (Stage 1) secondary endpoint: sputum culture conversion, modified intention-to-treat population in Provisional Guidelines
Time to endpoint Bedaquiline
(n = 21)Placebo
(n = 23)p-valueAbsolute difference (percentage points)(95% CI)No.(%) No. (%)Week 8 10 (47.6)2 (8.7)0.00438.9(12.363.1)Week 24 17 (81.0)15 (65.2)0.293 15.8(-11.941.9) Final 17 (81.0)13 (56.5)0.10224.5(-4.850.3)Abbreviation: 95% CI = 95% confidence interval.
Table 5. CDCs Summary of Study C208 (Stage 2) secondary endpoint: sputum culture conversion rates at weeks 24 and 72, modified intention-to-treat population in Provisional Guidelines
WeekBedaquiline
(n = 67)Placebo
(n = 66)p-valueAbsolute difference (percentage points)(95% CI)No.(%)No.(%)2452(77.6)38(57.6)0.01420.0(4.535.6)7247(70.1)37(56.1)0.09214.0 (-2.130.3)Abbreviation: 95% CI = 95% confidence interval.
Adverse Events (Safety Data)1-3
The safety analysis were pooled from three studies (C208 Stages 1 and 2, C209), comprising of 335 bedaquiline-exposed patients. The C208 Stage 1 trial was an 8 week-randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB; whereas, C208 Stage 2 was a 24-week study of similar design. The C209 trial was a 24-week open-label, noncomparative study where bedaquiline was administered as a part of an individualized regimen in previously treated pulmonary MDR-TB patients.
Deaths and Other Serious Adverse Events
A total of 36 deaths (30 in bedaquiline treated patients and 6 in placebo-treated group) were reported during the entire clinical development program of bedaquiline. In the C208 Stage 2 trial, there was a statistically significant increased mortality risk by week 120 in the bedaquiline treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value = 0.03, 95% CI 1.1%, 18.2%).
Table 6. Mortality in bedaquiline Phase II safety studiesa
No. of deathsBedaquiline armControl armStudy (Stage)DesignNo.%No.%C202Randomized, open-label, dose-ranging early bactericidal study using INH or RIF in control arm2/454.400C208 (Stage 1)Double-blind, randomized, placebo-controlled superiority trial2/238.72/1248.3C208 (Stage 2)Double-blind, randomized, placebo-controlled superiority trial10/79b12.64/81b4.9C209Noncomparative, single-arm, open-label trial16/2336.9No control armNo control armaPatients in the mortality analysis were followed for up to 6 months from the last recorded visit
bThese numbers account for one additional death in the bedaquiline group and 2 additional deaths in the placebo group since the end of the 120-week study and follow-up period for the C208 Stage 2 study. Thus, this accounts for the difference in mortality reported by the end of the 120-week evaluation period.
Table 7. Information on Deaths occurring during the C208 Stage 2 Trial
Group/
patientCause of death Exposure to study drug (days)Microbiologic conversionRisk factor for SAEBedaquiline4041Alcoholic poisoning109ResponderIntoxication at autopsy; 4 active drugs4153Tuberculosis168RelapseInterruption, noncompliance, cavitations, susceptible to all 5 background drugs4224Tuberculosis163Relapse< 3 active drugs, susceptible to 2 background drugs, interruption, cavitations5069Hepatic/hepatic cirrhosis168ResponderLiver cirrhosis; Recorded principal diagnosis: alcoholic liver cirrhosis; unknown susceptibility5067Septic shock/peritonitis170ResponderHeavy alcohol consumption and hepatitis (initial normal LFTs); Pre-XCR (resistant to fluoroquinolones (FQ)4399CVA168ResponderHypertension; unknown susceptibilityPlacebo4120Hemoptysis168NonconverterPre-XDR: <3 active drugs, 2 active drugs; cavitationTable 8. Information on Patients who were prematurely withdrawn and died (C208 Stage 2 Trial)
Follow-up of Withdrawn PatientsCause of Death (SAE)Exposure to study drug (days)Microbiologic ConversionRisk Factor for SAEReason for withdrawalBedaquiline4127TB-related29NonconverterCavitationsNoncompliance4145TB-related168RelapseCavitations; noncomplianceNoncompliance4464TB-related90NonconverterXDRXDR at baselinePlacebo4155TB-related165NonconverterCavitationsNoncomplianceSerious Adverse Events (SAEs)
C208 Stage 1: In addition to the death of one patient in the bedaquiline group (grade 4 myocardial infarction), two patients in the bedaquiline group experienced nonfatal SAEs (grade 4 diabetic ketoacidosis, road traffic accident).
C208 Stage 2: During the investigational treatment phase (24 week treatment with bedaquiline), six patients (7.4%) in the bedaquiline group and 1 patient (1.2%) in the placebo group had one or more SAEs. For the bedaquiline group, these included anemia, conductive deafness, bronchiectasis, pyothorax, alcohol poisoning. In the overall treatment period (24 week treatment with bedaquiline plus background regimen phase), 19 patients (24.1%) in the bedaquiline group and 15 patients (15.1%) in the placebo group experience one or more SAEs. For the bedaquiline group, these included anemia, lymphadenopathy mediastinal, conductive deafness, abdominal pain, acute pancreatitis, bronchiectasis, pneumonia, pulmonary tuberculosis, pyothorax, tuberculosis, alcohol poisoning, drug toxicity, soft tissue injury, cerebrovascular accident, hemiparesis, suicidal ideation, and hemoptysis.
C209: A total of 14 patients (6.0%) experienced SAEs during the investigational treatment period. All but one SAE was deemed unrelated to bedaquiline. One case of ECG QT prolongation occurred linked to bedaquiline use. These SAEs included vomiting, cholelithiasis, lung infection, pneumonia, tuberculosis, ECG QT prolongation, decreased appetite, dehydration, diabetes mellitus inadequate control, hyponatremia, pain in extremity, hallucination, and renal impairment. In the overall treatment period, 27 patients (11.6%) developed one or more SAE. These included vomiting and other gastrointestinal disorders, cholelithiasis and other hepatobiliary disorders, lung infection, pneumonia, tuberculosis, ECG QT prolongation, decreased appetite, dehydration, diabetes mellitus inadequate control, hyponatremia, pain in extremity, hallucination and other psychiatric disorders, and renal impairment and other renal/urinary disorders.
Common Adverse Events
T h e m o s t c o m m o n a d v e r s e r e a c t i o n s r e p o r t e d i n e"1 0 % o f p a t i e n t s t r e a t e d w i t h b e d a q u i l i n e a r e n a u s e a , a r t h r a l g i a , a n d h e a d a c h e . R e f e r t o T a b l e 9 . A d d i t i o n a l a d v e r s e e v e n t s r e p o r t e d i n e"1 0 % o f p a t i e n t s t r e a t e d w i t h b e d a q u i l i n e a n d w i t h a h i g h e r f r e q u e n c y t h an the placebo treatment group are hemoptysis and chest pain.
Table 9. Select Adverse Drug Reactions from the C208 Stage 2 Trial That Occurred More Frequently Than Placebo During Treatment with Bedaquiline
Adverse Drug ReactionsBedaquiline Treatment Group
N=79
n (%)Placebo Treatment Group
N = 81
n (%)Nausea30 (38.0)26 (32.1)Arthralgia26 (32.9)18 (22.2)Headache22 (27.8)10 (12.3)Transaminases Increased7 (8.9)1 (1.2)Blood Amylase Increased2 (2.5)1 (1.2)Hemoptysis14 (17.7)9 (11.1)Chest Pain9 (11.4)6 (7.4)Anorexia7 (8.9)3 (3.7)Rash6 (7.6)3 (3.7)Tolerability3
C208 Stage 1 Study:
Permanent discontinuations due to adverse events were not reported in the bedaquiline and placebo arm.
C208 Stage 2 Study
Permanent discontinuation due to adverse events occurred in four patients (5.1%) that received bedaquiline and five patients (6.2%) that received placebo arm
Temporary discontinuation due to adverse events occurred in 2 bedaquiline-treated patients and 3 placebo-treated patients.
C209 Study
Permanent discontinuation due to adverse events occurred in six patients (2.6%) treated with bedaquiline.
Temporary discontinuation due to adverse events occurred in four patients (1.7%) treated with bedaquiline.
Boxed Warnings1
Sdfsf
Contraindications1
None
Warnings and Precautions1
Increased Mortality: In the C208 Stage 2 study, an increased risk of death was seen with bedaquiline (9/79, 11.4%) compared to placebo (2/81, 2.5%). One death occurred during the 24 weeks of administration of Bedaquiline. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat TB, HIV status, or severity of disease could be observed. Only use bedaquiline when an effective treatment regimen cannot otherwise be provided.
QT Prolongation: Bedaquiline increases the QT interval. An ECG should be obtained prior to initiation of the drug, and at least 2, 12, and 24 weeks after starting treatment with bedaquiline. Check serum potassium, calcium, and magnesium levels at baseline and correct if necessary. Follow-up monitoring of electrolytes is needed if QT prolongation is detected. The following situations require close monitoring of ECG:
- Use with other QT prolong medications (e.g., fluoroquinolones and macrolides, clofazimine)
- History of Torsade de Pointes
- History of congenital long QT syndrome
- History of hypothyroidism and bradyarrhythmias
- History of uncompensated heart failure
- Serum calcium, magnesium, or potassium levels below the lower limits of normal
Discontinue bedaquiline and all other QT prolonging medications if the patient develops clinically significant ventricular arrhythmia or QTcF interval of > 500 ms (confirmed by repeat ECG). Monitor ECGs frequently to confirm that the QTc interval has returned to baseline. If syncope occurs, obtain an ECG to detect QT prolongation.
Hepatic-Related Adverse Drug Reactions: More hepatic-related adverse drug reactions were seen with bedaquiline plus other TB medications vs. TB medications alone. Avoid alcohol and hepatotoxic drugs while on bedaquiline, especially in patients with diminished hepatic reserve. Recommended Monitoring includes
-Monitor symptoms and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed.
-An increase of serum aminotransferase to 3xULN should be followed by repeat testing within 48 hours. Testing for viral hepatitis should be performed and other hepatotoxic medications discontinued.
-Evidence of new or worsening liver dysfunction (including clinically significant elevation of aminotransferases and/or bilirubin and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) in patients on bedaquiline should prompt additional evaluation by the prescriber.
-Discontinue bedaquiline if 1) aminotransferase elevations are accompanied by total bilirubin elevation >2xULN 2) aminotransferase elevations are >8xULN or 3) aminotransferase elevations persist beyond 2 weeks
Drug Interactions
-As bedaquiline is metabolized by CYP3A4, co-administration with CYP3A4 inducers (i.e., rifampin, rifapentine, and rifabutin) may reduce its systemic exposure and therapeutic effect. Thus, strong CYP3A4 inducers should be avoided while on bedaquiline treatment.
-Co-administration with CYP3A4 inhibitors may increase the systemic exposure and increase the risk of adverse effects with bedaquiline. Thus, while on bedaquiline therapy, patients should not use strong CYP3A4 inhibitors for greater than 14 days, unless the benefits of treatment outweigh the risks of the drug combination. Clinical monitoring for adverse effects is recommended in this situation.
HIV-TB Co-Infected patients: There is no clinical data on the combined use of bedaquiline with antiretrovirals in HIV-MDR-TB co-infected patients; there are limited data on bedaquiline use in HIV-MDR-TB co-infected patients (n=22).
Treatment Failure: Bedaquiline should be administered by DOT. Bedaquiline should be administered with at least 3 active TB drugs based on the patients isolate. If the patients fail to convert or relapse with treatment, isolates from the patient should be tested for bedaquiline minimum inhibitory concentrations.
Special Populations for Adults1-2
Pregnancy: Pregnancy Category B. This drug should only be used in pregnancy only if clearly needed.
Nursing Mothers: Unknown whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that drug is concentrated in breast milk. 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 drug to the mother.
Hepatic impairment: No dosage adjustment is necessary in mild-to-moderate hepatic impairment. It has not been studied in severe hepatic impairment patients and should be used with caution in these patients only when the benefits outweigh the risks; clinical monitoring for bedaquiline-related adverse reactions is recommended.
Renal impairment: Bedaquiline has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (< 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, bedaquiline should be used with caution
HIV Co-infection: Limited data are available on the use of in HIV co-infected patients.
Geriatric Patients: Clinical studies with bedaquiline did not have a sufficient number of patients > 65 years of age to determine whether geriatric patients respond differently than younger patients.
Postmarketing Safety Experience
No data available at this time.
Sentinel Events
No data available at this time.
Look-alike / Sound-alike (LA / SA) Error Risk Potential
As part of a Joint Commission standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from three data sources (Lexi-Comp, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion:
Table 10. Look-alike/Sound-alike Drugs
NME Drug NameLexi-CompFirst DataBankISMPClinical JudgmentBedaquiline
SirturoNone
NoneNone
NoneNone
NoneBentoquatam, Bexarotene
Sanctura
Drug Interactions1
CYP3A4 inducers
Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Co-administration of rifamycins (e.g., rifampin, rifapentine, and rifabutin) or other strong CYP3A4 inducers used systemically should therefore be avoided with bedaquiline.
CYP3A4 inhibitors
Co-administration of bedaquiline with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, the use of strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided while on bedaquiline, unless the benefit of treatment with the drug combination outweighs the risk. Appropriate clinical monitoring for bedaquiline-related adverse reactions is recommended.
Acquisition Costs
Refer to VA pricing sources for updated information.
Pharmacoeconomic Analysis
No pharmacoeconomic analysis published in the literature.
Conclusions
In conclusion, bedaquiline is indicated as part of combination therapy in adults with pulmonary MDR-TB.
Bedaquiline should only be used in situations where an effective treatment regimen cannot otherwise be provided. Bedaquiline has warning/precautions pertaining to increased mortality, QT prolongation, hepatic related drug adverse reactions, drugs interactions, co-infection with HIV and treatment failures.
References
Bedaquiline (Sirturo) Prescribing Information. Janssen Products. June 2013.
Mase S et al. Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis. MMWR Vol. 62; No. 9 October 25, 2013
FDA Review Documents. HYPERLINK "http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/204384Orig1s000TOC.cfm" http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/204384Orig1s000TOC.cfm
Chahine EB et al. Bedaquiline: A Novel Diarylquinoline for Multidrug-Resistant Tuberculosis. Annals of Pharmacotherapy. 2013:1-9.
Matteeli A, Carvalho ACC, Dooley KE, et al. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future microbiol. 2010;5(6):849-858.
Bedaquiline. Clinical trials.gov
MMWR Treatment of tuberculosis Guidelines from ATS, CDC and IDSA. 2003;52:RR-11.
Chan B et al. A review of tuberculosis: Focus on bedaquiline. Am J Health-Syst Pharm. 2013;70; 15.
Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009; 360:2397.
Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012;56(6):3271-
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