Bedaquiline

525.487

555.50

1308068-626-2

White solid

45.6

log Kow = 7.74 (est)

1.3±0.1 g/cm3

104 °C

378.8±32.9 °C

1.666

Insoluble

Tablets dispensed outside the original container should be stored in a tight light-resistant container with an expiration date not to exceed 3 months. Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).

3.66X10-16 mm Hg at 25 °C (est)

Specific optical rotation: -166.98 deg at 20 °C/D (c = 0.505 in dimethyl formamide)

Henry's Law constant = 4.41X10-18 atm-cu m/mol at 25 °C (est)

pKa1 = 1.57 (imine); pKa2 = 8.91 (amine); pKa3 = 13.61 (hydroxyl) (est)

White to almost white powder; practically insoluble in aqueous media/Bedaquiline fumarate/|White solid /Bedaquiline fumarate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including bedaquiline fumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Bedaquiline fumarate/

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P260, P264, P270, P273, P301+P310, P314, P321, P330, P391, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

IDENTIFICATION AND USE: Bedaquiline is a white solid. It is used as a antitubercular medication. HUMAN EXPOSURE AND TOXICITY: An increased risk of death was observed in patients receiving bedaquiline in a placebo-controlled clinical trial. In this study, there were 9 deaths in bedaquiline-treated patients; one death occurred during the 24 weeks of bedaquiline therapy and the median time to death for the other 8 patients was 329 days after the last dose of bedaquiline. Five of the 9 deaths in bedaquiline-treated patients and both deaths in placebo-treated patients were related to tuberculosis. The explanation for the imbalance in deaths in this study is not known; no correlation was demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity. Bedaquiline and the M2 metabolite are cationic amphiphilic substances and induce phospholipidosis. The cells of the monocytic phagocytic system are affected in all species. Data from in vitro studies using human monocyte cell-line indicated that the phospholipidogenic potential was highest for the M2 metabolite followed by M3 and the parent compound. ANIMAL STUDIES: In mouse and rat, single oral doses of 800 mg/kg produced lethality preceded by signs of general toxicity. Mortalities in mouse and dog after single and repeated doses were principally attributed to skeletal muscle/myocardial degeneration and/or pancreatitis. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. In embryofetal toxicity studies conducted in rat and rabbit bedaquiline appeared to have no adverse effects on the embryonal development and the incidence of variations and malformations in fetuses in bedaquiline groups were within normal ranges. Exposure to bedaquiline and the M2 metabolite in rat at the high dose was considerable (up to 6-7 times higher compared with expected human exposure), while in rabbit a maximum exposure ratio of 2 were achieved. However, in rabbit the high dose of 100 mg/kg caused deaths, one abortion and increases in pre and postimplantation losses. Bedaquiline had no effect on fertility in females up to the highest dose tested, 24 mg/kg. Male fertility appeared to be decreased with a NOAEL of 5 mg/kg. 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.

Liver test abnormalities occur in 8% to 12% of patients treated with multiple drug regimens that include bedaquiline. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications accounts for the abnormalities, but monitoring of liver tests at monthly intervals is recommended during bedaquiline therapy. Clinically apparent liver injury has been reported with bedaquiline therapy, but the clinical features, course and outcome of these cases has not been described. At least three deaths from end stage liver disease have been described in patients taking bedaquiline, but the attribution of the hepatic failure to bedaquiline has been questioned. The management of multidrug resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy.

Pharmacologic interaction (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may result in additive or synergistic effects on the QT interval.|Bedaquiline is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4. Concomitant use of bedaquiline with potent inhibitors of CYP3A4 (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of bedaquiline and increase the risk of adverse effects associated with the drug. Concomitant use of bedaquiline and systemic drugs that are potent inhibitors of CYP3A4 for a duration longer than 14 consecutive days should be avoided, unless the benefits of concomitant use outweigh the risks. Patients receiving such concomitant therapy should be monitored for bedaquiline-related adverse effects. Concomitant use of bedaquiline with potent inducers of CYP3A4, including rifamycins (e.g., rifampin, rifapentine, rifabutin), may reduce the AUC of bedaquiline and decrease the therapeutic effects of the drug. Concomitant use of bedaquiline with rifamycins or other potent inducers of CYP3A4 should be avoided.|Because concomitant use of bedaquiline and fluoroquinolones may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy.|Because concomitant use of bedaquiline and macrolides may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy.|For more Interactions (Complete) data for Bedaquiline (13 total), please visit the HSDB record page.

Bedaquiline has not been studied in patients with severe hepatic impairment. The drug should be used with caution in patients with severe hepatic impairment and only when the benefits outweigh the risks; such patients should be monitored for adverse effects.|Bedaquiline should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis.

EXPERIMENTAL: Bedaquiline is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

Bedaquiline is a diarylquinoline antimycobacterial drug used in combination with other antituberculosis medications in the treatment of multidrug resistant tuberculosis. The addition of bedaquiline to antituberculosis drug regimens has been linked to an increased rate of transient serum liver test abnormalities during treatment and to several instances of clinically apparent liver injury.

Antituberculosis Agents

Antitubercular Agents|Sirturo is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (= 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve Sirturo for use when an effective treatment regimen cannot otherwise be provided. Sirturo should be administered by directly observed therapy (DOT). This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB. /Included in US product label/|The safety and efficacy of Sirturo for the treatment of latent infection due to Mycobacterium tuberculosis have not been established. The safety and efficacy of Sirturo for the treatment of drug-sensitive TB have not been established. In addition, there are no data on the treatment with Sirturo of extra-pulmonary TB (e.g., central nervous system). The safety and efficacy of Sirturo for the treatment of infections caused by non-tuberculous mycobacteria (NTM) have not been established. Therefore, use of SIRTURO in these settings is not recommended.|For the first time in over 40 years, a new tuberculosis (TB) drug with a novel mechanism of action - bedaquiline - is available, and was granted accelerated approval by the United States Food and Drug Administration in December 2012. There is considerable interest in the potential of this drug to treat multidrug-resistant tuberculosis (MDR-TB). However, information about this new drug remains limited. It has only been through two Phase IIb trials for safety and efficacy. WHO is therefore issuing "interim policy guidance". This interim guidance provides advice on the inclusion of bedaquiline in the combination therapy of MDR-TB in accordance with the existing WHO Guidelines for the programmatic management of drug-resistant TB (2011 Update). The interim guidance lists five conditions that must be in place if bedaquiline is used to treat adults with MDR-TB: 1.Effective treatment and monitoring: Treatment must be closely monitored for effectiveness and safety, using sound treatment and management protocols approved by relevant national authorities. 2.Proper patient inclusion: Special caution is required when bedaquiline is used in people aged 65 and over, and in adults living with HIV. Use in pregnant women and children is not advised. 3.Informed consent: Patients must be fully aware of the potential benefits and harms of the new drug, and give documented informed consent before embarking on treatment. 4.Adherence to WHO recommendations: All principles on which WHO-recommended MDR-TB treatment regimens are based, must be followed, particularly the inclusion of four effective second-line drugs. In line with general principles of TB therapeutics, bedaquiline alone should not be introduced into a regimen in which the companion drugs are failing to show effectiveness. 5.Active pharmacovigilance and management of adverse events: Active pharmacovigilance measures must be in place to ensure early detection and proper management of adverse drug reactions and potential interactions with other drugs. WHO strongly recommends the acceleration of Phase III trials to generate a more comprehensive evidence base to inform future policy on bedaquiline. The Organization will review, revise, or update the interim guidance as additional information on efficacy and safety become available.|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 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500). ... This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline 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. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals who might use bedaquiline for the treatment of MDR TB for indicated and off-label uses. Aspects of these guidelines are not identical to current FDA-approved labeling for bedaquiline. Bedaquiline should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged =18 years with a diagnosis of pulmonary MDR TB (Food and Drug Administration. Sirturo [bedaquiline] tablets label. ... Use of the drug also can be considered for individual patients in other categories (e.g., persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions) when treatment options are limited. However, further study is required before routine use of bedaquiline can be recommended in these populations. A registry for persons treated with bedaquiline is being implemented by ... to track patient outcomes, adverse reactions, laboratory testing results (e.g., diagnosis, drug susceptibility, and development of drug resistance), use of concomitant medications, and presence of other comorbid conditions. Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported ... .

/BOXED WARNING/ WARNINGS: 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. Only use Sirturo when an effective treatment regimen cannot otherwise be provided. QT prolongation can occur with Sirturo. Use with drugs that prolong the QT interval may cause additive QT prolongation.|A higher incidence of adverse hepatic effects has been reported in patients receiving antituberculosis regimens containing bedaquiline compared with patients receiving regimens that did not contain the drug. Based on data from 2 clinical trials, reversible increases in serum aminotransferase concentrations to at least 3 times the upper limit of normal (ULN) were reported in 10.8 or 5.7% of patients receiving bedaquiline or placebo, respectively. Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) should be monitored at baseline, monthly during treatment, and as needed. Patients also should be monitored for symptoms of hepatic dysfunction. If signs or symptoms of new or worsening liver dysfunction (e.g., clinically important elevation in serum aminotransferases and/or bilirubin, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) develop, the patient should be promptly evaluated. If AST or ALT increase to greater than 3 times the ULN, liver function tests should be repeated within 48 hours. In addition, patients should be tested for viral hepatitis and other hepatotoxic drugs should be discontinued. Bedaquiline should be discontinued if elevated serum aminotransferase concentrations are accompanied by total bilirubin concentrations exceeding 2 times the ULN, serum aminotransferase concentrations exceed 8 times the ULN, or elevated aminotransferase concentrations persist for more than 2 weeks. Alcohol and other hepatotoxic drugs or herbal products should be avoided in patients receiving bedaquiline, especially in those with diminished hepatic reserve.|Prolongation of the QT interval has occurred in patients receiving bedaquiline. Concomitant use of bedaquiline with other drugs associated with QT interval prolongation may result in additive or synergistic effects on the QT interval. Documented cases of torsades de pointes have not been reported to date in patients receiving bedaquiline.|Safety and efficacy of bedaquiline have not been established in patients younger than 18 years of age.|For more Drug Warnings (Complete) data for Bedaquiline (10 total), please visit the HSDB record page.

The antileprosy drug clofazimine is also of interest for the treatment of multidrug-resistant tuberculosis. To understand possible resistance mechanisms, clofazimine-resistant Mycobacterium tuberculosis mutants were isolated in vitro, and, unexpectedly, found to be cross-resistant to bedaquiline. Mutations in the transcriptional regulator Rv0678, with concomitant upregulation of the multisubstrate efflux pump, MmpL5, accounted for this cross-resistance. Mutation in Rv0678 should therefore be considered a confounding factor for the treatment of tuberculosis with clofazimine or bedaquiline.

Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.|Bedaquiline is distributed into milk in rats; it is not known whether the drug is distributed into human milk.|The plasma protein binding of bedaquiline is > 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L.|After oral administration bedaquiline maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied in healthy volunteers (700 mg single-dose and once daily 400 multiple doses). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, bedaquiline should be taken with food to enhance its oral bioavailability.|For more Absorption, Distribution and Excretion (Complete) data for Bedaquiline (10 total), please visit the HSDB record page.

CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.|After a single dose the mean AUC0-24 hr of the major metabolite M2 was 2 to 7-fold higher than AUC0-24 hr of bedaquiline in mice and was generally similar to 2-fold lower in rats and dogs.|Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 uM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.|No chiral conversion of bedaquiline occurred in vivo after administration of bedaquiline to mice, rats, dogs, monkeys and humans. In hepatocytes and subcellular fractions from preclinical species and humans, the in vitro metabolism of (14)C-bedaquiline was via Phase I reactions and the most important pathway was N-demethylation to M2, which was followed by a second N-demethylation to M3, oxidation and epoxidation. M2 was the major circulating metabolite in all preclinical species as determined by radioactivity profiling and LC-MS/MS in the animals. No mass balance study with radiolabelled bedaquiline has been conducted in humans. It can therefore not be excluded that additional undetected metabolites may be formed in humans that are not formed in the animal species. M2-AUC0-24 hr plasma levels were generally comparable to 2-fold lower than those of bedaquiline in rats and dogs upon repeated administration of bedaquiline, and 3.5- to 4.5-fold lower in human subjects with MDR-TB. In addition to M2 and M3, a hydroxylated derivative of M2 (M20) and a dihydrodiol derivative of M2 (M11), were detected in human plasma. These two metabolites were also found in rats and dogs at similar relative concentrations.

The plasma concentration-time profiles of bedaquiline showed a multi-phasic decline with a long terminal elimination half life ranging from 2 to 3 days in mice, 3 to 5 days in male rats, 6 to 9 days in female rats and monkeys and up to 50 days in dogs.|The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months.

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3-4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival.|Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.|Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 /bedaquiline/ is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|There is no experience with the treatment of acute overdose with Sirturo. General measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) should be taken in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be achieved by gastric lavage or aided by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.

/EPIDEMIOLOGY STUDIES/ An increased risk of death was observed in patients receiving bedaquiline in a placebo-controlled clinical trial (11.4 versus 2.5%, based on data through week 120). In this study, there were 9 deaths in bedaquiline-treated patients; one death occurred during the 24 weeks of bedaquiline therapy and the median time to death for the other 8 patients was 329 days after the last dose of bedaquiline. Five of the 9 deaths in bedaquiline-treated patients and both deaths in placebo-treated patients were related to tuberculosis. The explanation for the imbalance in deaths in this study is not known; no correlation was demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity.|/ALTERNATIVE and IN VITRO TESTS/ Bedaquiline and the M2 metabolite are cationic amphiphilic substances (CADs) and induce phospholipidosis. The cells of the monocytic phagocytic system (MPS) are affected in all species. Data from in vitro studies using human monocyte cell-line indicated that the phospholipidogenic potential was highest for the M2 metabolite followed by M3 and the parent compound.

Oral: Tablets 100 mg (of bedaquiline), Sirturo (Janssen). /Bedaquiline fumarate/