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英文药名：Sirturo(Bedaquiline Tablets) 中文药名：贝达喹啉片 生产厂家：美国强生公司
No additional unique Adverse Reactions were identified from the uncontrolled Study 3. In both Studies 1 and 2, aminotransferase elevations of at least 3 times the upper limit of normal developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%]) than in the placebo treatment group. In Study 3, 22/230 (9.6%) patients had alanine aminotransferase or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal during the overall treatment period. Increased Mortality 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 tuberculosis-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 tuberculosis, HIV status, and severity of disease was observed. In the open-label Study 3, 6.9% (16/233) subjects died. The most common cause of death as reported by the investigator was TB (9 subjects). All but one subject who died of TB had not converted or had relapsed. The causes of death in the remaining subjects varied. 7 DRUG INTERACTIONS 7.1 CYP3A4 Inducers/Inhibitors Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4. CYP3A4 Inducers Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers should be avoided during treatment with SIRTURO [see Clinical Pharmacology (12.3)]. CYP3A4 inhibitors 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, such as ketoconazole or itraconazole, for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Clinical Pharmacology (12.3)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended. 7.2 Other Antimicrobial Medications No dose-adjustment of isoniazid or pyrazinamide is required during co-administration 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. 7.3 Antiretroviral Medications Lopinavir/ritonavir Although clinical data in HIV/MDR-TB co-infected patients on the combined use of lopinavir (400 mg)/ritonavir (100 mg) with SIRTURO are not available, use SIRTURO with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk [see Clinical Pharmacology (12.3)]. Nevirapine No dosage adjustment of bedaquiline is required when co-administered with nevirapine [see Clinical Pharmacology (12.3)]. Efavirenz Concomitant administration of bedaquiline and efavirenz, or other moderate CYP3A inducers, should be avoided [see Warnings and Precautions (5.4)]. 7.4 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 taking clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in subjects who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 8.3 Nursing Mothers 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. 8.4 Pediatric Use The safety and effectiveness of SIRTURO in pediatric patients have not been established. 8.5 Geriatric Use Because of limited data, differences in outcomes or specific risks with SIRTURO cannot be ruled out for patients 65 years of age and older. 8.6 Hepatic Impairment The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) [see Clinical Pharmacology (12.3)]. 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 (5.3)]. 8.7 Renal Impairment 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 (12.3)]. Monitor for adverse reactions of SIRTURO when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis. 10 OVERDOSAGE There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be achieved by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. 11 DESCRIPTION SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug. Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32H31BrN2O2∙C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following: SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) compared to the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation. Cardiac Electrophysiology In Study 1, the mean increases in QTcF, 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 QTcF during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study week 60. In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QTcF prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients taking SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QTcF segment duration in excess of 480 ms, whereas patients taking at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, and resulted in QTcF segment duration in excess of 500 ms in one patient. [See Warnings and Precautions (5.3)] 12.3 Pharmacokinetics Absorption After oral administration of SIRTURO 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 [700 mg single-dose (1.75 times the 400 mg loading dose)] [see Dosage and Administration (2.3)]. Administration of SIRTURO 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, SIRTURO should be taken with food to enhance its oral bioavailability. Distribution The plasma protein binding of bedaquiline is greater than 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 Liters. Metabolism 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. Elimination 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. Excretion Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. Specific Populations Hepatic Impairment: After single-dose administration of 400 mg SIRTURO to 8 patients with moderate hepatic impairment (Child-Pugh B), mean exposure to bedaquiline and M2 (AUC672h) was approximately 20% lower compared to healthy subjects. SIRTURO has not been studied in patients with severe hepatic impairment. [See Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Renal Impairment: 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%). In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO 200 mg three times per week, creatinine clearance was not found to influence the pharmacokinetic parameters of bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis bedaquiline concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly removed from plasma by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)]. Sex: In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO no clinically relevant difference in exposure between men and women were observed. Race/Ethnicity: In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO, systemic exposure (AUC) to bedaquiline was found to be 34% lower in Black patients than in patients from other race categories. This lower exposure was not considered to be clinically relevant as no clear relationship between exposure to bedaquiline and response has been observed in clinical trials of MDR-TB. Furthermore, response rates were comparable in patients of different race categories that completed 24 weeks of bedaquiline treatment. HIV Co-infection: There are limited data on the use of SIRTURO in HIV co-infected patients [see Drug Interactions (7)]. Geriatric Population: There are limited data on the use of SIRTURO in tuberculosis patients 65 years and older. In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO, age was not found to influence the pharmacokinetics of bedaquiline. Pediatric Population: The pharmacokinetics of SIRTURO in pediatric patients have not been evaluated. Drug-Drug Interactions 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 is an in vitro substrate of CYP3A4, and because of this, the following clinical drug interaction studies were performed. Ketoconazole: Co-administration of multiple-dose bedaquiline (400 mg once daily for 14 days) and multiple-dose ketoconazole (once daily 400 mg for 4 days) in healthy subjects increased the AUC24h, Cmax and Cmin of bedaquiline by 22% [90% CI (12; 32)], 9% [90% CI (-2, 21)] and 33% [90% CI (24, 43)] respectively [see Drug Interactions (7.1) and (7.4)]. Rifampin: In a drug interaction study of single-dose 300 mg bedaquiline and multiple-dose rifampin (once daily 600 mg for 21 days) in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52% [90% CI (-57; -46)] [see Drug Interactions (7.1)]. Antimicrobial agents: The combination of multiple-dose bedaquiline 400 mg once daily with multiple-dose isoniazid/pyrazinamide (300 mg/2000 mg once daily) in healthy subjects did not result in clinically relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide [see Drug Interactions (7.2)]. In a placebo-controlled study in patients with MDR-TB, no major impact of co-administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed. Lopinavir/ritonavir: In a drug interaction study in healthy volunteers of single-dose bedaquiline (400 mg) and multiple-dose lopinavir (400 mg)/ritonavir (100 mg) given twice daily for 24 days, the mean AUC of bedaquiline was increased by 22% [90% CI (11; 34)] while the mean Cmax was not substantially affected [see Drug Interactions (7.3)]. Nevirapine: Co-administration of multiple-dose nevirapine 200 mg twice daily for 4 weeks in HIV-infected patients with a single 400 mg dose of bedaquiline did not result in clinically relevant changes in the exposure to bedaquiline [see Drug Interactions (7.3)]. Efavirenz: Co-administration of a single dose of bedaquiline 400 mg and efavirenz 600 mg daily for 27 days to healthy volunteers resulted in approximately a 20% decrease in the AUCinf of bedaquiline; the Cmax of bedaquiline was not altered. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively. The effect of efavirenz on the pharmacokinetics of bedaquiline and M2 following steady-state administration of bedaquiline has not been evaluated [see Drug Interactions (7.3)]. 12.4 Microbiology Mechanism of Action SIRTURO is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis. Drug Resistance A potential for development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump have been associated with increased bedaquiline MIC values in isolates of M. tuberculosis. Cross-Resistance M. tuberculosis isolates from a clinical study in patients with MDR-TB that developed at least 4-fold increase in bedaquiline MIC were associated with upregulation of the MmpS5-MmpL5 efflux pump and were found to be cross-resistant to clofazimine. Activity In Vitro and in Clinical Infections SIRTURO has been shown to be active in vitro and in clinical infections against most isolates of M. tuberculosis [see Indications and Usage (1) and Clinical Studies (14)]. Susceptibility Test Methods In vitro susceptibility tests should be performed according to published methods1,2, and a MIC value should be reported. However, no correlation was seen between the culture conversion rates at Week 24 and baseline MICs in clinical studies (Table 2) and susceptibility test interpretive criteria for bedaquiline cannot be established at this time. A specialist in drug-resistant TB should be consulted in evaluating therapeutic options. When susceptibility testing is performed by resazurin microtiter assay (REMA, a broth microdilution method) or agar methods, a range of concentrations from 0.008 microgram per mL to 2.0 micrograms per mL should be assessed. The minimum inhibitory concentration (MIC) should be determined as the lowest concentration of bedaquiline that results in complete inhibition of growth by agar methods or the lowest concentration of bedaquiline that prevents a visible change of resazurin color from blue to pink by a broth method (REMA). All assays should be performed in polystyrene plates or tubes. Löwenstein-Jensen (LJ) medium should not be used for the susceptibility test. Bedaquiline working solution should be prepared in dimethylsulfoxide (DMSO). An inoculum of approximately 105 colony forming units/mL should be used for both liquid and solid media. The bedaquiline agar (left) and broth (REMA) (right) MIC distributions against clinical isolates resistant to isoniazid and rifampin from Studies 1, 2, and 3 are provided below. Figure 1: Bedaquiline MIC Distribution against Baseline MDRH&R-TB Isolates from Studies 1, 2, and 3 mITT Subjects: Agar Method (left) and Broth (REMA) Method (right) MICs for baseline M. tuberculosis isolates from subjects in Studies 1 and 3 and their sputum culture conversion rates at Week 24 are shown in Table 2 below. Table 2: Culture Conversion Rates (Week 24 Data Selection, No Overruling for Discontinuation) at Week 24 By Baseline Bedaquiline MIC for mITT Subjects from Study 1 and Study 3
Quality Control Susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of testing. Assays using standard bedaquiline powder should provide the following range of MIC values shown in Table 3. Table 3: Quality Control Ranges using Agar and Broth (REMA) Methods and M. tuberculosis H37Rv
13.1 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.
Patients received 24 weeks of SIRTURO or placebo for the first 24 weeks and received a combination of other antimycobacterial drugs for up to 96 weeks. Study 2 was a smaller placebo controlled study designed similarly to Study 1 except that SIRTURO or placebo was given for only 8 weeks instead of 24 weeks. Patients were randomized to either SIRTURO and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=23) or placebo and other drugs used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed MDR-TB based on subjects' baseline M. tuberculosis isolate obtained prior to randomization. The SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 8. At Weeks 8 and 24, the differences in culture conversion proportions were 38.9% (95% CI: [12.3%, 63.1%] and p-value: 0.004), 15.7% (95% CI: [-11.9%, 41.9%] and p-value: 0.32), respectively. Study 3 was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of SIRTURO as part of an individualized MDR-TB treatment regimen in 233 patients with sputum smear positive (within 6 months prior to screening) pulmonary MDR-TB. Patients received SIRTURO for 24 weeks in combination with antibacterial drugs. Upon completion of the 24 week treatment with SIRTURO, all patients continued to receive their background regimen in accordance with national TB program (NTP) treatment guidelines. A final evaluation was conducted at Week 120. Treatment responses to SIRTURO at week 120 were generally consistent with those from Study 1. 15 REFERENCES 1.Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiaceae, and other Aerobic Actinomycetes; Approved Standard – 2nd ed. CLSI document M24-A2. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087, 2011. 2.Martin A, Portaels F, Palomino JC. Colorimetric redox-indicator methods for the rapid detection of multidrug resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2007; 59 (2): 175-83. 16 HOW SUPPLIED/STORAGE AND HANDLING How supplied SIRTURO is supplied as uncoated white to almost white round biconvex 100 mg tablets with debossing of "T" over "207" on one side and "100" on the other side. The tablets are packaged in white high density polyethylene (HDPE) bottles with child-resistant polypropylene (PP) closure with induction seal liner. Each bottle contains 188 tablets. NDC 59676-701-01 Storage and handling Keep out of reach of children. Dispense in original container. Store tablets dispensed outside the original container 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). [See USP Controlled Room Temperature] 17 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. Administration Instructions 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. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1534c9ae-4948-4cf4-9f66-222a99db6d0e 美国扩大了强生公司的结核药物使用的范围 (路透社)-新的联邦指南将可能受益于治疗多重耐药结核杆菌(MDR-TB)的Johnson & Johnson公司药物Sirturo的患者人群范围扩大，这是40年来第一个获得美国审批的抗结核新药。 在美国疾病控制预防中心(CDC)发布的推荐意见中，适合人群超出了药物说明书中的所列的成人人群，给出了在儿童、孕妇及合并其他并发症(例如糖尿病、艾滋病)的患者的使用建议。 “关于如何最好地使用Sirturo的指南是随着MDR-TB比例持续增高而出台的，”在发布的CDS发病率及死亡率每周报道中，指南的首席作者CDC结核病消除分部的Dr.SundariMase说道。 虽然结核感染在美国少见，但是因为对药物监管的不到位导致出现对少数一些药外几乎所有药物都耐药的菌株，使之已经成为一个危害全球公众健康的问题。 这周发布的结合年报上，世界卫生组织称在2012年有860万患者感染结核，130万死于这一疾病。其提醒称有300万结核患者被卫生部门遗漏，耐药的超级菌株的感染已经危险到了对结核病的防控。 根据报道，2012年中27个国家共45万被MDR-TB感染，中国、印度及俄罗斯是受影响最厉害的国家。 “目前，美国是世界上唯一一个使用并推广这个药物的国家，”Mase说道，并提到中国也紧接着会开始使用。 这个药通常被称为bedaquiline，在去年十二月被美国食品药物管理局批准用于18岁以上的MDR-TB肺结核患者的联合治疗。 药物获准使用是根据已有的数据，但是在高感染风险的人群中并没有研究。 “CDS指南对于尚未研究的感染耐药性结核菌的其他患者给出了所谓“标识外”使用的建议，”Mase说道，她指出治疗结核的药物大多是“标识外”的。 “我们的专家顾问觉得缺少数据不代表不应该在这些人群中使用，如果不得到正确治疗的话可能导致真的很差的预后-死亡或严重疾病，”Mase说道。 强生公司药物的临床实验显示相比较安慰剂，治疗组的死亡风险升高。Mase说专家组仔细权衡过了数据。 在FDA批准这项药物时，其提示强生公司必需收集使用的具体数据，密切跟踪副反应发生情况。 Mase说道获得的数据并不能代表死亡是由于bedaquiline导致的 “出于存在安全考虑，大家认为如果我们仔细监测患者并能够发现严重副反应，给予快速报道并调查，没有理由因为全因死亡率的增加而限制谁使用药物，”她说道。 治疗典型TB病例是一个长期的过程，患者需要接受6个月的强有力复合抗生素治疗。很多患者不能完成治疗疗程，这是导致耐药菌株出现的一个因素。 “最重要的是要保证药物正确被使用，”强生公司Janssen部门全球药品事物领导ChrispinKambili在电话访问中说道。 Kambill说CDC指南以及世界卫生组织6月份发布的指南使用了谨慎的措辞以使这种药物不要产生耐药，耐药是很多目前存在的抗结核药物在使用多年后发生的情况。 作为结核研究的领军者之一，Kambili说：“很多人同意我们必须在新的抗结核药物使用的地方警惕这一罕见情况，这样滥用药物的风险就会变小” 新的CDC指南加了更多的条款来监测患者，并要求在实验室检查发现患有MDR-TB的患者中，使用强生公司药物至少要与4种其他药物一起使用，在诊断不清的患者至少与5种其他抗结核药物一起使用。 专家组还说对一些患者，这一药物可以使用超过24周，虽然还没有使用超过这么长疗程的研究存在。 Mase说道专家组觉得如果患者在治疗的头24周效果良好，那没有理由使用不超过24周。 指南还指明了剂量，直接观察保证治疗持续的重要性，以及医生只有在征询MDR-TB专家意见后使用这一药物的必要，这有助于CDC密切关注这一药物怎么被使用。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
