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ATC codes: J01XX08
EMLc
Indication
Multi-drug resistant tuberculous Mycobacterium ICD11 code: ML32.00
INN
Linezolid
Medicine type
Chemical agent
Antibiotic groups
List type
Complementary
Formulations
Parenteral > General injections > IV: 2 mg per mL in 300 mL bag
Oral > Liquid: 100 mg per 5 mL powder for oral liquid
Oral > Solid: 400 mg tablet ; 600 mg tablet
EML status history
First added in 2015 (TRS 994)
Sex
All
Age
Also recommended for children
Therapeutic equivalence
The recommendation is for this specific medicine
Patent information
Main patents have expired but secondary patents might remain active in some jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPal.org
Wikipedia
DrugBank
Expert Committee recommendation
Taking into consideration the significant public health need for new and effective treatments for MDR-TB, pre-XDR-TB and XDR-TB, the available data on effectiveness and safety for linezolid, and WHO guidelines for the programmatic management of drug-resistant tuberculosis, the Expert Committee recommended that linezolid be added to the complementary list of the EML and EMLc for the treatment of MDR/XDR-TB. The Committee considered that inclusion of linezolid on the EML and EMLc had the potential to promote availability of effective treatment combinations in countries with a heavy MDR/XDR-TB burden. The Committee recommended that linezolid should be reserved for use as part of a WHO-recommended MDR/XDR-TB regimen in patients for whom there are few or no other treatment alternatives. In addition, the Committee considered that linezolid should be introduced only in settings where close monitoring of patients and active pharmacovigilance can be ensured.
Background
Linezolid is an oxazolidinone antibiotic indicated in adults and children for treatment of infections caused by susceptible Gram-positive bacteria e.g. hospital- and community-acquired pneumonia, skin and soft tissue infections and vancomycin-resistant Enterococcus faecium infections. It is classified as a Group 5 second-line antituberculosis medicine in WHO’s guidelines for programmatic management of drug-resistant tuberculosis (1). WHO guidelines also recommend linezolid as an option for treatment of MDR/XDR-TB when adequate treatment regimens cannot be constructed with medications from other groups (2). Linezolid is used “off label” for the treatment of MDR/XDR‐TB.
Public health relevance
The Committee recognized there is an urgent and unmet public health need in the case of MDR-TB, that the evaluation of new drugs for this disease is a fast-moving field, and that current data related to toxicity are limited. The Expert Committee therefore recommended that linezolid be reviewed on an ongoing basis and considered at its next meeting as part of a review of the antituberculosis medicines section.
Benefits
Data regarding the effectiveness of linezolid for the treatment of MDR/XDR-TB are limited. However, on the basis of its documented activity against M. tuberculosis, both in vitro and in animal studies, linezolid has been used in salvage cases, to treat patients with extensive drug resistance or intolerance (3-5). Linezolid has been studied in RCTs (5-7) and in several retrospective and prospective case series (8-10) and further evaluated in meta‐analyses of MDR-TB and XDR‐TB patients (11, 12). In several countries linezolid has proved effective in achieving culture conversion in refractory XDR-TB. The overall percentage of patients with treatment success varied between 68% and 100% depending on the study and the outcome (sputum or culture conversion).
Harms
Adverse events attributable to linezolid occurred in approximately two thirds of patients (6, 12). In some cases adverse events resolved quickly while in others (15–25% of patients) they required reduction of the linezolid dosage or interruption of treatment. The main adverse events – occurring in more than 10% of cases – were anaemia, peripheral neuropathy, gastrointestinal disorders, optic neuritis and thrombocytopenia (12). The risk of adverse events increases as linezolid dose increases (11, 12). Acquired drug resistance to linezolid has also been observed (6).
Additional evidence
Published data on children are limited; they derive from case reports and small cohort studies and relate to fewer than 20 children. Most children on linezolid had culture conversion, generally within 1–3 months, and successful long-term outcome. One was lost to follow-up and there was one death (respiratory failure, culture-negative at the time of death). While some pharmacokinetic data are available, additional data are needed with regard to paediatric dosing of linezolid in MDR-TB, particularly for linezolid used in combination with medications that have similar adverse effects.
Cost / cost effectiveness
With regard to price, the Expert Committee noted that, in 2012, in countries where linezolid is patent-protected it was priced at approximately US$ 2500 per month of treatment (at a dose of 600 mg daily) (11). In India, where linezolid is not patented, the generic product is priced at US$ 50–70 per month. Linezolid is currently available through the Global Drug Facility of the Stop TB Partnership at a cost of US$ 107.00–109.60 for 20 x 600 mg tablets.
Other considerations
The Committee discussed the “off label” use of linezolid for the treatment of MDR/XDR‐TB. The Committee considered that the available evidence supporting this use of linezolid, while limited, was adequate, particularly considering the urgent public health need for effective later-line treatments for MDR/XDR-TB. The Committee also noted that, in some settings, it is recommended that use of linezolid for its licensed indications be reserved because of its potential for use in XDR-TB (13). To date, inclusion of linezolid on the EML/EMLc for its licensed indications has not been considered by the Expert Committee.
1. Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update. Geneva: World Health Organization; 2011. 2. Companion handbook to the WHO guidelines for the programmatic management of drugresistant tuberculosis Geneva: World Health Organization; 2014. Available from: http://www.who.int/tb/publications/pmdt_companionhandbook/en/ 3. Alcala L, Ruiz-Serrano MJ, Perez-Fernandez Turegano C, Garcia De Viedma D, Diaz-Infantes M, Marin-Arriaza M, et al. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother. 2003;47(1):416-7. 4. Cynamon MH, Klemens SP, Sharpe CA, Chase S. Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother. 1999;43(5):1189-91. 5. Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, et al. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008;178(11):1180-5. 6. Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-18. 7. Tang S, Yao L, Hao X, Zhang X, Liu G, Liu X, et al. Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China. Eur Respir J. 2015;45(1):161-70. 8. Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S. Linezolid in the treatment of multidrugresistant tuberculosis. Clin Infect Dis. 2010;50(1):49-55. 9. Tangg SJ, Zhang Q, Zheng LH, Sun H, Gu J, Hao XH, et al. Efficacy and safety of linezolid in the treatment of extensively drug-resistant tuberculosis. Jpn J Infect Dis. 2011;64(6):509-12. 10. Xu HB, Jiang RH, Li L, Xiao HP. Linezolid in the treatment of MDR-TB: a retrospective clinical study. Int J Tuberc Lung Dis. 2012;16(3):358-63. 11. Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012;16(4):447-54. 12. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40(6):1430-42. 13. Gupta D, Agarwal R, Aggarwal AN, Singh N, Mishra N, Khilnani GC, et al. Guidelines for diagnosis and management of community- and hospital-acquired pneumonia in adults: Joint ICS/NCCP(I) recommendations. Lung India. 2012;29(Suppl 2):S27-62.