Export

EN
FR
ATC codes: J04AB01
Indication
Multi-drug resistant tuberculous Mycobacterium ICD11 code: ML32.00
INN
Cycloserine
Medicine type
Chemical agent
Antibiotic groups
List type
Complementary Terizidone may be an alternative
Formulations
Oral > Solid: 250 mg solid oral dosage form
EML status history
First added in 1999 (TRS 895)
Changed in 2003 (TRS 920)
Changed in 2007 (TRS 950)
Changed in 2015 (TRS 994)
Sex
All
Age
Adolescents and adults
Therapeutic equivalence
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Wikipedia
DrugBank
Expert Committee recommendation
Taking into consideration the significant public health need for new and effective treatments for multidrug-resistant tuberculosis (MDR-TB), pre-extensively-drug resistant tuberculosis (XDR-TB) and XDR-TB, the available data on effectiveness and safety of terizidone and cycloserine, and WHO guidelines for the programmatic management of drug-resistant tuberculosis, the Expert Committee recommended that terizidone should be included on the complementary list of the EML as an alternative to cycloserine for the treatment of MDR/XDR-TB. The Committee recommended that this be indicated as a note alongside the current cycloserine listing. The Expert Committee recommended that terizidone be reserved for use as part of a WHO-recommended M/XDR-TB regimen in patients for whom there are few or no other treatment alternatives. In addition, the Committee considered that terizidone should be introduced only in settings where close monitoring of patients and active pharmacovigilance can be ensured.
Background
Terizidone is an antibiotic and a structural analogue of cycloserine, with a similar mode of action. It is used in place of cycloserine in some tuberculosis centres. Cycloserine is currently included in the complementary list of the EML and EMLc. Both cycloserine and terizidone are classified as oral bacteriostatic second‑line anti-TB drugs in WHO guidelines for the programmatic management of drug-resistant tuberculosis (1).
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 in this disease is a fast-moving field, and that current data related to toxicity are limited. The Expert Committee therefore recommended that terizidone be reviewed on an ongoing basis and considered at its next meeting as part of a review of the antituberculosis medicines section.
Benefits
There is scant evidence concerning terizidone in treatment of MDR-TB or XDR-TB. All studies are observational; most use a retrospective cohort design and describe use of multiple different drugs together in individualized treatment. Because treatment was individualized, one drug may have contributed more than others to bacteriological improvement and to final treatment outcomes. The percentage of included patients with MDR-TB varied: one study included no MDR-TB patients and one included only XDR patients. Very few of these studies provided data that allow comparison of treatment outcomes in those who received or did not receive one or another of the drugs of interest. A large meta-analysis of individual data for more than 9000 patients, assessing the role of individual drugs, is of only limited value since terizidone was given to just 12 patients at a single centre (2). It does show, however, that the use of cycloserine, as part of multidrug regimens, was significantly associated with treatment success (compared with failure, relapse or death). Given that terizidone is a structural analogue of cycloserine, the Expert Committee considered it was reasonable to assume that the two medicines have similar effects.
Harms
The assessment and reporting of adverse events in studies were limited. The data collection was not standardized, and validated systems to grade events were not used. Adverse events were common but were not attributed to a specific drug; estimates of toxicity due to specific drugs are thus extremely uncertain. A recent systematic review analysed the occurrence of adverse events with cycloserine and terizidone. Serious adverse events, mostly psychiatric and neurological, were similar in frequency and type for the two drugs (3).
Cost / cost effectiveness
Terizidone is currently available through the Global Drug Facility of the Stop TB Partnership at a cost of US$ 79.40 to 83.30 for 50 x 250 mg capsules.
Other considerations
The Committee did not recommend inclusion of terizidone on the EMLc at this time, recognizing that there are limited data on the use of terizidone in children and on how it compares with cycloserine, particularly in relation to adverse effects. The lack of a child-friendly dose form of terizidone was also noted. The Expert Committee recommended that evidence on the use and effects of terizidone in paediatric patients be reviewed at its next meeting.
1. Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update. Geneva: World Health Organization; 2011. 2. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. 3. Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. Int J Tuberc Lung Dis. 2013;17(10):1257-66.