The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
The Expert Committee did not recommend the addition of gatifloxacin to the
Complementary List of the EML and EMLc as a reserve second-line drug for the treatment of
multidrug-resistant tuberculosis. The Committee noted that gatifloxacin, in short therapy
regimens, did not show superiority in benefit–harm ratio to alternative fluoroquinolones
currently listed on the EML and EMLc (levofloxacin and moxifloxacin).
The application requested addition of gatifloxacin to the Complementary List of the
EML and EMLc as a reserve second-line drug for the treatment of multidrug-resistant
The 2016 update of the WHO treatment guidelines for drug-resistant tuberculosis positions
gatifloxacin as an alternative to other fluoroquinolones (specifically levofloxacin and
moxifloxacin) in Group A. Gatifloxacin may be included as part of both shorter regimens
for multidrug-resistant tuberculosis (MDR-TB) and longer regimens for MDR-TB and
extensively drug-resistant TB (XDR-TB) (1, 2).
Currently, the EML and EMLc include the fluoroquinolone, levofloxacin, for this indication,
with an asterisk and a note specifying that ofloxacin and moxifloxacin may be alternatives
based on availability and programme considerations. Ofloxacin was proposed for removal
from the Model Lists in a separate application to this meeting on the basis that it is no
longer recommended in the updated WHO treatment guidelines.
Public health relevance
It is estimated that 580 000 patients develop rifampicin-resistant or MDR-TB globally each
year and would need second-line TB treatment regimens to increase the likelihood of a
successful treatment outcome (3). In many low-resource settings, there are often too few
medicines available to compose a suitable regimen for drug-resistant TB, and stock-outs
of second-line drugs occur regularly (3).
Gatifloxacin was a mainstay fluoroquinolone of the shorter MDR-TB regimen until a
global shortage of quality-assured formulations of the medicine occurred following
safety concerns (4). Clinicians had to replace gatifloxacin with other later-generation
fluoroquinolones in both shorter and longer MDR-TB regimens. Given that gatifloxacin is
cheaper to manufacture than other later-generation fluoroquinolones, the inclusion of
gatifloxacin on the EML should encourage pharmaceutical manufacturers to produce this
A review of the available evidence for the effectiveness of, and adverse reactions to,
gatifloxacin was undertaken for the 2016 revision of the WHO treatment guidelines for
MDR-TB (1). The GRADE table of the evidence was presented in Annex 2 of the application
and the findings are summarized below.
There are few data on the effectiveness of gatifloxacin in either conventional 24-month
MDR-TB regimens or shorter MDR-TB regimens. Four observational studies were presented
(5–8); all were assessed as being of very low quality. The studies reported treatment success
versus failure, relapse or death in gatifloxacin-treated patients versus no gatifloxacin in
rifampicin-resistant or MDR-TB. (In the no gatifloxacin group, the other fluoroquinolone
used was ofloxacin, levofloxacin or moxifloxacin.) Treatment success was reported as 84%
for regimens with gatifloxacin compared with 64.9% for regimens without (relative benefit
not estimable; absolute effect 191 more successes per 1000; 95% confidence interval (CI)
Deaths among patients treated with gatifloxacin (2.7%) were lower than those in patients
who received another fluoroquinolone or no fluoroquinolone (8.6%), suggesting improved
outcome rather than any risk of excess mortality in patients exposed to gatifloxacin
(relative benefit not estimable; absolute effect 59 fewer per 1000; 95% CI 20–99).
Safety data were derived from five observational studies (5, 9–12). Serious adverse events
(Grade 3 or 4 or treatment stopped because of adverse effects) were reported in 3.6% of
gatifloxacin-treated patients compared with 8% of patients given treatments that did not
include gatifloxacin (relative and absolute effects were not estimable). Adverse events are
likely to be incompletely reported in some of the studies included in the review.
Reports of blood glucose disorders in patients treated with gatifloxacin for conditions
other than drug-resistant TB led the manufacturer to stop production of the drug in 2006
(4). Reports of severe dysglycaemia, hypoglycaemia and hyperglycaemia and diabetes led
to some countries removing gatifloxacin from their national formularies. A global shortage
in quality-assured formulations of this medicine ensued, with consequent negative
impacts on MDR-TB treatment regimens that included gatifloxacin. More recent reports of
treatment regimens for drug-susceptible TB that included gatifloxacin (400 mg once daily)
have shown no significant risk of hyperglycaemia associated with exposure (13).
Cost / cost effectiveness
A restart of the manufacture of quality-assured formulations of the medicine could
substantially lower the costs of TB treatment regimens by substituting for more expensive
The application suggested that gatifloxacin could be an important component of both
the intensive and the continuation phase of the shorter MDR-TB regimen recommended
by WHO (1, 2). The regimen is usually composed of pyrazinamide, ethambutol, isoniazid,
gatifloxacin (or moxifloxacin), kanamycin (or amikacin), protionamide (or ethionamide)
and clofazimine for 4 months (extended to 6 months in case of failure of sputum
conversion), followed by a continuation phase of pyrazinamide, ethambutol, gatifloxacin
(or moxifloxacin), and clofazimine for 5 months. Since May 2016, WHO has recommended
the shorter MDR-TB regimen in selected patients; gatifloxacin could thus have a central
role in a regimen that is offered to patients as a standard of care unless they have specific
exclusion criteria. Moreover, gatifloxacin could be the fluoroquinolone of choice for the
longer regimens for both MDR-TB and XDR-TB, which are usually composed of pyrazinamide
plus at least four second-line anti-TB drugs considered to be effective, including a latergeneration
fluoroquinolone, a second-line injectable, and two or more of: ethionamide (or
protionamide), cycloserine, linezolid or clofazimine.
In August 2012, WHO advised countries to introduce shorter MDR-TB regimen only under
operational research conditions, subject to the approval of a national ethics review and
with an appropriate assessment of the effectiveness and safety of treatment. In May
2016, following a review of evidence that accrued from such studies, WHO conditionally
recommended the use of a shorter MDR-TB regimen under normal programmatic conditions
in patients who fulfil the eligibility criteria for this treatment.
Generic manufacturers in India and Bangladesh are known to produce gatifloxacin tablets
for export; however, these manufacturers are not yet quality-assured. In October 2016,
WHO added gatifloxacin to the list of anti-TB medicines for which manufacturers will be
invited to submit an Expression of Interest for Active Pharmaceutical Ingredient (API) or
Finished Pharmaceutical Products to the WHO Prequalification Team. It is expected that a
number of manufacturers will respond to this invitation.
Listing of gatifloxacin was proposed as an alternative fluoroquinolone to levofloxacin and
moxifloxacin which are already included as reserve second-line medicines on the EML and
With the recommended deletion of ofloxacin, separate EML listings could be considered for
fluoroquinolones recommended as Group A alternatives in the updated WHO guidelines.
1. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. Geneva: World Health
Organization; 2016 (http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/
en/, accessed 10 February 2017).
2. Companion handbook to the WHO guidelines for the programmatic management of drugresistant
tuberculosis. Geneva: World Health Organization; 2014 (http://apps.who.int/iris/
bitstream/10665/130918/1/9789241548809_eng.pdf, accessed 10 February 2017).
3. Global tuberculosis report 2016. Geneva: World Health Organization; 2016 (http://apps.who.int/iris/bi
tstream/10665/250441/1/9789241565394-eng.pdf?ua=1, accessed 10 February 2017).
4. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C et al. Outpatient gatifloxacin
therapy and dysglycemia in older adults. N Engl J Med. 2006;354(13):1352–61.
5. Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P et al. Short, highly effective, and
inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med.
6. Butov DA, Efremenko YV, Prihoda ND, Yurchenko LI, Sokolenko NI, Arjanova OV et al. Adjunct immune
therapy of first-diagnosed TB, relapsed TB, treatment-failed TB, multidrug-resistant TB and TB/HIV.
7. Xu HB, Jiang RH, Xiao HP. Clofazimine in the treatment of multidrug-resistant tuberculosis. Clin
Microbiol Infect. 2012;18(11):1104–10.
8. 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.
9. Carroll MW, Lee M, Cai Y, Hallahan CW, Shaw PA, Min JH et al. Frequency of adverse reactions to
first- and second-line anti-tuberculosis chemotherapy in a Korean cohort. Int J Tuberc Lung Dis.
10. Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, Venkatesan P et al.
Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in
the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One. 2013;8(7):e67030.
11. Jo KW, Lee SD, Kim WS, Kim DS, Shim TS. Treatment outcomes and moxifloxacin susceptibility in
ofloxacin-resistant multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2014;18(1):39–43.
12. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T et al. A Phase II study of the
sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc
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13. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T et al. A four-month gatifloxacin-containing
regimen for treating tuberculosis. N Engl J Med. 2014;371(17):1588–98.