E-DRUG: E-DRUG: 4-drug fixed dose combinations for TB (cont)
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Dear TB-netters and E-druggers
I would like to comment on the important issue of recommended
strengths of anti-TB FDCs, in particular with regards to the 4-drug
FDC.
The 1998 WHO survey of the anti-TB drugs market showed that there is
a multitude of different strengths of FDCs available, and many of
these do not confirm to the strengths recommended by WHO.(1,2) This
situation may create confusion, making the prescription of the
correct treatment regimens difficult. Lack of standardization of the
strengths of FDCs will complicate the comparison of different
manufacturers' products. This may counteract the competition between
manufacturers, and possibly prevent the decrease in prices that
normally follows increased production volume.
WHO, IUATLD and collaborators are aware of the issue of
standardization of FDCs. The WHO TB Treatment Guidelines for National
tuberculosis programmes (3) and the WHO Model List of Essential Drugs
(4) includes recommendations for the 2-and 3-drug FDCs.
Recently, applications have been sent for a 4-drug FDC (R150 mg + H75
mg + Z400 mg + E275 mg) and three pediatric FDCs to be included in
the WHO Model List for Essential Drugs.
List 1 below describes all the WHO-recommended formulations of the
essential anti-TB drugs including the 4-drug FDC and the pediatric
FDCs.
The 4-drug FDC and the pediatric FDCs were recommended by the
Technical Research and Advisory Committee (TRAC), held at WHO,
Geneva, in August 1998. The recommendations for the strengths of the
these formulations were a consensus decision of world TB experts
based on bioavailability studies and the widely accepted recommended
doses (mg/kg bodyweight) for essential TB drugs as previously
published by WHO (List 2).
South Africa has registered a 4-drug FDC (R120 + H60 + Z300 + E225)
which does not comply with the WHO recommended strength of FDCs. It
does, however, comply with the WHO-recommended dose per body-weight
(List 2). Recently, a 4-drug FDC that fully complies with the WHO
recommended strengths has been submitted for registration in South
Africa. The decision on this submission is expected in the near
future.
As mentioned below by Richard, on the 27 April 1999 a meeting on
anti-TB FDCs was held in WHO, Geneva. The report from this meeting
provides information on the latest developments regarding anti-TB
FDCs and includes tables of recommended FDCs and their dosage
schedules.(5) Anyone who would be interested in this report should
feel free to contact me by email and request copies.
Best regards,
Bjorn Blomberg
Medical Officer
Communicable Diseases Cluster
World Health Organization, Geneva
Email: blombergb@who.ch
List 1. WHO-recommended strengths of formulations of essential anti-TB drugs
Rifampicin-containing FDCs for daily treatment:
RHZE: Rifampicin + isoniazid + pyrazinamide + ethambutol (Tablet) R
150 mg + H 75 mg + Z 400 mg + E 275 mg
RHZ: Rifampicin + isoniazid + pyrazinamide (Tablet) R 150 mg + H 75
mg + Z 400 mg RH: Rifampicin + isoniazid (Tablet) R 150 mg + H 75
mg, R 300 mg + H 150 mg,
Rifampicin-containing FDCs for intermittent treatment (3x weekly):
RHZ: Rifampicin + isoniazid + pyrazinamide (Tablet) R 150 mg + H 150
mg + Z 500 mg
RH: Rifampicin + isoniazid (Tablet) R 150 mg + H 150 mg
Pediatric FDCs for daily treatment:
RHZ: Rifampicin + isoniazid+ pyrazinamide (Tablet) R 60 mg + H 30 mg + Z 150 mg
RH: Rifampicin + isoniazid (Tablet, Dispersible form preferred) R 60
mg + H 30 mg
Pediatric FDCs for intermittent treatment (3x weekly):
RH: Rifampicin + isoniazid (Tablet, Dispersible form preferred) R 60
mg + H 60 mg *
Non-rifampicin containing FDCs:
TH: Thioacetazone + isoniazid (Tablet) T 50 mg + H 100 mg, T 150 mg + H 300 mg
HE: Isoniazid + ethambutol (Tablet) H 150 mg + E 400 mg
Single-drug formulations:
S - Streptomycin - (Powder for injection) 1g (as sulfate) in vial
R - Rifampicin - (Capsule or tablet) 150 mg, 300 mg
H - Isoniazid - (Tablet) 100 mg, 300 mg
Z - Pyrazinamide - (Tablet) 400 mg
E - Ethambutol - (Tablet) 100 mg, 400 mg
List 2: Recommended doses (mg/kg) for essential TB drugs
Anti-TB drug (abbreviation) - Mode of action - Recommended dose
(mg/kg) for a) daily use and b) intermittent use 3x per week and c)
2x per week*
Isoniazid (H) - Bactericidal a) 5 (4-6) b) 10 (8-12) c) 15 (13-17)
Rifampicin (R) - Bactericidal a) 10 (8-12) b) 10 (8-12) c) 10 (8-12)
Pyrazinamide (P) - Bactericidal a) 25 (20-30) b) 35 (30-40) c) 50 (40-60)
Ethambutol (E) - Bacteriostatic a) 15 (15-20) b) 30 (25-35) c) 45 (40-50)
Streptomycin (S) - Bactericidal a) 15 (12-18) b) 15 (12-18) c) 15 (12-18)
Thioacetazone (T) - Bacteriostatic a) 2.5 b+c) Not applicable
* WHO does not generally recommend twice weekly regimens. If a
patient receiving a twice-weekly regimen misses a dose of tablets,
this missed dose represents a bigger fraction of the total number of
treatment doses than if the patient were receiving a thrice weekly or
daily regimen. There is therefore a bigger risk of treatment failure.
Table 3. WHO Model List of Essential Drugs from December 1997
References:
1. Norval P, Blomberg B, Kitler M, Dye C, Spinaci S. Estimate of the
global market for fixed dose combination (FDC) tablets: Int J Tuberc
Lung Dis Supplement (in preparation), 1999.
2. Kitler ME. The fixed dose combination project. Geneva: World
Health Organization, 1998.
3. Maher D, Chaulet P, Spinaci S, Harries AD. Treatment of
tuberculosis. Guidelines for National Programmes. Geneva: World
Health Organization, 1997.
4. World Health Organization. Essential Drugs. WHO Model List
(revised in December 1997). WHO Drug Information 1998;12:22-25.
5. Laing R, Fourie B, Ellard G, et al. World Health Organization.
Fixed dose combination tablets for the treatment of tuberculosis.
Report from an informal meeting held in Geneva, Tuesday, 27 April
1999. Geneva: World Health Organization, 1999. WHO Document
WHO/CDS/CPC/TB/99.267. Available upon request from the Communicable
Diseases Country Support Team (CDS/CPC/CCS), World Health
Organization, 20 Avenue Appia, 1211 Geneva, Switzerland, fax:
+41-22-791 4199
[Thanks, Bjorn, for the overview. I only have a question about the August 1998
consensus meeting: apparently several Southern African TB programmes were not so
happy about WHO's 'heavy' tablet, and suggested that a 'light' 4-drug comb tablet
would be better dosable in the many sub-50kg TB patients in the region.
Indeed, the dose (mg per kg body weigth) is the same. Did WHO not consider the
lighter TB (and HIV+) patients a good reason to make lighter tablets which dose
better, especially sub-50 kg?
Obviously, one strength (heavy or light) would be better for all of us in the
world. But which one is easier to take and dose? WB]
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