STOP MUTATION

WITH FIXED-DOSE
COMBINATION (FDCs)

Priyanti Z Soepandi
Dept.of Respiratory Medicine Faculty of Medicine,
University of Indonesia, Persahabatan Hospital,
Jakarta
INTRODUCTION
 Tuberculosis (TB) has been a scourge of
mankind for thousand of years
 One of the largest heath problems in the
world
 Estimated 8 million new cases & at least 2
million death every year
 The emergence of MDR-TB  difficult &
expensive
 HIV has led to exponential increase TB cases
over recent years
Mutation
 In early clinical trial in which 173 patients were
treated with INH alone, resistant bacilli were found in
52% at second month and 71% at the end of third
month
 If only one tuberculosis drug is used, multiplication of
drug resistance strains occurs. This can be easily
avoided if combination therapy is used from the
commencement of treatment
 The differing actions of tuberculosis drugs provides a
theoretical basis for modern tuberculosis
chemotherapy

The used of antibiotics 5th edition

  Primary Resistance
 Drug resistance among new cases.
 Never received TB drugs or received them for < 1
month.
 Initial culture.

 Secondary (Acquired) Resistance

 Drug resistance in a patient who previously
received at least 1 month of TB therapy.

WHO/IUATLD Global Project Drug-Resistance Surveillance Report No. 2

How is MDR Tubeculosis produced?

Drug resistant bacilli are the consequence of

the following human errors:

 prescription of chemotherapy

 management of drug supply  inhibited by the use of FDCs

 case management

 process of drug delivery to the patient.

FIXED-DOSE COMBINATION
 Use of 2,3 & 4 drugs FDCs does not replace
proper case management & DOT
 Many advantages of FDCs
 WHO& IUTLD have recommended the use of
4 FDCs of proven bioavailability since 1994
but they are so far little used
 1999: WHO model List of Essential Drugs
(EDL) was updated to include 4 FDCs
 The end 1999: FDCs for children
Reduces risk of multi-drug
resistant TB (MDR-TB)
 Health care provider is restricted from
giving other dosages if FDCs are used
 Prevents monotherapy: patient receives
all the drugs at one time in a single
dose
 Health centre cannot run out of one of
the drugs since all are contained in a
single tablet
FDCs versus single drug
formulations
 Multidrug therapy is necessary to cure
TB
 The major advantage of using FDCs :
- simplified treatment & drug
management
- reduced probability of monotherapy
 By preventing monotherapy 
expected that FDCs can limit the risk
of emergence of drug resistant TB
Simplifying treatment
 Conventional : take a large number of tablets
(usually 9-16 / day for 2 months), followed by
3-9 tablets qd ( continuation phase)
 FDCs the number of tablets : 3-4 tablets / day
for the whole course of the treatment
 In Hong Kong only 1% of 312 patients who
received FDCs complained about size
compared 5% of 308 patients who received
single drugs
 Make treatment easier & minimizes the
probability of splitting the dose or of taking
only some of the drugs regimen
Simplifying treatment
 Improve patients compliance
 Limit prescription mistakes by simplifying
calculation of the dosages
 The problem of single drug :
1. no buffer stock
2. delays in receipt of orders
3. no replacements in hand on reaching the
expiry date
 FDCs it easier to calculate the drug needs
(fewer drug formulation order, shipments &
distribution involved orders, the efficiency of
the TB drug supply system is improved )
 Table 1. Difference between WHO 1993 &
1999 recommendation
WHO 1993 WHO 1999

Three weight groups in adults Defined weight groups in adults

(<33, 33-50, > 50 kg) more (30-37, 38-54, 55-70 kg) Hence
specifically tailored to individual
patients weight.

3 formulation 1 formulation

Possibility of underdosing/ Precision in dosage

overdosing

Problem in calculation/dispensing Simplifies prescription and

offers non-compliance of patient patient compliance

...
Table 2. Difference between WHO 1993 &
1999 recommendation
WHO 1993 WHO 1999

 Amount of drug in mg R 450, H 300 Amount of drug in mg R 450, H 225, Z

Z 1550, E 800 for 50 kg individual 1200, E 825 for 50 kg individual. More
refined calculation of dosage keeping
in mind clinical studies

Hepatotoxicity reported with this Lesser incidence of hepatoxicity with

dose of rifampicin rifampicin

More chances for MDR TB Lesser chances of MDR TB emerging

emerging
Table 3. DIFFERENCE BETWEEN WHO 1993 &
1999 RECOMMENDATIONS- a 50 kg
patient.

Year R H Z E

WHO 1993 450 300 1500 800

WHO 1999 450 225 1200 825

 Table 4. Example of the number of tablets to be taken daily
in the initial phase of anti-tuberculosis treatment
by a 50- kg patient either as single drugs or as a
fixed dose combination of four drugs
Single drug tablets No.of Fixed-dose No.of
Tablets Combination Tablets

Rifampicin (R)150mg 3 RHZE (150mg + 75mg + 3

400mg + 275mg)

Isoniazid (H) 300mg (100mg)a 1 (3)a

Pyrazinamide (Z) 500mg 3
Ethambutol (E) 400mg (100mg) 2 (8)

Total 9 (17) Total 3

a. Figures in parentheses refer to alternative dose formulations and related number of tablets
 Table 5. Recommended doses (per kg body
weight) of essential anti-tuberculosis drugs

Anti-tuberculosis drug Mode of action Recommended dose (mg/kg)

Daily 3 x per week

Isoniazid (H) Bactericidal 5 (4-6)a 10 (8-12)

Rifampicin (R)
Bactericidal 10 (8-12) 10 (8-12)
Pyrazinamide (P)
Bactericidal 25 (20-30) 35 (30-40)
Ethambutol (E)
Bacteriostatic 15 (15-20) 30 (25-35)
Streptomycin (S)
Bactericidal 15 (12-18) 15 (12-18)
Thioacetazone (T)
Bacteriostatic 2.5 Not applicable

a. Figure in parentheses are the dose ranges in mg/kg

FDCs & prevention of drug
resistance
 Several other common infectious diseases
can be treated with rifampicin
 Treating TB with monotherapy of rifampicin
rapidly leads to resistance  even if it given
for short periods
 Single drug formulations patients are more
prone to continue their treatment with one
drug & interrupting the others  thereby
creating a risk of monotherapy & selection of
drug-resistant mutants
 FDC- DOSE JUSTIFICATION (WHO)
R 150 H75 Z 400 E 275 (15kg BB/tablet)
(WHO cut off 30 – 37kg, 38 – 54 kg, 55 – 70 kg, > 70kg)

FDC - WHO - OPERATIONAL GUIDE

Table 6. The recommended strengths of fixed-dose combination formulations of essential
anti-tuberculosis drugs. (WHO Model List of Essential Drugs, 1999)

For daily use

Drug Forms Strengths

RHZE Tablet R 150mg + H 75mg + Z 400mg + E 275mg

RHZ Tablet R 150mg + H 75mg + Z 400mg

R 60mg + H 30mg + Z 150mg (paediatric)*
RH Tablet R 300mg + H 150mg
R 150mg + H 75mg
R 60mg + H 30mg (paediatric)*
EH Tablet H 150mg + E 400mg
TH Tablet T 50mg + H 100mg
T 150mg + H 300mg

For intermittent use 3 times weekly

Drug Forms Strengths
RHZ Tablet R 150mg + H 150mg + Z 500mg
Tablet R 150mg + H 150mg
RH
R 60mg + H 60mg (paediatric)*

E=ethambutol, H=isoniazid, R=rifampicin, S=streptomycin, T=thioacetazone, Z=pyrazinamide. * Dispersible form preferred

Table 7. Dosage schedule for FDCs of WHO recommended strengths

Initial phase Continuation phase

2 months 4 months 6 months
RHZE* or RHZ RH EH*
Patient Body weight Daily Daily 3x weekly Daily

Children# Up to 7 1 1 1 1
8-9 1.5 1.5 1.5 -
10-14 2 2 2 -
15-19 3 3 3 -

Adults 30-37 2 2 2 1.5

38-54## 3 3 3 2
55-70## 4 4 4 3
71 and more 5 5 5 3

* RHZE and EH (the ethambutol-containing FDCs) are only used for adults
# Referring to the use of pediatric formulations
## The composition of the 4FDC also ensures adequate doses of the drugs when 50kg is chosen as cut-off
point for changing between 3 and 4 tablets per day.
FDCs adverse effects
 Adverse reactions to drugs are not more common if
FDCs are used
 Whenever side-effects to one of the components in a
FDCs are suspect  need single-drug formulations
 under supervision
 Adverse drug reactions : 3-6 %
 More common in TB-HIV/AIDS patients
 Limited stocks of single- drugs tablet should be
available in higher level referral centers
FDCs can be used in some Special
situations
 Renal failure ; RHZ safe but reduce
dosage for E. Severe renal failure
 should receive pyridoxine to
prevent peripheral neuropathy
 Liver disease : Risk & benefit
should be considered
FDCs and the DOTS strategy
 Although it simplifies both prescribing and
drug taking  FDCs does not eliminate the
need for DOT
 WHO/IUATLD recommended strategy DOT
for FDCs & single-drug vital for successful
TB control
 FDCs of good quality facilitate accurate dose
delivery, and ensure cure when gives as DOT
Quality of FDCs
 Treatment with good quality is fundamental  poor
quality drugs will create drug resistance & fail to cure
patients
 Drug quality is important for all anti-TB drugs, there
are particular concern regarding the bioavailability of
rifampicin in FDCs
 If the bioavailability of rifampicin is inadequate as
might be case in substandard FDCs  treatment
failure and emergence of drug-resistant TB could
follow`
 Absolute requirement to purchase and use only
FDCs that have been proved to have full rifampicin
bioavailability
WHO QUALITY CONTROL NET
WORK FOR FDCs
 National Tuberculosis Research
Programmed, Medical Research Council,
Pretoria, South Africa

 Department of Pharmaceutics, National

Institute of Pharmaceutical, Education and
Research ( NIPER), Punjab, India
Preliminary study
 Health centers in South Sulawesi Province
(1999)
 Objective: To compare complaints, side effect
& treatment outcome in new smear (+)
patients treated with single-drug short course
( NTP) regimen with 4 FDCs
 Prospective study, randomly allocated to NTP
& FDCs
 NTP ; 162 patients & FDCs; 198 patients
RESULTS
 During intensive phase : GIT & muscle joint
complaints. GIT complaints lasting for 2
consecutive weeks  more frequent in NTP
patients  lower dose Z might be the reason
 2 patients with NTP developed jaundice
 Sputum conversion : 89 % NTP Vs 94 %
4 FDCs
 95 % of patients both regimen were cured
SUMMARY
 Simplification of treatment
- Minimize prescription errors
- increase patient and health worker compliance
- enable reduction of supervision

 Simplification of drug supply management

- calculating drug needs
- ordering, procurement
- distribution, storage
- reduce out-of-stock situation
SUMMARY
- ensure availability of high quality of drugs
- management of drug adverse reactions

 Decrease emergence of drug resistance, by means

of
- ensure delivery to the patient of the correct
dose of all drugs
- preventing monotherapy
 Stop mutation
 Drug quality is important for all anti-TB drugs, there
are particular concern regarding the bioavailability of
rifampicin in FDCs