Fixed-Dose-Combinations for Anti-tuberculosis Treatment

a Novartis company

Fixed-Dose-Combinations for Anti-tuberculosis Treatment

Dr. Angela Bartacek October 2003

2 Angela Bartacek, MD /

Most common infectious cause of death worldwide

One third of the world population infected

Global problem further complicated by a substantial

increase in multidrug resistant tuberculosis

JAMA 1999;282:677-686

WHO Report 2002

Global Tuberculosis Situation


Situation in Industrialised Countries

Incidence of TB is strongly influenced by migration of people from high-prevalence countries

Incidence of TB is high in ethnic minority groups

United Kingdom:

4,4/100.000 in indigenous white population

121/100.000 in natives from the Indian subcontinent

210/100.000 in Black African

United States:

Half of all cases occur in foreign born persons

Thorax 1999; 54(suppl.3): A5

N Engl J Med 2002; 347: 1850-9


Multi-Drug Resistance in EuropePopulation Patterns

Ann NY Acad Sci 2001;953:88-97

Denmark 1995

Denmark 1996

Denmark 1997

Denmark 1998

England & Wales 1997

Finland 1995

Finland 1996

Finland 1997

Germany 1997

Germany 1998

Italy 1998

Netherlands 1995

Northern Ireland 1997

Norway 1995

Norway 1997

Sweden 1994

Sweden 1995

Sweden 1996

Sweden 1997

Switzerland 1996

Switzerland 19970 5 10 15 20 25 30

Foreign-born

Indigenous

Per cent with TB drug resistance


Multi-Drug Resistance in Europe

Europe New Cases

Previously treated

Belgium 2.0

Czech Republic 1.6 11.5

Denmark 0.5 3.1

England and Wales

0.8 13.2

Estonia 14.1 37.8

Finland 0.0 0.0

France 0.0 3.1

Germany 0.9 6.3

Italy 1.2 33.9

Latvia 9.0 23.7

Netherlands 0.6 0.6

Northern Ireland 0.0

Europe New Cases

Previouslytreated

Norway 2.2 16.7

Poland 0.6 7.0

Russia

Tomsk Oblast

6.5 26.7

Ivanovo Oblast

9.0 25.9

Scotland 0.3 12.5

Slovakia 0.3 8.3

Slovenia 0.7 2.8

Spain 0.3 11.6

Sweden 0.6 8.3

Switzerland 0.0 12.5

N Engl J Med 2001;344:1296,1298


Causes of Drug ResistanceSystem Failures

Politics

- Lack of political commitment to TB-control

- Deterioration of health infrastructure (e.g. war)

- Immigration from endemic areas

- Increasing poverty and homelessness in industrialised countries

Health institutions

- Interruptions of drug supply

- Use of drugs of questionable quality

Drugs 1999 Oct; 58(4): 633-661


Causes of Drug ResistanceHuman Failures

Patients

- Misunderstandings

- Deliberate decision to leave out prescribed drugs because of perceived or real adverse events

- Deliberate decision to purchase only one medication to save money

Doctors

- Inproper drug prescription

- Inadequate drug regimes

- Inproper patient education

- Misuse of rifampicin for conditions other than TB

Int J Antimicrob Agents 1999; 13: 93-97

Ann Intern Med 1995;122:951-954


Prevention of Drug Resistance

Increased supervision of anti-tuberculosis treatment (DOTS)

Use of multiple drug combinations of isoniazid, rifampicin

and pyrazinamide for first 2 months followed by isoniazid and rifampicin for 4 months (new cases)

Addition of ethambutol in the initial phase (recommendation of CDC and WHO)

Use of fixed-dose-combinations of essential anti-tuberculosis drugs

Ann Intern Med 1995;122:951-954Drugs 1999;58(4):633-661


Fixed-Dose-Combinations (FDCs)

Most recent development in anti-TB control

Use is strongly encouraged by

American Thoracic Society

Centres for Disease Control (CDC)

WHO

IUATLD

Am J Respir Crit Care Med 1994;149:1359-74MMWR 2002;51(No.RR-8):1-52

Int J Tuberc Lung Dis 1999; 11 (Suppl 3):286-287


Advantages

Prevention of monotherapy

Simplification of prescription and administrationof drugs

Improvement of patient compliance

Improvement of drug stock management, shipping and distribution

Int J Tuberc Lung Dis 1999;3(11):362-367

Ann Int Med 1995;122:951-954

Bulletin of the WHO 2001;79:61-68


Prevention of Monotherapy

Prevention of

Prevention of selection of drug resistant mutants

Selective interruption of antituberculosis treatment by patients

Selection of certain drugs over other drugs through patients

Mistakes of dispensing

Out of stock situation for single antituberculosis substances

Expiry of medications

Misuse of rifampicin for conditions other than TB


Simplification of Prescription and Administration

Limitation of mistakes with dosage calculation

Easy adjustment of dose according to body weight

Simplification of dosage calculation

Limitation of over- or underdosing of patients

Relief of tuberculosis service under pressure

Prevention of selection of drug resistant mutants


WHO recommended Strenghts

Drug Strengths

4FDC

Daily use

Rifampicin + isoniazid + pyrazinamide + ethambutol

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

3FDC Rifampicin + isoniazid + pyrazinamide

R 150 mg + H 75 mg + Z 400 mgR 60 mg + H 30 mg + Z 150 mg (paediatric)

2FDC Rifampicin + isoniazid

Isoniazid + ethambutol

Thioacetazone + isoniazid

R 300 mg + H 150 mgR 150 mg + H 75 mgR 60 mg + H 30 mg (paediatric)

H 150 mg + 400 mg

T 50 mg + H 100 mg

3FDC

Intermittent use (3 times weekly)

Rifampicin + isoniazid + pyrazinamide

R 150 mg + H 150 mg + Z 500 mg

2FDC Rifampicin + isoniazid R 150 mg + H 150 mgR 60 mg + H 60 mg (paediatric)



WHO recommended Dosage Schedule (Adults)

Patient‘s body weight

(kg)

Initial phase:

2 months

Continuation phase:

4 months 6 months

RHZE daily RHZ daily RH daily RHx 3 weekly

EH daily

30-37 2 2 2 2 1.5

38-54 3 3 3 3 2

55-70 4 4 4 4 3

≥ 71 5 5 5 5 3



Improvement of Patients Compliance

In the typical patient reduction of number of tablets to be taken to as few as 3 to 4 tablets per day for the whole

course of treatment.

Better compliance

Prevention of Multidrug-Resistance

Possible reduction of patient supervision and relief of strained tuberculosis services.


Improvement of Drug Stock Management

Reduction of quantity of buffer stocks

Reduction of quantity in delays of order

Fewer logistical strains through exchange or missed exchange of medications reaching expiry date

Reduction of out-of-stock situation for single anti-tuberculosis drugs


Clinical Evidence BasePoints to consider

Bioavailability

MDR

Safety

Efficacy


Bioavailability

Inadequate bioavailability of rifampicin in many marketed FDC-preparations

Call of WHO and IUATLD to only use FDCs of proven bioavailability

In-vivo assessment of rifampicin bioavailability by means of bioequivalence studies with comparator preparation of reputable quality prior to registration

Int J Tuberc Lung Dis 1999; 3 (11):309-316Tubercle Lung Dis 1994; 75:180-181


Multi Drug Resistance

United Kingdom

High rate of rifampicin sold as FDCs (73 to 79%)

Low rate of drug resistance

United States

Low rate of rifampicin sold as FDCs (15 to 18%)

High rate of drug resistance

Int J Antimicrob Agents 1999; 13: 93-97

Ann Intern Med 1995;122:951-954


Safety

East African /British Medical Research Council

Singapore Tuberculosis Service /British Medical Research Council

British Thoracic Association

American Thoracic Association

Serious adverse events demandingwithdrawal of drugs are relatively rare



Safety

Hong Kong Chest Service / British Medical Research Council (1989)

Chaulet and Boulahbal (1995)

Drug adverse reactions are not more frequent with FDCs

Preliminary results of a 4-FDC trial in Indonesia (2003)

Statistically significant reduction in gastrointestinal and muscle-joint adverse events

Am Rev Respir Dis 1989; 140:1618-1622Tuber Lung Dis 1995; 76:407-412

Tuberculosis 2003; 83:183-186


Efficacy

US Public Health Study 21 (1990)n=1451

3FDC (RHZ)/single drugs

No significant differences in relapse rate (24 mo FU)(3.4% vs 2.6%; CI O.0% to 5.9% n.s)

Hong Kong Chest Service/British Medical Research Council (1991)n=1386

3FDC (RHZ)/single drugsn=840

No significant differences in relapse rates (30 mo FU)(range: 3% to 9% vs. 1% to 6%)

Singapore Tuberculosis Service/British Medical Research Council (1991)n=310

3FDC (RHZ)/single drugs

Slightly higher relapse rate in the combined formulation

(p=0.04)

Chaulet and Boulahbal (1995)n=250

3 FDC (RHZ)/single drugs

No significant differences in failure and relapse rate after EOT and 24 mo FU (1% u. 2%)

Tuber Lung Dis 1995;76:407-12Ann Intern Med 1990;112:397-406Am Rev Respir Dis 1991;143:700-6

Am Rev Respir Dis 1991;143:707-12


Efficacy4-FDCs

IUATLD Study C

WHO – 4 FDC / single drugs 1500 patients

Royal Netherlands Tuberculosis Association (Indonesia)

WHO – 4 FDC / single drugs 400 patients

Sandoz 4 FDC Study

WHO – 4 FDC /single drugs 1300 patients


EfficacyFirst Reports 4-FDC Studies (Indonesia)

360 patients 4 FDC Comparison

Sputum conversionrate (2 months)

94% 89%

Cure rate (6 months)

95% 95%

Tuberculosis 2003;83:183-186


EfficacyFirst Reports 4-FDC Studies (Sandoz)

Start in 30 centres in March 2003 (Egypt, India, Pakistan, Thailand, Philippines)

850 patients included by End September 2003

Audit of study centres and investigators‘ meetings in Egypt, India, Thailand (October 2003):

Report of equal efficacy

SAE reports show equal safety in both groups

Minor adverse events show a trend to reduced GI-complaints in the intensive phase

Clear patient preference for FDCs


Conclusion

Call by major institutions for replacement of single drugs through Fixed-Dose-Combinations in anti-tuberculosis therapy

Call by WHO and IUATLD to only use Fixed-Dose- Combinations of approved quality

Use of Fixed-Dose-Combinations is regarded as major step forward

in the aim to simplify anti-tuberculosis treatment and reduce drug

resistance

Fixed-Dose-Combinations for Anti-tuberculosis Treatment

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