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Fixed-Dose-Combinations for Anti-tuberculosis Treatment. Dr. Angela Bartacek October 2003. Global Tuberculosis Situation. Most common infectious cause of death worldwide One third of the world population infected Global problem further complicated by a substantial

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global tuberculosis situation
Global Tuberculosis Situation
  • 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
situation in industrialised countries
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 europe population patterns
Multi-Drug Resistance in EuropePopulation Patterns
  • 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 1997
  • Foreign-born
  • Indigenous
  • 0 5 10 15 20 25 30

Ann NY Acad Sci 2001;953:88-97

  • Per cent with TB drug resistance
multi drug resistance in europe
Multi-Drug Resistance in Europe

N Engl J Med 2001;344:1296,1298

causes of drug resistance system failures
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 resistance human failures
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
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 drugsAnn Intern Med 1995;122:951-954 Drugs 1999;58(4):633-661
fixed dose combinations fdcs
Fixed-Dose-Combinations (FDCs)
  • Most recent development in anti-TB control
  • Use is strongly encouraged byAmerican Thoracic Society

Centres for Disease Control (CDC)

WHO

IUATLD

Am J Respir Crit Care Med 1994;149:1359-74

MMWR 2002;51(No.RR-8):1-52

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

advantages
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 Monotherapy
  • Prevention of
  • 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
  • Prevention of selection of drug resistant mutants
simplification of prescription and administration
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
WHO recommended Strenghts

Bulletin of the WHO 2001;79:61-68

who recommended dosage schedule adults
WHO recommended Dosage Schedule (Adults)

Bulletin of the WHO 2001;79:61-68

improvement of patients compliance
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
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 base points to consider
Clinical Evidence BasePoints to consider
  • Bioavailability
  • MDR
  • Safety
  • Efficacy
bioavailability
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):309-316

Tubercle Lung Dis 1994; 75:180-181

multi drug resistance
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
Safety
  • East African /British Medical Research Council
  • Singapore Tuberculosis Service /British Medical Research Council
  • British Thoracic Association
  • American Thoracic Association
  • Serious adverse events demanding withdrawal of drugs are relatively rare

Bulletin of the WHO 2001;79:61-68

safety1
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; 140:1618-1622

Tuber Lung Dis 1995; 76:407-412

Tuberculosis 2003; 83:183-186

efficacy
Efficacy
  • Tuber Lung Dis 1995;76:407-12Ann Intern Med 1990;112:397-406Am Rev Respir Dis 1991;143:700-6Am Rev Respir Dis 1991;143:707-12
efficacy 4 fdcs
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

efficacy first reports 4 fdc studies sandoz
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
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