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Fixed-Dose-Combinations for Anti-tuberculosis Treatment

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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Fixed-Dose-Combinations for Anti-tuberculosis Treatment

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  1. Fixed-Dose-Combinations for Anti-tuberculosis Treatment Dr. Angela Bartacek October 2003

  2. 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

  3. 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

  4. 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

  5. Multi-Drug Resistance in Europe N Engl J Med 2001;344:1296,1298

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. WHO recommended Strenghts Bulletin of the WHO 2001;79:61-68

  14. WHO recommended Dosage Schedule (Adults) Bulletin of the WHO 2001;79:61-68

  15. 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.

  16. 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

  17. Clinical Evidence BasePoints to consider • Bioavailability • MDR • Safety • Efficacy

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. EfficacyFirst Reports 4-FDC Studies (Indonesia) • Tuberculosis 2003;83:183-186

  25. 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

  26. 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

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