1 / 26

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

Download Presentation

Fixed-Dose-Combinations for Anti-tuberculosis Treatment

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related