Selection of TB Medicines and Supplies

1. Selection of TB Medicines and Supplies

2. Unit Objective Understand basic principles of selection of appropriate formulations of essential tuberculosis medicines QUAN 1

3. Selection Management Procurement Use Support Distribution Policy and Legal Framework Pharmaceutical Management Cycle

4. Considerations for TB Drug Selection • Epidemiological profile (category I II III MDR mix: morbidity, drug resistance) • Evidence-based medicine • Bio-equivalence / Bio-availability • National Treatment Guidelines / Regimens for first-line and second-line therapies (patient treatment kits) • Drug formulations (tablets, fixed-dose combination tablets soluble tablets, powder in sachets) • Marketing approval/registration • Applied pharmaco-economics: • the most cost effective TB treatment = DOTS • Costs of different drugs, availability, delivery times

5. Medicine Selection Process • Review patterns of TB morbidity, drug resistance, and populations affected • Identify standard treatments in the TB program (e.g. DOTS regimens) • Develop a list of essential medicines and supplies to standardize drug availability: specify medicine, generic name, strength, dosage form and familiarity of health worker at treatment centers • Select specific 1st-line TB medicines • Select specific 2nd-line medicines for drug-resistant TB

6. Advantages of Selecting Appropriate Medicine Formulations • Controls prescribing habits (prevention of MDR-TB, controls limited resources) • Facilitates better purchase prices: — fewer number of products, economies of scale • Simplifies management of supplies and stock • Financial: short and long term savings and cost control • Improve treatment outcome

7. Selecting 1st-line Medicines (1) WHO-recommended formulations: anti-tuberculosis drugs • Separate drugs / Active ingredients • Rifampicin * (R) tablet / capsule, 150 mg, 300 mg • Isoniazid (H) tablet 100 mg, 300 mg • Pyrazinamide (Z) tablet 400 mg • Ethambutol (E) tablet 100 mg, 400 mg • Streptomycin (S) vial, 1 gr * Only as (FDCs); single formulations under special circumstances; develops resistance easily Note: thioacetazone (T) is discouraged by WHO: risk of severe toxicity, in HIV infected individuals

8. Selecting 1st-line Medicines (2) WHO-recommended formulations: anti-tuberculosis drugs Fixed-dose combinations of drugs (adult doses) • 4-FDC RHZE tablet R150/H75/Z400/E275 • 3-FDC RHZ tablet R150/H75/Z400 • 2-FDC RH tablet R150/H75; (R300/H150); R150/H150 • 2-FDC EH tablet E400/H150 Note: all in black are available from the GDF http://www.stoptb.org/gdf/drugsupply/drugs_available.asp Source: WHO. 2003. Treatment of Tuberculosis. Guidelines for National Programmes Geneva: WHO.

9. Selecting 1st-line Medicines (3) WHO-recommended formulations: anti-tuberculosis drugs Fixed-dose combinations of drugs (pediatric treatment) • 3-FDC RHZ R60/H30/Z150 • 2-FDC RH R60/H30 • 2-FDC RH R60/H60 (all are soluble tablets/granules) Note: all will be available from the GDF shortly http://www.stoptb.org/gdf/drugsupply/drugs_available.asp Source: WHO. 2003. Treatment of Tuberculosis. Guidelines for National Programmes Geneva: WHO.

10. Selecting 1st-line Medicines (4) Using fixed-dose combinations (FDC) • Advantages of FDCs • simplifies dose calculations, procurement and supply • provides patient with fewer tablets to swallow and provider to administer • reduces the risk of promoting drug-resistant TB / avoiding mono-therapy • H + R: 4 months continuation phase of treatment • H + E: useful: can be self-administered during the second phase but: may be less effective than H+R and extends treatment with extra 2 months!

11. Selecting 1st-line Medicines (5) • Cautions when using FDCs • Need demonstration of bioavailability (particularly for rifampicin) by independent labs • Need planning, coordination and training for initial switch-over and follow-on monitoring of treatment practices • Use of FDCs still require stocking of limited quantities of separate medicines for patients who experience adverse reactions (about 2%--WHO)

12. Selecting 1st-line Medicines (6) Advantages of using patient kits (full treatment for one patient for 6-8 months) • Solidly promotes rational drug use, DOTS expansion and recording and reporting system • Simplifies drug management • quantification of needs (1 patient = 1 kit) • stock management and distribution • provider adherence to treatment standards • patient acceptability of treatment (ownership of kit and all required medicines are always available) Disadvantages of Kits • Need more storage space in warehouse, depot and health facility • Not suitable for large clinics: >100 patients p.d.

13. Selecting 2nd-line Medicines (1) Requirements • Only do so after the country has a documented outbreak of multi-drug resistant (MDR) TB • Qualified specialists should make decisions for selecting 2nd-line medicines for the country, based on demonstrated drug-resistance patterns • Note: international recommendations and standard guidelines are still being developed

14. WHO-recommended for MDR TB Capreomycin Cycloserine Para-aminosalicylic acid Ethionamide Amikacin Kanamycin Ciprofloxacin Ofloxacin Levofloxacin Selecting 2nd-line Medicines (1)

15. Characteristics of 2nd-line Medicines • Limited supplyNumber of suppliers • Capremycin 1 g. vial few • Cylcoserine 250 mg tablet few • Ethionamide 250 mg tablet many • Kanamycin/amikacin 1 g. vial many • Para-aminosalicylic acid 4 g. sachet few • Ofloxacin/ciprofloxacin 200/250 mg tablet few • More medicines are needed for longer periods of time (up to 24 months) • More expensive—can be 100 to 1000 times as expensive as 1st-line TB medicines • Not as effective • More toxic

16. Criteria for Selecting 2nd line Medicines • Possible regimens • Use only standardized protocol • Individualize if standardized fails • Use empiric protocols, • if fails then individualized (Note: Comparative effectiveness has not been determined for any of the regimens) • Registration in the country • Acquisition costs and longest possible expiry date

17. Cautions for 2nd-line Medicines • Should not keep drugs in reserve—some have only 18 months shelf life • Using 2nd-line medicines incorrectly may seriously increase resistance to our “last-resort” TB treatment

18. Ancillary Medicines for 2nd line treatment: Managing Adverse Effects Categories of Adverse Reactions • Minor side effects • Toxic reactions • Hypersensitivity reactions • Idiosyncratic reactions • Reactions not classified in any of the above

19. Ancillary Medicines: Examples • Analgesics for headaches: aspirin, paracetamol • Anti-emetics: promethazine, metoclopramide • Anti-ulcer: anti-acids, ranitidine • Anti-fungal agents: fluconazole or clotrimazole • Anti-diarrheals: loperamide • Anti-depressants: amitriptyline, fluoxetine • Anti-convulsants: diazepam, phenytoin • Inhaled beclomethasone for bronchospasms • Epinephrine for systemic hypersensitivity reactions

20. Water for injection Needles and syringes Disinfectants, soaps, towels, and tissues Gloves and face masks Sputum cups Forms and labels ZN stains and other chemicals Microscopes Resuscitation equipment Slides Filter and lens paper Applicator Miscellaneous equipment for microscopy Culture media, Petri plates Autoclave, incubator, sterilizer BCG, PPD X-ray machine, film developer and fixer TB Supplies - Examples

21. Management Challenges (1) • Authority to select TB medicines ? • NTP manager • NDRA • Essential drug committee • National Pharmacy Board • Private sector

22. Selection: Management Challenges (2) • Lack of quality TB drugs registered in the country • Pressure from manufacturers and suppliers • Branded versus generic drugs (non-informative brand names) • Local biases: schools of thought, personal interests • Lack of skills to use selected drugs (e.g., FDC) • Unjustified selection of second-line drugs