Selection of TB Medicines and Supplies Unit

Selection of TB Medicines and Supplies

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

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

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

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 1 st-line TB medicines • Select specific 2 nd-line medicines for drug-resistant TB

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

Selecting 1 st-line Medicines (1) WHO-recommended formulations: anti-tuberculosis drugs • Separate drugs / Active ingredients § Rifampicin * (R) tablet / capsule, 150 mg, 300 mg § Isoniazid (H) tablet § Pyrazinamide (Z) tablet 400 mg § Ethambutol 100 mg, 400 mg § Streptomycin (S) vial, (E) tablet 100 mg, 300 mg 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

Selecting 1 st-line Medicines (2) WHO-recommended formulations: anti-tuberculosis drugs Fixed-dose combinations of drugs (adult doses) • 4 -FDC RHZE tablet • 3 -FDC RHZ tablet • 2 -FDC RH tablet • 2 -FDC EH tablet R 150/H 75/Z 400/E 275 R 150/H 75/Z 400 R 150/H 75; (R 300/H 150); R 150/H 150 E 400/H 150 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.

Selecting 1 st-line Medicines (3) WHO-recommended formulations: anti-tuberculosis drugs Fixed-dose combinations of drugs (pediatric treatment) § 3 -FDC RHZ § 2 -FDC RH R 60/H 30/Z 150 R 60/H 30 R 60/H 60 (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.

Selecting 1 st-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 monotherapy 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!

Selecting 1 st-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)

Selecting 1 st-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.

Selecting 2 nd-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 2 nd-line medicines for the country, based on demonstrated drug-resistance patterns • Note: international recommendations and standard guidelines are still being developed

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

Characteristics of 2 nd-line Medicines • Limited supply § § § Capremycin 1 g. vial Cylcoserine 250 mg tablet Ethionamide 250 mg tablet Kanamycin/amikacin 1 g. vial Para-aminosalicylic acid 4 g. sachet Ofloxacin/ciprofloxacin 200/250 mg tablet Number of suppliers few many 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 1 st-line TB medicines • Not as effective • More toxic

Criteria for Selecting 2 nd 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

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

Ancillary Medicines for 2 nd 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

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

TB Supplies - Examples • 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

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

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