Selection of TB Medicines & Supplies PSM Workshop to Develop GFATM PSM plans for HIV, TB and Malaria February 2006 Nairobi

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

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

Considerations for TB Drug Selection Epidemiological profile (category mix: morbidity, drug resistance) Evidence-based medicine Bio-equivalence /Bio-Availability Applied pharmaco-economics Standard treatment guidelines for first-line and second-line therapies (inclusion of fixed-dose combination [FDC]; kits) Marketing approval/registration

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

Advantages of Selecting Appropriate Medicine Formulations Controls prescribing habits (MDR, limited resources) Facilitates better purchase prices: —fewer number of products, economies of scale Simplifies management of supplies and stock Financial: short and long term Improve treatment outcome

Selecting 1st-line Medicines (1) Separate drugs  Rifampicin *(R) tablet / capsule, 150 mg, 300 mg  Isoniazid(H) tablet 100 mg, 300 mg  Pyrazinamide (Z) tablet 400 mg  Ethambutol (E) tablet100 mg, 400 mg  Streptomycin (S) vial1 gr * Under special circumstances only; develops resistance easily Note: thioacetazone (T) is discouraged by WHO: risk of severe toxicity, in HIV infected individuals WHO-recommended formulations: anti-tuberculosis drugs

Selecting 1st-line Medicines (2) Fixed-dose combinations of drugs (adult doses) 4-FDCRHZEtablet R150/H75/Z400/E275 3-FDCRHEtablet R150/H75/E275 2-FDCRHtablet R150/H75; R300/H150; R150/H150 2-FDCEHtablet E400/H150 Note: all are available from the GDF Source: WHO Treatment of Tuberculosis. Guidelines for National Programmes Geneva: WHO. WHO-recommended formulations: anti-tuberculosis drugs

Selecting 1st-line Medicines (3) Fixed-dose combinations of drugs (pediatric doses)  3-FDCRHZR60/H30/Z150  2-FDCRHR60/H30  2-FDCRHR60/H60 (all are soluble tablets/granules) Note: all will be available from the GDF shortly Source: WHO Treatment of Tuberculosis. Guidelines for National Programmes Geneva: WHO. WHO-recommended formulations: anti-tuberculosis drugs

Selecting 1st-line Medicines (4) 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: reduces the risk of mono-therapy with bactericidal drugs  H + E: useful: can be self-administered during the second phase but: may be less effective than H+R extends treatment with extra 2 months! Using fixed-dose combinations (FDC)

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

Selecting 1st-line Medicines (6) Advantages of using patient kits  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 medicines are always available) Disadvantages of Kits  Need more storage space in warehouse, depot and health facility (patient full treatment for 6-8 months)

1st line TB Medicines Can also be procured through Direct Procurement service of GDF Offers total package of Q.A. medicines for competitive prices plus monitoring visits Separate Presentation on D.P. service of GDF can be organised for those interested

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

Selecting 2nd-line Medicines (2) 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 drug-resistance patterns Note: international recommendations and standard guidelines developed through Green Light Committee (GLC) Requirements

Characteristics of 2 nd -line Medicines Limited supply Number of suppliers  Capreomycin 1 g. vialfew  Cylcoserine 250 mg tabletfew  Ethionamide 250 mg tabletmany  Kanamycin/amikacin 1 g. vialmany  Para-aminosalicylic acid 4 g. sachetfew  Ofloxacin/ciprofloxacin 200/250 mg tabletfew 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 expiry Using 2nd-line medicines incorrectly may seriously increase resistance to a “last- resort” treatment

2 nd line Medicines for MDR TB For GFATM Grantees CAN ONLY BE PROCURED after Green Light Committee (GLC) approval Offers several advantages but certain conditions are applied Separate Presentation on GLC can be organised for those interested

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

Ancillary Medicines: Examples Analgesics for headaches: aspirin, paracetamol Antiemetics: promethazine, metoclopramide Antiulcer: antacids, ranitidine Anti-fungal agents: fluconazole or clotrimazole Antidiarrheals: loperamide Antidepressants: amitriptyline, fluoxetine Anticonvulsants: 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 ?  NTP manager  NDRA  Essential drug committee  National Pharmacy Board  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