Selection of TB Medicines and Supplies

Selection of TB Medicines and Supplies

Unit Objective

QUAN 1

Understand basic principles of selection of appropriate formulations of essential tuberculosis medicines

Pharmaceutical Management Cycle

Selection

ProcurementManagementSupport

Distribution

Use

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 1st-line TB medicines

• Select specific 2nd-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 1st-line Medicines (1)

• 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

WHO-recommended formulations: anti-tuberculosis drugs

Selecting 1st-line Medicines (2)

Fixed-dose combinations of drugs (adult doses)

• 4-FDCRHZE tablet R150/H75/Z400/E275

• 3-FDCRHZ tablet R150/H75/Z400

• 2-FDCRH tablet R150/H75; (R300/H150); R150/H150

• 2-FDCEH 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.

WHO-recommended formulations: anti-tuberculosis drugs

Selecting 1st-line Medicines (3)

Fixed-dose combinations of drugs (pediatric treatment)

3-FDCRHZ R60/H30/Z150 2-FDCRH R60/H30 2-FDCRH R60/H60 (all are soluble tablets/granules)

Note: all will be available from the GDF shortlyhttp://www.stoptb.org/gdf/drugsupply/drugs_available.asp

Source: WHO. 2003. 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: 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!

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 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 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.

Selecting 2nd-line Medicines (1)

• 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

Requirements

Selecting 2nd-line Medicines (1)• WHO-recommended for MDR TB

Capreomycin Cycloserine Para-aminosalicylic acid Ethionamide Amikacin Kanamycin Ciprofloxacin Ofloxacin Levofloxacin

Characteristics of 2nd-line Medicines• Limited supply

Number 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

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

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

Ancillary Medicines for 2nd 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

• 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 ?NTP managerNDRA Essential drug committeeNational Pharmacy BoardPrivate 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