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National Tuberculosis Control Program ‐ Egypt

   

TB Drug Management Guidelines

    

2007 

   

Contents Contents .......................................................................................................................................... 1 FOREWORD.................................................................................Error! Bookmark not defined. ACKNOWLEDGEMENTS...........................................................Error! Bookmark not defined. LIST OF ABBREVIATIONS........................................................Error! Bookmark not defined. Introduction..................................................................................Error! Bookmark not defined. Understanding the TB drug management cycle........................Error! Bookmark not defined. Drug management of TB and DR-TB ........................................Error! Bookmark not defined. Drug management for TB is important for the following reasons:....... Error! Bookmark not defined. Understanding Drug Resistance Tuberculosis ..........................Error! Bookmark not defined. Section 1. .......................................................................................Error! Bookmark not defined. 

Selection and Quantification......................................................Error! Bookmark not defined. Selection criteria for TB drugs...................................................Error! Bookmark not defined. Advantages of using FDCs and patient kits ..........................Error! Bookmark not defined. II- Quantification: ......................................................................Error! Bookmark not defined. What is the importance of quantification?.................................Error! Bookmark not defined. Selecting second-line drugs .....................................................Error! Bookmark not defined. Treatment regimens for MDR-TB in Egypt.........................Error! Bookmark not defined. 

Section 2. .......................................................................................Error! Bookmark not defined. Procurement ...............................................................................Error! Bookmark not defined. Procurement mechanisms for second-line TB drugs .................Error! Bookmark not defined. 

Direct procurement ................................................................Error! Bookmark not defined. GLC quality assurance...........................................................Error! Bookmark not defined. 

Section 3. .......................................................................................Error! Bookmark not defined. Distribution ................................................................................Error! Bookmark not defined. Storage .......................................................................................Error! Bookmark not defined. 

Section 4. Use ...............................................................................Error! Bookmark not defined. Management Support.................................................................Error! Bookmark not defined. Why use indicators?...................................................................Error! Bookmark not defined. Drug Policy ................................................................................Error! Bookmark not defined. Quality Control ..........................................................................Error! Bookmark not defined. Important definitions: .............................................................Error! Bookmark not defined. 

FOREWORD

Tuberculosis in Egypt is considered an important public health problem. In terms of incidence of tuberculosis, Egypt is ranked among the mid-level incidence countries. The Ministry of Health and Population (MOHP) has established the National Tuberculosis Control Programme NTP. It is a detailed plan of action for effective TB control to reduce the prevalence of tuberculosis in the community as quick as possible to a level where it ceases to be a public health problem. NTP is adopting the UN Millennium Development Goals; by 2015, to halve TB prevalence and deaths rates, as compared with 1990 .

Treatment and control of TB depends on adequate supply of all drugs all time. The entire TB control strategy can be hampered by poor drug requirements estimate, inefficient procurement, mismanagement of drug distribution and storage or misuse of drugs This may result in an interruption of drug supply which can lead to patients defaulting from treatment and possibly acquiring multidrug resistance. This is the first edition of drug management guidelines produced by the National Tuberculosis Control Program of Egypt. NTP staff and international experts contributed to this edition. The Guide is meant for physicians, pharmacists& other staff involved in the drug management cycle of anti TB-drugs. It provides the reader with information on how to select and quantify drugs for national programs, taking into consideration the various types of TB cases and World Health Organization (WHO) recommendations. Dr. Essam Elmoghazy General Director of Chest Diseases Executive Manager NTP, Egypt Cairo, January 2007

ACKNOWLEDGEMENTS This document has been prepared by Dr. Sherry Victor, the drug management coordinator of NTP Egypt Special thanks go to Prof. Masoud Dara, Senior Consultant, Royal Tropical Institute in Amsterdam KNCV, for his valuable contributions. The NTP is grateful to those who, one way or the other, have contributed to this Guide, but are not mentioned here by name.

LIST OF ABBREVIATIONS Am Cfx Cm CS DOTS DRS DST E EPTB Eto FDCs FEFO GCT GDF GLC H HIV IDA IUATLD Km Lfx MOHP NTP Oflx PAS PTB R S SCC TB WHO Z

Amikacin Ciprofloxacin Capreomycin Cycloserine Directly Observed Treatment, Short course chemotherapy Drug Resistance Survey Drug susceptibility testing Ethambutol Extra-Pulmonary Tuberculosis Ethionamide Fixed Dose Combinations First expiry first out Governorate Co-coordinator for Tuberculosis Global Drug Facility Green Light Committee Isoniazid Human Immuno-deficiency Virus International Dispensary Agency International Union against Tuberculosis and Lung Disease Kanamycin Levofloxacin Ministry of Health & Population National Tuberculosis Control Programme Ofloxacin Para Amino Salicylic Acid Pulmonary Tuberculosis Rifampicin Streptomycin Short Course Chemotherapy Tuberculosis World Health Organization Pyrazinamide

Introduction

Tuberculosis (TB) continues to place a heavy burden on the world’s poorest countries, despite established diagnostic procedures, medicines and supplies for this disease. Among the top challenges faced by TB programs are lack of access to effective, high quality medicines, irrational treatment decisions and behaviors, and other financial priorities of some national health systems In recent years, the world donor community has stepped up its response to this crisis by creating several global initiatives. Efforts such as the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM); the Stop TB Partnership; the Global Drug Facility (GDF) for first-line medicines and the Green Light Committee (GLC) for second-line medicines are helping to provide needed resources. However, having adequate resources is only part of the solution. Health systems must be strengthened to be able to use scarce sources more efficiently. This document has been adapted from Management Sciences for Health (MSH) and World Health organization (WHO) Guidelines. It is also put in line with the Stop TB strategy to pursue quality Directly Observed Short Course Chemotherapy (DOTS) enhancement through effective drug supply system and addressing drug resistant Tuberculosis (DR-TB). It provides information and develops skills to facilitate a stepwise understanding for the drug management cycle and implementation of basic concepts and methods. With the document, users should be able to identify key weaknesses in their system and mechanisms to overcome them in selection, procurement, distribution, timely use, and management support of TB medicines.

Understanding the TB drug management cycle

The drug management cycle is a systematic approach you can use to ensure that all drugs for a complete TB treatment course are available and appropriately used according to an effective treatment strategy and timeline.

It emphasizes connections among four drug management activities:

• selection of drugs • procurement of selected drugs • distribution of procured drugs • use of distributed drugs

Each activity of the drug management cycle relies on the success of the previous activity and contributes to the effectiveness of the next activity. This is essential since any disturbances in the drug management cycle that interrupts the patients’ appropriate use of TB drugs may lead to treatment failure and ultimately promote the spread of drug-resistant TB.

Management support

Selection

Distribution

Use Procurement

Figure 1 Drug management cycle

Drug management of TB and DR-TB

The most widely available and effective strategy for controlling TB is known as DOTS. The word DOTS, is composed of the initials of words of the phrase: Directly Observed Treatment, Short course Chemotherapy. DOTS is the global standard for TB treatment and the strategy recommended by WHO for controlling TB. More than 140 countries had adopted DOTS by 2000.

The strategy's five elements are:

Sustained political commitment Access to quality-assured TB sputum microscopy for case detection Standardized short-course chemotherapy available for all TB cases, under

proper case management conditions Uninterrupted supply of quality-assured drugs Recording and reporting system enabling outcome assessment of each and

every patient and assessment of overall program performance

Advantages of DOTS:

Increase patient adherence to treatment. Increases TB cure rates. Low mortality from TB. Prevent further emergence of drug-resistant strains of TB. Integration of TB control with other health services.

The success of this strategy depends on direct observation during, at least, the first two months of treatment to ensure patient compliance. Treatment can be observed by anyone who is willing, trained, responsible, acceptable to the patient, and accountable to the TB control services. Treatment for tuberculosis consists of two different phases of special combinations of drugs, initial phase to kill the active bacilli, followed by continuation phase to sterilize the lesion and prevent relapse through eradicating the dormant bacilli once they are active.

Recommended treatment regimens for each patient category:

Tuberculosis Treatment Regimens

Treatment regimen Category

Tuberculosis Patients Initial Phase Continuation

Phase

I

New smear-positive patients; new smear negative patients pulmonary TB and extra pulmonary TB

2ERHZ Or

2SRHZ

4RH or

∗6EH

II

Previously treated patient. • relapse • treatment after interruption • treatment after failure

2SRHZE/1RHZE

5RHE

∗Not recommended by NTP treatment policy.

R = rifampicin; H = isoniazid; Z = pyrazinamide; E = ethambutol; S = streptomycin.

A regimen consists of two phases. The number before a phase is the duration of that phase in months.

4RH may be replaced by 6EH daily.... However, preliminary data from a recent clinical trial have shown that 6EH is much less effective than 4RH in terms of cure, with higher failure and relapse rates.

Whenever possible, drug susceptibility testing is recommended for patients who do not have sputum converted at the end of the initial phase to investigate the resistance profile.

Drug management for TB is important for the following reasons:

It is a key component of DOTS strategy. Ensures uninterrupted TB drugs supply and a buffer (safety) stock. Guarantees good-quality of the drugs. Ensures that patient is receiving the right dose for the right period of time in

order to achieve cure. TB drugs are costly when mismanaged but cost-effective when managed well. Countries that improve their drug management systems in order to cure TB are

also strengthening systems that will help them addressing the treatment of numerous other health problems.

Interruption of treatment or use of poor-quality drugs may have serious consequences, such as:-

Increase treatment failure rate. Increases morbidity Irregular TB treatment increases the likelihood of developing resistance More expensive, more toxic less effective drugs will be needed for a longer period of time to treat drug-resistant cases.

Increased costs to the TB program.

Understanding Drug Resistance Tuberculosis

(DR-TB) management & the Green Light Committee

DOTS was, and remains, the most cost-effective approach to detecting, curing cases and preventing the onset and spread of drug resistance.

Principle of DR-TB management:

A well implemented of DOTS is the first step in fighting DR-TB because it will help preventing the emergence of drug resistance. Thus, effective DOTS – based TB control program must be in place in area before investing the considerable resources necessary for the treatment of DR-TB. The Green Light Committee (GLC) was thus born in June 2000 as WHO partnership tom coordinate management of DR-TB

Activities of the GLC:

Hosted by WHO as a partnership; Assures creation of, and adoption of policies for proper management of drug-

resistant TB ; Reviews proposals for DR-TB projects and assists countries in their proper

implementation; Provides access to quality assured second-line drugs at concessionary prices; The GLC performs procurement activities for second-line drugs through its

procurement agent Currently the IDA, (a nonprofit foundation). International Dispensary Agency (IDA) is responsible for negotiation with

suppliers, procurement, quality assurance, and distribution of second-line TB drugs- and adds a 7 percent margin to the purchase prices to covers its operating expenses.

The GLC monitors approved projects, providing for technical assistance as needed, and collect global evidence for developing policy in controlling DR-TB.

Section 1 Selection and Quantification

I- Selection: the process of establishing and using a limited list of essential drugs. It involves: Reviewing health problems; Identifying the best clinical treatments; Choosing drugs, dosages, dosage form, and special packaging needs.

Selection criteria for TB drugs • Safe and efficient. • Quality assured, in terms of bioavailability and stability (shelf life) • Easy for usage by authorized personnel • Generic products are quiet equivalent regarding efficacy, safety, quality, price,

and availability • Fixed dose combination products are preferred over separate products • The total cost of treatment course, not only the unit cost of the drugs is an

important selection criterion. Drugs are selected according to: • Generic name. • Dosage form (for example, tablet, ampoule for injection) • Strength (for example, Rifampicin 150 mg + Isoniazid 75 mg) • Package presentations (for example, blisters containing 10 tablets, each, with 10

blisters per pack)

Selecting first-line drugs: The five first-line drugs: Isoniazid (H), Rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S). Recommended Dosage of Essential First-Line Anti-TB Drugs

Drug

(Abbreviation) Mode of Action

Recommended dose (Dose Range) mg / kg Body Weight Daily

Rifampicin (R) Bactericidal 10 (8–12) Isoniazid (H) Bactericidal 5 (4–6) Pyrazinamide (Z) Bactericidal 25 (20–30) Streptomycin (S) Bactericidal 15 (12–18) Ethambutol (E) Bacteriostatic, in lower dose 15 (15–20)

Also, consider selecting fixed-dose combinations (FDCs) of the first-line drugs and patient kits, since FDCs have proven effective over many years.

FDCs contain two, three, or four essential drugs in one tablet, depending on the treatment regimens selected by national TB programs. A patient kit contains a full course of treatment for TB (all drugs needed through treatment completion, either it is 6 months for category I treatment or 8 months for category II) in a box or a bag. These patients’ kits (drug boxes) are an important tool for ensuring correct drug treatment and avoiding interruptions of supply during treatment. Drug boxes are strongly recommended by WHO. When a TB patient is identified, the health worker determines the patient’s category of treatment and specifies the regimen needed and the dosages (based on the patient’s body weight). A drug box containing the appropriate regimen is labeled with the patient’s name and kept for him or her only. In this way, the health facility is certain to be able to provide the full course of drug treatment needed by the patient. The health worker and the patient can be confident that the patient will never come for treatment to find that the health facility has run out of drugs. Daily drug administration is simplified for the staff because the drugs are labeled for the patient and are pre-packaged in daily doses. Determining when the patient has completed the treatment is also easy, because the patient continues until all the drugs in the box have been taken as recommended. If your health facility does not receive anti-TB drugs pre-packaged as a complete regimen for one patient, WHO recommends assembling drug boxes.

Common Fixed Dose Combinations used in TB Control:

Drug Dosage Form Strength For Daily Use

Rifampicin + Isoniazide Tablet Tablet or pack of granules

( pediatric )

150 / 75 mg & 300 / 150 mg 60 / 30 mg

Rifampicin + Isoniazide + Pyrazinamide

Tablet Tablet or pack of granules

( pediatric )

150 / 75 / 400 mg 60 / 30 / 150 mg

Rifampicin + Isoniazide + Pyrazinamide + Ethambutol

Tablet 150 / 75 / 400 / 275 mg

Advantages of using FDCs and patient kits

• FDCs increase patient adherence to treatment as it provides the patient with fewer tablets to swallow.

• The two-, three-, or four- combinations reduce the risk of monotherapy with bactericidal drugs and thus decrease the threat of resistance to treatment.

• FDCs simplify dose calculations and procurement.

Some disadvantages of using FDCs and patient kits may include: • Personnel still need to be trained on quantification and adjustment of kits

according to body weight, inventory methods, and repacking. • Identifying the drugs causing any adverse effect may be difficult. • Patient’s kits may need larger storage space in central and local warehouses.

Dosage Schedules for Adults

Initial Phase Continuation Phase 2 Months 4 Months 6 Months Patient Body

Weight (kg)

RHZE (150 mg + 75 mg + 400 mg

+ 275 mg)

RH ( 150mg + 75

mg )

EH ( 400 mg + 150

mg )

30–39 2 2 1.5 40–54 3 3 2 55–70 4 4 3

71 and more 5 5 3 Dosage Schedules for children:

Initial Phase Continuation Phase 2 Months 4 Months Patient Body

Weight (kg)

RHZ (60mg + 30 mg + 150 mg)

RH ( 60 mg + 30 mg )

<7 1 1 8-9 1.5 1.5

10-14 2 2 15-19 3 3 20-24 4 4 25-29 5 5

The use of FDCs does not preclude the need to purchase and stock limited amounts of separate medicines for use in special regimens for patients with drug toxicity or special requirements (average of 2%) Independent laboratories should confirm bioavailability (particularly for R component)

Global Drug Facility (GDF):

A project of Stop TB partnership established in 2001 as a iniative to increase access to high quality TB drugs for DOTS expansion

GDF provides:

- Grants of first line drugs to support DOTS expansion - Direct procurement mechanisms for countries - White list of pre qualified manufacturers of high quality TB drugs - Ongoing technical support and annual monitoring missions - Standardized medicine products and user friendly packaging

Egypt applied successfully for GDF grants to be supplied on three successive years: First grant on 2004 for 1200 patients on Cat. I Second grant on 2006 for 5000 patients on Cat. I Third grant on 2007 for 5000 patients on Cat. I & 500 on Cat. II

II- Quantification: process of estimating the amount of drugs needed to ensure an uninterrupted supply to fully cover estimated TB treatment requirements over a period of time (usually one year). Maintaining an adequate drug supply in the district storeroom and in all the health facilities depends on accurate estimates of drug needs. An adequate drug supply means that all health facilities have enough anti-TB drugs in stock for the TB cases expected to start treatment (all categories of treatment). What is the importance of quantification? • Estimate and prepare the budget needed to purchase drugs • Avoid stock outs • Estimate needs for bulk purchase • Estimate the needs for manufacturers or suppliers to produce. Three options exist for quantification 1- Adjusted-consumption based: Quantification estimates are based on data from a similar region or health service where the number of expected TB cases is known. 2- Consumption based: This alternative method depends on estimates of past consumption. To use this method, the program needs quantities actually dispensed from health facilities and existing quantities in the storerooms and warehouses throughout the system. 3- Morbidity based:

This WHO-recommended method depends on estimates of the number of expected TB cases. The formula for calculating the number of tablets of oral anti-TB drugs and vials of streptomycin needed for expected cases in one year is as follows:

expected number of new cases in each treatment category

next year

X number of tablets or vials needed to

treat one case =

number of tablets or vials needed to treat

expected cases in each category next year

This calculation is repeated for each different tablet and vial used in the facility, until quantities of all drugs for all categories have been determined. How to fill in each number in this formula is described in the next steps. 1- Estimate the expected number of cases in each treatment category next year (Assume that the number of patients in each treatment category next year will be approximately the same as in the previous year)

2- Determine the number of tablets of oral anti-TB drugs and vials of

streptomycin needed to treat one case (The number of tablets or vials needed per case will depend on the regimen and

presentation of the drugs provided)

Estimated drug requirements to treat one adult patient in the 40–54 kg weight band

Drug Category I 2(HRZE) / 4(HR)

Category II 2(HRZE)S / 1(HRZE) /

5(HR)E Combination (HRZE) in mg: H 75, R 150, Z 400, E 275

3 tablets x 30 doses x 2 months = 180 tablets

3 tablets x 30 doses x 3 months = 270 tablets

Combination (HR): H 75 mg, R 150 mg

3 tablets x 30 doses x 4 months = 360 tablets

3 tablets x 30 doses x 5 months = 450 tablets

Ethambutol 400 mg 4 tablets x 30doses x 5 months =600 tablets

Streptomycin 1.0 gram vial

1 g x 30 doses x 2 months = 60 vials

Water for injection(5 ml) 1 vial x30 doses x 2 months =60 vials

3- Multiply the expected cases in the category by the number of tablets

needed to treat one case, e.g. 180 (HRZE) tablets are needed to treat one Category I case.

Repeat the calculation for each different tablet and for streptomycin vials. The sum of all these calculations is the quantity of tablets and vials needed in the district for all expected cases in the category

4-Determine the total amount of each drug that is required to treat all patients during one year for all regimens

5- Once you have calculated the quantity of each tablet and the vials of streptomycin needed to treat the expected cases for the year, you must increase the quantity to allow for reserve stock 25% at the peripheral level (health facility), 50 % at the intermediate level (governorate stores) by the GCT and 75% at the central level (central warehouse). This reserve stock of drugs is to allow for more cases than expected; for delays in procurement, delivery or distribution of drugs, theft, loss or damage due to accidents; or any combination of these factors. 6-Account for the amount of each drug that is in stock at the time of calculation of the drug needs. The stock should be subtracted from the quantities to be ordered.

Selecting second-line drugs

How does selection of second-line differ from selection of first-line? • Only a limited supply of second-line treatments is available. • More drugs are needed for longer periods of time (up to 24 months) than

with first-line treatment. • Second-line drugs are much more expensive (up to 100 times more) than

first line. • Second-line drugs are more toxic than and not as effective as first line.

WHO-recommended second-line drugs • This Model List does not imply that no other drugs could be useful for management of DR-TB, but simply these drugs, when used in accordance with appropriate therapeutic guidelines, cost effectively meet the needs of an important proportion of the population. • The order of the four groups is based on potency, evidence of efficacy, experience of use.

Grouping Drug (Abbreviation)

Mode of Action

Recommended dose (Dose Range) mg / kg Body Weight Daily

Group 1 – First-line oral antituberculosis agents Amikacin (ِِAm) Bactericidal 1 gm daily (15–20) Kanamycin (Km) Bactericidal 1 gm daily (15 ) Group 2 – Injectable

antituberculosis agents Capreomycin (Cm) Bactericidal 1 gm daily (15–20) Ciprofloxacin (Cfx) Bactericidal 1000-1500 daily Ofloxacin (Oflx) Bactericidal 800 daily Group 3 - Fluoroquinolones Levofloxacin (Lfx) Bactericidal 750 daily Cycloserine (Cs) Bacteriostatic 750 daily (10-15) Para-aminosalicylic acid (PAS) Bacteriostatic 150 daily

Group 4 – Oral second-line antituberculosis agents

Ethionamide (Eto) Bacteriostatic 750 daily (15-20) Class 1 – First-line oral anti-tuberculosis: The most potent and best tolerated anti-TB drugs. They should be used where there is laboratory evidence or clinical history to suggest their efficacy. Class 2 – injectable agents: - should be given to all patients in whom susceptibility is documented. - Streptomycin is the usual injectable agent of choice - Kanamycin or amikacin is the logical second choice given the low cost of these drugs and good experience of their use. They are considered to be similar and have close to 100 % cross resistance.

- If an isolate is resistant to both streptomycin and kanamycin, capreomycin should be used.

Class 3 – Fluoroquinolones:

- Should be used whenever the strain is susceptible. - The most potent according to in vitro studies in descending orders are:- 1- Moxifloxacin = Gatifloxacin 2- Levofloxacin

3- Ofloxacin = Ciprofloxacin - Long-term safety of the newer-generation Fluoroquinolones has not yet been fully evaluated.

Class 4 – Oral bacteriostatic second-line anti-tuberculosis drugs

- If only one is needed, ethionamide/protionamide is often added because of its proven efficacy and low cost. - If cost is not a constraint, PAS may be added first because the enteric- coated formulas are relatively well tolerated. - If two agents are needed, Cycloserine is commonly used in conjunction with ethionamide/protionamide or PAS. - Combination of ethionamide/protionamide and PAS has a high incidence of gastrointestinal adverse effects, - In addition, thioacetazone has cross-resistance with the thioamides (ethionamide and protionamide) and is considered a relatively weak antituberculosis agent. Different types of second-line treatment regimens are:—

I- Standardized II- Empiric and later individualized III- Individualized I- Standardized Designing treatment regimen depends on representative drug resistant survey (DRS) data of the general population. All patients in the patient group or category receive the same regimen.

II- Empiric and later individualized DST Pattern at national or

Sub-national level Previous treatment

of contacts Previous

treatment of patients

Individualized treatment DST

Empiric treatment

III-Individualized regimens The regimen is adjusted according to drug susceptibility testing (DST) results of

each individual patient

Treatment regimens for MDR-TB in Egypt

Drug sensitivity test to first line drugs must be confirmed before initiation of treatment.

Patient resistant to

Treatment regimen

RHSE Regimen I 3 months: canamycin daily + Ofloxacin + Cycloserine + Ethionamide + PAS then: 6 months canamycin 5 times a week + previous drugs then: 12 months Ofloxacin + Cycloserine + Ethionamide + PAS

RHS Regimen II 3 months: canamycin + Ofloxacin + Ethambutol + Ethionamide + Cycloserine then: 6 months: canamycin 5 times a week + previous drugs then: 12 months: Ofloxacin + Ethambutol + Ethionamide + Cycloserine

RH Regimen III 3 months streptomycin daily + Ethambutol + Pyrazinamide + Ofloxacin + PAS then: 6 months streptomycin 5 times a week + previous drugs then: 12 months: Ethambutol + Pyrazinamide + Ofloxacin + PAS

How does quantification of second-line drugs differ from first-line drugs: • Shelf life is usually short: 24–36 months for most drugs, 18 for cycloserine, and

treatment duration exceeds shelf life. • The lead-time may be longer because no local manufacturers may be located in

the country. • Ancillary drugs and supplies for managing adverse effects should be considered. • DR-TB management projects are new and expanding in most countries, unlike

first-line TB treatment, where countries have trained personnel with many years of experience estimating drug requirements.

• Reliable epidemiological data for DR-TB are not as readily available as for first-line treatment and data needed for quantification where individualized regimens are used are more difficult to aggregate.

What quantification methods exist? For a new project using standardized regimens, the order should be based on morbidity (number of cases × standardized regimen adopted).

Ancillary medicines for managing adverse effects (first and second-line anti – TB drugs):

• Antiemetics: chlorpromazine, promethazine, metoclopramide, dimenhydrinate, lorazepam,diazepam

• Antiulcer agents: antacids (magnesium and aluminium hydroxide), H2-blockers (ranitidine)

• Antifungal agents: fluconazole or clotrimazole • Antidiarrheals: loperamide • Dehydration agents: oral rehydration salts and intravenous fluids • Antidepressants: amitriptyline, fluoxetine • Anxiolytics: diazepam, clonazepam • Antipsychotics: haloperidol • Anticonvulsants: diazepam, phenytoin, carbamazepine • Prophylaxis of neurological complications: pyridoxine (vitamin B6) • Agents to treat peripheral neuropathy: amitriptyline, ibuprofen • Agents to treat vestibular symptoms: meclizine • Agents for cutaneous reactions: corticosteroid creams (hydrocortisone), anti-

pruritus lotions (calamine) • Analgesics for arthralgias and arthritis: ibuprofen, acetaminophen • Thyroid replacement hormones: levothyroxine • Diuretics: furosemide, amiloride • Agents for bronchospams: bronchodilators (albuterol), inhaled

corticosteroids (beclomethasone) • Agents for systemic hypersensitivity reactions: diphenhydramine,

prednisone, dexamethasone, epinephrine

Section 2 Procurement

Procurement: is the process of acquiring drugs and supplies, including those obtained by purchase and donation. An effective procurement process ensures the availability of the right drugs in the right quantities at reasonable prices, and at recognized standards of quality. Practice Effective Pharmaceutical Procurement The goals of procurement are:

• Procure the most cost-effective drugs in the right quantities; • Select reliable suppliers of high-quality products; • Ensure timely delivery.

To achieve these goals:

1. A clear and efficient procurement system through the Ministry of Health and Population is established involving the procurement department and the Drug regulatory Authority (at the central level)

2. The most appropriate procurement method is used, that is an open tender set by the Ministry of Health, and a request for bids open to all interested prequalified suppliers is declared.

3. Identifying drugs and their quantities based on standardized treatment regimens.

4. Assure quality of suppliers. 5. Providing specifications for drugs and packaging 6. Assuring TB drug quality. 7. Monitoring suppliers’ performance concerning lead times, products' quality,

supplier's services,

After procuring and receiving the drugs, you can help ensure the quality of drug products purchased by:

assuring that quality specifications are included in the drug supply contracts;

having each drug inspected for appearance of the product and its packaging;

having laboratory tests conducted to test the quality of the drug’s active ingredients;

Monitoring handling and storage conditions of the drug.

Undertake special monitoring of FDCs. Fixed-dose combination (FDC) drugs, especially combinations containing rifampicin, require special monitoring to assure quality, including laboratory testing and verifying bioavailability in humans.

Procurement mechanisms for second-line TB drugs Two options exist— • A competitive tender in international markets using procedures similar to those described for first-line drugs. • Direct procurement using the Green Light Committee mechanism Direct procurement Is an adequate mechanism when market forces fail, as is the case for second line TB drugs. This market failure can be explained by the fact that little demand exists for second-line drugs, which means few suppliers are interested in meeting the low demand; as a result, little competition exists, which, in turn, implies higher prices. The Green Light Committee was established with that purpose in mind. It functions as a pooled procurement mechanism for second-line TB drugs GLC quality assurance The GLC can feel confident that high-quality second-line TB drugs are being procured under IDA because IDA uses good distribution practices (according to WHO guidelines) and prequalifies manufacturers (it assesses quality assurance systems, audits manufacturing plants, performs laboratory analysis on batch samples, and sends information and documentation to facilitate registration of drugs in-country). Some challenges that countries have faced while procuring second-line drugs through the GLC have been noted. • It usually takes four months from the time an order is placed until the second-line drugs are delivered because no drugs are kept in stock by the procurement agent and manufacturers of second-line TB drugs produce these drugs on demand. • Special attention needs to be paid to inventory control because capreomycin and cycloserine have a particularly short shelf life, or expiry date (18 months from one supplier).

Section 3 Distribution

A distribution system ensures a continuous flow of drugs and supplies from a central point to the end-user facilities. Unlike most drugs, first-line TB drugs do not have effective substitutes if stock runs out. Good distribution ensures that all TB drugs are available in the quantities needed, at all points of administration to patients, at all times. A well run distribution system should:

Maintains a constant supply of drugs Keeps drugs in good condition Minimize drug losses due to spoilage and expiry Adhere to drugs storage conditions. Use available transport as efficiently as possible Provide information for forecasting drug needs

It is composed of four major elements:

1. The system’s design (degree of centralization, push versus pull ordering, number of different levels )

- Pull system: each level of the system determine what types and quantities are needed - Push system: the supply source determine the types and quantities to be delivered to the lower levels according to the plan 2. An information system (inventory control, records and forms,

consumption reports. information flow) Reliable management information is vital for coordinating the distribution network. The information system consists of forms and procedures to record inventory levels, and receipt and issue of drugs. Reports should be prepared regularly to summarize drug consumption. Individual health facilities report to governorate level which in turn report to the central level 3. Appropriate storage (locations, building design) 4. Delivery mechanism (collection versus delivery, choice of transport, vehicle

availability, and scheduling of deliveries). Common problems with requisition and transportation or delivery of TB drugs

• TB drugs do not arrive at the peripheral health facilities in time. • TB drugs do not arrive at the peripheral health facilities at regular intervals;

instead their delivery is sporadic. • Health facilities often run out of TB drugs. • Health facilities often have an oversupply of TB drugs, possibly leading to

expiry of these drugs.

Second-line TB drugs are considered alongside first-line drugs, because distribution mechanisms do not differ in every aspect. Some differences do exist, however. For example, second-line drugs have a shorter shelf life than first-line drugs, and drugs for treating adverse reactions should be kept in stock. Another difference is that inventory control and reordering of second-line drugs is based on consumption not morbidity, because even standardized regimens may be modified throughout a treatment course if results are poor or adverse reactions develop. What are inventory and inventory control? Inventory: is the total of all products kept on hand at any storage point. Inventory control: is the process of supply management aiming at providing sufficient stocks of drugs. The components of an effective inventory control are— • Keeping a balance between service (i.e. working or consumption) and stock (i.e. security) levels. Stock level (25 %) should always be in place during dispensing • Following a well-designed policy for the frequency of reordering needs. • Using standard methods to calculate reordering quantities. • Maintaining records that track receipt and distribution of all TB drugs.

Figure 2 Ideal Inventory Control Method

Working stock depends heavily on monthly drug consumption and lead time. Please see figure3 and note that— - Working stock is determined by the minimum and maximum stock levels needed. - Average inventory = safety stock (SS) + ½ working stock (WS). - If the quantity to be ordered is reduced, more frequent deliveries are needed. - Reducing quantity ordered may reduce holding costs but increases procurement and transportation costs.

For instance, the security stock level may be equivalent to three months of consumption in health facilities, and six months in the intermediate and central warehouse. The basic data to generate this information must be registered in electronic or manual records (bin cards)

Storage

Good storage practices in warehouses are essential to ensure that TB drugs are handled efficiently, waste is limited, and loss caused by expiry is kept to a minimum. Medical stores must have a system for classifying or organizing drugs, and must ensure that all employees know the system being used. Each medical store should maintain a standard list of stock items that includes all products they handle, with their specifications, including form, strength, and quantity per package. The list should be regularly updated. Mechanisms to improve TB stock management: • The stock area is divided into zones for easy location of different Products. • Ensure there is sufficient storage space. • Cleanliness of area is ensured. • Record the date and quantity received on stock cards or bin cards • Arrange products in the storage area to facilitate the first to expire or first in ,

the first- out (FEFO) • The environment of the warehouse protects drugs from factors that could

inhibit their effectiveness or use, such as, sunlight, heat, cold, moisture, pests, and theft.

The temperature, light and humidity in the main storeroom should be kept moderate. Though anti-TB drugs are very stable, a drug storeroom should not have excessive heat, light or humidity, as these can cause some drugs to spoil. For instance, some tablets, such as ethambutol, absorb humidity from the air and deteriorate.

Storage conditions can be improved by some simple measures. Temperature can be

tilation, reating drainage areas, and repairing any roof leaks quickly.

or drink in e storeroom. This will help to keep the storeroom clean and free of pests.

date. The shelf life remaining must be sufficient for the

products that will expire first in front of products with

roducts you received most recently may expire s

an the products you received earlier. Therefore, it is extremely important to lways check the expiration dates and to make sure the dates are visible while the

• If using pallets, stack cartons on pallets—

up and identification

labels, expiry dates, and manufacturing dates are visible. If this is not possible, write the product name and expiry date clearly on the visible side.

controlled by using fans, air vents or windows to increase ventilation, and by using insulating materials for the roof and ceiling. Direct light can be prevented from entering the room by hanging curtains or painting the window glass. Humidity can be controlled by increasing vencNo one should eat, drink or smoke in the storeroom. Do not keep foodth Following FEFO minimizes wastage from product expiry. ■ always issue products that will expire first, ensuring they are not too close to or past their expiration product to be used before the expiry date. ■ To facilitate FEFO, place a later expiry date. ■ Write expiry dates on stock cards, so stocks can be sent to facilities at least 6 months before they expire. Remember, the order in which you received products is not necessarily the order inwhich they will expire. P ooner thaproducts are in storage.

Arrange the storeroom and shelves as follows:

At least 10 cm (4 inches) off the floor At least 30 cm (1 foot) away from the walls and other Stacks No more than 2.5 m (8 feet) high (general rule). Arrange cartons so arrows point

Dispensing and consumption

Dispensing consists of all the activities that occur between the times the prescription is presented and the drug is issued to the patient. Dispensers (usually pharmacists, doctors, nurses, or other health care workers) should check patients’ understanding of instructions for taking the given drugs by asking each patient to repeat the instructions. According to the DOTS strategy, administration of TB drugs should be directly observed (DOT, or directly observed treatment). Although, in practice, DOTS is usually undertaken by the prescriber or dispenser the dose taken should be recorded on the proper forms immediately in order to accurately control drug consumption. Consumption reporting records are an essential component of an efficiently run dispensary. They serve primarily to— • Help verify stocks used • Assist with tracing problems in drugs issued to patients (who may have adverse side effects, for example) • Place orders (using the consumption method)

Section 4 Use

The “use” activity includes appropriate diagnosing, prescribing, and dispensing drugs by health providers, and their consumption by patients. Ideally, rational use of drugs includes the following criteria—

Correct drug &appropriate indication Appropriate dosage, administration, and duration of treatment Appropriate patient—that is, no contraindications exist and the likelihood of

adverse reaction is minimal Correct dispensing, including appropriate information for patients about the

prescribed drugs Given that patient adherence to TB treatment can be a considerable challenge. WHO recommends that TB programs implement a number of measures to facilitate the treatment process.

Providing free TB drugs. Using a patient-centered approach Using directly observed therapy. Use of fixed-dose combinations (FDCs): because these drugs significantly

reduce a patient’s pill burden and can significantly improve adherence levels. The challenge of treatment adherence I- Factors associated with the health facility

TB drug stock outs Poor organization of service delivery (Lack of privacy, inconvenient

opening hours, and long waiting times are barriers for patients' access to treatment.)

Poor quality of medical care (Inconsistent supervision of health facility staff, expired drugs and reagents, and poor attitudes of the staff members to patients )

Barriers to optimal performance (for example, a lack of budget for transport may be preventing them from tracking defaulters. A lack of supportive supervision.)

II- Factors associated with the patient • After they have started treatment, patients usually start to feel better. • Adverse reactions to TB drugs may result in similar patient behavior. • Patients may not believe the treatment is having any effect and thus

discontinue drug intake. Possible strategies to improve adherence to TB drugs

• Set up a system for direct observation of patients who are taking drugs. • Train & monitor prescribing practices. • Establish relations with private providers. • Provide unit dose packages. • Educate patients and communities. • Develop incentives and enablers for both providers and patients.

Management Support

Even if all four drug management activities are in place, they cannot be carried out well without management support. The management support component at the center of the drug management cycle represents a variety of different management support systems that are required during all activities of the cycle and at all organizational levels, from the national program level down to where drugs are prescribed and dispensed to patients.

Management support includes various subcomponents— • Organization and management • Financing and sustainability • Information management • Human resources management when planning for improvements in TB pharmaceutical management, the leader of a TB control program will need to develop these plans, mobilize internal and/or external funding support, implement the plans (taking into consideration management issues of organization, financing, information flow, and human resources), and monitor and evaluate the program’s performance prior to and following implementation of proposed changes. Indicator-based monitoring is an essential activity that should be routinely conducted by national tuberculosis programs. Why use indicators? Indicators provide the most solid base for monitoring and evaluation of the TB pharmaceutical supply system. They provide information about the rate at which the program is reaching the intended goals. When selecting an indicator, keep in mind that indicators are most effective when they are— • Simple: easily understood by everyone • Measurable

Quantitative: such as rates, ratios, percentages, common denominator (for example, population)

Qualitative: “yes,” “no” • Accountable: reflect an important dimension of performance • Reliable: can be collected consistently by different data collectors

• Time bounded: represent a true measure

The indicators are grouped under corresponding components of the pharmaceutical management cycle. The number assigned to each indicator corresponds to the detailed description of indicators

The description of the indicators may help identify what data need to be collected and where and how to calculate the indicator. Note that if the indicator number contains a K or C, the indicator is key (always needs to be collected) or complementary (used to broaden the monitoring of TB pharmaceutical management activities). The indicators without a number may also be used. TB partners may be able to provide the necessary technical assistance in setting up a TB drug indicator system based on local requirements. Drug Policy C-1. Percentage of NTP drug products included on the national essential drugs list

• Existence of a national TB drug policy to support national TB program goals • Number of suppliers of TB drugs registered in the country • Average number of days to register or re-register TB drugs • Cost of TB drug registration (single dose, combo pack, FDC)

Procurement Average lead time for orders placed for TB drugs during the last three procurements measured from the time order is submitted to procurement department or office for purchasing to the time order is received in warehouse Distribution K-1. Average percentage of time out of stock any kind of TB drugs

C-7. Average percentage of stock records that correspond with physical counts

• Percentage of facilities that store TB drugs according to standard TB storage specifications

• Value of expired TB drugs last quarter

Drug Use K-3. Percentage of new smear-positive patients with pulmonary TB who were prescribed correct drugs in conformity with the standard treatment guidelines C-6. Percentage of TB patients who receive treatment under direct observation regularly C-5. Percentage of TB outpatients who could correctly describe how the prescribed medication should be used Quality Control K-4. Percentage of TB drugs in the past three shipments that were accompanied with a batch certificate C-3. Percentage of TB drug samples that failed quality-control testing out of the total number of TB drug samples tested during the past year.

Important definitions:

Bioavailability: The availability of a drug in the body over time from the moment it enters the blood stream until it is metabolized or excreted. Measuring this availability helps to determine whether drugs with the same active ingredients, but manufactured by different companies, behave the same way inside the body.

Competitive negotiation: A method of procurement in which the buyer approaches a limited number of suppliers selected by the buyer and bargains with them to achieve specific price or service arrangements.

Direct procurement: The simplest, but often most expensive, method of procurement in which the buyer purchases an item from a single supplier at its quoted price.

Dosage form: The physical form in which a drug is produced or prepared for administration to a patient (e.g., as a tablet, capsule, intramuscular injection...etc)

DOTS: The official name for the WHO-recommended strategy for TB control and formerly an acronym for directly observed treatment, short course.

DOTS-Plus: A management initiative by the Stop TB Partnership for the control of drug-resistant TB (DR-TB), built on the five elements of the DOTS strategy. If a TB control program already uses DOTS, it can subscribe to this initiative and obtain lower prices for second-line TB drugs needed for treating DR-TB.

Drug product: The combination of an active ingredient (drug) in a specific amount (strength) and physical form (dosage form) (e.g., isoniazid 100 mg tablets).

Enabler: An item or action that helps a patient receive treatment, such as provision of transportation, bus fare, or funds for outreach, in contrast to an incentive or small reward, such as food.

Essential drugs: Drugs that satisfy the basic health care needs of the majority of a population (e.g., a country or community). Essential drugs are selected by considering the drugs needed to treat the common diseases affecting that population and standard treatment guidelines. Essential drugs should be available at all times in adequate amounts, in the appropriate dosage forms, and at a price that individuals and communities can afford.

First-line drugs: Drugs prescribed for initial therapy of the patient. If first-line drugs fail to successfully treat the infection, providers prescribe second-line drugs.

Global TB Drug Facility (GDF): is an initiative of the Global Partnership to Stop TB, housed in WHO & managed by Stop TB partnership secretariat It aims to supply quality assured, affordable drugs in a timely manner.

Multidrug-resistant tuberculosis (MDR-TB): Tuberculosis that is resistant to at least isoniazid and rifampicin, two of the most powerful first-line TB drugs.

National drug policy (NDP): A document containing a government’s goals for the pharmaceutical sector and the main strategies for reaching these goals. It provides a framework for coordinating activities of the public and private pharmaceutical sectors, NGOs, donors, and other interested groups. It serves as a valuable guide for improving access to drugs, use of drugs, and quality of drugs.

Prequalification: A process in drug procurement by which a buyer determines whether a supplier meets specific criteria before advertising tenders. The buyer later invites only suppliers who meet the prequalification criteria to bid on the drug tenders. Prequalification is one form of selecting suppliers.

Rational drug use: Programs achieve rational drug use when patients receive drugs appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community.

Selection of suppliers: A process in drug procurement by which buyers identify the suppliers from whom they can reliably order drugs of good quality at reasonable prices. Selection of suppliers can occur as prequalification, before tenders are advertised, or as post qualification, after tenders are advertised and bids are received. To select suppliers, buyers should require certificates from manufacturers indicating that the manufacturers are licensed and inspected by local authorities, gather information on suppliers’ reliability and product quality, inspect samples of products, and, if necessary, conduct laboratory tests of drugs that may be unstable or have problems with bioavailability.

Standard treatment guidelines (STGs): Recommended treatment practices for a diagnosed illness. DOTS recommend different treatment regimens depending on a TB patient’s situation. For example, the DOTS STGs specify different drug combinations and duration of therapy for patients who have recently developed active infectious TB and those who are being retreated due to previous treatment failure or relapse.

Tender: The procedure in which a buyer formally invites bids from suppliers for a particular contract. The contract defines the buyer’s specific terms and conditions. In an open tender, a buyer formally invites bids from any local or international manufacturer for the supply of drugs under their nonproprietary names. In a

restricted tender, a buyer limits bidding to suppliers who meet certain prequalification requirements.

Transparent: A feature of a process meaning that the process is so clear and open that outside parties can understand all actions and decisions.

Bin Card: Card that records recipients, issues, and balances held in the stores.

Detection rate: the number of cases that occur during a certain time period, divided by the size of the population during that time period; the case rate is often expressed in terms of a population size of 100,000 persons.

Index case: the first case among the number of similar cases which are epidemiological related. Also identified as a source of infection.

A smear-positive pulmonary TB: A patient with at least two sputum specimens positive for AFB Or, a patient with at least one sputum specimen positive for AFB, which is culture positive for M. tuberculosis, or with radiological abnormalities consistent with pulmonary TB.

A smear-negative pulmonary TB: A patient with two sets (taken at least two weeks apart) of at least three sputum specimens that are negative for AFB, radiological abnormalities consistent with pulmonary TB and a lack of clinical response to at least two weeks of a broad spectrum antibiotic.

New case: A patient who has never had treatment for TB or who has taken drugs for less than one month.

Relapse: A patient who is declared cured by a physician, after one full course of chemotherapy, and has become sputum smear-positive.

Treatment failure: A patient who, while on treatment, remained or became again smear-positive 5 months or later after commencing treatment; Or, a patient who was initially smear-negative before starting treatment and became smear-positive after the second month of treatment.

Treatment after interruption: A patient who interrupts his treatment for 2 months or more (defaulter) and returns with smear positive sputum.

Chronic case: A patient who remained or became again smear-positive after completing a fully supervised retreatment regimen.

وزارة الصحة و السكان الإدارة العامة للأمراض الصدرية البرنامج القومى لمكافحة الدرن

)ت الصنفآار (

: ........................................اســــــــــم الصنف : ..............................................تــاريــخ الإنتهــاء )( رقــم الصنـــف ............ جرد العام السابق الكمية المنصرفة

الكمية الواردة

رقم إذن الصرف

رقم إذن التوريد

الكمية المنصرفة

الكمية الواردة

رقم إذن الصرف

رقم إذن الرصيدالتوريد الجهه يخالتار الرصيد الجهه التاريخ

وزارة الصحة و السكان

الإدارة العامة للأمراض الصدرية البرنامج القومى لمكافحة الدرن

)التقرير الربع سنوي(

...............: ..محافظة

......................مستوصف / مستشفى

: .......................الربع

تاريخ الصلاحية الرصيد النهائىالمستهلك خلال

الربع

المنصرف لوحدات

اخرى اســـــم الصنف الرصيد اول الربع الوارد خلال الربع

275ايثامبيتول + 400يد بيرازينام+ 75ايزونيازيد +150 مبيسينريفا

75ايزونيازيد +150 مبيسينريفا

150ايزونيازيد +300 مبيسينريفا

300 ريفامبيسين

150ريفامبيسين

ريفامبيسين شراب

500ايثامبيتول

500بيرازيناميد

100ايزونيازيد

جم 1ستربتومايسن

References and suggestion for further readings:

1. Managing Pharmaceuticals and Commodities: A Guide for National Tuberculosis Programs (Rational

Pharmaceutical Management Plus, December 2005).

2. Guidelines for the programmatic management of drug-resistant tuberculosis (WHO / HTM / 2006.361)

3. Operational guide on the introduction and use of fixed dose combination drugs ( WHO /CDC / TB 2002.308)

4. National Tuberculosis Control Programme Guidelines, Egypt.