National Guidelines For Supply Chain Management in Drug Resistant Tuberculosis (DR-TB)

National TB Control Program Pakistan Ist edition September 2010 2nd edition April 2014

Contents Foreword ........................................................................................................................................ 3 List of Abbreviations .................................................................................................................... 4 Introduction ..................................................................................................................................... 6 Chapter 1 ......................................................................................................................................... 8 Definition of Drug Management and Selection .......................................................................... 8 Chapter 2 ....................................................................................................................................... 11 Procurement, Distribution, Storage and Use of SLD ................................................................ 11 Chapter 3 ....................................................................................................................................... 18 Management Support, M&E and Pharmacovigilance .............................................................. 18 Annex 1 ......................................................................................................................................... 20 Ancillary Medicines for Managing Adverse Effects to First and Second-Line TB Medicines 20 Annex 2 ......................................................................................................................................... 21 Supplies Needed to Manage First and Second-Line Tuberculosis ........................................... 21

Foreword Tuberculosis (TB) continues to be a major public health problem in Pakistan. The estimated incidence of all forms of TB in Pakistan is 410,000 cases per year according to the WHO Global TB Report 2013. The National TB Control Program in partnership with the Provincial TB Control Programs is implementing the DOTS strategy and has achieved 100% DOTS coverage in public sector in 2005. Through sustained commitment, strengthening of partnerships with the public and private sectors, and introduction of new initiatives, the program steadily improved case detection and treatment outcomes for TB patients. The notified cases of TB in year 2013 were 273,093.The Government of Pakistan is committed to control TB by achieving MDG targets through the New Stop TB Strategy. It 2009, NTP stepped forward and started managing M/XDR-TB in line with the New Stop TB Strategy (WHO 2006). The estimated MDR-TB cases among notified TB, according to WHO, are 11,400. The recent DRS study which was conducted in Pakistan showed that the estimated percentage of MDR in new notified TB cases is 4.3% and in retreatment cases is 19.4%. In order to combat the menace of MDR-TB, the NTP has taken important steps that include constitution of a Technical Working Group, development of MDR expansion plan and National Guidelines; establishment of National Reference Laboratory and labs at regional and peripheral level for Culture & Drug Susceptibility Testing; establishment of treatment sites for programmatic management of drug resistant TB (PMDT) in secondary and tertiary care hospitals both in Public and private sector, procurement of quality assured Second Line Drugs through the Global Drug Facility and a Drug Resistance Survey. NTP pursue the principle of high quality uninterrupted supply of anti TB medicines at all levels. To ensure this commitment, the National Guidelines for Supply Chain Management in DR-TB has been revised to update the first edition, the Tuberculosis Medicine Management guidelines for Second line treatment, which was published in 2010. The Guidelines focuses on Pharmaceutical Management Cycle and addresses policies relating to selection, procurement, distribution, use and management support for Second Line Drugs (SLD). The target audience for this document is the TB Program Managers, MDR and Drug Management Units at central level, Pharmacists and other technical officers at PMDT treatment sites, Provincial TB Control Managers, district level officers and others who are involved with management of TB Drugs. The technical and operational capacity of TB Control program both at National and Provincial level will be enhanced by proper implementation of policies and procedures laid down in these Guidelines. It will further facilitate development of skilled human resource for effective management of Anti TB medicines. It will also make possible efficient delivery of potent ATT medicines to DR TB cases and progress towards NTP’s stated objectives will be supported Dr. Ejaz Qadeer National Manager National TB Control Program Pakistan

List of Abbreviations

DMU DST FLD

Drug Management Unit Drug Susceptibility Testing First Line Drugs for TB treatment

GLC

Green Light Committee

MDR-TB

Multi drug-resistant tuberculosis

M&E

Monitoring and Evaluation program

NTP

National TB Control Program

PMIS

Pharmaceutical Management Information System

SLD

Second Line Drugs

TWG UN

Technical Working Group United Nations

WHO XDR-TB

World Health Organization Extensively drug-resistant tuberculosis

Drug Abbreviations

Anti-tuberculosis drugs Group

Description

1

First line oral ATT drugs

2

Injectable ATT drugs

3

Fluoroquinolones

4

Oral bacterio-static second line ATT drugs

Drug Isoniazid Rifampicin Ethambutol Pyrazinamide Rifabutin Kanamycin Amikacin Capreomycin Streptomycin Levofloxacin Moxifloxacin Ofloxacin Ethionamide Protionamide Cycloserine Terizidone P-aminosalicylic acid

Abbreviation H R E Z Rfb Km Am Cm S Lfx Mfx Ofx Eto Pto Cs Trd PAS

5

Anti tuberculosis Clofazimine drugs with unclear Linezolid efficacy or unclear Amoxycilline/Clavulanate role in DR-TB Thioacetazone treatment (not Clarithromycin recommended by Imipenem WHO for routine use in DR-TB patients) Antiretroviral drugs Class Name Non-nucleoside reverse transcriptase inhibitors Efavirens Nevirapine Nucleoside reverse transcriptase inhibitors Zidovudine Lamivudine Stavudine Didanosine Zalcitabine Abacavir Tenofovir

1

Cfz Lzd Amx/Clv Thz Clr Ipm

Abbreviations EFV NVP AZT 3TC D4T ddl ddC ABC TDF1

TDF is a nucleotide reverse transcriptase inhibitor but is typically grouped with this class of drugs.

Introduction Tuberculosis (TB) remains a major global health problem. In 2012, an estimated 8.6 million people developed TB and 1.3 million died from the disease (including 320 000 deaths among HIV-positive people)2. The number of TB deaths is unacceptably large given that most are preventable. Pakistan belongs to the league of 22 high TB burden countries in the world and is also on the list of the 27 high MDR-TB burden countries with an estimated 11000 (range: 0- 29000) MDR-TB cases among notified Pulmonary TB cases in 20123. A countrywide representative Drug Resistance Survey (DRS) has been conducted in 2012 and the preliminary results show that the estimated percentage of TB cases with MDR-TB are 4.3% and 19.4% among New and Retreated cases respectively. Factors like poverty, malnutrition, poor housing and sanitation, inadequate health care facilities, population migration and urbanization, political instability and refugee influx have all continued to aggravate the problem of TB and DR-TB. TB has infected human beings all over the world for a very long time. The emergence of mycobactericidal drugs like Streptomycin, Rifampicin, and Isoniazid in the first half of the 20th century along with adequate drug combination treatment protocols created hope that the disease could be adequately controlled. Towards the end of the previous century it was realized with dismay by the medical community that there is a rising incidence of TB, and in 1994 TB was declared a Global Emergency by WHO resulting in the formation of the STOP TB partnership. In addition, resistance to many anti- tuberculosis drugs was reported. The aspects of poor or unknown drug quality, inadequate regimens, poor availability of drugs with interrupted supplies, lacking health education, inadequate patient follow-up, poverty and malnutrition, and a lack of a political commitment and resource mobilization have all contributed to the emergence of drug resistant strains of Mycobacteria. MDR-TB, defined as TB caused by organisms that are resistant to Isoniazid and Rifampicin (two first-line anti-TB drugs) continues to threaten the progress Pakistan has made in controlling TB. Additionally, there is a growing concern about the emergence of XDR-TB, MDR-TB that is resistant to any one of the Fluoroquinolones and to at least one of the three injectable second-line drugs (Kanamycin, Amikacin or Capreomycin). Since MDR & XDR TB are resistant to some of the most powerful ATT (FLD & SLD) drugs, patients are left with treatment options that are often less effective, require prolonged treatment periods with very expensive drugs and are at higher risk for side effects and treatment failure. The current global picture of TB shows continued progress, but not fast enough. Globally in 2012, an estimated 450,000 people developed MDR-TB and there were an estimated 170,000 deaths from MDR-TB4. 2

WHO / Global TB Report 2013, http://www.who.int/tb/publications/global_report/en/ http://www.who.int/tb/publications/global_report/en/ 4 http://www.who.int/tb/publications/global_report/en/ 3

In 2009 Pakistan was approved through the previous GLC mechanism to start treatment for 400 MDR-TB patients. Programmatic Management of Drug Resistant TB (PMDT) was piloted in three hospitals in 2010 through Global Fund support. Table 1.3 shows the number of Drug Resistant TB (DR-TB) cases who were enrolled on treatment between 2009- 2013. Table 1.3 DR-TB enrolments Year 2009 Number of enrolled DR-TB cases 25

2010 2011 210 498

2012 892

2013 1570

In 2013 Pakistan was declared as an MDR-TB Waiting List-free country where all the patients, who were initially diagnosed with DR-TB and kept on a waiting list at PMDT Treatment sites, were enrolled on treatment. Scaling up of PMDT has been funded through Global Fund grant, targeting the enrolment of additional 8200 cases by 2015 in 30 designated PMDT sites and hospitals. At the time of revising these guidelines, there are 18 PMDT sites which are functioning and providing treatment for DR-TB patients in the country. These centres are public or private, and their PMDT work is coordinated and supported by the NTP. Treatment and management of multi drug resistance TB (MDR-TB) is expensive, prolonged, and associated with multiple adverse effects of drugs. These factors have contributed to poor patient compliance further increasing prevalence of MDR-TB in numerous communities. Factors like proper diagnosis and infection control measures, correct DOTS implementation, precise treatment prescription by knowledgeable medical providers, and comprehensive social support for the duration of the treatment are some of the important steps to bring the high burden of MDR-TB in Pakistan in line with the program’s strategic goal and objective which is to reduce the burden of MDR-TB in the country and achieve universal access to diagnosis and management of DR-TB cases by 2020. This supply chain management guideline provides guidance and recommendations to manage SLD in drug-resistant TB based on the WHO and other internationally recognized Guidelines for the programmatic management of drug-resistant tuberculosis.

Chapter 1 Definition of Drug Management and Selection Definition of Drug Management Drug management is a set of practices through which drug-requirements are quantified, procured and distributed all the way from supplier to the ultimate user ensuring the availability of good quality, safe, effective and appropriate use of medicines (and related products) and services in any health care settings. The following Drug Management Cycle summarizes the above said activities:

DM Cycle Selection

Use

Management

Procurement

Support

Distribution

5

Policy/Regulation Framework

Selection The National Guidelines for the Programmatic Management of DR-TB provides treatment strategy and designs for the selection of appropriate individualized treatment regimen for each DR-TB case based on the latest WHO and other well known International guidelines. Classes of Anti-Tuberculosis drugs in DR-TB management: Anti-Tuberculosis drugs are divided into five groups: Group 1 – First-line oral anti-tuberculosis drugs which include Isoniazid (H), Rifampicin (R), Ethambutol (E), and Pyrazinamide (Z)

Group 2 – Injectable anti-tuberculosis drugs which include Streptomycin (S), Kanamycin (Km), Amikacin (Am), Capreomycin (Cm), and Viomycin (Vi) Group 3 - Fluoroquinolones which include Ofloxacin (Ofx), Levofloxacin (Lfx), and Moxifloxacin (Mfx). Group 4 – Oral bacteriostatic second-line anti-tuberculous drugs such as Ethionamide (Eto), Protionamide (Pto), Cycloserine (Cs), Terizidone (Trd), and P-aminosalicylic acid (PAS) Group 5 – Anti-tuberculosis drugs with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients). These may include Clofazimine (Cfz), Amoxicillin/Clavulanate (Amx/Clv), Clarithromycin (Clr), Linezolid (Lzd), Thioacetazone(Thz), Imipenem/Cilastin(Imp/Cln),and High Dose INH. Hierarchy of drugs for DR- TB

Most efficacious and best tolerated Bactericidal Bactericidal less efficacious and poorly tolerated

Weak Anti TB action

A systematic approach is applied in treatment selection taking in consideration the patient’s previous history of SLD use and the DST pattern of each case to ensure a minimum of 4 essential or near essential core drugs for each treatment regimen. Often the patient requires 5 or more drugs to provide adequate treatment coverage. Lists of ancillary medicines for managing adverse effects to second-line TB medicines and supplies needed for diagnosing and managing TB cases are also provided in the Guidelines and are appended to this document as Annex 1 and Annex 2, respectively Compared to the FLDs, the SLDs are much more expensive (up to 100 times more). These medicines are needed for longer periods of time (up to 24 months) than with first-line treatment, their expiry dates are shorter (18 – 24 months), and their safety profiles are poor, causing more side effects than the FLDs. Treatment Code: The following code is an example on how treatment selection is written:

Chapter 2 Procurement, Distribution, Storage and Use of SLD Procurement In order to ensure WHO quality assured SLD supply to the MDR program in Pakistan, NTP is currently procuring SLD through the Global Drug Facility (GDF) which utilizes the services of an internationally renowned pharmaceutical supplier called IDA - a non-profit organization – which supports health care in low-and middle-income countries by providing high-quality drugs and medical supplies at the lowest possible price.5 However, due to the prolonged lead time of drug order (4-6 months) and the increasing difficulty to obtain the mandatory “No Objection Certificate” from the Government of Pakistan to import SLD of Indian Origin, there is a great need to get the WHO Prequalification Program operative in Pakistan so that most of these drugs can be procured locally. Quantification and Placing a SLD Order Request at the Central Level

There are important differences to be kept in mind for quantification of SLDs (as compared to the FLDs) as follows: • • • •

SLDs’ effective shelf life (18-24 months) is shorter than most FLDs and the treatment duration may even exceed shelf life. The lead time may be longer in case of international procurement. Ancillary medicines and supplies for managing adverse effects have to be considered. Data needed for quantification of individualized regimens is more difficult to collect, aggregate, and use for estimating medicines requirements.

Ordering second-line TB drugs is a very important activity that is done at this time at the central level. The Drug Order should be placed for at least 12 months supply at a time and should be submitted 9 months in advance to be on the safe side. Some SLD have short expiry date, including cycloserine, capreomycin and PAS. Deliveries of these drugs should be staggered in order to avoid expiration. The following points of information are very essential in placing a SLD Order Request for New Enrolled cohorts: 1- Treatment selection(s) used in the country.

5

More information on IDA can be found at: www.ida.foundation.org

2- Number of patients in the cohort and the percentage of patients using each drug (Amikacin, Capreomycin, PAS, etc.). 3- Completion of the SLD table which will be included in the Procurement Form that is developed by GDF Distribution and Storage Supply Chain distribution

The following graphic illustrates the drug supply distribution among the various levels:

Supply Chain Distribution between the central unit and each PMDT treatment site: o Takes place on a quarterly basis or more often as needed o Cover the estimated needs of SLD for currently enrolled as well as new estimated patients. Ancillary drugs and supplies should also be included. o The Patient’s ENRS Register, SLD Consumption rate and SLD stock balance sheets are reported to the central unit during the first week of each month for monthly M&E of SLD stocks, consumption and forecasted needs..

SLD management at the Treatment Site includes  Preparation of monthly (30 days supply) patient’s drug bags which include SLD drugs and, when available, ancillary drugs for adverse reactions and other drugs used to treat co-morbid diseases such as HIV or diabetes along with family planning supplies.  Patient drug bags should be assembled by the Pharmacy Team in approved and sealable bags and delivered to the DOT clinic by the treatment supporter.  A week in advance, the clinical team at the PMDT site will send to the pharmacy dispensary a signed prescription for each patient who is expected to come during the week for follow up management.  Each bag is verified by the person in charge at the pharmacy with the patient’s name, date and DR-TB # on the bag and the pharmacy logbook is signed by the treatment supporter who receives the bag.  The logbook should be kept at the pharmacy where drug bags are prepared and includes: o Patient DR-TB Registration Number o Date of: i.Prescription received, ii.Prepared by (Pharmacy Team), iii.Checked by (Pharmacy Team in charge ) and signed iv.Received by (Treatment supporter)  The prescription format should include the following information Patient’s name ………………………

DR-TB # No ……………………………

Drug

Dose Morning

Injectable (specify) Cycloserine 250 mg Ethionamide 250 mg Levofloxacin 500 mg Levofloxacin 250 mg PAS (specify brand) PZA 400 mg B6 50 mg Clofazamine Clarythromycin Amo/Clav Linezolid Others Others Others

Evening

SLD management at the DOT clinic (BMU, BHU level): When the medical and paramedic staff at the periphery are fully trained and oriented, they could be involved in the following SLD management:  Receive the monthly supply from the treatment center through the treatment supporter.  Prepare a weekly supply packed in separate daily bags marked for each day and time (e.g. Monday morning medicines)  Explain and handle the weekly supply to the treatment supporter for Daily DOT.  Monitor the patient on a weekly basis during the intensive phase, or bi-weekly during the continuation phase, for adverse reaction.  Prescribe Ancillary drugs by the physician as needed  Keep a record of each visit  Update a copy of the treatment card and communicate with the Clinician at the PMDT treatment center.  Refer the patient back to the PMDT treatment center with a copy of the treatment card on a monthly basis for follow up. Ancillary Drugs The following are some of the commonly used ancillary drugs that should be kept at both the PMDT site and DOT clinic.  Anti-emetics: metoclopramide, prochlorperazine  Anti-depressants: sertraline, fluoxetine  Anti-convulsants: phenytoin  Anti-psychotics: haloperidol, risperidone  Antihistamines: chlorpheniramine  Anti-diarrheals: loperamide  For neuropathic pain: amitriptyline  Family planning: depot medroxyprogesterone acetate  For physical pain: Paracetamol, Ibuprofen. Other Supply Needs In addition to SLD and ancillary drugs, there are needs for items such as:  Laboratory kits and reagents  Infection control measures such as, N95, surgical masks, gloves etc.  Medical supply such as Syringes, needles, and water for injection.  Approved needle disposal containers are also needed for each DR TB Supporter who is providing injections. These disposal containers need to be collected and disposed by the Community DR TB Team according to national protocol

Storage conditions

As a general principle all anti-TB medicines (whether FLD or SLD) are to be stored in dry, wellventilated premises at temperatures between 15–25 °C. Extraneous odors, other indications of poor hygiene, or environmental contamination, high humidity and intense light must be excluded. For those SLDs which need to be stored under defined conditions and shall require appropriate storage facilities, e.g. PAS (see table 1) cold chain will be maintained at all levels of the supply chain. SLDs shall be transported in such a way that their integrity is not impaired and the storage conditions are maintained throughout the supply chain and even during the time of consumption by the patients. Table 1: Storage of Second-Line TB Medicine No.

Medicine

Packing Unit

Dosage Form

Storage Conditions

Vial

Inj

Below 25 °C; In a dry place *

1

Capreomycin

2

Cycloserine

Alum strip

Cap

Below 25 °C; In a dry place

3

Ethionamide

Blister

Tab

Below 25 °C; Protected from light**

4

Prothionamide

Blister

Tab

Below 25 °C; Protected from light

5

Kanamycin

Vial

Inj

Below 25 °C; Protected from light

6

Sachet

Granules

8

Para-aminosalicylic acid (PASER) Para-aminosalicylic Acid 60% Ofloxacin

9

7

Granules

Below 15 °C; To be kept in cold chain in dry condition*** Below 25 °C; In a dry place

Blister

Tab

Below 25 °C; In a dry place

Levofloxacin

Blister

Tab

Below 25 °C; In a dry place

10

Moxifloxacine

Blister

Tab

Below 25 °C; In a dry place

11

Amikacin

Vial

Inj

Below 25 °C; Protected from light

12

Terizidone

Blister

Cap

Below 25 °C; Protected from light

* No more than 60% relative humidity in normal storage conditions ** To be provided to the patient in a light-resistant container *** Transport and storage throughout the supply chain must assure no breaks in the cold chain system Source: Product information sheets

Storage practices and conditions in the community For storage packs or containers for SLD, consider the following options:  Wooden boxes are durable, but can be difficult to take to and from the pharmacy.  Canvas bags are light and convenient, but may tear after several months, so a sufficient supply of replacement bags will be necessary.  Synthetic bags are heavier but more durable than canvas bags. Some are insulated and may help protect the drugs from extreme temperatures.  Most of the SLD can be kept at room temperature (less than 30 c) away from light.  PASER® is one of the brands of PAS that is available through the Global Drug Facility should be stored in a refrigerator in the pharmacy. However it is stable at room temperature for several weeks. This means that the monthly drug pack, once

delivered to the patient or DR-TB Supporter, does not need to be refrigerated unless temperatures are extremely high. At this time the NTP is not using this brand of PAS since heat-stable brands of PAS are also available through the Global Drug Facility.

Security Most of the SLDs are very costly and prone to theft and pilferage. Therefore, special measures must be taken for their safe keeping through improved inventory management and security procedures. The responsibility for establishing and maintaining a system for the safe and secure handling of medicines lies with the designated in-charge of the pharmacy or medical store. Such measures as necessary shall be devised in consultation with the senior medical and nursing staff The necessity to designate an in-charge of the medical store at each health facility and distribution point has already been alluded to in the FLD guidelines. Such a person shall have defined authority, responsibility and accountability for ensuring that a security management system is implemented and maintained. Access to all pharmacy stores shall be secured and all entrances shall have solid doors fitted with security locks requiring keys, digital lock or swipe-card access. Access shall be restricted to authorized individuals or persons accompanied by authorized individuals. The refrigerator must be kept locked when not in use Arrangements must be in place, (by means of introduction of standard operating procedures, induction programs, training courses and the carrying out of regular checks) to ensure a high degree of security awareness exists within the health facility staff with respect to medicines, prescription pads, prescription charts and medicines requisition books. Use of SLDs Access to SLDs must be accompanied by strong measures to ensure their rational use. Misuse of these drugs will result in loss of susceptibility to the second-line agents, producing resistant form of tuberculosis that will be extremely difficult to cure with currently available medicines. The measures necessary to promote rational use and dispensing of SLDs will be laid out in detail in the manual for rational use and dispensing of ATT drugs already planned to be developed by the NTP by the end of 2010. NTP mandates provision of laboratory facilities for DST to first and second line medicines in Pakistan so that individualized regimes could be used for MDR TB treatment. Rational dispensing and use of SLDs is also important when compared with FLDs when multiple treatment regimes might be in use. It also needs to be taken into account that SLDs are the last resource for the treatment of TB and the standardized or individualized regimens usually include the most potent medicines available; for that reason limited options exist for a change of regimen or even for lowering the dose of one or more medicines. Adverse drug reactions therefore must be identified rapidly and treated aggressively so patients will not default in their treatment.

The success of a rational drug use policy shall depend on successful implementation of an information loop consisting of steps involving assessment of the existing practices, identifying drug use problems and their causes, designing and implementing interventions and finally measuring the resulting outcome. A monitoring system has been laid out in the National Guidelines for DR-TB management.. It must also be reiterated here that to ensure implementation of rational use of SLDs, there will be periodic refresher trainings for prescriber and facilitators, as well as other relevant health care workers, regular monitoring of provider prescribing and medical records to ensure that each provider understands the treatment regimens and whether each patient is adhering to prescribed treatments. NTP is currently emphasizing an ambulatory-based model of DR-TB management throughout the country which involve the services of community health worker as a treatment supporter to ensure compliance by the patients’ towards treatment during intervals when not visiting the health center. NTP will undertake to develop skills and motivational training for the treatment supervisors at the treatment centers and through the field operations.

Chapter 3 Management Support, M&E and Pharmacovigilance Management Support The importance of this core function in reviewing the current practice of the four components of the SLD management cycle (i.e. selection, procurement, distribution/storage, and use) is particularly important and needs to be thorough and analytical to identify the weaknesses and invest necessary resources to overcome them. Management support is important for SLDs and DR-TB control should be into place. M&E of Pharmaceutical Management A special system has been established for Monitoring and Evaluation (M&E) of the MDR program in Pakistan which include the clinical and pharmaceutical management aspects to it. Both the MDR unit and the DMU will have the core responsibility to regularly monitor and provide feedback information on the performance of the clinical and pharmaceutical management system functions of SLDs. A step wise approach has already been laid down as follows: 1- Monthly review of the RD-TB register (ENRS of each PMDT site which include diagnostic testing, enrolment procedure, treatment selection and follow up management for each patient until treatment outcome is declared. 2- Monthly review of SLD balance sheet for each PMDT site including quantity of available drugs at the PMDT warehouse and expiry dates to ensure adequate stock level and proper consumption of drugs with near expiry dates. 3- Monthly review of an excel based SLD matrix sheet for each PMDT site to monitor individual and proper consumption practices for each patient with estimated monthly consumption of each drug for forecasting purposes. 4- Physical field visit and warehouse monitoring at each PMDT which include drug register, stock balance review, bin card assessment and other storage practices.

Pharmacovigilance A special chapter has been recently added at the National Guidelines for DR-TB management titled ”Practical Guidance on Pharmacovigilance of DR-TB Medicines”. The pharmacovigilance system contributes heavily to patient care and patient safety in relation to the use of medicines, especially with regard to the prevention of unintended harm from the use of medicines; to improve public health and safety in relation to the use of medicines by the provision of reliable, balanced information resulting in more rational use of medicines; and to assess the risk-benefit profiles of medicines, thus encouraging saer and more effective use of medicines and a resolution of the sometimes apparently conflicting interests of public health and individual patient welfare.

For more details on the Pharmacovigilance practice for DR-TB patients please refer to the National Guidelines for DR-TB management. Management Information System A TB pharmaceutical management information system (PMIS) has currently been developed for FLD. The TB PMIS design will be designed to incorporate the SLDs data as well. Once the software is developed and the NTP is trained in its use, the implementation of the PMIS will be the responsibility of the NTP. Disposal of Expiries and Wastage Since the MDR program started in Pakistan, a stringent M&E system has been in place for SLD to avoid the situation of allowing drugs at the central or PMDT sites warehouses to be expired before using the drug. Otherwise, procedures have been properly laid out in the FLD guidelines should this occur. Please refer to the relevant section of those guidelines for detailed information.

Annex 1 Ancillary Medicines for Managing Adverse Effects to First and Second-Line TB Medicines Therapeutic Category

Name of Medicine

Antiemetic

chlorpromazine, promethazine, metoclopramide, dimenhydrinate, lorazepam, diazepam antacids (magnesium and aluminum hydroxide), H2-blockers (ranitidine) fluconazole or clotrimazole loperamide oral rehydration salts and intravenous fluids amitriptyline, fluoxetine diazepam, clonazepam diphenhydramine, lorazepam haloperidol diazepam, phenytoin, carbamazepine pyridoxine (vitamin B6) amitriptyline, ibuprofen

Antiulcer agent Antifungal agent Antidiarrheal Dehydration agent Antidepressant Anxiolytic Hypnotic Antipsychotic Anticonvulsant Neurological prophylaxis Agent to treat peripheral neuropathy Agent to treat vestibular symptoms Agent for headaches Agent for cutaneous reactions Analgesic for arthralgias and arthritis Thyroid replacement hormone Diuretic Agent for bronchospams Agent for systemic hypersensitivity reactions

6

meclizine Opioid6 (codeine, dextroproxyphene, morphine) and non-opioid (paracetamol) analgesics corticosteroid creams (hydrocortisone), anti-pruritus lotions (calamine) ibuprofen, acetaminophen levothyroxine furosemide, amiloride bronchodilators (albuterol), inhaled corticosteroids (beclomethasone) diphenhydramine, prednisone, dexamethasone, epinephrine

Opioids are controlled items - not available in the market and have to be procured through special permission from the Interior Ministry – causing much problem for the patients and physicians.

Annex 2 Supplies Needed to Manage First and Second-Line Tuberculosis Water for injection Needles and syringes Disinfectants, soaps, towels, and tissues Gloves and face masks Forms and labels Intramuscular and intravenous injection supplies Intravenous administration sets Visual field and color vision testing charts Audiometers Bedside commode, emesis basins 11. Resuscitation equipment 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.