Operational Guide for National Tuberculosis Control Programmes on the Introduction and Use of Fixed-Dose Combination Drugs

PREFACE
The World Health Organization (WHO) has promoted the DOTS strategy as the essential, most cost-effective package for tuberculosis control since 1994. Today, the 148 countries that have adopted DOTS are intensifying their efforts to achieve the targets set for 2005 by the World Health Assembly: to detect 70% of sputum smear-positive infectious cases and to cure at least 85% of such cases. One key element of the DOTS strategy is the use of short-course chemotherapy regimens, proven by clinical trials to be highly efficacious, under proper case management conditions. This includes direct observation of patients taking their drugs at the correct dosage and for the proper period of time.

Ensuring that people with TB complete a full course of treatment is one of the major challenges for TB control. Direct observation of treatment is essential to help patients stay on treatment, even after symptoms have subsided following the first few weeks of chemotherapy. The risk is that uninformed patients (as well as uninformed and careless doctors) may change the regimen, avoiding one or more of the drugs they believe are no longer necessary, leading to treatment failure or relapse. In so doing, some of these patients will develop antimicrobial resistance to one or more drugs. As a consequence, the spread of strains of mycobacteria resistant to drugs may then occur in a community. This is how the well known multidrug-resistant tuberculosis (MDR-TB) outbreaks have developed and spread in many parts of the world.

There are various strategies to prevent this from happening. The first is to have proper health care systems and services in place, in such a way that patients with TB are fully educated, nurtured and monitored throughout the 6-8 months of treatment required to cure their disease. However, there are additional tools to ensure that drugs are properly used. One approach is through fixed-dose combination (FDC) tablets. Recent advances in the field of pharmacology have made it possible to develop quality combinations of up to four anti-TB drugs. In a single tablet, we are now able to deliver the two, three or four essential first-line drugs in the proper dosages, thus guaranteeing easy adoption of the WHOrecommended regimens. Both WHO and the International Union against Tuberculosis and Lung Disease (IUATLD) recommend the use of FDCs as a means to prevent monotherapy and reduce the risk of drug resistance.

However, prevention of drug resistance is just one of the potential benefits of the use of FDCs. FDCs simplify administration of drugs by reducing the number of pills a patient takes each day and decreasing the risk of incorrect prescriptions. It is much simpler to explain to patients that they need to take four tablets of the same type and colour, rather than a mixture of tablets of different shapes, colours and sizes. FDCs are also simpler for care-givers as they minimize the risk of confusion. Finally, drug procurement, in all its components (stock management, shipping, distribution), is simplified by FDCs. For these reasons, WHO includes FDCs for TB in its Model List of Essential Medicines and is recommending them to national TB programmes (NTPs).

Today, many NTPs are using 2-drug FDCs, some are using 3-drug FDCs, and a few have started using 4-drug FDCs. Some NTPs have hesitated to use FDCs because of concerns regarding cost and quality, particularly rifampicin bio-availability. In addition, registration and other regulatory obstacles have made it, at times, difficult for NTP managers to support introduction of FDCs in their programmes. These concerns have been addressed, and low cost, high quality 2-, 3- and 4-drug FDCs are now widely available. WHO has therefore developed this guide to facilitate the introduction of FDCs by NTPs. The guide is a tool that will help NTP managers to learn about the rationale behind FDCs, understand fully the need to ensure bioavailability of the products chosen, become acquainted with procurement mechanisms, familiarize themselves with regulatory requirements, and, finally, smoothly shift from regimens based on a single drug to those based on FDCs.

FDCs are important tools to further improve the quality of care for people with TB, and accelerate DOTS expansion to reach the global TB control targets for 2005. The guide has been requested by NTP managers and others involved in the treatment of people with TB, and will help ensure that FDC tools are used widely and effectively.

Dr J.W. Lee
Director
Stop TB Department, World Health Organization