6.5 Dosage of the longer MDR-TB regimen components

Dosages of individual medicines are often determined by body weight separately for adults and children. Suggested weight-based dosing schemes are provided in Annex I, and additional information about each of the Group A, B and C medicines is provided in the medicine information sheets (5). Doses may need to be adjusted because of accompanying medicines or comorbidities. In situations where there is a limited possibility of adjusting the dose because of the drug formulation (e.g. delamanid in children aged 3–5 years), the general principle is to consider inclusion of the medicine if the benefits are expected to outweigh the harms, and to aim for a dose that achieves the therapeutic range. Patients should then be monitored closely for adverse events, which should be managed as quickly and as effectively as possible if they occur.

All TB medicines can be started at the full dose. The emergence of drug reactions may also require the interruption – temporary or permanent – of an agent or changes to its dosage. If tolerance is an issue, cycloserine, ethionamide and PAS can start at a low dosage and then be increased (i.e. ramped up) gradually over a 2-week period (90). Most experience with the use of clofazimine in both shorter and longer regimens has been with a fixed daily dose throughout treatment; empirical evidence to support starting with a loading dose in MDR-TB regimens is lacking.¹²

Most agents are given in a single daily dose. Cycloserine and PAS may be given in split doses to reduce the likelihood of adverse reactions (ethionamide/prothionamide displays concentration-dependent killing of M. tuberculosis, so twice daily dosing should be avoided). Linezolid is usually given once daily. Bedaquiline and delamanid are taken together with the other medicines in the MDR-TB regimen; the second dose of delamanid is usually taken alone, so treatment supervision needs to factor this in too. Injectable agents (if absolutely needed) are also usually given intramuscularly once daily and the dose should not be split (with the exception of imipenem-cilastatin and meropenem, which are given intravenously in divided doses). Ideally, all medicines are taken with food, given that a light meal promotes absorption.¹³ Oral agents are usually given every day of the week. Bedaquiline is given daily for the first 2 weeks and three times weekly for the following 22 weeks.

Regarding missed doses, in general, if all the medications due on a given day are missed, then treatment is resumed the following day and an extra day of treatment is added to the end of the regimen. However, if a dose is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. This means that they should not add the missed dose at the end of the 2-week period. From the third week onwards, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the three-timesa-week regimen. If a delamanid dose is missed, patients should take it as soon as possible after it has been missed. However, if it is close to the time for the next scheduled dose, then the missed dose may be skipped, and the patient should not take a double dose to make up for a forgotten tablet.

¹² Clofazimine appears to act primarily as a sterilizing agent, implying that its role is less important in the first part of treatment. A high initial dose may also increase the risk of adverse reactions particularly given its relatively longer half-life, with cardiotoxicity being a particular concern (60).

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