Annex I: Dosage by weight band for medicines used in multidrug-resistant TB regimens, adults and children

 Dosing of medicines used in second-line multidrug-resistant-TB

 Dosing of medicines used in second-line multidrug-resistant-TB

 Dosing of medicines used in second-line multidrug-resistant-TB

Dosing of medicines used in second-line multidrug-resistant TB

Dosing of medicines used in second-line multidrug-resistant TB

Dosing of medicines used in second-line multidrug-resistant TB

(<15 y): follow the separate dose schedule for patients younger than 15 years of age; bd: two times a day; BPaL: regimen of bedaquiline, pretomanid and linezolid for 6–9 months; cap: capsule; HIV: human immunodeficiency virus; im: intramuscular; iv: intravenous; g: gram; kg: kilogram; mL: millilitre; mg: milligram; M/W/F: Monday, Wednesday, Friday; soln: solution; susp: suspension; MDR-TB: multidrug-resistant TB: MDR/RR-TB: multidrug- and rifampicin resistant tuberculosis; tab: tablet; WHO: World Health Organization

ᵃ Dosages were established by the guideline development groups for the WHO guidelines on drug-resistant tuberculosis treatment (2018 and 2020 updates) and the WHO Global Task Force on the Pharmacokinetics and Pharmacodynamics (PK/PD) of TB medicines and other experts. They are based on the most recent reviews and best practices in the treatment of MDR/RR-TB. For certain agents the dosages were informed by pharmacokinetic modelling results based on the principle of allometric scaling (Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008;48:303–32). Owing to the pharmacokinetic properties of certain medicines, the doses proposed may exceed the mg/kg per day ranges shown here in order to achieve blood concentrations similar to target levels in an average adult patient. In patients <30 kg, the schedule for those aged <15 years should be followed, unless otherwise indicated. If multiple dose options are given for one weight band, the lower or higher option should be selected, depending on whether the patient is at the lower or higher limit of the body weight range. Dosing more closely to the target mg/kg per day should be aimed for, and is more feasible with oral or parenteral fluids, and when solid forms of different dosages are available. Fractioning of tablets into halves or less should be avoided, if possible. Therapeutic drug monitoring is advised when the dose is at the upper and lower ends of the range, to minimize the adverse therapeutic consequences of over- and under-exposure, respectively (especially for injectable agents, linezolid and fluoroquinolones).

ᵇ Clinicians may decide to exceed these values in particular cases to improve therapeutic effect.

ᶜ No weight-based dosing is proposed.

ᵈ higher dose may be used except when: there is risk of toxicity; levels are expected to be lowered because of pharmacokinetic interactions, malabsorption or other reasons; or the strain has low-level drug resistance.

ᵉ Tablets are expected to become available in the near future.

ᶠ The weight-based daily dose is for 6 or 7 days per week administration (M/W/F scheduling may permit higher dosing). Volumes shown may differ by preparation. Streptomycin may be diluted in three different ways. For iv use, the volume may be increased.

ᵍ Amoxicillin/clavulanic acid is only recommended as a companion agent. Because of a lack of data from the latest analysis on longer MDR-TB regimens in adults, gatifloxacin, isoniazid and thioacetazone are not included in the grouping table of medicines used for longer regimens. Pretomanid is recommended to be used only as part of the package of the BPaL regimen.

ʰ Only available in combination with amoxicillin as co-amoxyclav (e.g. 500 mg amoxicillin/125 mg clavulanic acid fixed-dose combination). It is given with each dose of carbapenem, either as 125 mg bd or 125 mg 3 times daily.

ᶦ Use for age 14 years or older.

See the text of the handbook for more details on the use of medicines.

(>14 y): follow the separate dose schedule for patients older than 14 years of age; alt: alternate; bd: two times a day; cap: capsule; dt: dispersible tablet; g: gram; im: intramuscular; iv: intravenous; kg: kilogram; mL: millilitre; mg: milligram; M/W/F: Monday, Wednesday, Friday; soln: solution; susp: suspension; tab: tablet.

ᵃ Dosages were established by the guideline development groups for the WHO guidelines on drug-resistant tuberculosis treatment (2018 and 2020 updates) and the WHO Global Task Force on the Pharmacokinetics and Pharmacodynamics (PK/PD) of TB medicines and other experts. They are based on the most recent reviews and best practices in the treatment of MDR/RR-TB. For certain agents the dosages were informed by pharmacokinetic modelling results based on the principle of allometric scaling (Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008;48:303–32). Due to the pharmacokinetic properties of certain medicines the doses proposed may exceed the mg/kg/day ranges shown here in order to achieve blood concentrations similar to target levels in an average adult patient. In patients >30 kg, follow the schedule for >14 years old unless otherwise indicated. If multiple dose options are given for one weight band select the lower or higher option depending on whether the patient is at the lower or higher limit of the body weight range. Dosing more closely to the target mg/kg/d+B48ay should be aimed for, and is more feasible with oral or parenteral fluids and when solid forms of different dosage are available. Fractioning of tablets into halves or less should be avoided if possible. Therapeutic drug monitoring is advised when the dose is at the upper and lower ends of the range to minimize the adverse therapeutic consequences of over- and under-exposure respectively (especially for injectable agents, linezolid and fluoroquinolones).

ᵇ Clinicians may decide to exceed these values in particular cases to improve therapeutic effect.

ᶜ Dissolving in 10 mL of water may facilitate administration in patients in lower weight bands and avoids fractioning solid formulations, although bioavailability is uncertain (use of dispersible tablets is preferred if available).

ᵈ In individuals >44 kg a dose of 600 mg od is proposed.

ᵉ Tablets are expected to become available in the near future.

ᶠ May be used in children 3–5 years of age. Giving half a 50 mg adult tablet in these children does not result in the same blood levels observed in trials using the special 25 mg paediatric tablet. Bioavailability may further be altered when the 50 mg tablet is split, crushed or dissolved.

ᵍ Weight-based daily dose is for 6 or 7 days/week administration (M/W/F scheduling may permit higher dosing). Volumes shown may differ by preparation. Streptomycin may be diluted in three different ways. Dosing closer to the upper limit of the mg/kg/day is more desirable. For iv use, the volume may be increased.

ʰ These agents are only recommended as a companion agent (amoxicillin/clavulanic acid) or not included because of a lack of data from the latest analysis on longer MDR-TB regimens in adults (isoniazid).

ᶦ Only available in combination with amoxicillin as co-amoxyclav. Only to be used with carbapenems, in which case they are given together, e.g. 125 mg bd or 125 mg 3 times daily in the 24–30 kg weight band.

See the text of the handbook for more details on the use of medicines.

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