Usual Adult Dose for Tuberculosis - Resistant

Pretomanid: 200 mg orally once a day for 26 weeks
Bedaquiline: 400 mg orally once a day for 2 weeks followed by 200 mg orally 3 times a week (at least 48 hours between doses) for 24 weeks (for a total of 26 weeks)
Linezolid: Starting at 1200 mg/day orally for 26 weeks (with dose adjustment to 600 mg/day and further reduction to 300 mg/day or dose interruption as needed for known linezolid side effects of myelosuppression, peripheral neuropathy, and optic neuropathy)

Discontinuation of Dosing:

• If this drug or bedaquiline are discontinued, the entire combination regimen should also be discontinued.
• If linezolid is permanently discontinued during the initial 4 consecutive weeks of therapy, bedaquiline and this drug should also be discontinued; if linezolid is discontinued after the initial 4 weeks of consecutive therapy, administration of bedaquiline and this drug should continue.

• If the combination regimen is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of therapy; doses of linezolid alone (missed due to linezolid side effects) should not be made up.
• Dosing of the combination regimen can be extended beyond 26 weeks, if needed.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Data not available

Precautions

CONTRAINDICATIONS:
Combination regimen: Contraindications to bedaquiline and/or linezolid

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Before starting the combination regimen: Assess for signs/symptoms of liver disease (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly); obtain laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin)
• Before starting the combination regimen: Obtain CBC; obtain serum potassium, calcium, and magnesium and correct if abnormal; obtain ECG before staring therapy.
• Only use this drug in combination with bedaquiline and linezolid as part of the recommended dosing regimen.
• Administer the combination regimen by directly observed therapy (DOT) with food.
• Swallow the tablets whole with water.
• Emphasize to patients the need for compliance with the full course of therapy.

• Store below 30C (86F).
• Dispense only in original container; keep container tightly closed.

• Approval of indication based on limited clinical safety and efficacy data.
• This drug is indicated for use in a limited and specific patient population.
• Limitations of Use: This drug is not indicated in patients with drug-sensitive (DS) tuberculosis, latent infection due to Mycobacterium tuberculosis, extrapulmonary infection due to M tuberculosis, OR MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy.
• Limitations of Use: Safety and efficacy of this drug have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen.

• Cardiovascular: ECG (before starting therapy, and at least 2, 12, and 24 weeks after starting therapy; frequently if risk for QT prolongation; if syncope occurs)
• Hematologic: CBC in patients using linezolid (at least at baseline, at 2 weeks, and then monthly)
• Hepatic: For signs/symptoms of liver disease (at least at baseline, at 2 weeks, and then monthly during therapy and as needed); laboratory tests for ALT, AST, alkaline phosphatase, and bilirubin (at least at baseline, at 2 weeks, and then monthly during therapy and as needed); for viral hepatitides (if proof of new/worsening liver dysfunction)
• Metabolic: Serum potassium, calcium, and magnesium (at baseline; if QT prolongation detected)
• Ocular: Visual function in all patients

• Read the US FDA-approved patient labeling (Medication Guide) for this drug and bedaquiline.
• The combination regimen (pretomanid, bedaquiline, and linezolid) is for patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB; it must be administered by directly observed therapy.
• Promptly inform physician if changes in vision occur during linezolid therapy; obtain prompt ophthalmological evaluation if symptoms of visual impairment occur.
• Linezolid dosing may be modified or interrupted during therapy to manage the known linezolid side effects of myelosuppression, peripheral neuropathy, and optic neuropathy.
• This drug must be taken as part of a combination regimen with bedaquiline and linezolid; compliance with the full course of therapy must be emphasized. Avoid missing doses (unless directed by physician) and complete the entire course of therapy.
• Abstain from alcohol, hepatotoxic agents, and herbal products.