Precautions of Pretomanid

1. Risks Associated with the Combination Regimen

Pretomanid tablets are indicated as part of a combination regimen with bedaquiline and linezolid. Please refer to the prescribing information for bedaquiline and linezolid for additional risk information. The warnings and precautions associated with bedaquiline and linezolid also apply to their use in combination with pretomanid tablets.

2. Hepatotoxicity

Hepatic adverse reactions have been reported with the combination regimen of pretomanid tablets, bedaquiline, and linezolid. During treatment with pretomanid tablets, alcohol consumption and use of hepatotoxic drugs, including herbal supplements and drugs other than bedaquiline and linezolid, should be avoided, especially in patients with hepatic impairment.

Monitor symptoms and signs (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at least at baseline, at Week 2, then monthly during treatment, and as needed. If new or worsening evidence of hepatic impairment occurs, test for viral hepatitis and discontinue other hepatotoxic drugs. Interrupt the entire treatment regimen in the following situations:

Aminotransferase elevations accompanied by total bilirubin elevations greater than 2 times the upper limit of normal.

Aminotransferase elevations greater than 8 times the upper limit of normal.

Aminotransferase elevations greater than 5 times the upper limit of normal persisting for more than 2 weeks.

3. Myelosuppression

Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) has been reported with the combination regimen of pretomanid tablets, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia may be life-threatening. The observed hematologic abnormalities were reversible when linezolid administered as part of the combination regimen of pretomanid tablets, bedaquiline, and linezolid was reduced, interrupted, or discontinued. For patients receiving linezolid as part of the combination regimen of pretomanid tablets, bedaquiline, and linezolid, monitor complete blood counts at least at baseline, at Week 2, then monthly. For patients who develop or have worsening myelosuppression, consider reducing linezolid to half the initial dose or interrupting linezolid administration [see Dosage and Administration (2.2)].

4. Peripheral Neuropathy and Optic Neuropathy

Peripheral neuropathy and optic neuropathy have been reported with the combination regimen of pretomanid tablets, bedaquiline, and linezolid. Neuropathy is a known adverse reaction of prolonged linezolid use. Linezolid-associated neuropathy is generally reversible or improves with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid. When improvement of peripheral neuropathy is observed, consider resuming linezolid at half the initial dose. Monitor visual function in all patients receiving the combination regimen of pretomanid tablets, bedaquiline, and linezolid; if a patient develops symptoms of visual impairment, interrupt linezolid and perform an immediate ophthalmologic evaluation.

5. QT Interval Prolongation

QT interval prolongation has been reported with the combination regimen of pretomanid tablets, bedaquiline, and linezolid. QT interval prolongation is a known adverse reaction of bedaquiline. Obtain an ECG before starting treatment and at least at Weeks 2, 12, and 24 after starting the combination regimen of pretomanid tablets, bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. If QT interval prolongation is detected, monitor these electrolytes.

When patients receive bedaquiline as part of the combination regimen of pretomanid tablets, bedaquiline, and linezolid, the following conditions may increase the risk of QT interval prolongation: a history of torsades de pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, decompensated heart failure, or serum calcium, magnesium, or potassium levels below the lower limit of normal. If necessary, bedaquiline treatment may be considered after a favorable benefit-risk assessment and with frequent ECG monitoring in these patients.

If a patient develops clinically significant ventricular arrhythmia or a QTcF interval greater than 500 ms (confirmed by repeated ECG), discontinue the combination regimen of pretomanid tablets, bedaquiline, and linezolid. If syncope occurs, obtain an ECG to detect QT interval prolongation.

6. Drug Interactions

CYP3A4 Inducers

Pretomanid may be metabolized in part by CYP3A4. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., rifampin or efavirenz) during pretomanid treatment.

7. Reproductive Effects

Pretomanid caused testicular atrophy and impaired fertility in rats. Inform patients of the reproductive toxicity observed in animal studies and that the potential effect on human male fertility has not been adequately evaluated.

8. Lactic Acidosis

Lactic acidosis has been reported with the combination regimen of pretomanid tablets, bedaquiline, and linezolid. Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should be promptly medically evaluated, including assessment of bicarbonate and lactate levels, and consideration should be given to interrupting linezolid or the entire combination regimen of pretomanid tablets, bedaquiline, and linezolid.