pretomanid

Important safety information

Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor symptoms and signs and liver‑related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs. ( 5.2 ) • Myelosuppression was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor complete blood counts. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens. ( 5.3 ) • Peripheral and optic neuropathy were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens. ( 5.4 ) • QT prolongation was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops. ( 5.5 ) • Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated. ( 5.7 , 13.1 ) • Lactic acidosis was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Consider interrupting linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid dosing if significant lactic acidosis develops. ( 5.8 ) 5.1 Risks Associated with the Combination Treatment Regimen Pretomanid Tablet is indicated for use as part of a regimen in combination with bedaquiline and linezolid. Refer to the prescribing information for bedaquiline and linezolid for additional risk information. Warnings and Precautions related to bedaquiline and linezolid also apply to their use in the combination regimen with Pretomanid Tablets. 5.2 Hepatotoxicity Hepatic adverse reactions were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid [see Indications and Usage (1) ] while on Pretomanid Tablets, especially in patients with impaired hepatic function. Monitor symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at a minimum at baseline, at two weeks, and then monthly while on treatment and as needed. If evidence of new or worsening liver dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatment with the entire regimen if: • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal. • Aminotransferase elevations are greater than 8 times the upper limit of normal. • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks. 5.3 Myelosuppression Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia can be life threatening [see Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . When linezolid dosing, as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, was reduced, interrupted, or discontinued, the observed hematologic abnormalities were reversible. Complete blood counts should be monitored at a minimum at baseline, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Decreasing linezolid to half the initial dose or interrupting linezolid dosing should be considered in patients who develop or have worsening myelosuppression [see Dosage and Administration (2.2) ] . 5.4 Peripheral and Optic Neuropathy Peripheral neuropathy and optic neuropathy were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . Neuropathy is a known adverse reaction of long-term linezolid use. Neuropathy associated with linezolid is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at half the initial dose [see Dosage and Administration (2.2) ] . Monitor visual function in all patients receiving the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic evaluation. 5.5 QT Prolongation QT prolongation was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) , and Clinical Pharmacology (12.2) ] . QT prolongation is a known adverse reaction of bedaquiline. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor these electrolytes if QT prolongation is detected [see Adverse Reactions (6.1) ] . The following may increase the risk for QT prolongation when patients are receiving bedaquiline as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: a history of Torsade de Pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heart failure, or serum calcium, magnesium, or potassium levels below the lower limits of normal. If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit-risk assessment and with frequent ECG monitoring. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, obtain an ECG to detect QT prolongation. 5.6 Drug Interactions CYP3A4 Inducers Pretomanid may be in part metabolized by CYP3A4 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Avoid co‑administration of strong or moderate CYP3A4 inducers, such as rifampin or efavirenz, during treatment with pretomanid. 5.7 Reproductive Effects Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ] . 5.8 Lactic Acidosis Lactic acidosis was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid should be considered.