Pretomanid: uses, dosing, side effects & brands

The following serious adverse reactions are discussed here and elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.2) ] • Myelosuppression [see Warnings and Precautions (5.3) ] • Peripheral and Optic Neuropathy [see Warnings and Precautions (5.4) ] • QT Prolongation [see Warnings and Precautions (5.5) ] • Reproductive Effects [see Warnings and Precautions (5.7) ] • Lactic Acidosis [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥ 10%) are peripheral neuropathy, anemia, nausea, acne, vomiting, increased transaminases, headache, musculoskeletal pain, dyspepsia, rash, pruritus, decreased appetite, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, hemoptysis and hyperamylasemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions…

Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolid prescribing information. • Pretomanid Tablets used in combination with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid is contraindicated. ( 4 )

Strong or moderate CYP3A4 inducers such as rifampin or efavirenz: Avoid co-administration. ( 5.6 , 7.1 ) • Organic anion transporter-3 (OAT3) substrates: Monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. ( 7.2 ) 7.1 Effect of Other Drugs on Pretomanid CYP3A4 Inducers Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasma concentrations [see Clinical Pharmacology (12.3) ] . Avoid co-administration of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4 inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactions with CYP3A4. Lopinavir/Ritonavir Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid [see Clinical Pharmacology (12.3) ] . Lopinavir/ritonavir can be co-administered with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. 7.2 Effect of Pretomanid on Other Drugs Midazolam Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significant effect on the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy-midazolam [see Clinical Pharmacology (12.3) ] . The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be administered with CYP3A4 substrate drugs. Organic Anion Transporter-3 (OAT3), BCRP, OATP1B3 and P-gp Substrates The effect of co-administration of pretomanid on the pharmacokinetics of OAT3 substrates in humans is unknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter [see Clinical Pharmacology (12.3) ] , which could result in increased concentrations of OAT3 substrate drugs clinically and may increase the risk of adverse reactions associated with these drugs. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate, indomethacin, ciprofloxacin), increase monitoring for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reduction information. In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp [see Clinical Pharmacology (12.3) ] . No clinical studies have been performed to investigate these interactions. Therefore, it cannot be excluded that co-administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g., rosuvastatin, prazosin, glyburide, sulfasalazine) and P-gp substrates (e.g., digoxin, dabigatran etexilate, verapamil) may increase their exposure. If pretomanid is co-administered with substrates of OATP1B3, BCRP, or P-gp, increased monitoring for drug-related adverse reactions to the co-administered medicinal product should be performed.