Strong CYP3A Inducers

Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of LORBRENA.

Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists.

LORBRENA is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4)]. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA [see Dosage and Administration (2.3)].

Moderate CYP3A Inducers

Concomitant use of LORBRENA with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA [see Clinical Pharmacology (12.3)]. Avoid concomitant use of moderate CYP3A inducers with LORBRENA. If concomitant use is unavoidable, increase the LORBRENA dose [see Dosage and Administration (2.4)].

Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.5)].

Fluconazole

Concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid concomitant use of LORBRENA with fluconazole. If concomitant use cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.7)].

Certain CYP3A Substrates

LORBRENA is a moderate CYP3A inducer. Concomitant use of LORBRENA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

Certain P-glycoprotein (P-gp) Substrates

LORBRENA is a moderate P-gp inducer. Concomitant use of LORBRENA decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.