Interactions : אינטראקציות

7     DRUG INTERACTIONS

7.1   Effect of Other Drugs on LORVIQUA
Effect of CYP3A Inducers
Concomitant use of LORVIQUA with a strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of LORVIQUA . The effect of concomitant use of LORVIQUA with a moderate CYP3A inducer on lorlatinib plasma concentrations has not been studied.

Severe hepatotoxicity occurred in healthy subjects receiving LORVIQUA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORVIQUA 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 LORVIQUA and rifampin, which are both PXR agonists. The risk of hepatotoxicity with concomitant use of LORVIQUA and moderate CYP3A inducers that are also PXR agonists is unknown.

LORVIQUA 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 LORVIQUA . [see Dosage and Administration (2.3)].

Avoid concomitant use of LORVIQUA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as recommended [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

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 LORVIQUA .
Avoid concomitant use of LORVIQUA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORVIQUA dosage [see Dosage and Administration (2.4)].

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

Certain CYP3A Substrates
LORVIQUA is a moderate CYP3A inducer. Concomitant use of LORVIQUA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates.
Avoid concomitant use of LORVIQUA 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
LORVIQUA is a moderate P-gp inducer. Concomitant use of LORVIQUA decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORVIQUA 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.