ions (7%).
Table 3 Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*
Laboratory Abnormality LORBRENA
All Grades
(%) Grade 3 or 4
(%)
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
N=number of patients who had at least one on-study assessment for the parameter of interest.
*
Grades using NCI CTCAE version 4.0.
†
N=292.
‡
N=293.
§
N=291.
¶
N=290.
#
N=284.
Chemistry
Hypercholesterolemia† 96 18
Hypertriglyceridemia† 90 18
Hyperglycemia‡ 52 5
Increased AST† 37 2.1
Hypoalbuminemia§ 33 1.0
Increased ALT† 28 2.1
Increased lipase¶ 24 10
Increased alkaline phosphatase† 24 1.0
Increased amylase# 22 3.9
Hypophosphatemia† 21 4.8
Hyperkalemia‡ 21 1.0
Hypomagnesemia† 21 0
Hematology
Anemia‡ 52 4.8
Thrombocytopenia‡ 23 0.3
Lymphopenia† 22 3.4
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on LORBRENA
Effect of CYP3A Inducers
Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA. The effect of concomitant use of LORBRENA with a moderate CYP3A inducer on lorlatinib plasma concentrations has not been studied.
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. The risk of hepatotoxicity with concomitant use of LORBRENA and moderate CYP3A inducers that are also PXR agonists is unknown.
LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.
Avoid concomitant use of LORBRENA 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)].
Effect of Strong CYP3A Inhibitors
Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid the concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce LORBRENA dose as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
7.2Effect of LORBRENA on Other Drugs
CYP3A Substrates
Concomitant use of LORBRENA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (1 |
