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Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of Lorlatinib with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 50% of subjects, Grade 3 ALT or AST elevations occurred in 33% and Grade 2 ALT or AST elevations occurred in 8%. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); the median time to recovery was 18 days in subjects with Grade 3 or 4 ALT or AST elevations and 7 days in subjects with Grade 2 ALT or AST elevations.
Lorlatinib 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 Lorlatinib.
A broad spectrum of central nervous system (CNS) effects can occur in patients receiving Lorlatinib. These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 52% of the 476 patients who received 100 mg Lorlatinib once daily in clinical trials. Cognitive effects occurred in 28% of the 476 patients; 2.9% of these events were severe (Grade 3 or 4). Mood effects occurred in 21% of patients; 1.7% of these events were severe. Speech effects occurred in 11% of patients; 0.6% of these events were severe. Psychotic effects occurred in 7% of patients; 0.6% of these events were severe. Mental status changes occurred in 1.3% of patients; 1.1% of these events were severe. Seizures occurred in 1.9% of patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 12% of patients. The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% of patients required permanent discontinuation of Lorlatinib for a CNS effect; 10% required temporary discontinuation and 8% required dose reduction.
Withhold and resume at the same dose or at a reduced dose or permanently discontinue Lorlatinib based on severity.
Increases in serum cholesterol and triglycerides can occur in patients receiving Lorlatinib. Grade 3 or 4 elevations in total cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides occurred in 19% of the 476 patients who received 100 mg Lorlatinib once daily. The median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of patients required temporary discontinuation and 1% and 3% of patients required dose reduction of Lorlatinib for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Eighty-three percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days.
Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating Lorlatinib, 1 and 2 months after initiating Lorlatinib, and periodically thereafter. Withhold and resume at the same dose for the first occurrence; resume at the same or a reduced dose of Lorlatinib for recurrence based on severity.
PR interval prolongation and atrioventricular (AV) block can occur in patients receiving Lorlatinib. In 476 patients who received 100 mg Lorlatinib once daily and who had a baseline electrocardiography (ECG), 1.9% experienced AV block and 0.2% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating Lorlatinib and periodically thereafter. Withhold and resume at a reduced dose or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.
Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with Lorlatinib. ILD/pneumonitis occurred in 1.9% of patients who received 100 mg Lorlatinib once daily, including Grade 3 or 4 ILD/pneumonitis in 0.6% of patients. Four patients (0.8%) discontinued Lorlatinib for ILD/pneumonitis.
Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold Lorlatinib in patients with suspected ILD/pneumonitis. Permanently discontinue Lorlatinib for treatment-related ILD/pneumonitis of any severity.
Hypertension can occur in patients receiving Lorlatinib. Hypertension occurred in 13% of patients who received 100 mg Lorlatinib once daily, including Grade 3 or 4 in 6% of patients. The median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued Lorlatinib for hypertension.
Control blood pressure prior to initiation of Lorlatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with Lorlatinib. Withhold and resume at a reduced dose or permanently discontinue Lorlatinib based on severity.
Hyperglycemia can occur in patients receiving Lorlatinib. Hyperglycemia occurred in 9% of patients who received 100 mg Lorlatinib, including Grade 3 or 4 in 3.2% of patients. The median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued Lorlatinib for hyperglycemia.
Assess fasting serum glucose prior to initiation of Lorlatinib and monitor periodically thereafter. Withhold and resume at a reduced dose or permanently discontinue Lorlatinib based on severity.
Based on findings from animal studies and its mechanism of action, Lorlatinib can cause fetal harm when administered to a pregnant woman. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on area under the curve (AUC).
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since Lorlatinib can render hormonal contraceptives ineffective, during treatment with Lorlatinib and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Lorlatinib and for 3 months after the final dose.
FDA,2021.03
