Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
General
Patients treated with LORBRENA (lorlatinib) must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.
Drug-Drug Interactions
Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers
Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 6 subjects (50%), Grade 3 ALT or AST elevations occurred in 4 subjects (33%) and Grade 2 ALT or AST elevations occurred in 1 subject (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.
No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY).
Carcinogenesis and Mutagenesis
Please see 16 NON-CLINICAL TOXICOLOGY.
Cardiovascular
Atrioventricular (AV) Block
PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving LORBRENA. In 476 patients who received 100 mg LORBRENA daily in Study B7461001 (n=327) and Study B7461006 (n=149) and who had a baseline electrocardiography (ECG), 9 patients (1.9%) experienced AV block and 1 patient (0.2%) experienced Grade 3 AV block and underwent pacemaker placement (see 10.2 Pharmacodynamics).
For those patients who develop AV block, dose modification may be required (see 4 DOSAGE AND ADMINISTRATION).
Hypertension
Hypertension can occur in patients receiving LORBRENA (see 8 ADVERSE REACTIONS). Hypertension occurred in 62 patients (13%) who received 100 mg LORBRENA once daily in Study B7461001 and Study B7461006, including Grade 3 or 4 in 29 patients (6.1%). The median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 11 patients (2.3%) temporarily discontinued LORBRENA for hypertension.
Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 4 DOSAGE AND ADMINISTRATION).
Driving and Operating Machinery
LORBRENA has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience central nervous system effects (see 8.2 Clinical Trial Adverse Reactions, Nervous System Disorders).
Endocrine and Metabolism
Hyperlipidemia
The use of LORBRENA has been associated with increases in serum cholesterol and triglycerides (see 8 ADVERSE REACTIONS). Grade 3 or 4 elevations in total cholesterol occurred in 87 patients (18%) and Grade 3 or 4 elevations in triglycerides occurred in 92 patients (19%) of the 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (n=327) and in Study B7461006 (n=149). The median time to onset for both hypercholesterolemia and hypertriglyceridemia was 15 days. The median duration of hypercholesterolemia and hypertriglyceridemia was 451 and 427 days, respectively. No patient was permanently discontinued from treatment with lorlatinib associated with hypercholesterolemia or hypertriglyceridemia. Eighteen (4%) and 33 (7%) patients required temporary discontinuation and 6 (1%) and 13 (3%) patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Three hundred ninety‑seven patients (83%) required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days.
Initiation, or increase in the dose, of lipid-lowering agents is recommended (see 4 DOSAGE AND ADMINISTRATION).
Hyperglycemia
Hyperglycemia can occur in patients receiving LORBRENA (see 8 ADVERSE REACTIONS). Hyperglycemia occurred in 44 patients (9.2%) who received 100 mg LORBRENA once daily in Study B7461001 and Study B7461006, including Grade 3 or 4 in 15 patients (3.2%). The median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued LORBRENA for hyperglycemia.
Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 4 DOSAGE AND ADMINISTRATION).
Monitoring and Laboratory Tests
ALK Testing
Patients treated with LORBRENA must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.
Liver Function Tests
No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY).
Pancreatic enzymes - Lipase and amylase increase
Patients should be monitored for lipase and amylase elevations prior to the start of LORBRENA treatment and periodically thereafter as clinically indicated.
ECG Monitoring
Monitor ECG prior to initiating LORBRENA and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 4 DOSAGE AND ADMINISTRATION).
Hypertension
Control blood pressure prior to initiation of LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORBRENA. Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 7 WARNINGS AND PRECAUTIONS, Hypertension, 4 DOSAGE AND ADMINISTRATION).
Hyperlipidemia
Monitor serum cholesterol and triglycerides before initiating LORBRENA, 2, 4, and 8 weeks, after initiating LORBRENA, and periodically thereafter. Withhold and resume at the same dose for the first occurrence: resume at the same or a reduced dose of LORBRENA for recurrence based on severity (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; 4 DOSAGE AND ADMINISTRATION; 8.2 Clinical Trial Adverse Reactions).
Hyperglycemia
Assess fasting serum glucose prior to initiation of LORBRENA and monitor periodically thereafter (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; 4 DOSAGE AND ADMINISTRATION)
Neurologic
Central Nervous System Effects
Central nervous system (CNS) effects have been observed in patients receiving LORBRENA (see 8.2 Clinical Trial Adverse Reactions). These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 246 (52%) of the 476 patients who received 100 mg LORBRENA once daily in clinical trials (see 8.2 Clinical Trial Adverse Reactions). Cognitive effects occurred in 132 (28%) of the 476 patients; in 14 patients (2.9%) these events were severe (Grade 3 or 4). Mood effects occurred in 102 patients (21%); in 8 patients (1.7%) these events were severe. Speech effects occurred in 50 patients (11%); in 3 patients (0.6%) these events were severe. Psychotic effects occurred in 33 patients (7%); in 3 patients (0.6%) these events were severe. Mental status changes occurred in 6 patients (1.3%); in 5 patients (1.1%) these events were severe. Seizures occurred in 9 patients (1.9%) patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 55 patients (12%). The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 10 patients (2.1%) required permanent discontinuation of LORBRENA for a CNS effect; 46 patients (10%) required temporary discontinuation and 36 patients (8%) required dose reduction.
Dose modification may be required for those patients who develop CNS effects. Permanent discontinuation of LORBRENA is recommended in patients diagnosed with Grade 4 CNS effects (see 4 DOSAGE AND ADMINISTRATION).
Reproductive Health: Female and Male Potential
Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORBRENA. A highly effective non-hormonal method of contraception is required for female patients during treatment with LORBRENA because lorlatinib can render hormonal contraceptives ineffective (see 9 DRUG INTERACTIONS). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 21 days after completing therapy.
During treatment with LORBRENA and for at least 97 days after the final dose, advise male patients with female partners of reproductive potential to use effective contraception, including a condom, and advise male patients with pregnant partners to use condoms.
- Fertility
Based on nonclinical safety findings, male and female fertility may be compromised during treatment with LORBRENA (see 16 NON-CLINICAL TOXICOLOGY). It is not known whether LORBRENA affects female fertility. Men should seek advice on effective fertility preservation before treatment.
Respiratory
ILD/Pneumonitis
Severe or life-threatening pulmonary adverse reactions consistent with pneumonitis have occurred with LORBRENA. Pneumonitis occurred in 9 patients (1.9%) who received 100 mg LORBRENA once daily in Study B7461001 (n=327) and in Study B7461006 (n=149), including Grade 3 or 4 pneumonitis in 3 patients (0.6%). Four patients (0.8%) discontinued LORBRENA 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 LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity (see 4 DOSAGE AND ADMINISTRATION).
7.1 Special Populations
7.1.1 Pregnant Women
Studies in animals have shown embryo-fetal toxicity (see 16 NON-CLINICAL TOXICOLOGY). There are no data in pregnant women using LORBRENA. LORBRENA may cause fetal harm when administered to a pregnant woman.
LORBRENA is not recommended during pregnancy or for women of childbearing potential not using contraception.
7.1.2 Breast-feeding
It is not known whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborn child cannot be excluded.
LORBRENA should not be used during breast-feeding. Breast-feeding should be discontinued during treatment with LORBRENA and for 7 days after the last dose.
7.1.3 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
7.1.4 Geriatrics
Among patients from Study B7461001 who received 100 mg LORBRENA orally once daily (n=295), 241 patients were < 65 years and 54 patients were ≥65 years. Among patients from Study B7461006 who received 100 mg LORBRENA orally once daily (n=149), 90 patients were < 65 years and 59 patients were ≥65 years. The following adverse events were more frequently reported in patients ≥65 years: cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain and rash. The limited data on the safety and efficacy of LORBRENA in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see 10 CLINICAL PHARMACOLOGY). No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years and younger patients.