Hyperlipidemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see Adverse Reactions). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4, and 8 weeks after initiating lorlatinib; and periodically thereafter. Initiation, or increase in the dose, of lipid-lowering agents is required (see Dosage & Administration).
Central nervous system effects: Central nervous system (CNS) effects have been observed in patients receiving lorlatinib including psychotic effects, changes in cognitive function, mood, speech, and mental status changes, (see Adverse Reactions). Dose modification or discontinuation may be required for those patients who develop CNS effects (see Dosage & Administration).
Atrioventricular block: PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving LORVIQUA. Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see Dosage & Administration).
Left ventricular ejection fraction decrease: Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. Based on the available clinical study data, it is not possible to determine a causal relationship between effects on changes in cardiac contractility and lorlatinib. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered.
Lipase and amylase increase: Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see Adverse Reactions). Median time of occurrence of increase in serum lipase and amylase is 70 days (range: 7 to 696 days) and 41 days (range: 7 to 489 days), respectively. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see Dosage & Administration).
Pneumonitis: Severe or life-threatening pulmonary adverse drug reactions consistent with pneumonitis have occurred with lorlatinib (see Adverse Reactions). Any patient who presents with worsening of respiratory symptoms indicative of pneumonitis (e.g. dyspnea, cough, and fever) should be promptly evaluated for pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see Dosage & Administration).
Hypertension: Hypertension has been reported in patients receiving lorlatinib (see Adverse Reactions).
Blood pressure should be controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see Dosage & Administration).
Hyperglycemia: Hyperglycemia has occurred in patients receiving lorlatinib (see Adverse Reactions).
Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see Dosage & Administration).
Drug-drug interactions: In a study conducted in healthy volunteers, the concomitant use of lorlatinib and rifampin, a strong CYP3A inducer was associated with increases of ALT and AST with no increase of total bilirubin and alkaline phosphatase (see Interactions). Concomitant use of any strong CYP3A inducer is contraindicated (see Contraindications and Interactions). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started. 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 Interactions).
Effects on Ability to Drive and Use Machines: Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see Adverse Reactions).
Use in Pregnancy: Fertility and pregnancy: Based on animal data and mechanism of action, there is a risk of fetal harm if exposed to LORVIQUA (see Pharmacology: Pharmacodynamics and Pharmacology: Toxicology: Preclinical Safety Data under Actions). Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORVIQUA. A highly effective non-hormonal method of contraception is required for female patients during treatment with LORVIQUA, because lorlatinib can render hormonal contraceptives ineffective (see Interactions and Use in Pregnancy & Lactation). 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 LORVIQUA and for at least 97 days after the final dose, male patients with female partners of reproductive potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see Use in Pregnancy & Lactation). Male fertility may be compromised during treatment with lorlatinib (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Men should seek advice on effective fertility preservation before treatment.