Dosage of Lorlatinib

This product should be administered under the guidance of a physician experienced in antineoplastic therapy. The specific dosage regimen shall be formulated comprehensively based on the patient’s tumor type, clinical stage, individual tolerance and treatment response. The following is the routine recommended usage; please refer to the detailed instructions below for actual administration.

Non-Small Cell Lung Cancer

Oral administration: 100 mg once daily. Continue treatment until disease progression or intolerable toxic reactions occur.

Dose Adjustment for Toxic Reactions

In the CROWN study, approximately 49% of patients receiving lorlatinib at the recommended dose required treatment interruption due to adverse reactions, and 21% required dose reduction. The most common triggers included edema, peripheral neuropathy, cognitive dysfunction, pneumonia, hypercholesterolemia, hypertriglyceridemia, or mood disorders. Among patients with prior treatment history, 48% needed treatment interruption and 24% required at least one dose reduction due to similar adverse reactions.

If dose reduction is necessary, the first adjustment is to 75 mg once daily. If further reduction is required, the dose can be adjusted to 50 mg once daily. For patients who cannot tolerate 50 mg daily, permanent discontinuation of lorlatinib is required.

Central Nervous System (CNS) Adverse Reactions

For Grade 1 CNS adverse reactions: Continue treatment at the original dose, or interrupt treatment until symptoms return to baseline. Treatment can be resumed at the original dose or a one-level reduced dose.

For Grade 2 or 3 CNS adverse reactions: Interrupt treatment until symptoms resolve to Grade 0 or 1. Resume treatment at a one-level reduced dose.

For Grade 4 CNS adverse reactions: Permanently discontinue lorlatinib.

Hyperlipidemia

In case of Grade 4 hypercholesterolemia and/or hypertriglyceridemia (serum cholesterol > 500 mg/dL or serum triglycerides > 1000 mg/dL), interrupt treatment and initiate appropriate lipid-lowering therapy, increase the dose of existing lipid-lowering drugs, or switch the lipid-lowering regimen. Treatment may be resumed at the original dose after symptoms resolve to Grade 2 or lower.

If severe hypercholesterolemia and/or hypertriglyceridemia recur despite optimal lipid-lowering therapy, resume treatment at a one-level reduced dose.

Atrioventricular (AV) Block

For second-degree AV block: Interrupt treatment until the PR interval is < 200 milliseconds. Resume treatment at a one-level reduced dose.

For third-degree AV block: Interrupt treatment until a cardiac pacemaker is implanted or the PR interval is < 200 milliseconds. If a pacemaker is implanted, treatment can be resumed at the original dose; if no pacemaker is implanted, resume treatment at a one-level reduced dose.

If third-degree AV block recurs: Implant a cardiac pacemaker or permanently discontinue lorlatinib.

Interstitial Lung Disease (ILD)/Pneumonitis

Permanently discontinue lorlatinib in patients who develop any grade of treatment-related ILD/pneumonitis.

Hypertension

For Grade 3 hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg; requiring pharmacologic intervention with more than one antihypertensive agent or an intensified treatment regimen than before): Interrupt treatment. Resume treatment at the original dose after blood pressure decreases to Grade 1 or lower (systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg).

If Grade 3 hypertension recurs: Interrupt lorlatinib treatment until blood pressure drops to Grade 1 or lower, then resume at a reduced dose. Permanent discontinuation is required if blood pressure cannot be effectively controlled despite optimal antihypertensive therapy.

For Grade 4 hypertension (life-threatening or requiring urgent intervention): Interrupt lorlatinib treatment. After blood pressure decreases to Grade 1 or lower, treatment may be resumed at a reduced dose or permanently discontinued.

If Grade 4 hypertension recurs: Permanently discontinue lorlatinib.

Hyperglycemia

If Grade 3 hyperglycemia (blood glucose > 250 mg/dL) persists despite optimal antihyperglycemic therapy: Interrupt treatment until blood glucose is controlled to the target level. Resume treatment at a one-level reduced dose.

For Grade 4 hyperglycemia: Interrupt treatment until blood glucose is controlled to the target level. Resume treatment at a one-level reduced dose.

Permanent discontinuation is required if blood glucose cannot be consistently controlled to the target level.

Other Toxic Reactions

For other Grade 1 or 2 adverse reactions: Continue treatment at the original dose or reduce the dose by one level.

For other Grade 3 or 4 adverse reactions: Interrupt treatment until symptoms resolve to Grade 2 or lower or return to baseline. Resume treatment at a one-level reduced dose.

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of lorlatinib with strong CYP3A inducers is prohibited.

Concomitant use with moderate CYP3A inducers should be avoided. If coadministration cannot be avoided, adjust the lorlatinib dose to 125 mg once daily.

Concomitant use with strong CYP3A inhibitors should be avoided. If coadministration cannot be avoided, reduce the lorlatinib dose from 100 mg daily to 75 mg daily, or from 75 mg daily to 50 mg daily.

Concomitant use of lorlatinib with fluconazole should be avoided. If coadministration cannot be avoided, reduce the initial lorlatinib dose from 100 mg daily to 75 mg daily.

FDA,2021.03