Dosage and Administration of Lorlatinib: Recommended Dosage, Dose Modification

Lorlatinib was first approved in Japan in September 2018, followed by approval from the U.S. Food and Drug Administration (FDA) in November of the same year, and in the European Union in March 2019.

Indications of Lorlatinib

Lorlatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Recommended Dosage of Lorlatinib

The recommended dosage is 100 mg orally once daily.

Select patients for the treatment of metastatic NSCLC based on the presence of ALK positivity in tumor specimens.

Treatment should be continued until disease progression or unacceptable toxicity occurs.

Administration Recommendations for Lorlatinib

Lorlatinib may be taken with or without food.

Lorlatinib tablets should be swallowed whole; do not chew, crush, or split tablets.

Do not take lorlatinib tablets that are broken, cracked, or otherwise damaged.

If a dose is missed, take it as soon as possible unless it is less than 4 hours until the next scheduled dose. Do not take two doses at the same time to make up for a missed dose.

If vomiting occurs after taking a dose, do not take an additional dose; take the next dose at the scheduled time.

Monitoring Recommendations for Lorlatinib

Monitor blood pressure 2 weeks after initiation of treatment and at least monthly thereafter during treatment.

Monitor serum cholesterol and triglycerides prior to initiation, during the first and second months of treatment, and periodically thereafter.

Monitor electrocardiogram (ECG) prior to initiation and periodically thereafter.

Obtain fasting serum glucose prior to initiation and monitor periodically thereafter.

Dose Modification for Adverse Reactions of Lorlatinib

First dose reduction: 75 mg orally once daily.

Second dose reduction: 50 mg orally once daily.

Patients who cannot tolerate 50 mg orally once daily should permanently discontinue lorlatinib.

Dose Modification in Specific Populations

1. Dose Modification in Renal Impairment

Mild or moderate renal impairment (eGFR 30 to 89 mL/min):

No dose modification is recommended.

Severe renal impairment (eGFR 15 to <30 mL/min):

75 mg orally once daily.

2. Dose Modification in Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to 1.5 × ULN with any AST):

No dose modification is recommended.

Moderate or severe hepatic impairment:

No available data.

Dose Modification for Specific Adverse Reactions

1. Central Nervous System (CNS) Adverse Reactions

Grade 1:

Continue treatment at the same dose, or withhold treatment until recovery to baseline. Resume treatment at the same or reduced dose.

Grade 2 or 3:

Withhold treatment until recovery to Grade 0 or 1. Resume treatment at a reduced dose.

Grade 4:

Permanently discontinue lorlatinib.

2. Hyperlipidemia

Grade 4 hypercholesterolemia or Grade 4 hypertriglyceridemia:

Withhold treatment until recovery to Grade 2 or lower. Resume treatment at the same dose.

If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume treatment at a reduced dose.

3. Atrioventricular (AV) Block

Second‑degree AV block:

Withhold treatment until PR interval <200 msec. Resume treatment at a reduced dose.

First occurrence of third‑degree AV block:

Withhold treatment until a pacemaker is implanted or PR interval <200 msec.

If a pacemaker is implanted, resume treatment at the same dose.

If a pacemaker is not implanted, resume treatment at a reduced dose.

Recurrent third‑degree AV block:

Implant a pacemaker or permanently discontinue lorlatinib.

4. Interstitial Lung Disease (ILD)/Pneumonitis

Any grade treatment‑related ILD/pneumonitis:

Permanently discontinue lorlatinib.

5. Hypertension

Grade 3:

Withhold treatment until hypertension improves to Grade 1 or lower, then resume at the same dose.

If Grade 3 hypertension recurs, withhold until recovery to Grade 1 or lower and resume at a reduced dose.

If adequate hypertension control cannot be achieved with optimal medical therapy, permanently discontinue lorlatinib.

Grade 4:

Withhold treatment until recovery to Grade 1 or lower, then resume at a reduced dose or permanently discontinue.

If Grade 4 hypertension recurs, permanently discontinue lorlatinib.

6. Hyperglycemia

Grade 3 or 4 hyperglycemia despite antihyperglycemic treatment:

Withhold treatment until hyperglycemia is adequately controlled, then resume at the next lower dose.

If adequate control cannot be achieved with medical therapy, permanently discontinue lorlatinib.