LORBRENA® (lorlatinib) Therapy Management Strategies

Timing and incidence of select adverse reactions^1-4*

The ARs selected were the most frequently reported (≥20%) in the pooled safety population of patients in the CROWN and Phase 1/2 trials (N=476).^2,3

Based on pooled data from the CROWN and Phase 1/2 trials (N=476; LORBRENA US Prescribing Information).²

Based on a 36-month follow-up of the CROWN trial (n=149).¹

Based on results of the CROWN trial at 18 months of follow-up (n=149; LORBRENA US Prescribing Information).^1,2,5

Based on data from a post hoc analysis of the CROWN trial at 18 months of follow-up (n=149).^1,2,5

Based on data from the Phase 1/2 trial (n=295).⁴

Review tips for proactive counseling and preemptive monitoring to help support patients during their treatment:

Hyperlipidemia

Therapy management guidance^2,5-7

The median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia
Hyperlipidemia was generally managed with lipid-lowering agents and dose interruptions, and in more severe (Grade ≥3) cases, dose modification
- 83% of patients required initiation of lipid-lowering medications
- Median time to start of lipid-lowering therapy: 17 days
- Pitavastatin, pravastatin, or rosuvastatin are recommended statins based on their drug interaction potential
  - If high-intensity statin therapy is needed, a statin such as rosuvastatin is recommended based on its low involvement with CYP450 enzymes that are able to interact with LORBRENA
Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter
Incidence of dose interruption due to hyperlipidemia in the LORBRENA clinical trials:
- 3.4% due to hypercholesterolemia and 7% due to hypertriglyceridemia in the LORBRENA first-line trial
- 3.4% due to hypercholesterolemia and 6% due to hypertriglyceridemia in the Phase 1/2 trial

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Laboratory abnormality⁴	Dosage modifications⁴
Mild OR moderate	Cholesterol ULN-400 mg/dL OR Triglycerides 150-500 mg/dL	Introduce or modify lipid-lowering therapy (LLT) Continue at the same LORBRENA dose
Severe	Cholesterol >400-500 mg/dL OR Triglycerides >500-1000 mg/dL	Introduce LLT or increase dosage of ongoing LLT, or change to a new LLT Continue at the same LORBRENA dose without interruption
Life-threatening	Cholesterol >500 mg/dL OR Triglycerides >1000 mg/dL	Introduce LLT or increase dosage of ongoing LLT, or change to a new LLT Withhold LORBRENA dose until hyperlipidemia is moderate or mild before rechallenging at same dose while maximizing LLT If severe hyperlipidemia recurs despite maximal LLT, reduce LORBRENA by 1 dose level (by 25 mg)

Laboratory abnormality⁴

Dosage modifications⁴

Mild OR moderate

Cholesterol ULN-400 mg/dL
OR
Triglycerides 150-500 mg/dL

Introduce or modify lipid-lowering therapy (LLT)

Continue at the same LORBRENA dose

Severe

Cholesterol >400-500 mg/dL
OR
Triglycerides >500-1000 mg/dL

Introduce LLT or increase dosage of ongoing LLT, or change to a new LLT

Continue at the same LORBRENA dose without interruption

Life-threatening

Cholesterol >500 mg/dL
OR
Triglycerides >1000 mg/dL

Introduce LLT or increase dosage of ongoing LLT, or change to a new LLT

Withhold LORBRENA dose until hyperlipidemia is moderate or mild before rechallenging at same dose while maximizing LLT

If severe hyperlipidemia recurs despite maximal LLT, reduce LORBRENA by 1 dose level (by 25 mg)

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Dosage modification guidance for hyperlipidemia²

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Adverse reaction grade	Dosage modifications
Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to Grade ≤2 Resume LORBRENA at the same dose If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia

Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to Grade ≤2

Resume LORBRENA at the same dose

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

CYP450=cytochrome P450; ULN=upper limit of normal.

Central nervous system (CNS) effects

A broad spectrum of CNS effects can occur in patients receiving LORBRENA^2,6,8

These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep
Patients should be assessed for mood and cognition before initiating LORBRENA and should be monitored for CNS effects by the entire healthcare team and their caregiver(s) during treatment
Patients without a primary caregiver should receive frequent calls and be referred to resources such as therapists or social workers
Concomitant medications should be considered as a potential contributing factor
In pooled clinical trial data, CNS effects led to permanent discontinuation in 2.1% of patients, temporary discontinuation in 10% of patients, and dose reduction in 8% of patients

Dosage modification guidance²

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Adverse reaction grade	Dosage modifications
Grade 1	Continue at the same dose or withhold dose until recovery to baseline Resume LORBRENA at the same dose or at a reduced dose
Grade 2 OR Grade 3	Withhold dose until Grade 0 or 1 Resume LORBRENA at a reduced dose
Grade 4	Permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 1

Continue at the same dose or withhold dose until recovery to baseline

Resume LORBRENA at the same dose or at a reduced dose

Grade 2 OR Grade 3

Withhold dose until Grade 0 or 1

Resume LORBRENA at a reduced dose

Grade 4

Permanently discontinue LORBRENA

The data in the Warnings and Precautions section of the Prescribing Information reflect exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (n=327) and in Study B7461006 (n=149).²

CNS: Cognitive effects

Therapy management guidance^2,6-8

The most commonly reported cognitive effects were memory impairment, cognitive disorder, and amnesia
Patients and their caregivers should be instructed to report any changes in cognitive function to the patient’s healthcare professional
The possibility of cognitive-related adverse reactions should be discussed with patients and caregivers prior to initiating LORBRENA treatment, along with advice on how to minimize the impact on daily activities (eg, setting reminders)
Cognitive effects were generally Grades 1-2 and reversible after dose modification
In the LORBRENA first-line trial, cognitive effects led to permanent discontinuation in 1.3% of patients and dose interruptions in 4.0% of patients
In the Phase 1/2 trial, cognitive effects led to permanent discontinuation in 0.7% of patients, dose interruptions in 4.4% of patients, and dose reductions in 4.1% of patients

Dosage modification guidance for cognitive effects²

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Adverse reaction grade	Dosage modifications
Grade 1	Continue at the same dose or withhold dose until recovery to baseline Resume LORBRENA at the same dose or at a reduced dose
Grade 2 OR Grade 3	Withhold dose until Grade 0 or 1 Resume LORBRENA at a reduced dose
Grade 4	Permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 1

Continue at the same dose or withhold dose until recovery to baseline

Resume LORBRENA at the same dose or at a reduced dose

Grade 2 OR Grade 3

Withhold dose until Grade 0 or 1

Resume LORBRENA at a reduced dose

Grade 4

Permanently discontinue LORBRENA

CNS: Mood effects

Therapy management guidance^2,4,6,8

The most commonly reported mood effects were irritability, anxiety, depression, and affect lability
Effects on mood should be discussed with patients prior to treatment initiation, particularly in those with preexisting psychiatric conditions
Patients and their caregivers should be instructed to report any changes in mood to the patient’s healthcare professional
Mood effects were generally Grades 1-2, temporary, and reversible after dose modification
In the LORBRENA first-line trial, mood effects led to dose interruptions in 4.0% of patients
In the Phase 1/2 trial, mood effects led to permanent discontinuation in 0.7% of patients, dose interruptions in 3.1% of patients, and dose reductions in 3.1% of patients

Dosage modification guidance²

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Adverse reaction grade	Dosage modifications
Grade 1	Continue at the same dose or withhold dose until recovery to baseline Resume LORBRENA at the same dose or at a reduced dose
Grade 2 OR Grade 3	Withhold dose until Grade 0 or 1 Resume LORBRENA at a reduced dose
Grade 4	Permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 1

Continue at the same dose or withhold dose until recovery to baseline

Resume LORBRENA at the same dose or at a reduced dose

Grade 2 OR Grade 3

Withhold dose until Grade 0 or 1

Resume LORBRENA at a reduced dose

Grade 4

Permanently discontinue LORBRENA

CNS: Speech effects

Therapy management guidance^2,4

Speech effects have been reported by patients as a perception of slowed speech or difficulty in word finding
Patients and their caregivers should be instructed to report any changes in speech to the patient's healthcare professional

Dosage modification guidance^2,4

Speech effects were generally mild in severity and reversible upon dose modification or discontinuation, if needed

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Adverse reaction grade	Dosage modifications
Grade 1	Continue at the same dose or withhold dose until recovery to baseline Resume LORBRENA at the same dose or at a reduced dose
Grade 2 OR Grade 3	Withhold dose until Grade 0 or 1 Resume LORBRENA at a reduced dose
Grade 4	Permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 1

Continue at the same dose or withhold dose until recovery to baseline

Resume LORBRENA at the same dose or at a reduced dose

Grade 2 OR Grade 3

Withhold dose until Grade 0 or 1

Resume LORBRENA at a reduced dose

Grade 4

Permanently discontinue LORBRENA

Hypertension

Therapy management guidance²

Hypertension occurred in 13% of patients who received LORBRENA 100 mg once daily in pooled data from the 2 trials (N=476), including Grade 3 or 4 in 6% of patients
2.3% of patients temporarily discontinued LORBRENA for hypertension
Control blood pressure prior to initiation of LORBRENA
Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORBRENA

Management strategies for hypertension²

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Adverse reaction grade	Dosage modifications
Grade 3	SBP ≥160 mmHg or DBP ≥100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated	Withhold LORBRENA until hypertension has recovered to Grade ≤1 (SBP <140 mmHg and DBP <90 mmHg) Resume LORBRENA at the same dose If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade ≤1, and resume at a reduced dose If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue LORBRENA
Grade 4	Life-threatening consequences, urgent intervention indicated	Withhold LORBRENA until recovery to Grade ≤1 Resume at a reduced dose or permanently discontinue LORBRENA If Grade 4 hypertension recurs, permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 3

SBP ≥160 mmHg or DBP ≥100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated

Withhold LORBRENA until hypertension has recovered to Grade ≤1 (SBP <140 mmHg and DBP <90 mmHg)

Resume LORBRENA at the same dose

If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade ≤1, and resume at a reduced dose

If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue LORBRENA

Grade 4

Life-threatening consequences, urgent intervention indicated

Withhold LORBRENA until recovery to Grade ≤1

Resume at a reduced dose or permanently discontinue LORBRENA

If Grade 4 hypertension recurs, permanently discontinue LORBRENA

DBP=diastolic blood pressure; SBP=systolic blood pressure.

Hyperglycemia

Therapy management guidance²

Hyperglycemia occurred in 9% of patients who received LORBRENA 100 mg once daily in pooled data from the 2 trials (N=476), including Grade 3 or 4 in 3.2% of patients
0.8% of patients temporarily discontinued LORBRENA for hyperglycemia

Dosage modification guidance for hyperglycemia²

Assess fasting serum glucose prior to initiation of LORBRENA and monitor periodically thereafter

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Adverse reaction grade	Dosage modifications
Grade 3 (>250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled Resume LORBRENA at the next lower dosage If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue LORBRENA

Adverse reaction grade

Dosage modifications

Grade 3 (>250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4

Withhold LORBRENA until hyperglycemia is adequately controlled

Resume LORBRENA at the next lower dosage

If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue LORBRENA

Weight gain

Therapy management guidance^2,8

An increase in appetite has been reported by some patients, suggesting that body weight increase may potentially be associated with increased caloric intake and a heightened desire to eat; however, causality has not been determined
Patients should be advised of likely weight gain of some degree
Dose modifications may help manage more severe cases of weight gain
Counseling on food intake, dietary advice from a nutritionist, and exercise may be effective weight-management strategies for some patients
Lifestyle modifications are preferred over LORBRENA dose reductions

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or at a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or at a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Edema

Therapy management guidance^2,6-8

Prior to LORBRENA dose modification, consider the following to manage low-grade edema in LORBRENA-treated patients:
- Compression stockings
- Leg elevation
- Lifestyle modifications (increased exercise and limiting dietary salt)
- Diuretics (usually furosemide)
If edema persists or worsens, follow general dose-modification guidance for LORBRENA until:
- Edema resolves to Grade ≤2 (if not a safety risk)
- Edema resolves to baseline; rechallenge at a reduced dose
In the LORBRENA first-line trial, edema led to dose interruptions in 5% of patients and dose reductions in 5% of patients
Edema was the most common cause of dose interruptions (7%) and reductions (6%) in the Phase 1/2 trial

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Peripheral neuropathy

Therapy management guidance^2,4,6,7

Most reports of peripheral neuropathy were mild (Grades 1-2) and generally reversible following standard medical therapy or dose modification
Treatment with vitamin B₁ and vitamin B₆ and medications for pain associated with peripheral neuropathy may provide symptom relief for some patients
For carpal tunnel syndrome, the use of a night splint may provide improvement
In the LORBRENA first-line trial, peripheral neuropathy led to dose reduction in 3.4% of patients
In the Phase 1/2 trial, peripheral neuropathy led to dose interruptions in 5% of patients and dose reductions in 4.7% of patients

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Increased lipase

Dosage modification guidance for increased lipase^2,7

In the Phase 1/2 trial, dose interruption was required in 3.7% of patients due to increased lipase

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Gastrointestinal (GI) effects

Therapy management guidance^2,4

GI effects were generally mild in severity
Dose modifications due to GI effects were rare

Constipation and diarrhea may be managed with standard medical therapy

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or at a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or at a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Atrioventricular (AV) block and other electrocardiography (ECG) findings

Therapy management guidance^2,4

In 476 patients who received LORBRENA at a dose of 100 mg orally once daily in pooled data from the 2 studies and who had a baseline ECG:
- 1.9% experienced AV block
- 0.2%* experienced Grade 3 AV block and underwent pacemaker placement
Before starting LORBRENA, patients should be:
- Informed about potential risks of AV block
- Advised to contact their healthcare professional immediately if they experience new chest pain or discomfort, heartbeat changes, palpitations, dizziness, lightheadedness, fainting, or changes in or new use of heart or blood pressure medication
Monitor ECG prior to initiating LORBRENA and periodically thereafter
For patients with preexisting PR prolongation, ECG monitoring should be conducted throughout treatment

Dosage modification guidance for AV block²

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Adverse reaction grade	Dosage modifications
Second-degree AV block	Withhold LORBRENA until PR interval is <200 ms Resume LORBRENA at a reduced dose
First occurrence of complete AV block	Withhold LORBRENA until pacemaker placed, OR PR interval <200 ms If a pacemaker is placed, resume LORBRENA at the same dose If no pacemaker is placed, resume LORBRENA at a reduced dose
Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA

*Patient had preexisting second-degree AV block.⁴

Interstitial lung disease (ILD)/Pneumonitis

Therapy management guidance²

In pooled data from the 2 trials, 4 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 (eg, dyspnea, cough, and fever)

Dosage modification guidance for ILD/pneumonitis²

Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis
Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity

Other adverse reactions

Dosage modification guidance for other adverse reactions²

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Adverse reaction grade	Dosage modifications
Grade 1 OR Grade 2	Continue LORBRENA at same dose or at a reduced dose
Grade 3 OR Grade 4	Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline Resume LORBRENA at a reduced dose

Adverse reaction grade

Dosage modifications

Grade 1 OR Grade 2

Continue LORBRENA at same dose or at a reduced dose

Grade 3 OR Grade 4

Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline

Resume LORBRENA at a reduced dose

Management strategies include those found within the product labeling as well as additional considerations drawn from publications by Bauer, et al. and Reed, et al. (see references below).

Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

ECG=electrocardiography.

Therapy Management Guide

This brochure provides an overview of the safety profile for LORBRENA and includes therapy management strategies.

View

NEXT: Dosing information

References

Solomon BJ, Bauer TM, Mok TSK, et al. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir Med. 2023;11(4):354-366.

LORBRENA^® (lorlatinib) Prescribing Information. Pfizer Inc; August 2024.

Solomon BJ, Bauer TM, Ou SI, et al. Post hoc analysis of lorlatinib intracranial efficacy and safety in patients with ALK-positive advanced non–small-cell lung cancer from the phase III CROWN study. J Clin Oncol. 2022;40(31):3593-3602.

Bauer TM, Felip E, Solomon BJ, et al. Clinical management of adverse events associated with lorlatinib. Oncologist. 2019;24(8):1103-1110.

Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029.

Liu G, Mazieres J, Stratmann J, et al. A pragmatic guide for management of adverse events associated with lorlatinib. Lung Cancer. 2024;191:107535.

Pfizer Inc. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. ClinicalTrials.gov identifier: NCT03052608. Updated December 12, 2024. Accessed June 13, 2025. https://clinicaltrials.gov/study/NCT03052608?term=NCT03052608&rank=1

Reed M, Rosales ALS, Chioda MD, et al. Consensus recommendations for management and counseling of adverse events associated with lorlatinib: a guide for healthcare practitioners. Adv Ther. 2020;37:3019-3030

IMPORTANT SAFETY INFORMATION

Contraindications: LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity.

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 ALT or AST elevations occurred in 50% of subjects, Grade 3 in 33% of subjects, and Grade 2 in 8% of subjects. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); median time to recovery in subjects with Grade 3 or 4 or Grade 2 ALT or AST elevations was 18 days and 7 days, respectively. LORBRENA 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 LORBRENA.

Central Nervous System (CNS) Effects: A broad spectrum of CNS effects can occur; overall, CNS effects occurred in 52% of the 476 patients receiving LORBRENA. These included seizures (1.9%, sometimes in conjunction with other neurologic findings), psychotic effects (7%; 0.6% severe [Grade 3 or 4]), and changes in cognitive function (28%; 2.9% severe), mood (including suicidal ideation) (21%; 1.7% severe), speech (11%; 0.6% severe), mental status (1.3%; 1.1% severe), and sleep (12%). Median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% and 10% of patients required permanent or temporary discontinuation of LORBRENA, respectively, for a CNS effect; 8% required dose reduction. Withhold and resume at same or reduced dose or permanently discontinue based on severity.

Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur. 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 LORBRENA. 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 LORBRENA 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 LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Withhold and resume at same dose for the first occurrence; resume at same or reduced dose of LORBRENA for recurrence based on severity.

Atrioventricular (AV) Block: PR interval prolongation and AV block can occur. In 476 patients who received LORBRENA at a dose of 100 mg orally 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 LORBRENA and periodically thereafter. Withhold and resume at reduced or same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.9% of patients, including Grade 3 or 4 ILD/pneumonitis in 0.6% of patients. 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.

Hypertension: Hypertension can occur. Hypertension occurred in 13% of patients, including Grade 3 or 4 in 6% of patients. Median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued LORBRENA for hypertension. Control blood pressure prior to initiating LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Hyperglycemia: Hyperglycemia can occur. Hyperglycemia occurred in 9% of patients, including Grade 3 or 4 in 3.2% of patients. 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. Assess fasting serum glucose prior to initiating LORBRENA and monitor periodically thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Embryo-fetal Toxicity: LORBRENA can cause fetal harm. 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 LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA 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 LORBRENA and for 3 months after the final dose.

Adverse Reactions: In the pooled safety population of 476 patients who received 100 mg LORBRENA once daily, the most frequent (≥ 20%) adverse reactions were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent (≥ 20%) Grade 3-4 laboratory abnormalities in patients receiving LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

In previously untreated patients, serious adverse reactions occurred in 34% of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). In the Phase 1/2 study, serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).

Drug Interactions: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Avoid concomitant use with moderate CYP3A inducers, strong CYP3A inhibitors, and fluconazole. If concomitant use of moderate CYP3A inducers cannot be avoided, increase the LORBRENA dose as recommended. If concomitant use with a strong CYP3A inhibitor or fluconazole cannot be avoided, reduce the LORBRENA dose as recommended. Avoid concomitant use of LORBRENA with CYP3A substrates and P-gp substrates, which may reduce the efficacy of these substrates.

Lactation: Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment. The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the dose of LORBRENA for patients with severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment.

Please see Full Prescribing Information.

INDICATION

LORBRENA^® (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.

Please see Full Prescribing Information.