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Dosing

Recommended Dosing

Dose Modification

Dosage Modifications for Adverse Reactions

The Recommended Dose of LORBRENA Is 100 mg Once Daily Until Disease Progression or Unacceptable ToxicityRecommended Dosing
  • Take LORBRENA at the same time each day, with or without food
  • Swallow tablets whole. Do not chew, crush, or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact
Tablet not actual size.
Dose Modification
  • Dose modifications may be required based on individual safety and tolerability​​​​​​​
Tablets not actual size.Until disease progression or unacceptable toxicity.
  • Permanently discontinue LORBRENA in patients who are unable to tolerate the 50-mg dose once daily
Contraindications
  • LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity
Concomitant use of strong or moderate CYP3A INDUCERS
  • Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA
  • ​​​​​​​Avoid concomitant use of moderate CYP3A inducers with LORBRENA. If concomitant use with moderate CYP3A inducers is unavoidable, increase the LORBRENA dose to 125 mg once daily
Dosage modifications for strong CYP3A INHIBITORS
 
  • Avoid concomitant use of LORBRENA with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily​​​​​​​
  • ​​​​​​​In patients who have had a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A inhibitor, reduce the LORBRENA dose to 50 mg orally once daily​​​​​​​
  • ​​​​​​​If concomitant use of a strong CYP3A inhibitor is discontinued, increase the LORBRENA dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to the dose that was used before starting the strong inhibitor​​​​​​​
 
Dosage modification for FLUCONAZOLE
  • Avoid concomitant use of LORBRENA with fluconazole. If concomitant use is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily
Dosage modification for SEVERE RENAL IMPAIRMENT
  • Reduce the recommended dosage of LORBRENA for patients with severe renal impairment (CLcr 15 to <30 mL/min, estimated by Cockcroft-Gault) from 100 mg to 75 mg orally once daily​​​​​​​
CLcr=creatinine clearance.
Dosage Modifications for Adverse Reactions
Scroll left to view table
Adverse reaction Dosage modifications
Central nervous system effects 
Grade 1
  • Continue at the same dose or withhold the 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
Hyperlipidemia
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
Atrioventricular (AV) block
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
Interstitial lung disease (ILD)/Pneumonitis 
Any Grade treatment-related ILD/pneumonitis 
  • Permanently discontinue LORBRENA
Hypertension
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), then 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)
 

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

  • Withhold LORBRENA until recovery to Grade ≤1
 
  • Resume at a reduced dose or permanently discontinue LORBRENA
 
  • If Grade 4 hypertension recurs, permanently discontinue LORBRENA
Hyperglycemia
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
Other adverse reactions
Grade 1 OR Grade 2 
  • Continue LORBRENA at same dose or reduced dose
Grade 3 OR Grade 4 
  • Withhold LORBRENA until symptoms resolve to Grade ≤2 or baseline
 
  • Resume LORBRENA at reduced dose
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

To report an adverse event, please call 1-800-438-1985

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PP-LOR-USA-0507
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PP-LOR-USA-0507
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.
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.

Please see full Prescribing Information.

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