Lorbrena

LORBRENA^® 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.

Tablets:

• •25 mg: 8 mm round, tan, immediate release, film-coated, debossed with "Pfizer" on one side and "25" and "LLN" on the other side
• •100 mg: 8.5 mm × 17 mm oval, lavender, immediate release, film-coated, debossed with "Pfizer" on one side and "LLN 100" on the other side

Lactation: Advise not to breastfeed. (

• •Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA. (
  2.4 Concomitant Use of Strong CYP3A Inducers

  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

  [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7.1), Clinical Pharmacology (12.3)]

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

  [see Drug Interactions (7.1)]

  .

  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

  [see Contraindications (4), Drug Interactions (7.1)]

  .
  )
• •Central Nervous System (CNS) Effects: CNS effects include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Withhold and resume LORBRENA at same or reduced dose or permanently discontinue LORBRENA based on severity. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.2 Central Nervous System Effects

  A broad spectrum of central nervous system (CNS) effects can occur in patients receiving LORBRENA. These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 52% of the 476 patients who received 100 mg LORBRENA once daily in clinical trials

  [see Adverse Reactions (6.1)]

  . Cognitive effects occurred in 28% of the 476 patients; 2.9% of these events were severe (Grade 3 or 4). Mood effects occurred in 21% of patients; 1.7% of these events were severe. Speech effects occurred in 11% of patients; 0.6% of these events were severe. Psychotic effects occurred in 7% of patients; 0.6% of these events were severe. Mental status changes occurred in 1.3% of patients; 1.1% of these events were severe. Seizures occurred in 1.9% of patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 12% of patients. The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% of patients required permanent discontinuation of LORBRENA for a CNS effect; 10% required temporary discontinuation and 8% required dose reduction.

  Withhold and resume at the same dose or at a reduced dose or permanently discontinue LORBRENA based on severity

  [see Dosage and Administration (2.3)]

  .
  )
• •Hyperlipidemia: Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENA at same or reduced dose based on severity. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.3 Hyperlipidemia

  Increases in serum cholesterol and triglycerides can occur in patients receiving LORBRENA

  [see Adverse Reactions (6.1)]

  . 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 100 mg LORBRENA once daily. The 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 the same dose for the first occurrence; resume at the same or a reduced dose of LORBRENA for recurrence based on severity

  [see Dosage and Administration (2.3)].
  )
• •Atrioventricular Block: Withhold and resume LORBRENA at same or reduced dose based on severity. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.4 Atrioventricular Block

  PR interval prolongation and atrioventricular (AV) block can occur in patients receiving LORBRENA

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

  In 476 patients who received 100 mg LORBRENA 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 a reduced dose or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker

  [see Dosage and Administration (2.3)]

  .
  )
• •Interstitial Lung Disease/Pneumonitis: Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.5 Interstitial Lung Disease/Pneumonitis

  Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with LORBRENA. ILD/pneumonitis occurred in 1.9% of patients who received 100 mg LORBRENA once daily, 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

  [see Dosage and Administration (2.3)]

  .
  )
• •Hypertension: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold LORBRENA, then dose reduce or permanently discontinue. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.6 Hypertension

  Hypertension can occur in patients receiving LORBRENA

  [see Adverse Reactions (6.1)]

  . Hypertension occurred in 13% of patients who received 100 mg LORBRENA once daily, including Grade 3 or 4 in 6% of patients. The 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 initiation of LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORBRENA. Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity

  [see Dosage and Administration (2.3)]

  .
  )
• •Hyperglycemia: Assess fasting serum glucose prior to starting LORBRENA and regularly during treatment. If not adequately controlled with optimal medical management, withhold LORBRENA, then consider dose reduction or permanently discontinue, based on severity. (
  2.3 Dosage Modifications for Adverse Reactions

  The recommended dose reductions are:

  • •First dose reduction: LORBRENA 75 mg orally once daily
  • •Second dose reduction: LORBRENA 50 mg orally once daily

  Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily.

  Dosage modifications for adverse reactions of LORBRENA are provided in Table 1.

  pacemaker placed

  OR

  PR interval less than 200 ms.

  If a pacemaker is placed, resume LORBRENA at the same dose.
  
  If no pacemaker is placed, resume LORBRENA at a reduced dose.

  Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions

  1.000000000000000e+00

  2.000000000000000e+00

  Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Dosage Modifications
  Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
  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 [see Warnings and Precautions (5.3)]
  Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia	Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal 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 [see Warnings and Precautions (5.4)]
  Second-degree AV block	Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose.
  First occurrence of complete AV block	Withhold LORBRENA until
  Recurrent complete AV block	Place pacemaker or permanently discontinue LORBRENA.
  Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]
  Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
  Hypertension [see Warnings and Precautions (5.6)]
  Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 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 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, 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 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
  Hyperglycemia [see Warnings and Precautions (5.7)]
  Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then 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 less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose.
  ,
  5.7 Hyperglycemia

  Hyperglycemia can occur in patients receiving LORBRENA

  [see Adverse Reactions (6.1)]

  . Hyperglycemia occurred in 9% of patients who received 100 mg LORBRENA, including Grade 3 or 4 in 3.2% of patients. The 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 initiation of LORBRENA and monitor periodically thereafter. Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity

  [see Dosage and Administration (2.3)]

  .
  )
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective non-hormonal method of contraception. (
  5.8 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, LORBRENA can cause fetal harm when administered to a pregnant woman. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on area under the curve (AUC).

  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

  [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]

  .
  ,
  7.2 Effect of LORBRENA on Other Drugs

  Certain CYP3A Substrates

  LORBRENA is a moderate CYP3A inducer. Concomitant use of LORBRENA decreases the concentration of CYP3A substrates

  [see Clinical Pharmacology (12.3)]

  , which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

  Certain P-glycoprotein (P-gp) Substrates

  LORBRENA is a moderate P-gp inducer. Concomitant use of LORBRENA decreases the concentration of P-gp substrates

  [see Clinical Pharmacology (12.3)]

  , which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , LORBRENA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on LORBRENA use in pregnant women. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on AUC

  (see Data)

  . Advise a pregnant woman of the potential risk to a fetus.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

  Data

  Animal Data

  Preliminary embryo-fetal development studies investigating the administration of lorlatinib during the period of organogenesis were conducted in rats and rabbits. In rabbits, lorlatinib administration resulted in abortion and total loss of pregnancy at doses of 15 mg/kg (approximately 3 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 4 mg/kg (approximately 0.6 times the human exposure at the recommended dose of 100 mg) toxicities included increased post-implantation loss and malformations including rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, administration of lorlatinib resulted in total loss of pregnancy at doses of 4 mg/kg (approximately 5 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 1 mg/kg (approximately equal to the human exposure at the recommended dose of 100 mg) there was increased post-implantation loss, decreased fetal body weight, and malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify pregnancy status in females of reproductive potential prior to initiating LORBRENA

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  LORBRENA can cause embryo-fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  .

  Females

  Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENA and for at least 6 months after the final dose. Advise females of reproductive potential to use a non-hormonal method of contraception, because LORBRENA can render hormonal contraceptives ineffective

  [see Drug Interactions (7.2)]

  .

  Males

  Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for at least 3 months after the final dose

  [see Nonclinical Toxicology (13.1)]

  .

  Infertility

  Males

  Based on findings from animal studies, LORBRENA may transiently impair male fertility

  [see Nonclinical Toxicology (13.1)]

  .
  )