LORBRENA® Dosage and Administration

(lorlatinib)

2 DOSAGE AND ADMINISTRATION

     

2.1 Patient Selection

Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)].

Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)].

Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact.

Take LORBRENA at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose.

Do not take an additional dose if vomiting occurs after LORBRENA but continue with the next scheduled dose.

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.

Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions
Adverse Reaction*Dosage Modifications
Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
*
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

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

1.
pacemaker placed OR
2.
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.

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.

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)].

2.5 Concomitant Use of Moderate CYP3A Inducers

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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.6 Dosage Modification 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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.7 Dosage Modification for Fluconazole

Avoid concomitant use of LORBRENA with fluconazole [see Clinical Pharmacology (12.3)]. If concomitant use is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.8 Dosage Modification for Severe Renal Impairment

Reduce the recommended dosage of LORBRENA for patients with severe renal impairment (creatinine clearance [CLcr] 15 to < 30 mL/min, estimated by Cockcroft-Gault) from 100 mg to 75 mg orally once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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Medication Guide

Health Professional Information

Dosage and Administration

2 DOSAGE AND ADMINISTRATION

     

2.1 Patient Selection

Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)].

Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)].

Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact.

Take LORBRENA at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose.

Do not take an additional dose if vomiting occurs after LORBRENA but continue with the next scheduled dose.

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.

Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions
Adverse Reaction*Dosage Modifications
Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
*
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

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

1.
pacemaker placed OR
2.
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.

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.

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)].

2.5 Concomitant Use of Moderate CYP3A Inducers

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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.6 Dosage Modification 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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.7 Dosage Modification for Fluconazole

Avoid concomitant use of LORBRENA with fluconazole [see Clinical Pharmacology (12.3)]. If concomitant use is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.8 Dosage Modification for Severe Renal Impairment

Reduce the recommended dosage of LORBRENA for patients with severe renal impairment (creatinine clearance [CLcr] 15 to < 30 mL/min, estimated by Cockcroft-Gault) from 100 mg to 75 mg orally once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
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Dosage and Administration

2 DOSAGE AND ADMINISTRATION

     

2.1 Patient Selection

Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)].

Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)].

Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact.

Take LORBRENA at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose.

Do not take an additional dose if vomiting occurs after LORBRENA but continue with the next scheduled dose.

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.

Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions
Adverse Reaction*Dosage Modifications
Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
*
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

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

1.
pacemaker placed OR
2.
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.

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.

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)].

2.5 Concomitant Use of Moderate CYP3A Inducers

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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.6 Dosage Modification 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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.7 Dosage Modification for Fluconazole

Avoid concomitant use of LORBRENA with fluconazole [see Clinical Pharmacology (12.3)]. If concomitant use is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.8 Dosage Modification for Severe Renal Impairment

Reduce the recommended dosage of LORBRENA for patients with severe renal impairment (creatinine clearance [CLcr] 15 to < 30 mL/min, estimated by Cockcroft-Gault) from 100 mg to 75 mg orally once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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