Lorbrena

 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.

 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.

 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.

 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)].

 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)].

 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)].

 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)].

 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)].

Pregnancy

 Lactation

 Females and Males of Reproductive Potential

Pediatric Use

The safety and effectiveness of LORBRENA in pediatric patients have not been established.

Geriatric Use

Of the patients in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg LORBRENA orally once daily, 18% and 40% of patients, respectively, were aged 65 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST). The recommended dose of LORBRENA has not been established for patients with moderate (total bilirubin ≥ 1.5 to 3.0 × ULN with any AST) or severe (total bilirubin > 3.0 × ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)].

 Renal Impairment

Reduce the dose when administering LORBRENA to patients with severe (CLcr 15 to <30 mL/min, estimated by Cockcroft Gault) renal impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild or moderate (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault) renal impairment [see Clinical Pharmacology (12.3)].

 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 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

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

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

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

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

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

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)].