Lorbrena Drug Information

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.

Patient Selection

Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens. 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. 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. Table 1 Recommended LORBRENA Interstitial Lung Disease (ILD)/Pneumonitis for Drug Interactions 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. 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. 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. Fluconazole Avoid concomitant use of LORBRENA with fluconazole.

Recommended Dosage for Severe Hepatic Impairment

The recommended dosage of LORBRENA for patients with severe hepatic impairment (Child-Pugh C) is 50 mg orally once daily.

Recommended Dosage for Renal Impairment

The recommended dosage of LORBRENA for patients with creatinine clearance 15 to < 30 mL/min (estimated by Cockcroft‑Gault) is 75 mg orally once daily.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions section reflects exposure to % were exposed for 6 months or longer and 61% were exposed for greater than 1 year. Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study) The safety of LORBRENA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease.

Fatal adverse reactions occurred in % of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENA was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENA.

Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%). Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461006.

Table 3 Laboratory Abnormalities Worsening from Baseline in ≥ Previously Treated ALK-Positive Metastatic NSCLC The data described below reflect exposure to LORBRENA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial. The most frequent (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in ≥20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure % of patients required dose interruption. Approximately 24% of patients required at least 1 dose reduction for adverse reactions. Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001.

Table 4 Adverse Reactions Occurring in ≥10% of Patients in Study B7461001 Adverse reactions were graded using NCI CTCAE version 4.03. Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%). Table 5 Worsening Laboratory Values Occurring in ≥

Effect of Other Drugs on LORBRENA 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. Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA.

Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists. Moderate CYP3A Inducers Avoid concomitant use of moderate CYP3A inducers with LORBRENA.

If concomitant use is unavoidable, increase the LORBRENA dose. Strong CYP3A Inhibitors Avoid concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENA dosage.

Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. Fluconazole Avoid concomitant use of LORBRENA with fluconazole.

Effect of LORBRENA on Other Drugs Certain CYP3A 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. LORBRENA is a moderate CYP3A inducer.

Concomitant use of LORBRENA decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates. LORBRENA is a moderate P-gp inducer.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, 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 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.

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

LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity. Concomitant use with strong CYP3A inducers.