These Highlights Do Not Include All The Information Needed To Use Lorbrena Safely And Effectively. See Full Prescribing Information For Lorbrena.

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 [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months.

Serious adverse reactions occurred in 34% of 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 treated with LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6.7% 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. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). 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.

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

LORBRENA (lorlatinib) is a kinase inhibitor for oral administration. The molecular formula is C₂₁H₁₉FN₆O₂ (anhydrous form) and the molecular weight is 406.41 Daltons. The chemical name is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11] benzoxadiazacyclotetradecine-3-carbonitrile. The chemical structure is shown below:

Lorlatinib is a white to off-white powder with a pKa of 4.92. The solubility of lorlatinib in aqueous media decreases over the range pH 2.55 to pH 8.02 from 32.38 mg/mL to 0.17 mg/mL. The log of the distribution coefficient (octanol/water) at pH 9 is 2.45.

LORBRENA is supplied as tablets containing 25 mg or 100 mg of lorlatinib with the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate. The film-coating contains hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, lactose monohydrate, macrogol/polyethylene glycol (PEG) 3350, triacetin, titanium dioxide, ferrosoferric oxide/black iron oxide, and iron oxide red.

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 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)].

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

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.

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)].

LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5.1)].

The following adverse reactions are described elsewhere in the labeling:

• •
  Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1)]
• •
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
• •
  Hyperlipidemia [see Warnings and Precautions (5.3)]
• •
  Atrioventricular Block [see Warnings and Precautions (5.4)]
• •
  Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5)]
• •
  Hypertension [see Warnings and Precautions (5.6)]
• •
  Hyperglycemia [see Warnings and Precautions (5.7)]

• •
  Strong CYP3A Inducers: Contraindicated. (2.4, 7.1)
• •
  Moderate CYP3A Inducers: Avoid concomitant use. If concomitant use cannot be avoided, increase the LORBRENA dose. (2.4, 7.1)
• •
  Strong CYP3A Inhibitors: Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. (2.4, 7.1)
• •
  Fluconazole: Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. (2.4, 7.1)
• •
  Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates for which minimal concentration changes may lead to serious therapeutic failures. (7.2)
• •
  Certain P-gp Substrates: Avoid concomitant use with P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. (7.2)

In patients with CL_cr 15 to <30 mL/min (estimated by Cockcroft‑Gault), the recommended dosage of LORBRENA is 75 mg orally once daily [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with CLcr 30 to 89 mL/min (estimated by Cockcroft‑Gault) [see Clinical Pharmacology (12.3)].

Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.

At the recommended dosage, the mean (coefficient of variation [CV] %) maximum plasma concentration (C_max) is 577 ng/mL (42%) and the AUC_0-24h is 5,650 ng·h/mL (39%). Steady-state lorlatinib C_max increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage).

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.

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.

In patients with severe hepatic impairment (Child-Pugh C), the recommended dosage of LORBRENA is 50 mg orally once daily [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) to moderate (Child-Pugh B) hepatic impairment [see Clinical Pharmacology (12.3)].

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.

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.

In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.

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)].

• •
  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, 5.1)
• •
  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, 5.2)
• •
  Hyperlipidemia: Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENA at same or reduced dose based on severity. (2.3, 5.3)
• •
  Atrioventricular Block: Withhold and resume LORBRENA at same or reduced dose based on severity. (2.3, 5.4)
• •
  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, 5.5)
• •
  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, 5.6)
• •
  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, 5.7)
• •
  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, 7.2, 8.1, 8.3)

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)].

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. (8.2)

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 LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA 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 Grade 3–4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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)].

Table 11 describes the available strengths and package configurations for LORBRENA:

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)].

Distended abdomen, skin rash, and increased cholesterol and triglycerides occurred in animals. These findings were accompanied by hyperplasia and dilation of the bile ducts in the liver and acinar atrophy of the pancreas in rats at 15 mg/kg/day and in dogs at 2 mg/kg/day (approximately 8 and 0.5 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). All effects were reversible within the recovery period.

The recommended dosage of LORBRENA for patients with creatinine clearance [CL_cr] 15 to < 30 mL/min (estimated by Cockcroft‑Gault) is 75 mg orally once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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.

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)].

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)].

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)].

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)].

Pfizer

NDC 0069-0227-01

Lorbrena^®

(lorlatinib) tablets

25 mg

30 Tablets

Rx only

The recommended dosage of LORBRENA for patients with severe hepatic impairment (Child-Pugh C) is 50 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Pfizer

NDC 0069-0231-01

Lorbrena^®

(lorlatinib) tablets

100 mg

30 Tablets

Rx only

Carcinogenicity studies have not been conducted with lorlatinib. Lorlatinib was aneugenic in an in vitro assay in human lymphoblastoid TK6 cells and positive for micronuclei formation in vivo in the bone marrow of rats. Lorlatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Dedicated fertility studies were not conducted with lorlatinib. Findings in male reproductive organs occurred in repeat-dose toxicity studies and included lower testicular, epididymal, and prostate weights; testicular tubular degeneration/atrophy; prostatic atrophy; and/or epididymal inflammation at 15 mg/kg/day and 7 mg/kg/day in rats and dogs, respectively (approximately 8 and 2 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). The effects on male reproductive organs were reversible.

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)].

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 [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months.

Serious adverse reactions occurred in 34% of 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 treated with LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6.7% 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. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). 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.

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

LORBRENA (lorlatinib) is a kinase inhibitor for oral administration. The molecular formula is C₂₁H₁₉FN₆O₂ (anhydrous form) and the molecular weight is 406.41 Daltons. The chemical name is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11] benzoxadiazacyclotetradecine-3-carbonitrile. The chemical structure is shown below:

Lorlatinib is a white to off-white powder with a pKa of 4.92. The solubility of lorlatinib in aqueous media decreases over the range pH 2.55 to pH 8.02 from 32.38 mg/mL to 0.17 mg/mL. The log of the distribution coefficient (octanol/water) at pH 9 is 2.45.

LORBRENA is supplied as tablets containing 25 mg or 100 mg of lorlatinib with the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate. The film-coating contains hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, lactose monohydrate, macrogol/polyethylene glycol (PEG) 3350, triacetin, titanium dioxide, ferrosoferric oxide/black iron oxide, and iron oxide red.

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 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)].

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

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.

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)].

LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5.1)].

The following adverse reactions are described elsewhere in the labeling:

• •
  Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1)]
• •
  Central Nervous System Effects [see Warnings and Precautions (5.2)]
• •
  Hyperlipidemia [see Warnings and Precautions (5.3)]
• •
  Atrioventricular Block [see Warnings and Precautions (5.4)]
• •
  Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5)]
• •
  Hypertension [see Warnings and Precautions (5.6)]
• •
  Hyperglycemia [see Warnings and Precautions (5.7)]

• •
  Strong CYP3A Inducers: Contraindicated. (2.4, 7.1)
• •
  Moderate CYP3A Inducers: Avoid concomitant use. If concomitant use cannot be avoided, increase the LORBRENA dose. (2.4, 7.1)
• •
  Strong CYP3A Inhibitors: Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. (2.4, 7.1)
• •
  Fluconazole: Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. (2.4, 7.1)
• •
  Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates for which minimal concentration changes may lead to serious therapeutic failures. (7.2)
• •
  Certain P-gp Substrates: Avoid concomitant use with P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. (7.2)

In patients with CL_cr 15 to <30 mL/min (estimated by Cockcroft‑Gault), the recommended dosage of LORBRENA is 75 mg orally once daily [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with CLcr 30 to 89 mL/min (estimated by Cockcroft‑Gault) [see Clinical Pharmacology (12.3)].

Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.

At the recommended dosage, the mean (coefficient of variation [CV] %) maximum plasma concentration (C_max) is 577 ng/mL (42%) and the AUC_0-24h is 5,650 ng·h/mL (39%). Steady-state lorlatinib C_max increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage).

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.

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.

In patients with severe hepatic impairment (Child-Pugh C), the recommended dosage of LORBRENA is 50 mg orally once daily [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) to moderate (Child-Pugh B) hepatic impairment [see Clinical Pharmacology (12.3)].

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.

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.

In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.

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)].

• •
  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, 5.1)
• •
  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, 5.2)
• •
  Hyperlipidemia: Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENA at same or reduced dose based on severity. (2.3, 5.3)
• •
  Atrioventricular Block: Withhold and resume LORBRENA at same or reduced dose based on severity. (2.3, 5.4)
• •
  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, 5.5)
• •
  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, 5.6)
• •
  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, 5.7)
• •
  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, 7.2, 8.1, 8.3)

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)].

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. (8.2)

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 LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA 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 Grade 3–4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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)].

Table 11 describes the available strengths and package configurations for LORBRENA:

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)].

Distended abdomen, skin rash, and increased cholesterol and triglycerides occurred in animals. These findings were accompanied by hyperplasia and dilation of the bile ducts in the liver and acinar atrophy of the pancreas in rats at 15 mg/kg/day and in dogs at 2 mg/kg/day (approximately 8 and 0.5 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). All effects were reversible within the recovery period.

The recommended dosage of LORBRENA for patients with creatinine clearance [CL_cr] 15 to < 30 mL/min (estimated by Cockcroft‑Gault) is 75 mg orally once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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.

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)].

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)].

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)].

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)].

Pfizer

NDC 0069-0227-01

Lorbrena^®

(lorlatinib) tablets

25 mg

30 Tablets

Rx only

The recommended dosage of LORBRENA for patients with severe hepatic impairment (Child-Pugh C) is 50 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Pfizer

NDC 0069-0231-01

Lorbrena^®

(lorlatinib) tablets

100 mg

30 Tablets

Rx only

Carcinogenicity studies have not been conducted with lorlatinib. Lorlatinib was aneugenic in an in vitro assay in human lymphoblastoid TK6 cells and positive for micronuclei formation in vivo in the bone marrow of rats. Lorlatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Dedicated fertility studies were not conducted with lorlatinib. Findings in male reproductive organs occurred in repeat-dose toxicity studies and included lower testicular, epididymal, and prostate weights; testicular tubular degeneration/atrophy; prostatic atrophy; and/or epididymal inflammation at 15 mg/kg/day and 7 mg/kg/day in rats and dogs, respectively (approximately 8 and 2 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). The effects on male reproductive organs were reversible.

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)].