ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. 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)] 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)] Most common (incidence >=20%) adverse reactions and Grade 3-4 laboratory abnormalities are edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or www.pfizer.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LORBRENULL in 476 patients who received 100 mg LORBRENULL once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENULL, 75% were exposed for months or longer and 61% were exposed for greater than year. In this pooled safety population, the most frequent adverse reactions in >= 20% of 476 patients who received LORBRENULL 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 LORBRENULL were hypercholesterolemia (21%) and hypertriglyceridemia (21%).. Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)The safety of LORBRENULL was evaluated in 149 patients with ALK-positive NSCLC in 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 LORBRENULL was 16.7 months (4 days to 34.3 months) and 76% received LORBRENULL for at least 12 months.Serious adverse reactions occurred in 34% of patients treated with LORBRENULL; 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 LORBRENULL 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 LORBRENULL due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENULL was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENULL. The most frequent adverse reactions that led to dose interruptions of LORBRENULL 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 LORBRENULL. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).Tables and summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENULL in Study B7461006.Table Adverse Reactions (>=10% for all NCI CTCAE Grades or >=2% for Grades 3-4) in Patients Treated with LORBRENULL in Study B7461006Adverse reactions were graded using NCI CTCAE version 4.03. Adverse ReactionLORBRENULLN=149CrizotinibN=142All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.Psychiatric Mood effectsMood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). 16250Nervous system Peripheral neuropathyPeripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). 342150.7 Cognitive effectsCognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation). 21260 Headache170180.7 Dizziness110140 Sleep effectsSleep effects (including insomnia, nightmare, sleep disorder, somnambulism). 111.3100Respiratory Dyspnea202.7162.1 Cough160180 Respiratory failure2.7200Vascular disorders Hypertension18102.10Ocular Vision disorderVision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 180390.7Gastrointestinal Diarrhea211.3520.7 Nausea150.7522.1 Constipation170300.7 Vomiting130.7391.4Musculoskeletal and connective tissue Arthralgia190.7110 MyalgiaMyalgia (including musculoskeletal pain, myalgia). 150.770 Back pain150.7110 Pain in extremity17080General EdemaEdema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 564401.4 Weight gain3817132.1 FatigueFatigue (including asthenia, fatigue). 191.3322.8 Pyrexia171.3131.4 Chest pain111.3140.7Infections Upper respiratory tract infectionUpper respiratory tract infection (including upper respiratory infection). 110.77.71.4 Pneumonia7.428.53.5 Bronchitis6.722.10Skin RashRash (including dermatitis acneiform, maculopapular rash, rash). 1108.50Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).Table Laboratory Abnormalities Worsening from Baseline in >=20% of Patients in Study B7461006Laboratory AbnormalityLORBRENULLN=149CrizotinibN=142All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time.N=number of patients who had at least one on-study assessment for the parameter of interest.Chemistry HypertriglyceridemiaN=149 (LORBRENULL). N=141 (crizotinib). 9522270 Hypercholesterolemia 9119120 Increased creatinine 810.7992.1 Increased GGT 526416 Increased AST 482753.5 Hyperglycemia 487272.1 Increased ALT 442.7754.3 Increased CPK 392645 Hypoalbuminemia 360.7616 Increased lipase 287345 Increased alkaline phosphatase 230500.7 Hyperkalemia 211.3272.1 Increased amylaseN=148 (LORBRENULL). 201.4321.4Hematology Anemia 482382.8 Activated PTTN=138 (LORBRENULL). N=135 (crizotinib). 250140 Lymphopenia 232.7436 Thrombocytopenia 23070.7. Previously Treated ALK-Positive Metastatic NSCLCThe data described below reflect exposure to LORBRENULL in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENULL 100 mg orally once daily in Study B7461001, multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORBRENULL was 12.5 months (1 day to 35 months) and 52% received LORBRENULL for >=12 months. Patient characteristics were: median age of 53 years (19 to 85 years), age >=65 years (18%), female (58%), White (49%), Asian (37%), and ECOG performance status or (96%).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.Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORBRENULL for adverse reactions occurred in 8% of patients.The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%). Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).Tables and summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENULL in Study B7461001.Table Adverse Reactions Occurring in >=10% of Patients in Study B7461001Adverse reactions were graded using NCI CTCAE version 4.03. Adverse ReactionLORBRENULL (N=295)All Grades (%)Grade or (%)Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.Psychiatric Mood effectsMood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation). 231.7Nervous system Peripheral neuropathyPeripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance). 472.7 Cognitive effectsCognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). 272 Headache180.7 Dizziness160.7 Speech effectsSpeech effects (including aphasia, dysarthria, slow speech, speech disorder) 120.3 Sleep effectsSleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) 100Respiratory Dyspnea275 Cough180Ocular Vision disorderVision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 150.3Gastrointestinal Diarrhea220.7 Nausea180.7 Constipation150 Vomiting121Musculoskeletal and connective tissue Arthralgia230.7 MyalgiaMyalgia (including musculoskeletal pain, myalgia). 170 Back pain130.7 Pain in extremity130.3General EdemaEdema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 573.1 FatigueFatigue (including asthenia, fatigue). 260.3 Weight gain244.4 Pyrexia120.7Infections Upper respiratory tract infectionUpper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). 120Skin RashRash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash). 140.3Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).Table Worsening Laboratory Values Occurring in >=20% of Patients in Study B7461001Grades using NCI CTCAE version 4.03. Laboratory AbnormalityLORBRENULLAll Grades(%)Grade or 4(%)Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. N=number of patients who had at least one on-study assessment for the parameter of interest.Chemistry HypercholesterolemiaN=292. 9618 Hypertriglyceridemia 9018 HyperglycemiaN=293. 525 Increased AST 372.1 HypoalbuminemiaN=291. 331 Increased ALT 282.1 Increased lipaseN=290. 2410 Increased alkaline phosphatase 241 Increased amylaseN=284. 223.9 Hypophosphatemia 214.8 Hyperkalemia 211 Hypomagnesemia 210Hematology Anemia 524.8 Thrombocytopenia 230.3 Lymphopenia 223.4.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.


13.2Animal Toxicology and/or Pharmacology. 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 mg/kg/day (approximately 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 mg/kg/day in rats and dogs, respectively (approximately and times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). The effects on male reproductive organs were reversible.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Lorlatinib is 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 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.. 12.2Pharmacodynamics. Exposure-response relationships for Grade or hypercholesterolemia and for any Grade or 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.. Cardiac ElectrophysiologyIn 295 patients who received LORBRENULL at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation >=200 ms after starting LORBRENULL. The prolongation of PR interval occurred in concentration-dependent manner. Atrioventricular block occurred in 1% of patients.In 275 patients who received LORBRENULL at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.. 12.3Pharmacokinetics. Steady-state lorlatinib maximum plasma concentration (Cmax) 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 times the recommended dosage). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ngh/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.. AbsorptionThe median lorlatinib Tmax was 1.2 hours (0.5 to hours) following single oral 100 mg dose and hours (0.5 to 23 hours) following 100 mg orally once daily at steady-state.The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration.. Effect of FoodThere was no clinically significant effect on lorlatinib pharmacokinetics following administration of LORBRENULL with high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat).. DistributionLorlatinib was 66% bound to plasma proteins at concentration of 2.4 uM. The blood-to-plasma ratio was 0.99, in vitro. The mean (CV%) steady-state volume of distribution (Vss) was 305 (28%) following single intravenous dose.. EliminationThe mean plasma half-life (t 1/2 of lorlatinib was 24 hours (40%) after single oral 100 mg dose of LORBRENULL. The mean oral clearance (CL/F) was 11 L/h (35%) following single oral 100 mg dose and increased to 18 L/h (39%) at steady-state, suggesting autoinduction.. MetabolismLorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in vitro.In plasma, benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive.. ExcretionFollowing single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).. Specific PopulationsNo clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5 ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment (total bilirubin >= 1.5 ULN with any AST) on lorlatinib pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].. Patients with Severe Renal ImpairmentFollowing administration of single oral 100 mg dose of LORBRENULL, lorlatinib AUCinf increased by 42% in subjects with severe renal impairment (CLcr 15 to <30 mL/min, estimated by Cockcroft-Gault) compared to subjects with normal renal function (CLcr >= 90 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of lorlatinib have not been studied in patients with end-stage renal disease requiring hemodialysis.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Strong CYP3A Inducers on Lorlatinib: Rifampin (a strong CYP3A inducer that also activates PXR) 600 mg once daily for days (Days to 8) coadministered with single oral 100 mg dose of LORBRENULL on Day reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade to increases in ALT or AST occurred within days. Grade ALT or AST elevations occurred in 50%, Grade ALT or AST elevations in 33%, and Grade ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within to 34 days (median 15 days) [see Drug Interactions (7.1)].. Effect of Moderate CYP3A Inducers on Lorlatinib: Modafinil (a moderate CYP3A inducer) decreased AUCinf by 23% and decreased Cmax by 22% of single oral 100 mg dose of LORBRENULL [see Drug Interactions (7.1)].. Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole (a strong CYP3A inhibitor) increased AUCinf by 42% and increased Cmax by 24% of single oral 100 mg dose of LORBRENULL [see Drug Interactions (7.1)].. Effect of Fluconazole on Lorlatinib: Fluconazole is predicted to increase steady-state AUCtau and Cmax of lorlatinib by 59%, and 28%, respectively, following concomitant oral administration of 100 mg of LORBRENULL once daily and 200 mg fluconazole once daily [see Drug Interactions (7.1)].. Effect of Moderate CYP3A Inhibitors on Lorlatinib: No clinically significant effect on steady-state lorlatinib pharmacokinetics is predicted when used concomitantly with verapamil or erythromycin.. Effect of Lorlatinib on CYP3A Substrates: LORBRENULL 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of single oral mg dose of midazolam (a sensitive CYP3A substrate) [see Drug Interactions (7.2)].. Effect of Lorlatinib on CYP2B6 Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 25% and Cmax by 27% of single oral 100 mg dose of bupropion (a sensitive CYP2B6 substrate).. Effect of Lorlatinib on CYP2C9 Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 43% and Cmax by 15% of single oral 100 mg dose of tolbutamide (a sensitive CYP2C9 substrate).. Effect of Lorlatinib on UGT1A Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 45% and Cmax by 28% of single oral 100 mg dose of acetaminophen (a UGT1A substrate).. Effect of Lorlatinib on P-gp Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 67% and Cmax by 63% of single oral 60 mg dose of fexofenadine (a P-gp substrate) [see Drug Interactions (7.2)].. Effect of Acid-Reducing Agents on Lorlatinib: Concomitant use of proton pump inhibitor, rabeprazole, did not have clinically significant effect on lorlatinib pharmacokinetics.. In Vitro Studies. Effect of Lorlatinib on CYP Enzymes: Lorlatinib is time-dependent inhibitor as well as an inducer of CYP3A and activates PXR, with the net effect in vivo being induction. Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib and the major circulating metabolite, M8, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. M8 does not inhibit CYP3A.M8 does not induce CYP1A2, CYP2B6, or CYP3A.. Effects of Lorlatinib on UDP-glucuronosyltransferase (UGT): Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.. Effect of Lorlatinib on Transporter Systems: Lorlatinib is an inhibitor of P-gp and activates PXR (potential to induce P-gp), with the net effect in vivo being induction. Lorlatinib inhibits organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP). Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, or systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)The efficacy of LORBRENULL for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (Study B7461006; NCT03052608). Patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANULL ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, at least weeks (for stereotactic or partial radiation) or weeks (for whole brain irradiation) prior to randomization. Patients with severe acute or chronic psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior, were excluded.Patients were randomized 1:1 to receive LORBRENULL 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Additional efficacy outcome measures were overall survival (OS) and tumor assessment related data by BICR, including overall response rate (ORR), and duration of response (DOR). In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial overall response rate (IC-ORR) and intracranial duration of response (IC-DOR) by BICR.A total of 296 patients were randomized to LORBRENULL (n=149) or crizotinib (n=147). The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age >=65 years (35%), 59% female, 49% White, 44% Asian, and 0.3% Black. The ECOG performance status at baseline was or in 96% of patients. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions.Efficacy results from Study B7461006 as assessed by BICR are summarized in Table and Figure 1. Results demonstrated significant improvement in PFS for the LORBRENULL arm over the crizotinib arm. At the data cutoff point OS data was not mature.Table Efficacy Results in Study B7461006 (CROWN)Efficacy ParameterLORBRENULLN=149CrizotinibN=147Abbreviations: CI=confidence interval; N=number of patients; NE=not estimable; PFS=progression free survival.Progression-free survival Number of events, (%)41 (28%)86 (59%) Progressive disease, (%)32 (22%)82 (56%) Death, (%)9 (6%)4 (3%) Median, months (95% CI)Based on the Brookmeyer and Crowley method. NE (NE, NE)9.3 (7.6, 11.1) Hazard ratio (95% CI)Hazard ratio based on Cox proportional hazards model. 0.28 (0.19, 0.41) p-valuep-value based on 1-sided stratified log-rank test. <0.0001Overall response rate Overall response rate (95% CI)Using exact method based on binomial distribution. 76% (68, 83)58% (49, 66) Complete response3%0% Partial response73%58%Duration of response Number of responders, n11385 Median, months (Range)NE (0.9, 31.3)11 (1.1, 27.5) Response duration >=6 months, (%)101 (89%)53 (62%) Response duration >=12 months, (%)79 (70%)23 (27%) Response duration >=18 months, (%)34 (30%)9 (11%)Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BICR in Study B7461006 (CROWN)The results of prespecified exploratory analyses of intracranial response rate in 30 patients with measurable CNS lesions at baseline as assessed by BICR are summarized in Table 7.Table Intracranial Response Rate in Patients with Measurable Intracranial Lesions in CROWNIntracranial Tumor Response AssessmentLORBRENULLN=17CrizotinibN=13Abbreviations: CI=confidence interval; N/n=number of patients.Intracranial response rate (95% CI)Using exact method based on binomial distribution. 82% (57, 96)23% (5, 54) Complete response71%8%Duration of response Number of responders, n143 Response duration >=12 months, (%)11 (79%)0. Figure 1. ALK-Positive Metastatic NSCLC Previously Treated with an ALK Kinase InhibitorThe efficacy of LORBRENULL was demonstrated in subgroup of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK kinase inhibitors who were enrolled in non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study (Study B7461001; NCT01970865). Patients included in this subgroup were required to have metastatic disease with at least measurable target lesion according to RECIST v1.1, ECOG performance status of to 2, and documented ALK rearrangement in tumor tissue as determined by fluorescence in situ hybridization (FISH) assay or by Immunohistochemistry (IHC), and received LORBRENULL 100 mg orally once daily. Patients with asymptomatic CNS metastases, including patients with stable or decreasing steroid use within weeks prior to study entry, were eligible. Patients with severe, acute, or chronic psychiatric conditions including suicidal ideation or behavior were excluded. In addition, for patients with ALK-positive metastatic NSCLC, the extent and type of prior treatment was specified for each individual cohort (see Table 8). The major efficacy outcome measures were ORR and intracranial ORR, according to RECIST v1.1, as assessed by Independent Central Review (ICR) committee. Data were pooled across all subgroups listed in Table 8. Additional efficacy outcome measures included DOR, and intracranial DOR.A total of 215 patients were enrolled across the subgroups in Table 8. The distribution of patients by type and extent of prior therapy is provided in Table 8. The demographic characteristics across all 215 patients were: 59% female, 51% White, 34% Asian, and the median age was 53 years (29 to 85 years) with 18% of patients >=65 years. The ECOG performance status at baseline was or in 96% of patients. All patients had metastatic disease and 95% had adenocarcinoma. Brain metastases as identified by ICR were present in 69% of patients; of these, 60% had received prior radiation to the brain and 60% (n=89) had measurable disease per ICR.Table Extent of Prior Therapy in the Subgroup of Patients with Previously Treated ALK-Positive Metastatic NSCLC in Study B7461001Extent of prior therapyNumber of patientsAbbreviations: ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer.Prior crizotinib and no prior chemotherapyChemotherapy administered in the metastatic setting. 29Prior crizotinib and 1-2 lines of prior chemotherapy 35Prior ALK inhibitor (not crizotinib) with or without prior chemotherapy 28Two prior ALK inhibitors with or without prior chemotherapy 75Three prior ALK inhibitors with or without prior chemotherapy 48Total215Efficacy results for Study B7461001 are summarized in Tables and 10.Table Efficacy Results in Study B7461001Efficacy ParameterOverall N=215Abbreviations: CI=confidence interval; N=number of patients.Overall response ratePer Independent Central Review. (95% CI)Using exact method based on binomial distribution. 48% (42, 55) Complete response4% Partial response44%Duration of response Median, monthsEstimated using the Kaplan-Meier method. (95% CI)12.5 (8.4, 23.7)An assessment of intracranial ORR and the duration of response for CNS metastases in the subgroup of 89 patients in Study B7461001 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 10. Of these, 56 (63%) patients received prior brain radiation, including 42 patients (47%) who completed brain radiation treatment at least months before starting treatment with LORBRENULL.Table 10Intracranial Response Rate in Patients with Measurable Intracranial Lesions in Study B7461001Efficacy ParameterIntracranial N=89Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.Intracranial response ratePer Independent Central Review. (95% CI)Using exact method based on binomial distribution. 60% (49, 70) Complete response21% Partial response38%Duration of response Median, monthsEstimated using the Kaplan-Meier method. (95% CI)19.5 (12.4, NR)In exploratory analyses conducted in subgroups defined by prior therapy, the response rates to LORBRENULL were:ORR 39% (95% CI: 30, 48) in 119 patients who received crizotinib and at least one other ALK inhibitor, with or without prior chemotherapyORR 31% (95% CI: 9, 61) in 13 patients who received alectinib as their only ALK inhibitor, with or without prior chemotherapyORR 46% (95% CI: 19, 75) in 13 patients who received ceritinib as their only ALK inhibitor, with or without prior chemotherapy. ORR 39% (95% CI: 30, 48) in 119 patients who received crizotinib and at least one other ALK inhibitor, with or without prior chemotherapy. ORR 31% (95% CI: 9, 61) in 13 patients who received alectinib as their only ALK inhibitor, with or without prior chemotherapy. ORR 46% (95% CI: 19, 75) in 13 patients who received ceritinib as their only ALK inhibitor, with or without prior chemotherapy.

CLINICAL TRIALS EXPERIENCE SECTION.


6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LORBRENULL in 476 patients who received 100 mg LORBRENULL once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENULL, 75% were exposed for months or longer and 61% were exposed for greater than year. In this pooled safety population, the most frequent adverse reactions in >= 20% of 476 patients who received LORBRENULL 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 LORBRENULL were hypercholesterolemia (21%) and hypertriglyceridemia (21%).. Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)The safety of LORBRENULL was evaluated in 149 patients with ALK-positive NSCLC in 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 LORBRENULL was 16.7 months (4 days to 34.3 months) and 76% received LORBRENULL for at least 12 months.Serious adverse reactions occurred in 34% of patients treated with LORBRENULL; 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 LORBRENULL 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 LORBRENULL due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENULL was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENULL. The most frequent adverse reactions that led to dose interruptions of LORBRENULL 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 LORBRENULL. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).Tables and summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENULL in Study B7461006.Table Adverse Reactions (>=10% for all NCI CTCAE Grades or >=2% for Grades 3-4) in Patients Treated with LORBRENULL in Study B7461006Adverse reactions were graded using NCI CTCAE version 4.03. Adverse ReactionLORBRENULLN=149CrizotinibN=142All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.Psychiatric Mood effectsMood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). 16250Nervous system Peripheral neuropathyPeripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). 342150.7 Cognitive effectsCognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation). 21260 Headache170180.7 Dizziness110140 Sleep effectsSleep effects (including insomnia, nightmare, sleep disorder, somnambulism). 111.3100Respiratory Dyspnea202.7162.1 Cough160180 Respiratory failure2.7200Vascular disorders Hypertension18102.10Ocular Vision disorderVision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 180390.7Gastrointestinal Diarrhea211.3520.7 Nausea150.7522.1 Constipation170300.7 Vomiting130.7391.4Musculoskeletal and connective tissue Arthralgia190.7110 MyalgiaMyalgia (including musculoskeletal pain, myalgia). 150.770 Back pain150.7110 Pain in extremity17080General EdemaEdema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 564401.4 Weight gain3817132.1 FatigueFatigue (including asthenia, fatigue). 191.3322.8 Pyrexia171.3131.4 Chest pain111.3140.7Infections Upper respiratory tract infectionUpper respiratory tract infection (including upper respiratory infection). 110.77.71.4 Pneumonia7.428.53.5 Bronchitis6.722.10Skin RashRash (including dermatitis acneiform, maculopapular rash, rash). 1108.50Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).Table Laboratory Abnormalities Worsening from Baseline in >=20% of Patients in Study B7461006Laboratory AbnormalityLORBRENULLN=149CrizotinibN=142All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time.N=number of patients who had at least one on-study assessment for the parameter of interest.Chemistry HypertriglyceridemiaN=149 (LORBRENULL). N=141 (crizotinib). 9522270 Hypercholesterolemia 9119120 Increased creatinine 810.7992.1 Increased GGT 526416 Increased AST 482753.5 Hyperglycemia 487272.1 Increased ALT 442.7754.3 Increased CPK 392645 Hypoalbuminemia 360.7616 Increased lipase 287345 Increased alkaline phosphatase 230500.7 Hyperkalemia 211.3272.1 Increased amylaseN=148 (LORBRENULL). 201.4321.4Hematology Anemia 482382.8 Activated PTTN=138 (LORBRENULL). N=135 (crizotinib). 250140 Lymphopenia 232.7436 Thrombocytopenia 23070.7. Previously Treated ALK-Positive Metastatic NSCLCThe data described below reflect exposure to LORBRENULL in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENULL 100 mg orally once daily in Study B7461001, multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORBRENULL was 12.5 months (1 day to 35 months) and 52% received LORBRENULL for >=12 months. Patient characteristics were: median age of 53 years (19 to 85 years), age >=65 years (18%), female (58%), White (49%), Asian (37%), and ECOG performance status or (96%).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.Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORBRENULL for adverse reactions occurred in 8% of patients.The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%). Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).Tables and summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENULL in Study B7461001.Table Adverse Reactions Occurring in >=10% of Patients in Study B7461001Adverse reactions were graded using NCI CTCAE version 4.03. Adverse ReactionLORBRENULL (N=295)All Grades (%)Grade or (%)Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.Psychiatric Mood effectsMood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation). 231.7Nervous system Peripheral neuropathyPeripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance). 472.7 Cognitive effectsCognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). 272 Headache180.7 Dizziness160.7 Speech effectsSpeech effects (including aphasia, dysarthria, slow speech, speech disorder) 120.3 Sleep effectsSleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) 100Respiratory Dyspnea275 Cough180Ocular Vision disorderVision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 150.3Gastrointestinal Diarrhea220.7 Nausea180.7 Constipation150 Vomiting121Musculoskeletal and connective tissue Arthralgia230.7 MyalgiaMyalgia (including musculoskeletal pain, myalgia). 170 Back pain130.7 Pain in extremity130.3General EdemaEdema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 573.1 FatigueFatigue (including asthenia, fatigue). 260.3 Weight gain244.4 Pyrexia120.7Infections Upper respiratory tract infectionUpper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). 120Skin RashRash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash). 140.3Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).Table Worsening Laboratory Values Occurring in >=20% of Patients in Study B7461001Grades using NCI CTCAE version 4.03. Laboratory AbnormalityLORBRENULLAll Grades(%)Grade or 4(%)Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. N=number of patients who had at least one on-study assessment for the parameter of interest.Chemistry HypercholesterolemiaN=292. 9618 Hypertriglyceridemia 9018 HyperglycemiaN=293. 525 Increased AST 372.1 HypoalbuminemiaN=291. 331 Increased ALT 282.1 Increased lipaseN=290. 2410 Increased alkaline phosphatase 241 Increased amylaseN=284. 223.9 Hypophosphatemia 214.8 Hyperkalemia 211 Hypomagnesemia 210Hematology Anemia 524.8 Thrombocytopenia 230.3 Lymphopenia 223.4.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. LORBRENULL is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5.1)].. Concomitant use with strong CYP3A inducers. (4).

DESCRIPTION SECTION.


11DESCRIPTION. LORBRENULL (lorlatinib) is 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 white to off-white powder with 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 is 2.45.LORBRENULL 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.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. Recommended dosage: 100 mg orally once daily. (2.2)Severe Renal Impairment: 75 mg orally once daily. (2.8, 8.7, 12.3). 2.1Patient Selection Select patients for the treatment of metastatic NSCLC with LORBRENULL 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.. 2.2Recommended Dosage. The recommended dosage of LORBRENULL 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 LORBRENULL at the same time each day. If dose is missed, then take the missed dose unless the next dose is due within hours. Do not take doses at the same time to make up for missed dose.Do not take an additional dose if vomiting occurs after LORBRENULL but continue with the next scheduled dose.. 2.3Dosage Modifications for Adverse Reactions. The recommended dose reductions are:First dose reduction: LORBRENULL 75 mg orally once dailySecond dose reduction: LORBRENULL 50 mg orally once dailyPermanently discontinue LORBRENULL in patients who are unable to tolerate 50 mg orally once daily.Dosage modifications for adverse reactions of LORBRENULL are provided in Table 1.Table Recommended LORBRENULL Dosage Modifications for Adverse ReactionsAdverse ReactionGrade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dosage ModificationsAbbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.Central Nervous System Effects [see Warnings and Precautions (5.2)]Grade 1Continue at the same dose or withhold the dose until recovery to baseline. Resume LORBRENULL at the same dose or at reduced dose.Grade OR Grade 3Withhold dose until Grade or 1. Resume LORBRENULL at reduced dose.Grade 4Permanently discontinue LORBRENULL.Hyperlipidemia [see Warnings and Precautions (5.3)]Grade hypercholesterolemia OR Grade hypertriglyceridemiaWithhold LORBRENULL until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal to Grade 2. Resume LORBRENULL at the same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume LORBRENULL at reduced dose.Atrioventricular (AV) Block [see Warnings and Precautions (5.4)]Second-degree AV blockWithhold LORBRENULL until PR interval is less than 200 ms. Resume LORBRENULL at reduced dose.First occurrence of complete AV blockWithhold LORBRENULL untilpacemaker placed OR PR interval less than 200 ms. If pacemaker is placed, resume LORBRENULL at the same dose. If no pacemaker is placed, resume LORBRENULL at reduced dose.Recurrent complete AV blockPlace pacemaker or permanently discontinue LORBRENULL.Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5)]Any Grade treatment-related ILD/PneumonitisPermanently discontinue LORBRENULL.Hypertension [see Warnings and Precautions (5.6)]Grade (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 LORBRENULL until hypertension has recovered to Grade or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENULL at the same dose.If Grade hypertension recurs, withhold LORBRENULL until recovery to Grade or less, and resume at reduced dose.If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue LORBRENULL.Grade (life-threatening consequences, urgent intervention indicated)Withhold LORBRENULL until recovery to Grade or less, and resume at reduced dose or permanently discontinue LORBRENULL.If Grade hypertension recurs, permanently discontinue LORBRENULL.Hyperglycemia [see Warnings and Precautions (5.7)]Grade ((greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4Withhold LORBRENULL until hyperglycemia is adequately controlled, then resume LORBRENULL at the next lower dosage.If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue LORBRENULL.Other Adverse ReactionsGrade OR Grade 2Continue LORBRENULL at same dose or reduced dose.Grade OR Grade 4Withhold LORBRENULL until symptoms resolve to less than or equal to Grade or baseline. Resume LORBRENULL at reduced dose.. First dose reduction: LORBRENULL 75 mg orally once daily. Second dose reduction: LORBRENULL 50 mg orally once daily. pacemaker placed OR PR interval less than 200 ms.. 2.4Concomitant Use of Strong CYP3A Inducers. LORBRENULL is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENULL [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7.1), Clinical Pharmacology (12.3)] .. 2.5Concomitant Use of Moderate CYP3A Inducers. Avoid concomitant use of moderate CYP3A inducers with LORBRENULL. If concomitant use with moderate CYP3A inducers is unavoidable, increase the LORBRENULL dose to 125 mg once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 2.6Dosage Modification for Strong CYP3A Inhibitors. Avoid concomitant use of LORBRENULL with strong CYP3A inhibitors. If concomitant use with strong CYP3A inhibitor is unavoidable, reduce the starting dose of LORBRENULL from 100 mg orally once daily to 75 mg orally once daily.In patients who have had dose reduction to 75 mg orally once daily due to adverse reactions and who initiate strong CYP3A inhibitor, reduce the LORBRENULL dose to 50 mg orally once daily.If concomitant use of strong CYP3A inhibitor is discontinued, increase the LORBRENULL dose (after 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)].. 2.7Dosage Modification for Fluconazole. Avoid concomitant use of LORBRENULL with fluconazole [see Clinical Pharmacology (12.3)]. If concomitant use is unavoidable, reduce the starting dose of LORBRENULL from 100 mg orally once daily to 75 mg orally once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 2.8Dosage Modification for Severe Renal Impairment Reduce the recommended dosage of LORBRENULL 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)].

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. Tablets:25 mg: mm round, tan, immediate release, film-coated, debossed with Pfizer on one side and 25 and LLN on the other side100 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. 25 mg: 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. Tablets: 25 mg or 100 mg. (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Strong CYP3A Inducers: Contraindicated. (2.4, 7.1)Moderate CYP3A Inducers: Avoid concomitant use. If coadministration cannot be avoided, increase the LORBRENULL dose. (2.5, 7.1)Strong CYP3A Inhibitors: Avoid concomitant use; reduce LORBRENULL dose if concomitant use cannot be avoided. (2.6, 7.1)Fluconazole: Avoid concomitant use; reduce LORBRENULL dose if concomitant use cannot be avoided. (2.7, 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) Strong CYP3A Inducers: Contraindicated. (2.4, 7.1). Moderate CYP3A Inducers: Avoid concomitant use. If coadministration cannot be avoided, increase the LORBRENULL dose. (2.5, 7.1). Strong CYP3A Inhibitors: Avoid concomitant use; reduce LORBRENULL dose if concomitant use cannot be avoided. (2.6, 7.1). Fluconazole: Avoid concomitant use; reduce LORBRENULL dose if concomitant use cannot be avoided. (2.7, 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) 7.1Effect of Other Drugs on LORBRENULL. Strong CYP3A InducersConcomitant use of LORBRENULL with strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of LORBRENULL.Severe hepatotoxicity occurred in healthy subjects receiving LORBRENULL with rifampin, strong CYP3A inducer. In 12 healthy subjects receiving single 100 mg dose of LORBRENULL with multiple daily doses of rifampin, Grade or increases in ALT or AST occurred in 83% of subjects and Grade increases in ALT or AST occurred in 8%. possible mechanism for hepatotoxicity is through activation of the pregnane receptor (PXR) by LORBRENULL and rifampin, which are both PXR agonists.LORBRENULL is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4)]. Discontinue strong CYP3A inducers for plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENULL [see Dosage and Administration (2.3)].. Moderate CYP3A InducersConcomitant use of LORBRENULL with moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENULL [see Clinical Pharmacology (12.3)]. Avoid concomitant use of moderate CYP3A inducers with LORBRENULL. If concomitant use is unavoidable, increase the LORBRENULL dose [see Dosage and Administration (2.4)].. Strong CYP3A InhibitorsConcomitant use with strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of LORBRENULL. Avoid concomitant use of LORBRENULL with strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENULL dosage [see Dosage and Administration (2.5)].. FluconazoleConcomitant use of LORBRENULL with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of LORBRENULL. Avoid concomitant use of LORBRENULL with fluconazole. If concomitant use cannot be avoided, reduce the LORBRENULL dosage [see Dosage and Administration (2.7)].. 7.2Effect of LORBRENULL on Other Drugs. Certain CYP3A SubstratesLORBRENULL is moderate CYP3A inducer. Concomitant use of LORBRENULL decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENULL 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) SubstratesLORBRENULL is moderate P-gp inducer. Concomitant use of LORBRENULL decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENULL 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating LORBRENULL [see Use in Specific Populations (8.1)].. ContraceptionLORBRENULL can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. FemalesAdvise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENULL and for at least months after the final dose. Advise females of reproductive potential to use non-hormonal method of contraception, because LORBRENULL can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENULL and for at least months after the final dose [see Nonclinical Toxicology (13.1)].. Infertility. MalesBased on findings from animal studies, LORBRENULL may transiently impair male fertility [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.


8.5Geriatric Use. Of the patients in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg LORBRENULL 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 SUBSECTION.


8.6Hepatic 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 LORBRENULL 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)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. Table 11 describes the available strengths and package configurations for LORBRENULL:Table 11 LORBRENULL TabletsPackage ConfigurationStrength (mg)NDCDescription30 count bottle with child-resistant closure250069-0227-018 mm round, tan, immediate release film-coated, debossed with Pfizer on one side and 25 and LLN on the other side30 count bottle with child-resistant closure1000069-0231-018.5 mm 17 mm oval, lavender, immediate release, film-coated, debossed with Pfizer on one side and LLN 100 on the other side. Store at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. LORBRENULL(R) 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.. LORBRENULL is kinase inhibitor 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. (1, 2.1).

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A InducersInform patients of the potential risk of hepatoxicity with the concomitant use of strong CYP3A inducers.Advise patients to inform their healthcare providers of all medications they are taking, including prescription medicines, over-the-counter drugs, vitamins, and herbal products (e.g., St. Johns wort) [see Warnings and Precautions (5.1)].. Central Nervous System (CNS) EffectsAdvise patients to notify their healthcare provider if they experience new or worsening CNS symptoms [see Warnings and Precautions (5.2)].. HyperlipidemiaInform patients that serum cholesterol and triglycerides will be monitored during treatment. Advise patients that initiation or an increase in the dose of lipid-lowering agents may be required [see Warnings and Precautions (5.3)].. Atrioventricular (AV) BlockInform patients of the risks of AV block. Advise patients to contact their healthcare provider immediately to report new or worsening cardiac symptoms [see Warnings and Precautions (5.4)].. Interstitial Lung Disease (ILD)/PneumonitisInform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.5)].. HypertensionAdvise patients of the risks of hypertension and to promptly report signs or symptoms of hypertension to their healthcare provider. Advise patients with hypertension that antihypertension medications may need to be initiated or adjusted during treatment with LORBRENULL [see Warnings and Precautions (5.6)] . HyperglycemiaInform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with newly occurring hyperglycemia during treatment with LORBRENULL that antihyperglycemic medications may need to be initiated. Inform patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment with LORBRENULL [see Warnings and Precautions (5.7)].. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENULL and for at least months after the final dose [see Use in Specific Populations (8.3)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LORBRENULL and for at least months after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. LactationAdvise women not to breastfeed during treatment with LORBRENULL and for days after the final dose [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential that LORBRENULL may transiently impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

LACTATION SECTION.


8.2Lactation. Risk SummaryThere are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENULL and for days after the final dose.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. Lorlatinib is 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 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.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 mg/kg/day in rats and dogs, respectively (approximately and times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). The effects on male reproductive organs were reversible.. 13.2Animal Toxicology and/or Pharmacology. 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 mg/kg/day (approximately 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 25 mg Tablet Bottle Label. PfizerNDC 0069-0227-01Lorbrena(R) (lorlatinib) tablets 25 mg30 TabletsRx only. PRINCIPAL DISPLAY PANEL 25 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.


8.4Pediatric Use. The safety and effectiveness of LORBRENULL in pediatric patients have not been established.

PHARMACODYNULLMICS SECTION.


12.2Pharmacodynamics. Exposure-response relationships for Grade or hypercholesterolemia and for any Grade or 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.. Cardiac ElectrophysiologyIn 295 patients who received LORBRENULL at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation >=200 ms after starting LORBRENULL. The prolongation of PR interval occurred in concentration-dependent manner. Atrioventricular block occurred in 1% of patients.In 275 patients who received LORBRENULL at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. Steady-state lorlatinib maximum plasma concentration (Cmax) 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 times the recommended dosage). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ngh/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.. AbsorptionThe median lorlatinib Tmax was 1.2 hours (0.5 to hours) following single oral 100 mg dose and hours (0.5 to 23 hours) following 100 mg orally once daily at steady-state.The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration.. Effect of FoodThere was no clinically significant effect on lorlatinib pharmacokinetics following administration of LORBRENULL with high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat).. DistributionLorlatinib was 66% bound to plasma proteins at concentration of 2.4 uM. The blood-to-plasma ratio was 0.99, in vitro. The mean (CV%) steady-state volume of distribution (Vss) was 305 (28%) following single intravenous dose.. EliminationThe mean plasma half-life (t 1/2 of lorlatinib was 24 hours (40%) after single oral 100 mg dose of LORBRENULL. The mean oral clearance (CL/F) was 11 L/h (35%) following single oral 100 mg dose and increased to 18 L/h (39%) at steady-state, suggesting autoinduction.. MetabolismLorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in vitro.In plasma, benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive.. ExcretionFollowing single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).. Specific PopulationsNo clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5 ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment (total bilirubin >= 1.5 ULN with any AST) on lorlatinib pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].. Patients with Severe Renal ImpairmentFollowing administration of single oral 100 mg dose of LORBRENULL, lorlatinib AUCinf increased by 42% in subjects with severe renal impairment (CLcr 15 to <30 mL/min, estimated by Cockcroft-Gault) compared to subjects with normal renal function (CLcr >= 90 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of lorlatinib have not been studied in patients with end-stage renal disease requiring hemodialysis.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Strong CYP3A Inducers on Lorlatinib: Rifampin (a strong CYP3A inducer that also activates PXR) 600 mg once daily for days (Days to 8) coadministered with single oral 100 mg dose of LORBRENULL on Day reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade to increases in ALT or AST occurred within days. Grade ALT or AST elevations occurred in 50%, Grade ALT or AST elevations in 33%, and Grade ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within to 34 days (median 15 days) [see Drug Interactions (7.1)].. Effect of Moderate CYP3A Inducers on Lorlatinib: Modafinil (a moderate CYP3A inducer) decreased AUCinf by 23% and decreased Cmax by 22% of single oral 100 mg dose of LORBRENULL [see Drug Interactions (7.1)].. Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole (a strong CYP3A inhibitor) increased AUCinf by 42% and increased Cmax by 24% of single oral 100 mg dose of LORBRENULL [see Drug Interactions (7.1)].. Effect of Fluconazole on Lorlatinib: Fluconazole is predicted to increase steady-state AUCtau and Cmax of lorlatinib by 59%, and 28%, respectively, following concomitant oral administration of 100 mg of LORBRENULL once daily and 200 mg fluconazole once daily [see Drug Interactions (7.1)].. Effect of Moderate CYP3A Inhibitors on Lorlatinib: No clinically significant effect on steady-state lorlatinib pharmacokinetics is predicted when used concomitantly with verapamil or erythromycin.. Effect of Lorlatinib on CYP3A Substrates: LORBRENULL 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of single oral mg dose of midazolam (a sensitive CYP3A substrate) [see Drug Interactions (7.2)].. Effect of Lorlatinib on CYP2B6 Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 25% and Cmax by 27% of single oral 100 mg dose of bupropion (a sensitive CYP2B6 substrate).. Effect of Lorlatinib on CYP2C9 Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 43% and Cmax by 15% of single oral 100 mg dose of tolbutamide (a sensitive CYP2C9 substrate).. Effect of Lorlatinib on UGT1A Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 45% and Cmax by 28% of single oral 100 mg dose of acetaminophen (a UGT1A substrate).. Effect of Lorlatinib on P-gp Substrates: LORBRENULL 100 mg orally once daily for 15 days decreased AUCinf by 67% and Cmax by 63% of single oral 60 mg dose of fexofenadine (a P-gp substrate) [see Drug Interactions (7.2)].. Effect of Acid-Reducing Agents on Lorlatinib: Concomitant use of proton pump inhibitor, rabeprazole, did not have clinically significant effect on lorlatinib pharmacokinetics.. In Vitro Studies. Effect of Lorlatinib on CYP Enzymes: Lorlatinib is time-dependent inhibitor as well as an inducer of CYP3A and activates PXR, with the net effect in vivo being induction. Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib and the major circulating metabolite, M8, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. M8 does not inhibit CYP3A.M8 does not induce CYP1A2, CYP2B6, or CYP3A.. Effects of Lorlatinib on UDP-glucuronosyltransferase (UGT): Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.. Effect of Lorlatinib on Transporter Systems: Lorlatinib is an inhibitor of P-gp and activates PXR (potential to induce P-gp), with the net effect in vivo being induction. Lorlatinib inhibits organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP). Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, or systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K.

PREGNULLNCY SECTION.


8.1Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], LORBRENULL can cause embryo-fetal harm when administered to pregnant woman. There are no available data on LORBRENULL 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 pregnant woman of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.. Data. Animal DataPreliminary 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 times the human exposure at the recommended dose of 100 mg) or greater. At dose of 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 mg/kg (approximately times the human exposure at the recommended dose of 100 mg) or greater. At dose of 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.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)3/2021Dosage and Administration, Patient Selection (2.1)3/2021Dosage and Administration, Dosage Modifications for Adverse Reactions (2.3)3/2021Dosage and Administration, Strong CYP3A Inducers (2.4)1/2021Dosage and Administration, Moderate CYP3A Inducers (2.5)1/2021Dosage and Administration, Severe Renal Impairment (2.8)2/2021Warnings and Precautions (5)3/2021Warnings and Precautions, Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers (5.1)1/2021Warnings and Precautions, Central Nervous System Effects (5.2)1/2021.

RENULLL IMPAIRMENT SUBSECTION.


8.7Renal Impairment. Reduce the dose when administering LORBRENULL 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)].

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONLORBRENULL (lor-BREN-ah)(lorlatinib)tabletsThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised: March 2021What is the most important information should know about LORBRENULLLORBRENULL may cause serious side effects, including:Liver problems due to interactions with other medicines. It is important to know what medicines should not be taken with LORBRENULL.Central nervous system (CNS) effects. LORBRENULL may cause CNS effects, including:problems with thinking, such as forgetfulness or confusionchanges in mood, such as depression and thoughts about suicide or dyingpsychotic effects, such as seeing or hearing things that are not real (hallucinations)seizureschanges in speechchanges in sleepTell your healthcare provider if you experience new or worsening symptoms of these CNS effects during treatment with LORBRENULL. Increases in the cholesterol and triglycerides (lipid) levels in your blood. Most people will have an increase in the lipid levels in their blood during treatment with LORBRENULL.If you have increases in the lipid levels in your blood during treatment with LORBRENULL, your healthcare provider may need to start you on medicine to lower the levels. If you are already taking medicine to lower the lipid levels in your blood, your healthcare provider may need to increase your dose of that medicine.Your healthcare provider should do blood tests to check the lipid levels in your blood before starting treatment, to months after starting treatment, and during treatment with LORBRENULL. Heart problems. LORBRENULL may cause very slow or abnormal heartbeats. Your healthcare provider should check your heart rhythm (electrocardiogram or EKG) before starting and during treatment with LORBRENULL. Tell your healthcare provider right away if you feel dizzy or faint or have abnormal heartbeats. In some people, these problems are severe and your healthcare provider may need to have you stop taking LORBRENULL or have pacemaker placed.Lung problems. LORBRENULL may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those from lung cancer. Tell your healthcare provider right away if you have any new or worsening symptoms of lung problems, including trouble breathing, shortness of breath, cough, or fever.High blood pressure (hypertension). Your healthcare provider should check your blood pressure before starting treatment, weeks after starting treatment, and then at least every month during treatment with LORBRENULL. Your healthcare provider may need to start or change your blood pressure medicine if you have high blood pressure during treatment with LORBRENULL. Tell your healthcare provider right away if you get signs or symptoms of high blood pressure, including: headaches, dizziness, blurred vision, chest pain or shortness of breath.High blood sugar (hyperglycemia). LORBRENULL may increase your blood sugar levels. Your healthcare provider should do blood tests to check your blood sugar levels before starting and during treatment with LORBRENULL. Your healthcare provider may need to start or change your blood sugar medicine to control your blood sugar levels. Tell your healthcare provider right away if you get new or worsening signs and symptoms of high blood sugar, including:feeling very thirstyneeding to urinate more than usualfeeling very hungryfeeling sick to your stomachfeeling weak or tiredfeeling confused If you have serious side effects during treatment with LORBRENULL, your healthcare provider may change your dose, stop your treatment for period of time, or completely stop treatment with LORBRENULL. See What are possible side effects of LORBRENULL for more information about side effects. What is LORBRENULLLORBRENULL is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC):that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your body. Your healthcare provider will perform test to make sure that LORBRENULL is right for you.It is not known if LORBRENULL is safe and effective in children.Do not take LORBRENULL if you take certain other medicines called strong CYP3A inducers. Ask your healthcare provider for list of these medicines if you are not sure.Before taking LORBRENULL, tell your healthcare provider about all of your medical conditions, including if you:have kidney problemshave had episodes of depression or seizureshave high levels of cholesterol or triglycerides in your bloodhave problems with your heart beathave lung or breathing problemshave high blood pressurehave diabetes or high blood sugarare pregnant or plan to become pregnant. LORBRENULL can harm your unborn baby.Your healthcare provider will do pregnancy test before you start treatment with LORBRENULL.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LORBRENULL.Females who are able to become pregnant should use effective non-hormonal birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with LORBRENULL. Talk to your healthcare provider about birth control choices that are right for you during this time.Males who have female partners who are able to become pregnant should use effective birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. are breastfeeding or plan to breastfeed. It is not known if LORBRENULL passes into your breast milk. Do not breastfeed during treatment with LORBRENULL and for days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. LORBRENULL may affect the way other medicines work and other medicines may affect the way LORBRENULL works causing side effects. Know the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine. How should take LORBRENULLTake LORBRENULL exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking LORBRENULL unless your healthcare provider tells you to.Swallow LORBRENULL tablets whole. Do not chew, crush, or split LORBRENULL tablets. Do not take LORBRENULL tablets if they are broken, cracked, or not intact.Take LORBRENULL time day, at the same time each day.You may take LORBRENULL with or without food.If you miss dose, take it as soon as you remember. However, if it is close to the time of your next dose (within hours), just take your next dose at your regular time. Do not take doses of LORBRENULL at the same time to make up for the missed dose.If you vomit after taking dose of LORBRENULL, do not take an extra dose. Take your next dose at your regular time.What are the possible side effects of LORBRENULLSee What is the most important information should know about LORBRENULLThe most common side effects of LORBRENULL include:swelling in your arms, legs, hands and feet (edema)numbness and tingling feeling in your joints or arms and legs (peripheral neuropathy)weight gainproblems with thinking, such as forgetfulness or confusiontiredness (fatigue)difficulty breathingpain in your jointsdiarrheachanges in mood, such as depression and irritabilityhigh cholesterol and triglyceride levels in the bloodcoughLORBRENULL may cause decreased fertility in males. In males, this could affect your ability to father child. Talk to your healthcare provider if you have concerns about fertility.These are not all of the possible side effects of LORBRENULL. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LORBRENULLStore LORBRENULL at room temperature between 68F to 77F (20C to 25C).Keep LORBRENULL and all medicines out of the reach of children.General information about the safe and effective use of LORBRENULL.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use LORBRENULL for condition for which it was not prescribed. Do not give LORBRENULL to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about LORBRENULL that is written for health professionals.What are the ingredients in LORBRENULLActive ingredient: lorlatinibInactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.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.For more information, go to www.LORBRENULL.com.LAB-1163-4.0. Liver problems due to interactions with other medicines. It is important to know what medicines should not be taken with LORBRENULL.. Central nervous system (CNS) effects. LORBRENULL may cause CNS effects, including:problems with thinking, such as forgetfulness or confusionchanges in mood, such as depression and thoughts about suicide or dyingpsychotic effects, such as seeing or hearing things that are not real (hallucinations)seizureschanges in speechchanges in sleepTell your healthcare provider if you experience new or worsening symptoms of these CNS effects during treatment with LORBRENULL. problems with thinking, such as forgetfulness or confusion. changes in mood, such as depression and thoughts about suicide or dying. psychotic effects, such as seeing or hearing things that are not real (hallucinations). seizures. changes in speech. changes in sleep. Increases in the cholesterol and triglycerides (lipid) levels in your blood. Most people will have an increase in the lipid levels in their blood during treatment with LORBRENULL.If you have increases in the lipid levels in your blood during treatment with LORBRENULL, your healthcare provider may need to start you on medicine to lower the levels. If you are already taking medicine to lower the lipid levels in your blood, your healthcare provider may need to increase your dose of that medicine.Your healthcare provider should do blood tests to check the lipid levels in your blood before starting treatment, to months after starting treatment, and during treatment with LORBRENULL. If you have increases in the lipid levels in your blood during treatment with LORBRENULL, your healthcare provider may need to start you on medicine to lower the levels. If you are already taking medicine to lower the lipid levels in your blood, your healthcare provider may need to increase your dose of that medicine.. Your healthcare provider should do blood tests to check the lipid levels in your blood before starting treatment, to months after starting treatment, and during treatment with LORBRENULL.. Heart problems. LORBRENULL may cause very slow or abnormal heartbeats. Your healthcare provider should check your heart rhythm (electrocardiogram or EKG) before starting and during treatment with LORBRENULL. Tell your healthcare provider right away if you feel dizzy or faint or have abnormal heartbeats. In some people, these problems are severe and your healthcare provider may need to have you stop taking LORBRENULL or have pacemaker placed.. Lung problems. LORBRENULL may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those from lung cancer. Tell your healthcare provider right away if you have any new or worsening symptoms of lung problems, including trouble breathing, shortness of breath, cough, or fever.. High blood pressure (hypertension). Your healthcare provider should check your blood pressure before starting treatment, weeks after starting treatment, and then at least every month during treatment with LORBRENULL. Your healthcare provider may need to start or change your blood pressure medicine if you have high blood pressure during treatment with LORBRENULL. Tell your healthcare provider right away if you get signs or symptoms of high blood pressure, including: headaches, dizziness, blurred vision, chest pain or shortness of breath.. High blood sugar (hyperglycemia). LORBRENULL may increase your blood sugar levels. Your healthcare provider should do blood tests to check your blood sugar levels before starting and during treatment with LORBRENULL. Your healthcare provider may need to start or change your blood sugar medicine to control your blood sugar levels. Tell your healthcare provider right away if you get new or worsening signs and symptoms of high blood sugar, including:. feeling very thirsty. needing to urinate more than usual. feeling very hungry. feeling sick to your stomach. feeling weak or tired. feeling confused that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, and that has spread to other parts of your body. have kidney problems. have had episodes of depression or seizures. have high levels of cholesterol or triglycerides in your blood. have problems with your heart beat. have lung or breathing problems. have high blood pressure. have diabetes or high blood sugar. are pregnant or plan to become pregnant. LORBRENULL can harm your unborn baby.Your healthcare provider will do pregnancy test before you start treatment with LORBRENULL.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LORBRENULL.Females who are able to become pregnant should use effective non-hormonal birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with LORBRENULL. Talk to your healthcare provider about birth control choices that are right for you during this time.Males who have female partners who are able to become pregnant should use effective birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Your healthcare provider will do pregnancy test before you start treatment with LORBRENULL.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LORBRENULL.Females who are able to become pregnant should use effective non-hormonal birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with LORBRENULL. Talk to your healthcare provider about birth control choices that are right for you during this time.Males who have female partners who are able to become pregnant should use effective birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Females who are able to become pregnant should use effective non-hormonal birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with LORBRENULL. Talk to your healthcare provider about birth control choices that are right for you during this time.. Males who have female partners who are able to become pregnant should use effective birth control during treatment with LORBRENULL and for at least months after the final dose of LORBRENULL.. are breastfeeding or plan to breastfeed. It is not known if LORBRENULL passes into your breast milk. Do not breastfeed during treatment with LORBRENULL and for days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time.. Take LORBRENULL exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking LORBRENULL unless your healthcare provider tells you to.. Swallow LORBRENULL tablets whole. Do not chew, crush, or split LORBRENULL tablets. Do not take LORBRENULL tablets if they are broken, cracked, or not intact.. Take LORBRENULL time day, at the same time each day.. You may take LORBRENULL with or without food.. If you miss dose, take it as soon as you remember. However, if it is close to the time of your next dose (within hours), just take your next dose at your regular time. Do not take doses of LORBRENULL at the same time to make up for the missed dose.. If you vomit after taking dose of LORBRENULL, do not take an extra dose. Take your next dose at your regular time.. See What is the most important information should know about LORBRENULL. swelling in your arms, legs, hands and feet (edema). numbness and tingling feeling in your joints or arms and legs (peripheral neuropathy). weight gain. problems with thinking, such as forgetfulness or confusion. tiredness (fatigue). difficulty breathing. pain in your joints. diarrhea. changes in mood, such as depression and irritability. high cholesterol and triglyceride levels in the blood. cough. Store LORBRENULL at room temperature between 68F to 77F (20C to 25C).. Logo.

SPL UNCLASSIFIED SECTION.


2.1Patient Selection Select patients for the treatment of metastatic NSCLC with LORBRENULL 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.

STORAGE AND HANDLING SECTION.


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

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], LORBRENULL can cause embryo-fetal harm when administered to pregnant woman. There are no available data on LORBRENULL 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 pregnant woman of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.. Data. Animal DataPreliminary 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 times the human exposure at the recommended dose of 100 mg) or greater. At dose of 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 mg/kg (approximately times the human exposure at the recommended dose of 100 mg) or greater. At dose of 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.. 8.2Lactation. Risk SummaryThere are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENULL and for days after the final dose.. 8.3Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating LORBRENULL [see Use in Specific Populations (8.1)].. ContraceptionLORBRENULL can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. FemalesAdvise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENULL and for at least months after the final dose. Advise females of reproductive potential to use non-hormonal method of contraception, because LORBRENULL can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENULL and for at least months after the final dose [see Nonclinical Toxicology (13.1)].. Infertility. MalesBased on findings from animal studies, LORBRENULL may transiently impair male fertility [see Nonclinical Toxicology (13.1)].. 8.4Pediatric Use. The safety and effectiveness of LORBRENULL in pediatric patients have not been established.. 8.5Geriatric Use. Of the patients in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg LORBRENULL 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.. 8.6Hepatic 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 LORBRENULL 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)].. 8.7Renal Impairment. Reduce the dose when administering LORBRENULL 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)].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Discontinue strong CYP3A inducers for plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENULL. (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 LORBRENULL at same or reduced dose or permanently discontinue LORBRENULL based on severity. (2.3, 5.2)Hyperlipidemia: Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENULL at same or reduced dose based on severity. (2.3, 5.3)Atrioventricular Block: Withhold and resume LORBRENULL at same or reduced dose based on severity. (2.3, 5.4)Interstitial Lung Disease/Pneumonitis: Immediately withhold LORBRENULL in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENULL for treatment-related ILD/pneumonitis of any severity. (2.3, 5.5)Hypertension: Monitor blood pressure after weeks and then at least monthly during treatment. For severe hypertension, withhold LORBRENULL, then dose reduce or permanently discontinue. (2.3, 5.6)Hyperglycemia: Assess fasting serum glucose prior to starting LORBRENULL and regularly during treatment. If not adequately controlled with optimal medical management, withhold LORBRENULL, 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 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). Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Discontinue strong CYP3A inducers for plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENULL. (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 LORBRENULL at same or reduced dose or permanently discontinue LORBRENULL based on severity. (2.3, 5.2). Hyperlipidemia: Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENULL at same or reduced dose based on severity. (2.3, 5.3). Atrioventricular Block: Withhold and resume LORBRENULL at same or reduced dose based on severity. (2.3, 5.4). Interstitial Lung Disease/Pneumonitis: Immediately withhold LORBRENULL in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENULL for treatment-related ILD/pneumonitis of any severity. (2.3, 5.5). Hypertension: Monitor blood pressure after weeks and then at least monthly during treatment. For severe hypertension, withhold LORBRENULL, then dose reduce or permanently discontinue. (2.3, 5.6). Hyperglycemia: Assess fasting serum glucose prior to starting LORBRENULL and regularly during treatment. If not adequately controlled with optimal medical management, withhold LORBRENULL, 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 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). 5.1Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers. Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving single dose of LORBRENULL with multiple daily doses of rifampin, strong CYP3A inducer. Grade alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 50% of subjects, Grade ALT or AST elevations occurred in 33% and Grade ALT or AST elevations occurred in 8%. ALT or AST elevations occurred within days and returned to within normal limits after median of 15 days (7 to 34 days); the median time to recovery was 18 days in subjects with Grade or ALT or AST elevations and days in subjects with Grade ALT or AST elevations [see Drug Interactions (7.1)]. LORBRENULL is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENULL [see Contraindications (4), Drug Interactions (7.1)].. 5.2Central Nervous System Effects. broad spectrum of central nervous system (CNS) effects can occur in patients receiving LORBRENULL. 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 LORBRENULL 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 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 LORBRENULL for CNS effect; 10% required temporary discontinuation and 8% required dose reduction.Withhold and resume at the same dose or at reduced dose or permanently discontinue LORBRENULL based on severity [see Dosage and Administration (2.3)].. 5.3Hyperlipidemia. Increases in serum cholesterol and triglycerides can occur in patients receiving LORBRENULL [see Adverse Reactions (6.1)]. Grade or elevations in total cholesterol occurred in 18% and Grade or elevations in triglycerides occurred in 19% of the 476 patients who received 100 mg LORBRENULL 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 LORBRENULL 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 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 LORBRENULL, and months after initiating LORBRENULL, and periodically thereafter. Withhold and resume at the same dose for the first occurrence; resume at the same or reduced dose of LORBRENULL for recurrence based on severity [see Dosage and Administration (2.3)]. 5.4Atrioventricular Block. PR interval prolongation and atrioventricular (AV) block can occur in patients receiving LORBRENULL [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. In 476 patients who received 100 mg LORBRENULL once daily and who had baseline electrocardiography (ECG), 1.9% experienced AV block and 0.2% experienced Grade AV block and underwent pacemaker placement.Monitor ECG prior to initiating LORBRENULL and periodically thereafter. Withhold and resume at reduced dose or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without pacemaker [see Dosage and Administration (2.3)].. 5.5Interstitial Lung Disease/Pneumonitis. Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with LORBRENULL. ILD/pneumonitis occurred in 1.9% of patients who received 100 mg LORBRENULL once daily, including Grade or ILD/pneumonitis in 0.6% of patients. Four patients (0.8%) discontinued LORBRENULL 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 LORBRENULL in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENULL for treatment-related ILD/pneumonitis of any severity [see Dosage and Administration (2.3)].. 5.6Hypertension. Hypertension can occur in patients receiving LORBRENULL [see Adverse Reactions (6.1)]. Hypertension occurred in 13% of patients who received 100 mg LORBRENULL once daily, including Grade or 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 LORBRENULL for hypertension.Control blood pressure prior to initiation of LORBRENULL. Monitor blood pressure after weeks and at least monthly thereafter during treatment with LORBRENULL. Withhold and resume at reduced dose or permanently discontinue LORBRENULL based on severity [see Dosage and Administration (2.3)].. 5.7Hyperglycemia. Hyperglycemia can occur in patients receiving LORBRENULL [see Adverse Reactions (6.1)]. Hyperglycemia occurred in 9% of patients who received 100 mg LORBRENULL, including Grade or 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 LORBRENULL for hyperglycemia.Assess fasting serum glucose prior to initiation of LORBRENULL and monitor periodically thereafter. Withhold and resume at reduced dose or permanently discontinue LORBRENULL based on severity [see Dosage and Administration (2.3)].. 5.8Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, LORBRENULL can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENULL can render hormonal contraceptives ineffective, during treatment with LORBRENULL and for at least months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENULL and for months after the final dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].