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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the Warnings and Precautions section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3–4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)

The safety of LORBRENA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months.

Serious adverse reactions occurred in 34% of patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients treated with LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENA was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).

Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461006.

Table 2 Adverse Reactions (≥10% for all NCI CTCAE Grades or ≥2% for Grades 3–4) in Patients Treated with LORBRENA in Study B7461006*
Adverse Reaction	LORBRENA N=149		Crizotinib N=142
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
* Adverse reactions were graded using NCI CTCAE version 4.03. † Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). ‡ Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). § Cognitive 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). ¶ Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism). # Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). Þ Myalgia (including musculoskeletal pain, myalgia). ß Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). à Fatigue (including asthenia, fatigue). è Upper respiratory tract infection (including upper respiratory infection). ð Rash (including dermatitis acneiform, maculopapular rash, rash).
Psychiatric
Mood effects†	16	2	5	0
Nervous system
Peripheral neuropathy‡	34	2	15	0.7
Cognitive effects§	21	2	6	0
Headache	17	0	18	0.7
Dizziness	11	0	14	0
Sleep effects¶	11	1.3	10	0
Respiratory
Dyspnea	20	2.7	16	2.1
Cough	16	0	18	0
Respiratory failure	2.7	2	0	0
Vascular disorders
Hypertension	18	10	2.1	0
Ocular
Vision disorder#	18	0	39	0.7
Gastrointestinal
Diarrhea	21	1.3	52	0.7
Nausea	15	0.7	52	2.1
Constipation	17	0	30	0.7
Vomiting	13	0.7	39	1.4
Musculoskeletal and connective tissue
Arthralgia	19	0.7	11	0
MyalgiaÞ	15	0.7	7	0
Back pain	15	0.7	11	0
Pain in extremity	17	0	8	0
General
Edemaß	56	4	40	1.4
Weight gain	38	17	13	2.1
Fatigueà	19	1.3	32	2.8
Pyrexia	17	1.3	13	1.4
Chest pain	11	1.3	14	0.7
Infections
Upper respiratory tract infectionè	11	0.7	7.7	1.4
Pneumonia	7.4	2	8.5	3.5
Bronchitis	6.7	2	2.1	0
Skin
Rashð	11	0	8.5	0

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

Table 3 Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in Study B7461006
Laboratory Abnormality	LORBRENA N=149		Crizotinib N=142
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 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.
* N=149 (LORBRENA). † N=141 (crizotinib). ‡ N=148 (LORBRENA). § 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=138 (LORBRENA). # N=135 (crizotinib).
Chemistry
Hypertriglyceridemia*†	95	22	27	0
Hypercholesterolemia*†	91	19	12	0
Increased creatinine*†	81	0.7	99	2.1
Increased GGT*†	52	6	41	6
Increased AST*†	48	2	75	3.5
Hyperglycemia*†	48	7	27	2.1
Increased ALT*†	44	2.7	75	4.3
Increased CPK*†	39	2	64	5
Hypoalbuminemia*†	36	0.7	61	6
Increased lipase*†	28	7	34	5
Increased alkaline phosphatase*†	23	0	50	0.7
Hyperkalemia*†	21	1.3	27	2.1
Increased amylase‡§	20	1.4	32	1.4
Hematology
Anemia*†	48	2	38	2.8
Activated PTT¶#	25	0	14	0
Lymphopenia*†	23	2.7	43	6
Thrombocytopenia*†	23	0	7	0.7

Previously Treated ALK-Positive Metastatic NSCLC

The data described below reflect exposure to LORBRENA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 12.5 months (1 day to 35 months) and 52% received LORBRENA 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 0 or 1 (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 LORBRENA 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 1 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 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001.

Table 4 Adverse Reactions Occurring in ≥10% of Patients in Study B7461001*
Adverse Reaction	LORBRENA (N=295)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
* Adverse reactions were graded using NCI CTCAE version 4.03. † Mood 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). ‡ Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance). § Cognitive 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). ¶ Speech effects (including aphasia, dysarthria, slow speech, speech disorder) # Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) Þ Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). ß Myalgia (including musculoskeletal pain, myalgia). à Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). è Fatigue (including asthenia, fatigue). ð Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). ø Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).
Psychiatric
Mood effects†	23	1.7
Nervous system
Peripheral neuropathy‡	47	2.7
Cognitive effects§	27	2
Headache	18	0.7
Dizziness	16	0.7
Speech effects¶	12	0.3
Sleep effects#	10	0
Respiratory
Dyspnea	27	5
Cough	18	0
Ocular
Vision disorderÞ	15	0.3
Gastrointestinal
Diarrhea	22	0.7
Nausea	18	0.7
Constipation	15	0
Vomiting	12	1
Musculoskeletal and connective tissue
Arthralgia	23	0.7
Myalgiaß	17	0
Back pain	13	0.7
Pain in extremity	13	0.3
General
Edemaà	57	3.1
Fatigueè	26	0.3
Weight gain	24	4.4
Pyrexia	12	0.7
Infections
Upper respiratory tract infectionð	12	0
Skin
Rashø	14	0.3

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).

Table 5 Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*
Laboratory Abnormality	LORBRENA
Laboratory Abnormality	All Grades (%)	Grade 3 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.
* Grades using NCI CTCAE version 4.03. † N=292. ‡ N=293. § N=291. ¶ N=290. # N=284.
Chemistry
Hypercholesterolemia†	96	18
Hypertriglyceridemia†	90	18
Hyperglycemia‡	52	5
Increased AST†	37	2.1
Hypoalbuminemia§	33	1
Increased ALT†	28	2.1
Increased lipase¶	24	10
Increased alkaline phosphatase†	24	1
Increased amylase#	22	3.9
Hypophosphatemia†	21	4.8
Hyperkalemia‡	21	1
Hypomagnesemia†	21	0
Hematology
Anemia‡	52	4.8
Thrombocytopenia‡	23	0.3
Lymphopenia†	22	3.4