Rozlytrek

5 WARNINGS AND PRECAUTIONS Congestive Heart Failure (CHF) : Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For new onset or worsening CHF, withhold ROZLYTREK, reassess LVEF and institute appropriate medical management. Reduce dose or permanently discontinue ROZLYTREK based on severity of CHF or worsening LVEF. ( 2.7 , 5.1 ) Central Nervous System (CNS) Effects: CNS adverse reactions including cognitive impairment, mood disorders, dizziness, and sleep disturbances can occur with ROZLYTREK. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue ROZLYTREK based on severity. ( 2.7 , 5.2 ) Skeletal Fractures: ROZLYTREK increases the risk of fractures. Promptly evaluate patients with signs or symptoms of fractures. ( 5.3 ) Hepatotoxicity : Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on severity. If withheld, resume ROZLYTREK at same or reduced dose based on severity. ( 2.7 , 5.4 ) Hyperuricemia : Assess serum uric acid levels prior to initiation and periodically during treatment with ROZLYTREK. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume at same or reduced dose upon improvement based on severity. ( 2.7 , 5.5 ) QT Interval Prolongation : Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity. ( 2.7 , 5.6 ) Vision Disorders : Withhold for new visual changes or changes that interfere with activities of daily living until improvement or stabilization. Conduct an ophthalmological evaluation as appropriate. Resume at same or reduced dose upon improvement or stabilization. ( 2.7 , 5.7 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.8 , 8.1 , 8.3 ) 5.1 Congestive Heart Failure Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1) ]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients. Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.7) ] . 5.2 Central Nervous System Effects A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances. Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued ROZLYTREK due to cognitive adverse reactions. Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued ROZLYTREK due to mood disorders. Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued ROZLYTREK due to dizziness. Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances. The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (n = 90) compared to those who did not (n = 48). Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity [see Dosage and Administration (2.7) ] . 5.3 Skeletal Fractures ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 76 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 25% of pediatric patients experienced fractures [see Use in Specific Population (8.4) ] . In adult and pediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in pediatric patients some fractures occurred with no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some adult patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In two pediatric patients, bilateral femoral neck fractures occurred. A total of 41 fracture events were reported in 19 pediatric patients, with 13 patients who experienced more than one occurrence of fracture. Among the 19 pediatric patients who experienced fractures, 17 patients were less than 12 years of age. Among the 41 fracture events, 27 fracture events resolved, 4 fracture events resolved with sequelae and 3 events were resolving. The median time to fracture was 3.8 months (range 0.3 to 18.5 months) in adults and 4.3 months (range: 2 months to 28.7 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 16% of pediatric patients who experienced fractures. Five pediatric patients discontinued treatment due to fractures. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures. 5.4 Hepatotoxicity Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 – 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests [see Adverse Reactions (6.1) ] . The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% patients. Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose [see Dosage and Administration (2.7) ] . 5.5 Hyperuricemia Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia. Assess serum uric acid levels prior to initiation of ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity [see Dosage and Administration (2.7) ] . 5.6 QT Interval Prolongation Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTcF interval > 500 ms [see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ]. Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes prior to initiation of ROZLYTREK and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue [see Dosage and Administration (2.7) ] . 5.7 Vision Disorders Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (17%), Grade 2 (2.8%) and Grade 3 (0.8%) [see Adverse Reactions (6.1) ] . Vision disorders occurring in ≥ 1% included blurred vision (9%), photophobia (5%), diplopia (3.1%), visual impairment (2%), photopsia (1.1%), cataract (1.1%), and vitreous floaters (1.1%). For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose [see Dosage and Administration (2.7) ] . 5.8 Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure [see Warnings and Precautions (5.1) ] Central Nervous System Effects [see Warnings and Precautions (5.2) ] Skeletal Fractures [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hyperuricemia [see Warnings and Precautions (5.5) ] QT Interval Prolongation [see Warnings and Precautions (5.6) ] Vision Disorders [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. ROZLYTREK was studied in one dose-finding trial in adults [ALKA (n = 57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)]. The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumors (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received ROZLYTREK 600 mg orally once daily. The doses ranged from 100 mg/m 2 to 1600 mg/m 2 once daily in adults and 250 mg/m 2 to 750 mg/m 2 once daily in pediatric patients. Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue. Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%). Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK. The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%). The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders. Table 7 summarizes the adverse reactions observed in these 355 patients. Table 7. Adverse Reactions (≥ 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Adverse Reactions ROZLYTREK n = 355 All Grades (%) Grade ≥ 3 Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea. (%) General Fatigue Includes fatigue, asthenia 48 5 Edema Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 40 1.1 Pyrexia 21 0.8 Gastrointestinal Constipation 46 0.6 Diarrhea 35 2.0 Nausea 34 0.3 Vomiting 24 0.8 Abdominal pain Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness 16 0.6 Nervous System Dysgeusia 44 0.3 Dizziness Includes dizziness, vertigo, dizziness postural 38 0.8 Dysesthesia Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia 34 0.3 Cognitive impairment Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes 27 4.5 Peripheral sensory neuropathy Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy 18 1.1 Headache 18 0.3 Ataxia Includes ataxia, balance disorder, gait disturbances 17 0.8 Sleep Includes hypersomnia, insomnia, sleep disorder, somnolence 14 0.6 Mood disorders Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation 10 0.6 Respiratory, Thoracic and Mediastinal Dyspnea 30 6 Cough 24 0.3 Musculoskeletal and Connective Tissue Myalgia Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain 28 1.1 Arthralgia 21 0.6 Muscular weakness 12 0.8 Back pain 12 1 Pain in extremity 11 0.3 Metabolism and Nutritional Increased weight 25 7 Decreased appetite 13 0.3 Dehydration 10 1.1 Eye Vision disorders Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters 21 0.8 Infections Urinary tract infection 13 2.3 Lung infection Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection 10 6 Vascular Hypotension Includes hypotension, orthostatic hypotension 18 2.8 Skin and Subcutaneous Tissue Rash Includes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular 11 0.8 Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%) . Table 8 summarizes the laboratory abnormalities. Table 8. Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Laboratory Abnormality ROZLYTREK NCI CTCAE Grade All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Chemistry Increased creatinine Based on NCI CTCAE v5.0 73 2.1 Hyperuricemia 52 10 Increased AST 44 2.7 Increased ALT 38 2.9 Hypernatremia 35 0.9 Hypocalcemia 34 1.8 Hypophosphatemia 30 7 Increased lipase 28 10 Hypoalbuminemia 28 2.9 Increased amylase 26 5.4 Hyperkalemia 25 1.5 Increased alkaline phosphatase 25 0.9 Hyperglycemia NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected NE 3.8 Hematology Anemia 67 9 Lymphopenia 40 12 Neutropenia 28 7 Safety in Pediatric Patients The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression. Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year. The median age of patients who received ROZLYTREK was 6 years (range: 0 to 17); 51% were females; 68% were White, 18% Asian, 7% Black or African American, and 7% were other races. Serious adverse reactions occurred in 45% of patients who received ROZLYTREK. Serious adverse reactions in > 2% of patients included skeletal fractures (12%), pneumonia (5%), pyrexia (5%), hydrocephalus (5%), device related infection (4%), hypoxia (4%), dyspnea (3%), headache (3%), gait disturbance (3%), pain (3%), upper respiratory infection (3%), and sepsis (3%). Permanent discontinuation of ROZLYTREK due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture. Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea. Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients. Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight. Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Table 9. Adverse Reactions (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Adverse Reaction ROZLYTREK (n=76) All Grades (%) Grade 3 or 4 (%) General Disorders Pyrexia 43 1.3 Fatigue Includes fatigue, asthenia 30 2.6 Gastrointestinal Disorders Constipation 41 1.3 Vomiting 38 0 Diarrhea 37 0 Nausea 34 0 Abdominal Pain 20 2.6 Investigations Increased Weight 39 18 Respiratory, Thoracic And Mediastinal Disorders Cough 33 1.3 Nasal Congestion 20 0 Musculoskeletal And Connective Tissue Disorders Pain in Extremity 26 2.6 Skeletal Fracture Includes clavicle fracture, tibia fracture, femur fracture, fibula fracture, foot fracture, fracture, pathological fracture, limb fracture, lower limb fracture, pelvic fracture, spinal compression fracture, stress fracture, ulna fracture 25 11 Metabolism And Nutrition Disorders Decreased Appetite 24 1.3 Nervous System Disorders Headache 22 2.6 Infections Upper Respiratory Tract Infection 20 1.3 Urinary Tract Infection 20 2.6 Clinically relevant adverse reactions in <20% of patients who received ROZLYTREK included pruritus, rash, urinary incontinence, eye pain and photophobia. Tables 10 summarizes the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Table 10. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Laboratory Abnormality ROZLYTREK The denominator used to calculate the rate varied from 67 to 76 based on the number of patients with a baseline value and at least one post-treatment value. All values based on NCI CTCAE v5.0 All Grades (%) Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Hematology Decreased Hemoglobin 53 7 Decreased Neutrophils 53 22 Decreased Leukocytes 46 1.3 Increased Lymphocytes 33 3 Chemistry Increased Creatinine 84 5 Increased AST 61 2.7 Increased ALT 53 2.6 Increased Sodium 38 1.4 Increased Magnesium 32 5 Increased Alkaline Phosphatase 25 0 Decreased Glucose 26 0 Increased Potassium 25 2.7 Decreased Albumin 24 9 Increased Calcium 21 8 Increased Bilirubin 20 8 Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.

<table width="90%" ID="Tb7"><caption>Table 7. Adverse Reactions (&#x2265; 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Adverse Reactions</th><th styleCode="Rrule" colspan="2">ROZLYTREK n = 355</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade &#x2265; 3<footnote ID="Tb7ft1">Grades 3 &#x2013; 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea. </footnote> (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote ID="Tb7ft2">Includes fatigue, asthenia</footnote></td><td styleCode="Rrule">48</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote ID="Tb7ft3">Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling</footnote></td><td styleCode="Rrule">40</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">46</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">35</td><td styleCode="Rrule">2.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">34</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote ID="Tb7ft4">Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous System</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia</td><td styleCode="Rrule">44</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness<footnote ID="Tb7ft5">Includes dizziness, vertigo, dizziness postural</footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysesthesia<footnote ID="Tb7ft6">Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia</footnote></td><td styleCode="Rrule">34</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cognitive impairment<footnote ID="Tb7ft7">Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes</footnote></td><td styleCode="Rrule">27</td><td styleCode="Rrule">4.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral sensory neuropathy<footnote ID="Tb7ft8">Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy</footnote></td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Ataxia<footnote ID="Tb7ft9">Includes ataxia, balance disorder, gait disturbances</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sleep<footnote ID="Tb7ft10">Includes hypersomnia, insomnia, sleep disorder, somnolence</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Mood disorders<footnote ID="Tb7ft11">Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, Thoracic and Mediastinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">30</td><td styleCode="Rrule">6<footnoteRef IDREF="Tb7ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal and Connective Tissue</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia<footnote ID="Tb7ft12">Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain</footnote></td><td styleCode="Rrule">28</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Muscular weakness</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and Nutritional</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased weight</td><td styleCode="Rrule">25</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dehydration</td><td styleCode="Rrule">10</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Eye</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vision disorders<footnote ID="foot4l">Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters</footnote></td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">13</td><td styleCode="Rrule">2.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lung infection<footnote ID="foot4m">Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">6<footnoteRef IDREF="Tb7ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypotension<footnote ID="Tb7ft13">Includes hypotension, orthostatic hypotension </footnote></td><td styleCode="Rrule">18</td><td styleCode="Rrule">2.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and Subcutaneous Tissue</content></td></tr><tr><td styleCode="Lrule Rrule"> Rash<footnote ID="Tb7ft14">Includes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular </footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.8</td></tr></tbody></table>

<table width="90%" ID="Tb8"><caption>Table 8. Laboratory Abnormalities (&#x2265; 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2">ROZLYTREK NCI CTCAE Grade</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">All Grades (%)<footnote ID="Tb8ft1">Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. </footnote></th><th styleCode="Rrule">Grade 3 or 4 (%)<footnoteRef IDREF="Tb8ft1"/></th></tr></thead><tfoot><tr><td colspan="3" align="left">AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased creatinine<footnote>Based on NCI CTCAE v5.0</footnote></td><td styleCode="Rrule">73</td><td styleCode="Rrule">2.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperuricemia</td><td styleCode="Rrule">52</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased AST</td><td styleCode="Rrule">44</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased ALT</td><td styleCode="Rrule">38</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypernatremia</td><td styleCode="Rrule">35</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypocalcemia</td><td styleCode="Rrule">34</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypophosphatemia</td><td styleCode="Rrule">30</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased lipase</td><td styleCode="Rrule">28</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoalbuminemia</td><td styleCode="Rrule">28</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased amylase </td><td styleCode="Rrule">26</td><td styleCode="Rrule">5.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperkalemia</td><td styleCode="Rrule">25</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased alkaline phosphatase</td><td styleCode="Rrule">25</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperglycemia<footnote ID="Tb8ft3">NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected</footnote></td><td styleCode="Rrule">NE<footnoteRef IDREF="Tb8ft3"/></td><td styleCode="Rrule">3.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">67</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lymphopenia</td><td styleCode="Rrule">40</td><td styleCode="Rrule">12</td></tr><tr><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">28</td><td styleCode="Rrule">7</td></tr></tbody></table>

<table width="85%" ID="Tb9"><caption>Table 9. Adverse Reactions (&#x2265;20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th valign="middle" rowspan="2" styleCode="Lrule Rrule">Adverse Reaction</th><th colspan="2" styleCode="Botrule Rrule">ROZLYTREK (n=76)</th></tr><tr><th align="center" styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">43</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Includes fatigue, asthenia</footnote></td><td styleCode="Rrule">30</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">41</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">38</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">37</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">34</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Pain </td><td styleCode="Rrule">20</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased Weight </td><td styleCode="Rrule">39</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic And Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">33</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasal Congestion </td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal And Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in Extremity</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Skeletal Fracture<footnote>Includes clavicle fracture, tibia fracture, femur fracture, fibula fracture, foot fracture, fracture, pathological fracture, limb fracture, lower limb fracture, pelvic fracture, spinal compression fracture, stress fracture, ulna fracture</footnote></td><td styleCode="Rrule">25</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Metabolism And Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased Appetite</td><td styleCode="Rrule">24</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper Respiratory Tract Infection </td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.3</td></tr><tr><td styleCode="Lrule Rrule"> Urinary Tract Infection </td><td styleCode="Rrule">20</td><td styleCode="Rrule">2.6</td></tr></tbody></table>