PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics for entrectinib and its pharmacologically active major circulating metabolite M5 were characterized in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumors, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of ROZLYTREK. The pharmacokinetic parameters for entrectinib and M5 are described in Table 11.Table 11. Pharmacokinetic Parameters for Entrectinib and Metabolite M5ParameterEntrectinib MeanGeometric mean (% CV)M5Mean (% CV)AUCD1 (nMh)31800 (48%)10200 (82%)AUCss (nMh)48000 (77%)24000 (97%)CmaxD1 (nM)2250 (58%)622 (79%)Cmaxss (nM)3130 (80%)1250 (90%)Racc(AUC) 1.55 (49%)2.84 (93%). AbsorptionThe maximum entrectinib plasma concentration was reached - hours after oral administration of 600 mg dose.Entrectinib exposure following single oral dose (600 mg) of ROZLYTREK oral pellets was not clinically significant compared to ROZLYTREK capsule administered with light meal (250 calories: 25% fat) in healthy subjects. In STARTRK-2, STARTRK-NG and TAPISTRY studies, ROZLYTREK was administered without regard to food in patients.Entrectinib exposure of single dose (600 mg) of ROZLYTREK capsules as suspension with water or milk, administered orally or through nasogastric or gastric tube, was not clinically significant compared to administration of intact ROZLYTREK capsules in healthy subjects under fasted conditions.. Effect of FoodA high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have significant effect on entrectinib exposure of ROZLYTREK capsules.. DistributionEntrectinib and its active major metabolite M5 are both 99% bound to human plasma proteins in vitro.The estimated apparent volume of distribution (V/F) was 551 and 81.1 for entrectinib and M5, respectively.. EliminationThe estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.. MetabolismEntrectinib is metabolized primarily by CYP3A4 (~76%). The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.. ExcretionFollowing oral administration of single oral dose of [14C]-labeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of entrectinib were observed based on sex, race (White, Asian and Black), mild to moderate renal impairment (CLcr 30 to 90 mL/min) and mild hepatic impairment (total bilirubin <= ULN with aspartate aminotransferase ULN or total bilirubin 1.0 1.5 times ULN with any aspartate aminotransferase). The impact of severe renal impairment on the pharmacokinetics of entrectinib is unknown.. Hepatic ImpairmentFollowing administration of single oral dose of ROZLYTREK 100 mg (1/6 of the recommended dose), the entrectinib AUCINF was increased by 39% for the mild, 39% for the moderate, and 23% for the severe hepatic impairment groups compared to the normal hepatic function group. The combined AUClast of entrectinib and M5 was increased by 16% for the mild, 16% for the moderate, and 4% for the severe hepatic impairment groups compared to the normal hepatic function group. Large variability in systemic exposure of entrectinib was observed in the hepatic impairment groups.. Pediatric Patients 6 monthsIn pediatric patients older than months administered 300 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients receiving 300 mg/m2 of ROZLYTREK once daily is within the range of the adults treated with 600 mg of ROZLYTREK once daily.The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].. Pediatric Patients 1 to <= monthsIn pediatric patients 1 to <= months administered 250 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients was at the lower range of the adults administered 600 mg of ROZLYTREK once daily.The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].. Drug Interaction Studies. Clinical Studies. Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with single 100 mg dose of ROZLYTREK capsule increased entrectinib AUC0-INF by 6-fold and Cmax by 1.7-fold [see Drug Interactions (7.1)]. Coadministration of moderate CYP3A inhibitor with ROZLYTREK capsule is predicted to increase entrectinib AUC0-Tau by 3-fold and Cmax by 2.9-fold. Based on physiologically based pharmacokinetic (PBPK) modelling, similar magnitude of the effect is expected in children as young as years old.. Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC0-INF by 77% and Cmax by 56% [see Drug Interactions (7.1)]. Coadministration of moderate CYP3A inducer with ROZLYTREK capsule is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.. Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of proton pump inhibitor (PPI), lansoprazole with single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC by 25% and Cmax by 23%. Coadministration of lansoprazole, with single 600 mg dose of ROZLYTREK capsule as oral suspension in water increased entrectinib AUC by 25% and Cmax by 17%. These changes are not likely to be clinically significant.. Effect of Entrectinib on CYP Substrates: Coadministration of 600 mg dose of ROZLYTREK capsule once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21% [see Drug Interactions (7.1)].. Effect of Entrectinib on Transporters: Coadministration of single 600 mg dose of ROZLYTREK capsule with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin Cmax by 28% and AUC by 18%.. In Vitro StudiesEntrectinib is not substrate of P-gp or BCRP, but M5 is substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

ADVERSE REACTIONS SECTION.

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)] 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 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 months or longer and 84 (24%) patients exposed for 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: 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/m2 to 1600 mg/m2 once daily in adults and 250 mg/m2 to 750 mg/m2 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 or 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 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 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-NGAdverse ReactionsROZLYTREKn 355All Grades (%)Grade >= 3Grades - 5, inclusive of fatal adverse reactions, including events of pneumonia and events of dyspnea. (%)General FatigueIncludes fatigue, asthenia 485 EdemaIncludes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 401.1 Pyrexia210.8Gastrointestinal Constipation460.6 Diarrhea352.0 Nausea340.3 Vomiting240.8 Abdominal painIncludes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness 160.6Nervous System Dysgeusia440.3 DizzinessIncludes dizziness, vertigo, dizziness postural 380.8 DysesthesiaIncludes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia 340.3 Cognitive impairmentIncludes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes 274.5 Peripheral sensory neuropathyIncludes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy 181.1 Headache180.3 AtaxiaIncludes ataxia, balance disorder, gait disturbances 170.8 SleepIncludes hypersomnia, insomnia, sleep disorder, somnolence 140.6 Mood disordersIncludes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation 100.6Respiratory, Thoracic and Mediastinal Dyspnea306 Cough240.3Musculoskeletal and Connective Tissue MyalgiaIncludes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain 281.1 Arthralgia210.6 Muscular weakness120.8 Back pain121 Pain in extremity110.3Metabolism and Nutritional Increased weight257 Decreased appetite130.3 Dehydration101.1Eye Vision disordersIncludes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters 210.8Infections Urinary tract infection132.3 Lung infectionIncludes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection 106 Vascular HypotensionIncludes hypotension, orthostatic hypotension 182.8Skin and Subcutaneous Tissue RashIncludes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular 110.8Clinically 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 summarizes the laboratory abnormalities.Table 8. Laboratory Abnormalities (>= 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NGLaboratory AbnormalityROZLYTREKNCI CTCAE GradeAll Grades (%)Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. Grade or (%) AST: Aspartate Aminotransferase; ALT: Alanine AminotransferaseChemistry Increased creatinineBased on NCI CTCAE v5.0 732.1 Hyperuricemia5210 Increased AST442.7 Increased ALT382.9 Hypernatremia350.9 Hypocalcemia341.8 Hypophosphatemia307 Increased lipase2810 Hypoalbuminemia282.9 Increased amylase 265.4 Hyperkalemia251.5 Increased alkaline phosphatase250.9 HyperglycemiaNE Not evaluable. Grade and could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected NE 3.8Hematology Anemia679 Lymphopenia4012 Neutropenia287. Safety in Pediatric PatientsThe safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with 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 months or longer and 38% were exposed for greater than one year.The median age of patients who received ROZLYTREK was years (range: 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 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-2Adverse ReactionROZLYTREK(n=76)All Grades(%)Grade or 4(%)General Disorders Pyrexia431.3 FatigueIncludes fatigue, asthenia 302.6Gastrointestinal Disorders Constipation411.3 Vomiting380 Diarrhea370 Nausea340 Abdominal Pain 202.6Investigations Increased Weight 3918Respiratory, Thoracic And Mediastinal Disorders Cough331.3 Nasal Congestion 200Musculoskeletal And Connective Tissue Disorders Pain in Extremity262.6 Skeletal FractureIncludes 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 2511Metabolism And Nutrition Disorders Decreased Appetite241.3Nervous System Disorders Headache222.6Infections Upper Respiratory Tract Infection 201.3 Urinary Tract Infection 202.6Clinically 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-2Laboratory AbnormalityROZLYTREKThe denominator used to calculate the rate varied from 67 to 76 based on the number of patients with baseline value and at least one post-treatment value. All values based on NCI CTCAE v5.0 All Grades(%)Grade or (%)AST: Aspartate Aminotransferase; ALT: Alanine AminotransferaseHematology Decreased Hemoglobin537 Decreased Neutrophils5322 Decreased Leukocytes461.3 Increased Lymphocytes333Chemistry Increased Creatinine845 Increased AST612.7 Increased ALT532.6 Increased Sodium381.4 Increased Magnesium325 Increased Alkaline Phosphatase250 Decreased Glucose260 Increased Potassium252.7 Decreased Albumin249 Increased Calcium218 Increased Bilirubin208Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK) with IC50 values of 0.1 to nM. Entrectinib also inhibits JAK2 and TNK2 with IC50 values 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK.Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 2.2 in multiple animal species (mice, rats, and dogs) and demonstrated in vivo anti-tumor activity in mice with intracranial implantation of TRKA- and ALK-driven tumor cell lines.. 12.2 Pharmacodynamics. Entrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.. Cardiac ElectrophysiologyAcross clinical trials, 3.1% of 355 patients, who received ROZLYTREK at doses ranging from 100 mg to 2600 mg daily under fasting or fed conditions (75% received 600 mg orally once daily) and had at least one post-baseline ECG assessment, experienced QTcF interval prolongation of 60 ms after starting ROZLYTREK and 0.6% had QTc interval 500 ms [see Warnings and Precautions (5.6)]. 12.3 Pharmacokinetics. The pharmacokinetics for entrectinib and its pharmacologically active major circulating metabolite M5 were characterized in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumors, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of ROZLYTREK. The pharmacokinetic parameters for entrectinib and M5 are described in Table 11.Table 11. Pharmacokinetic Parameters for Entrectinib and Metabolite M5ParameterEntrectinib MeanGeometric mean (% CV)M5Mean (% CV)AUCD1 (nMh)31800 (48%)10200 (82%)AUCss (nMh)48000 (77%)24000 (97%)CmaxD1 (nM)2250 (58%)622 (79%)Cmaxss (nM)3130 (80%)1250 (90%)Racc(AUC) 1.55 (49%)2.84 (93%). AbsorptionThe maximum entrectinib plasma concentration was reached - hours after oral administration of 600 mg dose.Entrectinib exposure following single oral dose (600 mg) of ROZLYTREK oral pellets was not clinically significant compared to ROZLYTREK capsule administered with light meal (250 calories: 25% fat) in healthy subjects. In STARTRK-2, STARTRK-NG and TAPISTRY studies, ROZLYTREK was administered without regard to food in patients.Entrectinib exposure of single dose (600 mg) of ROZLYTREK capsules as suspension with water or milk, administered orally or through nasogastric or gastric tube, was not clinically significant compared to administration of intact ROZLYTREK capsules in healthy subjects under fasted conditions.. Effect of FoodA high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have significant effect on entrectinib exposure of ROZLYTREK capsules.. DistributionEntrectinib and its active major metabolite M5 are both 99% bound to human plasma proteins in vitro.The estimated apparent volume of distribution (V/F) was 551 and 81.1 for entrectinib and M5, respectively.. EliminationThe estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.. MetabolismEntrectinib is metabolized primarily by CYP3A4 (~76%). The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.. ExcretionFollowing oral administration of single oral dose of [14C]-labeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of entrectinib were observed based on sex, race (White, Asian and Black), mild to moderate renal impairment (CLcr 30 to 90 mL/min) and mild hepatic impairment (total bilirubin <= ULN with aspartate aminotransferase ULN or total bilirubin 1.0 1.5 times ULN with any aspartate aminotransferase). The impact of severe renal impairment on the pharmacokinetics of entrectinib is unknown.. Hepatic ImpairmentFollowing administration of single oral dose of ROZLYTREK 100 mg (1/6 of the recommended dose), the entrectinib AUCINF was increased by 39% for the mild, 39% for the moderate, and 23% for the severe hepatic impairment groups compared to the normal hepatic function group. The combined AUClast of entrectinib and M5 was increased by 16% for the mild, 16% for the moderate, and 4% for the severe hepatic impairment groups compared to the normal hepatic function group. Large variability in systemic exposure of entrectinib was observed in the hepatic impairment groups.. Pediatric Patients 6 monthsIn pediatric patients older than months administered 300 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients receiving 300 mg/m2 of ROZLYTREK once daily is within the range of the adults treated with 600 mg of ROZLYTREK once daily.The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].. Pediatric Patients 1 to <= monthsIn pediatric patients 1 to <= months administered 250 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients was at the lower range of the adults administered 600 mg of ROZLYTREK once daily.The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].. Drug Interaction Studies. Clinical Studies. Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with single 100 mg dose of ROZLYTREK capsule increased entrectinib AUC0-INF by 6-fold and Cmax by 1.7-fold [see Drug Interactions (7.1)]. Coadministration of moderate CYP3A inhibitor with ROZLYTREK capsule is predicted to increase entrectinib AUC0-Tau by 3-fold and Cmax by 2.9-fold. Based on physiologically based pharmacokinetic (PBPK) modelling, similar magnitude of the effect is expected in children as young as years old.. Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC0-INF by 77% and Cmax by 56% [see Drug Interactions (7.1)]. Coadministration of moderate CYP3A inducer with ROZLYTREK capsule is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.. Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of proton pump inhibitor (PPI), lansoprazole with single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC by 25% and Cmax by 23%. Coadministration of lansoprazole, with single 600 mg dose of ROZLYTREK capsule as oral suspension in water increased entrectinib AUC by 25% and Cmax by 17%. These changes are not likely to be clinically significant.. Effect of Entrectinib on CYP Substrates: Coadministration of 600 mg dose of ROZLYTREK capsule once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21% [see Drug Interactions (7.1)].. Effect of Entrectinib on Transporters: Coadministration of single 600 mg dose of ROZLYTREK capsule with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin Cmax by 28% and AUC by 18%.. In Vitro StudiesEntrectinib is not substrate of P-gp or BCRP, but M5 is substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1ROS1-Positive Non-Small Cell Lung Cancer. The efficacy of ROZLYTREK was evaluated in pooled subgroup of patients with ROS1-positive metastatic NSCLC who received ROZLYTREK at various doses and schedules (90% received ROZLYTREK 600 mg orally once daily) and were enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status <= 2, measurable disease per RECIST 1.1, >= 18 months of follow-up from first post-treatment tumor assessment, and no prior therapy with ROS1 inhibitor. Identification of ROS1 gene fusion in tumor specimens was prospectively determined in local laboratories using either fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR) laboratory-developed tests. All patients were assessed for CNS lesions at baseline. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR). Intracranial response according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) was assessed by BICR. Tumor assessments with imaging were performed every weeks.Efficacy was assessed in 92 patients with ROS1-positive NSCLC. The median age was 53 years (range: 27 to 86); female (65%); White (48%), Asian (45%), and Black (5%); and Hispanic or Latino (2.4%); never smoked (59%); and ECOG performance status or (88%). Ninety-nine percent of patients had metastatic disease, including 42% with CNS metastases; 96% had adenocarcinoma; 65% received prior platinum-based chemotherapy for metastatic or recurrent disease and no patient had progressed in less than months following platinum-based adjuvant or neoadjuvant therapy. ROS1 positivity was determined by NGS in 79%, FISH in 16%, and PCR in 4%. Twenty-five percent had central laboratory confirmation of ROS1 positivity using an analytically validated NGS test.Efficacy results are summarized in Table 12.Table 12. Efficacy Results in ROS1-Positive NSCLC Patients per BICR AssessmentEfficacy Parameters ROZLYTREKn 92 Confidence Interval (CI) calculated using the Clopper-Pearson method.Overall Response Rate (95% CI)74% (64, 83) Complete Response15% Partial Response59%Duration of Response (DOR)Observed DOR = 68Range (months)2.4, 55.2denotes ongoing response DOR >= months75% DOR >= 12 months57% DOR >= 18 months38%Among the 92 patients, 10 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within months prior to study entry. Responses in intracranial lesions were observed in of these 10 patients.. 14.2NTRK Gene Fusion-Positive Solid Tumors. Efficacy in Adult PatientsThe efficacy of ROZLYTREK was evaluated in pooled subgroup of adult patients with unresectable or metastatic solid tumors with NTRK gene fusion enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease; measurable disease per RECIST v1.1; at least years of follow-up from first post-treatment tumor assessment; and no prior therapy with TRK inhibitor. Patients received ROZLYTREK at various doses and schedules (94% received ROZLYTREK 600 mg orally once daily) until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories or central laboratory using various nucleic acid-based tests. The major efficacy outcome measures were ORR and DOR, as determined by BICR according to RECIST v1.1. Intracranial response according to RECIST v1.1 as evaluated by BICR. Tumor assessments with imaging were performed every weeks.Efficacy was assessed in the first 54 adult patients with solid tumors with an NTRK gene fusion enrolled into these trials. The median age was 58 years (range: 21 to 83); female (59%); White (80%), Asian (13%) and Hispanic or Latino (7%); and ECOG performance status (43%) or (46%). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. All patients had received prior treatment for their cancer including surgery (n 43), radiotherapy (n 36), or systemic therapy (n 48). Forty patients (74%) received prior systemic therapy for metastatic disease with median of prior systemic regimen and 17% (n 9) received or more prior systemic regimens. The most common cancers were sarcoma (24%), lung cancer (19%), salivary gland tumors (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%). total of 52 (96%) patients had an NTRK gene fusion detected by NGS and (4%) had an NTRK gene fusion detected by other nucleic acid-based tests. Eighty-three percent of patients had central laboratory confirmation of NTRK gene fusion using an analytically validated NGS test.Efficacy results are summarized in Tables 13, 14, and 15.Table 13. Efficacy Results for Adult Patients with Solid Tumors Harboring NTRK Gene FusionsEfficacy Parameter ROZLYTREKn 54 Overall Response Rate (95% CI)59% (45, 72) Complete Response13% Partial Response46%Duration of ResponseObserved DOR = 32Range (months)2.8, 47.8denotes ongoing response with duration >= months72% with duration >= months66% with duration >= 12 months56%Table 14. Efficacy by Tumor TypeTumor Type Patientsn 54ORRDOR%95% CIRange(months)MASC: mammary analogue secretory carcinoma; NA not applicable due to small numbers or lack of response; PR partial response.Sarcoma1346%19%, 75%2.8, 33.6denotes ongoing response Non-small cell lung cancer1060%26%, 88%3.7, 47.8 Salivary (MASC)786%42%, 100%2.8, 38.5 Breast cancer683%36%, 100%4.2, 42.3 Thyroid cancer560%NA7.9, 31.5 Colorectal cancer425%NA15.1Neuroendocrine cancers3CRNA32.9 Pancreatic cancer3PR, PRNA7.1, 12.9Gynecological cancers2PRNA38.2Cholangiocarcinoma1PRNA9.3Table 15. Efficacy Results by NTRK Gene Fusion PartnerNTRK PartnerPatientsn 54ORRDOR%95% CIRange (months)PR partial response; PD progressive disease; SD stable disease; NA not applicable due to small numbers or lack of response; NE not evaluable.ETV6 NTRK32572%51%, 88%2.8, 47.8denotes ongoing response TPM3 NTRK1450%7%, 93%2.8, 15.1TPR NTRK14100%40%, 100%5.6, 33.6 LMNA NTRK12PR, PDNA4.2SQSTM1 NTRK12PR, PDNA18.8 PEAR1 NTRK12SD, NENANAEML4 NTRK32PR, NENA13.2CD74 NTRK11PRNA10.4PLEKHA6 NTRK11PRNA9.3CDC42BPA NTRK11PRNA29.4EPS15L1 NTRK11PRNA3.7RBPMS NTRK31PRNA4.6ERC1 NTRK11SDNANAPDIA3 NTRK11SDNANATRIM33 NTRK11SDNANAAKAP13 NTRK31SDNANAKIF7 NTRK31SDNANAFAM19A2 NTRK31PDNANACGN NTRK11NENANASQSTM1 NTRK21NENANAAmong the subset of patients who received prior systemic therapy for metastatic disease, the ORR was 53%, similar to that seen in the overall population. Among the 54 adult patients, had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within months of study entry. Responses in intracranial lesions were observed in of these patients.. Efficacy in Pediatric PatientsThe efficacy of ROZLYTREK was evaluated in pediatric patients with unresectable or metastatic solid tumors with NTRK gene fusion enrolled in one of two multicenter, open-label clinical trials: STARTRK-NG (NCT02650401) and TAPISTRY (NCT04589845). To be included in the analysis, patients were required to have received at least dose of ROZLYTREK; measurable or evaluable disease at baseline; at least months of follow-up; and no prior therapy with TRK inhibitor. 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. The major efficacy outcome measure was overall response rate (ORR) as assessed by BICR according to RECIST v1.1 for extracranial tumors and according to Response Assessment in Neuro-Oncology (RANO) for primary central nervous system (CNS) tumors. An additional efficacy outcome measure was DOR as evaluated by BICR.Efficacy was assessed in 33 pediatric patients with NTRK fusion-positive solid tumors treated with ROZLYTREK. The median age was years (range: months to 15 years); male (52%); White (58%), Asian (30%), other races (9%), Black or African American (3.0%), and Hispanic or Latino (9%). Seventy-one percent of patients had locally advanced disease and 29% had metastatic disease. Eighty-five percent of patients had received prior treatment for their cancer including surgery (n=20), radiotherapy (n=7) and/or systemic therapy (n=22). The sites for metastatic disease included other (4 patients), brain (3 patients) and lung (2 patients).Efficacy results are summarized in Tables 16 and 17.Table 16. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK Gene FusionsEfficacy ParameterIncludes patients with measurable and evaluable disease. BICR analysis by RECIST v1.1 for solid tumors (16 patients) and by RANO criteria for primary CNS tumors (17 patients) ROZLYTREKn 33 NE not estimableOverall Response Rate (95% CI)70% (51, 84) Complete Response42% Partial Response27%Duration of ResponseObserved DOR = 23 Median in months (95% CI)25.4 (14.3, NE) with duration >= 12 months43%Table 17. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK Gene Fusions by Tumor TypeTumor Type Patientsn 33ORRDOR%95% CIRange(months)NA not applicable due to small numbers or lack of responsePrimary CNSMedian time to first objective response for patients with primary CNS tumors was 1.9 months 1753%28%, 77%5.5, 30.4denotes ongoing response Infantile fibrosarcoma888%47%, 100%3.7, 24 Spindle Cell6100%54%, 100%3.7, 12.9 Sarcoma (other)10%Patient with evaluable but non-measurable disease at baseline NANAMelanoma1100%NA42.4 Table 18. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK by Gene Fusion PartnerNTRK PartnerPatientsn 33ORRDOR%95% CIRange (months)PR partial response; PD progressive disease; SD stable disease; NA not applicable due to small numbers or lack of responseETV6 NTRK3786%42%, 100%11.9 42.4denotes ongoing response LMNA NTRK1580%28%, 99%7.4 12.9 TPM3 NTRK13100%29%, 100%3.7 24.0 TPR NTRK1367%9%, 99%8.1 14.3EML4-NTRK3250%1.3%, 99%13.8 BCAN-NTRK11CRNA11.8 EML1-NTRK21CRNA11.8QKI-NTRK21CRNA11.1 TFG-NTRK31CRNA3.7 KANK1-NTRK21PRNA5.5KIF5B-NTRK21PRNA12.9 TNS3-NRTK21PRNA9.5ARHGEF2-NTRK11SDNANAKIF21B-NTRK11SDNANABCR-NTRK21SDNANAGKAP1-NTRK21SDNANADNM3-NTRK21PDNANAPARP6-NTRK31PDNANA.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial 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.Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for months or longer and 84 (24%) patients exposed for 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: 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/m2 to 1600 mg/m2 once daily in adults and 250 mg/m2 to 750 mg/m2 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 or 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 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 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-NGAdverse ReactionsROZLYTREKn 355All Grades (%)Grade >= 3Grades - 5, inclusive of fatal adverse reactions, including events of pneumonia and events of dyspnea. (%)General FatigueIncludes fatigue, asthenia 485 EdemaIncludes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 401.1 Pyrexia210.8Gastrointestinal Constipation460.6 Diarrhea352.0 Nausea340.3 Vomiting240.8 Abdominal painIncludes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness 160.6Nervous System Dysgeusia440.3 DizzinessIncludes dizziness, vertigo, dizziness postural 380.8 DysesthesiaIncludes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia 340.3 Cognitive impairmentIncludes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes 274.5 Peripheral sensory neuropathyIncludes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy 181.1 Headache180.3 AtaxiaIncludes ataxia, balance disorder, gait disturbances 170.8 SleepIncludes hypersomnia, insomnia, sleep disorder, somnolence 140.6 Mood disordersIncludes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation 100.6Respiratory, Thoracic and Mediastinal Dyspnea306 Cough240.3Musculoskeletal and Connective Tissue MyalgiaIncludes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain 281.1 Arthralgia210.6 Muscular weakness120.8 Back pain121 Pain in extremity110.3Metabolism and Nutritional Increased weight257 Decreased appetite130.3 Dehydration101.1Eye Vision disordersIncludes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters 210.8Infections Urinary tract infection132.3 Lung infectionIncludes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection 106 Vascular HypotensionIncludes hypotension, orthostatic hypotension 182.8Skin and Subcutaneous Tissue RashIncludes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular 110.8Clinically 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 summarizes the laboratory abnormalities.Table 8. Laboratory Abnormalities (>= 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NGLaboratory AbnormalityROZLYTREKNCI CTCAE GradeAll Grades (%)Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. Grade or (%) AST: Aspartate Aminotransferase; ALT: Alanine AminotransferaseChemistry Increased creatinineBased on NCI CTCAE v5.0 732.1 Hyperuricemia5210 Increased AST442.7 Increased ALT382.9 Hypernatremia350.9 Hypocalcemia341.8 Hypophosphatemia307 Increased lipase2810 Hypoalbuminemia282.9 Increased amylase 265.4 Hyperkalemia251.5 Increased alkaline phosphatase250.9 HyperglycemiaNE Not evaluable. Grade and could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected NE 3.8Hematology Anemia679 Lymphopenia4012 Neutropenia287. Safety in Pediatric PatientsThe safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with 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 months or longer and 38% were exposed for greater than one year.The median age of patients who received ROZLYTREK was years (range: 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 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-2Adverse ReactionROZLYTREK(n=76)All Grades(%)Grade or 4(%)General Disorders Pyrexia431.3 FatigueIncludes fatigue, asthenia 302.6Gastrointestinal Disorders Constipation411.3 Vomiting380 Diarrhea370 Nausea340 Abdominal Pain 202.6Investigations Increased Weight 3918Respiratory, Thoracic And Mediastinal Disorders Cough331.3 Nasal Congestion 200Musculoskeletal And Connective Tissue Disorders Pain in Extremity262.6 Skeletal FractureIncludes 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 2511Metabolism And Nutrition Disorders Decreased Appetite241.3Nervous System Disorders Headache222.6Infections Upper Respiratory Tract Infection 201.3 Urinary Tract Infection 202.6Clinically 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-2Laboratory AbnormalityROZLYTREKThe denominator used to calculate the rate varied from 67 to 76 based on the number of patients with baseline value and at least one post-treatment value. All values based on NCI CTCAE v5.0 All Grades(%)Grade or (%)AST: Aspartate Aminotransferase; ALT: Alanine AminotransferaseHematology Decreased Hemoglobin537 Decreased Neutrophils5322 Decreased Leukocytes461.3 Increased Lymphocytes333Chemistry Increased Creatinine845 Increased AST612.7 Increased ALT532.6 Increased Sodium381.4 Increased Magnesium325 Increased Alkaline Phosphatase250 Decreased Glucose260 Increased Potassium252.7 Decreased Albumin249 Increased Calcium218 Increased Bilirubin208Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. (2.1)Evaluate left ventricular ejection fraction, serum uric acid levels and QT interval and electrolytes prior to ROZLYTREK initiation. (2.2)Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. (2.3)Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. (2.3)Administer ROZLYTREK capsules, capsules prepared as suspension, or pellets once daily, with or without food. (2.4)Adult Dosage for ROS1-Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. (2.5)Adult and Pediatric Dosage for NTRK Gene Fusion-Positive Solid Tumors: Adults: 600 mg orally once daily. (2.6)Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (2.6) AgeRecommended Daily Dosage>6 months<=0.50 m2: 300 mg/m2 0.51 to 0.80 m2: 200 mg0.81 to 1.10 m2: 300 mg1.11 to 1.50 m2: 400 mgBSA >=1.51 m2: 600 mg once daily>1 month to <=6 months250 mg/m2 once daily Modify dosage of ROZLYTREK if coadministration with moderate or strong CYP3A inhibitors cannot be avoided. (2.8)See preparation and administration instructions. (2.9). Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. (2.1). Evaluate left ventricular ejection fraction, serum uric acid levels and QT interval and electrolytes prior to ROZLYTREK initiation. (2.2). Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. (2.3). Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. (2.3). Administer ROZLYTREK capsules, capsules prepared as suspension, or pellets once daily, with or without food. (2.4). Adult Dosage for ROS1-Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. (2.5). Adult and Pediatric Dosage for NTRK Gene Fusion-Positive Solid Tumors: Adults: 600 mg orally once daily. (2.6)Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (2.6) AgeRecommended Daily Dosage>6 months<=0.50 m2: 300 mg/m2 0.51 to 0.80 m2: 200 mg0.81 to 1.10 m2: 300 mg1.11 to 1.50 m2: 400 mgBSA >=1.51 m2: 600 mg once daily>1 month to <=6 months250 mg/m2 once daily Adults: 600 mg orally once daily. (2.6). Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (2.6). Modify dosage of ROZLYTREK if coadministration with moderate or strong CYP3A inhibitors cannot be avoided. (2.8). See preparation and administration instructions. (2.9). 2.1Patient Selection. Select patients for the treatment of metastatic NSCLC with ROZLYTREK based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens [see Clinical Studies (14.1)]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.Information on FDA-approved tests for the detection of ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.Select patients for treatment of locally advanced or metastatic solid tumors with ROZLYTREK based on the presence of NTRK gene fusion in tumor or plasma specimens [see Clinical Studies (14.2)]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.Information on FDA-approved tests for the detection of NTRK gene fusion(s) in solid tumors is available at http://www.fda.gov/CompanionDiagnostics.. Select patients for the treatment of metastatic NSCLC with ROZLYTREK based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens [see Clinical Studies (14.1)]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.Information on FDA-approved tests for the detection of ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.. Select patients for treatment of locally advanced or metastatic solid tumors with ROZLYTREK based on the presence of NTRK gene fusion in tumor or plasma specimens [see Clinical Studies (14.2)]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.Information on FDA-approved tests for the detection of NTRK gene fusion(s) in solid tumors is available at http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Evaluation and Testing Before Initiating ROZLYTREK. Before initiating ROZLYTREK, evaluate:left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.1)] serum uric acid levels [see Warnings and Precautions (5.5)] QT interval and electrolytes [see Warnings and Precautions (5.6)] left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.1)] serum uric acid levels [see Warnings and Precautions (5.5)] QT interval and electrolytes [see Warnings and Precautions (5.6)] 2.3ROZLYTREK Dosage Form Overview. The physician should prescribe the most appropriate dosage form of ROZLYTREK according to the dose required and patient needs.ROZLYTREK is available in two dosage forms, and can be administered either as capsules swallowed whole, capsules made into an oral suspension (or for enteral tube administration) and as oral pellets swallowed with soft food.. ROZLYTREK Capsules 100 mg and 200 mgWhole capsules: For patients who can swallow whole capsules and whose doses are multiples of 100 mg.Capsules prepared as an oral suspension:For patients who have difficulty or are unable to swallow capsules or who require enteral administration (e.g., gastric or nasogastric tube). [see Dosage and Administration (2.7)]. For dose increments of 10 mg, only use capsules prepared as suspension. Whole capsules: For patients who can swallow whole capsules and whose doses are multiples of 100 mg.. Capsules prepared as an oral suspension:For patients who have difficulty or are unable to swallow capsules or who require enteral administration (e.g., gastric or nasogastric tube). [see Dosage and Administration (2.7)]. For dose increments of 10 mg, only use capsules prepared as suspension. For patients who have difficulty or are unable to swallow capsules or who require enteral administration (e.g., gastric or nasogastric tube). [see Dosage and Administration (2.7)]. For dose increments of 10 mg, only use capsules prepared as suspension. ROZLYTREK Oral Pellets 50 mg per packetPellets sprinkled on one or more spoonfuls of soft food:For patients who have difficulty or are unable to swallow capsules but can swallow soft food and whose doses are multiples of 50 mg. [see Dosage and Administration (2.7)].Do not use pellets for preparation of suspension.Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare dose.Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.. Pellets sprinkled on one or more spoonfuls of soft food:For patients who have difficulty or are unable to swallow capsules but can swallow soft food and whose doses are multiples of 50 mg. [see Dosage and Administration (2.7)].Do not use pellets for preparation of suspension.Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare dose.Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.. For patients who have difficulty or are unable to swallow capsules but can swallow soft food and whose doses are multiples of 50 mg. [see Dosage and Administration (2.7)].. Do not use pellets for preparation of suspension.. Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare dose.. Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.. 2.4ROZLYTREK Administration Overview. Administer ROZLYTREK capsules, capsules prepared as suspension, or pellets once daily, with or without food.If dose of ROZYTREK is missed, make up that dose unless the next dose is due within 12 hours.If vomiting occurs immediately after taking dose of ROZLYTREK, repeat that dose.. Administer ROZLYTREK capsules, capsules prepared as suspension, or pellets once daily, with or without food.. If dose of ROZYTREK is missed, make up that dose unless the next dose is due within 12 hours.. If vomiting occurs immediately after taking dose of ROZLYTREK, repeat that dose.. 2.5ROZLYTREK Recommended Dosage for ROS1-Positive Non-Small Cell Lung Cancer. The recommended dosage of ROZLYTREK is 600 mg orally once daily with or without food until disease progression or unacceptable toxicity.. 2.6ROZLYTREK Recommended Dosage for NTRK Gene Fusion-Positive Solid Tumors. The recommended dosages of ROZLYTREK for the treatment of adult and pediatric patients with NTRK Gene Fusion-Positive Solid Tumors are provided in Table 1.Administer the recommended dosage of ROZLYTREK capsules and oral pellets with or without food until disease progression or unacceptable toxicity.Sprinkle ROZLYTREK oral pellets on one or more spoonfuls of soft food as vehicle.Table 1. Recommended dosage for Adults and Pediatric patients for the Treatment of NTRK Gene Fusion-Positive Solid TumorsPatient PopulationRecommended Dosage of ROZLYTREKDuration of TreatmentAdultsPediatric patients with BSA >= 1.51 m2:600 mg orally once dailyUntil disease progression or unacceptable toxicity.Pediatric patients 6 months:see Table Pediatric patients 1 month to <= months:250 mg/m2 orally once dailyTo enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)]. The recommended dosages of ROZLYTREK for the treatment of pediatric patients older than months with NTRK Gene Fusion-Positive Solid Tumors is provided in Table 2.Table 2. Recommended dosage for Pediatric Patients Older than Months for the Treatment of NTRK Gene Fusion-Positive Solid TumorsBody Surface Area (BSA)BSA categories and recommended dosage above are based on closely matching exposures to target dose of 300 mg/m2 Recommended DosageOrally Once Daily <=0.50 m2 300 mg/m2 To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)]. 0.51 to 0.80 m2 200 mg0.81 to 1.10 m2 300 mg1.11 to 1.50 m2 400 mg>= 1.51 m2 600 mg. 2.7ROZLYTREK Dosage Modifications for Adverse Reactions. The recommended dosage reductions of ROZLYTREK for the management of adverse reactions for adults and pediatric patients are provided in Table 3.Table 3. Recommended Dose Reductions for ROZLYTREK for the Management of Adverse ReactionsStarting Dose once dailyFirst dose reductionSecond dose reduction250 mg/m2 or 300 mg/m2 Reduce the once daily dose to two thirds of the starting doseTo enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)]. Reduce the once daily dose to one third of the starting dose Permanently discontinue ROZLYTREK in patients who are unable to tolerate ROZLYTREK after two dose reductions.200 mg150 mg once daily 100 mg once daily 300 mg200 mg once daily100 mg once daily400 mg300 mg once daily200 mg once daily 600 mg400 mg once daily200 mg once dailyTable provides the ROZLYTREK recommended dosage modifications for the management of adverse reactions.Table 4. ROZLYTREK Dosage Modifications for the Management of Adverse ReactionsAdverse ReactionSeveritySeverity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Dosage ModificationCongestive Heart Failure [see Warnings and Precautions (5.1)] Grade or 3Withhold ROZLYTREK until recovered to less than or equal to Grade 1. Resume at reduced dose. Grade 4Permanently discontinue ROZLYTREK.Central Nervous System Effects [see Warnings and Precautions (5.2)] Intolerable Grade 2Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.Resume at same dose or reduced dose, as clinically appropriate.Grade 3Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.Resume at reduced dose.Grade 4Permanently discontinue ROZLYTREK. Hepatotoxicity [see Warnings and Precautions (5.4)] Grade 3Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.Resume at same dose if resolution occurs within weeks.Permanently discontinue if adverse reaction does not resolve within weeks.Resume at reduced dose for recurrent Grade events that resolve within weeks.Grade 4Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.Resume at reduced dose if resolution occurs within weeks.Permanently discontinue if adverse reaction does not resolve within weeks.Permanently discontinue for recurrent Grade events.ALT or AST greater than times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis).Permanently discontinue ROZLYTREK.Hyperuricemia [see Warnings and Precautions (5.5)] Symptomatic or Grade 4Initiate urate-lowering medication. Withhold ROZLYTREK until improvement of signs or symptoms.Resume ROZLYTREK at same or reduced dose.QT Interval Prolongation [see Warnings and Precautions (5.6)] QTc greater than 500 msWithhold ROZLYTREK until QTc interval recovers to baseline.Resume at same dose if factors that cause QT prolongation are identified and corrected.Resume at reduced dose if other factors that cause QT prolongation are not identified.Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmiaPermanently discontinue ROZLYTREK. Vision Disorders [see Warnings and Precautions (5.7)] Grade or aboveWithhold ROZLYTREK until improvement or stabilization. Resume at same dose or reduced dose, as clinically appropriate.Anemia or Neutropenia [see Adverse Reactions (6.1)] Grade or 4Withhold ROZLYTREK until recovery to less than or equal to Grade 2. Resume at the same dose or reduced dose, as clinically appropriate.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade or 4Withhold ROZLYTREK until adverse reaction resolves or improves to recovery or improvement to Grade or baseline. Resume at the same or reduced dose if resolution occurs within weeks.Permanently discontinue if adverse reaction does not resolve within weeks.Permanently discontinue for recurrent Grade events.. Withhold ROZLYTREK until recovered to less than or equal to Grade 1. Resume at reduced dose. Permanently discontinue ROZLYTREK.. Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.. Resume at same dose or reduced dose, as clinically appropriate.. Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.. Resume at reduced dose.. Permanently discontinue ROZLYTREK. Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.. Resume at same dose if resolution occurs within weeks.. Permanently discontinue if adverse reaction does not resolve within weeks.. Resume at reduced dose for recurrent Grade events that resolve within weeks.. Withhold ROZLYTREK until recovery to less than or equal to Grade or to baseline.. Resume at reduced dose if resolution occurs within weeks.. Permanently discontinue if adverse reaction does not resolve within weeks.. Permanently discontinue for recurrent Grade events.. Permanently discontinue ROZLYTREK.. Initiate urate-lowering medication. Withhold ROZLYTREK until improvement of signs or symptoms.. Resume ROZLYTREK at same or reduced dose.. Withhold ROZLYTREK until QTc interval recovers to baseline.. Resume at same dose if factors that cause QT prolongation are identified and corrected.. Resume at reduced dose if other factors that cause QT prolongation are not identified.. Permanently discontinue ROZLYTREK. Withhold ROZLYTREK until improvement or stabilization. Resume at same dose or reduced dose, as clinically appropriate.. Withhold ROZLYTREK until recovery to less than or equal to Grade 2. Resume at the same dose or reduced dose, as clinically appropriate.. Withhold ROZLYTREK until adverse reaction resolves or improves to recovery or improvement to Grade or baseline. Resume at the same or reduced dose if resolution occurs within weeks.. Permanently discontinue if adverse reaction does not resolve within weeks.. Permanently discontinue for recurrent Grade events.. 2.8ROZLYTREK Dosage Modifications for Drug Interactions. Moderate and Strong CYP3A Inhibitors. Adults and Pediatric Patients Years and OlderAvoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the ROZLYTREK dose as shown in Table and limit coadministration to 14 days or less.Table 5. Recommended Dose Modifications of ROZYLTREK for Concomitant Use with Moderate or Strong CYP3A Inhibitors for Adults and Pediatric Patients Years and OlderStarting doseFor pediatric patients with starting dose less than 200 mg, avoid coadministration with moderate or strong CYP3A inhibitorsModerate CYP3A inhibitorStrong CYP3A inhibitor200 mg50 mg once daily50 mg on alternate days300 mg100 mg once daily50 mg once daily400 mg200 mg once daily50 mg once daily600 mg200 mg once daily100 mg once dailyAfter discontinuation of strong or moderate CYP3A inhibitor for to elimination half-lives, resume the ROZLYTREK dose that was taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. 2.9ROZLYTREK Preparation and Administration Instructions ROZLYTREK CapsulesSwallow capsules whole. Do not crush or chew the capsules.. ROZLYTREK Capsules Prepared as Suspension for Oral or Enteral Tube AdministrationIt is recommended that healthcare provider discuss with the patient or caregiver, the volume of water or milk to be added and oral suspension to withdraw, prior to administration of the first dose (see Table 6).Table provides the ROZLYTREK dose and volume of room temperature drinking water or milk required to prepare an oral suspension. Instruct patients or caregivers to carefully open capsule(s) and pour the contents into room temperature drinking water or milk to prepare an oral suspension. Let sit for 15 minutes.Table 6. Preparation of ROZLYTREK Capsules as an Oral SuspensionDose of ROZLYTREK to be administeredDose needed for suspension (using 100 mg or 200 mg capsules, as appropriate)Volume of water or milk to be addedVolume of oral suspension to withdraw and administer20 mg100 mg5 mL1 mL30 mg100 mg5 mL1.5 mL40 mg100 mg5 mL2 mL50 mg100 mg5 mL2.5 mL60 mg100 mg5 mL3 mL70 mg100 mg5 mL3.5 mL80 mg100 mg5 mL4 mL90 mg100 mg5 mL4.5 mL100 mg100 mg5 mL5 mL110 mg200 mg10 mL5.5 mL120 mg200 mg10 mL6 mL130 mg200 mg10 mL6.5 mL140 mg200 mg10 mL7 mL150 mg200 mg10 mL7.5 mL200 mg200 mg10 mL10 mL300 mg300 mg15 mL15 mL400 mg400 mg20 mL20 mL600 mg600 mg30 mL30 mLAdminister ROZLYTREK oral suspension immediately after preparation.Discard any unused suspension if not used within hours.Instruct patients to drink water after taking the oral suspension to ensure ROZLYTREK has been completely swallowed.. Enteral Tube AdministrationIf enteral administration (e.g., gastric or nasogastric tube) is required, administer the oral suspension via the tube. Use an enteral tube that is FR or higher to administer dosing volumes of mL or higher. Instruct patients to divide dosing volumes of mL or higher into at least two aliquots and flush the tube after each administration. Flush the tube with volume of water or milk that is equal to the aliquot administered. For dose volume of 30 mL, divide into at least three (10 mL) aliquots. The tube should be flushed with water or milk after delivering each aliquot of ROZLYTREK.Refer to the Instructions for Use for detailed instructions on preparation and administration of ROZLYTREK capsules as an oral suspension via an enteral tube.. ROZLYTREK Oral PelletsSprinkle pellets on one or more spoonfuls of soft food (e.g., applesauce, yogurt, or pudding) and take within 20 minutes of preparation. Do not crush or chew to avoid bitter taste.The patient should drink water after taking the pellets to ensure the drug has been completely swallowed.Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare dose.Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.Refer to the Instructions for Use for detailed instructions on preparation and administration of ROZLYTREK oral pellets.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Congestive Heart FailureInform patients of the risks of CHF and advise patients to contact their healthcare provider immediately for any new or worsening signs or symptoms of CHF [see Warnings and Precautions (5.1)].. Inform patients of the risks of CHF and advise patients to contact their healthcare provider immediately for any new or worsening signs or symptoms of CHF [see Warnings and Precautions (5.1)].. Central Nervous System EffectsAdvise patients to inform their healthcare provider if they experience new or worsening central nervous system symptoms. Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.2)].. Advise patients to inform their healthcare provider if they experience new or worsening central nervous system symptoms. Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.2)].. Skeletal FracturesInform patients that bone fractures have been reported in patients taking ROZLYTREK. Advise patients to report symptoms such as pain, changes in mobility, or deformity to their healthcare provider [see Warnings and Precautions (5.3)].. Inform patients that bone fractures have been reported in patients taking ROZLYTREK. Advise patients to report symptoms such as pain, changes in mobility, or deformity to their healthcare provider [see Warnings and Precautions (5.3)].. HepatotoxicityAdvise patients that they will need to undergo laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.4)].. Advise patients that they will need to undergo laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.4)].. HyperuricemiaAdvise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5)].. Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5)].. QT Interval ProlongationInform patients of the risks of QT interval prolongation and to advise patients to contact their healthcare provider immediately for any symptoms of QT interval prolongation [see Warnings and Precautions (5.6)].. Inform patients of the risks of QT interval prolongation and to advise patients to contact their healthcare provider immediately for any symptoms of QT interval prolongation [see Warnings and Precautions (5.6)].. Vision DisordersAdvise patients to inform their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)].. Advise patients to inform their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)].. Embryo-Fetal ToxicityAdvise pregnant women and 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, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with ROZLYTREK and for weeks after the last dose.Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose.. Advise pregnant women and 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, 8.3)].. Advise females of reproductive potential to use effective contraception during treatment with ROZLYTREK and for weeks after the last dose.. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose.. LactationAdvise females not to breastfeed during treatment with ROZLYTREK and for week after the last dose [see Use in Specific Populations (8.2)]. Advise females not to breastfeed during treatment with ROZLYTREK and for week after the last dose [see Use in Specific Populations (8.2)]. Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking ROZLYTREK [see Drug Interactions (7)].. Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking ROZLYTREK [see Drug Interactions (7)].. AdministrationInstruct patients and caregivers to read the Instructions for Use before the patient starts using ROZLYTREK, and each time the patient gets refill as there may be new information they need to know.For capsules taken as an oral suspension or for administration by enteral tube: Provide patients and caregivers with measuring device (e.g., oral syringe, measuring cup) to prepare and measure their prescribed dose if taking ROZLYTREK capsules as an oral suspension. Instruct patients and/or caregivers how to use the measuring device provided and inform patients they may need to measure out portion of oral suspension prepared to receive the prescribed dosage. If not taken immediately after preparation, store no longer than hours at room temperature below 30C (86F) [see Dosage and Administration (2.9)].For pellets: Instruct patients and caregivers that ROZLYTREK oral pellets should be sprinkled on one or more spoonfuls of soft food (e.g., applesauce, yogurt, or pudding) and must be taken within 20 minutes of preparation. Oral pellets are not suitable for enteral administration due to potential for clogging in tubing [see Dosage and Administration (2.9)].Instruct patients if they miss dose to make up that dose unless the next dose is due within 12 hours.Instruct patients if they vomit immediately after taking dose of ROZLYTREK to take dose as soon as possible [Dosage and Administration (2.4)]. Instruct patients and caregivers to read the Instructions for Use before the patient starts using ROZLYTREK, and each time the patient gets refill as there may be new information they need to know.. For capsules taken as an oral suspension or for administration by enteral tube: Provide patients and caregivers with measuring device (e.g., oral syringe, measuring cup) to prepare and measure their prescribed dose if taking ROZLYTREK capsules as an oral suspension. Instruct patients and/or caregivers how to use the measuring device provided and inform patients they may need to measure out portion of oral suspension prepared to receive the prescribed dosage. If not taken immediately after preparation, store no longer than hours at room temperature below 30C (86F) [see Dosage and Administration (2.9)].. For pellets: Instruct patients and caregivers that ROZLYTREK oral pellets should be sprinkled on one or more spoonfuls of soft food (e.g., applesauce, yogurt, or pudding) and must be taken within 20 minutes of preparation. Oral pellets are not suitable for enteral administration due to potential for clogging in tubing [see Dosage and Administration (2.9)].. Instruct patients if they miss dose to make up that dose unless the next dose is due within 12 hours.. Instruct patients if they vomit immediately after taking dose of ROZLYTREK to take dose as soon as possible [Dosage and Administration (2.4)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEROZLYTREK(R) [roz lye trek](entrectinib)capsules, for oral useThis Instructions for Use contains information on how to prepare and take or give ROZLYTREK capsules.Before StartingRead this Instructions for Use before giving ROZLYTREK capsules for the first time and each time you get refill. There may be new information.ROZLYTREK capsules can be swallowed whole or prepared as suspension and taken or given by mouth or through nasogastric tube (NG tube) or gastrostomy tube (G tube) feeding tube.Important Information You Need to Know Before Taking or Giving ROZLYTREK CapsulesYour healthcare provider or pharmacist should show you how to correctly prepare and take or give dose of ROZLYTREK capsules. Always take or give ROZLYTREK capsules exactly as your healthcare provider tells you.Do not take or give ROZLYTREK to someone else until you have been shown how to properly prepare and take or give ROZLYTREK.Wash your hands before and after preparing, taking, or giving ROZLYTREK.Check the expiration date and check the product for damage before use. Do not use if expired or damaged.Dosing of ROZLYTREK capsules to be swallowed wholeYour healthcare provider will decide the right dose of ROZLYTREK for you or your child.Your healthcare provider will tell you what your daily dose of ROZLYTREK is.Swallow ROZLYTREK capsules whole, with or without food.Swallow whole capsules with drinking water, as directed by your healthcare provider. Do not crush or chew the capsules.Dosing of ROZLYTREK capsules prepared as suspension to be taken by mouth or through feeding tubeIf you or your child cannot swallow capsules whole, ROZLYTREK capsules can be prepared as suspension and taken or given by mouth or through feeding tube. For doses of mL or higher, NG or feeding tube size French or larger should be used.Your healthcare provider or pharmacist will show you how to prepare and take or give dose of ROZLYTREK capsules prepared as suspension.Table shows the prescribed dose, the number and strength of capsules needed, the amount of water or milk needed to mix the capsules, and the amount of suspension needed to give for the prescribed dose.Your healthcare provider will tell you the number of capsules to use, the amount of liquid needed to mix the capsules, and the amount of suspension (mL) to take or give to get the correct dose of ROZLYTREK.You may need to measure smaller amount of suspension than you prepared to take or give the correct prescribed dose of ROZLYTREK.Table 1. Preparation of ROZLYTREK capsules as suspensionPrescribed dose of ROZLYTREK to be givenNumber of 100 mg or 200 mg capsules neededAmount of water or milk needed to mix the capsulesAmount of suspension to take or give20 mgOne 100 mg5 mL1 mL30 mgOne 100 mg5 mL1.5 mL40 mgOne 100 mg5 mL2 mL50 mgOne 100 mg5 mL2.5 mL60 mgOne 100 mg5 mL3 mL70 mgOne 100 mg5 mL3.5 mL80 mgOne 100 mg5 mL4 mL90 mgOne 100 mg5 mL4.5 mL100 mgOne 100 mg5 mL5 mL110 mgOne 200 mg10 mL5.5 mL120 mgOne 200 mg10 mL6 mL130 mgOne 200 mg10 mL6.5 mL140 mgOne 200 mg10 mL7 mL150 mgOne 200 mg10 mL7.5 mL200 mgOne 200 mg10 mL10 mL300 mgThree 100 mg 15 mL15 mL400 mgTwo 200 mg20 mL20 mL600 mgThree 200 mg30 mL30 mLSupplies needed to prepare and take or give ROZLYTREK as suspension:the number of capsules needed for your prescribed dosea clean empty cupa paper towela cup of room temperature drinking water or milkan oral syringe (provided by your healthcare provider or pharmacist)Preparing ROZLYTREK capsules as suspensionStep 1. Wash your hands.Step 2. Count the number of capsules you will need to give the prescribed dose.Step 3. Place clean empty cup on paper towel.Figure AStep 4. Tap the capsules to loosen the contents inside (medicine).Step 5. While holding each capsule above the clean cup, open the capsule by gently pressing in on the capsule and twisting both sides apart.Pour the medicine into the clean cup (Figure A).Step 6. Tap both sides of the capsule shell and check to make sure all the medicine has gone into the cup. If the medicine is spilled outside of the cup, go to Step D1 for clean-up instructions, then start over at Step 1. Step 7. Push the syringe plunger all the way down to remove any air in the oral syringe (Figure B).Figure BStep 8. Place the syringe tip into the room temperature cup of drinking water or milk.Measure the proper amount of liquid (mL) by pulling up on the syringe plunger to draw the liquid into the syringe (Figure C). Your healthcare provider will tell you how much liquid to use.Do not use any other type of liquid.Figure CStep 9. Check that the correct amount of liquid (mL) is in the syringe (Figure ).Figure DStep 10. Add the liquid to the cup that contains the medicine by holding the barrel of the syringe and pushing the syringe plunger all the way down (Figure E).Figure EStep 11. Let the mixture sit for 15 minutes (Figure F). Note: It is important to do this to get an even mixture, otherwise you may not get the correct dose. Figure FStep 12. Swirl the cup several times to evenly mix the medicine in the liquid (Figure G). Note: The medicine does not dissolve in the liquid and the suspension will be cloudy if you have used water.Figure GStep 13. Push the syringe plunger all the way down to remove any air in the syringe (Figure H).Figure HStep 14. Swirl the cup of medicine again before placing the syringe in the cup (Figure I).Figure IStep 15. Place the syringe tip right away into the cup and slowly pull up the plunger to draw up the correct amount (mL) of suspension (Figure J). Do not wait to draw up the suspension. If it sits for too long, the medicine may settle to the bottom, and you may not get the correct dose.Figure JStep 16. Check that the correct amount of suspension (mL) is in the syringe (Figure K).Figure KStep 17. With the tip of the syringe pointing up, check that: you have withdrawn the correct amount (mL) there are no large bubbles (Figure L) Note: If you have not withdrawn the correct amount (mL), or if there are large bubbles inside: put the syringe into the cup againpush the suspension back into the cupthen draw up the suspension again (start at Step 12).Give ROZLYTREK right away after it is drawn up into the syringe. NOTE: Throw away the suspension if you do not take or give it within hours of preparing the suspension and start over at step 1. Figure Giving ROZLYTREK capsules prepared as suspension by mouth Step A1. Sit your child upright when you give dose of ROZLYTREK by mouth (Figure M).Place the oral syringe into the mouth with the tip along either cheek.Slowly push the plunger all the way down.Giving ROZLYTREK too fast may cause choking.Figure MStep A2. Check that there is no suspension left in the oral syringe (Figure N).If suspension remains in the oral syringe, repeat step A1.Figure NStep A3. Give sips of water right after taking or giving the prescribed dose of ROZLYTREK (Figure O).You can breastfeed or give your child milk if they still taste the medicine after you give the dose. Go to Step D1 for clean-up instructions. Figure Giving ROZLYTREK capsules prepared as suspension through gastrostomy tube (G tube)To take or give ROZLYTREK through G tube review the manufacturers instructions and consult your healthcare provider. Make sure that the tube is at least French or larger to prevent clogging of the tube if your dose (amount of suspension) is mL or higher.To take or give ROZLYTREK doses of mL or higher, split the dose in half and give it in parts. Flush the tube with the same amount of water or milk after giving each part.To take or give ROZLYTREK doses of 30 mL, split the dose into at least three 10 mL parts. Flush the tube with the same amount of water or milk after giving each part. Step B1Place the oral syringe tip into the tube. Slowly push the plunger all the way down to give ROZLYTREK (Figure P).Figure PStep B2Check that there is no suspension left in the oral syringe (Figure Q).If suspension remains in the oral syringe, repeat step B1.Figure QStep B3Flush the tube with water or milk right after giving ROZLYTREK (Figure R).If you need to split the amount of suspension to give it through the tube, also split the amount of water or milk you use to flush the tube in the same way.Ask your healthcare provider if you are not sure how much water or milk to use to flush the tube.Go to Step D1 for clean up instructions.Figure Giving ROZLYTREK capsules prepared as suspension through nasogastric tube (NG tube)If you are giving ROZLYTREK through an NG tube, review the manufacturer instructions and consult your healthcare provider. Make sure that the tube is at least French or larger to prevent clogging of the tube if your dose (amount of suspension) is mL or higher.To take or give ROZLYTREK doses of mL or higher, split the dose in half and give it in parts. Flush the tube with the same amount of water or milk after giving each part.To take or give ROZLYTREK doses of 30 mL, split the dose into at least three 10 mL parts. Flush the tube with the same amount of water or milk after giving each part. Step C1Place the syringe tip into the NG tube. Slowly press the plunger all the way down to give ROZLYTREK (Figure S).Figure SStep C2Check that there is no suspension left in the syringe (Figure T).If suspension remains in the syringe, repeat step C1.Figure TStep C3Flush the NG tube with water or milk right after giving ROZLYTREK (Figure U).If you need to split the amount of suspension to give it through the NG tube, also split the amount of water or milk you use to flush the tube in the same way.Ask your healthcare provider if you are not sure how much water or milk to use to flush the NG tube.Go to Step D1 for clean up instructions.Figure Cleaning up and disposing of ROZLYTREKStep D1Wash your hands and all the texts used to give ROZLYTREK.Remove the syringe plunger from the syringe barrel.Use only clean water to rinse the syringe parts and the cup used to prepare the suspension. Let all texts dry before the next use. Put the syringe plunger back into the syringe barrel when dry.Throw away (discard of) the disposable texts in your household trash. Storing ROZLYTREKStore ROZLYTREK capsules at room temperature between 68F to 77F (20C to 25C). Do not store ROZLYTREK prepared as suspension for more than hours at room temperature below 86F (30C). Throw away any unused suspension if it is not used within hours of preparation. Store ROZLYTREK capsules in the original container and keep the bottle tightly closed to protect from moisture.Keep ROZLYTREK and all medicines out of the reach of children. Distributed by: Genentech USA, Inc. Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990ROZLYTREK(R) is registered trademark of Genentech, Inc.(C)2023 Genentech, Inc. For more information, go to www.ROZLYTREK.com or call 1-877-436-3683.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 10/2023. Your healthcare provider or pharmacist should show you how to correctly prepare and take or give dose of ROZLYTREK capsules. Always take or give ROZLYTREK capsules exactly as your healthcare provider tells you.. Do not take or give ROZLYTREK to someone else until you have been shown how to properly prepare and take or give ROZLYTREK.. Wash your hands before and after preparing, taking, or giving ROZLYTREK.. Check the expiration date and check the product for damage before use. Do not use if expired or damaged.. Your healthcare provider will decide the right dose of ROZLYTREK for you or your child.. Your healthcare provider will tell you what your daily dose of ROZLYTREK is.. Swallow ROZLYTREK capsules whole, with or without food.. Swallow whole capsules with drinking water, as directed by your healthcare provider. Do not crush or chew the capsules.. the number of capsules needed for your prescribed dose. clean empty cup. paper towel. cup of room temperature drinking water or milk. an oral syringe (provided by your healthcare provider or pharmacist). If the medicine is spilled outside of the cup, go to Step D1 for clean-up instructions, then start over at Step 1.. you have withdrawn the correct amount (mL) there are no large bubbles (Figure L). put the syringe into the cup again. push the suspension back into the cup. then draw up the suspension again (start at Step 12).. Wash your hands and all the texts used to give ROZLYTREK.. Remove the syringe plunger from the syringe barrel.. Use only clean water to rinse the syringe parts and the cup used to prepare the suspension. Let all texts dry before the next use. Put the syringe plunger back into the syringe barrel when dry.. Throw away (discard of) the disposable texts in your household trash.. Store ROZLYTREK capsules at room temperature between 68F to 77F (20C to 25C). Do not store ROZLYTREK prepared as suspension for more than hours at room temperature below 86F (30C). Throw away any unused suspension if it is not used within hours of preparation. Store ROZLYTREK capsules in the original container and keep the bottle tightly closed to protect from moisture.. Image. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. Figure O. Figure P. Figure Q. Figure R. Figure S. Figure T. Figure U.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONROZLYTREK(R) (roz lye trek)(entrectinib)capsules ROZLYTREK(R) (roz lye trek)(entrectinib)oral pelletsThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised 1/2024What is the most important information should know about ROZLYTREKROZLYTREK may cause serious side effects, including:Congestive heart failure. ROZLYTREK may cause congestive heart failure or make the congestive heart failure that you already have worse. Your healthcare provider will do tests before your treatment and may do tests during your treatment with ROZLYTREK to check your heart function. Tell your healthcare provider right away if you have any of the following signs and symptoms of congestive heart failure:persistent coughing or wheezingtrouble breathing when lying downsudden weight gain increasing shortness of breathtiredness, weakness, or fatigueswelling in ankles, feet, or legs Central nervous system (CNS) effects. ROZLYTREK may cause dizziness, changes in your mood, or may affect how you think and cause confusion, hallucinations, and problems with concentration, attention, memory, speaking, understanding what your hear or read, and sleep. Tell your healthcare provider right away if you have any of these symptoms.Bone fractures. ROZLYTREK may increase your risk for bone fractures. Bone fractures may happen with or without fall or other injury. Tell your healthcare provider if you develop pain, changes in movement, or bone abnormalities.Liver problems (hepatotoxicity). Your healthcare provider will do blood tests to check your liver function during treatment with ROZLYTREK. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:loss of appetitenausea or vomitingpain in your upper right stomach areayellowing of your skin or the white part of your eyesdark urineIncreased uric acid level in your blood (hyperuricemia). ROZLYTREK may cause too much uric acid in your blood. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the uric acid level in your blood. Your healthcare provider may prescribe medications if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia:red, hot, tender, or swollen joints, especially in your big toe pain in your stomach-area or sidesnausea or vomitingpink or brown urineChanges in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the electrical activity of your heart and your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast during your treatment with ROZLYTREK. These may be symptoms related to QT prolongation.Vision problems. ROZLYTREK may cause vision problems. Your healthcare provider may stop ROZLYTREK and refer you to an eye specialist if you develop severe vision problems during treatment with ROZLYTREK. Tell your healthcare provider right away if you have any loss of vision or any change in vision, including:double visionblurry visionnew or increased floatersseeing flashes of lightlight hurting your eyesYour healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop ROZLYTREK if you develop certain side effects during treatment with ROZLYTREK.What is ROZLYTREKROZLYTREK is prescription medicine used to treat: Adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by an abnormal ROS1 gene.Adults and children month of age and older with solid tumors (cancer) that: are caused by certain abnormal NTRK genes, and have spread or if surgery to remove their cancer is likely to cause severe complications, and there is no satisfactory alternative treatment option or the cancer grew or spread on other treatment. It is not known if ROZLYTREK is safe and effective in children with ROS1 NSCLC or in children under month of age with NTRK solid tumors. Before taking ROZLYTREK, tell your healthcare provider about all your medical conditions, including if you:have liver or kidney problemshave any heart problems, including condition called long QT syndromehave nervous system (neurological) problemshave or have had eye or vision problemsare pregnant or plan to become pregnant. ROZLYTREK can cause harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ROZLYTREK. Females who can become pregnant: Your healthcare provider will do pregnancy test before you start treatment with ROZLYTREK.Use effective birth control (contraception) during treatment with ROZLYTREK and for at least weeks after the last dose. Males with female partners that can become pregnant: Use effective birth control (contraception) during treatment with ROZLYTREK and for months after the last dose. are breastfeeding or plan to breastfeed. It is not known if ROZLYTREK passes into your breast milk. Do not breastfeed during treatment with ROZLYTREK and for days (1 week) after the last dose of ROZLYTREK. 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 and over-the-counter medicines, vitamins, or herbal supplements.Taking ROZLYTREK with certain other medicines may affect the amount of ROZLYTREK or other medicine in your blood and may cause side effects or affect the way that ROZLYTREK or the other medicine work. 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 ROZLYTREKTake ROZLYTREK exactly as your healthcare provider tells you. Do not change your dose or stop taking ROZLYTREK unless your healthcare provider tells you to.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ROZLYTREK if you develop certain side effects.Take ROZLYTREK time each day with or without food.Your healthcare provider will either prescribe: ROZLYTREK capsules to be swallowed whole or prepared and taken or given as suspension or ROZLYTREK oral pellets to be sprinkled on or more spoonfuls of soft food before taking. If you miss dose of ROZLYTREK, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time.If you vomit right after taking dose of ROZLYTREK, you may take the dose again.See the detailed Instructions for Use for information on how to give or take dose of ROZLYTREK capsules or oral pellets.If you are taking whole ROZLYTREK capsules:Swallow whole capsules with drinking water, as directed by your healthcare provider.Do not crush or chew the capsule.If you are taking ROZLYTREK capsules prepared as suspension:Carefully open the prescribed number of capsules and pour the contents into room temperature drinking water or milk. Your healthcare provider will tell you how much water or milk to use, how much suspension to take or give, and provide you with measuring device like an oral syringe or measuring cup.Let the suspension sit for 15 minutes before taking.You may need to take less suspension than you prepared depending on your prescribed dose.Drink water after taking the suspension to make sure you have swallowed all the medicine.If you do not take the suspension right away, you can store it for up to hours at room temperature below 86F (30C). Throw away (discard) the unused suspension if it is not used within hours of preparation.If you cannot swallow and have gastric or nasogastric tube, the suspension can be given through the feeding tube.If you are taking ROZLYTREK oral pellets:Sprinkle the prescribed number of packets of pellets on or more spoonfuls of soft food like applesauce, yogurt, or pudding, and take within 20 minutes of sprinkling the pellets on the soft food. Do not crush or chew the pellets to avoid bitter taste.Drink water after taking the prescribed dose to make sure you have swallowed all the medicine.Use the whole packet of pellets. Do not use part of the packet to try to prepare dose.Do not use the pellets to make suspension.Do not give the pellets through gastric or nasogastric tube because the pellets may clog the feeding tube.What should avoid while taking ROZLYTREKYou should not drink grapefruit juice or eat grapefruit during your treatment with ROZLYTREK. It may increase the amount of entrectinib in your blood to harmful level and increase your chance of getting side effects.Do not drive or operate heavy machinery until you know how ROZLYTREK affects you. If you experience dizziness, fainting, tiredness, blurred vision, memory loss, changes in mental status, confusion, or hallucinations, do not drive or operate heavy machines until your symptoms resolve.What are the possible side effects of ROZLYTREKROZLYTREK may cause serious side effects, including:See What is the most important information should know about ROZLYTREK The most common side effects of ROZLYTREK include:tirednessconstipationchange in taste swellingdizzinessdiarrheanauseaabnormal touch sensation shortness of breathmuscle painconfusion, mental status changes, memory problems, and hallucinationsweight gaincoughvomitingfeverjoint painvision changesThese are not all the possible side effects of ROZLYTREK.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ROZLYTREKROZLYTREK capsulesStore ROZLYTREK at room temperature between 68F to 77F (20C to 25C). Store ROZLYTREK capsules in the original container and keep the bottle tightly closed to protect from moisture.ROZLYTREK oral pelletsStore ROZLYTREK oral pellets at room temperature between 68F to 77F (20C to 25C).Store ROZLYTREK oral pellets in the original container to protect from moisture.Keep ROZLYTREK and all medicines out of the reach of children.General information about the safe and effective use of ROZLYTREK.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ROZLYTREK for condition for which it was not prescribed. Do not give ROZLYTREK to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ROZLYTREK that is written for health professionals.What are the ingredients in ROZLYTREKActive ingredient: entrectinib Inactive ingredients: Capsules: tartaric acid, lactose anhydrous, hypromellose, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.Yellow opaque capsule shell: hypromellose, titanium dioxide, and yellow iron oxideOrange opaque capsule shell: hypromellose, titanium dioxide, and FD&C Yellow No. Printing ink: shellac, propylene glycol, strong ammonia solution, and FD&C Blue No. aluminum lake Pellets: tartaric acid, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearateFilm-coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron oxide, and ferrosoferric oxideDistributed by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990ROZLYTREK(R) is registered trademark of Genentech, Inc. (C)2024 Genentech, Inc.For more information, go to www.ROZLYTREK.com or call 1-877-436-3683.. Congestive heart failure. ROZLYTREK may cause congestive heart failure or make the congestive heart failure that you already have worse. Your healthcare provider will do tests before your treatment and may do tests during your treatment with ROZLYTREK to check your heart function. Tell your healthcare provider right away if you have any of the following signs and symptoms of congestive heart failure:. persistent coughing or wheezing. trouble breathing when lying down. sudden weight gain increasing shortness of breath. tiredness, weakness, or fatigue. swelling in ankles, feet, or legs Central nervous system (CNS) effects. ROZLYTREK may cause dizziness, changes in your mood, or may affect how you think and cause confusion, hallucinations, and problems with concentration, attention, memory, speaking, understanding what your hear or read, and sleep. Tell your healthcare provider right away if you have any of these symptoms.. Bone fractures. ROZLYTREK may increase your risk for bone fractures. Bone fractures may happen with or without fall or other injury. Tell your healthcare provider if you develop pain, changes in movement, or bone abnormalities.. Liver problems (hepatotoxicity). Your healthcare provider will do blood tests to check your liver function during treatment with ROZLYTREK. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:. loss of appetite. nausea or vomiting. pain in your upper right stomach area. yellowing of your skin or the white part of your eyes. dark urine. Increased uric acid level in your blood (hyperuricemia). ROZLYTREK may cause too much uric acid in your blood. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the uric acid level in your blood. Your healthcare provider may prescribe medications if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia:. red, hot, tender, or swollen joints, especially in your big toe pain in your stomach-area or sides. nausea or vomiting. pink or brown urine. Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the electrical activity of your heart and your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast during your treatment with ROZLYTREK. These may be symptoms related to QT prolongation.. Vision problems. ROZLYTREK may cause vision problems. Your healthcare provider may stop ROZLYTREK and refer you to an eye specialist if you develop severe vision problems during treatment with ROZLYTREK. Tell your healthcare provider right away if you have any loss of vision or any change in vision, including:. double vision. blurry vision. new or increased floaters. seeing flashes of light. light hurting your eyes. Adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by an abnormal ROS1 gene.. Adults and children month of age and older with solid tumors (cancer) that: are caused by certain abnormal NTRK genes, and have spread or if surgery to remove their cancer is likely to cause severe complications, and there is no satisfactory alternative treatment option or the cancer grew or spread on other treatment. are caused by certain abnormal NTRK genes, and have spread or if surgery to remove their cancer is likely to cause severe complications, and there is no satisfactory alternative treatment option or the cancer grew or spread on other treatment.. have liver or kidney problems. have any heart problems, including condition called long QT syndrome. have nervous system (neurological) problems. have or have had eye or vision problems. are pregnant or plan to become pregnant. ROZLYTREK can cause harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ROZLYTREK. Females who can become pregnant: Your healthcare provider will do pregnancy test before you start treatment with ROZLYTREK.Use effective birth control (contraception) during treatment with ROZLYTREK and for at least weeks after the last dose. Males with female partners that can become pregnant: Use effective birth control (contraception) during treatment with ROZLYTREK and for months after the last dose. Your healthcare provider will do pregnancy test before you start treatment with ROZLYTREK.. Use effective birth control (contraception) during treatment with ROZLYTREK and for at least weeks after the last dose.. Use effective birth control (contraception) during treatment with ROZLYTREK and for months after the last dose.. are breastfeeding or plan to breastfeed. It is not known if ROZLYTREK passes into your breast milk. Do not breastfeed during treatment with ROZLYTREK and for days (1 week) after the last dose of ROZLYTREK. Talk to your healthcare provider about the best way to feed your baby during this time. Take ROZLYTREK exactly as your healthcare provider tells you. Do not change your dose or stop taking ROZLYTREK unless your healthcare provider tells you to.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ROZLYTREK if you develop certain side effects.. Take ROZLYTREK time each day with or without food.. Your healthcare provider will either prescribe: ROZLYTREK capsules to be swallowed whole or prepared and taken or given as suspension or ROZLYTREK oral pellets to be sprinkled on or more spoonfuls of soft food before taking. ROZLYTREK capsules to be swallowed whole or prepared and taken or given as suspension or ROZLYTREK oral pellets to be sprinkled on or more spoonfuls of soft food before taking.. If you miss dose of ROZLYTREK, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time.. If you vomit right after taking dose of ROZLYTREK, you may take the dose again.. Swallow whole capsules with drinking water, as directed by your healthcare provider.. Do not crush or chew the capsule.. Carefully open the prescribed number of capsules and pour the contents into room temperature drinking water or milk. Your healthcare provider will tell you how much water or milk to use, how much suspension to take or give, and provide you with measuring device like an oral syringe or measuring cup.. Let the suspension sit for 15 minutes before taking.. You may need to take less suspension than you prepared depending on your prescribed dose.. Drink water after taking the suspension to make sure you have swallowed all the medicine.. If you do not take the suspension right away, you can store it for up to hours at room temperature below 86F (30C). Throw away (discard) the unused suspension if it is not used within hours of preparation.. If you cannot swallow and have gastric or nasogastric tube, the suspension can be given through the feeding tube.. Sprinkle the prescribed number of packets of pellets on or more spoonfuls of soft food like applesauce, yogurt, or pudding, and take within 20 minutes of sprinkling the pellets on the soft food. Do not crush or chew the pellets to avoid bitter taste.. Drink water after taking the prescribed dose to make sure you have swallowed all the medicine.. Use the whole packet of pellets. Do not use part of the packet to try to prepare dose.. Do not use the pellets to make suspension.. Do not give the pellets through gastric or nasogastric tube because the pellets may clog the feeding tube.. You should not drink grapefruit juice or eat grapefruit during your treatment with ROZLYTREK. It may increase the amount of entrectinib in your blood to harmful level and increase your chance of getting side effects.. Do not drive or operate heavy machinery until you know how ROZLYTREK affects you. If you experience dizziness, fainting, tiredness, blurred vision, memory loss, changes in mental status, confusion, or hallucinations, do not drive or operate heavy machines until your symptoms resolve.. See What is the most important information should know about ROZLYTREK tiredness. constipation. change in taste swelling. dizziness. diarrhea. nausea. abnormal touch sensation shortness of breath. muscle pain. confusion, mental status changes, memory problems, and hallucinations. weight gain. cough. vomiting. fever. joint pain. vision changes. Store ROZLYTREK at room temperature between 68F to 77F (20C to 25C). Store ROZLYTREK capsules in the original container and keep the bottle tightly closed to protect from moisture.. Store ROZLYTREK oral pellets at room temperature between 68F to 77F (20C to 25C).. Store ROZLYTREK oral pellets in the original container to protect from moisture.. Yellow opaque capsule shell: hypromellose, titanium dioxide, and yellow iron oxide. Orange opaque capsule shell: hypromellose, titanium dioxide, and FD&C Yellow No. . Printing ink: shellac, propylene glycol, strong ammonia solution, and FD&C Blue No. aluminum lake. Film-coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron oxide, and ferrosoferric oxide.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], ROZLYTREK can cause fetal harm when administered to pregnant woman. There are no available data on ROZLYTREK use in pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose (see Data). Advise pregnant women 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 is 2% to 4% and 15% to 20%, respectively.. Data. Human DataPublished reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.. Animal DataEntrectinib administration to pregnant rats during the period of organogenesis at dose of 200 mg/kg [resulting in exposures up to 2.7 times the human exposure (AUC) at the 600 mg dose] resulted in maternal toxicity and fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly), but not embryolethality. Lower fetal weights and reduced skeletal ossification occurred at doses >= 12.5 and 50 mg/kg [approximately 0.2 and 0.9 times the human exposure (AUC) at the 600 mg dose], respectively.. 8.2 Lactation. Risk SummaryThere are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential serious adverse reactions in breastfed children from ROZLYTREK, advise lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for days after the last dose.. 8.3Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK [see Use in Specific Populations (8.1)].. ContraceptionROZLYTREK 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 contraception during treatment with ROZLYTREK and for at least weeks following the last dose [see Use in Specific Populations (8.1)].. MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for months following the last dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of ROZLYTREK have been established in pediatric patients older than month of age [Clinical Studies (14.2)]. Use of ROZLYTREK in these age groups is supported by evidence from adequate and well-controlled studies of ROZLYTREK in adults and pediatric patients with additional population pharmacokinetic data demonstrating that the exposure of drug substance in pediatric patients greater than month of age is expected to be in the adult range, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients.The safety and effectiveness of ROZLYTREK have not been established in pediatric patients with ROS1-positive NSCLC.. Juvenile Animal Toxicity DataIn 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day to day 97 (approximately equivalent to neonate to adulthood). Entrectinib resulted in:decreased body weight gain and delayed sexual maturation at doses >= mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose),deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses >= mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose), anddecreased femur length at doses >= 16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).. decreased body weight gain and delayed sexual maturation at doses >= mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose),. deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses >= mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose), and. decreased femur length at doses >= 16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).. 8.5 Geriatric Use. Of the 355 patients who received ROZLYTREK across clinical trials, 25% were 65 years or older, and 5% were 75 years of age or older. Clinical studies of ROZLYTREK did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger patients.. 8.6 Renal Impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr 30 to 90 mL/min calculated by Cockcroft-Gault equation). ROZLYTREK has not been studied in patients with severe renal impairment (CLcr 30 mL/min) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment. The effect of moderate hepatic impairment (total bilirubin 1.5 3.0 times ULN with any aspartate aminotransferase) or severe hepatic impairment (total bilirubin >3.0 times ULN with any aspartate aminotransferase) on the safety of ROZLYTREK at the recommended dosage is unknown. Consider the risk-benefit profile of ROZLYTREK prior to determining whether to administer ROZLYTREK to patients with moderate to severe hepatic impairment. Monitor for ROZLYTREK adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

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 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 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 fetus and use of effective contraception. (5.8, 8.1, 8.3) 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 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 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 fetus and use of effective contraception. (5.8, 8.1, 8.3) 5.1Congestive Heart Failure. Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade (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 months of study entry. Among the 12 patients with CHF, the median time to onset was months (range: 11 days to 12 months). ROZLYTREK was interrupted in of these patients (50%) and discontinued in of these patients (17%). CHF resolved in 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 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 reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.7)].. 5.2Central Nervous System Effects. 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 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 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required 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 month (range: day to months). Mood disorders occurring in >= 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 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 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 dizziness occurred in 2.2% of patients. Ten percent of patients required 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 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required 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)].. 5.3Skeletal 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 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. 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, fracture events resolved with sequelae and 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: 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.. 5.4Hepatotoxicity. 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 - 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 weeks (range: day to 29.5 months). The median time to onset of increased ALT was weeks (range: 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 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)].. 5.5Hyperuricemia. 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 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)].. 5.6QT 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 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)].. 5.7Vision Disorders. Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade (17%), Grade (2.8%) and Grade (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)].. 5.8Embryo-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 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 fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for weeks following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].