Rozlytrek

1 INDICATIONS AND USAGE ROZLYTREK is a kinase inhibitor indicated for the treatment of: Adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. ( 1.1 ) Adult and pediatric patients older than 1 month of age with solid tumors that: have a neurotrophic tyrosine receptor kinase ( NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. ( 1.2 ) 1.1 ROS1 -Positive Non-Small Cell Lung Cancer ROZLYTREK is indicated for the treatment of adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test. 1.2 NTRK Gene Fusion-Positive Solid Tumors ROZLYTREK is indicated for the treatment of adult and pediatric patients older than 1 month of age with solid tumors that: have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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 a 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 ) Age Recommended Daily Dosage >6 months ≤0.50 m 2 : 300 mg/m 2 0.51 to 0.80 m 2 : 200 mg 0.81 to 1.10 m 2 : 300 mg 1.11 to 1.50 m 2 : 400 mg BSA ≥1.51 m 2 : 600 mg once daily >1 month to ≤6 months 250 mg/m 2 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 ) 2.1 Patient 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 a 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. 2.2 Recommended 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) ] 2.3 ROZLYTREK 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 mg 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 a suspension. ROZLYTREK Oral Pellets 50 mg per packet 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 a dose. Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube. 2.4 ROZLYTREK Administration Overview Administer ROZLYTREK capsules, capsules prepared…

5 WARNINGS AND PRECAUTIONS Congestive Heart Failure (CHF) : Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For new onset or worsening CHF, withhold ROZLYTREK, reassess LVEF and institute appropriate medical management. Reduce dose or permanently discontinue ROZLYTREK based on severity of CHF or worsening LVEF. ( 2.7 , 5.1 ) Central Nervous System (CNS) Effects: CNS adverse reactions including cognitive impairment, mood disorders, dizziness, and sleep disturbances can occur with ROZLYTREK. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue ROZLYTREK based on severity. ( 2.7 , 5.2 ) Skeletal Fractures: ROZLYTREK increases the risk of fractures. Promptly evaluate patients with signs or symptoms of fractures. ( 5.3 ) Hepatotoxicity : Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on severity. If withheld, resume ROZLYTREK at same or reduced dose based on severity. ( 2.7 , 5.4 ) Hyperuricemia : Assess serum uric acid levels prior to initiation and periodically during treatment with ROZLYTREK. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume at same or reduced dose upon improvement based on severity. ( 2.7 , 5.5 ) QT Interval Prolongation : Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity. ( 2.7 , 5.6 ) Vision Disorders : Withhold for new visual changes or changes that interfere with activities of daily living until improvement or stabilization. Conduct an ophthalmological evaluation as appropriate. Resume at same or reduced dose upon improvement or stabilization. ( 2.7 , 5.7 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.8 , 8.1 , 8.3 ) 5.1 Congestive Heart Failure Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1) ]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients. Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue […

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Moderate and Strong CYP3A Inhibitors : For adult and pediatric patients 2 years and older, reduce the dose of ROZLYTREK if coadministration of moderate or strong CYP3A inhibitors cannot be avoided. ( 2.8 , 7.1 ) For pediatric patients less than 2 years, avoid coadministration with ROZLYTREK. ( 7.1 ) Moderate and Strong CYP3A Inducers : Avoid coadministration with ROZLYTREK. ( 7.1 ) Drugs That Prolong QTc Interval : Avoid concomitant use with ROZLYTREK. ( 7.2 ) 7.1 Effect of Other Drugs on ROZLYTREK Moderate and Strong CYP3A Inhibitors Adults and Pediatric Patients 2 Years and Older Coadministration of ROZLYTREK with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations [see Clinical Pharmacology (12.3) ], which could increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors with ROZLYTREK. If coadministration is unavoidable, reduce the ROZLYTREK dose [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. Pediatric Patients less than 2 Years Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors [see Clinical Pharmacology (12.3) ] . Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A. Moderate and Strong CYP3A Inducers Coadministration of ROZLYTREK with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce ROZLYTREK efficacy. Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK . 7.2 Drugs That Prolong QTc Interval QTc interval prolongation can occur with ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.6) , Clinical Pharmacology (12.2) ] .

8.1 Pregnancy Risk Summary Based 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 a 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 a 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 Data Published 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 Data Entrectinib administration to pregnant rats during the period of organogenesis at a 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure [see Warnings and Precautions (5.1) ] Central Nervous System Effects [see Warnings and Precautions (5.2) ] Skeletal Fractures [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hyperuricemia [see Warnings and Precautions (5.5) ] QT Interval Prolongation [see Warnings and Precautions (5.6) ] Vision Disorders [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. ROZLYTREK was studied in one dose-finding trial in adults [ALKA (n = 57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)]. The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumors (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received ROZLYTREK 600 mg orally once daily. The doses ranged from 100 mg/m 2 to 1600 mg/m 2 once daily in adults and 250 mg/m 2 to 750 mg/m 2 once daily in pediatric patients. Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue. Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%). Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK. The most frequent adverse re…