These highlights do not include all the information needed to use ROZLYTREK® safely and effectively. See full prescribing information for ROZLYTREK. ROZLYTREK® (entrectinib) capsules, for oral use ROZLYTREK® (entrectinib) oral pellets Initial U.S. Approval: 2019

1 INDICATIONS AND USAGE

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:

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.

• 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.

2 DOSAGE AND ADMINISTRATION

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.

SPL UNCLASSIFIED SECTION

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.

SPL UNCLASSIFIED SECTION

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 as a suspension, or pellets once daily, with or without food.
• If a dose of ROZYTREK is missed, make up that dose unless the next dose is due within 12 hours.
• If vomiting occurs immediately after taking a dose of ROZLYTREK, repeat that dose.

2.5 ROZLYTREK 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.

2.6 ROZLYTREK 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 a vehicle.

The recommended dosages of ROZLYTREK for the treatment of pediatric patients older than 6 months with NTRK Gene Fusion-Positive Solid Tumors is provided in Table 2.

2.7 ROZLYTREK 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 4 provides the ROZLYTREK recommended dosage modifications for the management of adverse reactions.

2.8 ROZLYTREK Dosage Modifications for Drug Interactions

SPL UNCLASSIFIED SECTION

Moderate and Strong CYP3A Inhibitors

SPL UNCLASSIFIED SECTION

Adults and Pediatric Patients 2 Years and Older

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the ROZLYTREK dose as shown in Table 5 and limit coadministration to 14 days or less.

After discontinuation of a strong or moderate CYP3A inhibitor for 3 to 5 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)].

2.9 ROZLYTREK Preparation and Administration Instructions

SPL UNCLASSIFIED SECTION

ROZLYTREK Capsules

Swallow capsules whole. Do not crush or chew the capsules.

SPL UNCLASSIFIED SECTION

ROZLYTREK Capsules Prepared as a Suspension for Oral or Enteral Tube Administration

It is recommended that a 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 6 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.

Administer ROZLYTREK oral suspension immediately after preparation.

Discard any unused suspension if not used within 2 hours.

Instruct patients to drink water after taking the oral suspension to ensure ROZLYTREK has been completely swallowed.

SPL UNCLASSIFIED SECTION

Enteral Tube Administration

If enteral administration (e.g., gastric or nasogastric tube) is required, administer the oral suspension via the tube. Use an enteral tube that is 8 FR or higher to administer dosing volumes of 3 mL or higher. Instruct patients to divide dosing volumes of 3 mL or higher into at least two aliquots and flush the tube after each administration. Flush the tube with a volume of water or milk that is equal to the aliquot administered. For a 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.

SPL UNCLASSIFIED SECTION

ROZLYTREK Oral Pellets

Sprinkle pellets on one or more spoonfuls of a soft food (e.g., applesauce, yogurt, or pudding) and take within 20 minutes of preparation. Do not crush or chew to avoid a 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 a 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.

3 DOSAGE FORMS AND STRENGTHS

Capsules:

Pellets:

• 100 mg: Size 2 yellow opaque body and cap, with "ENT 100" printed in blue ink on body.
• 200 mg: Size 0 orange opaque body and cap, with "ENT 200" printed in blue ink on body.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1)]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients.

Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.7)].

5.2 Central Nervous System Effects

A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances.

Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued ROZLYTREK due to cognitive adverse reactions.

Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued ROZLYTREK due to mood disorders.

Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued ROZLYTREK due to dizziness.

Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances.

The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (n = 90) compared to those who did not (n = 48).

Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity [see Dosage and Administration (2.7)].

5.3 Skeletal Fractures

ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 76 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 25% of pediatric patients experienced fractures [see Use in Specific Population (8.4)]. In adult and pediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in pediatric patients some fractures occurred with no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some adult patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In two pediatric patients, bilateral femoral neck fractures occurred. A total of 41 fracture events were reported in 19 pediatric patients, with 13 patients who experienced more than one occurrence of fracture. Among the 19 pediatric patients who experienced fractures, 17 patients were less than 12 years of age. Among the 41 fracture events, 27 fracture events resolved, 4 fracture events resolved with sequelae and 3 events were resolving. The median time to fracture was 3.8 months (range 0.3 to 18.5 months) in adults and 4.3 months (range: 2 months to 28.7 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 16% of pediatric patients who experienced fractures. Five pediatric patients discontinued treatment due to fractures.

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures.

5.4 Hepatotoxicity

Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 – 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose [see Dosage and Administration (2.7)].

5.5 Hyperuricemia

Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia.

Assess serum uric acid levels prior to initiation of ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity [see Dosage and Administration (2.7)].

5.6 QT Interval Prolongation

Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTcF interval > 500 ms [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes prior to initiation of ROZLYTREK and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue [see Dosage and Administration (2.7)].

5.7 Vision Disorders

Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (17%), Grade 2 (2.8%) and Grade 3 (0.8%) [see Adverse Reactions (6.1)]. Vision disorders occurring in ≥ 1% included blurred vision (9%), photophobia (5%), diplopia (3.1%), visual impairment (2%), photopsia (1.1%), cataract (1.1%), and vitreous floaters (1.1%).

For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose [see Dosage and Administration (2.7)].

5.8 Embryo-Fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Congestive Heart Failure [see Warnings and Precautions (5.1)]
• Central Nervous System Effects [see Warnings and Precautions (5.2)]
• Skeletal Fractures [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hyperuricemia [see Warnings and Precautions (5.5)]
• QT Interval Prolongation [see Warnings and Precautions (5.6)]
• Vision Disorders [see Warnings and Precautions (5.7)]

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/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 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.

Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).

Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK. The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%).

The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.

Table 7 summarizes the adverse reactions observed in these 355 patients.

Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%).

Table 8 summarizes the laboratory abnormalities.

SPL UNCLASSIFIED SECTION

Safety in Pediatric Patients

The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression. Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year.

The median age of patients who received ROZLYTREK was 6 years (range: 0 to 17); 51% were females; 68% were White, 18% Asian, 7% Black or African American, and 7% were other races.

Serious adverse reactions occurred in 45% of patients who received ROZLYTREK. Serious adverse reactions in > 2% of patients included skeletal fractures (12%), pneumonia (5%), pyrexia (5%), hydrocephalus (5%), device related infection (4%), hypoxia (4%), dyspnea (3%), headache (3%), gait disturbance (3%), pain (3%), upper respiratory infection (3%), and sepsis (3%).

Permanent discontinuation of ROZLYTREK due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture.

Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea.

Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients. Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight.

Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).

Clinically relevant adverse reactions in <20% of patients who received ROZLYTREK included pruritus, rash, urinary incontinence, eye pain and photophobia.

Tables 10 summarizes the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).

Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on ROZLYTREK

SPL UNCLASSIFIED SECTION

Moderate and Strong CYP3A Inhibitors

SPL UNCLASSIFIED SECTION

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)].

SPL UNCLASSIFIED SECTION

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.

SPL UNCLASSIFIED SECTION

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

SPL UNCLASSIFIED SECTION

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.

SPL UNCLASSIFIED SECTION

Data

SPL UNCLASSIFIED SECTION

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.

SPL UNCLASSIFIED SECTION

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.

8.2 Lactation

SPL UNCLASSIFIED SECTION

Risk Summary

There 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 a lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for 7 days after the last dose.

8.3 Females and Males of Reproductive Potential

SPL UNCLASSIFIED SECTION

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK [see Use in Specific Populations (8.1)].

SPL UNCLASSIFIED SECTION

Contraception

ROZLYTREK can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

SPL UNCLASSIFIED SECTION

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for at least 5 weeks following the last dose [see Use in Specific Populations (8.1)].

SPL UNCLASSIFIED SECTION

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 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 1 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 1 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.

SPL UNCLASSIFIED SECTION

Juvenile Animal Toxicity Data

In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Entrectinib resulted in:

• decreased body weight gain and delayed sexual maturation at doses ≥ 4 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 ≥ 8 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)].

11 DESCRIPTION

Entrectinib is a kinase inhibitor. The molecular formula for entrectinib is C31H34F2N6O2 and the molecular weight is 560.64 Daltons. The chemical name is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide. The chemical structure of entrectinib is as follows:

Entrectinib is white to pale pink powder.

SPL UNCLASSIFIED SECTION

Capsules:

ROZLYTREK (entrectinib) capsules for oral use are supplied as printed hard-shell capsules containing 100 mg (yellow opaque HPMC capsule) or 200 mg of entrectinib (orange opaque HPMC capsule). Inactive ingredients are tartaric acid, lactose anhydrous, hypromellose, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

The yellow opaque capsule shell contains hypromellose, titanium dioxide, and yellow iron oxide. The orange opaque capsule shell contains hypromellose, titanium dioxide, and FD&C yellow #6. The printing ink contains shellac, propylene glycol, strong ammonia solution, and FD&C blue #2 aluminum lake.

SPL UNCLASSIFIED SECTION

Pellets:

ROZLYTREK (entrectinib) oral pellets are supplied as brownish orange or grayish orange, round film-coated pellets in packets. Each packet contains 50 mg of entrectinib and the following inactive ingredients: tartaric acid, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate.

The film-coating contains polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron oxide, and ferrosoferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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 2 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.

SPL UNCLASSIFIED SECTION

Cardiac Electrophysiology

Across 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 a 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.

SPL UNCLASSIFIED SECTION

Absorption

The maximum entrectinib plasma concentration was reached 4 – 6 hours after oral administration of a 600 mg dose.

Entrectinib exposure following a single oral dose (600 mg) of ROZLYTREK oral pellets was not clinically significant compared to ROZLYTREK capsule administered with a 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 a single dose (600 mg) of ROZLYTREK capsules as a suspension with water or milk, administered orally or through a nasogastric or gastric tube, was not clinically significant compared to administration of intact ROZLYTREK capsules in healthy subjects under fasted conditions.

SPL UNCLASSIFIED SECTION

Effect of Food

A high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have a significant effect on entrectinib exposure of ROZLYTREK capsules.

SPL UNCLASSIFIED SECTION

Distribution

Entrectinib 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 L and 81.1 L for entrectinib and M5, respectively.

SPL UNCLASSIFIED SECTION

Elimination

The 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.

SPL UNCLASSIFIED SECTION

Metabolism

Entrectinib 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.

SPL UNCLASSIFIED SECTION

Excretion

Following oral administration of a 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%).

SPL UNCLASSIFIED SECTION

Specific Populations

No 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.

SPL UNCLASSIFIED SECTION

Hepatic Impairment

Following administration of a 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.

SPL UNCLASSIFIED SECTION

Pediatric Patients > 6 months

In pediatric patients older than 6 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)].

SPL UNCLASSIFIED SECTION

Pediatric Patients > 1 to ≤ 6 months

In pediatric patients > 1 to ≤ 6 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)].

SPL UNCLASSIFIED SECTION

Drug Interaction Studies

SPL UNCLASSIFIED SECTION

Clinical Studies

SPL UNCLASSIFIED SECTION

Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with a 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 a 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, a similar magnitude of the effect is expected in children as young as 2 years old.

SPL UNCLASSIFIED SECTION

Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with a single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC0-INF by 77% and Cmax by 56% [see Drug Interactions (7.1)]. Coadministration of a moderate CYP3A inducer with ROZLYTREK capsule is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.

SPL UNCLASSIFIED SECTION

Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC by 25% and Cmax by 23%.

Coadministration of lansoprazole, with a 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.

SPL UNCLASSIFIED SECTION

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)].

SPL UNCLASSIFIED SECTION

Effect of Entrectinib on Transporters: Coadministration of a 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%.

SPL UNCLASSIFIED SECTION

In Vitro Studies

Entrectinib is not a substrate of P-gp or BCRP, but M5 is a substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were not conducted with entrectinib. Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay; however, an in vitro assay in cultured human peripheral blood lymphocytes did demonstrate a potential for abnormal chromosome segregation (aneugenicity). Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.

Dedicated fertility studies were not conducted with entrectinib. With the exception of dose-dependent decreases in prostate weight in male dogs, there were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and dogs at doses resulting in exposures of up to approximately 3.2-fold the human exposure (AUC) at the 600 mg dose.

14 CLINICAL STUDIES

14.1 ROS1-Positive Non-Small Cell Lung Cancer

The efficacy of ROZLYTREK was evaluated in a 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 v 1.1, ≥ 18 months of follow-up from first post-treatment tumor assessment, and no prior therapy with a ROS1 inhibitor. Identification of ROS1 gene fusion in tumor specimens was prospectively determined in local laboratories using either a 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 8 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 0 or 1 (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 6 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.

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 2 months prior to study entry. Responses in intracranial lesions were observed in 7 of these 10 patients.

14.2 NTRK Gene Fusion-Positive Solid Tumors

SPL UNCLASSIFIED SECTION

Efficacy in Adult Patients

The efficacy of ROZLYTREK was evaluated in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with a 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 2 years of follow-up from first post-treatment tumor assessment; and no prior therapy with a 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 a central laboratory using various nucleic acid-based tests. The major efficacy outcome measures were ORR and DOR, as determined by a BICR according to RECIST v1.1. Intracranial response according to RECIST v1.1 as evaluated by BICR. Tumor assessments with imaging were performed every 8 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 0 (43%) or 1 (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 a median of 1 prior systemic regimen and 17% (n = 9) received 3 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%). A total of 52 (96%) patients had an NTRK gene fusion detected by NGS and 2 (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.

Among 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, 4 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.

SPL UNCLASSIFIED SECTION

Efficacy in Pediatric Patients

The efficacy of ROZLYTREK was evaluated in pediatric patients with unresectable or metastatic solid tumors with a 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 1 dose of ROZLYTREK; measurable or evaluable disease at baseline; at least 6 months of follow-up; and no prior therapy with a 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 4 years (range: 2 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

SPL UNCLASSIFIED SECTION

Capsules

SPL UNCLASSIFIED SECTION

How Supplied

• 100 mg hard capsules: Size 2 yellow opaque, with "ENT 100" printed in blue ink; available in HDPE bottles of 30 capsules: NDC 50242-091-30
• 200 mg hard capsules: Size 0 orange opaque, with "ENT 200" printed in blue ink; available in HDPE bottles of 90 capsules: NDC 50242-094-90

STORAGE AND HANDLING SECTION

Storage:

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

Store ROZLYTREK capsules in the original container and keep the bottle tightly closed in order to protect from moisture.

Storage time should not exceed 2 hours (below 30°C (86°F)) if capsules are prepared as an oral suspension using drinking water or milk. Discard any unused suspension if not used within 2 hours of preparation.

SPL UNCLASSIFIED SECTION

Pellets

SPL UNCLASSIFIED SECTION

How Supplied

• ROZLYTREK oral pellets are supplied as brownish orange to grayish orange, round pellets, available in: 42-count carton (each packet contains 50 mg entrectinib): NDC 50242-623-42

STORAGE AND HANDLING SECTION

Storage:

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

Store ROZLYTREK oral pellets in the original container in order to protect from moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

SPL UNCLASSIFIED SECTION

Congestive Heart Failure

• 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)].

SPL UNCLASSIFIED SECTION

Central Nervous System Effects

• 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)].

SPL UNCLASSIFIED SECTION

Skeletal Fractures

• 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)].

SPL UNCLASSIFIED SECTION

Hepatotoxicity

• 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)].

SPL UNCLASSIFIED SECTION

Hyperuricemia

• Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5)].

SPL UNCLASSIFIED SECTION

QT Interval Prolongation

• 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)].

SPL UNCLASSIFIED SECTION

Vision Disorders

• Advise patients to inform their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)].

SPL UNCLASSIFIED SECTION

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a 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 5 weeks after the last dose.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.

SPL UNCLASSIFIED SECTION

Lactation

• Advise females not to breastfeed during treatment with ROZLYTREK and for 1 week after the last dose [see Use in Specific Populations (8.2)].

SPL UNCLASSIFIED SECTION

Drug Interactions

• 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)].

SPL UNCLASSIFIED SECTION

Administration

• Instruct patients and caregivers to read the Instructions for Use before the patient starts using ROZLYTREK, and each time the patient gets a 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 a 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 a portion of oral suspension prepared to receive the prescribed dosage. If not taken immediately after preparation, store no longer than 2 hours at room temperature below 30°C (86°F) [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 a 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 a dose to make up that dose unless the next dose is due within 12 hours.
• Instruct patients if they vomit immediately after taking a dose of ROZLYTREK to take a dose as soon as possible [Dosage and Administration (2.4)].

SPL UNCLASSIFIED SECTION

ROZLYTREK (entrectinib)

Distributed by:Genentech USA, Inc. A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

ROZLYTREK® is a registered trademark of Genentech, Inc.

©2024 Genentech, Inc. All rights reserved.

SPL PATIENT PACKAGE INSERT SECTION

INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USEROZLYTREK® [roz lye trek](entrectinib)capsules, for oral use

This Instructions for Use contains information on how to prepare and take or give ROZLYTREK capsules.

Read this Instructions for Use before giving ROZLYTREK capsules for the first time and each time you get a refill. There may be new information.

ROZLYTREK capsules can be swallowed whole or prepared as a suspension and taken or given by mouth or through a nasogastric tube (NG tube) or gastrostomy tube (G tube) feeding tube.

If you or your child cannot swallow capsules whole, ROZLYTREK capsules can be prepared as a suspension and taken or given by mouth or through a feeding tube. For doses of 3 mL or higher, a NG or G feeding tube size 8 French or larger should be used.

Your healthcare provider or pharmacist will show you how to prepare and take or give a dose of ROZLYTREK capsules prepared as a suspension.

Table 1 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 a smaller amount of suspension than you prepared to take or give the correct prescribed dose of ROZLYTREK.

Supplies needed to prepare and take or give ROZLYTREK as a suspension:

Distributed by:Genentech USA, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

ROZLYTREK® is a registered trademark of Genentech, Inc.

©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 a 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.

INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USEROZLYTREK® [roz lye trek](entrectinib)oral pellets

This Instructions for Use contains information on how to prepare and take or give ROZLYTREK oral pellets.

Read this Instructions for Use before giving ROZLYTREK oral pellets for the first time and each time you get a refill. There may be new information.

Sprinkle ROZLYTREK oral pellets on 1 or more spoonfuls of a soft food before taking or giving.

Do not use ROZLYTREK oral pellets to prepare a suspension.

Do not give or take ROZYLTREK oral pellets through a gastrostomy tube (G Tube) or nasogastric tube (NG Tube) because the pellets may clog the feeding tube.

Supplies needed to prepare and take or give ROZLYTREK oral pellets:

Distributed by:Genentech USA, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

ROZLYTREK® is a registered trademark of Genentech, Inc.

©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 should show you how to properly prepare and take or give a daily dose of ROZLYTREK oral pellets. Always take or give ROZLYTREK oral pellets exactly as your healthcare provider tells you.
• Do not take ROZLYTREK oral pellets or give it 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.