Rozlytrek^®

entrectinib

Indications & Important Safety Information

INDICATIONS

ROS1‑Positive Non-Small Cell Lung Cancer

ROZLYTREK^® (entrectinib) 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.

NTRK Gene Fusion‑Positive Solid Tumors

ROZLYTREK^® (entrectinib) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

WARNINGS and PRECAUTIONS

Congestive Heart Failure

• Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 12 patients (3.4%), including Grade 3 (2.3%). The median time to onset was 2 months (range: 11 days to 12 months). Of these 12 patients, ROZLYTREK was interrupted in 6 (50%) and discontinued in 2 (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

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. Of 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. 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 355 patients. In 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
• 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 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

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. 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 patients
• In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (eg, 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 (eg, 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

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. Median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). 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% of 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

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 initiating 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

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
• 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 at baseline 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

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%). 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

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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the final dose

Most Common Adverse Reactions

• The most common adverse reactions (≥20%) were fatigue (48%), constipation (46%), dysgeusia (44%), edema (40%), dizziness (38%), diarrhea (35%), nausea (34%), dysesthesia (34%), dyspnea (30%), myalgia (28%), cognitive impairment (27%), increased weight (25%), cough (24%), vomiting (24%), pyrexia (21%), arthralgia (21%), and vision disorders (21%)

DRUG INTERACTIONS

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, which could increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors. If coadministration is unavoidable, reduce the ROZLYTREK dose.
• Pediatric Patients less than 2 Years.
  Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors
• 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, which may reduce ROZLYTREK efficacy. Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK

Drugs That Prolong QT Interval

• QTc interval prolongation can occur with ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval

ADDITIONAL IMPORTANT SAFETY INFORMATION

Lactation
Risk Summary

• Because of the potential adverse reactions in breastfed children from ROZLYTREK, advise a lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for 7 days after the final dose

Pediatric Use

• The safety and effectiveness of ROZLYTREK have been established in pediatric patients older than 1 month of age. 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

Hepatic Impairment

• Monitor for ROZLYTREK adverse reactions more frequently since these patients may be at increased risk

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see additional Important Safety Information in the full ROZLYTREK Prescribing Information.