Rozlytrek
(entrectinib)Rozlytrek Prescribing Information
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.
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.
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.
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)]
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.
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.
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.
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.
| Patient Population | Recommended Dosage of ROZLYTREK | Duration of Treatment |
|---|---|---|
| ||
| Adults Pediatric patients with BSA ≥ 1.51 m2: | 600 mg orally once daily | Until disease progression or unacceptable toxicity. |
| Pediatric patients > 6 months: | see Table 2 | |
| Pediatric patients > 1 month to ≤ 6 months: | 250 mg/m2 orally once daily * | |
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.
| Body Surface Area (BSA) * | Recommended Dosage Orally Once Daily |
|---|---|
| |
| ≤0.50 m2 | 300 mg/m2 † |
| 0.51 to 0.80 m2 | 200 mg |
| 0.81 to 1.10 m2 | 300 mg |
| 1.11 to 1.50 m2 | 400 mg |
| ≥ 1.51 m2 | 600 mg |
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.
| Starting Dose once daily | First dose reduction | Second dose reduction | |
|---|---|---|---|
| |||
| 250 mg/m2 or 300 mg/m2 | Reduce the once daily dose to two thirds of the starting dose * | Reduce the once daily dose to one third of the starting dose * | Permanently discontinue ROZLYTREK in patients who are unable to tolerate ROZLYTREK after two dose reductions. |
| 200 mg | 150 mg once daily | 100 mg once daily | |
| 300 mg | 200 mg once daily | 100 mg once daily | |
| 400 mg | 300 mg once daily | 200 mg once daily | |
| 600 mg | 400 mg once daily | 200 mg once daily | |
Table 4 provides the ROZLYTREK recommended dosage modifications for the management of adverse reactions.
| Adverse Reaction | Severity * | Dosage Modification |
|---|---|---|
| ||
| Congestive Heart Failure [see Warnings and Precautions (5.1)] | Grade 2 or 3 |
|
| Grade 4 |
| |
| Central Nervous System Effects [see Warnings and Precautions (5.2)] | Intolerable Grade 2 |
|
| Grade 3 |
| |
| Grade 4 |
| |
| Hepatotoxicity [see Warnings and Precautions (5.4)] | Grade 3 |
|
| Grade 4 |
| |
| ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis). |
| |
| Hyperuricemia [see Warnings and Precautions (5.5)] | Symptomatic or Grade 4 |
|
| QT Interval Prolongation [see Warnings and Precautions (5.6)] | QTc greater than 500 ms |
|
| Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia |
| |
| Vision Disorders [see Warnings and Precautions (5.7)] | Grade 2 or above |
|
| Anemia or Neutropenia [see Adverse Reactions (6.1)] | Grade 3 or 4 |
|
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 or 4 |
|
ROZLYTREK Dosage Modifications for Drug Interactions
Moderate and Strong CYP3A Inhibitors
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.
| Starting dose * | Moderate CYP3A inhibitor | Strong CYP3A inhibitor |
|---|---|---|
| ||
| 200 mg | 50 mg once daily | 50 mg on alternate days |
| 300 mg | 100 mg once daily | 50 mg once daily |
| 400 mg | 200 mg once daily | 50 mg once daily |
| 600 mg | 200 mg once daily | 100 mg once daily |
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)].
ROZLYTREK Preparation and Administration Instructions
ROZLYTREK Capsules
Swallow capsules whole. Do not crush or chew the capsules.
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.
| Dose of ROZLYTREK to be administered | Dose needed for suspension (using 100 mg or 200 mg capsules, as appropriate) | Volume of water or milk to be added | Volume of oral suspension to withdraw and administer |
|---|---|---|---|
| 20 mg | 100 mg | 5 mL | 1 mL |
| 30 mg | 100 mg | 5 mL | 1.5 mL |
| 40 mg | 100 mg | 5 mL | 2 mL |
| 50 mg | 100 mg | 5 mL | 2.5 mL |
| 60 mg | 100 mg | 5 mL | 3 mL |
| 70 mg | 100 mg | 5 mL | 3.5 mL |
| 80 mg | 100 mg | 5 mL | 4 mL |
| 90 mg | 100 mg | 5 mL | 4.5 mL |
| 100 mg | 100 mg | 5 mL | 5 mL |
| 110 mg | 200 mg | 10 mL | 5.5 mL |
| 120 mg | 200 mg | 10 mL | 6 mL |
| 130 mg | 200 mg | 10 mL | 6.5 mL |
| 140 mg | 200 mg | 10 mL | 7 mL |
| 150 mg | 200 mg | 10 mL | 7.5 mL |
| 200 mg | 200 mg | 10 mL | 10 mL |
| 300 mg | 300 mg | 15 mL | 15 mL |
| 400 mg | 400 mg | 20 mL | 20 mL |
| 600 mg | 600 mg | 30 mL | 30 mL |
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.
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.
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.
Capsules:
- 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.
Pellets:
- 50 mg: Supplied as brownish orange or grayish orange pellets in packets.
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.
Lactation
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.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK [see Use in Specific Populations (8.1)].
Contraception
ROZLYTREK can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
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)].
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)].
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.
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).
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.
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)].
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)].
None.
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)].
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)].
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.
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)].
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)].
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)].
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)].
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)].