Drug Interaction Studies

Clinical Studies Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with a single 100 mg ROZLYTREK dose increased entrectinib AUC0-INF by 6-fold and Cmax by 1.7-fold 

Coadministration of a moderate CYP3A inhibitor with ROZLYTREK is predicted to increase entrectinib AUC0-Tau by 3-fold and Cmax by 2.9-fold.

Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with a single 600 mg ROZLYTREK dose reduced entrectinib AUC0-INF by 77% and Cmax by 56% 

Coadministration of a moderate CYP3A inducer with ROZLYTREK is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.

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

Effect of Entrectinib on CYP Substrates: Coadministration of ROZLYTREK 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21% 

Effect of Entrectinib on Transporters: Coadministration of a single 600 mg ROZLYTREK dose with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin Cmax by 28% and AUC by 18%.

 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.

CI-   • Congestive Heart Failure: Assess left ventricular ejection fraction prior to initiation  in patients with symptoms or known risk factors for CHF.

 ADVERSE REACTIONS

­ 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. 

• Hepatotoxicity: Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on severity. If withheld, resume ROZLYTREK at same or reduced dose based on severity. 

• Hyperuricemia: Assess serum uric acid levels prior to initiation and periodically during treatment with ROZLYTREK. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with uratelowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume at same or reduced dose upon improvement based on severity. 

• QT Interval Prolongation: Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity. 

• Vision Disorders: Withhold for new visual changes or changes that interfere with activities of daily living until improvement or stabilization. Conduct an ophthalmological evaluation as appropriate. Resume at same or reduced dose upon improvement or stabilization. 

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 

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 

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.

Hepatotoxicity • Advise patients that they will need to undergo laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity

Hyperuricemia • Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia

 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

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

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 

Use in Specific Populations. • Advise females of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks after the final dose.    

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

Lactation • Advise females not to breastfeed during treatment with ROZLYTREK and for 1 week after the final dose 

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 

Administration

• Advise patients to swallow ROZLYTREK capsules whole.

• 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 

Distributed by: Genentech USA, Inc. A Member of the Roche Group ROZLYTREKTM is a trademark of 1 DNA Way Genentech, Inc. South San Francisco, CA 94080-4990 ©2019 Genentech, Inc. All rights reserved. Reference ID: 4477931

 CLINICAL PHARMACOLOGY

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.

2. Pharmacodynamics Entrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.

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 postbaseline ECG assessment, experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTc interval > 500 ms 

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 timedependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of ROZLYTREK.

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. 

 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.

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.

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.

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%).

Specific Populations

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age (12 years to 86 years), sex, race (White, Asian and Black), body weight (32 to 130 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min) and mild hepatic impairment (total bilirubin = 1.5 times ULN).

The impact of moderate to severe hepatic impairment or severe renal impairment on the pharmacokinetics of entrectinib is unknown.

Pediatric Patients The predicted systemic exposures for body surface area-based doses of 600 mg (BSA > 1.50 m2 ), 500 mg (BSA of 1.11 to 1.50 m2 ) and 400 mg (BSA of 0.91 to 1.10 m2 ) in pediatric patients 12 years and older are comparable to the exposure in adults at the 600 mg dose 

USE IN SPECIFIC POPULATIONS 

1. Pregnancy Risk Summary

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action ROZLYTREK can cause fetal harm when administered to a pregnant woman

 There are no available data on ROZLYTREK use in pregnant women.

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.

2. 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 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.

3. Females and Males of Reproductive Potential

Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK 

Contraception ROZLYTREK can cause embryo-fetal harm when administered to a pregnant woman.

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for at least 5 weeks following the final dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months following the final dose 

4. Pediatric Use

The safety and effectiveness of ROZLYTREK in pediatric patients aged 12 years and older with solid tumors that have an NTRK gene fusion have been established.

There is limited clinical experience with ROZLYTREK in pediatric patients. The safety of ROZLYTREK in pediatric patients 12 years of age and older was established based on extrapolation of data in adults and data from 30 pediatric patients enrolled in STARTRK-NG. 

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.

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) 

7. Hepatic Impairment

No dose adjustment is recommended for patients with mild (total bilirubin = 1.5 times ULN) hepatic impairment. ROZLYTREK has not been studied in patients with moderate (total bilirubin > 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment