ROZLYTREK Hard capsule Ref.[10280] Active ingredients: Entrectinib

Source: FDA, National Drug Code (US) Revision Year: 2020

1. Indications and Usage

1.1 ROS1-Positive Non-Small Cell Lung Cancer

ROZLYTREK is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive.

1.2 NTRK Gene Fusion-Positive Solid Tumors

ROZLYTREK is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that:

have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
are metastatic or where surgical resection is likely to result in severe morbidity, and
have either progressed following treatment or have no satisfactory alternative therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

2. Dosage and Administration

2.1 Patient Selection

Select patients for the treatment of metastatic NSCLC with ROZLYTREK based on the presence of ROS1 rearrangement(s) in tumor specimens [see Clinical Studies (14.1)]. An FDA-approved test for detection of ROS1 rearrangement(s) in NSCLC for selecting patients for treatment with ROZLYTREK is not available.

Select patients for treatment of locally advanced or metastatic solid tumors with ROZLYTREK based on the presence of a NTRK gene fusion [see Clinical Studies (14.2)]. An FDA-approved test for the detection of NTRK gene fusion in solid tumors is not available.

2.2 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.

2.3 Recommended Dosage for NTRK Gene Fusion-Positive Solid Tumors

Adults

The recommended dosage of ROZLYTREK in adults is 600 mg orally once daily with or without food until disease progression or unacceptable toxicity.

Pediatric Patients 12 Years and Older (Adolescents)

The recommended dosage of ROZLYTREK is based on body surface area (BSA) as shown in Table 1 below. Take ROZLYTREK orally once daily with or without food until disease progression or unacceptable toxicity.

Table 1. Dosing in Pediatric Patients 12 Years and Older (Adolescents):

Body Surface Area (BSA)	Recommended Dosage (Orally once daily)
Greater than 1.50 m²	600 mg
1.11 to 1.50 m²	500 mg
0.91 to 1.10 m²	400 mg

2.4 Dosage Modifications for Adverse Reactions

The recommended dosage reductions for adverse reactions are provided in Table 2.

Table 2. Recommended Dose Reductions for ROZLYTREK Adverse Reactions:

Action	Adults and Pediatric Patients 12 Years and Older with BSA Greater than 1.50 m² (Orally once daily)	Pediatric Patients 12 Years and Older with BSA of 1.11 to 1.50 m² (Orally once daily)	Pediatric Patients 12 Years and Older with BSA of 0.91 to 1.10 m² (Orally once daily)
First dose reduction	400 mg	400 mg	300 mg
Second dose reduction*	200 mg	200 mg	200 mg

* For a subsequent modification, permanently discontinue ROZLYTREK in patients who are unable to tolerate ROZLYTREK after two dose reductions.

Table 3 describes dosage modifications for specific adverse reactions.

Table 3. Recommended Dosage Modifications for ROZLYTREK for Adverse Reactions:

Adverse Reaction	Severity*	Dosage Modification
Congestive Heart Failure [see Warnings and Precautions (5.1)]	Grade 2 or 3	• Withhold ROZLYTREK until recovered to less than or equal to Grade 1. • Resume at reduced dose.
	Grade 4	• Permanently discontinue ROZLYTREK.
Central Nervous System Effects [see Warnings and Precautions (5.2)]	Intolerable Grade 2	• Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. • Resume at same dose or reduced dose, as clinically appropriate.
	Grade 3	• Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. • Resume at reduced dose.
	Grade 4	• Permanently discontinue ROZLYTREK.
Hepatotoxicity [see Warnings and Precautions (5.4)]	Grade 3	• Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. • Resume at same dose if resolution occurs within 4 weeks. • Permanently discontinue if adverse reaction does not resolve within 4 weeks. • Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks.
	Grade 4	• Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. • Resume at reduced dose if resolution occurs within 4 weeks. • Permanently discontinue if adverse reaction does not resolve within 4 weeks. • Permanently discontinue for recurrent Grade 4 events.
	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).	• Permanently discontinue ROZLYTREK.
Hyperuricemia [see Warnings and Precautions (5.5)]	Symptomatic or Grade 4	• Initiate urate-lowering medication. • Withhold ROZLYTREK until improvement of signs or symptoms. • Resume ROZLYTREK at same or reduced dose.
QT Interval Prolongation [see Warnings and Precautions (5.6)]	QTc greater than 500 ms	• Withhold ROZLYTREK until QTc interval recovers to baseline. • Resume at same dose if factors that cause QT prolongation are identified and corrected. • Resume at reduced dose if other factors that cause QT prolongation are not identified.
	Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia	• Permanently discontinue ROZLYTREK.
Vision Disorders [see Warnings and Precautions (5.7)]	Grade 2 or above	• Withhold ROZLYTREK until improvement or stabilization. • Resume at same dose or reduced dose, as clinically appropriate.
Anemia or Neutropenia [see Adverse Reactions (6.1)]	Grade 3 or 4	• Withhold ROZLYTREK until recovery to less than or equal to Grade 2. • Resume at the same dose or reduced dose, as clinically appropriate.
Other Clinically Relevant Adverse Reactions	Grade 3 or 4	• Withhold ROZLYTREK until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline. • Resume at the same or reduced dose, if resolution occurs within 4 weeks. • Permanently discontinue if adverse reaction does not resolve within 4 weeks. • Permanently discontinue for recurrent Grade 4 events.

* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 .0.

2.5 Dosage Modifications for Drug Interactions

Moderate and Strong CYP3A Inhibitors

Adults and Pediatric Patients 12 Years and Older with BSA Greater than 1.50 m²:

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the ROZLYTREK dose as follows:

Moderate CYP3A Inhibitors: 200 mg orally once daily
Strong CYP3A Inhibitors: 100 mg orally 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)].

2.6 Administration

Swallow capsules whole. Do not open, crush, chew, or dissolve the contents of the capsule.

If a patient misses a dose, instruct patients to make up that dose unless the next dose is due within 12 hours.

If a patient vomits immediately after taking a dose, instruct patients to repeat that dose.

16.2. Storage and Handling

Store below 30°C (86°F).

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