Rozlytrek

ROZLYTREK is a kinase inhibitor indicated for the treatment of:

• Adult patients with
  ROS1-
  positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. (
  1.1

  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.
  )
• 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. (

• Select patients for treatment based on the presence of
  ROS1
  rearrangement(s) or
  NTRK
  gene fusion. (
  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.
  )
• Evaluate left ventricular ejection fraction, serum uric acid levels and QT interval and electrolytes prior to ROZLYTREK initiation. (
  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)]
  )
• Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. (
  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.

  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.
  )
• Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. (
  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.

  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.
  )
• Administer ROZLYTREK capsules, capsules prepared as a suspension, or pellets once daily, with or without food. (
  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.
  )
• Adult Dosage for
  ROS1-
  Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. (
  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.
  )
• Adult and Pediatric Dosage for
  NTRK
  Gene Fusion-Positive Solid Tumors:
  • Adults: 600 mg orally once daily. (
    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.

    Table 1. Recommended dosage for Adults and Pediatric patients for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

    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/m2orally once daily To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)].

    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.

    Table 2. Recommended dosage for Pediatric Patients Older than 6 Months for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

    Body Surface Area (BSA) BSA categories and recommended dosage above are based on closely matching exposures to a target dose of 300 mg/m2	Recommended Dosage Orally Once Daily
    ≤0.50 m2	300 mg/m2 To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)].
    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
    )
  • Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (
    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.

    Table 1. Recommended dosage for Adults and Pediatric patients for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

    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/m2orally once daily To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)].

    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.

    Table 2. Recommended dosage for Pediatric Patients Older than 6 Months for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

    Body Surface Area (BSA) BSA categories and recommended dosage above are based on closely matching exposures to a target dose of 300 mg/m2	Recommended Dosage Orally Once Daily
    ≤0.50 m2	300 mg/m2 To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9)].
    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
    )

  Age	Recommended Daily Dosage
  >6 months	≤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 BSA ≥1.51 m2: 600 mg once daily
  >1 month to ≤6 months	250 mg/m2 once daily

• Modify dosage of ROZLYTREK if coadministration with moderate or strong CYP3A inhibitors cannot be avoided. (
  2.8 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 5and limit coadministration to 14 days or less.

  Table 5. Recommended Dose Modifications of ROZYLTREK for Concomitant Use with Moderate or Strong CYP3A Inhibitors for Adults and Pediatric Patients 2 Years and Older

  Starting dose For pediatric patients with a starting dose less than 200 mg, avoid coadministration with moderate or strong CYP3A inhibitors	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)].
  )
• See preparation and administration instructions. (
  2.9 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 6provides 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.

  Table 6. Preparation of ROZLYTREK Capsules as an Oral Suspension

  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.

• Lactation
  : Advise not to breastfeed. (
  8.2 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 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.
  )