entrectinib (Rx)

Brand and Other Names:Rozlytrek
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 100mg
  • 200mg

Non-small Cell Lung Cancer

Indicated for metastatic non-small cell lung cancer (NSCLC) in adults whose tumors are ROS1-positive

600 mg PO qDay

Continue until disease progression or unacceptable toxicity

Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors

Indicated for patients 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 progressed following treatment or have no satisfactory alternative therapy

600 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dosage modifications for adverse reactions

  • First dose reduction: 400 mg qDay
  • Second dose reduction: 200 mg qDay
  • Permanently discontinue if toxicities persist or recur following 2 dose reductions

Congestive heart failure

  • Grade 2 or 3: Withhold until recovered to Grade ≤1; resume at reduced dose
  • Grade 4: Permanently discontinue

Central nervous system effects

  • Intolerable Grade 2: Withhold until recovered to Grade ≤1; resume at reduced dose, as clinically appropriate
  • Grade 3: Withhold until recovered to Grade ≤1; resume at reduced dose
  • Grade 4: Permanently discontinue

Hepatoxicity

  • Grade 3
    • Withhold until recovered to Grade ≤1; resume at reduced dose;
    • If resolution occurs within 4 weeks, resume at same dose
    • If adverse reaction persists after 4 weeks, permanently discontinue
    • For recurrent Grade 3 events that resolve within 4 weeks, resume at a reduced dose
  • Grade 4
    • Withhold until recovered to Grade ≤1; resume at reduce dose;
    • If adverse reaction does not resolve within 4 weeks or Grade 4 events recurs, permanently discontinue
  • Elevated ALT or AST
    • ALT or AST >3x ULN with concurrent total bilirubin >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Hyperuricemia

  • Symptomatic or Grade 4: Initiate urate-lowering therapy; withhold until improvement of signs or symptoms; resume at same or reduced dose

QTc prolongation

  • QTc >500 ms
    • Withhold until QTc interval recovers to baseline
    • Resume at same dose if causes of QT prolongation are identified and corrected
    • Resume at reduced dose if other causes of QT prolongation are not identified
  • Life-threatening arrhythmia
    • Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia: Permanently discontinue

Vision disorders

  • Grade ≥2: Withhold until improvement or stabilization; resume at same dose or reduced dose, as clinically appropriate

Anemia or neutropenia

  • Grade 3 or 4: Withhold until recovery to Grade≤2; resume at same or reduced dose, as clinically appropriate

Other clinically relevant adverse reactions

  • Grade 3 or 4
    • Withhold until adverse reaction resolves to Grade 1 or baseline
    • Resume at same or reduced dose if resolved within 4 weeks
    • Permanently discontinue if adverse reaction does not resolve within 4 weeks or Grade 4 events recurs

Coadministration of moderate and strong CYP3A inhibitors

  • Avoid coadministration
  • If coadministration is unavoidable, reduce entrectinib dose as follows:
    • Moderate CYP3A Inhibitors: 200 mg PO qDay
    • Strong CYP3A Inhibitors: 100 mg PO qDay
    • After discontinuation of strong or moderate CYP3A inhibitor for 3-5 elimination half-lives, resume entrectinib dose taken prior to initiating the CYP3A inhibitor

Renal impairment

  • Mild-to-moderate (CrCl 30 to <90 mL/min): No dosage adjustment necessary
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Mild (total bilirubin ≤1.5x ULN): No dosage adjustment necessary
  • Moderate-to-severe (total bilirubin >1.5x ULN): Not studied

Dosing Considerations

Patient selection

  • Select patients for treatment based on the following:
    • NSCLC: Presence of ROS1 rearrangement
    • Locally advanced or metastatic solid tumors: Presence of a NTRK gene fusion
    • FDA-approved tests for detecting ROS1 rearrangement for NSCLC and NTRK gene fusion in solid tumors are not available

Dosage Forms & Strengths

capsule

  • 100mg
  • 200mg

Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors

Indicated for adult and pediatric patients (≥12 years) 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 progressed following treatment or have no satisfactory alternative therapy

<12 years: Safety and efficacy not established

≥12 years

  • Recommended dosage is based on body surface area (BSA)
    • 0.91-1.1 m2: 400 mg PO qDay
    • 1.11-1.5 m2: 500 mg PO qDay
    • >1.5 m2: 600 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dosage modifications of adverse reactions

  • BSA 0.91-1.1 m2
    • First dose reduction: 300 mg qDay
    • Second dose reduction: 200 mg qDay
  • BSA >1.11 m2
    • First dose reduction: 400 mg qDay
    • Second dose reduction: 200 mg qDay
  • If toxicities persist or recur following 2 dose reductions, permanently discontinue

Congestive heart failure

  • Grade 2 or 3: Withhold until recovered to Grade ≤1; resume at reduced dose
  • Grade 4: Permanently discontinue

Central nervous system effects

  • Intolerable Grade 2: Withhold until recovered to Grade ≤1; resume at reduced dose, as clinically appropriate
  • Grade 3: Withhold until recovered to Grade ≤1; resume at reduced dose
  • Grade 4: Permanently discontinue

Hepatoxicity

  • Grade 3
    • Withhold until recovered to Grade ≤1
    • If resolution occurs within 4 weeks, resume at same dose
    • If adverse reaction persists after 4 weeks, permanently discontinue
    • For recurrent Grade 3 events that resolve within 4 weeks, resume at reduced dose
  • Grade 4
    • Withhold until recovered to Grade ≤1If resolution occurs within 4 weeks, resume at reduced dose
    • If adverse reaction does not resolve within 4 weeks or Grade 4 events recurs, permanently discontinue
  • Elevated ALT or AST
    • ALT or AST >3x ULN with concurrent total bilirubin >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Hyperuricemia

  • Symptomatic or Grade 4: Initiate urate-lowering therapy; withhold until improvement of signs or symptoms; resume at same or reduced dose

QTc prolongation

  • QTc >500 ms
    • Withhold until QTc interval recovers to baseline
    • Resume at same dose if causes of QT prolongation are identified and corrected
    • Resume at reduced dose if other causes of QT prolongation are not identified
  • Life-threatening arrhythmia
    • Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia: Permanently discontinue

Vision disorders

  • Grade ≥2: Withhold until improvement or stabilization; resume at same dose or reduced dose, as clinically appropriate

Anemia or neutropenia

  • Grade 3 or 4: Withhold until recovery to Grade ≤2; resume at same or reduced dose, as clinically appropriate

Other clinically relevant adverse reactions

  • Grade 3 or 4
    • Withhold until adverse reaction resolves to Grade 1 or baseline
    • Resume at same or reduced dose if resolved within 4 weeks
    • Permanently discontinue if adverse reaction does not resolve within 4 weeks or Grade 4 events recurs

Coadministration of moderate and strong CYP3A inhibitors

  • Avoid coadministration
  • If coadministration is unavoidable, reduce entrectinib dose as follows:
    • Moderate CYP3A Inhibitors: 200 mg PO qDay
    • Strong CYP3A Inhibitors: 100 mg PO qDay
    • After discontinuation of strong or moderate CYP3A inhibitor for 3-5 elimination half-lives, resume entrectinib dose taken prior to initiating the CYP3A inhibitor

Renal impairment

  • Mild-to-moderate (CrCl 30 to <90 mL/min): No dosage adjustment necessary
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Mild (total bilirubin ≤1.5x ULN): No dosage adjustment necessary
  • Moderate-to-severe (total bilirubin >1.5x ULN): Not studied

Dosing Considerations

Patient selection

  • Select patients for treatment based on the following:
    • NSCLC: Presence of ROS1 rearrangement
    • Locally advanced or metastatic solid tumors: Presence of a NTRK gene fusion
    • FDA-approved tests for detecting ROS1 rearrangement for NSCLC and NTRK gene fusion in solid tumors are not available
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Interactions

Interaction Checker

and entrectinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Increased creatinine (73%)
            • Anemia (67%)
            • Hyperuricemia (52%)
            • Fatigue (48%)
            • Constipation (46%)
            • Dysgeusia (44%)
            • Increased AST (44%)
            • Edema (40%)
            • Lymphopenia (40%)
            • Increased ALT (38%)
            • Hyponatremia (35%)
            • Diarrhea (35%)
            • Dysesthesia (34%)
            • Nausea (34%)
            • Hypocalcemia (34%)
            • Hypophosphatemia (30%)
            • Dyspnea (30%)
            • Increased lipase (28%)
            • Hypoalbuminemia (28%)
            • Dizziness (28%)
            • Neutropenia (28%)
            • Myalgia (28%)
            • Cognitive impairment (27%)
            • Increased amylase (26%)
            • Hyperkalemia (25%)
            • Increased weight (25%)
            • Increased alkaline phosphatase (25%)
            • Cough (24%)
            • Vomiting (24%)
            • Pyrexia (21%)
            • Arthralgia (21%)
            • Vision disorders (21%)
            • Peripheral sensory neuropathy (18%)
            • Headache (18%)
            • Hypotension (18%)
            • Ataxia (17%)
            • Abdominal pain (16%)
            • Sleep (14%)
            • Urinary tract infection (13%)
            • Decreased appetite (13%)
            • Muscular weakness (12%)
            • Back pain (12%)
            • Extremity pain (11%)
            • Rash (11%)

            Grade 3 or 4

            • Lymphopenia (12%)

            1-10%

            All grades

            • Mood disorders (10%)
            • Dehydration (10%)
            • Lung infection (10%)
            • Anemia (9%)
            • Neutropenia (7%)
            • Pneumonia (3.9%)
            • Dyspnea (3.7%)
            • Pleural effusion (3.4%)
            • Sepsis (2.5%)
            • Pulmonary embolism (2.3%)
            • Respiratory failure (2%)
            • Pyrexia (2%)

            Grade 3 or 4

            • Increased lipase (10%)
            • Hyperuricemia (10%)
            • Hypophosphatemia (7%)
            • Increased weight (7%)
            • Dyspnea (6%)
            • Lung infection (5-6%)
            • Increased amylase (5.4%)
            • Fatigue/asthenia (5%)
            • Cognitive disorders (4.5%)
            • Hyperglycemia (3.8%)
            • Pulmonary embolism (3.4%)
            • Hypoxia (3.4%)
            • Pleural effusion (3.1%)
            • Hypoalbuminemia (2.9%)
            • Increased ALT (2.9%)
            • Hypotension (2.8%)
            • Increased AST (2.7%)
            • Syncope (2.5%)
            • Urinary tract infection (2.3-2.5%)
            • Increased creatinine (2.1%)
            • Diarrhea (2%)
            • Hypocalcemia (1.8%)
            • Dehydration (1.1%)
            • Myalgia (1.1%)
            • Back pain (1%)

            <1%

            Grade 3 or 4

            • Increased alkaline phosphatase (0.9%)
            • Hyponatremia (0.9%)
            • Rash (0.8%)
            • Vision disorders (0.8%)
            • Muscular weakness (0.8%)
            • Ataxia (0.8%)
            • Arthralgia (0.6%)
            • Mood disorders (0.6%)
            • Sleep disorders (0.6%)
            • Decreased appetite (0.3%)
            • Pain in extremity (0.3%)
            • Cough (0.3%)
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            Warnings

            Contraindications

            None

            Cautions

            Increase of fractures reported; promptly evaluate patients with signs or symptoms (eg, pain, changes in mobility, deformity) of fractures

            Increased liver transaminase reported; monitor liver tests every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated

            Hyperuricemia reported, as well as elevated uric acid levels; assess serum uric acid levels prior to initiation and periodically during treatment

            Vision disorders have occurred, including blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, and vitreous floaters

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

            QT prolongation

            • QT prolongation reported; patients with at least 1 post-baseline ECG assessment experienced prolonged QT interval of >60 ms after starting treatment
            • Assess QT interval and electrolytes at baseline and periodically during treatment
            • Adjust monitoring frequency based on risk factors such as congestive heart failure (CHF), electrolyte abnormalities, or concomitant medications known to prolong the QTc interval

            CNS adverse reactions

            • CNS adverse reactions reported, including cognitive impairment, mood disorders, dizziness, and sleep disturbances
            • Advise patients and caregivers of these risks
            • Instruct patients not to drive or operate hazardous machinery if experiencing CNS adverse reactions

            Congestive heart failure

            • CHF occurred in clinical trials
            • Among patients with CHF, median time to onset was 2 months
            • Myocarditis in the absence of CHF was also documented
            • Assess left ventricular ejection fraction before initiation in patients with symptoms or known risk factors for CHF
            • Monitor 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

            Drug interaction overview

            Entrectinib is a CYP3A4 substrate

            • Moderate and strong CYP3A inhibitors
              • Coadministration with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations, which could increase frequency or severity of adverse reactions
              • Avoid coadministration
              • If coadministration is unavoidable, reduce dose
              • Grapefruit products are CYP3A4 inhibitors; avoid these products during treatment
            • Moderate and strong CYP3A inducers
              • Coadministration with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations, which may reduce entrectinib efficacy
              • Avoid coadministration
            • Drugs that prolong QT interval
              • QTc interval prolongation can occur
              • Avoid coadministration with other products with a known potential to prolong QT interval
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            Pregnancy & Lactation

            Pregnancy

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

            No data available on use in pregnant women

            Verify pregnancy status of females of reproductive potential before initiating treatment

            Animal data

            • Administration of entrectinib to pregnant rats during organogenesis resulted in malformations at maternal exposures ~2.7 times the human exposure at the 600-mg dose
            • Advise pregnant women of the potential risk to a fetus

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 5 weeks following the final dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months following the final dose

            Lactation

            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

            Owing to the potential adverse reactions in breastfed children from entrectinib, advise a lactating woman to discontinue breastfeeding during treatment and for 7 days after the final dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            An inhibitor of tropomyosin receptor tyrosine kinases (TRKs) 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); also, inhibits JAK2 and TNK2

            Major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK

            Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation

            Absorption

            Steady-state achieved within 1 week for entrectinib and 2 weeks for M5

            Peak plasma time: 4-6 hr (entrectinib plasma level; 600-mg dose)

            Peak plasma concentration

            • Single dose: 2250 nM (entrectinib); 622 nM (M5)
            • Steady-state: 3130 nM (entrectinib); 1,250 nM (M5

            AUC

            • Single dose: 31,800 nM·hr (entrectinib); 10,200 nM·hr (M5)
            • Steady-state: 48,000 nM·hr (entrectinib); 24,000 nM·hr (M5)

            Distribution

            Protein bound: >99% (entrectinib and M5)

            Vd: 551 L (entrectinib); 81.1 L (M5)

            Metabolism

            Metabolized primarily by CYP3A4 (~76%); forms active metabolite M5 (formed by CYP3A4); 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

            Elimination

            Clearance: 19.6 L/hr (entrectinib); 52.4 L/hr (M5)

            Half-life: 20 hr (entrectinib); 40 hr (M5)

            Excretion: Feces (83% [36% as unchanged entrectinib; 22% as M5]) urine (3%)

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            Administration

            Oral Administration

            Take orally with or without food

            Swallow capsules whole; do not open, crush, chew, or dissolve contents of capsule

            Missed dose

            • If dose is missed, take missed dose unless the next dose is due within 12 hr
            • If patient vomits immediately after taking a dose, repeat that dose

            Storage

            Store <30ºC (86ºF)

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.