larotrectinib (Rx)

Brand and Other Names:Vitrakvi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 25mg
  • 100mg

oral solution

  • 20mg/mL

Solid Tumors

Indicated for treatment of 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 have no alternative treatments or have progressed following treatment

100 mg PO BID

Continue until disease progression or until unacceptable toxicity

Dosage Modifications

Dosage modifications for adverse reactions

  • Body Surface Area (BSA) ≥1 m²
    • First occurrence: 75 mg BID
    • Second occurrence: 50 mg BID
    • Third occurrence: 100 mg qDay

For Grade ≥3 adverse reactions

  • Withhold treatment until reaction resolves or improves to Grade ≤1
  • Resume at next dosage modification if resolved within 4 weeks
  • Permanently discontinue if does not resolve within 4 weeks

Coadministration with strong CYP3A4 inhibitors

  • Avoid use with strong CYP3A4 inhibitors
  • If coadministration cannot be avoided, reduce dose by 50%
  • Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inhibitor

Coadministration with strong CYP3A4 inducers

  • Avoid use with strong CYP3A4 inducers
  • If coadministration cannot be avoided, double larotrectinib dose
  • Once strong CYP3A4 inducer is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inducer

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate to severe (Child-Pugh B or C): Reduce starting dose by 50%

Renal impairment

  • Mild to severe: No dosage adjustment necessary

Dosing Considerations

Patient selection is based on presence of a NTRK gene fusion in tumor specimens; an FDA-approved test for detection of NTRK gene fusion is not currently available

Indication approved under accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

Dosage Forms & Strengths

capsule

  • 25mg
  • 100mg

oral solution

  • 20mg/mL

Solid Tumors

Indicated for treatment of patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no alternative treatments or have progressed following treatment

Body surface area (BSA) <1 m²: 100 mg/m² PO BID

BSA ≥1 m²: 100 mg PO BID

Continue until disease progression or until unacceptable toxicity

Dosage Modifications

Dosage modifications for adverse reactions

  • BSA <1 m²
    • First occurrence: 75 mg/m² BID
    • Second occurrence: 50 mg/m² BID
    • Third occurrence: 25 mg/m² BID
  • BSA ≥1 m²
    • First occurrence: 75 mg BID
    • Second occurrence: 50 mg BID
    • Third occurrence: 100 mg qDay

For Grade ≥3 adverse reactions

  • Withhold treatment until reaction resolves or improves to Grade ≤1
  • Resume at next dosage modification if resolved within 4 weeks
  • Permanently discontinue if does not resolve within 4 weeks

Coadministration with strong CYP3A4 inhibitors

  • Avoid use with strong CYP3A4 inhibitors
  • If coadministration cannot be avoided, reduce dose by 50%
  • Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inhibitor

Coadministration with strong CYP3A4 inducers

  • Avoid use with strong CYP3A4 inducers
  • If coadministration cannot be avoided, double larotrectinib dose
  • Once strong CYP3A4 inducer is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inducer

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate to severe (Child-Pugh B or C): Reduce starting dose by 50%

Renal impairment

  • Mild to severe: No dosage adjustment necessary

Dosing Considerations

Patient selection is based on presence of a NTRK gene fusion in tumor specimens; an FDA-approved test for detection of NTRK gene fusion is not currently available

Indication approved under accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

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Interactions

Interaction Checker

and larotrectinib

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            All grades of severity are listed unless indicated

            >10%

            Increased AST/ALT (45%)

            Anemia (42%)

            Fatigue (37%)

            Hypoalbuminemia (35%)

            Increased alkaline phosphatase (30%)

            Nausea (29%)

            Dizziness (28%)

            Vomiting (26%)

            Cough (26%)

            Constipation (23%)

            Neutropenia (23%)

            Diarrhea (22%)

            Pyrexia (18%)

            Dyspnea (18%)

            Peripheral edema (15%)

            Increased weight (15%)

            Headache (14%)

            Arthralgia (14%)

            Myalgia (14%)

            Muscular weakness (13%)

            Decreased appetite (13%)

            Abdominal pain (13%)

            Back pain (12%)

            Pain in extremity (12%)

            Hypertension (11%)

            1-10%

            Nasal congestion (10%)

            Fall (10%)

            Anemia, Grade 3 or 4 (10%)

            Neutropenia, Grade 3 or 4 (7%)

            Increased weight, Grade 3 or 4 (4%)

            Fatigue, Grade 3 or 4 (3%)

            Increased alkaline phosphatase, Grade 3 or 4 (3%)

            Increased AST/ALT, Grade 3 or 4 (45%)

            Diarrhea, Grade 3 or 4 (2%)

            Dyspnea, Grade 3 or 4 (2%)

            Decreased appetite, Grade 3 or 4 (2%)

            Hypertension, Grade 3 or 4 (2%)

            Hypoalbuminemia, Grade 3 or 4 (3%)

            Pyrexia, Grade 3 or 4 (1%)

            Nausea, Grade 3 or 4 (1%)

            Vomiting, Grade 3 or 4 (1%)

            Arthralgia, Grade 3 or 4 (1%)

            Myalgia, Grade 3 or 4 (1%)

            Back pain, Grade 3 or 4 (1%)

            Pain in extremity, Grade 3 or 4 (1%)

            Fall, Grade 3 or 4 (1%)

            Constipation, Grade 3 or 4 (1%)

            Dizziness, Grade 3 or 4 (1%)

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            Warnings

            Contraindications

            None

            Cautions

            Neurologic adverse reactions (any grade) occurred; majority of neurologic adverse reactions occurred within first 3 months of treatment; advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions

            Increased transaminases of any grade occurred; median time to onset of increased AST/ALT was 2 months; monitor liver tests every 2 weeks during first month of treatment, then monthly thereafter, and as clinically indicated

            Can cause fetal harm when administered to pregnant women (see Pregnancy)

            Drug interactions overview

            • Larotrectinib is a substrate of CYP3A4 (major); also a P-gp and BCRP substrate
            • Larotrectinib moderately inhibits CYP3A4
            • Strong CYP3A4 inhibitors
              • Coadministration with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations and potentially result in higher incidence of adverse reactions
              • Avoid use with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice; if coadministration of strong CYP3A4 inhibitors cannot be avoided, modify dose as recommended
            • Strong CYP3A4 inducers
              • Coadministration with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease efficacy
              • Avoid use with strong CYP3A4 inducers; if coadministration of strong CYP3A4 inducers cannot be avoided, modify dose as recommended
            • Sensitive CYP3A4 substrates
              • Coadministration with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase incidence and/or severity of adverse reactions
              • Avoid use with sensitive CYP3A4 substrates; if coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor for increased adverse reactions of these drugs
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            Pregnancy

            Pregnancy

            Based on literature reports, findings from animal studies, and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman

            There are no available data on use in pregnant women

            Verify pregnancy status in females of reproductive potential prior to initiation

            Animal data

            • Administration of larotrectinib to pregnant rats and rabbits during organogenesis resulted in malformations at maternal exposures were ~11- and 0.7-times (observed at 100 mg PO BID)

            Contraception

            • Females of reproductive potential: Advise to use of effective contraception during treatment and for at least 1 week after last dose
            • Males: Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose

            Infertility

            • Based on histopathological findings in reproductive tracts of female rats in a 1-month repeated-dose study, fertility may be reduced

            Lactation

            There are no data on presence of larotrectinib or its metabolites in human milk and its effects on the breastfed child or on milk production

            Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 1 week after 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

            Highly selective inhibitor of tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC

            TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3; chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines

            In tumor models, larotrectinib demonstrates antitumor activity in cells by activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK overexpression

            Absorption

            Steady-state reached within 3 days

            Peak plasma concentration: 788 ng/mL (capsule)

            Peak plasma concentration of oral solution was 36% higher in healthy subjects compared with capsules

            Peak plasma time: 1 hr (capsule)

            AUC: 4351 ng·hr/mL (capsule; similar with oral solution)

            Bioavailability: 34%

            Distribution

            Vd (steady-state): 48 L

            Protein bound: 70%

            Metabolism

            Metabolized predominantly by CYP3A4

            Elimination

            Half-life: 2.9 hr

            Clearance: 98 L/hr

            Excretion: Feces (58% [5% unchanged]); urine (39% [20% unchanged])

            Pharmacogenomics

            Selecting patients for treatment is based on the presence of a NTRK gene fusion in solid tumor specimens

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            Administration

            Oral Administration

            Capsules or oral solution may be used interchangeably

            Missed dose (within 6 hr of next scheduled dose): Do not make up a missed dose

            Vomit dose: Take next dose at scheduled time

            Capsules: Swallow whole with water; do not chew or crush

            Storage

            Capsules: Store at room temperature 20-25°C (68-77°F); temperature excursions permitted between 15-30°C (59-86°F)

            Oral solution: Refrigerate oral solution at 2-8°C (36-46°F); do not freeze; discard any oral solution remaining after 90 days of first opening bottle

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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.