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Larotrectinib

Medically reviewed by Drugs.com. Last updated on Aug 13, 2019.

Pronunciation

(LAR oh TREK ti nib)

Index Terms

  • Larotrectinib Sulfate
  • LOXO-101
  • TRK Inhibitor LOXO-101

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as sulfate:

Vitrakvi: 25 mg, 100 mg

Solution, Oral, as sulfate:

Vitrakvi: 20 mg/mL (100 mL) [contains methylparaben, propylene glycol]

Brand Names: U.S.

  • Vitrakvi

Pharmacologic Category

  • Antineoplastic Agent, Tropomyosin Receptor Kinase (TRK) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Larotrectinib is a potent and highly selective small-molecule inhibitor of the 3 tropomyosin receptor kinase (TRK) proteins, TRKA, TRKB, and TRKC (Drilon 2018). TRKA, TRKB, and TRKC are encoded by neurotrophic receptor tyrosine kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving fusions of NTRK genes may result in constitutively-activated chimeric TRK fusion proteins, acting as an oncogenic driver to promote cell proliferation and survival in tumor cell lines. Larotrectinib has anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.

Distribution

48 L

Metabolism

Hepatic; primarily via CYP3A4; forms an O-linked glucuronide metabolite

Excretion

Feces (58%; 5% unchanged); Urine (39%; 20% unchanged)

Time to Peak

~1 hour

Half-Life Elimination

2.9 hours

Protein Binding

70%; to plasma proteins

Special Populations: Renal Function Impairment

Following oral administration of a single 100 mg larotrectinib dose in subjects with end-stage renal disease (requiring dialysis), the larotrectinib AUC0-∞ increased 1.5-fold and Cmax increased 1.3-fold, compared to subjects with normal renal function (CrCl ≥90 mL/minute [estimated by Cockcroft-Gault]).

Special Populations: Hepatic Function Impairment

Larotrectinib clearance is reduced in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C). Following oral administration of a single 100 mg larotrectinib dose, the larotrectinib AUC0-∞ increased 1.3-fold in subjects with mild impairment (Child-Pugh class A), 2-fold in subjects with moderate impairment (Child-Pugh class B), and 3.2-fold in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function. The larotrectinib Cmax increased 1.5-fold in subjects with severe impairment, compared to subjects with normal hepatic function.

Use: Labeled Indications

Solid tumors: Treatment of solid tumors (in adult and pediatric patients) that have a neurotrophic receptor tyrosine 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 satisfactory alternative treatments or that have progressed following treatment.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Solid tumors (with neurotrophic receptor tyrosine kinase [NTRK] gene fusion): Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Drilon 2018).

Dosage adjustment for CYP3A inhibitors/inducers:

Strong CYP3A4 inhibitors: Avoid concomitant use of larotrectinib with strong CYP3A4 inhibitors. If concomitant use cannot be avoided, reduce the larotrectinib dose by 50%. When the strong CYP3A4 inhibitor is discontinued, increase the larotrectinib dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor have elapsed) to the dose that was used prior to initiation of the CYP3A4 inhibitor.

Strong CYP3A4 inducers: Avoid concomitant use of larotrectinib with strong CYP3A4 inducers. If concomitant use cannot be avoided, double the larotrectinib dose. When the strong CYP3A4 inducer has been discontinued, reduce the larotrectinib dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inducer) to the dose that was used prior to initiating the CYP3A4 inducer.

Missed doses: Do not make up the missed dose within 6 hours of the next scheduled dose. If vomiting occurs, take the next dose at the scheduled time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Capsule and oral solution may be used interchangeably.

Solid tumor (unresectable or metastatic) with presence of neurotrophic receptor tyrosine kinase (NTRK) gene fusion: Infants, Children, and Adolescents: Oral:

BSA <1 m2: 100 mg/m2/dose twice daily; continue until disease progression or unacceptable toxicity

BSA ≥1 m2: 100 mg twice daily; continue until disease progression or unacceptable toxicity

Dosing adjustment for toxicity:

Grade 3 or 4 adverse reactions: Withhold treatment until adverse reaction resolves or improves to baseline or grade 1. Resume with appropriate dosage modification if resolutions occurs within 4 weeks. Permanently discontinue if not resolved within 4 weeks or if unable to tolerate after 3 dose modifications.

Dose modification:

First modification:

BSA <1 m2: 75 mg/m2/dose twice daily

BSA ≥1 m2: 75 mg twice daily

Second modification:

BSA <1 m2: 50 mg/m2/dose twice daily

BSA ≥1 m2: 50 mg twice daily

Third modification:

BSA <1 m2: 25 mg/m2/dose twice daily

BSA ≥1 m2: 100 mg once daily

Dosing adjustment for concomitant therapy:

Coadministration with strong CYP3A4 inhibitors: Avoid coadministration with strong CYP3A4 inhibitors. If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the larotrectinib dose by 50%. When the strong CYP3A4 inhibitor is discontinued, increase the larotrectinib dose (after 3 to 5 elimination half-lives of the CYP3A4 inhibitor have elapsed) to the larotrectinib dose that was used prior to initiation of the CYP3A4 inhibitor.

Coadministration with strong CYP3A4 inducers: Avoid coadministration with strong CYP3A4 inducers. If coadministration with a strong CYP3A4 inducer cannot be avoided, double the larotrectinib dose. When the strong CYP3A4 inducer is discontinued, decrease the larotrectinib dose (after 3 to 5 elimination half-lives of the CYP3A4 inducer have elapsed) to the larotrectinib dose that was used prior to initiation of the CYP3A4 inducer.

Dosing: Adjustment for Toxicity

Recommended dosage reduction levels:

Usual initial dose: 100 mg twice daily (100 mg/m2 twice daily if BSA is <1 m2).

First dose reduction level: 75 mg twice daily (75 mg/m2 twice daily if BSA is <1 m2).

Second dose reduction level: 50 mg twice daily (50 mg/m2 twice daily if BSA is <1 m2).

Third dose reduction level: 100 mg once daily (25 mg/m2 twice daily if BSA is <1 m2).

Discontinue permanently if unable to tolerate larotrectinib after 3 dose reductions.

Grade 3 or 4 adverse reactions: Withhold larotrectinib until adverse reaction resolves to baseline or grade 1; if resolution occurs within 4 weeks, resume at the next lower dosage level. Discontinue permanently if the adverse reaction does not resolve within 4 weeks.

Administration

Oral: Administer with or without food. Swallow capsules whole with water; do not chew or crush capsules. Use caution when measuring the oral solution; an oral syringe should be used to assure the proper dose is administered. The capsules or oral solution may be used interchangeably.

Dietary Considerations

Avoid grapefruit or grapefruit juice during therapy.

Storage

Capsules: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F).

Solution: Store at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard unused portion of oral solution 90 days after initial opening of the bottle.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer half-life. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor half-life. Consider therapy modification

CYP3A4 Substrates (High risk with Inhibitors): Larotrectinib may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Larotrectinib. Management: Avoid use of grapefruit juice with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Following discontinuation of grapefruit juice, resume the previous dose of larotrectinib. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Larotrectinib. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (15%), hypertension (11%)

Central nervous system: Neurotoxicity (53%), fatigue (37%), dizziness (28%), headache (14%), myasthenia (13%)

Endocrine & metabolic: Hypoalbuminemia (35%), weight gain (15%)

Gastrointestinal: Nausea (29%), vomiting (26%), constipation (23%), diarrhea (22%), abdominal pain (13%), decreased appetite (13%)

Hematologic & oncologic: Anemia (42%; grades 3/4: 10%), neutropenia (23%; grades 3/4: 7%)

Hepatic: Increased serum alanine aminotransferase (45%), increased serum aspartate aminotransferase (45%), increased serum alkaline phosphatase (30%)

Neuromuscular & skeletal: Arthralgia (14%), myalgia (14%), back pain (12%), limb pain (12%)

Respiratory: Cough (26%), dyspnea (18%)

Miscellaneous: Fever (18%)

1% to 10%:

Central nervous system: Falling (10%), delirium (grade 3: 2%), abnormal gait (grade 3: 1%), dysarthria (grade 3: 1%), paresthesia (grade 3: 1%)

Respiratory: Nasal congestion (10%)

Frequency not defined:

Cardiovascular: Pericardial effusion, syncope

Central nervous system: Cerebral edema, memory impairment

Dermatologic: Cellulitis, enterocutaneous fistula

Endocrine & metabolic: Dehydration, hyponatremia, increased amylase, increased serum lipase

Gastrointestinal: Intestinal obstruction (small intestine), intestinal perforation

Hematologic & oncologic: Acute myelocytic leukemia

Hepatic: Jaundice

Infection: Sepsis

Neuromuscular & skeletal: Asthenia, tremor

Respiratory: Pleural effusion

<1%, postmarketing, and/or case reports: Encephalopathy

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia and neutropenia have been observed (usually grades 1 or 2).

• Gastrointestinal toxicity: Nausea, vomiting, constipation, and diarrhea may occur (usually mild).

• Hepatotoxicity: Transaminase increase (of any grade) commonly occurred with larotrectinib; grade 3 AST or ALT elevations were reported; grade 4 ALT elevations occurred rarely. The median time to onset of AST and ALT elevation was 2 months (range: 1 month to 2.6 years for AST elevation and 1 month to 1.1 years for ALT elevation). AST and ALT elevations leading to dose modifications and/or permanent discontinuation have occurred. Monitor liver functions tests (including ALT and AST) every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. May require treatment interruption, dosage reduction, and/or permanent discontinuation (based on the severity). Reduced initial doses are recommended in patients with preexisting moderate to severe hepatic impairment.

• Neurotoxicity: Neurologic adverse reactions (of any grade) commonly occurred with larotrectinib, including grade 3 and 4 neurotoxicity. Most neurologic adverse reactions occurred within the first 3 months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium, dysarthria, dizziness, gait disturbance, and paresthesia; grade 4 encephalopathy was reported (rare). Neurologic adverse reactions leading to dose modification included dizziness, gait disturbance, delirium, memory impairment, and tremor. Advise patients and caregivers of the potential for neurotoxicity. Patients experiencing neurotoxicity should not perform tasks requiring mental alertness (eg, driving or operating heavy machinery) if they are experiencing neurologic adverse reactions. May require treatment interruption, dosage reduction, and/or permanent discontinuation (based on the severity).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use: Select patients for treatment based on the presence of a neurotrophic receptor tyrosine kinase (NTRK) gene fusion in tumor specimen(s).

Monitoring Parameters

Assess neurotrophic receptor tyrosine kinase (NTRK) gene fusion status in tumor specimen (prior to treatment initiation). Monitor liver functions tests (including ALT and AST) every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated; pregnancy test (prior to treatment in females of reproductive potential). Monitor for signs/symptoms of neurotoxicity. Monitor adherence.

Pregnancy Considerations

Based the mechanism of action and available human and animal data, larotrectinib may cause fetal harm if administered to a pregnant female.

Larotrectinib interferes with TRK signaling; obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis have been observed in persons with congenital mutations in TRK pathway proteins.

Pregnancy status should be evaluated prior to therapy; females of reproductive potential should use effective contraception during therapy and for at least 1 week after the final larotrectinib dose. Males with female partners of reproductive potential should also use effective contraception during therapy and for 1 week after the final larotrectinib dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, diarrhea, cough, rhinitis, weight gain, muscle pain, joint pain, muscle weakness, back pain, painful extremities, or lack of appetite. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), severe headache, dizziness, passing out, vision changes, confusion, difficulty speaking, change in balance, burning or numbness feeling, memory impairment, tremors, severe loss of strength and energy, swelling of arms or legs, shortness of breath, falls, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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