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Larotrectinib

Medically reviewed by Drugs.com. Last updated on Sep 27, 2020.

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 concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 Larotrectinib. 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's half-life. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Larotrectinib. 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's 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

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

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

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

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 Inhibitors: May increase the serum concentration of Larotrectinib. Exceptions: Carvedilol; Dronedarone; Erythromycin (Systemic); Itraconazole; Ketoconazole (Systemic); Ombitasvir, Paritaprevir, and Ritonavir; Ritonavir; Verapamil. Monitor therapy

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

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

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification

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).

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.

Reproductive Considerations

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.

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.

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

• Constipation

• Diarrhea

• Abdominal pain

• Cough

• Stuffy nose

• Weight gain

• Muscle pain

• Joint pain

• Muscle weakness

• Back pain

• Painful extremities

• Lack of appetite

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Severe headache

• Dizziness

• Passing out

• Vision changes

• Confusion

• Trouble speaking

• Change in balance

• Burning or numbness feeling

• Trouble with memory

• Tremors

• Severe loss of strength and energy

• Swelling of arms or legs

• Shortness of breath

• Falls

• Infection

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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

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