larotrectinib

General

Genetic Implications: Genetic Implications

Pronunciation:
lar-oh-trek-ti-nib


Trade Name(s)

  • Vitrakvi

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

Genetic implication Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or are likely to result in severe morbidity with surgical resection, and have either progressed following treatment or have no satisfactory alternative therapy.

Action

Acts as an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes), which ultimately inhibits growth of cancer cell lines.

Therapeutic Effect(s):

Decreased spread of certain solid tumors.

Pharmacokinetics

Absorption: 34% absorbed following oral administration; absorption reduced with high-fat meals.

Distribution: Well distributed to tissues.

Metabolism and Excretion: Primarily metabolized in the liver by the CYP3A4 isoenzyme. 58% excreted in feces (5% as unchanged drug), 39% excreted in urine (20% as unchanged drug).

Half-life: 2.9 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown1 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • OB:   Pregnancy (may cause fetal harm)
  •  Lactation:  Lactation.

Use Cautiously in:

  • Moderate or severe hepatic impairment (↓ dose)
  • Rep:   Women of reproductive potential and men with female partners of reproductive potential.

Adverse Reactions/Side Effects

CV: hypertension, peripheral edema

EENT: nasal congestion

GI: abdominal pain, constipation, diarrhea, hypoalbuminemia, hepatotoxicity, ↑ liver enzymes, nausea, vomiting

GU: dehydration, ↓ fertility

Hemat: anemia, neutropenia

Metabolic: ↓ appetite, ↑ weight

MS: arthralgia, muscle weakness, myalgia

Neuro: dizziness, fatigue, falls, headache, delirium, dysarthria, gait disturbance, memory impairment, paresthesia, tremor

Resp: cough, dyspnea

Misc: fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Strong CYP3A4 inhibitors, including  itraconazole , may significantly ↑ levels; avoid concurrent use; if need to use strong CYP3A4 inhibitor, ↓ larotrectinib dose.
  •  Strong CYP3A4 inducers, including  rifampin , may significantly ↓ levels; avoid concurrent use; if need to use strong CYP3A4 inducer, double larotrectinib dose.
  • May ↑ levels of  CYP3A4 substrates ; avoid concurrent use with CYP3A4 substrates with a narrow therapeutic index.

Drug-Natural Products:

 St. John's wort  may significantly ↓ levels; avoid concurrent use.

Drug-Food:

Grapefruit juice may significantly ↑ levels; avoid concurrent use.

Route/Dosage

PO (Adults and Children with BSA ≥1 m2): 100 mg twice daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor– 50 mg twice daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inducer– 200 mg twice daily until disease progression or unacceptable toxicity.

PO (Children  with BSA <1 m2): 100 mg/m2  twice daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor– 50 mg/m2  twice daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inducer– 200 mg/m2  twice daily until disease progression or unacceptable toxicity.

Hepatic Impairment 
(Adults and Children with BSA ≥1 m2): Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment– 50 mg twice daily until disease progression or unacceptable toxicity.

Hepatic Impairment 
(Children with BSA <1 m2): Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment– 50 mg/m2  twice daily until disease progression or unacceptable toxicity.

Availability

Capsules: 25 mg, 100 mg

Oral solution: 20 mg/mL

Assessment

  • Assess for signs and symptoms of neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paresthesia, memory impairment, tremor) periodically during therapy. Usually occur during first 3 mo of therapy.

Lab Test Considerations:

Genetic implication Patient selection is based on presence of a NTRK gene fusion in tumor specimens. Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.

  • Verify negative pregnancy test before starting therapy.
  • Monitor ALT and AST every 2 wk during 1st mo of therapy, then monthly and as clinically indicated. Hold or permanently discontinue larotrectinib based on severity. If held, modify dose when resumed. May cause hypoalbuminemia and ↑ alkaline phosphatase.
  • May cause anemia and neutropenia.

Implementation

  • Dose modification schedule: For Grade 3 or 4 adverse reactions,  hold larotrectinib until improves to baseline or Grade 1. Resume at next lower dose if resolved within 4 wk. If no resolution within 4 wk, permanently discontinue.  First dose reduction:  75 mg PO twice daily.  Second reduction:  50 mg twice daily.  Third reduction:  100 mg once daily. If unable to tolerate after dose reductions, discontinue permanently.
  • PO Administer twice daily without regard to food.  DNC: Swallow capsules whole; do not open, break, or chew.  Oral solutions and capsule are interchangeable. Store oral solution in refrigerator; do not freeze. Discard unused solution 90 days after opening bottle.

Patient/Family Teaching

  • Instruct patient to take larotrectinib as directed. If vomiting occurs after dose, omit dose and take next dose at scheduled time. Take missed doses as soon as remembered up to 6 hr before next dose. Do not change dose or stop taking larotrectinib without consulting health care professional. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Advise patient to avoid grapefruit juice during therapy.
  • Caution patient that larotrectinib may cause dizziness. Advise patient to avoid driving or other activities requiring alertness until response to drug is known.
  • Advise patient to notify health care professional if signs and symptoms of new or worsening neurotoxicity (confusion; difficulty speaking; dizziness; coordination problems; tingling, numbness, or burning sensation in hands and feet) or liver problems (loss of appetite, nausea or vomiting, pain on upper right side of stomach) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's Wort.
  • Rep:  May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception and to avoid breastfeeding during and for 1 wk after last dose. May impair female fertility.
  • Emphasize importance of regular lab tests to monitor for side effects.

Evaluation/Desired Outcomes

Decreased tumor spread.

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