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Larotrectinib

Class
Targeted therapy
Subclass
Tyrosine kinase inhibitors
Substance name
Larotrectinib
Brand names
Vitrakvi®
Common formulations
Capsule
Dosage and administration
Adults patients
Treatment of solid tumors in patients with NTRK gene fusion • Unresectable or metastatic
•
100 mg PO BID until disease progression or unacceptable toxicity
Taken with or without food. Withhold larotrectinib in case of grade 3 or 4 adverse reactions until resolution or improvement to baseline or grade 1. Resume at the next dosage modification (first occurrence: 75 mg BID; second occurrence: 50 mg BID; third occurrence: 100 mg once daily) if resolution occurs within 4 weeks. Discontinue permanently if an adverse reaction does not resolve within 4 weeks or if unable to tolerate 100 mg once daily.
Indications for use
Labeled indications
Adults
•
Treatment of solid tumors in patients with NTRK gene fusion (unresectable or metastatic)
Safety risks
Contraindications
Hypersensitivity to larotrectinib or its components
Concomitant use of strong CYP3A4 inducers
•
Double larotrectinib dose if co-administration of a strong or moderate CYP3A4 inducer cannot be avoided.
Concomitant use of strong CYP3A4 inhibitors
•
Reduce larotrectinib dose by 50% if co-administration of a strong CYP3A4 inhibitor cannot be avoided.
Warnings and precautions
Bone fracture
•
Maintain a high level of suspicion, as larotrectinib has been associated with an increased risk of skeletal fractures.
Decreased serum larotrectinib levels
•
Use caution in patients taking moderate CYP3A4 inducers. Double larotrectinib dose.
Dizziness, cognitive impairment, mood changes, sleeping disorder
•
Use caution in patients performing activities requiring mental alertness, such as driving or operating machinery. Withhold or permanently discontinue larotrectinib depending on the severity.
Hepatotoxicity
•
Maintain a high level of suspicion, as larotrectinib has been associated with an increased risk of hepatotoxicity, including drug-induced liver injury. Obtain LFTs before initiating larotrectinib and monitor every 2 weeks during the first 2 months of treatment, and monthly thereafter. Withhold larotrectinib in case of AST or ALT ≥ 5× ULN with TBIL ≤ 2× ULN until recovery to ≤ grade 1 or return to baseline. Discontinue permanently if a grade 4 AST or ALT elevation occurs after resuming larotrectinib or in case of AST or ALT > 3× ULN with TBIL > 2× ULN.
Specific populations
Renal impairment
CrCl 0-90 mL/min
•
Use acceptable. No dose adjustment required.
Renal replacement therapy
Any modality
•
Use acceptable. No dose adjustment required.
Hepatic impairment
Child-Pugh A (mild)
•
Use acceptable. No dose adjustment required.
Child-Pugh B (moderate)
•
Reduce dose by 50%. Monitor liver function tests.
Child-Pugh C (severe)
•
Reduce dose by 50%. Monitor liver function tests.
Pregnancy and breastfeeding
Pregnancy
All trimesters • Australia Category: D
•
Do not use. Evidence of fetal harm in humans. Advise women of reproductive age to use effective contraception during treatment with larotrectinib and for at least 1 week after the last dose.
Breastfeeding
Do not use during breastfeeding.
•
Advise females not to breastfeed for 1 week after the last dose.
Unknown amount excreted in breastmilk.
Unknown drug levels in breastfed infants.
Adverse reactions
Very common > 10%
•
Anemia, cognitive impairment, ↓ WBC count, ↓ blood lymphocyte count, ↓ blood neutrophil count, ↓ serum albumin, ↓ serum calcium, dehydration, ↑ serum TBIL, ↑ serum ALP, ↑ serum ALT, peripheral edema, skin rash, facial edema, abdominal pain, constipation, diarrhea, dizziness, vertigo, cough, fatigue, asthenia, dyspnea, fever, headache, loss of appetite, mood changes, musculoskeletal pain, nasal congestion, nausea, vomiting, ↑ serum AST, weight gain, urinary tract infections, upper respiratory tract infections
Common 1-10%
•
Agitation, irritability, bone fracture, pneumonia, anxiety, depression, insomnia, muscle weakness, somnolence
Interactions
Drug(s)
Check Interactions
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