Dosing & Uses
Dosage Forms & Strengths
capsule
- 25mg
- 100mg
oral solution
- 20mg/mL
Solid Tumors
Indicated for adults and pediatric 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
- Unable to tolerate 100 mg qDay: Permanently discontinue
Grade ≥3 adverse reactions
- Withhold until reaction resolves or improves to baseline or Grade ≤1
- Resolved within 4 weeks: Resume at next dosage modification
- Unresolved within 4 weeks: Permanently discontinue
Strong CYP3A4 inhibitors
- Avoid coadministration
- If unavoidable, reduce larotrectinib dose by 50%
- Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken before initiating CYP3A4 inhibitor
Strong CYP3A4 inducers
- Avoid coadministration
- If unavoidable, 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
Verify pregnancy status in females of reproductive potential before initiation
Patient selection
- Select patients based on presence of a NTRK gene fusion in tumor specimens
- Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics
Dosage Forms & Strengths
capsule
- 25mg
- 100mg
oral solution
- 20mg/mL
Solid Tumors
ndicated for adults and pediatric 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
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: Not to exceed 25 mg/m2 BID; remain on 25 mg/m2 BID even if BSA becomes >1 m2 during treatment
- Unable to tolerate 25 mg/m2 BID: Permanently discontinue
BSA ≥1 m2
- First occurrence: 75 mg BID
- Second occurrence: 50 mg BID
- Third occurrence: 100 mg qDay
- Unable to tolerate 100 mg qDay: Permanently discontinue
Grade ≥3 adverse reactions
- Withhold until reaction resolves or improves to baseline or Grade ≤1
- Resolved within 4 weeks: Resume at next dosage modificatio
- Unresolved within 4 weeks: Permanently discontinue
Strong CYP3A4 inhibitors
- Avoid coadministration
- If unavoidable, reduce larotrectinib dose by 50%
- Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken before initiating CYP3A4 inhibitor
Strong CYP3A4 inducers
- Avoid coadministration
- If unavoidable, double larotrectinib dose
- Once strong CYP3A4 inducer is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken before 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
Verify pregnancy status in females of reproductive potential before initiation
Patient selection
- Select patients based on presence of a NTRK gene fusion in tumor specimens
- Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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%)
Warnings
Contraindications
None
Cautions
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
Skeletal fractures reported; promptly evaluate patients with signs or symptoms of potential fracture (eg, pain, changes in mobility, deformity); no data are available on effects on healing of known fractures or risk of future fractures
CNS effects
- CNS adverse reactions (eg, dizziness, cognitive impairment, mood disorders, sleep disturbances)
- Cognitive impairment included memory impairment, confused state, disturbance in attention, delirium, and cognitive disorders; median onset time: 5.6 months (range: 2 days to 41 months)
- Mood disorders included anxiety, depression, agitation, and irritability; median onset time: 3.9 months (range: 1 day to 40.5 months)
- Consult on the risks; advise patients not to drive or operate hazardous machinery if experiencing neurologic adverse reactions
- Withhold or permanently discontinue based on severity
- If withheld, modify dosage when resumed
Drug interaction overview
- Major CYP3A4 substrate; also a P-gp and BCRP substrate
- Moderately inhibits CYP3A4
-
Strong CYP3A4 inhibitors
- Avoid coadministration, including grapefruit or grapefruit juice
- Strong CYP3A4 inhibitors may increase larotrectinib plasma concentrations and potentially result in higher incidence of adverse reactions
- If unavoidable, modify dose as recommended
-
Strong CYP3A4 inducers
- Avoid coadministration
- Strong CYP3A4 inducers may decrease larotrectinib plasma concentrations, which may decrease efficacy
- If unavoidable, modify dose as recommended
-
Sensitive CYP3A4 substrates
- Avoid coadministration
- Larotrectinib may increase plasma concentrations of sensitive CYP3A4 substrates, which may increase incidence and/or severity of adverse reactions
- If unavoidable, monitor for increased adverse reactions of drugs that are sensitive CYP3A4 substrates
Pregnancy
Pregnancy
Based on literature reports, findings from animal studies, and its mechanism of action, embryofetal harm may occur when administered to pregnant females
There are no available data on use in pregnant females
Verify pregnancy status in females of reproductive potential before initiation
Animal data
- Administration 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: Use effective contraception during treatment and for at least 1 week after last dose
- Males with female partners of reproductive potential: 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 breastfed children or on milk production
Advise females 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.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
Administration
Oral Administration
Take with or without food
Swallow capsules whole with water; do not chew or crush
Capsules or oral solution may be used interchangeably
Missed dose (within 6 hr of next scheduled dose): Do not make up missed dose
Vomit dose: Take next dose at scheduled time
Storage
Capsules: Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30°C (59-86°F)
Oral solution: Refrigerate at 2-8°C (36-46°F); do not freeze; discard any oral solution remaining after 90 days of first opening bottle
Images
Patient Handout
Formulary
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Adding plans allows you to:
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- Compare formulary status to other drugs in the same class.
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