Dosing & Uses
Dosage Forms & Strengths
capsule
- 25mg
- 100mg
oral solution
- 20mg/mL
Solid Tumors
Indicated for treatment of 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
For Grade ≥3 adverse reactions
- Withhold treatment until reaction resolves or improves to Grade ≤1
- Resume at next dosage modification if resolved within 4 weeks
- Permanently discontinue if does not resolve within 4 weeks
Coadministration with strong CYP3A4 inhibitors
- Avoid use with strong CYP3A4 inhibitors
- If coadministration cannot be avoided, reduce dose by 50%
- Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inhibitor
Coadministration with strong CYP3A4 inducers
- Avoid use with strong CYP3A4 inducers
- If coadministration cannot be avoided, 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
Patient selection is based on presence of a NTRK gene fusion in tumor specimens; an FDA-approved test for detection of NTRK gene fusion is not currently available
Indication approved under accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
Dosage Forms & Strengths
capsule
- 25mg
- 100mg
oral solution
- 20mg/mL
Solid Tumors
Indicated for treatment of patients with solid tumors that have a 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: 25 mg/m² BID
- BSA ≥1 m²
- First occurrence: 75 mg BID
- Second occurrence: 50 mg BID
- Third occurrence: 100 mg qDay
For Grade ≥3 adverse reactions
- Withhold treatment until reaction resolves or improves to Grade ≤1
- Resume at next dosage modification if resolved within 4 weeks
- Permanently discontinue if does not resolve within 4 weeks
Coadministration with strong CYP3A4 inhibitors
- Avoid use with strong CYP3A4 inhibitors
- If coadministration cannot be avoided, reduce dose by 50%
- Once strong CYP3A4 inhibitor is discontinued for 3-5 elimination half-lives, resume larotrectinib at dose taken prior to initiating CYP3A4 inhibitor
Coadministration with strong CYP3A4 inducers
- Avoid use with strong CYP3A4 inducers
- If coadministration cannot be avoided, 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
Patient selection is based on presence of a NTRK gene fusion in tumor specimens; an FDA-approved test for detection of NTRK gene fusion is not currently available
Indication approved under accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
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
Neurologic adverse reactions (any grade) occurred; majority of neurologic adverse reactions occurred within first 3 months of treatment; advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions
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 when administered to pregnant women (see Pregnancy)
Drug interactions overview
- Larotrectinib is a substrate of CYP3A4 (major); also a P-gp and BCRP substrate
- Larotrectinib moderately inhibits CYP3A4
- Strong CYP3A4 inhibitors
- Coadministration with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations and potentially result in higher incidence of adverse reactions
- Avoid use with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice; if coadministration of strong CYP3A4 inhibitors cannot be avoided, modify dose as recommended
- Strong CYP3A4 inducers
- Coadministration with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease efficacy
- Avoid use with strong CYP3A4 inducers; if coadministration of strong CYP3A4 inducers cannot be avoided, modify dose as recommended
- Sensitive CYP3A4 substrates
- Coadministration with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase incidence and/or severity of adverse reactions
- Avoid use with sensitive CYP3A4 substrates; if coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor for increased adverse reactions of these drugs
Pregnancy
Pregnancy
Based on literature reports, findings from animal studies, and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman
There are no available data on use in pregnant women
Verify pregnancy status in females of reproductive potential prior to initiation
Animal data
- Administration of larotrectinib 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: Advise to use of effective contraception during treatment and for at least 1 week after last dose
- Males: Advise males with female partners of reproductive potential to 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 the breastfed child or on milk production
Because of the potential for serious adverse reactions in breastfed children, advise women 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
Capsules or oral solution may be used interchangeably
Missed dose (within 6 hr of next scheduled dose): Do not make up a missed dose
Vomit dose: Take next dose at scheduled time
Capsules: Swallow whole with water; do not chew or crush
Storage
Capsules: Store at room temperature 20-25°C (68-77°F); temperature excursions permitted between 15-30°C (59-86°F)
Oral solution: Refrigerate oral solution 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:
- View the formulary and any restrictions for each plan.
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- Compare formulary status to other drugs in the same class.
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