Larotrectinib (Monograph)

Brand name: Vitrakvi
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a potent and selective inhibitor of tropomyosin receptor kinase (TRK) A, TRK-B, and TRK-C.

Uses for Larotrectinib

Solid Tumors with Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion

Treatment of solid tumors harboring an NTRK fusion (without a known acquired mutation for resistance) in adults and pediatric patients who have metastatic disease or are not candidates for surgical resection because of the likelihood of severe morbidity; the drug is indicated in such patients who have no satisfactory alternative treatments or have disease that has progressed following prior treatment (designated an orphan drug by FDA for these cancers).

Accelerated approval based on overall response rate and duration of response. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Confirmation of the presence of NTRK fusion in tumor specimens is necessary prior to initiation of therapy.

International experts recommend considering treatment with a selective TRK inhibitor (e.g., entrectinib, larotrectinib) in adult patients with TRK fusion-positive cancers including radioactive iodine-refractory thyroid carcinoma, colorectal cancer (if alternative treatments are not suitable, but also may be considered in the first-line setting), non-small cell lung cancer, soft tissue sarcoma, salivary gland carcinoma, and other TRK fusion-positive cancers without other effective or suitable treatment options.

International experts state that because NTRK gene fusions are pathognomonic in infantile fibrosarcoma, consider selective TRK inhibitor as first-line systemic therapy in patients with unresectable or metastatic infantile fibrosarcoma. May also consider in pediatric patients with other TRK fusion-positive cancers, including unresectable/metastatic non-rhabdomyosarcoma soft tissue sarcoma, differentiated thyroid carcinoma (if standard therapy is not effective or suitable), unresectable/metastatic glioma, and other TRK fusion-positive cancers without other effective or suitable treatment options.

Larotrectinib Dosage and Administration

General

Pretreatment Screening

Confirm presence of a neurotrophic receptor tyrosine kinase (NTRK) gene fusion in tumor specimens. Information on FDA-approved tests are available at [Web].
Verify pregnancy status prior to initiating larotrectinib therapy in females of reproductive potential.
Obtain liver function tests (ALT, AST, alkaline phosphatase, bilirubin) prior to initiation of therapy.

Patient Monitoring

Monitor liver function tests every 2 weeks for the first 2 months of therapy and then monthly thereafter or more frequently following the occurrence of grade 2 or greater AST or ALT elevation.
Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity).

Administration

Oral Administration

Capsules

Administer orally twice daily without regard to meals.

Swallow capsules whole with a full glass of water; do not chew or crush.

If a dose is missed, may be taken up to 6 hours prior to next dose; do not take within 6 hours of the next scheduled dose.

If vomiting occurs following administration, do not take a replacement dose. Administer next dose at regularly scheduled time.

Oral Solution

Administer orally twice daily without regard to meals.

Use an oral dosing syringe; follow the patient instructions provided by the manufacturer.

If a dose is missed, may be taken up to 6 hours prior to next dose; do not take within 6 hours of the next scheduled dose.

If vomiting occurs following administration, do not take a replacement dose. Administer next dose at regularly scheduled time.

Dosage

Available as larotrectinib sulfate; dosage expressed in terms of larotrectinib.

Oral solution and capsules may be interchanged at equal doses.

Pediatric Patients

Solid Tumors with NTRK Fusion

Oral

Body surface area (BSA) <1 m²: 100 mg/m² twice daily.

BSA ≥1 m²: 100 mg twice daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adults

Solid Tumors with NTRK Fusion

Oral

100 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

If grade 2 of higher liver function test abnormalities occur, refer to Table 2. For all other grade 3 or 4 adverse reactions, withhold larotrectinib therapy. If the grade 3 or 4 adverse reaction resolves to grade 1 or baseline within 4 weeks of withholding larotrectinib, resume the drug at a reduced dosage (or discontinue) as described in Table 1. If the grade 3 or 4 adverse reaction does not resolve within 4 weeks of withholding larotrectinib, permanently discontinue the drug.

If BSA increases to >1 m² in pediatric patients following dosage reduction to 25 mg/m²twice daily, do not increase dosage. Maximum dose should be 25 mg/m²twice daily at the third dosage modification

Table 1. Recommended Dosage Reductions for Larotrectinib Toxicity.1
Dosage Modification	Dosage Modification after Recovery from Toxicity Adult and Pediatric Patients with BSA ≥1 m² (Starting Dosage = 100 mg twice daily)	Dosage Modification after Recovery from Toxicity Pediatric Patients with BSA <1 m² (Starting Dosage = 100 mg/m² twice daily)
First	Restart at 75 mg twice daily	Restart at 75 mg/m² twice daily
Second	Restart at 50 mg twice daily	Restart at 50 mg/m² twice daily
Third	Restart at 100 mg once daily	Restart at 25 mg/m² twice daily
Fourth	Permanently discontinue larotrectinib	Permanently discontinue larotrectinib

Table 2. Dosage Modifications for Hepatotoxicity1
Severity	Dosage Modification
AST or ALT ≥5 times ULN with bilirubin ≤2 times ULN	Withhold until recovery to grade 1 or baseline then resume therapy at the next lower dose level Permanently discontinue if grade 4 AST and/or ALT elevation occurs after resuming therapy
AST or ALT >3 times ULN with total bilirubin >2 times ULN in the absence of alternative etiologies	Permanently discontinue therapy

Concomitant Use with CYP3A4 Inhibitors or Inducers

Avoid concomitant use of larotrectinib with strong inhibitors of CYP3A4; however, if concomitant use cannot be avoided, reduce the dosage of larotrectinib by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m² twice daily reduced to 50 mg/m² twice daily). After the potent CYP3A4 inhibitor has been discontinued for 3–5 elimination half-lives, resume the larotrectinib dosage used prior to initiation of the strong CYP3A4 inhibitor.

Avoid concomitant use of larotrectinib with strong inducers of CYP3A4; however, if concomitant use cannot be avoided, double the dosage of larotrectinib (e.g., dosage of 100 mg twice daily increased to 200 mg twice daily; dosage of 100 mg/m² twice daily increased to 200 mg/m² twice daily). In addition, for concurrent use with a moderate CYP3A4 inducer, double the dosage of larotrectinib. After the strong or moderate CYP3A4 inducer has been discontinued for 3–5 elimination half-lives, resume the larotrectinib dosage used prior to initiation of the CYP3A4 inducer.

Special Populations

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh class B or C): Reduce initial dosage by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m² twice daily reduced to 50 mg/m² twice daily).

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Larotrectinib

Contraindications

None.

Warnings/Precautions

CNS Effects

Adverse neurologic effects (i.e., dizziness, cognitive impairment, mood disorders, sleep disturbances) reported in 42%; grade 3–4 in severity in 3.9% of patients. Median time to onset of cognitive impairment (reported in 11% of patients) was 5.6 months (range: 2 days to 41 months). Median time to onset of mood disorders (reported in 14% of patients) was 3.9 months (range: 1 day to 40.5 months).

If neurologic events occur, therapy interruption followed by dosage reduction or permanent discontinuance of drug may be necessary. Advise patients not to drive or operate machinery.

Skeletal Fractures

Skeletal fractures, mostly associated with minimal or moderate trauma, reported. Median time to onset of fracture was 11.6 months (range: 0.9–45.8 months). No data regarding effects of larotrectinib on fracture healing or risk of future fractures.

Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity).

Hepatotoxicity

Hepatotoxicity, including drug-induced liver injury, reported. Median time to occurrence of elevated ALT or AST concentration was 2.1–2.3 months (range: 1 day to 4.3 years).

Obtain liver function tests (ALT, AST, alkaline phosphatase, bilirubin) before larotrectinib initiation. Monitor liver function tests every 2 weeks for the first 2 months of therapy and then monthly thereafter or more frequently following occurrence of grade 2 or greater AST or ALT elevation.

If hepatotoxicity occurs, therapy interruption followed by dosage reduction or permanent discontinuance of drug may be necessary.

Embryo-fetal Toxicity

Based on its mechanism of action and animal findings, larotrectinib may cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals. Crosses placenta in animals.

Possible association between decreased TRK-mediated signaling and obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis based on data from individuals with congenital mutations in the TRK pathway.

Perform pregnancy test prior to initiating larotrectinib therapy in females of reproductive potential. Avoid pregnancy during therapy and for ≥1 week after drug discontinuance. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception while receiving the drug and for ≥1 week after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether larotrectinib distributes into milk, affects milk production, or affects nursing infants.

Females should not breast-feed during therapy and for 1 week following drug discontinuance.

Females and Males of Reproductive Potential

Verify pregnancy status prior to initiating larotrectinib therapy in females of reproductive potential. Advise females of reproductive potential and males with such female partners to use effective contraception while receiving the drug and for ≥1 week after discontinuance of therapy.

Results of animal studies suggest larotrectinib may impair female fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients <28 days of age. Efficacy of larotrectinib for solid tumors harboring NTRK fusion in pediatric patients is supported by 3 noncomparative studies that included 12 patients ≥28 days of age. Based on limited safety data in 92 pediatric patients receiving the drug, adverse effects reported more frequently in pediatric patients compared with adults included pyrexia, vomiting, diarrhea, rash, upper respiratory tract infection, nasopharyngitis, otitis media, rhinitis, increased AST concentrations, neutropenia, leukopenia, hyperkalemia, and increased lymphocyte count.

No differences in pharmacokinetics observed between pediatric patients and adults.

Geriatric Use

In clinical trials evaluating larotrectinib, 19% of patients were ≥65 years of age and 5% were ≥75 years of age. Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger patients.

Hepatic Impairment

Systemic exposure increased in individuals with moderate or severe hepatic impairment (Child-Pugh class B or C); dosage adjustment is necessary.

Systemic exposure not substantially altered in individuals with mild hepatic impairment (Child-Pugh class A).

Renal Impairment

Systemic exposure not substantially altered in individuals with end-stage renal disease requiring dialysis.

No dosage adjustment is necessary in patients with renal impairment of any severity.

Common Adverse Effects

Adverse effects (reported in >20% of patients): Increased AST concentrations, increased ALT concentrations, anemia, musculoskeletal pain, fatigue, hypoalbuminemia, neutropenia, increased alkaline phosphatase concentrations, cough, leukopenia, constipation, diarrhea, dizziness, hypocalcemia, nausea, vomiting, pyrexia, lymphopenia, abdominal pain.

Drug Interactions

Metabolized principally by CYP3A4.

Inhibits CYP3A4 in vitro. Does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations in vitro.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, and OATP1B3 in vitro. Does not inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, bile salt export pump (BSEP), multidrug and toxin extrusion (MATE) transporter 1, and MATE2K at clinically relevant concentrations in vitro.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Strong or moderate inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to larotrectinib) and increased risk of toxicity. Avoid concomitant use with strong inhibitors of CYP3A4. If concomitant use cannot be avoided, reduce larotrectinib dosage by 50% (e.g., dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m² twice daily reduced to 50 mg/m² twice daily). After the strong CYP3A4 inhibitor is discontinued for 3–5 elimination half-lives, resume the larotrecrinib dosage used prior to initiation of the CYP3A4 inhibitor. If used concomitantly with a moderate CYP3A4 inhibitor, monitor patients more frequently for adverse reactions and reduce dosage of larotrectinib based on severity of the adverse reaction.

Strong or moderate inducers of CYP3A4: Potential pharmacokinetic interaction (decreased systemic exposure to larotrectinib) and reduced larotrectinib efficacy. Avoid concomitant use with strong inducers of CYP3A4. If concomitant use cannot be avoided, double dosage of larotrectinib (e.g., dosage of 100 mg twice daily increased to 200 mg twice daily; dosage of 100 mg/m² twice daily increased to 200 mg/m² twice daily). Also double the dosage of larotrectinib with concomitant use of a moderate CYP3A4 inducer. After the strong or moderate CYP3A4 inducer has been discontinued for 3–5 elimination half-lives, resume dosage of larotrectinib used prior to initiation of the CYP3A4 inducer.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to CYP3A4 substrate) and increased adverse effects. Avoid concomitant use with sensitive CYP3A4 substrates. If concomitant use cannot be avoided, monitor for CYP3A4 substrate-related toxicity.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Grapefruit or grapefruit juice	Potential increased systemic exposure to larotrectinib and increased risk of toxicity	Avoid concomitant use
Itraconazole	Increased peak plasma concentrations and AUC of larotrectinib by 2.8- and 4.3-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce larotrectinib dosage by 50% When itraconazole is discontinued, return larotrectinib dosage (after 3–5 elimination half-lives of itraconazole) to prior dosage
Midazolam	Potential increased peak plasma concentrations and AUC of midazolam (a CYP3A4 substrate) and increased toxicity	Avoid concomitant use; if concomitant use cannot be avoided, monitor for midazolam toxicity
Rifampin	Multiple-dose rifampin (potent CYP3A inducer) decreased peak plasma concentration and AUC of larotrectinib by 71 and 81%, respectively Single-dose rifampin (P-gp inhibitor) increased peak plasma concentration and AUC of larotrectinib by 1.8- and 1.7-fold	Avoid concomitant use; if concomitant use cannot be avoided, double dosage of larotrectinib When rifampin is discontinued, return larotrectinib dosage (after 3–5 elimination half-lives of rifampin) to prior dosage
St. John’s wort (Hypericum perforatum)	Potential decreased systemic exposure of larotrectinib and reduced efficacy	Avoid concomitant use; if concomitant use cannot be avoided, double dosage of larotrectinib When St. John's wort is discontinued, return larotrectinib dosage (after 3–5 elimination half-lives of St. John's wort) to prior dosage

Larotrectinib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure increases in a dose-proportional manner over a dose range of 100–400 mg and in a slightly more than dose-proportional manner over a dose range of 600–900 mg.

Peak plasma concentrations achieved in approximately 1 hour following oral administration of larotrectinib capsules.

Steady-state concentrations are achieved within 3 days.

Mean absolute oral bioavailability is 34% following oral administration of larotrectinib capsules.

AUC of oral solution similar to that observed with larotrectinib capsules; however, peak plasma concentrations are 36% higher following administration of the oral solution.

Food

Administration with a high-fat meal decreased peak plasma concentrations by 35% and delayed time to peak plasma concentrations by 2 hours, but did not substantially affect the extent of absorption.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased by 1.3- or 2-fold, respectively; peak plasma concentrations similar to those in individuals with normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): AUC and peak plasma concentrations increased by 3.2- and 1.5-fold, respectively.

End-stage renal disease requiring dialysis: AUC and peak plasma concentrations increased by 1.5- and 1.3-fold, respectively.

Moderate or severe renal impairment (Cl_cr ≤60 mL/minute): Pharmacokinetics not studied.

Age (28 days to 82 years), sex, or body weight (3.8–179 kg) does not affect pharmacokinetics of larotrectinib.

Distribution

Extent

Crosses placenta in animals.

Not known whether larotrectinib is distributed into milk.

Plasma Protein Binding

70% (independent of larotrectinib concentration).

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (58% [5% as unchanged drug]) and urine (39% [20% as unchanged drug]).

Half-life

2.9 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Solution

2–8°C. Do not freeze.

Discard 100 mL oral solution 90 days after first opening bottle.

Discard 50 mL oral soution 31 days after first opening bottle.

Actions

Potent and selective inhibitor of TRK-A, TRK-B, and TRK-C.
TRK-A, TRK-B, and TRK-C are encoded by NTRK1, NTRK2, and NTRK3 and are involved in the initiation of various cascades of intracellular signaling events (i.e., Ras/MAPK/ERK, PI3K/Akt, and PLCγ1/Pkc signal transduction pathways) that lead to cell proliferation, differentiation, apoptosis, and regulation of processes critical to neuron survival in the central and peripheral nervous systems.
Chromosomal rearrangements of NTRK1, NTRK2, and NTRK3 genes result in formation of a constitutively active chimeric TRK oncogenic fusion protein and dysregulation of TRK signaling and subsequent tumorigenesis.
Inhibits wild-type TRK-A, TRK-B, and TRK-C.
Induces antitumor activity in cell lines with TRK expression from constitutive activation, deletion of a protein regulatory domain, or overexpression of wild-type TRK.
Inhibits tyrosine kinase nonreceptor 2 (TNK2).
Clinical resistance attributed to secondary point mutations of the NTRK kinase domain in 90% of cases. Demonstrates minimal activity in cell lines with point mutations in the TRK-A kinase domain, including the acquired resistance mutation G595R. Acquired resistance also identified in cells lines with G623R, G696A, and F617L point mutations in the TRK-C kinase domain.

Advice to Patients

Instruct patients to read the manufacturer's patient information.
Advise patients to take larotrectinib exactly as prescribed and to not alter the dosage or discontinue therapy unless advised to do so by their clinician. Advise patients to swallow larotrectinib capsules whole and to not chew or crush the capsules.
Advise patients to take a missed dose as soon as it is remembered unless the dose was missed by more than 6 hours, in which case they should not take the missed dose. If a dose is vomited, administer the next dose at the regularly scheduled time.
Risk of adverse neurologic effects. Importance of informing clinician if new or worsening manifestations of neurologic events (e.g., confusion; dizziness; problems with concentration, attention, or memory; mood changes; sleep disturbance) occur. Advise patients to avoid driving or operating hazardous machinery if they experience neurologic events.
Risk of skeletal fractures. Importance of informing clinician if signs or symptoms of skeletal fractures (e.g., pain, changes in mobility, deformity) occur.
Risk of hepatotoxicity; importance of regular liver function test monitoring. Importance of immediately informing clinician if signs or symptoms of hepatotoxicity (e.g., loss of appetite, nausea, vomiting, abdominal pain [especially right upper quadrant pain]) occur.
Risk of fetal harm. Advise females of reproductive potential to avoid pregnancy and to use effective contraceptive methods while receiving larotrectinib and for ≥1 week following discontinuance of therapy. Advise males who are partners of such females that they should use effective methods of contraception while receiving the drug and for ≥1 week after the drug is discontinued. Importance of females informing their clinicians if they become pregnant during therapy or think they may be pregnant. Advise males and females of reproductive potential of potential risk to the fetus.
Advise females to avoid breast-feeding while receiving larotrectinib and for 1 week after discontinuance of therapy.
Risk of impaired female fertility.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort [Hypericum perforatum], grapefruit, grapefruit juice), as well as any concomitant illnesses (e.g., hepatic impairment).
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Larotrectinib is obtained through specialty pharmacy providers. Consult manufacturer's website for specific availability information.

Larotrectinib Sulfate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	25 mg (of larotrectinib)	Vitrakvi	Bayer
		100 mg (of larotrectinib)	Vitrakvi	Bayer
	Solution	20 mg (of larotrectinib) per mL	Vitrakvi (available in a package containing one 100-mL bottle or a package of 2 bottles each containing 50 mL)	Bayer