Vitrakvi
(Larotrectinib)Dosage & Administration
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Vitrakvi Prescribing Information
Indications and Usage (VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that:
Select patients for therapy based on an FDA-approved test [see Dosage and Administration (2.1)]. VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that:
Select patients for therapy based on an FDA-approved test. | 4/2025 |
Dosage and Administration (Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens[see Clinical Studies (14)] .In patients with secretory breast cancer, mammary analogue secretory cancer (MASC), congenital mesoblastic nephroma (CMN), or infantile fibrosarcoma, consider treatment without confirmation of NTRK rearrangements in tumor specimens.Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics. | 4/2025 |
Warnings and Precautions (Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI (n=444), all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients. Among the 49 patients with cognitive impairment, 6% required a dose modification, and 18% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥ 1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%). Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption. Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification, and 5% required dose interruption. Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification, and 3.7% required dose interruption. Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)] .Skeletal fractures can occur in patients taking VITRAKVI. Among 444 patients who received VITRAKVI across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures. Hepatotoxicity including drug-induced liver injury (DILI) has occurred in patients taking VITRAKVI. In patients who received VITRAKVI (n=444), increased AST of any grade occurred in 62% of patients and increased ALT of any grade occurred in 61%. Grade 3-4 increased AST or ALT occurred in 7% and 8% of patients, respectively [see Adverse Reactions (6.1)] . The median time to onset of increased AST was 1.9 months (range: 4 days to 3.8 years). The median time to onset of increased ALT was 1.9 months (range: 1 day to 4.9 years). Increased AST and ALT leading to dose modifications occurred in 1.6% and 3.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 4 (0.9%) patients.There have been reports from clinical studies and postmarketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 × ULN. Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and monitor every 2 weeks during the first 2 months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue VITRAKVI based on severity [see Dosage and Administration (2.4)] . | 4/2025 |
- have a neurotrophic receptor tyrosine 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 satisfactory alternative treatments or that have progressed following treatment.
Select patients for treatment with VITRAKVI based on the presence of a
Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.
- Select patients for treatment with VITRAKVI based on the presence of a NTRKgene fusion (,
2.1 Patient SelectionSelect patients for treatment with VITRAKVI based on the presence of a
NTRKgene fusion in tumor specimens[see Clinical Studies (14)].In patients with secretory breast cancer, mammary analogue secretory cancer (MASC), congenital mesoblastic nephroma (CMN), or infantile fibrosarcoma, consider treatment without confirmation ofNTRKrearrangements in tumor specimens.Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.
).14 CLINICAL STUDIESThe efficacy of VITRAKVI was evaluated in pediatric and adult patients with unresectable or metastatic solid tumors with a
NTRKgene fusion enrolled in one of three multicenter, open-label, single-arm clinical trials: Study LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease.Adult patients received VITRAKVI 100 mg orally twice daily and pediatric patients (18 years or younger) received VITRAKVI 100 mg/m2up to a maximum dose of 100 mg orally twice daily until unacceptable toxicity or disease progression. Identification of positive
NTRKgene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) (89%), fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR).NTRKgene fusions were inferred in 14 patients who had a documentedETV6 or NTRK 3translocation identified by FISH. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.The assessment of efficacy was based on 339 patients with solid tumors with an
NTRKgene fusion enrolled across the three clinical trials. Baseline characteristics were: median age 38 years (range: 18 days to 90 years); 39% <18 years of age; 51% female; 57% White, 28% Asian, 2.4% Black or African American; 6% Hispanic or Latino and ECOG performance status (PS) 0-1 (88%) or 2 (10%). Sixty-three percent of patients had metastatic disease, including patients with brain metastases, and 22% had locally advanced, unresectable disease. Ninety-two percent of patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy, including RAI. Seventy percent of all patients had received prior systemic therapy in the unresectable or metastatic setting excluding RAI; 30% were treatment naive, 33% had received 1 prior therapy and 37% percent had received 2 or more prior therapies with a median of one prior systemic regimen.Efficacy results are summarized in Tables 5, 6, and 7.
Table 5 Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions Efficacy Parameter VITRAKVI
N = 339+ Denotes ongoing response. Overall response rate(95% CI)60% (55%, 65%) Complete response rate 24%5% were pathological complete response. Patients undergoing a surgical resection whose post-operative pathologic assessment showed no viable tumor cells and negative margins were pathological complete responders provided that no other sites of disease were present. Partial response rate 36% Duration of response (DOR) N = 204 Median (months) (95% CI) 43.3Kaplan-Meier estimates(32.5, NENE: Not evaluable) Range (months) 0.0+, 73.7+ % with Observed DOR> 12 months 64% % with Observed DOR> 24 months 45% Table 6 Efficacy Results by Tumor Type Tumor Type Patients
(N=339)ORR DOR
Range (months)% 95% CI NA = not applicable due to small numbers or lack of response; NE = not evaluable; SD = stable disease; PD = progressive disease.
+ Denotes ongoing response.Soft tissue sarcoma 70 70% (58%, 80%) 0.0+, 72.7+ Infantile fibrosarcoma 49 94% (83%, 99%) 1.6+, 73.7+ Primary CNS 49 27% (15%, 41%) 1.9+, 57.5+ Lung 30 70% (51%, 85%) 1.9+, 56.2+ Thyroid 30 63% (44%, 80%) 3.7, 72.4+ Differentiated 23 78% (56%, 93%) 4.9, 72.4+ Non-differentiated 7 14% (0%, 58%) 3.7Observed values at data cutoff, not a range. Salivary gland 25 84% (64%, 95%) 7.4, 65.2+ MASC 14 79% (49%, 95%) 7.7, 59.1 ColorectalColorectal Tumor Type includes 23 colon cancers and 1 rectal cancer. 24 46% (26%, 67%) 3.9, 45.2+ Breast 14 57% (29%, 82%) 7.4, 58.2+ Secretory 6 83% (36%, 100%) 11.1, 58.2+ Non-secretory 8 38% (9%, 76%) 7.4, 12.5+ Melanoma 11 45% (17%, 77%) 1.9+, 23.2+ Pancreas 7 14% (0%, 58%) 5.8 Gastrointestinal stromal tumor 5 80% (28%, 99%) 9.5, 50.4+ Cholangiocarcinoma 4 2 SD, 2 NE NA NA Bone sarcoma 3 33% (1%, 91%) 9.5 Gastric 3 2 PD, NE NA NA Cancer of unknown primary 2 100% (16%, 100%) 5.6, 7.4 Congenital mesoblastic nephroma 2 100% (16%, 100%) 32.9, 44.5 Prostate 2 SD, PD NA NA Appendix 1 SD NA NA Cervix 1 SD NA NA Duodenal 1 PD NA NA Esophageal 1 PD NA NA External auditory canal 1 100% (3%, 100%) 33.8+ Hepatic 1 NE NA NA Thymus 1 PD NA NA Urothelial 1 PD NA NA Uterus 1 NE NA NA The ORR for patients with
NTRK1fusions (n=142) was 59% (95% CI: 51, 67),NTRK2fusions (n=44) was 32% (95% CI: 19, 48) andNTRK3fusions (n=142) was 67% (95% CI: 59, 75).Table 7 Efficacy Results by NTRK Fusion Partner NTRKPartnerIncludes fusion partners which are represented by 3 or more patients in the efficacy analysis set. Does not represent all potential fusion partners.Patients
(N=339)ORR DOR Range
(months)% 95% CI PD = progressive disease; SD = stable disease; NA = not applicable.
+ Denotes ongoing response.ETV6-NTRK3 102 80% (71%, 88%) 0.0+, 66.7+ TPM3-NTRK1 63 67% (54%, 78%) 0.8+, 73.7+ LMNA-NTRK1 29 69% (49%, 85%) 3.4, 70.7+ Inferred ETV6-NTRK3 14 93% (66%, 100%) 1.6+, 73.4+ TPR-NTRK1 10 60% (26%, 88%) 3.0+, 38.7+ EML4-NTRK3 6 50% (12%, 88%) 7.9, 40.7+ IRF2BP2-NTRK1 4 100% (40%, 100%) 3.7, 47.8+ BCR-NTRK2 3 67% (9%, 99%) 9.2+, 11.0 GKAP1-NTRK2 3 2 SD, 1 PD NA NA NACC2-NTRK2 3 33% (1%, 91%) 3.7Observed values at data cutoff, not a range. RBPMS-NTRK3 3 67% (9%, 99%) 3.3+, 23.0 SQSTM1-NTRK1 3 67% (9%, 99%) 9.9, 12.9+ - Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater: 100 mg orally twice daily ()
2.2 Recommended DosageRecommended Dosage in Adult and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater
The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1 Meter-Squared
The recommended dosage of VITRAKVI is 100 mg/m2orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
- Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1 Meter-Squared: 100 mg/m2 orally twice daily ()
2.2 Recommended DosageRecommended Dosage in Adult and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater
The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1 Meter-Squared
The recommended dosage of VITRAKVI is 100 mg/m2orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
- Capsules: 25 mg, 100 mg ()
3 DOSAGE FORMS AND STRENGTHS- Capsules: 25 mg, 100 mg
- Oral Solution: 20 mg/mL
Capsules
- 25 mg: white opaque hard gelatin capsule, size 2, with blue printing of "BAYER" cross and "25 mg" on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate.
- 100 mg: white opaque hard gelatin capsule, size 0, with blue printing of "BAYER" cross and "100 mg" on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate.
Oral Solution packaged in one bottle containing 100 mL
- 20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.
Oral Solution packaged in two bottles each containing 50 mL
- 20 mg/mL: colorless to yellow or orange or red or brownish solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.
- Oral Solution: 20 mg/mL ()
3 DOSAGE FORMS AND STRENGTHS- Capsules: 25 mg, 100 mg
- Oral Solution: 20 mg/mL
Capsules
- 25 mg: white opaque hard gelatin capsule, size 2, with blue printing of "BAYER" cross and "25 mg" on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate.
- 100 mg: white opaque hard gelatin capsule, size 0, with blue printing of "BAYER" cross and "100 mg" on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate.
Oral Solution packaged in one bottle containing 100 mL
- 20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.
Oral Solution packaged in two bottles each containing 50 mL
- 20 mg/mL: colorless to yellow or orange or red or brownish solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate.
- Lactation: Advise not to breastfeed. ()
8.2 LactationRisk Summary
There are no data on the presence of larotrectinib or its metabolites in human milk and no data on 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 with larotrectinib and for 1 week after the last dose.
- Hepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. (,
2.7 Dosage Modifications for Patients with Hepatic ImpairmentReduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].)8.7 Renal ImpairmentNo dose adjustment is recommended for patients with renal impairment of any severity
[see Clinical Pharmacology (12.3)].
None.