SAFETY

ADVERSE REACTIONS OCCURRING IN ≥10% OF PATIENTS TREATED WITH VITRAKVI^®1

Table of demographic and patient baseline characteristics in clinical trials

12% of patients permanently discontinued treatment due to adverse reactions¹

20% of patients were 65 years and older; no overall differences in safety or effectiveness were observed between patients 65 years and older and younger adult patients¹

NO CARDIAC MONITORING REQUIRED WITH VITRAKVI¹

Obtain liver function tests (ALT,^p AST,^p ALP,^p and bilirubin) before initiation of treatment and 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.¹

Clinically relevant adverse reactions occurring in ≤10% of patients include fractures (7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients).¹

The safety of VITRAKVI was evaluated in 444 patients, in 3 clinical trials.¹

^aThe adverse reaction identifies a composite term.

^bNational Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.

^cGrade 4 adverse reaction: 1 of cognitive impairment, 1 of pyrexia.

^dIncludes: arthralgia, back pain, bone pain, flank pain, groin pain, growing pains, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, and tendon pain.

^eIncludes: fatigue, asthenia.

^fIncludes: face edema, generalized edema, lip edema, localized edema, edema, edema genital, edema peripheral, periorbital edema, and swelling.

^gIncludes: cough, productive cough, and upper-airway cough syndrome.

^hIncludes: dyspnea, and dyspnea exertional.

ⁱIncludes: dizziness, dizziness postural, and vertigo.

^jIncludes: amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucination, hallucination visual, memory impairment, mental impairment, mental status changes.

^kIncludes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.

^lIncludes: dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculopapular, rash papular, rash pruritic, and rash pustular.

^mIncludes: agitation, anxiety, depression, depressed mood, euphoric mood, fear, feeling jittery, irritability, panic attack, psychomotor hyperactivity, restlessness.

ⁿIncludes: insomnia, sleep disorder, somnolence.

^oIncludes: cystitis, cystitis escherichia, escherichia urinary tract infection, kidney infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, and urinary tract infection.

^pALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase.

Laboratory Abnormalities Occurring in ≥20% of Patients Treated With VITRAKVI¹

^qBased on NCI-CTCAE v4.03.¹

^rDenominator for each laboratory parameter is based on the number of patients with a baseline and post treatment laboratory value available, which ranged from 416 to 442 patients.¹

View Patient Cases

Reference

VITRAKVI [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; April 2025. Return to content

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Indication

VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that:

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 therapy based on an FDA-approved test.

Important Safety Information

Warnings and Precautions

Central Nervous System Effects: 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, 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.
Skeletal Fractures: 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: 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. 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 x 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.
Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of VITRAKVI.

Adverse Reactions

The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (62%), increased ALT (61%), anemia (45%), hypoalbuminemia (44%), musculoskeletal pain (41%), increased alkaline phosphatase (40%), leukopenia (37%), lymphopenia (35%), neutropenia (34%), hypocalcemia (32%), fatigue (31%), vomiting (30%), cough (29%), constipation (27%), pyrexia (26%), diarrhea (26%), nausea (25%), abdominal pain (24%), dizziness (22%), and rash (21%).

Drug Interactions

Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended.

Use in Specific Populations

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the last dose.

For important risk and use information about VITRAKVI, please see the full Prescribing Information.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

For Bayer products, you can report these directly to Bayer by clicking here.

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