Vitrakvi
(larotrectinib)Dosage & Administration
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Vitrakvi Prescribing Information
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 [see Dosage and Administration (2.1)].
Patient Selection
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.
Recommended Dosage
Recommended 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/m2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
Dosage Modifications for Adverse Reactions
For Grade 2 and higher liver function test abnormalities, refer to Section 2.4, Table 2, Dosage Modifications for Hepatotoxicity.
For all other Grade 3 or 4 adverse reactions:
- Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks.
- Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks.
The recommended dosage reductions for VITRAKVI for adverse reactions are provided in Table 1.
| Dosage Reduction | Adult and Pediatric Patients with Body Surface Area of 1 m2 or Greater | Pediatric Patients with Body Surface Area Less Than 1 m2 |
|---|---|---|
| ||
| First | 75 mg orally twice daily | 75 mg/m2 orally twice daily |
| Second | 50 mg orally twice daily | 50 mg/m2 orally twice daily |
| Third | 100 mg orally once daily | 25 mg/m2 orally twice daily * |
Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.
Dosage Modifications for Hepatotoxicity
The recommended dosage modifications for VITRAKVI liver function test abnormalities are provided in Table 2.
For CTCAE Grade 2 ALT and/or AST elevation, monitor liver function frequently as clinically indicated, to establish whether a dose interruption or reduction is required [see Warnings and Precautions (5.3)].
| Severity * | Dosage Modification |
|---|---|
| ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal | |
| |
| AST or ALT ≥ 5 × ULN with bilirubin ≤ 2 × ULN [see Warnings and Precautions (5.3)] |
|
| AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes |
|
Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors
Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Dosage Modifications for Coadministration with Strong or Moderate CYP3A4 Inducers
Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. Additionally, for coadministration with a moderate CYP3A4 inducer, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose that was used prior to initiating the CYP3A4 inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Dosage Modifications for Patients with Hepatic Impairment
Reduce 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)].
Administration
VITRAKVI capsule or oral solution may be used interchangeably.
Do not make up a missed dose within 6 hours of the next scheduled dose.
If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time.
Capsules
Swallow capsules whole with water. Do not chew or crush the capsules.
Oral Solution packaged in one bottle containing 100 mL
- Store the glass bottle of VITRAKVI oral solution in the refrigerator. Discard any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle.
- Prior to preparing an oral dose for administration, refer to the Instructions for Use.
Oral Solution packaged in two bottles each containing 50 mL
- Store the glass bottles of VITRAKVI oral solution in the refrigerator. Discard any unused VITRAKVI oral solution remaining after 31 days of first opening the bottle.
- Prior to preparing an oral dose for administration, refer to the Instructions for Use.
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.
Pregnancy
Risk Summary
Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data
Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily).
Lactation
Risk 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.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI [see Use in Specific Populations (8.1)].
Contraception
VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise female patients of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the last dose.
Infertility
Females
Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, VITRAKVI may reduce fertility [See Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients. [see Adverse Reactions (6.1), Clinical Studies (14)].
The efficacy of VITRAKVI was evaluated in 131 pediatric patients and is described in the Clinical Studies section [see Clinical Studies (14)]. The safety of VITRAKVI was evaluated in 154 pediatric patients who received VITRAKVI. Of these 154 patients, 31% were <1 month to < 2 years (n = 47), 49% were 2 years to < 12 years (n = 75), and 21% were 12 years to < 18 years (n = 32); 25% had metastatic disease, 44% had locally advanced disease, and 31% had primary CNS; and 82% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy, including radioactive iodine therapy (RAI). The most common cancers were infantile fibrosarcoma (32%), primary CNS tumors (31%), soft tissue sarcoma (27%), and thyroid cancer (4%). The median duration of exposure was 14.8 months (range: 0.4 months to 87.4 months).
Due to the small number of pediatric and adult patients, the single arm design of clinical studies of VITRAKVI, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adverse reactions occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were vomiting (51% versus 18%), pyrexia (47% versus 15%), cough (36% versus 23%), diarrhea (34% versus 21%), upper respiratory tract infection (33% versus 10%), headache (25% versus 13%), nasopharyngitis (20% versus 7%), nasal congestion (18% versus 7%), gastroenteritis (13% versus 2%), and rhinitis (12% versus 0%).
Laboratory abnormalities occurring more frequently (at least a 10% increase in per-patient incidence) in pediatric patients compared to adult patients were AST increased (75% versus 55% in adults), ALT increased (69% versus 57% in adults), neutrophil count decrease (59% versus 20% in adults), leukocyte count decrease (46% versus 32% in adults), hyperkalemia (39% versus 16%), glucose decrease (29% versus 13% in adults), and lymphocyte increase (25% versus 1%). Three of the 154 pediatric patients discontinued VITRAKVI due to an adverse reaction associated with a laboratory abnormality (1 patient with Grade 3 increased ALT and 2 patients with Grade 3 decreased neutrophil count).
The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults [see Clinical Pharmacology (12.3)].
Juvenile Animal Toxicity Data
Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 6 and 22.5mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatric populations from newborn to adulthood. The doses of 2/6 mg/kg twice daily [approximately 0.7 times the human exposure (AUC) at the clinical dose of 100 mg twice daily] and 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND 9 to 99; a definitive cause of death was not identified in the majority of cases.
The main findings were transient central nervous system-related signs including head flick, tremor, and circling in both sexes. An increase in the number of errors in a maze swim test occurred in females at exposures of approximately 4 times the human exposure (AUC) at the clinical dose of 100 mg twice daily. Decreased growth and delays in sexual development occurred in the mid- and high-dose groups. Mating was normal in treated animals, but a reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily).
Geriatric Use
Of 444 patients in the overall safety population who received VITRAKVI, 20% of patients were ≥ 65 years of age and 6% of patients were ≥ 75 years of age. No overall differences in safety or effectiveness of VITRAKVI were observed between patients 65 years and older and younger adult patients.
Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3)]. Reduce VITRAKVI dose as recommended [see Dosage and Administration (2.7)].
Renal Impairment
No dose adjustment is recommended for patients with renal impairment of any severity [see Clinical Pharmacology (12.3)].
None.
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 (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
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 [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)].
Embryo-Fetal Toxicity
Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, 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 [see Use in Specific Populations (8.1, 8.3)].