Vitrakvi (larotrectinib sulfate)

Dosage of larotrectinib sulfate is expressed in terms of larotrectinib.

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

Table 1. Recommended Dosage Reductions for Larotrectinib Toxicity.

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

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 2. Dosage Modifications for Hepatotoxicity

Severity Dosage Modification AST or ALT >=5 times ULN with Withhold until recovery to grade 1 bilirubin <=2 times ULN 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 Permanently discontinue therapy bilirubin >2 times ULN in the absence of alternative etiologies

Larotrectinib is administered orally (as capsules or oral solution) twice daily without regard to meals; the capsule or oral solution may be used interchangeably. The capsules should be swallowed whole with water; they should not be chewed or crushed. The oral solution should be administered using an oral dosing syringe according to the manufacturer's directions.

If a dose of larotrectinib is missed, the dose may be taken up to 6 hours prior to the next dose; do not take within 6 hours of the next scheduled dose. If vomiting occurs following administration of larotrectinib, a replacement dose should not be administered; take the next dose at the regularly scheduled time.

Larotrectinib capsules should be stored at room temperature of 20-25degreesC (excursions permitted between 15-30degreesC).

Larotrectinib 20 mg/mL oral solution (packaged in one bottle containing 100 mL) should be stored in a refrigerator at 2-8degreesC; the oral solution should not be frozen. Unused portions of this larotrectinib oral solution should be discarded after 90 days of opening the bottle.

Larotrectinib 20 mg/mL oral solution (packaged in two bottles each containing 50 mL) should be stored in a refrigerator at 2-8degreesC; the oral solution should not be frozen. Unused portions of this larotrectinib oral solution should be discarded after 31 days of opening the bottles.

No dosing information is available for this tab.

No dosing information is available for this tab.

Larotrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.

In vitro studies indicate that larotrectinib is an inhibitor of CYP3A4. In vitro, larotrectinib does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.

In vitro, larotrectinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate for organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, or OATP1B3. In vitro studies indicate that larotrectinib 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.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*None.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in >20% of patients receiving larotrectinib include increased AST concentrations, increased ALT concentrations, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase concentrations, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Efficacy of larotrectinib in pediatric patients with solid tumors harboring a neurotrophic receptor tyrosine kinase (NTRK) gene fusion was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients. Some adverse effects and laboratory abnormalities occurred more frequently in pediatric patients compared with adults; however, because the studies were uncontrolled, it is unclear whether this effect was related to larotrectinib or to other confounding factors (e.g., differences in susceptibility to infection).

No differences in pharmacokinetics were observed between pediatric patients and adults.

Larotrectinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

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.

It is not known whether larotrectinib or its metabolites are distributed into human milk. Because of the potential for serious adverse reactions to larotrectinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 1 week after the last dose. The effects of the drug on breast-fed infants or on the production of milk are unknown.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In clinical trials evaluating larotrectinib, 20% of patients receiving larotrectinib were 65 years of age or older, while 6% were 75 years of age or older. No overall differences in safety or efficacy of larotrectinib were seen between patients >=65 years of age and younger adult patients.