Version May 2024
Solid tumors (with neurotrophic tyrosine receptor kinase [NTRK] gene fusion): Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Ref).
Missed dose: Do not make up the missed dose within 6 hours of the next scheduled dose. If vomiting occurs, take the next dose at the scheduled time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Hepatic impairment prior to treatment initiation:
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh classes B and C): Reduce the initial larotrectinib dose by 50%.
Hepatotoxicity during treatment:
ALT or AST ≥5 times ULN with bilirubin ≤2 times ULN: Withhold larotrectinib until recovery to ≤ grade 1 or baseline; resume at the next lower dosage level. Discontinue permanently if grade 4 AST and/or ALT elevation occurs after resuming larotrectinib.
ALT or AST >3 times ULN with bilirubin >2 times ULN (in absence of other causes): Discontinue larotrectinib permanently.
|
Dosage modification |
Patients with a BSA of ≥1 m2 |
|---|---|
|
Usual initial dose |
100 mg twice daily |
|
First dose reduction level |
75 mg twice daily |
|
Second dose reduction level |
50 mg twice daily |
|
Third dose reduction level |
100 mg once daily |
|
Discontinue permanently if unable to tolerate larotrectinib after 3 dose reductions | |
Grade 3 or 4 adverse reactions: Withhold larotrectinib until adverse reaction resolves to baseline or grade 1; if resolution occurs within 4 weeks, resume at the next lower dosage level. Discontinue permanently if the adverse reaction does not resolve within 4 weeks.
Refer to adult dosing.
(For additional information see "Larotrectinib: Pediatric drug information")
Dosage guidance:
Safety: Dosing presented as a fixed mg dose, and as mg/m2; use caution.
Solid tumor (unresectable or metastatic) with presence of neurotrophic receptor tyrosine kinase (NTRK) gene fusion:
Infants, Children, and Adolescents:
BSA <1 m2: Oral: 100 mg/m2/dose twice daily; continue until disease progression or unacceptable toxicity.
BSA ≥1 m2: Oral: 100 mg twice daily; continue until disease progression or unacceptable toxicity.
Dosing adjustment for toxicity:
Infants, Children, and Adolescents: Oral:
|
BSA |
First dose reduction |
Second dose reduction |
Third dose reductiona |
|---|---|---|---|
|
a Permanently discontinue if unable to tolerate larotrectinib after 3 dose reductions. | |||
|
b Maintain dose at 25 mg/m2 twice daily even if BSA increases to ≥1 m2 during treatment. | |||
|
BSA <1 m2 |
75 mg/m2 twice daily |
50 mg/m2 twice daily |
25 mg/m2 twice dailyb |
|
BSA ≥1 m2 |
75 mg twice daily |
50 mg twice daily |
100 mg once daily |
Grade 3 or 4 adverse reactions: Withhold treatment until adverse reaction resolves or improves to baseline or ≤ grade 1. Resume with appropriate dosage modification if resolution occurs within 4 weeks. Permanently discontinue if not resolved within 4 weeks or if unable to tolerate after 3 dose reductions.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment is necessary for any degree of renal impairment.
Baseline hepatic impairment:
Mild impairment: No dosage adjustment is necessary.
Moderate to severe impairment: Reduce initial dose by 50%.
Hepatotoxicity during treatment:
ALT or AST ≥5 × ULN with bilirubin ≤2 × ULN: Withhold larotrectinib until recovery to ≤ grade 1 or baseline; resume at the next lower dosage level. Discontinue permanently if grade 4 AST and/or ALT elevation occurs after resuming larotrectinib.
|
BSA |
First dose reduction |
Second dose reduction |
Third dose reductiona |
|---|---|---|---|
|
a Permanently discontinue if unable to tolerate larotrectinib after 3 dose reductions. | |||
|
b Maintain dose at 25 mg/m2 twice daily even if BSA increases to ≥1 m2 during treatment. | |||
|
BSA <1 m2 |
75 mg/m2 twice daily |
50 mg/m2 twice daily |
25 mg/m2 twice dailyb |
|
BSA ≥1 m2 |
75 mg twice daily |
50 mg twice daily |
100 mg once daily |
ALT or AST >3 × ULN with bilirubin >2 × ULN (in absence of other causes): Discontinue larotrectinib permanently.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adult and pediatric patients.
>10%:
Cardiovascular: Edema (19%; includes facial edema, genital edema)
Dermatological: Skin rash (19%)
Endocrine & metabolic: Hypoalbuminemia (36%), hypocalcemia (25%), weight gain (14%)
Gastrointestinal: Abdominal pain (21%), constipation (27%), decreased appetite (12%), diarrhea (27%; grades 3/4: 1%), nausea (25%; grades 3/4: <1%), vomiting (25%; grades 3/4: <1%)
Genitourinary: Urinary tract infection (12%)
Hematologic & oncologic: Anemia (42%; grades 3/4: 10%), leukopenia (28%; grades 3/4: 2%), lymphopenia (22%; grades 3/4: 6%), neutropenia (36%; grades 3/4: 14%)
Hepatic: Increased serum alanine aminotransferase (45%), increased serum alkaline phosphatase (34%), increased serum aspartate aminotransferase (52%)
Nervous system: Cognitive dysfunction (11%; including amnesia, aphasia, hallucination, mental status changes), dizziness (27%), fatigue (36%; including asthenia), headache (15%), mood disorder (14%)
Neuromuscular & skeletal: Musculoskeletal pain (42%; includes arthralgia, back pain, limb pain, myalgia)
Respiratory: Cough (32%), dyspnea (17%), nasal congestion (11%), upper respiratory tract infection (13%)
Miscellaneous: Fever (24%)
1% to 10%:
Nervous system: Agitation (3%), anxiety (5%), confusion (3%), delirium (2%), depression (4%), disturbance in attention (3%), drowsiness (3%), insomnia (7%), irritability (3%), memory impairment (4%), myasthenia (10%), sleep disturbance (10%)
Neuromuscular & skeletal: Bone fracture (7% to 9%)
Frequency not defined:
Endocrine & metabolic: Dehydration
Respiratory: Pneumonia
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to larotrectinib or any component of the formulation.
Concerns related to adverse effects:
• CNS effects: Cognitive impairment, mood disorders, dizziness, and sleep disturbance have been reported with larotrectinib. Approximately 40% of patients experienced CNS effects (all grades) and about 4% as grade 3 to 4. Cognitive impairment (including memory impairment, confusion, attention disturbance, delirium, and cognitive disorders) occurred in 11% of patients; symptoms occurred at a median onset of 5.6 months (range: 2 days to 41 months). Grade 3 cognitive impairment requiring dose modification or interruption was reported. Mood disorders and sleep disturbances were reported in 10% to 14% of patients. Mood disorders included anxiety, depression, agitation, and irritability and occurred at a median onset of 3.9 months (range: 1 day to 40.5 months); grade 3 mood disorders occurred rarely. Sleep disturbances included insomnia, somnolence, and sleep disorder; there were no grade 3 or 4 events. Dizziness also occurred in 27% of patients; grade 3 dizziness occurred in 1% of patients. Cognitive impairment, mood disorders, dizziness, and sleep disturbances may require therapy interruption, dose reduction, and/or therapy discontinuation (based on toxicity severity). Caution patients about performing tasks that require mental alertness (eg, operating machinery or driving).
• Fractures: The risk of skeletal fractures is increased with larotrectinib therapy; fractures occurred more frequently in pediatric patients (9%) than adults (7%) in clinical trials. Most fractures occurred with minimal or moderate trauma. Radiologic abnormalities (possibly indicative of tumor involvement at the site of fracture) were reported in some patients. Most fractures involved the femur, hip, or acetabulum. Promptly evaluate for signs/symptoms of fractures, such as pain, changes in mobility, or deformity. No data are available on larotrectinib effects on healing of confirmed fractures or risk of future fractures.
• Hepatotoxicity: Hepatotoxicity, including drug-induced liver injury, has been reported. Transaminase increase (of any grade) commonly occurred with larotrectinib; grade 3 AST or ALT elevations were reported; grade 4 ALT elevations occurred rarely. The median time to onset of AST and ALT elevation was 2 months (range: 1 month to 4.3 years for AST elevation and 1 month to 4.2 years for ALT elevation). AST and ALT elevations leading to dose modifications and/or permanent discontinuation have occurred.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Select patients for treatment based on the presence of a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in tumor specimen(s). Information on approved tests is available at http://www.fda.gov/companiondiagnostics.
Pediatric patients reported a higher incidence of pyrexia (45% vs 13%) and neutrophil count decrease (60% vs 16%) compared to adults; due to small number of patients studied, it is unknown if reported differences are due to patient age or other factors.
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as sulfate:
Vitrakvi: 25 mg, 100 mg
Solution, Oral, as sulfate:
Vitrakvi: 20 mg/mL (100 mL) [contains methylparaben, propylene glycol]
Vitrakvi: 20 mg/mL (50 mL) [contains sodium benzoate]
No
Capsules (Vitrakvi Oral)
25 mg (per each): $259.90
100 mg (per each): $779.70
Solution (Vitrakvi Oral)
20 mg/mL (per mL): $207.91
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as sulfate:
Vitrakvi: 25 mg, 100 mg
Solution, Oral, as sulfate:
Vitrakvi: 20 mg/mL (100 mL) [contains methylparaben, propylene glycol]
Oral: Administer with or without food. The capsules or oral solution may be used interchangeably.
Capsules: Swallow capsules whole with water; do not chew or crush capsules.
Oral solution: Use caution when measuring the oral solution; an oral syringe (provided) should be used when measuring to assure the proper dose is administered. Clean the oral syringe following each dose. See package labeling for detailed cleaning instructions; do not boil. Each oral syringe may be used over a 7-day period; discard after 7 days of use or if oral syringe is damaged, markings are illegible, or if it becomes difficult to move the plunger.
Oral: Administer with or without food. If vomiting occurs after dose is administered, do not repeat dose and administer the next dose at the scheduled time.
Capsule: Swallow whole with water; do not chew or crush capsules.
Oral solution: Use the provided oral syringe to measure doses; each syringe may be used over a 7-day period; discard after 7 days of use or if damaged, markings illegible, or if it becomes difficult to move the plunger. Do not use a household teaspoon to measure dose (over- or under-dosing may occur). For infants and young children, administer the dose against the inside of the cheek. Following each dose, the syringe should be cleaned; do not boil; see package labeling for detailed cleaning instructions.
Missed dose: Do not make up the missed dose within 6 hours of the next scheduled dose.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Larotrectinib may cause reproductive toxicity and teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Solid tumors: Treatment of solid tumors (in adult and pediatric patients) that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion (as detected by an approved test) 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.
Larotrectinib may be confused with alectinib, entrectinib, lapatinib, lenvatinib, lonafarnib, lorlatinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of BCRP/ABCG2, CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor's half-life. Risk D: Consider therapy modification
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Larotrectinib. Management: Avoid use of grapefruit juice with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Following discontinuation of grapefruit juice, resume the previous dose of larotrectinib. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
St John's Wort: May decrease the serum concentration of Larotrectinib. Management: Avoid use of St John's wort with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Grapefruit may increase larotrectinib plasma levels. Management: Grapefruit or grapefruit juice should be avoided during therapy.
Pregnancy status should be evaluated prior to therapy; females of reproductive potential should use effective contraception during therapy and for 1 week after the final larotrectinib dose. Males with female partners of reproductive potential should also use effective contraception during therapy and for 1 week after the final larotrectinib dose.
Based the mechanism of action and available human and animal data, larotrectinib may cause fetal harm if administered to a pregnant female.
Larotrectinib interferes with TRK signaling; obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis have been observed in persons with congenital mutations in TRK pathway proteins.
It is not known if larotrectinib is present in breast milk. Due to the potential for adverse events in a breastfed infant, breastfeeding is not recommended during therapy and for 1 week after the final larotrectinib dose.
Avoid grapefruit or grapefruit juice during therapy.
Assess neurotrophic tyrosine receptor kinase (NTRK) gene fusion status in tumor specimen (prior to treatment initiation). Monitor LFTs (including ALT, AST, ALP, and bilirubin) prior to treatment initiation, every 2 weeks during the first 2 months of treatment, then monthly thereafter, and as clinically indicated. Evaluate pregnancy status (prior to treatment in females of reproductive potential). Monitor for signs/symptoms of neurotoxicity and skeletal fractures. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Larotrectinib is a potent and highly selective small-molecule inhibitor of the 3 tropomyosin receptor kinase (TRK) proteins, TRKA, TRKB, and TRKC (Drilon 2018). TRKA, TRKB, and TRKC are encoded by neurotrophic tyrosine receptor kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving fusions of NTRK genes may result in constitutively-activated chimeric TRK fusion proteins, acting as an oncogenic driver to promote cell proliferation and survival in tumor cell lines. Larotrectinib has anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.
Distribution: 48 L.
Protein binding: 70%; to plasma proteins.
Metabolism: Hepatic; primarily via CYP3A4; forms an O-linked glucuronide metabolite.
Bioavailability: Capsules: 34% (range: 32 to 37%).
Half-life elimination: 2.9 hours.
Time to peak: ~1 hour.
Excretion: Feces (58%; 5% unchanged); Urine (39%; 20% unchanged).
Clearance: 98 L/hour.
Altered kidney function: Following oral administration of a single 100 mg larotrectinib dose in subjects with end-stage renal disease (requiring dialysis), the larotrectinib AUC0-∞ increased 1.5-fold and Cmax increased 1.3-fold, compared to subjects with normal renal function (CrCl ≥90 mL/minute [estimated by Cockcroft-Gault]).
Hepatic function impairment: Larotrectinib clearance is reduced in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C). Following oral administration of a single 100 mg larotrectinib dose, the larotrectinib AUC0-∞ increased 1.3-fold in subjects with mild impairment (Child-Pugh class A), 2-fold in subjects with moderate impairment (Child-Pugh class B), and 3.2-fold in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function. The larotrectinib Cmax increased 1.5-fold in subjects with severe impairment, compared to subjects with normal hepatic function.
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