Adult: In patients who have neurotrophic tyrosine receptor 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 treatment options or that have progressed following treatment: 100 mg bid, continued until disease progression or unacceptable toxicity. Dosage modification and dosing interruption or discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines). Child: BSA ≥1 m2: 100 mg bid, continued until disease progression or unacceptable toxicity. BSA <1 m2: 100 mg/m2 bid, continued until disease progression or unacceptable toxicity. Dosage modification and dosing interruption or discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).
Special Patient Group
Patients taking concurrent strong CYP3A4 inhibitor: Avoid if possible. If coadministration is necessary, reduce dose by 50%. After the inhibitor has been discontinued for at least 3-5 elimination half-lives, resume larotrectinib at the dose taken prior to initiating the strong CYP3A4 inhibitor.
Patients taking concomitant strong CYP3A4 inducer: Avoid if possible. If coadministration is necessary, double the larotrectinib dose. After the inducer has been discontinued for at least 3-5 elimination half-lives, resume larotrectinib at the dose taken prior to initiating the strong CYP3A4 inducer.
Hepatic Impairment
Moderate (Child-Pugh class B) to severe (Child-Pugh class C): Reduce the initial dose by 50%.
Administration
May be taken with or without food. Avoid grapefruit or grapefruit juice. Cap: Swallow whole, do not chew/crush.
Contraindications
Pregnancy and lactation.
Special Precautions
Coadministration with strong CYP3A4 inhibitor and inducer. Moderate to severe hepatic impairment. Children.
Adverse Reactions
Significant: Increased hepatic transaminases (any grade), including AST or ALT; neurological effects of any grade (e.g. dizziness, delirium, dysarthria, gait disturbance, paraesthesia, memory impairment, tremor; rarely, encephalopathy); skeletal fractures. Blood and lymphatic system disorders: Anaemia, neutropenia. Gastrointestinal disorders: Nausea, vomiting, constipation, dysgeusia, abdominal pain, diarrhoea. General disorders and administration site conditions: Fatigue, fever, peripheral oedema. Injury, poisoning and procedural complications: Fall. Investigations: Increased blood alkaline phosphatase, increased weight (abnormal weight gain). Metabolism and nutrition disorders: Decreased appetite, hypoalbuminaemia. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscle weakness, back pain, pain in the extremity. Nervous system disorders: Headache. Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea, nasal congestion. Vascular disorders: Hypertension.
Patient Counseling Information
This drug may cause dizziness and fatigue, if affected, do not drive or operate machinery. Females of childbearing potential and males (with non-pregnant partner of childbearing potential) must use effective contraceptive methods during therapy and for at least 1 month after the final dose.
Monitoring Parameters
Confirm the presence of NTRK gene fusion in tumour specimens and pregnancy status (in females of childbearing potential) prior to starting therapy. Monitor LFTs including AST and ALT at baseline, every 2 weeks during the 1st month, then monthly thereafter, and as clinically indicated. Monitor for signs and symptoms of neurotoxicity.
Drug Interactions
May increase plasma concentrations with strong CYP3A4, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole). May decrease plasma concentrations with strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin). May increase plasma concentrations of CYP3A4 substrates (e.g. alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).
Food Interaction
May increase plasma concentrations with grapefruit or grapefruit juice. May decrease plasma concentrations with St. John’s wort.
Action
Description: Mechanism of Action: Larotrectinib is an ATP-competitive, potent and highly selective inhibitor of tropomyosin receptor kinase (TRK) proteins; TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Chromosomal rearrangements involving in-frame fusions of NTRK genes may lead to constitutively-activated TRK fusion proteins that act as the oncogenic driver, promoting cell proliferation and tumour cell line survival. Larotrectinib demonstrates antitumour action 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. Pharmacokinetics: Absorption: Bioavailability: Cap: 34% (range: 32-37%). Time to peak plasma concentration: Approx 1 hour. Distribution: Plasma protein binding: 70%. Metabolism: Metabolised in the liver mainly by CYP3A4 isoenzyme into an O-linked glucuronide metabolite. Excretion: Via faeces (58%, 5% as unchanged drug); urine (39%, 20% as unchanged drug). Elimination half-life: 2.9 hours.
Chemical Structure
Larotrectinib Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 46188928, Larotrectinib. https://pubchem.ncbi.nlm.nih.gov/compound/Larotrectinib. Accessed July 27, 2021.
Storage
Cap: Store between 20-25°C. Oral solution: Store between 2-8°C. Do not freeze. Follow applicable procedures for receiving, handling, administration, and disposal.
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