Larotrectinib, also known by its brand name Vitrakvi, is a medication used in the treatment of cancer. It belongs to a class of drugs called tyrosine kinase inhibitors (TKIs).

Larotrectinib is specifically used for the treatment of certain solid tumors that have a genetic alteration called a neurotrophic receptor tyrosine kinase (NTRK) gene fusion. NTRK gene fusions occur when two genes, NTRK1, NTRK2, or NTRK3, become joined together, resulting in the production of abnormal TRK proteins. These abnormal proteins can drive the growth of cancer cells.

Larotrectinib works by inhibiting the activity of these abnormal TRK proteins, thereby blocking the signals that promote cancer cell growth. By targeting the specific genetic alteration, larotrectinib has shown effectiveness in treating cancers harboring NTRK gene fusions across various sites in the body, including lung, thyroid, colorectal, and other cancers.

Larotrectinib (Vitrakvi) Uses:

• Solid tumors [Ref]:
  • It is indicated in children and adult patients for the treatment of solid tumors that have an NTRK (neurotrophic receptor tyrosine kinase) gene fusion without a known acquired resistance mutation.
  • Eligible patients include metastatic disease or where surgical resection is not possible and may result in morbidity, patients win whom a satisfactory alternative treatment is not available, or in patients with disease progression with the treatment.

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Larotrectinib (Vitrakvi) Dose in Adults:

Larotrectinib (Vitrakvi) Dose in the treatment of Solid tumors (with neurotrophic receptor tyrosine kinase [NTRK] gene fusion):

• Larotrectinib is taken by mouth in the form of capsules or a liquid solution.
• For the treatment of solid tumors with a specific genetic alteration called NTRK gene fusion, the recommended dose is 100 mg taken twice daily.
• This dosage is continued until there is disease progression (the cancer worsens) or the patient experiences unacceptable side effects.

Dosage adjustment for CYP3A inhibitors/inducers:

If a patient is taking larotrectinib and needs to use medications that are strong CYP3A4 inhibitors (medications that can increase the levels of larotrectinib in the body) or strong CYP3A4 inducers (medications that can decrease the levels of larotrectinib in the body), dosage adjustments may be necessary. Here are the recommendations:

• Strong CYP3A4 inhibitors:
  • It is generally advised to avoid using strong CYP3A4 inhibitors together with larotrectinib.
  • However, if it's necessary to use them, the larotrectinib dose should be reduced by 50%.
  • When the strong CYP3A4 inhibitor is stopped, the larotrectinib dose should be increased to the dose that was used before starting the CYP3A4 inhibitor.
  • This should be done after a period of 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor, which is the time it takes for the medication to be mostly eliminated from the body.
• Strong CYP3A4 inducers:
  • It is generally advised to avoid using strong CYP3A4 inducers together with larotrectinib.
  • If concomitant use is necessary, the larotrectinib dose should be doubled.
  • When the strong CYP3A4 inducer is discontinued, the larotrectinib dose should be reduced to the dose that was used before starting the CYP3A4 inducer.
  • This should be done after a period of 3 to 5 elimination half-lives of the strong CYP3A4 inducer.

Missed doses:

• If a dose of larotrectinib is missed, it's important not to take a double dose or make up for the missed dose within 6 hours of the next scheduled dose.
• Simply continue with the regular dosing schedule and take the next dose at the scheduled time.
• In case vomiting occurs after taking a dose of larotrectinib, it is advised to take the next scheduled dose at its designated time.
• Do not take an additional dose to compensate for the vomited dose.

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Larotrectinib (Vitrakvi) Dose in Children:

Note: Capsule and oral solution may be used interchangeably.

Larotrectinib (Vitrakvi) Dose in the treatment of unresectable or metastatic solid tumors with the presence of neurotrophic receptor tyrosine kinase (NTRK) gene fusion:

Dose for Infants, Children, and Adolescents (Oral):

Body Surface Area (BSA)	Dose
BSA < 1 m²	100 mg/m²/dose twice daily
BSA ≥ 1 m²	100 mg twice daily

Note: Larotrectinib should be continued until there is disease progression (when the cancer worsens) or unacceptable toxicity (severe side effects that cannot be tolerated).

Dosing Adjustment for Toxicity (Grade 3 or 4 adverse reactions):

• Withhold treatment until adverse reaction resolves or improves to baseline or grade 1.
• Resume treatment with appropriate dosage modification if resolution occurs within 4 weeks.
• Permanently discontinue Larotrectinib if adverse reaction does not resolve within 4 weeks or if unable to tolerate after 3 dose modifications.

Dose Modification:

Modification Number	BSA < 1 m²	BSA ≥ 1 m²
First	75 mg/m²/dose twice daily	75 mg twice daily
Second	50 mg/m²/dose twice daily	50 mg twice daily
Third	25 mg/m²/dose twice daily	100 mg once daily

Dosing Adjustment for Concomitant Therapy:

• Coadministration with strong CYP3A4 inhibitors: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If unavoidable, reduce larotrectinib dose by 50%. When the strong CYP3A4 inhibitor is discontinued, increase larotrectinib dose (after 3 to 5 elimination half-lives of the CYP3A4 inhibitor) to the dose used prior to starting the CYP3A4 inhibitor.
• Coadministration with strong CYP3A4 inducers: Avoid use of strong CYP3A4 inducers with larotrectinib. If unavoidable, double the larotrectinib dose. When the strong CYP3A4 inducer is discontinued, reduce the larotrectinib dose (after 3 to 5 elimination half-lives of the CYP3A4 inducer) to the dose used prior to starting the CYP3A4 inducer.

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Pregnancy Risk Category: N (not assigned)

• Larotrectinib has the potential to harm the developing fetus if taken by pregnant women.
• It affects a signaling pathway called TRK, and individuals with certain genetic mutations in this pathway have experienced conditions such as obesity, developmental delays, cognitive impairment, insensitivity to pain, and reduced sweating.
• Therefore, before starting larotrectinib, a woman's pregnancy status should be assessed, and if she is of reproductive age, she should use effective contraception during treatment and for at least one week after the last dose of larotrectinib.
• Similarly, men taking larotrectinib who have female partners capable of becoming pregnant should also use effective contraception during treatment and for one week after the final dose.

Use of Larotrectinib while breastfeeding

• The presence of larotrectinib in breast milk is not known, and it is unclear whether it can pass into breast milk.
• To ensure the safety of the infant, it is advised not to breastfeed during larotrectinib therapy and for at least one week after the final dose of larotrectinib.
• This recommendation is made to minimize any potential adverse effects that could occur in a breastfed infant.

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Larotrectinib (Vitrakvi) Dose in Kidney Disease:

Adjustment in the dose is not necessary in patients with kidney disease.

Larotrectinib (Vitrakvi) Dose in Liver disease:

Hepatic impairment prior to treatment initiation:

Prior to initiating treatment with larotrectinib, the hepatic (liver) function of the patient should be assessed.

• If the patient has mild hepatic impairment (Child-Pugh class A), no adjustment to the larotrectinib dose is necessary.
• If the patient has moderate to severe hepatic impairment (Child-Pugh classes B and C), the initial dose of larotrectinib should be reduced by 50% to ensure safety.

Hepatotoxicity during treatment:

• During the course of treatment, if the patient experiences grade 3 or 4 hepatic adverse reactions (severe liver-related side effects), larotrectinib should be temporarily stopped until the adverse reaction resolves to baseline or grade 1.
• If the resolution occurs within 4 weeks, the treatment can be resumed at the next lower dosage level.
• However, if the adverse reaction does not resolve within 4 weeks or if the patient is unable to tolerate larotrectinib even after three dose reductions, larotrectinib should be permanently discontinued.

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Common Side Effects of Larotrectinib (Vitrakvi):

• Cardiovascular:
  • Peripheral Edema
  • Hypertension
• Central nervous system:
  • Neurotoxicity
  • Fatigue
  • Dizziness
  • Headache
  • Myasthenia
• Endocrine & metabolic:
  • Hypoalbuminemia
  • Weight gain
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
  • Abdominal pain
  • Decreased appetite
• Hematologic & oncologic:
  • Anemia
  • Neutropenia
• Hepatic:
  • Increased serum alanine aminotransferase
  • Increased serum aspartate aminotransferase
  • Increased serum alkaline phosphatase
• Neuromuscular & skeletal:
  • Arthralgia
  • Myalgia
  • Back pain
  • Limb pain
• Respiratory:
  • Cough
  • Dyspnea
• Miscellaneous:
  • Fever

Less Common Side Effects of Larotrectinib (Vitrakvi):

• Central nervous system:
  • Falling
  • Delirium
  • Abnormal gait
  • Dysarthria
  • Paresthesia
• Respiratory:
  • Nasal congestion

Rare side effects of Larotrectinib (Vitrakvi):

• Cardiovascular:
  • Pericardial effusion
  • Syncope
• Central nervous system:
  • Cerebral edema
  • Memory impairment
• Dermatologic:
  • Cellulitis
  • Enterocutaneous fistula
• Endocrine & metabolic:
  • Dehydration
  • Hyponatremia
  • Increased amylase
  • Increased serum lipase
• Gastrointestinal:
  • Intestinal obstruction (small intestine)
  • Intestinal perforation
• Hematologic & oncologic:
  • Acute myelocytic leukemia
• Hepatic:
  • Jaundice
• Infection:
  • Sepsis
• Neuromuscular & skeletal:
  • Asthenia
  • Tremor
• Respiratory:
  • Pleural effusion

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Contraindications to Larotrectinib (Vitrakvi):

• The manufacturer did not mention any contraindications.

Warnings and precautions

Suppression of bone marrow

• Bone marrow suppression refers to a condition where the bone marrow, which is responsible for producing blood cells, is affected and may lead to a decrease in the production of red blood cells (anemia) or white blood cells (neutropenia).
• In the treatment with larotrectinib, if bone marrow suppression occurs, additional treatment may be necessary to manage this condition effectively.
• The specific treatment approach will depend on the severity and type of bone marrow suppression experienced by the patient.

Gastrointestinal toxicities:

• Gastrointestinal toxicity is a possible side effect of larotrectinib treatment.
• It may manifest as symptoms such as nausea, vomiting, constipation, or diarrhea.
• These gastrointestinal side effects are generally mild in nature.
• If any of these symptoms occur, it is important to inform your healthcare provider, who can provide guidance and support in managing them effectively.
• They may recommend medications or lifestyle modifications to alleviate these gastrointestinal symptoms and ensure your comfort during treatment with larotrectinib.

Hepatotoxicity

• Hepatotoxicity, which refers to liver damage, can occur with larotrectinib treatment.
• Transaminase enzymes, specifically AST and ALT, may increase in levels.
• This increase can be of any grade, but grade 3 elevations in AST or ALT have been reported more commonly, while grade 4 elevations are rare.
• The onset of AST and ALT elevation typically occurs within a median time of 2 months, but the range can vary from 1 month to 2.6 years for AST elevation and 1 month to 1.1 years for ALT elevation.
• Regular monitoring of liver function tests, including ALT and AST, is essential during larotrectinib treatment.
• Initially, liver function tests should be performed every 2 weeks for the first month, and then monthly thereafter or as clinically indicated.
• If elevations in AST or ALT occur, dose modifications, treatment interruption, dosage reduction, or even permanent discontinuation of larotrectinib may be necessary based on the severity of the elevation.
• For patients with preexisting moderate to severe hepatic impairment, it is recommended to start larotrectinib at reduced initial doses.
• This adjustment is made to ensure the safety and appropriate management of hepatic function in such patients.

Neurotoxicity:

• Neurotoxicity, which refers to adverse effects on the nervous system, can occur with larotrectinib treatment.
• These neurologic adverse reactions can range from mild to severe, with some cases reaching grade 3 or 4 severity.
• Most neurologic adverse reactions occur within the first 3 months of starting treatment, but the onset can vary from 1 day to 2.2 years.
• Grade 3 neurologic adverse reactions include symptoms such as delirium, difficulty speaking, dizziness, problems with walking, and abnormal sensations (paresthesia), while grade 4 encephalopathy is rare.
• Dose modifications may be necessary if patients experience neurologic adverse reactions like dizziness, problems with walking, delirium, memory problems, or tremors.
• It is important to inform patients and caregivers about the potential for neurotoxicity.
• If patients experience neurologic adverse reactions, they should avoid activities that require mental alertness, such as driving or operating heavy machinery.
• Depending on the severity, treatment interruption, dosage reduction, or permanent discontinuation of larotrectinib may be required.

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Larotrectinib: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
ARIPiprazole	CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Substrates (High risk with Inhibitors)	Larotrectinib may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dofetilide	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Flibanserin	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
NiMODipine	CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
P-glycoprotein/ABCB1 Inducers	May decrease the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Larotrectinib.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Risk Factor 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 half-life.
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 half-life.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
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.
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.
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.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Triazolam	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors.
Ubrogepant	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg.
Risk Factor X (Avoid combination)
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Lasmiditan	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Pimozide	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide.

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Monitoring parameters:

Assess NTRK gene fusion status:

• Before starting larotrectinib treatment, it is important to evaluate the presence of NTRK gene fusion in the tumor specimen.
• This helps determine the appropriateness of the treatment approach.

Regular liver function tests:

• During the initial month of larotrectinib treatment, liver function tests, including ALT and AST, should be performed every 2 weeks.
• After the first month, these tests should be conducted monthly or as advised by the healthcare provider.
• Monitoring liver function helps detect any potential hepatotoxicity.

Pregnancy test for females:

• Prior to initiating larotrectinib in females who are of reproductive potential, a pregnancy test should be performed to ensure the safety of the treatment.
• Effective contraception should be used by females and their male partners during larotrectinib therapy and for at least one week after the final dose.

Monitoring for neurotoxicity:

• Keep a close watch for signs and symptoms of neurotoxicity during larotrectinib treatment.
• Neurologic adverse reactions can occur, ranging from mild to severe.
• Promptly report any changes in mental alertness, balance, memory, or abnormal sensations to the healthcare provider.

Ensuring adherence:

• It is crucial to adhere to the prescribed treatment regimen and follow the healthcare provider's instructions.
• Regularly take the prescribed larotrectinib dose and report any missed doses or difficulties in adhering to the treatment plan.

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How to administer Larotrectinib (Vitrakvi)?

Oral administration:

• Larotrectinib can be taken with or without food.
• Swallow the capsules whole with water, without chewing or crushing them.

Oral solution:

• When using the oral solution, caution should be exercised while measuring the dose.
• It is recommended to use an oral syringe to ensure accurate dosing.

Interchangeability:

• The capsules and oral solution of larotrectinib can be used interchangeably, depending on the patient's preference or specific needs.

Following these administration instructions helps ensure the proper delivery of the medication and maximize its effectiveness.

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Mechanism of action of Larotrectinib (Vitrakvi):

	Larotrectinib
Targets	TRKA, TRKB, TRKC proteins
Encoded by	NTRK1, NTRK2, NTRK3 genes
Mechanism of Action	Inhibits constitutively-activated TRK fusion proteins in tumor cells
Effects	Blocks abnormal TRK fusion proteins' oncogenic effects
Action	Inhibits tumor cell proliferation and promotes cell survival
Effective in	Tumors with constitutive TRK protein activation due to gene fusions, protein deletions, or overexpression
Larotrectinib, by targeting and inhibiting the abnormal TRK fusion proteins resulting from NTRK gene rearrangements, shows effectiveness in suppressing tumor growth and improving patient outcomes in cases where TRK protein activation is implicated in tumorigenesis.

Distribution:

• Larotrectinib has a distribution volume of approximately 48 liters.

Protein Binding:

• It binds to plasma proteins, with a binding rate of 70%.

Metabolism:

• Larotrectinib undergoes hepatic metabolism, primarily through the action of the enzyme CYP3A4.
• It is metabolized into an O-linked glucuronide metabolite.

Bioavailability:

• The bioavailability of Larotrectinib in capsule form is approximately 34%, with a range of 32% to 37%.
• This indicates the percentage of the administered dose that reaches the systemic circulation.

Elimination Half-life:

• The elimination half-life of Larotrectinib is 2.9 hours.
• This refers to the time it takes for half of the drug concentration in the bloodstream to be eliminated from the body.

Time to Peak:

• Larotrectinib reaches its peak concentration in the bloodstream in approximately 1 hour after administration.

Excretion:

• Larotrectinib is primarily excreted in the feces (58%), with approximately 5% of the drug being excreted unchanged.
• It is also excreted in the urine (39%), with around 20% of the drug being excreted unchanged.

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International Brands of Larotrectinib:

• Vitrakvi

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Larotrectinib Brand Names in Pakistan:

No Brands Available in Pakistan.