Larotrectinib - Uses, Dosage, Side Effects, and Drug Warnings

Overview:

Larotrectinib is a tropomyosin receptor kinase (TRK) inhibitor with antineoplastic activity. Larotrectinib binds to tropomyosin receptor kinase, thereby preventing neurotrophin-TRK interaction and TRK activation, resulting in cellular apoptosis and the inhibition of cellular growth in tumors that overexpress TRK. Tropomyosin receptor kinase is activated by neurotrophins, mutated in various types of cancer cells, and plays an essential role in tumor cell growth and survival. Larotrectinib is an innovative new cancer therapy medication targeting key, specific genetic biomarkers of cancer rather than particular types of tumors.

How Does Larotrectinib Work?

Tropomyosin receptor kinases such as TRKA, TRKB, and TRKC control neurons' growth, survival, and differentiation when combined with endogenous neurotrophin ligands. The NTRK1, NTRK2, and NTRK3 genes encode the TRKA, TRKB, and TRKC. The rearrangement of the chromosomes causing the fusions of these genes with various partners, translocations in the TRK kinase domains, mutations in the TRK ligand-binding site, amplifications of NTRK, or the expression of TRK splice variants results in the formation of chimeric TRK fusion proteins which in turn can act on cancer cells promoting cell proliferation and survival in tumor cells.

Larotrectinib inhibits TRKs, including TRKA, B, and C. Larotrectinib has been found to cause anti-tumor activity in cells with TRK proteins activations occurring from deletion of a protein regulatory domain, gene fusions, or in cells with TRK protein overexpression. Larotrectinib has negligible activity in cell lines with point mutations in the TRKA kinase domain.

Uses of Larotrectinib:

Larotrectinib is indicated for the treatment of adults and children with solid tumors with either of the following:

• Have a neurotrophic receptor tyrosine kinase gene fusion without an acquired resistance mutation.

• Metastatic tumors, where surgical resection could lead to fatality.

• Have no alternative treatments or have already progressed after the treatment.

Dosage Restrictions:

Route of Administration - Oral.

Dosage Strengths -

• Capsules - 25 mg and 100 mg.

• Solution - 20 mg/mL.

Dosage Forms -

1. Capsules:

• 25 mg - Opaque, white gelatin capsule, size 2, with LOXO and LARO 25 mg printed on them.
• 100 mg - Opaque, white gelatin capsule, size 0, with LOXO and LARO 100 mg printed on them.

2. Oral Solution:

• 20 mg/mL - Clear yellowish to an orange solution.

Special Considerations:

• Geriatric: There is not much data on the use of Larotrectinib on people aged 65 and above to determine how they respond differently from younger individuals.

• Hepatic Impairment: No dose adjustment is needed for individuals with mild hepatic impairment. In contrast, the dose of Larotrectinib should be reduced in people with moderate to severe hepatic impairment.

• Renal Impairment: No adjustment of dose is necessary for individuals with renal impairment.

• Pregnancy: Larotrectinib can harm the embryo when administered to a pregnant woman. It can also lead to birth defects and miscarriages.

• Breastfeeding: Not much data is available on the presence of the drug or its metabolites in human milk. Women are advised to abstain from breastfeeding because of the possible risk of serious adverse reactions in breastfed children.

• Females and Males of Reproductive Age: The females of reproductive potential should use effective contraception during treatment with Larotrectinib.

Warnings and Precautions:

• Neurotoxicity - Most neurologic side effects with Larotrectinib occurred in the first three months of treatment, such as delirium, dysarthria, dizziness, gait disturbance, and paresthesia. Side effects leading to dose modification included dizziness, disturbance in gait, delirium, memory impairment, and tremor.

• Hepatotoxicity - Larotrectinib has been found to increase the level of aspartate aminotransferase and alanine transaminase.

• Embryo-Fetal Toxicity - Larotrectinib may cause fetal harm when administered to a pregnant woman.

For Patients

What Is Cancer?

Cancer is a condition in which there is an uncontrollable growth of some of the body cells, spreading to other body parts of the body. Uncontrolled growth can start anywhere in the body. Cell division is the process where the cells grow and multiply so as to form new cells. On becoming old or damaged, the cells die, and new cells take their place. Sometimes there is a change in the process, and abnormal or damaged cells grow and multiply instead. These abnormal cells may form tumors or lumps of tissue. Tumors can be cancerous (malignant) or not cancerous (benign).

The malignant tumors spread into the nearby tissues and travel to different body parts. This process is known as metastasis.

Benign tumors do not spread across the body. After removal, the benign tumors do not grow back, whereas the cancerous tumors do.

Why Is Larotrectinib Prescribed for Cancer?

Larotrectinib is a medicine that is used to treat a specific type of solid tumors in adults and children of one month of age and older that have spread to other body parts or cannot be treated successfully with surgery. This medication is prescribed in the absence of other treatments or if the tumor worsens after other treatments. Larotrectinib belongs to a class of medications known as kinase inhibitors. It acts by blocking the action of the abnormal protein that commands the cancer cells to multiply, thus slowing the growth of tumors.

Facts One Should Know About Larotrectinib:

How Should One Take Larotrectinib?

• Larotrectinib is available as a capsule and an oral solution.

• It is taken with or without food twice daily.

• Larotrectinib should be taken around the same times daily.

• The directions mentioned on the prescription should be followed carefully.

• Take the medication as directed, not more or less.

• The capsules should be swallowed completely with water and not chewed or crushed.

• With the help of an oral syringe, accurately measure and take the correct dose of the solution. Do not use a teaspoon to measure the medication. The oral syringe should be replaced after using it for seven days or on the damage.

• In case of giving the solution to a kid, place the tip of the syringe into the child's mouth against the cheek.

• If the child vomits up a dose or one is unsure whether the entire dose was administered, another dose should not be given.

• Do not repeat the dose after immediately vomiting the medicine.

What To Discuss With the Doctor Before Starting Larotrectinib?

• The doctor should be informed about any allergy to Larotrectinib, any of its ingredients, or any other medications.

• Inform the doctor in case of other non-prescription and prescription medications, vitamins, nutritional supplements, and herbal products that one is taking or plans to take. Do not forget to mention any of the following: Antifungals, such as Itraconazole and Ketoconazole, Avanafil, Clarithromycin, and Buspirone. Medications for human immunodeficiency virus or acquired immunodeficiency syndromes such as Efavirenz, Indinavir, Nelfinavir, Nevirapine, Ritonavir, and Saquinavir. Medications suppress the immune system such as Everolimus, Sirolimus, and Tacrolimus, Lovastatin, Midazolam, Nefazodone, Pioglitazone, Rifabutin, and Rifampin. Medications for seizures such as Carbamazepine, Phenobarbital, Phenytoin, Sildenafil, Simvastatin, and Vardenafil.

• Inform the doctor if one is taking St. John's wort. Do not take St. John's wort while on Larotrectinib.

• The doctor should be informed if one has conditions affecting the nervous system or any liver disease.

• The doctor should be informed if one is pregnant or planning to conceive.

• Inform the doctor if one is breastfeeding. One should not breastfeed during the treatment and for one week after the final dose.

• Larotrectinib may cause drowsiness, dizziness, or confusion. Do not drive a car or operate machines unless one knows how the medication affects them.

Is Larotrectinib Safe?

The medication is safe if taken as prescribed.

Is Larotrectinib Effective?

Yes, Larotrectinib has been found to be effective in treating solid metastatic tumors with a high risk of resection.

What Are the Side Effects of Larotrectinib?

Larotrectinib has the following side effects:

• Constipation.

• Diarrhea.

• Cough.

• Vomiting.

• Nausea.

• Stomach pain.

• Headache.

• Nasal congestion.

• Weight gain.

• Muscle weakness.

• Increased thirst.

• Change in the color or amount of urine.

• Dry skin.

• Fainting.

• Muscle, joint, or back pain.

Serious side effects include the following:

• Burning sensation of hands and feet.

• Slow or difficult speech.

• Accidental falling.

• Tingling or numbness in hands and feet.

• Fever.

• Swelling in hands, feet, ankles, or lower legs.

• Pale skin.

• Appetite loss.

• Yellowing of the skin or eyes.

• Stomach pain in the upper right side.

• Shortness of breath.

• Tiredness or weakness.

Can One Stop Taking Larotrectinib Without the Doctor's Approval?

Larotrectinib should not be stopped without the doctor's consent.

Are There Any Dietary Restrictions to Consider When Taking Larotrectinib?

One should not take grapefruit or grapefruit juice while on this medication.

How Should One Store Larotrectinib?

The medication should be kept in a tightly closed container and out of the kid's reach. The capsules should be stored at room temperature, away from heat and moisture. The oral solution should be kept in the refrigerator tightly closed. It should not be frozen.

How Should One Dispose of Larotrectinib?

Any unused oral solution should be disposed of after 90 days of opening the bottle for the first time. Unused medications should be removed in special ways so that pets, children, and other people cannot take them. The medication should not be flushed in the toilet. Instead, it should be disposed of through a medicine take-back program.

What To Do in Case of Overdose?

During an overdose, the poison control team should be contacted. If the person has collapsed, had a seizure, has trouble breathing, or is unconscious, emergency services should be called immediately.

For Doctors

Indications -

Larotrectinib is indicated in treating adults and kids with solid tumors. Tumors meeting the following criteria:

• Have a neurotrophic receptor tyrosine kinase gene fusion without a known acquired resistance mutation.

• The tumors are metastatic, and their surgical resection might cause fatality.

• Have no alternative treatments or have progressed even after the treatment.

What Is the Pharmacology of Larotrectinib?

Description:

Larotrectinib is the inhibitor of the enzyme kinase. Chemically it is Larotrectinib sulfate. The molecular formula and weight are C21H24F2N6O6S, and 526.51 g/mol for the sulfate salt and 428.44 g/mol for the free base, respectively. Larotrectinib sulfate is an off-white to yellowish solid that does not absorb moisture. The aqueous solubility of Larotrectinib at 37ᴼC is pH-dependent.

Components -

Capsule:

1. Active Ingredients - Larotrectinib.

2. Inactive Ingredients - Gelatin, titanium dioxide, and edible ink.

Oral Solution:

1. Active Ingredients - Larotrectinib.

2. Inactive ingredients - Purified water, hydroxypropyl betadex, sucrose, glycerin, sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol, and flavoring. Preservatives methylparaben and potassium sorbate.

Clinical Pharmacology

Mechanism of Action -

Larotrectinib inhibits the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. The genes NTRK1, NTRK2, and NTRK3, encode TRKA, B, and C. Chromosomal rearrangements involving the fusion of the genes with other partners can result in constitutively-activated chimeric TRK fusion proteins. These proteins act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. Larotrectinib has shown anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or cells with TRK protein overexpression. Larotrectinib causes minimal activity in cell lines with point mutations in the TRKA kinase domain, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to Larotrectinib include G623R, G696A, and F617L.

Pharmacodynamics-

Cardiac Electrophysiology:

At a 9-fold higher than the recommended adult dose, Larotrectinib does not prolong the QTc intervals to any clinically relevant extent.

Pharmacokinetics

• Mean Cmax- 788 ng/mL

• Median Tmax- One hour

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

A. Distribution

• Steady-State Plasma Levels- 48 Liters.

• Time to Approach Steady-State Levels- 3 days.

• Binding to Plasma Proteins- 70 percent.

B. Metabolism

Larotrectinib is metabolized by CYP3A4. After an oral administration of a single radiolabeled 100 mg dose of Larotrectinib on healthy subjects, unchanged Larotrectinib constituted around 19 percent, and an O-linked glucuronide constituted around 26 percent of the major circulating radioactive drug components in the plasma.

C. Excretion

After a single dose administration, 58 percent of the administered radioactivity was recovered in feces, and 39 percent recovered in urine.

Recovery of Larotrectinib:

Feces - 58 percent

Urine - 39 percent

D. Elimination

The mean clearance of Larotrectinib is 98 L/h, and the half-life is 2.9 hours after oral administration of the drug.

Special Considerations:

1) Pregnancy: Larotrectinib can harm the embryo when administered to a pregnant woman. It can also lead to birth defects and miscarriages.

2) Breastfeeding: Not much data is available on the presence of the drug or its metabolites in human milk. Women are advised to abstain from breastfeeding because of the risk of serious adverse reactions in breastfed children.

3) Females and Males of Reproductive Age: The females of reproductive potential should use effective contraception during treatment with Larotrectinib and for one week after the final dose. The males with female partners of reproductive potential should use effective contraception during treatment with Larotrectinib and for one week after the last dose.

4) Geriatric: There is not much data on the use of Larotrectinib on people aged 65 and above to assess whether they respond differently from younger people.

5) Hepatic Impairment: No dose adjustment is needed for individuals with mild hepatic impairment. In contrast, the dose of Larotrectinib should be reduced in people with moderate to severe hepatic impairment.

6) Renal Impairment: No adjustment of dose is necessary for individuals with renal impairment.

Drug Interactions

• Abrocitinib - When combined with Abrocitinib, the serum concentration of Larotrectinib can be increased.

• Amprenavir - When combined with Amprenavir, the metabolism of Larotrectinib can be decreased.

• Bupivacaine - In combination with Bupivacaine with Larotrectinib, the severity of methemoglobinemia can be increased.

What Have Clinical Trials Shown With Regard to Larotrectinib?

The efficacy of Larotrectinib was evaluated in pediatric and adult patients with solid metastatic tumors or tumors which could not be resected with an NTRK gene fusion in one of three open-label, multicenter, single-arm clinical trials: Study LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).

Adult patients were given Larotrectinib, an oral dose of 100 mg twice daily, and kids (18 years or younger) received 100 mg/m2 to 100 mg orally twice daily. Positive NTRK gene fusion status was determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization. The major outcome was based on the overall response and duration of response, as determined by a blinded independent review committee (BIRC). The efficacy evaluation was based on the patients with solid tumors along with an NTRK gene fusion across the three clinical trials with baseline characteristics like age 45 years (range four months to 76 years), 22 percent less than 18 years of age, and 78 percent more than or equal to 18 years of age, and ECOG performance status 0 to1 (93 percent) or 2 (7 percent). 82 percent of them had metastasis, and 18 percent had locally advanced unresectable cancer. Ninety-eight percent of patients got treatment for their cancer before. Of these, 82 percent received systemic therapy, and 35 percent received three or more prior systemic regimens.

Patient Counseling Information:

• The individual should read the FDA-approved patient labeling (patient information and instructions for use).

• Neurotoxicity: The patients should be advised to notify their healthcare provider of new or worsening neurotoxicity. The patients should not drive or operate machinery if they experience neurologic adverse reactions.

• Hepatotoxicity: The patients must undergo laboratory tests to monitor liver function.

• Embryo-Fetal Toxicity: The males and females of reproductive age should be advised of the potential risk to a fetus.

Administration Instructions-

• Larotrectinib should be taken exactly as per the doctor's advice.

• One should not change the dose or stop taking Larotrectinib unless advised by the doctor.

• Larotrectinib is available in capsules and as an oral solution.

• In the case of the oral solution, the doctor will provide the Larotrectinib oral solution and oral syringes.

• The doctor would show how to measure and give a dose of Larotrectinib correctly.

• Larotrectinib is usually taken by mouth twice daily.

• The capsule should be swallowed whole and not chewed or crushed.

• Larotrectinib should be taken with or without food.

• If one vomits after taking a dose of Larotrectinib, wait and take the next dose at your scheduled time.

• On missing a dose of Larotrectinib, please take it as soon as remember unless the next scheduled dose is due within six hours.

• Take the next dose at the normal time.

• In case of an overdose, call the doctor.

Complications or Side Effects:

• Increased liver enzymes.

• Hypoalbuminemia.

• Anemia.

• Fatigue.

• Increased alkaline phosphatase.

• Cough.

• Nausea.

• Dizziness.

• Vomiting.

• Constipation.

• Neutropenia.

• Diarrhea.

• Pyrexia.

• Dyspnea.

• Peripheral edema.

• Increased weight.

• Headache.

• Arthralgia.

• Myalgia.

• Muscular weakness.

• Decreased appetite.

• Abdominal pain.

• Back pain.

• Pain in extremities.

• Hypertension.