Consumer medicine information

Vitrakvi

Larotrectinib

BRAND INFORMATION

Brand name

Vitrakvi

Active ingredient

Larotrectinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vitrakvi.

What is in this leaflet

This leaflet answers some common questions about Vitrakvi. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Vitrakvi against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What VITRAKVI is used for

Vitrakvi contains the active substance larotrectinib. It is used to treat a type of cancer called “Tyrosine Receptor Kinase (TRK) fusion cancer”. These cancers can appear in many different parts of the body.

Vitrakvi is used in adults and babies from 1 month old.

TRK fusion cancers always have a change in a gene called “Neurotrophic Tyrosine Receptor Kinase” (NTRK). The alteration in this gene causes the body to make a protein called “TRK fusion”. TRK fusion protein can cause uncontrolled cell growth and cancer.

Vitrakvi stops the TRK fusion proteins working and may slow or stop the cancer growing. It may also help to shrink the cancer.

Ask your doctor if you have any questions on how Vitrakvi works, or why this medicine has been prescribed for you.

This medicine is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 1 month.

Before you take VITRAKVI

When you must not take it

Do not take Vitrakvi if:

  • you have an allergy to larotrectinib (the active ingredient) or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant or are beast-feeding.

If you are not sure whether you should start using this medicine, talk to your Doctor or health care professional.

If you have not told your doctor about any of the above, tell your doctor or health care professional before you start taking Vitrakvi.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines including any that you get without a prescription from your pharmacy, supermarket, naturopath or health food shop such as vitamins, dietary supplements or herbal medicines.

Some medicines may affect the way Vitrakvi works or Vitrakvi may affect how other medicines work and cause serious side effects. In particular, tell your doctor if you are taking anything in this list or any other medicines:

  • Medicines that may increase the amount of larotrectinib in your blood and increase the risk of side effect such as:
    - itraconazole, ketoconazole, posaconazole and voriconazole, clarithromycin, telithromycin - used to treat fungal and bacterial infections
    - atazanavir, indinavir, nelfinavir, ritonavir, saquinavir - used to treat HIV infection
    - nefadozone - used to treat depression
  • Medicines that may decrease the amount of larotrectinib in your blood and make Vitrakvi less effective such as:
    - phenytoin, carbamazepine and phenobarbital - medicines used to treat seizures
    - St. John’s wort - herbal medicine used to treat depression
    - Rifampicin - used to treat bacterial infections
  • Medicines which larotrectinib may decrease the amount of how much of them is found in the blood and make them less effective, such as:
    - alfentanil - used as a narcotic pain medication
    - cyclosporine, sirolimus, tacrolimus - used to prevent organ rejection in patients after transplantation
    - Quinidine - used to treat abnormal heart rhythms
    - dihydroergotamine, ergotamine - used in migraine or cluster headache attack
    - fentanyl - used to treat chronic pain
    - pimozide - antipsychotic drug used to control motor or verbal tics

These medicines may be affected by Vitrakvi or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take VITRAKVI

Before starting the therapy, a test will be used to determine whether you have NRTK gene alteration.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Always take this medicine exactly as your doctor or pharmacist has told you. It is important to do this as long as your doctor tells you. Check with your doctor, pharmacist, or nurse if you are not sure.

If you do not understand the instructions on the box or bottle, ask your doctor or pharmacist for help.

How much to take

Adults (from 18 years):

  • the recommended dose of Vitrakvi in adults is 100 mg, two times a day (=200 mg total per day).
  • You will either take 1 capsule of 100 mg or 4 capsules of 25 mg to make a total dose of 100 mg, two times a day.
  • Your doctor will review your dose and change it as needed.

Babies and children (from 1 month old up to 18 years):

  • Your child’s doctor will work out the right dose for your child.
  • The maximum recommended dose is 100 mg (maximum of 1 capsule of 100 mg per dose, or 4 capsules of 25 mg per dose, or 5mL of the 20mg/mL solution), two times a day (=200 mg total per day).
  • Your child’s doctor will review your dose and change it as needed.

How to take it

Swallow Vitrakvi capsules whole with a full glass of water.

Do not open, chew or crush the capsule.

Vitrakvi can be taken with or without food.

Do not eat grapefruit or drink grapefruit juice while taking Vitrakvi. This may increase the amount of Vitrakvi in your body.

If you or your child vomit (are sick) after taking Vitrakvi:

Do not take an extra dose, just take your next dose at the usual time.

For oral solution you need a bottle adapter (28 mm diameter) and a syringe that can be used to give medicines by mouth. Use a 1 mL syringe with 0.1 mL marks for doses less than 1 mL. Use a 5 mL syringe with 0.2 mL marks for doses of 1 mL or more.

  • Press the bottle cap and turn it anti- clockwise to open the bottle.
  • Put the bottle adapter into the bottle neck and make sure it is well fixed.
  • Push the plunger fully into the syringe and then put the syringe in the adapter opening. Turn the bottle upside down.
  • Fill the syringe with small amount of solution by pulling the plunger down, then push the plunger upwards to remove any large bubbles that are in the syringe.
  • Pull the plunger down to the mark equal to the dose in mL prescribed by your doctor.
  • Turn the bottle the right way up and take the syringe out of the adapter.
  • Put the syringe in the mouth, pointing towards the inside of the cheek – this will help you swallow the medicine naturally. Slowly press the plunger in.
  • Put the bottle cap on and tightly close the bottle - leave the adapter in the bottle.

If necessary, Vitrakvi may be administered via a nasogastric feeding tube. For details how to do so, please ask your doctor, pharmacist or nurse.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you or your child vomit (are sick) after taking Vitrakvi, do not take an extra dose; just take your next dose at the usual time.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you stop taking Vitrakvi

Do not stop taking this medicine without talking to your doctor first. It is important to take Vitrakvi for as long as your doctor prescribes it for you.

If you are not able to take the medicine as your doctor prescribed, or you feel you do not need it anymore, contact your doctor right away.

If you have further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

If you forget to take it

Do not take a double dose to make up for the dose that you missed.

Take your next dose at the usual time

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much Vitrakvi, immediately contact your doctor, pharmacist, nurse or the Poisons Information Centre for advice, or go to Accident and Emergency at the nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

You can contact the Poisons Information Centre by dialling:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766.

Take the medicine package and this leaflet with you. You may be at a higher risk of experiencing the side effects described in Side Effects section.

While you are using VITRAKVI

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Vitrakvi.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell your doctor, pharmacist or nurse straight away if you get any of these symptoms during treatment:

nervous system problems such as feeling dizzy, difficulty walking normally, tingling, feeling numb, or a burning feeling in your hands and feet.

Vitrakvi can increase the amount of some substances in the blood which are made by the liver. Your doctor will do blood tests before and during treatment to check the level of these substances and check how well your liver is working.

Your doctor may reduce the dose of Vitrakvi and may delay or stop Vitrakvi treatment permanently (see also section ‘Side Effects’).

If you become pregnant while taking this medicine, tell your doctor immediately.

  • Avoid becoming pregnant during treatment with Vitrakvi. Based on how Vitrakvi works, the risk of permanent harm or birth defects to the baby cannot be ruled out.
  • If you are able to become pregnant, your doctor may do a pregnancy test before you start treatment with Vitrakvi.
  • You should also use effective methods of contraception while taking Vitrakvi and for at least one month after the last dose of Vitrakvi. Ask your doctor about the best method of contraception for you. Tell your doctor if you think you are pregnant or plan on becoming pregnant.
  • If you become pregnant during treatment with Vitrakvi or in the first month after your last dose, tell your doctor straight away.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Vitrakvi to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not give this medicine to infants under 1 month of age as it is not known if Vitrakvi is safe and effective in these infants.

Do not breast-feed while taking this medicine and for 3 days after the last dose of Vitrakvi. There are no data on the presence of larotrectinib in human milk, the effects of larotrectinib on the breastfed child, or the effects of larotrectinib on milk production.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Things to be careful of

Be careful driving or operating machinery until you know how Vitrakvi affects you. This medicine may cause dizziness, tiredness and nausea in some people. If you have any of these symptoms, do not drive, cycle, use any tools or machines or do anything else that could be dangerous. Children should be careful when riding bicycles or climbing trees.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Vitrakvi.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor as soon as possible if you notice any of the following:

  • Difficulty walking normally (gait disturbance)
  • Abnormal sense of touch, tingling (paraesthesia)
  • Change in how things taste (dysgeusia)
  • Weight increase

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Dizziness
  • Feeling tired (fatigue)
  • Stomach upset, including feeling sick (nausea), being sick (vomiting) or constipation
  • Muscle pain (myalgia)
  • Muscle weakness
  • Reduction in the number of red blood cells which makes you feeling tired, looking pale and you may feel your heart pumping (anaemia)

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress. These includes:

  • Increased liver enzymes shown in blood tests (called “alanine aminotransferase” and “aspartate aminotransferase”)
  • Decrease number of white blood cells (called “neutrophils” and “leukocytes”)
  • Abnormal results of tests to check for liver disease or bone disorders (high levels of “alkaline phosphatase”)

Your doctor will tell you if there are any changes in your blood test that might need treatment.

After using VITRAKVI

Storage

For capsules, store below 25°C (77°F).

For solution, keep refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze.

Do not store Vitrakvi or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Store in the original package to protect it from moisture.

Keep the bottle tightly closed.

Do not use this medicine if you notice that capsules look damaged.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Vitrakvi comes in two forms; capsules and solution.

  • Vitrakvi 25 mg hard capsules are white opaque hard gelatin capsule, size 2, with blue printing of “BAYER” cross and “25 mg” on body of capsule
  • Vitrakvi 100 mg hard capsules are white opaque hard gelatin capsule, size 0, with blue printing of “BAYER” cross and “100 mg” on body of capsule
  • Vitrakvi 20 mg/mL oral solution are 100 mL clear yellow to orange liquid solution

Ingredients

The active ingredient in Vitrakvi is larotrectinib; it comes in capsules and solution forms.

For capsule

Active ingredient:

larotrectinib

Inactive ingredients:

  • Gelatin
  • Titanium dioxide
  • Printing ink –blue: Shellac, FD&C Blue #2 aluminium lake, titanium dioxide, propylene glycol, ammonia solution and dimethicone

For solution

Active ingredient:

larotrectinib

Inactive ingredients:

  • Purified water
  • Hydroxypropyl betadex
  • Sodium citrate
  • Ora-Sweet®: purified water, sucrose, glycerol, sorbitol, citric acid, sodium dihydrogen phosphate, flavouring and preservative agents - methylparahydroxybenzoate and potassium sorbate
  • Natural Masking Type Flavor: glycerol, natural flavour ingredients
  • Natural Bitterness Masking Type Flavor: glycerol, natural flavour ingredients
  • Bitterness Masking Flavor: propylene glycol, natural flavour
  • FONATECH® Taste Modifier Flavor: propylene glycol, glycerol, natural flavour

Supplier

Vitrakvi is supplied in Australia by:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Australian registration number:

  • Vitrakvi 25 mg hard capsules: AUST R 320237
  • Vitrakvi 100 mg hard capsules: AUST R 320238
  • Vitrakvi 20mg/mL oral solution: AUST R 320239

This leaflet was prepared in September 2020.

®Registered Trademark of the Bayer Group, Germany.

® Bayer Australia Ltd.

All rights reserved.

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Vitrakvi

Active ingredient

Larotrectinib

Schedule

S4

 

1 Name of Medicine

Vitrakvi (larotrectinib).

2 Qualitative and Quantitative Composition

Vitrakvi 25 mg hard capsules.

Each capsule contains larotrectinib sulfate, equivalent to 25 mg of larotrectinib.

Vitrakvi 100 mg hard capsules.

Each capsule contains larotrectinib sulfate, equivalent to 100 mg of larotrectinib.

Vitrakvi 20 mg/mL oral solution.

Each mL oral solution contains larotrectinib sulfate, equivalent to 20 mg of larotrectinib.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vitrakvi 25 mg hard capsules.

White opaque hard gelatin capsule, size 2, with blue printing of "BAYER" cross and "25 mg" on body of capsule.

Vitrakvi 100 mg hard capsules.

White opaque hard gelatin capsule, size 0, with blue printing of "BAYER" cross and "100 mg" on body of capsule.

Vitrakvi 20 mg/mL oral solution.

Colourless to yellow or orange or red or brownish liquid solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Vitrakvi (larotrectinib) has provisional approval in Australia for the treatment of adult and paediatric patients with locally advanced or metastatic solid tumours that:
have a 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 either progressed following treatment or who have no satisfactory alternative therapy.
The decision to approve this indication has been made on the basis of objective response rate (ORR) and duration of response from single-arm clinical studies. The sponsor is required to submit further clinical data to confirm the clinical benefit of the medicine.

4.2 Dose and Method of Administration

Treatment with Vitrakvi should be initiated by physicians experienced in the administration of anticancer therapies.
The presence of an NTRK gene fusion in a tumour specimen should be confirmed by a validated test prior to initiation of treatment with Vitrakvi. (See Section 5.1 Pharmacodynamic Properties, Clinical trials).

Method of administration.

For oral use.
Vitrakvi is available as a capsule or oral solution formulation with equivalent oral bioavailability, and may be used interchangeably.

Capsule.

The patient should be advised to swallow the capsule whole with water.
Due to the bitter taste of the active ingredient, the capsule should not be opened, chewed, or crushed.

Oral solution.

Administer the oral solution by mouth or enterally by naso- or gastric-feeding tube with a dosing syringe.
The oral solution can be administered with or without food using an oral syringe of 1 mL or 5 mL volume or enterally by using a nasogastric feeding tube.
For doses below 1 mL, a 1 mL oral syringe should be used. The calculated dose volume should be rounded to the nearest 0.1 mL.
For doses of 1 mL and higher, a 5 mL oral syringe should be used. The dose volume should be calculated to the nearest 0.2 mL.
Vitrakvi should not be mixed with feeding formulas, if administered via nasogastric feeding tube. Mixing with the feeding formulas could lead to tube blockages.
Instructions for use.

Oral syringe.

Use a suitable oral syringe with CE marking and bottle adapter (28 mm diameter) if applicable.
For volumes less than 1 mL, use a 1 mL oral syringe with 0.1 mL graduation.
For volumes of 1 mL and higher, use a 5 mL oral syringe with 0.2 mL graduation.
Open the bottle: press the bottle cap and turn it counter-clockwise.
Insert the bottle adapter into the bottle neck and ensure it is well fixed.
Take the oral syringe and ensure that the plunger is fully depressed. Put the oral syringe in the adapter opening. Turn the bottle upside down.
Fill the oral syringe with small amount of solution by pulling the plunger down, then push the plunger upwards to remove any bubbles.
Pull the plunger down to the graduation mark equal to the quantity in mL as prescribed.
Turn the bottle the right way up and remove the oral syringe from the bottle adapter.
Slowly depress the plunger, directing the liquid towards the inside cheek to allow for natural swallowing.
Close the bottle with the original bottle cap (leaving the adapter in place).

Nasogastric feeding tube.

Use a suitable nasogastric feeding tube. The outer diameter of the nasogastric feeding tube should be selected based on the patient characteristics. Typical tube diameter, tube lengths and derived prime volumes are presented in Table 1.
The feeding should be stopped, and the tube flushed with at least 10 mL water.
Note: See exceptions regarding neonates and patients with fluid restrictions in the sub-point directly below.
A suitable syringe should be used to administer Vitrakvi to the nasogastric feeding tube.
The tube should be flushed again with at least 10 mL water to ensure Vitrakvi is delivered and to clear the tube.
Neonates and children with fluid restrictions may require minimal flushing volume of 0.5 to 1 mL or flushing with air to deliver Vitrakvi.
Restart the feeding.

Dosage regimen.

Adults.

The recommended dose of Vitrakvi in adults is 100 mg taken orally, twice daily until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Paediatric.

Dosing in paediatric patients is based on body surface area (BSA). The recommended dose of Vitrakvi in paediatric patients (1 month to 18 years) is 100 mg/m2 taken orally, twice daily with a maximum of 100 mg per dose until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Missed dose.

If a dose is missed, the patient should not take two doses at the same time to make up for a missed dose. Patients should take the next dose at the next scheduled time. If the patient vomits after taking a dose, the patient should not take an additional dose to make up for vomiting.

Dose modification.

Recommended dose modifications for Vitrakvi are provided in Table 2.
Vitrakvi should be permanently discontinued in patients who are unable to tolerate Vitrakvi after three dose modifications.
For all Grade 2 adverse reactions, continued dosing may be appropriate, though close monitoring to ensure no worsening of the toxicity is advised.
For adverse reactions ≥ Grade 3 not referring to liver function test abnormalities:
Vitrakvi should be withheld until the adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dose modification if resolution occurs within 4 weeks.
Vitrakvi should be permanently discontinued if an adverse reaction does not resolve within 4 weeks.
For dose modifications in case of liver function test abnormalities while receiving therapy with Vitrakvi, see Table 3 (for further information and frequency of laboratory evaluations in patients, see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

Additional information on special populations.

Co-administration with CYP3A4 inhibitors and inducers.

Co-administration with strong CYP3A4 inhibitors.

Avoid co-administration of strong CYP3A4 inhibitors with Vitrakvi including grapefruit or grapefruit juice. If co-administration of a strong CYP3A4 inhibitor cannot be avoided, reduce the Vitrakvi dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Vitrakvi dose taken prior to initiating the CYP3A4 inhibitor; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Co-administration with strong or moderate CYP3A4 inducers.

Avoid co-administration of strong or moderate CYP3A4 inducers with Vitrakvi. If co-administration of a strong CYP3A4 inducer cannot be avoided, double the Vitrakvi dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the Vitrakvi dose taken prior to initiating the CYP3A4 inducer; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Patients with hepatic impairment. The starting dose of Vitrakvi should be reduced by 50% in patients with moderate (Child Pugh B) to severe (Child Pugh C) hepatic impairment. No dose adjustment is recommended for patients with mild hepatic impairment (Child Pugh A) (see Section 5.2 Pharmacokinetic Properties).
Patients with renal impairment. Clinical data from a pharmacokinetic study indicate that larotrectinib exposure was increased 1.46-fold in patients with end-stage renal disease (see Section 5.2 Pharmacokinetic Properties). No dose adjustment is required for patients with renal impairment.
Paediatric patients. Clinical data indicate that systemic exposure in paediatric patients (1 month to 18 years of age) at body surface area (BSA) adjusted dose was similar to that in adults given the dose of 100 mg BID (see Section 5.2 Pharmacokinetic Properties).
Elderly. Clinical data indicate that age has no effect on the systemic exposure of larotrectinib (see Section 5.2 Pharmacokinetic Properties). No dose adjustment is necessary in elderly patients.
Gender. Population pharmacokinetic analyses indicate that gender has no effect on the systemic exposure of larotrectinib (see Section 5.2 Pharmacokinetic Properties).
No dose adjustment is necessary.
Body weight. Population pharmacokinetic analyses indicate that body weight has no effect on the systemic exposure of larotrectinib (see Section 5.2 Pharmacokinetic Properties).
No dose adjustment is necessary.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

Neurologic reactions.

Neurologic reactions including dizziness, gait disturbance and paraesthesia were reported in patients receiving larotrectinib (see Section 4.8 Adverse Effects (Undesirable Effects)). For the majority of neurologic reactions, onset occurred within the first three months of treatment.
Caution patients about driving and using machines, until they are reasonably certain Vitrakvi therapy does not affect them adversely. Withholding, reducing, or discontinuing Vitrakvi dosing should be considered, depending on the severity and persistence of these symptoms (see Section 4.2 Dose and Method of Administration; Section 4.7 Effects on Ability to Drive and Use Machines).

Hepatotoxicity.

Abnormalities of liver function tests including increased ALT, AST, ALP and bilirubin have been observed in patients treated with Vitrakvi (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of ALT and AST increases occurred in the first 3 months of treatment. Cases of hepatotoxicity with increases in ALT and/or AST of Grade 2, 3 or Grade 4 severity and increases in bilirubin ≥ 2 x ULN have been reported in adult patients.
In patients with hepatic transaminase elevations, withhold, modify dose or permanently discontinue Vitrakvi based on the severity (see Section 4.2 Dose and Method of Administration).
Monitor for liver function including ALT, AST, ALP and bilirubin, before the first dose, and then every 2 weeks during the first month, then monthly for the next 6 months of treatment, then periodically during treatment. In patients who develop transaminase elevations, more frequent testing as clinically indicated is needed (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Patients with hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Patients with renal impairment.

Use in the elderly.

See Section 4.8 Adverse Effects (Undesirable Effects).

Paediatric use.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Paediatric patients.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicinal products on larotrectinib.

Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of Vitrakvi with strong or moderate CYP3A inhibitors, P-gp and BCRP inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit or grapefruit juice) may increase larotrectinib plasma concentrations.
Co-administration of Vitrakvi with strong or moderate CYP3A inducers and strong P-gp inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or St. John's wort) may decrease larotrectinib plasma concentrations.

Effect of CYP3A, P-gp and BCRP inhibitors on larotrectinib.

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg Vitrakvi dose with itraconazole (a strong CYP3A inhibitor and P-gp and BCRP inhibitor) 200 mg once daily for 7 days increased larotrectinib Cmax and AUC by 2.8-fold and 4.3-fold, respectively. See Section 4.2 Dose and Method of Administration.
Physiologically based pharmacokinetic (PBPK) modeling predicts co-administration of Vitrakvi with moderate CYP3A4 inhibitors (fluconazole or diltiazem) will increase Vitrakvi Cmax by up to 1.9-fold and AUC by up to 2.7-fold.
Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg Vitrakvi dose with a single dose of 600 mg rifampin (a P-gp and BCRP inhibitor) increased larotrectinib Cmax and AUC by 1.8-fold and 1.7-fold, respectively (see Section 4.2 Dose and Method of Administration).

Effect of CYP3A and P-gp inducer on larotrectinib.

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg dose of Vitrakvi capsules with rifampin (a strong CYP3A and P-gp inducer) 600 mg once daily for 11 days decreased the AUC of larotrectinib by 81% and of Cmax by 71% as compared to Vitrakvi administered alone.
Physiologically based pharmacokinetic (PBPK) modeling predicts co-administration of Vitrakvi with a moderate CYP3A4 inducer (efavirenz) will decrease Cmax of Vitrakvi by 60% and AUC by 72% compared to Vitrakvi administered alone (see Section 4.2 Dose and Method of Administration).

Effect of other transporter inhibitors on larotrectinib.

In vitro, larotrectinib is not a substrate for the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.

Effect of gastric pH-elevating agents on larotrectinib.

Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the gastrointestinal tract (GI) larotrectinib is fully soluble over entire pH range of the GI tract. Therefore, larotrectinib, is unlikely to be affected by pH-modifying agents.

Effect of larotrectinib on CYP3A substrates.

Clinical data in healthy adult subjects indicate that co-administration of Vitrakvi (100 mg twice daily for 10 days) increased the Cmax and AUC of oral midazolam (a sensitive CYP3A substrate) 1.7-fold compared to midazolam alone, suggesting that larotrectinib is a weak inhibitor of CYP3A.
Exercise caution with concomitant use of CYP3A substrates with narrow therapeutic range (e.g. alfentanil, cyclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus) in patients taking Vitrakvi. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking Vitrakvi, dose modification of the CYP3A substrates may be required due to adverse reactions.

Effect of larotrectinib on other CYP and transporter substrates.

In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.
In vitro studies indicate that larotrectinib induces CYP2B6 but does not induce CYP1A2.
In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations and is unlikely to affect clearance of substrates of these transporters.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical data on the effect of larotrectinib on fertility. No relevant effects on fertility were observed in repeat-dose toxicity studies in rats and monkeys. (See Section 5.3 Preclinical Safety Data).
(Category C)
There are no clinical data on the use of larotrectinib in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis demonstrated no teratogenicity or adverse effects on foetal development at doses that produced maternal exposures up to approximately 32 (rats) and 16 (rabbits) times the human exposure (AUC0-24), respectively, at the recommended dose (see Section 5.3 Preclinical Safety Data). Vitrakvi crosses the placenta in animals.
Based on its mechanism of action, the risk of foetal harm cannot be excluded when larotrectinib is administered to a pregnant woman (see Section 5.1 Pharmacodynamic Properties). Advise pregnant women of the potential risk to a foetus.

Childbearing potential/ contraception.

Based on the mechanism of action, foetal harm cannot be excluded when administering larotrectinib to a pregnant woman. Females of childbearing potential should have a pregnancy test prior to starting treatment with Vitrakvi.
Advise female patients of reproductive potential to use highly effective contraception during treatment with Vitrakvi and for at least one month after the final dose.
For males of reproductive potential with a non-pregnant female partner of child-bearing potential, advise use of highly effective contraception during treatment with Vitrakvi and for at least one month after the final dose.
 There are no data on the presence of larotrectinib in human milk, the effects of larotrectinib on the breastfed child, or the effects of larotrectinib on milk production. Because of the unknown risk of larotrectinib in nursing infants, advise a nursing woman to discontinue breastfeeding during treatment with larotrectinib and for 3 days (6 plasma half-lives of larotrectinib and its metabolites) following the final dose.

4.7 Effects on Ability to Drive and Use Machines

Neurologic reactions have been reported in patients receiving larotrectinib which may influence the ability to drive and use machines. Caution patients about driving and using machines, until they are reasonably certain Vitrakvi therapy does not affect them adversely (see Section 4.4 Special Warnings and Precautions for Use).

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia).

Summary of the safety profile.

The safety of Vitrakvi was evaluated in 444 patients (overall safety population) with locally advanced or metastatic solid tumors, irrespective of NTRK gene fusion status, who received at least one dose of Vitrakvi in one of three clinical trials, Studies 1, 2 ("NAVIGATE"), and 3 ("SCOUT"). The majority (91%) of adult patients (18 years and older) received 100 mg Vitrakvi taken twice daily as their starting dose. Three paediatric dose levels were evaluated with 91% of paediatric patients having received a starting dose of 100 mg/m2 (with a maximum of 100 mg) taken twice daily. Median time on treatment for the overall safety population was 9.63 months (range: 0 to 87.4).
The overall safety population characteristics were comprised of patients with a median age of 44 years (range: 0 to 90) with 35% of patients being paediatric patients.
Most commonly (> 20%) reported adverse reactions with Vitrakvi were ALT increased, AST increased, vomiting, anaemia, constipation, fatigue, diarrhoea, nausea, and dizziness.
The majority of adverse reactions were Grade 1 or 2. The highest grades reported with Vitrakvi were Grade 4 neutrophil count decreased, ALT and AST increased, blood alkaline phosphatase increased, leukocyte count decreased, muscular weakness, platelet count decreased and Grade 3 anaemia, weight increased, diarrhoea, fatigue, gait disturbance, vomiting, dizziness, myalgia, paraesthesia, nausea, and constipation. There were no fatal adverse reactions.
Permanent discontinuation of Vitrakvi for treatment emergent adverse events attributed to study drug occurred in 2% of patients (ALT increase, AST increased, amylase increased, emotional poverty, enterocutaneous fistula, gamma-glutamyl transferase increased, hypoventilation, lipase increased, muscular weakness, nausea, and neutrophil count decreased). The majority of events leading to dose reduction occurred in the first three months of treatment.

Tabulated list of adverse reactions.

The adverse drug reactions reported in the clinical trials and post-marketing in patients treated with Vitrakvi are shown in Table 4. They are classified according to the system organ class (MedDRA version 25.0). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention:
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness.
See Table 5.

Description of selected adverse reactions.

Neurologic reactions.

In the overall safety database (N = 444), the maximum grade neurologic adverse reaction observed was Grade 3 which was observed in 12 (3%) patients and included dizziness (< 1%), gait disturbance (< 1%) and paraesthesia (< 1%). Maximum Grade 2 adverse reactions occurred in less than 5% of patients and Grade 1 events accounted for a majority of events reported. No Grade 4 adverse reactions were reported. Neurologic reactions leading to dose modifications or interruptions included dizziness (8 patients), paraesthesia (3 patients) and gait disturbance (4 patients). The adverse reaction gait disturbance led to treatment discontinuation in one patient. In the majority of cases, patients with evidence of anti-tumor activity who required a dose reduction were able to continue dosing at a reduced dose and/or schedule (see Section 4.4 Special Warnings and Precautions for Use).

Hepatotoxicity.

Abnormalities of liver function tests including increased ALT, AST, ALP and bilirubin have been observed in patients treated with Vitrakvi.
In the overall safety database (N = 444), the maximum grade transaminase elevation observed was Grade 4 ALT increase in four patients (≤ 1%) and AST increase in three patients (< 1%). Grade 3 events occurred in 18 (5%) patients for ALT increased and 16 patients (4%) for AST increased. The majority of Grade 3 elevations were transient appearing in cycles 1-2 of treatments and resolving to Grade 1 by cycles 3-4. Grade 2 ALT and AST increases were observed in 28 patients (6%) and 25 patients (6%), respectively. Grade 1 ALT and AST increases were observed in 91 (20%) and 92 (21%) patients, respectively. Most Grade 1 and 2 transaminase increases did not worsen through continued non-modified dosing.
ALT and AST increases leading to dose modifications or interruptions occurred in 28 (6%) patients and 26 (6%) patients, respectively (see Section 4.4 Special Warnings and Precautions for Use).
Cases of hepatotoxicity with increases in ALT and/or AST of Grade 2, 3 or Grade 4 severity and increases in bilirubin ≥ 2 x ULN have been reported in adult patients. In some cases, the dose of Vitrakvi was withheld and restarted at a reduced dose, while in other cases treatment was permanently discontinued (see Section 4.4 Special Warnings and Precautions for Use).

Laboratory test abnormalities.

Laboratory relevant adverse reactions which meet the internal ADR criteria are shown in Table 6 for laboratory abnormalities.

Additional information on special populations.

Paediatric patients.

Of 444 patients treated with Vitrakvi, 154 (35%) patients were from birth to 18 years of age. Safety profile in the paediatric population (< 18 years) was consistent in types of reported adverse events to those observed in the adult population.
The majority of adverse reactions were Grade 1 or 2 in severity and were resolved without Vitrakvi dose modification or discontinuation. The adverse reactions of vomiting (51% versus 18% in adults), diarrhoea (34% versus 21% in adults), leukocyte count decrease (21% versus 10% in adults), neutrophil count decrease (30% versus 9% in adults), platelet count decreased (12% versus 6% in adults) and transaminase elevations (ALT 40% versus 28% in adults and AST 39% versus 26% in adults) were more frequent in paediatric patients compared to adults. Elevations in liver enzymes in children < 1 years of age may be due to immaturity of liver function.

Elderly patients.

Of 444 patients in the overall safety population who received Vitrakvi, 88 (20%) patients were ≥ 65 years of age and 25 (6%) patients were ≥ 75 years of age. Safety profile in elderly patients (≥ 65 years) is consistent with that seen in younger patients (< 65 years). The adverse reactions, dizziness, gait disturbance, fatigue, and anaemia were more frequent in patients ≥ 65 years of age.

4.9 Overdose

For general advice on overdose management, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre.
There is no known antidote for Vitrakvi. The treatment of overdose with Vitrakvi should consist of general supportive measures.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, other antineoplastic agents. ATC code: L01EX12.

Mechanism of action.

Larotrectinib is an orally-bioavailable, adenosine triphosphate (ATP)-competitive, potent and highly selective TRK kinase inhibitor that was rationally designed to avoid activity with off-target kinase. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively.
In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel chimeric oncogenic proteins are aberrantly expressed driving constitutive kinase activity subsequently activating downstream cell signaling pathways involved in cell proliferation and survival leading to TRK fusion cancer.
Larotrectinib demonstrated potent inhibition of TRK proteins and inhibition of proliferation of tumor cells in a concentration-dependent manner. In TRK fusion-driven mouse xenograft models larotrectinib treatment induced a significant reduction of tumor growth.
Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutation in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

Pharmacodynamic effects.

Cardiac electrophysiology.

In 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg, Vitrakvi did not prolong the QT interval to any clinically relevant extent and there was no relationship between exposure (Cmax) and changes in the QT interval.

Clinical trials.

The efficacy and safety of Vitrakvi were demonstrated in three multicentre, open-label, single-arm clinical studies in adult and paediatric cancer patients (Table 7).
Patients with and without documented NTRK gene fusion were allowed to participate in Study 1 and Study 3 ("SCOUT"). Patients enrolled to Study 2 ("NAVIGATE") were required to have TRK fusion cancer. The pooled analysis set of efficacy includes 164 patients with TRK fusion cancer enrolled across the three studies who had measurable disease assessed by RECIST, a non-CNS primary tumor and received at least one dose of larotrectinib. These patients were required to have received prior standard therapy appropriate for their tumor type and stage of disease or who, in the opinion of the Investigator, would have had to undergo radical surgery (such as limb amputation, facial resection, or paralysis causing procedure), or were unlikely to tolerate, or derive clinically meaningful benefit from available standard of care therapies in the advanced disease setting. Identification of NTRK gene fusions relied upon the molecular test methods next generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) or other similarly certified laboratories.
For the pooled efficacy analysis, the primary efficacy endpoint was overall response rate (ORR), as determined by an Independent Review Committee (IRC). ORR was defined as the proportion of patients with the best overall response of confirmed complete response (CR) or confirmed partial response (PR) based on RECIST version 1.1 for solid tumors. Secondary efficacy endpoints for the pooled analysis included time to first response, duration of response and disease-control rate (DCR; best overall response of CR, PR, or stable disease lasting 16 or more weeks). Additional secondary efficacy endpoints were progression-free survival (PFS) and overall survival (OS) and time on treatment.
Baseline characteristics for the pooled 164 patients with solid tumors harbouring an NTRK gene fusion were as follows: median age 42 years (range 0.1-84 years); 34% < 18 years of age, and 66% ≥ 18 years; 77% White and 49% male; and ECOG PS* 0-1 (86%), 2 (12%), or 3 (2%). Ninety-four percent of patients had received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. Of these, 77% had received prior systemic therapy with a median of 2 prior systemic treatment regimens received. Twenty seven percent of all patients had received 3 or more prior systemic therapies and 51% of all patients had received 1-2 prior systemic therapies. Twenty two percent of all patients had received no prior systemic therapy.
The most common tumor types represented were soft tissue sarcoma (22%), infantile fibrosarcoma (20%), thyroid cancer (16%), salivary gland tumor (13%) and lung cancer (8%).
* Eastern Cooperative Oncology Group (ECOG) Performance Status.

Efficacy results.

The pooled efficacy results for overall response rate, duration of response and time to first response, stable disease and disease control rate are presented in Table 8.
Responses were seen in patients regardless of their age, tumor type, NTRK gene involved or NTRK gene fusion partner. In the paediatric sub-population (n = 55), the ORR was 91%.

Pooled primary analysis set.

At the time of analysis, the median duration of response had not been reached, an estimated 76% [95% CI: 67, 85] of responses lasted 12 months or longer and 67% [95% CI: 55, 78] of responses lasted 24 months or longer. The disease control rate is 84% (137/164) [95% CI: 77, 89]. Ninety percent (90%) [95% CI: 85, 95] of patients treated were alive one year after the start of therapy and 82% [95% CI: 75, 90] after two years with the median for overall survival not yet being reached. Median progression free survival was 33.4 months at the time of the analysis, with a progression free survival rate of 66% [95% CI: 58, 74] after 1 year and 58% [95% CI: 48, 67] after 2 years.
A reduction in tumor size was observed in 81% (n = 144) patients with NTRK gene fusions, regardless of age, prior treatment, tumor type, NTRK gene involved or NTRK gene fusion partner. Changes in target lesion size are illustrated in a Waterfall plot in Figure 1. The median change in tumor size was a decrease of 68%.

Patients with primary CNS tumors.

Twenty four patients with primary CNS tumors and measurable disease at baseline were enrolled in Study 2 ("NAVIGATE") and in Study 3 ("SCOUT"). All CNS tumor patients had received prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy).
Of the 24 patients with primary CNS confirmed response was observed in 5 patients (21%) with 2 of the 24 patients (8%) being complete responders and 3 (12.5%) being partial responders. In 2 additional patients (8%) a not yet confirmed partial response was observed. Further, 15 patients (63%) had stable disease. Two patients (8%) had a progressive disease.
At the time of data cut-off, time on treatment ranged from 1.2 to 21.4 months and was ongoing in 15 out of 24 patients with one of these patients receiving post-progression treatment.

Health-related quality of life outcomes.

Paediatric and adult patients with TRK fusion cancer treated with Vitrakvi experienced clinically meaningful improvement in health-related quality of life (HRQoL) as evaluated by the EORTC QLQ-C30, EQ-5D 5L VAS and PedsQL questionnaires. Within 2 months of treatment, rapid and sustained improvements were seen in the majority of the functional domains of the questionnaires. Overall health status results are presented in Table 9.

5.2 Pharmacokinetic Properties

In cancer patients given Vitrakvi capsules, peak plasma levels (Cmax) of larotrectinib were achieved at approximately 1 hour after dosing. Half-life (t1/2) is approximately 3 hours and steady state is reached within 8 days. Systemic accumulation is 1.6-fold at steady state. At the recommended dose of 100 mg taken twice daily, steady-state arithmetic mean (± standard deviation) Cmax and daily AUC in adults were 914 ± 445 nanogram/mL and 5410 ± 3813 nanogram*h/mL, respectively.

Absorption.

Vitrakvi is available as a capsule and oral solution formulation.
The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 100 mg oral dose.
In healthy adult subjects, the bioavailability of larotrectinib in the oral solution formulation was similar to the capsule, with Cmax 36% higher with the oral solution formulation.
Larotrectinib Cmax was reduced by approximately 35% and there was no effect on AUC in healthy subjects administered Vitrakvi after a high-fat and high-calorie meal compared to the Cmax and AUC after overnight fasting.

Distribution.

The mean volume of distribution (Vss) of larotrectinib in healthy adult subjects was 48 L following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose. Binding of larotrectinib to human plasma proteins in vitro was approximately 70% and was independent of drug concentration. The blood-to-plasma concentration ratio was approximately 0.9.

Metabolism.

Larotrectinib was metabolized predominantly by CYP3A4/5 in vitro. Following oral administration of a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib (19%) and an O-glucuronide that is formed following loss of the hydroxypyrrolidine-urea moiety (26%) were the major circulating radioactive drug components.

Excretion.

The half-life of larotrectinib in plasma of cancer patients given 100 mg twice daily of Vitrakvi was approximately 3 hours. Mean clearance (CL) of larotrectinib was approximately 34 L/h following intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose of Vitrakvi.
Following oral administration of 100 mg radiolabeled larotrectinib to healthy adult subjects, 58% of the administered radioactivity was recovered in faeces and 39% was recovered in urine. The fraction excreted as unchanged drug in urine was 29% following IV microtracer dose, indicating that direct renal excretion accounted for 29% of total clearance.

Additional information on special populations.

Paediatric patients.

Based on population pharmacokinetic analyses exposure (Cmax and AUC) in paediatric patients (1 month to < 3 months of age) at the recommended dose of 100 mg/m2 with a maximum of 100 mg BID was 3-fold higher than in adults (≥ 18 years of age) given the dose of 100 mg BID. At the recommended dose, the Cmax in paediatric patients (≥ 3 months to < 12 years of age) was higher than in adults, but the AUC was similar to that in adults. For paediatric patients older than 12 years of age, the recommended dose is likely to give similar Cmax and AUC as observed in adults.
Data defining exposure in small children (1 month to < 6 years of age) at the recommended dose is limited (n = 33).

Elderly.

AUC in patients > 65 years or > 80 years were similar to those in younger patients (< 65 years).

Patients with hepatic impairment.

A pharmacokinetic study was conducted in subjects with mild (Child Pugh A), moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment, and in healthy adult control subjects with normal hepatic function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib AUC0-inf was observed in subjects with mild, moderate and severe hepatic impairment of 1.3, 2 and 3.2-fold, respectively, versus those with normal hepatic function. Cmax was observed to increase slightly by 1.1, 1.1 and 1.5-fold, respectively.

Patients with renal impairment.

A pharmacokinetic study was conducted in subjects with end stage renal disease requiring dialysis, and in healthy adult control subjects with normal renal function matched for age, body mass index and sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib Cmax and AUC0-inf, of 1.25 and 1.46-fold, respectively, was observed in renally impaired subjects versus those with normal renal function.

5.3 Preclinical Safety Data

The safety pharmacology of larotrectinib was evaluated in several in vitro and in vivo studies that assessed effects on the CV, CNS, respiratory, and GI systems in various species (rat, mouse, dog, cynomolgus monkey). Larotrectinib had no adverse effects on hemodynamic parameters and ECG intervals in telemetered monkeys at exposures (Cmax) which are approximately 6-fold the human therapeutic exposures. Larotrectinib had no neurobehavioral findings in rats and did not affect neuromuscular function in mice.
Larotrectinib had no effects on respiratory function in rats; at exposures (Cmax) at least 8-times the human therapeutic exposures. In rats, larotrectinib accelerated intestinal transit and increased gastric secretion and acidity.
Systemic toxicity was assessed in studies with daily oral administration up to 13-weeks in rats and monkeys. Dose limiting skin lesions were only seen in rats and were primarily responsible for mortality and morbidity. Skin lesions were not seen in monkeys.
Clinical signs of gastrointestinal toxicity were dose limiting in monkeys. The following additional relevant findings were observed in both species: increased body weight and food consumption; an adaptive response in the liver secondary to induction of drug metabolizing enzymes; elevated serum liver enzymes (ALT and/or AST); histopathological changes in lymphoid tissues without corresponding changes in white blood cell counts; in rats, pancreatic changes; minor, reversible changes on red blood cell parameters; and increased heart weights without histopathological correlate were reported. In rats severe toxicity (STD10) was observed at doses corresponding to 1- to 2-times the human AUC at the recommended clinical dose. No relevant systemic toxicity was observed in monkeys at exposures which correspond to > 10-times the human AUC at the recommended clinical dose.
Larotrectinib was administered to juvenile rats from postnatal day (PND) 7 to 70. Pre-weaning mortality (before PND 21) was observed at the high dose corresponding to 2.5- to 4-times the AUC at the recommended dose. Growth and nervous system effects were seen at 0.5- to 4-times the AUC at the recommended dose. The male growth reduction was associated with delayed puberty. Nervous system effects and reduced body weight in females demonstrated partial recovery.
Larotrectinib was not teratogenic and embryotoxic when dosed daily during the period of organogenesis to pregnant rats and rabbits at maternotoxic doses, i.e. corresponding to 32-times (rats) and 16-times (rabbits) the human AUC at the recommended clinical dose. Larotrectinib crosses the placenta in both species.
Fertility studies with larotrectinib have not been conducted. Larotrectinib had no effects on spermatogenesis in rats and on male reproductive organs in rats and monkeys at doses corresponding to approximately 2-times (rats) and 10-times (monkeys) the human AUC at the recommended clinical dose.
In a 1-month study in rats, fewer corpora lutea, increased incidence of anestrus and decreased uterine weight with uterine atrophy were observed and these effects were reversible. No effects on female reproductive organs were seen in the 13-week study in rats and monkeys at doses corresponding to approximately 3-times (rats) and approximately 17-times (monkeys) the human AUC at the recommended clinical dose.
In juvenile animals, a decrease in pregnancy rate was reported despite normal mating at the high-dose corresponding to 3-times the AUC at the recommended paediatric dose.

Genotoxicity.

Larotrectinib was not mutagenic in bacterial reverse mutation (Ames) assays and in in vitro mammalian mutagenesis assays. Larotrectinib was negative in the in vivo mouse micronucleus test.

Carcinogenicity.

Carcinogenicity studies have not been performed with larotrectinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsules.

Gelatin; titanium dioxide; printing ink - blue: shellac, FD and C Blue # 2 aluminium lake, titanium dioxide, propylene glycol, ammonia solution, dimethicone.

Oral solution.

Purified water, hydroxypropyl betadex, sucralose, sodium citrate, sodium benzoate, strawberry flavour, citric acid.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Capsules.

Store below 25°C; temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted.

Oral solution.

Store at 2° to 8°C (36° to 46°F). Refrigerate. Do not freeze.

6.5 Nature and Contents of Container

Capsule.

56 counted (HDPE) bottle closed with polypropylene (PP) closure.

Oral solution.

Each carton contains two amber glass bottles containing 50 mL oral solution each and capped with a child-resistant polypropylene (PP) screw cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: (3S)-N-{5-[(2R)-2-(2,5-Difluorophenyl)-1-pyrrolidinyl] pyrazolo[1,5a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate.
Empirical name: C21H24F2N6O6S (sulfate salt form).
Molecular weight: 526.51 g/mol (sulfate salt form).

7 Medicine Schedule (Poisons Standard)

S4 Prescription Only Medicine.

Summary Table of Changes