Consumer medicine information

Cabometyx

Cabozantinib

BRAND INFORMATION

Brand name

Cabometyx

Active ingredient

Cabozantinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cabometyx.

SUMMARY CMI

Cabometyx®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using CABOMETYX?

CABOMETYX contains the active ingredient cabozantinib. CABOMETYX is used to treat patients with advanced kidney cancer (advanced renal cell carcinoma), liver cancer, or a type of thyroid cancer called differentiated thyroid cancer.
For more information, see Section 1. Why am I using CABOMETYX? in the full CMI.

2. What should I know before I use CABOMETYX?

Do not use if you have ever had an allergic reaction to cabozantinib or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use CABOMETYX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CABOMETYX and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use CABOMETYX?

  • The usual dose is 60 mg taken once a day. Your doctor will decide on the right dose for you.
  • CABOMETYX should not be taken with food. Grapefruit juice should be avoided while using this medicine.

More instructions can be found in Section 4. How do I use CABOMETYX? in the full CMI.

5. What should I know while using CABOMETYX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using CABOMETYX.
  • Tell your doctor immediately if you become pregnant.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not take CABOMETYX 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.
Driving or using machines
  • Treatment with CABOMETYX may make you feel tired or weak and can affect your ability to drive or operate machines.
Looking after your medicine
  • Keep your medicine in the original container in a cool, dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using CABOMETYX? in the full CMI.

6. Are there any side effects?

Like all medicines, CABOMETYX can cause side effects, although not everybody gets them. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.
Tell your doctor straight away if you notice any of the following side effects, you may need urgent medical attention:

  • pain in the abdomen (belly), feeling sick, vomiting, constipation, fever. These may be signs of a hole that develops in your stomach or intestine (common).
  • vomiting blood, black stools, bloody urine, headache, coughing up blood. These may be signs of severe bleeding inside your body (very common).
  • swelling, pain in your hands and feet, or shortness of breath. These may be signs of blood clots or oedema (common).
  • feeling drowsy or confused, loss of consciousness. These may be signs of liver problems (common).
  • coughing, difficulty breathing. These may be signs of a lung infection (common).
  • kidney failure including abrupt loss of kidney function (common).

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Cabometyx®

Active ingredient(s): cabozantinib

Consumer Medicine Information (CMI)

This leaflet provides important information about using CABOMETYX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using CABOMETYX.

Where to find information in this leaflet:

1. Why am I using CABOMETYX?
2. What should I know before I use CABOMETYX?
3. What if I am taking other medicines?
4. How do I use CABOMETYX?
5. What should I know while using CABOMETYX?
6. Are there any side effects?
7. Product details

1. Why am I using CABOMETYX?

CABOMETYX contains the active ingredient cabozantinib (as cabozantinib (S)-malate). CABOMETYX is a multi-kinase inhibitor.

It works by blocking the action of proteins called receptor tyrosine kinases (RTKs), which are involved in the growth of cells and the development of new blood vessels that supply them. These proteins can be present in high amounts in cancer cells, and by blocking their action CABOMETYX can slow down the rate at which the tumour grows and help to cut off the blood supply that the cancer needs.

CABOMETYX is used to treat:

  • advanced stages of a type of kidney cancer called renal cell carcinoma (RCC)
  • liver cancer in adults who have been previously treated with a specific anticancer medicine (sorafenib)
  • a type of thyroid cancer called differentiated thyroid cancer (DTC), in adults and children 12 years of age and older, that has spread (locally advanced or metastatic), and,
    - has progressed after treatment with a medicine called VEGFR-targeted treatment, and,
    - when the DTC can no longer be treated with radioactive iodine, or patients are not able to receive radioactive iodine treatment.

CABOMETYX may also be given in combination with another medicine called nivolumab to treat advanced kidney cancer (RCC). It is important that you also read the Consumer Medicine Information of nivolumab.

2. What should I know before I use CABOMETYX?

Warnings

Do not use CABOMETYX if:

  • you are allergic to cabozantinib, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

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

Check with your doctor if you:

  • have intolerance to some sugars. The tablets contain lactose.
  • have high blood pressure.
  • have, or have had, an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.
  • have diarrhoea.
  • have a recent history of significant bleeding.
  • have had surgery within the last month (or if surgical procedures are planned), including dental surgery.
  • have inflammatory bowel disease (for example, Crohn's disease or ulcerative colitis, diverticulitis, or appendicitis).
  • have a recent history of blood clot in the leg, stroke, or heart attack.
  • have liver or kidney disease.
  • have a pre-existing heart condition, slow heart rate or are taking medicine to prevent abnormal heart rhythm.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

You should avoid becoming pregnant while being treated with CABOMETYX.

CABOMETYX should not be taken during pregnancy. Your doctor will discuss the risks with you.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed while taking CABOMETYX and for at least 4 months after treatment has finished, as cabozantinib and/or its metabolites may be excreted in breast milk and be harmful to your child.

If you or your partner could become pregnant, you must use a safe and effective form of contraception (such as a condom or coil) to avoid becoming pregnant while you are being treated with CABOMETYX. You should also do this for at least 4 months after stopping treatment. Discuss with your doctor what may be appropriate contraception for you.

Tell your doctor if you are taking oral contraceptives.

If you take CABOMETYX whilst using oral contraceptives, the oral contraceptives may be ineffective.

Tell your doctor if you or your partner plan to become pregnant in the future.

CABOMETYX may affect your fertility.

Children and Teenagers

  • CABOMETYX is not recommended for children or adolescents for treatment of liver or kidney cancer.
  • CABOMETYX can be used to treat children and adolescents 12 years of age or older with thyroid cancer.
  • It is not known if CABOMETYX is safe and effective in children younger than 12 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with CABOMETYX and affect how it works.

You should tell your doctor about every medicine, but in particular if you are taking:

  • Medicines that treat fungal infections, such as itraconazole, ketoconazole, and posaconazole.
  • Medicines used to treat bacterial infections (antibiotics) such as erythromycin, clarithromycin, and rifampicin.
  • Allergy medicines such as fexofenadine.
  • Medicines to treat angina pectoris (chest pain owing to inadequate blood supply to the heart) such as ranolazine.
  • Medicines used to treat epilepsy or fits such as phenytoin, carbamazepine, and phenobarbital.
  • Herbal preparations containing St. John's Wort (Hypericum perforatum), sometimes used for treating depression or depression-related conditions such as anxiety.
  • Medicines used to thin the blood, such as warfarin and dabigatran etexilate.
  • Medicines to treat high blood pressure or other heart conditions, such as ambrisentan, digoxin, and tolvaptan.
  • Medicines for diabetes, such as saxagliptin and sitagliptin.
  • Medicines used to treat gout, such as colchicine.
  • Medicines used to treat HIV or AIDS, such as efavirenz, ritonavir, maraviroc and emtricitabine.
  • Medicines used to prevent transplant rejection (ciclosporin) and ciclosporin-based regimens in rheumatoid arthritis and psoriasis.
  • Medicines used for contraception such as oral contraceptives, as they may be ineffective whilst using CABOMETYX.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect CABOMETYX.

4. How do I use CABOMETYX?

How much to take

  • The usual dose of CABOMETYX is 60 mg taken once a day.
  • When CABOMETYX is given in combination with nivolumab for the treatment of advanced kidney cancer, the recommended dose of CABOMETYX is 40 mg once a day.
  • Your doctor will decide on the right dose for you.
  • Follow the instructions provided and use CABOMETYX until your doctor tells you to stop.

How to take CABOMETYX

  • Swallow the tablet whole with a full glass of water.
  • Do not crush the tablets.
  • CABOMETYX should not be taken with food. You should not eat anything for at least 2 hours before taking CABOMETYX and for 1 hour after taking the medicine.
  • Avoid consuming grapefruit juice or grapefruit-containing products for as long as you are using this medicine, as they may increase the levels of CABOMETYX in your blood.

When to take CABOMETYX

  • CABOMETYX should be taken at about the same time each day.
  • When CABOMETYX is given in combination with nivolumab, you will first be given nivolumab followed by CABOMETYX.
  • Continue taking your medicine for as long as your doctor tells you.

If you forget to use CABOMETYX

CABOMETYX should be used regularly at the same time each day. If there are still 12 hours or more before your next dose is due, then take the missed dose as soon as you remember.

If your next dose is due in less than 12 hours, skip the dose you missed and take your next dose when you are meant to.

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

If you use too much CABOMETYX

If you think that you have used too much CABOMETYX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using CABOMETYX?

Things you should do

Call your doctor straight away if you:

Remind any doctor or pharmacist you visit that you are using CABOMETYX.

You should also tell your dentist that you are taking CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX.

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

If you become pregnant while taking CABOMETYX, tell your doctor immediately. Do not stop treatment without first discussing it with your doctor.

Keep all of your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not take CABOMETYX 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 stop taking your medicine or lower the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CABOMETYX affects you.

Treatment with CABOMETYX may make you feel tired or weak and can affect your ability to drive or operate machines.

Looking after your medicine

  • Keep your medicine in the original container.
  • If you take it out of its original container it may not keep well.
  • Store your tablets in a cool, dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
Signs of severe or uncontrollable bleeding inside your body:
  • vomiting blood
  • black stools
  • bloody urine
  • headache
  • coughing up blood
Signs of a gastrointestinal perforation, a hole that develops in your stomach or intestine:
  • pain in the abdomen (belly)
  • nausea (feeling sick)
  • vomiting
  • constipation
  • fever
Gastrointestinal/muscle related:
  • A painful tear or abnormal connection of the tissues in your body (fistula)
Signs of liver problems:
  • feeling drowsy or confused
  • loss of consciousness
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Signs of lung infection:
  • Serious lung infection (pneumonia)
  • Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing), blood clots in the lung
Signs of kidney problems:
  • Kidney failure (including abrupt loss of kidney function)
Signs of a condition called posterior reversible encephalopathy syndrome (PRES):
  • fits
  • headaches
  • confusion
  • finding it difficult to concentrate
Signs of bone damage in the jaw (osteonecrosis):
  • pain in the mouth, teeth and/or jaw
  • swelling or sores inside the mouth
  • numbness or a feeling of heaviness in the jaw
  • loosening of a tooth
Heart or circulatory system related:
  • Changes in the rhythm or rate of the heartbeat, fast heart rate, inflammation of the heart muscle (myocarditis)
Nervous system related:
  • A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain Barré syndrome)
  • Inflammation of the brain (encephalitis)
Other serious side effects:
  • Swelling, pain in your hands and feet, or shortness of breath.
  • Blood clots in the veins, arteries and lungs
  • Stroke
  • Fits
  • Heart attack
  • Wound complications, particularly a wound that does not heal.
  • An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

Less serious side effectsWhat to do
Infection related:
  • Abscess (collection of pus, with swelling and inflammation)
  • Infections of the upper respiratory tract
Metabolism related:
  • Decreased appetite, weight loss, altered sense of taste
  • Dehydration (lack of fluids)
Hormone related:
  • Reduced thyroid activity (symptoms can include tiredness, weight gain, constipation, feeling cold and dry skin)
  • Increased thyroid activity (symptoms can include rapid heart rate, sweating and weight loss)
  • Adrenal glands not working properly (symptoms can include weakness, tiredness, weight loss, low blood pressure)
  • Inflammation of the pituitary gland situated at the base of the brain (hypophysitis), swelling of the thyroid gland (thyroiditis)
Nervous system related:
  • Fatigue, weakness, headache, dizziness
  • Numbness, tingling, burning sensation or pain in the limbs
  • Muscle weakness and tiredness without atrophy (myasthenic syndrome)
Ear and hearing related:
  • Ringing in ears (tinnitus)
Eye and vision related:
  • Dry eyes
  • Inflammation of the eye (which causes pain and redness) and blurred vision
Heart or circulatory system related:
  • High blood pressure (hypertension)
Speak to your doctor if you have any of these less serious side effects and they worry you.
Breathing or respiratory system related:
  • Shortness of breath
  • Cough and nose bleeding
  • Fluid around the lungs
Gastrointestinal related:
  • Stomach upset (diarrhoea, nausea, vomiting, constipation, indigestion, abdominal pain)
  • Redness, swelling or pain in the mouth or throat
  • Difficulty in speaking, hoarseness, cough
  • Dry mouth and pain in the mouth
  • Inflammation of the stomach (gastritis)
  • A burning or stinging sensation of the tongue
  • Difficulty in swallowing
  • Gastro-oesophageal reflux disease (bringing up stomach acid)
  • Inflammation of the pancreas (severe upper stomach pain, often with nausea and vomiting)
  • Haemorrhoids (piles)
  • Inflammation of the colon (colitis)
Liver or gallbladder related:
  • Inflammation of the liver (hepatitis)
  • Decrease in bile flow from the liver
Skin related:
  • Blisters, pain of the hands or soles of the feet, rash or redness of the skin
  • Dry skin, severe itching of skin, acne
  • Thickening of the outer layer of the skin
  • Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
  • Alopecia (hair loss and thinning), hair colour change
  • Hives (itchy rash)
Speak to your doctor if you have any of these less serious side effects and they worry you.
Muscle or bone related:
  • Pain in the arms, hands, legs or feet, or joints
  • Muscle spasms
  • Muscle weakness and aching muscles
  • Muscle tenderness of weakness, not caused by exercise (myopathy)
  • Inflammation of the joints (arthritis) and pain in joints (arthralgia)
Kidney or bladder related:
  • Protein in urine (seen in tests)
  • Inflammation of the kidney
General:
  • Pain, chills
  • Chest pain
Blood test related:
  • Low levels of red blood cells (anaemia)
  • Low levels of blood platelets
  • Low level of white blood cells
  • Low level of albumin in blood
  • Changes in blood tests used to monitor general health and function of your organs (including the liver and kidney), low levels of electrolytes (like magnesium, or potassium)
  • Increased or decreased blood glucose level
  • Decrease in levels of calcium, sodium and phosphate in the blood
  • Increase in level of potassium in the blood
  • Increase in the level of bilirubin in the blood (which may result in jaundice/yellow skin or eyes)
  • Increase in amylase levels in the blood
  • Increase in lipase levels in the blood
  • Increase in cholesterol or trygliceride levels in the blood
  • Increase in some white blood cells called eosinophils
Speak to your doctor if you have any of these less serious side effects and they worry you

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What CABOMETYX contains

Active ingredient
(main ingredient)		cabozantinib
(as cabozantinib (S) -malate)
Other ingredients
(inactive ingredients)		microcrystalline cellulose
lactose
hyprolose
croscarmellose sodium
colloidal anhydrous silica
magnesium stearate
hypromellose
titanium dioxide
triacetin
iron oxide yellow
Potential allergenslactose

Do not take this medicine if you are allergic to any of these ingredients.

This medicine does not contain gluten, tartrazine or any other azo dyes.

What CABOMETYX looks like

CABOMETYX 20 mg film-coated tablets are yellow, round with no score, and identified with "XL" on one side and "20" on the other side. (AUST R 283800)

CABOMETYX 40 mg film-coated tablets are yellow, triangle shaped with no score, and identified with "XL" on one side and "40" on the other side. (AUST R 283801)

CABOMETYX 60 mg film-coated tablets are yellow, oval shaped with no score, and identified with "XL" on one side and "60" on the other side. (AUST R 283799)

CABOMETYX tablets are available in a plastic bottle with 30 tablets.

The bottle contains three silica gel desiccant canisters. Keep the canisters in the bottle and do not swallow the desiccant canisters.

Australian Sponsor of CABOMETYX

Ipsen Pty Ltd
Level 5, 627 Chapel Street
South Yarra VIC 3141

Cabometyx® is a registered trademark of Exelixis, Inc., licensed to Ipsen Pharma S.A.S.

This leaflet was prepared in April 2023.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Cabometyx

Active ingredient

Cabozantinib

Schedule

S4

 

1 Name of Medicine

Cabozantinib (S)-malate.

2 Qualitative and Quantitative Composition

Cabometyx tablets contain cabozantinib (S)-malate equivalent to either 20 mg, 40 mg or 60 mg of cabozantinib as the active ingredient.
Each film-coated tablet contains either: 15.54 mg lactose (20 mg tablet), 31.07 mg lactose (40 mg tablet) or 46.61 mg lactose (60 mg tablet).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cabometyx 20 mg film-coated tablets are yellow, round with no score, and debossed with "XL" on one side and "20" on the other side of the tablet.
Cabometyx 40 mg film-coated tablets are yellow triangle shaped with no score, and debossed with "XL" on one side and "40" on the other side of the tablet.
Cabometyx 60 mg film-coated tablets are yellow oval shaped with no score, and debossed with "XL" on one side and "60" on the other side of the tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Renal cell carcinoma (RCC).

Cabometyx is indicated as monotherapy for the treatment of advanced renal cell carcinoma (RCC):
in treatment-naive adults with intermediate or poor risk;
in adults following prior treatment with vascular endothelial growth factor targeted therapy.
Cabometyx in combination with nivolumab is indicated for the first-line treatment of advanced renal cell carcinoma.

Hepatocellular carcinoma (HCC).

Cabometyx is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.

Differentiated thyroid carcinoma (DTC).

Cabometyx is indicated as monotherapy for the treatment of adult and paediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that has progressed during or after prior VEGFR-targeted therapy and who are radioactive iodine (RAI) refractory or ineligible.

4.2 Dose and Method of Administration

Therapy with Cabometyx should be initiated by a physician experienced in the administration of anticancer medicinal products.

Cabometyx as monotherapy.

For RCC, HCC and DTC, the recommended dose of Cabometyx in adults is 60 mg once daily.
For DTC only, the recommended dose of Cabometyx in paediatric patients aged 12 years and older is based on body weight: ≥ 40 kg: 60 mg once daily; < 40 kg: 40 mg once daily.
Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Cabometyx in combination with nivolumab in first-line advanced RCC.

The recommended dose of Cabometyx is 40 mg once daily in combination with nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks. Cabometyx treatment should continue until disease progression or unacceptable toxicity. Nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression (see the Australian Product Information for nivolumab for dosage and administration recommendations for nivolumab).

Treatment modification.

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction of Cabometyx therapy (see Table 1 and see Section 4.4 Special Warnings and Precautions for Use).
When dose reduction is necessary in monotherapy, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.
When dose reduction is necessary in paediatric patients aged 12 years and older and weighing less than 40 kg, it is recommended to reduce the dose to 20 mg of Cabometyx once daily, and then to 20 mg every other day.
When Cabometyx is administered in combination with nivolumab, it is recommended to reduce the dose to 20 mg of Cabometyx once daily, and then to 20 mg every other day (refer to the Australian Product Information for nivolumab for recommended treatment modification for nivolumab).
Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, could become serious or intolerable.
If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.

Special populations.

Elderly patients.

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended.

Race.

No dose adjustment is necessary based on ethnicity (see Section 5.2 Pharmacokinetic Properties).

Patients with renal impairment.

Cabozantinib should be used with caution in patients with mild or moderate renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.

Patients with hepatic impairment.

In patients with mild hepatic impairment, no dose adjustment is required. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). There is no clinical experience in patients with severe hepatic impairment (Child Pugh C) so, cabozantinib is not recommended for use in these patients (see Section 5.2 Pharmacokinetic Properties).

Patients with cardiac impairment.

There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made.

Paediatric population.

The safety and efficacy of cabozantinib in children and adolescents aged < 18 years have not yet been established.
Cabometyx should not be used in children with DTC aged less than 12 years old. The dosing regimen for paediatric patients with DTC is based on simulated pharmacokinetic data (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Cabometyx is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before and 1 hour after taking Cabometyx.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

As most events that require dose modification or interruption occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if this is necessary. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting).
Management of suspected adverse reactions may require temporary interruption or dose reduction of cabozantinib therapy (see Section 4.2 Dose and Method of Administration).
In renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy, dose reductions and dose interruptions due to an adverse event occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial (METEOR). The median daily dose of cabozantinib was 43 mg. Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.
In treatment-naive renal cell carcinoma, dose reductions and dose interruptions occurred in 46% and 73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN). The median daily dose of cabozantinib was 50.3 mg in this study.
Safety and efficacy of cabozantinib has not been evaluated in patients with NYHA Class 3 or 4 Heart Failure and patients with endobronchial manifestations of RCC.
When cabozantinib is given in combination with nivolumab in first-line advanced renal cell carcinoma, dose interruption or reduction due to an AE of either cabozantinib or nivolumab occurred in 83% of patients: 46% cabozantinib only, 3% nivolumab only, and 28% both drugs in the clinical trial (CA2099ER).
In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptions occurred in 62% and 84%, respectively, of cabozantinib-treated patients in the clinical trial (CELESTIAL). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised in patients with mild or moderate hepatic impairment.
In differentiated thyroid carcinoma, dose reductions and dose interruptions occurred in 67% and 71% respectively of cabozantinib treated patients in the clinical trial (COSMIC-311). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 57 days and to first dose interruption was 38.5 days.

Hepatotoxicity.

Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinib treatment (i.e. where no alternative cause is evident), the dose modification advice in Table 1 should be followed (see Section 4.2 Dose and Method of Administration).
When cabozantinib is given in combination with nivolumab, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC (see Section 4.8 Adverse Effects (Undesirable Effects)). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see Section 4.2 Dose and Method of Administration; refer to the Product Information for nivolumab).
Rare instances of vanishing bile duct syndrome have been reported. All cases have occurred in patients who have received immune checkpoint inhibitors, either before or concurrently with cabozantinib treatment.
Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (also see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. Cabometyx is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as cabozantinib has not been studied in this population and exposure might be increased in these patients.

Hepatic encephalopathy.

In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting, decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, these non-hepatic effects may be precipitating factors for the development of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.

Perforations and fistulas.

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses and sepsis. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.

Gastrointestinal (GI) disorders.

Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1).

Thromboembolic events.

Events of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. In the HCC study (CELESTIAL), portal vein thrombosis was observed with cabozantinib, including one fatal event. Patients with a history of portal vein invasion appeared to be at higher risk of developing portal vein thrombosis. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant thromboembolic complication.

Haemorrhage.

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage. Cabozantinib should be used with caution in patients receiving systemic anticoagulation in the context of a considered benefit risk assessment.
In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence with cabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCC population may include tumour invasion of major blood vessels and the presence of underlying liver cirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplatelet agents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk for bleeding were also excluded from this study.

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Thrombocytopenia.

In the HCC study (CELESTIAL), thrombocytopenia and decreased platelets were reported. Platelet levels should be monitored during cabozantinib treatment and the dose modified according to the severity of the thrombocytopenia (see Table 1).

Wound complications.

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery or invasive dental procedures, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.

Osteonecrosis of the jaw.

Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib treatment. Patients should be advised to maintain good oral hygiene practices. Cabozantinib treatment should be stopped at least 28 days prior to dental surgery or invasive dental procedures, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.

Hypertension.

Hypertension, including hypertensive crisis has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. After cabozantinib initiation, blood pressure should be monitored early and regularly and treated as needed with appropriate anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib treatment should be interrupted until blood pressure is controlled, after which cabozantinib can be resumed at a reduced dose. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Diarrhoea.

Diarrhoea has been observed with cabozantinib, and can be severe. If diarrhoea cannot be managed with standard antidiarrhoeal treatment, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when diarrhoea has been resolved to grade 1.

Palmar-plantar erythrodysaesthesia syndrome.

Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.

Proteinuria.

Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Posterior reversible encephalopathy syndrome.

Posterior Reversible Encephalopathy Syndrome (PRES) has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.

Prolongation of QT interval.

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.

Thyroid dysfunction.

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of cabozantinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during cabozantinib treatment. Thyroid function should be monitored periodically throughout treatment with cabozantinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice.

Biochemical laboratory test abnormalities.

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). Hypocalcaemia has been observed with cabozantinib at a higher frequency and/or increased severity (including Grade 3 and 4) in patients with thyroid cancer compared to patients with other cancers. It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1).

CYP3A4 inducers and inhibitors.

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

P-glycoprotein substrates.

Cabozantinib was an inhibitor (IC50 = 7.0 microM), but not a substrate, of P-glycoprotein (P-gp) transport activities in vitro. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g. fexofenadine, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

MRP2 inhibitors.

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excipient related warnings.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Use in hepatic impairment.

Liver function should be monitored in patients with known intra-hepatic metastasis as clinically indicated.

Use in the elderly.

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended.

Paediatric use.

The safety and effectiveness of Cabometyx for the treatment of differentiated thyroid cancer (DTC) in paediatric patients aged 12 years and older is based on simulated pharmacokinetic data derived from the adequate and well-controlled studies of Cabometyx in adults. The additional population pharmacokinetic data demonstrated that cabozantinib exposure is within the same range between adults and paediatric patients aged 12 years and older at the recommended dosages.
Physeal widening has been observed in children with open growth plates when treated with cabozantinib. Therefore, physeal and longitudinal growth monitoring is recommended in children with open growth plates.
The safety and effectiveness of Cabometyx in paediatric patients less than 12 years of age have not been established.
In juvenile rat studies, target organs for toxicity were generally similar to those seen in adult animals. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Adverse effects on the developing reproductive systems were also noted. The findings in juvenile rats indicate a potential risk for children and adolescents.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on cabozantinib.

CYP3A4 inhibitors and inducers.

Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore, co-administration of strong CYP3A4 inhibitors (e.g. ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.
Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John's Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.

Gastric pH modifying agents.

Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e. PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.

MRP2 inhibitors.

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.

Bile salt-sequestering agents.

Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see Section 5.2 Pharmacokinetic Properties). The clinical significance of these potential interactions is unknown.

Effect of cabozantinib on other medicinal products.

The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.
Because of high plasma protein binding levels of cabozantinib (see Section 5.2 Pharmacokinetic Properties) a plasma protein displacement interaction with warfarin may be possible. In case of such combination, INR values should be monitored.

P-glycoprotein substrates.

Cabozantinib was an inhibitor (IC50 = 7.0 microM), but not a substrate, of P-gp transport activities in vitro. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g. fexofenadine, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, saxagliptin, sitagliptin, tolvaptan) while receiving cabozantinib.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in rats have shown reduced male and female fertility at exposure levels (AUC) similar to human clinical exposure. Further, hypospermatogenesis was observed in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.
There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib. Both men and women should be advised to seek advice and consider fertility preservation before treatment.
(Category D)
There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryofoetal lethality and teratogenic effects. The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.
Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as "effective methods of contraception", they should be used together with another method, such as a barrier method (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Cabozantinib crossed the placenta in rats and rabbits. In embryofetal development studies in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryofetal lethality at ≥ 0.03 mg/kg/day. Foetal findings included delayed ossification and skeletal variations at ≥ 0.01 mg/kg/day and foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail at 0.6 mg/kg/day.
In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg/day. Exposures (AUC) at doses causing adverse embryofetal effects in rats and rabbits were well below the human AUC at the recommended dose.
 It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Cabozantinib appeared to be excreted in the milk of rats as significant levels of cabozantinib were detected in the plasma of breast-fed pups. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

4.7 Effects on Ability to Drive and Use Machines

Cabozantinib has minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse 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.

Cabozantinib as monotherapy.

Summary of safety profile.

The most common serious adverse drug reactions in the RCC population (≥ 1% incidence) are pneumonia, abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia, and palmar-plantar erythrodysaesthesia syndrome (PPES).
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, fatigue, nausea, decreased appetite, PPES, hypertension, weight decreased, vomiting, dysgeusia, constipation, and AST increased. Hypertension was observed more frequently in the treatment naive RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).
The most common serious adverse drug reactions in the HCC population (≥ 1% incidence) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, decreased appetite, PPES, fatigue, nausea, hypertension and vomiting.
The most frequent serious adverse reactions in the DTC population with a median duration of treatment of 6.03 months (range 0.2 - 18.8) (≥ 1% incidence) are diarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep vein thrombosis, hypocalcaemia, osteonecrosis of jaw, pain, palmar-plantar erythrodysaesthesia syndrome (PPES), vomiting and renal impairment.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the DTC population included diarrhoea, PPES, hypertension, fatigue, decreased appetite, nausea, alanine aminotransferase increased, aspartate aminotransferase increased and hypocalcaemia.

Tabulated list of adverse reactions.

Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC and DTC (n=1128), or reported after post-marketing use of cabozantinib, are listed in Table 2. The adverse reactions are listed by MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Cabozantinib in combination with nivolumab in first-line advanced RCC.

Summary of safety profile.

When cabozantinib is administered in combination with nivolumab, refer to the Product Information for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, please refer to the nivolumab Product Information.
In the dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n =320), with a minimum follow up of 16 months, the most common serious adverse reactions (≥ 1%) were: diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting and dehydration.
The most frequent adverse reactions (≥ 25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decreased appetite, nausea and abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Tabulated list of adverse reactions.

Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 3, according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions.

Data for the following reactions are based on patients who received Cabometyx 60 mg once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy, in treatment-naive RCC, in HCC following prior systemic therapy and in DTC in patient refractory or not candidate to radioactive iodine (RAI) who have progressed during or after prior systemic therapy or in patients who received Cabometyx 40 mg once daily in combination with nivolumab in first-line advanced RCC (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Gastrointestinal (GI) perforation.

In the study in RCC following prior VEGF-targeted therapy (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.
In the treatment-naive RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.
In the HCC study (CELESTIAL), GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks.
In the DTC study (COSMIC-311), GI perforation grade 4 was reported in one patient (0.6%) of cabozantinib-treated patients and occurred after 14 weeks of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of GI perforations was 1.3% (4/320) treated patients.
Fatal perforations have occurred in the cabozantinib clinical program.

Hepatic encephalopathy.

In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks.
No cases of hepatic encephalopathy were reported in the RCC studies (METEOR, CABOSUN and CA2099ER) or in the DTC study (COSMIC-311).

Diarrhoea.

In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.
In the treatment-naive RCC study (CABOSUN), diarrhoea was reported in 73% of cabozantinib-treated patients (57/78); Grade 3-4 events in 10%.
In the HCC study (CELESTIAL), diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3-4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.
In the DTC study (COSMIC-311), diarrhoea was reported in 62% of cabozantinib treated patients (105/170); Grade 3-4 events in 7.6%. Diarrhoea led to dose reduction and interruption in 24/170 (14%) and 36/170 (21%) of subjects respectively.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of diarrhoea was reported in 63.8% (204/320) of treated patients; Grade 3-4 events in 6.9% (22/320). Median time to onset of all events was 12.6 weeks. Dose delay or reduction occurred in 24.4% (78/320) and discontinuation in 0.6% (2/320) of patients with diarrhoea, respectively.

Fistulas.

In the study in RCC following prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients, and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder were Grade 2. Median time to onset was 30.3 weeks.
In the treatment-naive RCC study (CABOSUN), no cases of fistulas were reported.
In the HCC study (CELESTIAL), fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.
In the DTC study (COSMIC-311), fistulas (two anal and one pharyngeal) were reported in 1.8% (3/170) of the cabozantinib treated patients.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.
Fatal fistulas have occurred in the cabozantinib clinical program.

Haemorrhage.

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of severe haemorrhagic events (Grade ≥ 3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.
In the treatment-naive RCC study (CABOSUN), the incidence of severe haemorrhagic events (Grade ≥ 3) was 5.1% (4/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥ 3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.
In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (grade ≥ 3) was 2.4% in cabozantinib-treated patients (4/170). Median time to onset was 80.5 days.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥ Grade 3 haemorrhage was in 1.6% (5/320) of treated patients.
Fatal haemorrhages have occurred in the cabozantinib clinical program.

Posterior reversible encephalopathy syndrome (PRES).

No cases of PRES were reported in the METEOR, CABOSUN or CA2099ER or CELESTIAL studies, but PRES has been reported in one patient in the DTC study (COSMIC-311) and rarely in other clinical studies (in 2/4872 subjects; 0.04%).

Elevated liver enzymes when cabozantinib is combined with nivolumab in RCC.

In a clinical study of previously untreated patients with RCC receiving cabozantinib in combination with nivolumab, a higher incidence of Grades 3 and 4 ALT increased (9.8%) and AST increased (7.9%) were observed. In patients with grade ≥ 2 increased ALT or AST (n=83): median time to onset was 2.3 months (range: 2.0 to 88.3 weeks), 28% received corticosteroids for median duration of 1.7 weeks (range: 0.9 to 52.3 weeks), and resolution to Grades 0-1 occurred in 89% with median time to resolution of 2.1 weeks (range: 0.4 to 83.6 weeks).
Among the 44 patients who were rechallenged with either nivolumab (n=11) or cabozantinib (n=9) monotherapy or with both (n=24), Grade ≥ 2 increased ALT or AST was observed in 2 patients receiving nivolumab, 2 patients receiving cabozantinib, and 7 patients receiving both nivolumab and cabozantinib. There were no Grade 5 hepatic events.

Hypothyroidism.

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).
In the treatment-naive RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).
In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (4/170), all grade 1-2, none requiring modification of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not been established.
In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to be treated symptomatically.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor.

Mechanism of action.

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects.

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac electrophysiology.

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 - 15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg once daily) was observed in a controlled clinical study in medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF > 500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

Clinical trials.

Renal cell carcinoma (RCC).

Controlled study in RCC patients who have received prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR).

The safety and efficacy of Cabometyx for the treatment of renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy were evaluated in a randomised, open-label, multicentre Phase 3 study (METEOR). Patients (N = 658) with advanced RCC with a clear cell component who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) were randomised (1:1) to receive Cabometyx (N = 330) or everolimus (N = 328). Patients could have received other prior therapies, including cytokines, and antibodies targeting VEGF, the programmed death 1 (PD-1) receptor, or its ligands. Patients with treated brain metastases were allowed. Progression-free survival (PFS) was assessed by a blinded independent radiology review committee, and the primary analysis was conducted among the first 375 subjects randomised. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter.
The baseline demographic and disease characteristics were similar between the Cabometyx and everolimus arms. The majority of the patients were male (75%), with a median age of 62 years. Seventy-one percent (71%) received only one prior VEGFR TKI; 41% of patients received sunitinib as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Centre criteria for prognostic risk category, 46% were favourable (0 risk factors), 42% were intermediate (1 risk factor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%). The median duration of treatment was 7.6 months (range 0.3 - 20.5) for patients receiving Cabometyx and 4.4 months (range 0.21 - 18.9) for patients receiving everolimus.
A statistically significant improvement in PFS was demonstrated for Cabometyx compared to everolimus (Figure 1 and Table 4). A planned interim analysis of OS was conducted at the time of the PFS analysis and did not reach the interim boundary for statistical significance (HR = 0.68 [0.51, 0.90], p = 0.006). In a subsequent unplanned interim analysis of OS, a statistically significant improvement was demonstrated for patients randomised to Cabometyx as compared with everolimus (median of 21.4 months vs. 16.5 months; HR = 0.66 [0.53, 0.83], p = 0.0003; Figure 2 and Table 5).
Exploratory analyses of PFS and OS in the ITT population have also shown consistent results in favour of Cabometyx compared to everolimus across different subgroups according to age (< 65 vs. ≥ 65, sex, MSKCC risk group (favourable, intermediate, poor), ECOG status (0 vs. 1), time from diagnosis to randomisation (< 1 year vs. ≥ 1 year), tumour MET status (high vs. low vs. unknown), bone metastases (absence vs. presence), visceral metastases (absence vs. presence), visceral and bone metastases (absence vs. presence), number of prior VEGFR-TKIs (1 vs. ≥ 2), duration of first VEGFR-TKI (≤ 6 months vs. > 6 months).
Objective response rate findings are summarised in Table 6.

Controlled study in treatment-naive RCC patients (CABOSUN).

The safety and efficacy of Cabometyx for the treatment of treatment-naive renal cell carcinoma were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N = 157) with previously untreated, locally advanced or metastatic RCC with a clear cell component were randomized (1:1) to receive Cabometyx (N = 79) or sunitinib (N = 78). Patients had to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). Approximately 75% of patients had a nephrectomy prior to onset of treatment.
For intermediate risk disease, one or two of the following risk factors were met, while for poor risk, three or more factors were met: time from diagnosis of RCC to systemic treatment < 1 year, Hgb < LLN, Corrected calcium > ULN, KPS < 80%, Neutrophil count > ULN and Platelet count > ULN.
The primary endpoint was PFS. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 12 weeks.
The baseline demographic and disease characteristics were similar between the Cabometyx and sunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥ 3 risk factors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOG performance status of 2. Thirty-six percent (36%) of patients had bone metastases.
A statistically significant improvement in PFS as retrospectively assessed by a blinded Independent Radiology Committee (IRC) was demonstrated for Cabometyx compared to sunitinib (Figure 3 and Table 7). The results from the Investigator determined analysis and IRC-determined analysis of PFS were consistent.
Patients with both positive and negative MET status showed a favourable effect with Cabometyx compared to sunitinib, with greater activity in patients with a positive MET status compared to patients with a negative MET status (HR = 0.32 (0.16, 0.63) vs 0.67 (0.37, 1.23)) respectively.
Cabometyx treatment was associated with a trend for longer survival compared to sunitinib (Table 7). The study was not powered for the OS analysis and the data are immature.
Objective response rate (ORR) findings are summarized in Table 7.

Controlled study of cabozantinib in combination with nivolumab in previously untreated RCC patients (CA2099ER).

The safety and efficacy of cabozantinib 40 mg in combination with nivolumab 240 mg for the first-line treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open label study (CA2099ER). The study included patients (18 years or older) with advanced or metastatic RCC with a clear cell component, Karnofsky Performance Status (KPS) > 70%, and measurable disease as per RECIST v1.1 were included regardless of their PD-L1 status or IMDC risk group. The study excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression, patients who had prior treatment with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, poorly controlled hypertension despite antihypertensive therapy, active brain metastases and uncontrolled adrenal insufficiency. Patients were stratified by IMDC prognostic score, PD-L1 tumour expression, and region.
A total of 651 patients were randomised to receive either cabozantinib 40 mg once daily orally in combination with nivolumab 240 mg (n=323) administered intravenously every 2 weeks or sunitinib (n = 328) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off. Treatment continued until disease progression or unacceptable toxicity with nivolumab administration up to 24 months. Treatment beyond initial Investigator-assessed RECIST version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug, as determined by investigator. First tumour assessment post-baseline was performed at 12 weeks (± 7 days) following randomisation. Subsequent tumour assessments occurred at every 6 weeks (± 7 days) until Week 60, then every 12 weeks (± 14 days) until radiographic progression, confirmed by the Blinded Independent Central review (BICR).
Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 28-90) with 38.4% ≥ 65 years of age and 9.5% ≥ 75 years of age. The majority of patients were male (73.9%) and white (81.9%), and 23.2% and 76.5% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of treatment was 14.26 months (range: 0.2 27.3 months) in cabozantinib with nivolumab treated patients and was 9.23 months (range: 0.8 27.6 months) in sunitinib treated patients. Patient distribution by IMDC risk categories was 22.6% favourable, 57.6% intermediate, and 19.7% poor.
The primary efficacy outcome measure was PFS as determined by a BICR. Additional efficacy measures included OS and ORR as key secondary endpoints for hierarchical statistical testing.
The study demonstrated a statistically significant benefit in PFS, OS, and ORR for patients randomised to cabozantinib in combination with nivolumab as compared to sunitinib.
The Kaplan Meier curves for PFS and OS (with a minimum follow up of 10.6 months) in all risk patients are shown in Figure 4 and Figure 5.
Efficacy results from the primary analysis (minimum follow up 10.6 months) are shown in Table 8.
PFS, OS, ORR benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of tumour PD L1 expression.
PFS benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of the IMDC risk category. Median PFS for the favourable risk group was not reached for cabozantinib in combination with nivolumab, and was 12.81 months in the sunitinib arm (HR = 0.60; 95% CI: 0.37, 0.98). Median PFS for the intermediate risk group was 17.71 months for cabozantinib in combination with nivolumab and was 8.38 months in the sunitinib arm (HR = 0.54; 95% CI: 0.41, 0.73). Median PFS for the poor risk group was 12.29 months for cabozantinib in combination with nivolumab and was 4.21 months in the sunitinib arm (HR = 0.36; 95% CI: 0.23, 0.58).
Hepatocellular carcinoma.

Controlled study in patients who have received sorafenib (CELESTIAL).

The safety and efficacy of Cabometyx were evaluated in a randomized, double-blind, placebo-controlled Phase 3 study (CELESTIAL). Patients (N = 707) with HCC not amenable to curative treatment and who had previously received sorafenib for advanced disease were randomised (2:1) to receive Cabometyx (N = 470) or placebo (N = 237). Patients could have received one other prior systemic therapy for advanced disease in addition to sorafenib. Randomisation was stratified by aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region (Asia, other regions) and by presence of extrahepatic spread of disease and/or macrovascular invasions (Yes, No).
The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints were progression-free survival (PFS) and objective response rate (ORR), as assessed by the Investigator using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments were conducted every 8 weeks. Subjects continued blinded study treatment after radiological disease progression whilst they experienced clinical benefit or until the need for subsequent systemic or liver-directed local anticancer therapy. Crossover from placebo to cabozantinib was not allowed during the blinded treatment phase.
The baseline demographic and disease characteristics were similar between the Cabometyx and placebo arms and are shown below for all 707 randomised patients:
Male: 82%; Median age: 64 years. Caucasian: 56%, Asian: 34%; ECOG performance status (PS) 0: 53% or ECOG PS 1: 47%. Child Pugh A: 99%, Child Pugh B: 1%.
Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV), 40% other (neither HBV nor HCV).
Presence of macroscopic vascular invasion and/or extra-hepatic tumour spread: 78%.
Alfa-fetoprotein (AFP) levels ≥ 400 microgram/L: 41%.
Loco-regional transarterial embolisation or chemoinfusion procedures: 44%.
Radiotherapy prior to cabozantinib treatment: 37%.
Median duration of sorafenib treatment: 5.32 months.
Seventy-two percent (72%) of patients had received one and 28% had received 2 prior systemic therapy regimens for advanced disease.
A statistically significant improvement in OS was demonstrated for Cabometyx compared to placebo (Table 9 and Figures 6 and 7).
PFS and ORR findings are summarized in Table 9.
The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancer therapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receiving these therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use of NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was 0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan-Meier estimates for median duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placebo arm, an estimated 4.2-month difference in the medians.
Non-disease specific quality of life (QoL) was assessed using the EuroQoL EQ-5D-5L. A negative effect of Cabometyx versus placebo on the EQ-5D utility index score was observed during the first weeks of treatment. Only limited QoL data are available after this period.
Differentiated thyroid carcinoma (DTC).

Controlled study in patients who have received prior systemic therapy and refractory to radioactive iodine (COSMIC-311).

The safety and efficacy of Cabometyx was evaluated in COSMIC-311, a randomised (2:1), double-blind, placebo-controlled, multicentre trial in patients with radioiodine refractory differentiated thyroid cancer who have progressed after VEGFR targeting therapy. Patients were randomised (N=258) to receive Cabometyx 60 mg orally once daily (N=170) or placebo (N=88).
Randomisation was stratified by prior receipt of lenvatinib (yes vs. no) and age (≤ 65 years vs. > 65 years). Eligible patients randomised to placebo were allowed to cross-over to Cabometyx upon confirmation of progressive disease by blinded independent radiology review committee (BIRC). Subjects continued blinded study treatment as long as they experienced clinical benefit or until there was unacceptable toxicity. The primary efficacy outcome measures were progression-free survival (PFS) in the ITT population, and objective response rate (ORR) in the first 100 randomised patients, as assessed by BIRC per RECIST 1.1. Tumour assessments were conducted every 8 weeks after randomisation during the first 12 months on study, then every 12 weeks thereafter. Overall survival (OS) was an additional endpoint.
The primary analysis of PFS (median follow up 6.2 months) included 187 randomised patients, 125 to Cabometyx and 62 to placebo. Baseline demographics and disease characteristics were generally balanced for both treatment groups. The median age was 66 years (range 32 to 85 years), 51% being ≥ 65 years of age, 13% being ≥ 75 years of age. The majority of patients were white (70%), 18% of patients were Asian and 55% were female. Histologically, 55% had a confirmed diagnosis of papillary thyroid carcinoma, 48% had follicular thyroid carcinoma including 17% patients with Hurthle cell thyroid cancer. Metastases were present in 95% of the patients: lungs in 68%, lymph nodes in 67%, bone in 29%, pleura in 18% and liver in 15%. Five patients had not received prior RAI due to ineligibility, 63% had received prior lenvatinib, 60% had received prior sorafenib and 23% had received both sorafenib and lenvatinib. Baseline ECOG performance status was 0 (48%) or 1 (52%).
The median duration of treatment was 4.4 months in the cabozantinib arm and 2.3 months in the placebo arm.
The trial demonstrated a statistically significant improvement in PFS (median follow up 6.2 months) for patients randomised to Cabometyx compared with placebo. Efficacy results are summarised in Table 10. The trial did not demonstrate a statistically significant improvement in ORR for patients randomised to Cabometyx (n=67) compared with placebo (n=33) (15% vs. 0%, p=0.0281). An updated analysis of PFS and OS was performed with median follow up of 10.1 months.
Exploratory analyses of PFS in the ITT population have also shown consistent results in favour of Cabometyx compared to placebo across different subgroups according to prior lenvatinib, prior sorafenib, number of prior VEGFR, age (≤ 65 years or > 65 years), histology type (papillary or follicular).
No clinically significant differences in patient-reported outcomes were observed between patients given Cabometyx and patients given placebo.
See Figure 8.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.
Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.
A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.
Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation (Cabometyx) compared to the capsule formulation (Cometriq) was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet (Cabometyx) and capsule (Cometriq) formulations.

Distribution.

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212 L. Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function.

Metabolism.

Cabozantinib was metabolised in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: cabozantinib-N-oxide, cabozantinib amide cleavage product, cabozantinib monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (cabozantinib-N-oxide and cabozantinib amide cleavage product), which possess < 1% of the on-target kinase inhibition potency of parent cabozantinib, each represent < 10% of total drug-related plasma exposure.
Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralising antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by > 80% in a NADPH-catalysed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (i.e. a < 20% reduction).

Excretion.

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy volunteers following oral administration of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.8 L/hr. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations.

Renal impairment.

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Hepatic impairment.

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n = 1425) and mild hepatic impairment (n = 558). There is limited data in patients with moderate hepatic impairment (n = 15) as per NCI-ODWG (National Cancer Institute - Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

Race.

A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race.

Paediatrics.

The dosing regimen for paediatric patients with DTC is based on simulation performed with the population pharmacokinetic analysis done in adult patients with DTC, by considering weight allometric scaling.

5.3 Preclinical Safety Data

Genotoxicity.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays (bacterial reverse mutation assay, chromosomal aberration assay using human lymphocytes and a mouse micronucleus test).

Carcinogenicity.

The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. Cabozantinib was not carcinogenic in the 26-week carcinogenicity study in rasH2 transgenic mice at doses ≤ 15 mg/kg/day, resulting in exposures approximately 4 times the human AUC at the recommended clinical dose of 60 mg/day. In the 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or in combination with malignant pheochromocytoma of the adrenal medulla in both sexes at doses ≥ 0.1 mg/kg/day, resulting in exposures well below the intended exposure in humans. The clinical relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low.
Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the intended human therapeutic exposure.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet content.

Microcrystalline cellulose, lactose, hyprolose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film-coating.

Hypromellose, titanium dioxide, triacetin, iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, 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

Store below 25°C.

6.5 Nature and Contents of Container

Cabometyx 20 mg film-coated tablets are available as a pack size of 30 film-coated tablets in a HDPE bottle with a polypropylene child-resistant closure and three silica gel desiccant canisters.
Cabometyx 40 mg film-coated tablets are available as a pack size of 30 film-coated tablets in a HDPE bottle with a polypropylene child-resistant closure and three silica gel desiccant canisters.
Cabometyx 60 mg film-coated tablets are available as a pack size of 30 film-coated tablets in a HDPE bottle with a polypropylene child-resistant closure and three silica gel desiccant canisters.

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.

Cabometyx contains the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate.
Cabozantinib (S)-malate is a white to off-white, non-hygroscopic, crystalline substance. It is practically insoluble above pH of 4 and in water.
The molecular formula is C28H24FN3O5.C4H6O5 and the molecular weight is 635.6 Daltons as malate salt.

CAS number.

CAS Number: 1140909-48-3.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes