CABOMETYX 60 mg FILM-COATED TABLETS

Introduction

Package Leaflet: Information for the Patient

CABOMETYX 20mg film-coated tablets

CABOMETYX 40mg film-coated tablets

CABOMETYX 60mg film-coated tablets

cabozantinib

Read the entire package leaflet carefully before starting to take this medication, as it contains important information for you.

• Keep this package leaflet, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medication has been prescribed to you only, and you should not give it to others, even if they have the same symptoms as you, as it may harm them.
• If you experience side effects, consult your doctor, even if they are not listed in this package leaflet. See section 4.

Contents of the package leaflet

1. What is CABOMETYX and what is it used for
2. What you need to know before taking CABOMETYX
3. How to take CABOMETYX
4. Possible side effects
5. Storage of CABOMETYX
6. Package contents and additional information

1. What is CABOMETYX and what is it used for

What is CABOMETYX

CABOMETYX is a cancer medication that contains the active substance cabozantinib. It is used in adults to treat:

• advanced kidney cancer called advanced renal cell carcinoma
• liver cancer when a specific anticancer medication (sorafenib) is no longer able to stop the progression of the disease.
• advanced neuroendocrine tumors: tumors that originate in the pancreas, stomach, intestines, lung, or other organs. It is administered when patients with these tumors no longer respond to a previous treatment option.

CABOMETYX is also used to treat locally advanced or metastatic differentiated thyroid cancer, a type of cancer in the thyroid gland, in adults when treatments with radioactive iodine and anticancer medications are no longer able to stop the progression of the disease.

CABOMETYX may be administered in combination with nivolumab for advanced kidney cancer. It is essential that you also read the package leaflet for nivolumab. If you have any questions about these medications, consult your doctor.

How does CABOMETYX work?

CABOMETYX blocks the action of proteins called tyrosine kinase receptors (RTK), which are involved in cell growth and the development of new blood vessels that supply blood to these cells. These proteins may be present in high amounts in cancer cells, and by blocking their action, this medication can slow down the rate at which the tumor grows and help interrupt the blood supply that the cancer needs.

2. What you need to know before taking CABOMETYX

Do not take CABOMETYX

• if you are allergic to cabozantinib or any of the other components of this medication (listed in section 6).

Warnings and precautions

Consult your doctor or pharmacist before starting to take CABOMETYX:

• If you have high blood pressure.
• If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in the wall of a blood vessel
• If you have diarrhea.
• If you have a recent history of significant bleeding.
• If you have undergone surgery in the last month (or if you have any scheduled), including dental surgery.
• If you have inflammatory bowel disease (such as Crohn's disease, ulcerative colitis, diverticulitis, or appendicitis).
• If you have a recent history of blood clots in the leg, stroke, or heart attack.
• If you have thyroid problems. Inform your doctor if you get tired more easily, if you feel colder than others, or if your voice becomes deeper while taking this medication.
• If you have liver or kidney disease.

Consult your doctor if you experience any of the above.

You may need treatment, or your doctor may decide to change the dose of CABOMETYX or interrupt treatment altogether. Also, consult section 4 "Possible side effects".

You should also inform your dentist that you are taking this medication. It is essential for you to have good oral care during treatment.

Children and adolescents

CABOMETYX is not recommended for use in children and adolescents. The effects of this medication in individuals under 18 years of age are unknown.

Other medications and CABOMETYX

Tell your doctor or pharmacist if you are taking, or have recently taken, any other medications, including those purchased without a prescription. This is because CABOMETYX may affect how other medications work. Similarly, some medications may affect how CABOMETYX works. This may require your doctor to change the dose(s) you take. You should inform your doctor about any medication, but especially if you are taking:

• Medications for treating fungal infections, such as itraconazole, ketoconazole, and posaconazole
• Medications used to treat bacterial infections (antibiotics), such as erythromycin, clarithromycin, and rifampicin
• Medications for allergies, such as fexofenadine
• Medications for treating angina (chest pain due to inadequate blood supply to the heart), such as ranolazine
• Medications used to treat epilepsy or seizures, such as phenytoin, carbamazepine, and phenobarbital
• Herbal medications containing St. John's Wort (Hypericum perforatum), which is sometimes used to treat depression or depression-related conditions, such as anxiety
• Anticoagulant medications, such as warfarin and dabigatran etexilate
• Medications for high blood pressure or other heart conditions, such as aliskiren, ambrisentan, dabigatran etexilate, digoxin, talinolol, and tolvaptan
• Medications for diabetes, such as saxagliptin and sitagliptin
• Medications for treating gout, such as colchicine
• Medications used to treat HIV or AIDS, such as efavirenz, ritonavir, maraviroc, and emtricitabine
• Medications used to prevent rejection after a transplant (cyclosporin) and treatment regimens with cyclosporin in rheumatoid arthritis and psoriasis

CABOMETYX with food

Avoid taking products that contain grapefruit juice during the entire time you use this medication, as they may increase the levels of this medication in the blood.

Pregnancy, breastfeeding, and fertility

Pregnancy should be avoided during treatment with CABOMETYX.If you or your partner may become pregnant, you should use adequate contraceptive methods during the entire treatment and for at least four months after treatment ends. Discuss with your doctor which contraceptive methods are appropriate while taking this medication (see also "Other medications and CABOMETYX").

Consult your doctor if you or your partner becomes pregnant or plans to become pregnant during treatment with this medication.

Discuss with your doctor BEFORE starting to take this medicationif you or your partner are planning to have a child after treatment ends. There is a possibility that treatment with this medication could affect your fertility.

Women taking this medication should stop breastfeeding during treatment and for at least four months after treatment ends, as cabozantinib and/or its metabolites may be excreted in breast milk and be harmful to the infant.

If you take this medication while using oral contraceptives, oral contraception may be ineffective. You should also use a barrier contraceptive method (e.g., condom or diaphragm) while taking this medication and for a minimum of 4 months after treatment ends.

Driving and using machines

Be cautious when driving or using machines. Keep in mind that treatment with CABOMETYX may make you feel tired or weak and may affect your ability to drive and use machines.

CABOMETYX contains lactose

This medication contains lactose (a type of sugar). If your doctor has told you that you have an intolerance to certain sugars, consult with them before taking this medication.

CABOMETYX contains sodium

This medication contains less than 1 mmol (23 mg of sodium) per tablet; this is, essentially "sodium-free".

3. How to take CABOMETYX

Follow exactly the administration instructions for this medication as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Continue taking this medication until your doctor decides to interrupt treatment. If you experience severe side effects, your doctor may decide to change the dose or interrupt treatment earlier than initially planned. Your doctor will tell you if it is necessary to adjust your dose.

You should take CABOMETYX once a day. The usual dose is 60 mg, but your doctor will decide which dose is appropriate for you.

When this medication is administered in combination with nivolumab for the treatment of advanced kidney cancer, the recommended dose of CABOMETYX is 40 mg daily.

Do nottake CABOMETYX with food.

Do nottake any food for at least two hours before and for one hour after taking this medication.

Swallow the tablet with a full glass of water. Do not crush the tablets.

If you take more CABOMETYX than you should

If you have taken more of this medication than you were told to, talk to a doctor or go to the hospital immediately with the tablets and this package leaflet.

If you forget to take CABOMETYX

• If there are 12 or more hours until the next dose, take the missed dose immediately. Take the next dose at the usual time.
• If there are less than 12 hours until the next dose, do not take the missed dose. Take the next dose at the usual time.

If you interrupt treatment with CABOMETYX

Interrupting your treatment may interrupt the effect of your medication. Do not interrupt treatment with this medication unless you have discussed it with your doctor.

When this medication is administered in combination with nivolumab, you will first receive nivolumab followed by CABOMETYX.

Consult the package leaflet for nivolumab to understand how to use this medication. If you have any other questions about the use of this medication, ask your doctor.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. If you experience adverse effects, your doctor may tell you to take CABOMETYX at a lower dose. Your doctor may also prescribe other medicines to help control the adverse effects.

Report immediately to your doctor if you notice any of the following adverse effects, as you may need urgent medical treatment:

• Symptoms such as abdominal pain, nausea (discomfort), vomiting, constipation, or fever. These symptoms can be a consequence of a gastrointestinal perforation, a hole in the stomach or intestine that can be life-threatening. Gastrointestinal perforation is frequent (it can affect up to 1 in 10 people).
• Severe or uncontrolled bleeding with symptoms such as: blood in vomit, black stools, blood in urine, headache, coughing up blood. It is frequent (it can affect up to 1 in 10 people).
• Feeling of drowsiness, confusion, or loss of consciousness. This can be due to liver problems that are frequent (they can affect up to 1 in 10 people).
• Swelling, or difficulty breathing. They are very frequent (they can affect more than 1 in 10 people).
• A wound that does not heal. It is infrequent (it can affect 1 in 100 people).
• Seizures, headache, confusion, or difficulty concentrating. These can be signs of a disease called posterior reversible encephalopathy syndrome (PRES). PRES is infrequent (it can affect 1 in 100 people).
• Pain in the mouth, teeth, and/or jaw, inflammation, or ulcers in the mouth, numbness, or a feeling of heaviness in the jaw, or noticing a loose tooth. These can be symptoms of bone damage in the jaw (osteonecrosis). It is infrequent (it can affect 1 in 100 people).

Other adverse effects with CABOMETYX administered alone may be:

Very frequent adverse effects(can affect more than 1 in 10 people)

• Anemia (low levels of red blood cells that carry oxygen), low levels of platelets (cells that help blood clot)
• Reduced thyroid activity, whose symptoms can include fatigue, weight gain, constipation, feeling cold, and dry skin
• Decreased appetite, weight loss, altered sense of taste
• Decrease in the amount of magnesium, potassium, or calcium in the blood
• Decrease in the amount of albumin protein in the blood (which transports substances such as hormones, medicines, and enzymes throughout the body).
• Headache, dizziness
• High blood pressure (hypertension)
• Bleeding
• Difficulty speaking, hoarseness (dysphonia), cough, and difficulty breathing
• Gastrointestinal disorders, such as diarrhea, nausea, vomiting, constipation, indigestion, and abdominal pain
• Redness, swelling, or pain in the mouth or throat (stomatitis)
• Rash, sometimes with blisters, itching, pain in the hands or soles of the feet, rash, or intense itching of the skin
• Pain in the arms, hands, legs, or feet, pain in joints
• Feeling of being tired or weak, inflammation of the oral and gastrointestinal mucosa, inflammation of the arms and legs
• Weight loss
• Abnormal liver function tests (increase in liver enzymes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase)

Frequent adverse effects(can affect up to 1 in 10 people)

• Abscess (accumulation of pus with swelling and inflammation)
• Dehydration
• Decrease in phosphate or sodium levels in the blood
• Increase in potassium levels in the blood
• Increase in the level of bilirubin waste product in the blood (which can cause jaundice/yellowing of the eyes or skin)
• Increase (hyperglycemia) or decrease (hypoglycemia) of sugar levels in the blood
• Inflammation of the nerves (causing numbness, weakness, tingling, or burning in the arms and legs)
• Ringing in the ears (tinnitus)
• Blood clots in the veins, decreased blood pressure (hypotension)
• Blood clots in the lungs, inflammation of the nasal mucosa (allergic rhinitis)
• Inflammation of the pancreas, painful tearing or abnormal connection of body tissues (fistula), gastroesophageal reflux disease (reflux of stomach acid), hemorrhoids (piles), dry mouth, and mouth pain, difficulty swallowing, flatulence
• Intense itching of the skin, hair loss (alopecia) and thinner hair, dry skin, acne, change in hair color, thickening of the outer layer of the skin, redness of the skin
• Muscle spasms
• Protein in urine (observed in analysis)
• Abnormal liver function tests (increase in liver enzymes gamma-glutamyl transferase in blood)
• Abnormal kidney function tests (increase in creatinine levels in blood)
• Increase in the level of the enzyme that breaks down fats (lipase) and the enzyme that breaks down starch (amylase)
• Increase in cholesterol or triglyceride levels in the blood
• Low levels of white blood cells (which are important for fighting infection)
• Lung infection (pneumonia)

Infrequent adverse effects(can affect up to 1 in 100 people)

• Seizures, stroke
• Severe increase in blood pressure
• Blood clots in the arteries
• Decrease in liver bile flow
• Painful or burning sensation on the tongue (glossodynia)
• Heart attack
• Clot/embolus that traveled through the arteries and got stuck
• Lung collapse with air leaking into the space between the lung and the chest wall, which often causes difficulty breathing (pneumothorax)

Frequency not known (proportion of people affected not known)

• Increase and weakening of the wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections)
• Inflammation of the blood vessels in the skin (cutaneous vasculitis)

The following adverse effects have been reported with CABOMETYX in combination with nivolumab:

Very frequent adverse effects(can affect more than 1 in 10 people)

• Infections in the upper respiratory tract
• Reduced thyroid activity; symptoms can include fatigue, weight gain, constipation, feeling cold, and dry skin
• Increased thyroid activity; symptoms can include rapid heartbeat, sweating, and weight loss
• Decreased appetite, altered sense of taste
• Headache, dizziness
• High blood pressure (hypertension)
• Difficulty speaking, hoarseness (dysphonia), cough, and difficulty breathing
• Gastrointestinal disorders, including diarrhea, nausea, vomiting, indigestion, abdominal pain, and constipation
• Redness, swelling, or pain in the mouth or throat (stomatitis)
• Rash, sometimes with blisters, itching, pain in the hands or soles of the feet, rash, or intense itching of the skin
• Pain in the joints (arthralgia), muscle spasms, muscle weakness, and sore muscles
• Protein in urine (detected in analysis)
• Feeling of being tired or weak, fever, and edema (swelling)
• Abnormal liver function tests (increase in liver enzymes aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase in blood, elevated blood levels of bilirubin waste product)
• Abnormal kidney function tests (increase in creatinine in blood)
• High (hyperglycemia) or low (hypoglycemia) sugar levels in the blood
• Anemia (low levels of red blood cells that carry oxygen), low levels of white blood cells (which are important for fighting infection), low levels of platelets (cells that help blood clot)
• High levels of the enzyme that breaks down fats (lipase) and the enzyme that breaks down starch (amylase)
• Decrease in phosphate levels
• Increase or decrease in potassium levels
• Decrease or increase in blood levels of calcium, magnesium, or sodium
• Decrease in body weight

Frequent adverse effects(can affect up to 1 in 10 people)

• Severe lung infection (pneumonia)
• Increase in certain white blood cells called eosinophils
• Allergic reaction (including anaphylactic reaction)
• Decrease in the secretion of hormones produced by the adrenal glands (glands located above the kidneys)
• Dehydration
• Inflammation of the nerves (causing numbness, weakness, tingling, or burning in the arms and legs)
• Ringing in the ears (tinnitus)
• Dry eyes and blurred vision
• Changes in heart rate or frequency, rapid heartbeat
• Blood clots in the blood vessels
• Inflammation of the lungs (pneumonitis, characterized by cough and difficulty breathing), blood clots in the lung, fluid around the lungs
• Nosebleeds
• Inflammation of the colon (colitis), dry mouth, mouth pain, inflammation of the stomach (gastritis), and hemorrhoids (piles)
• Inflammation of the liver (hepatitis)
• Dry skin and redness of the skin
• Hair loss (alopecia) and thinner hair, change in hair color
• Inflammation of the joints (arthritis)
• Kidney failure (including sudden loss of kidney function)

• Pain, chest pain
• Increase in triglyceride levels in the blood
• Increase in cholesterol levels in the blood

Infrequent adverse effects(can affect 1 in 100 people)

• Allergic reactions related to the infusion of the medicine nivolumab
• Inflammation of the pituitary gland located at the base of the brain (hypophysitis), inflammation of the thyroid gland (thyroiditis)
• A temporary inflammation of the nerves that causes pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); muscle weakness and fatigue without atrophy (myasthenic syndrome)
• Inflammation of the brain
• Inflammation of the eye (causing pain and redness)
• Inflammation of the heart muscle
• Clot/embolus that traveled through the arteries and got stuck
• Inflammation of the pancreas (pancreatitis), intestinal perforation, burning or painful sensation on the tongue (glossodynia)
• Skin disease with thickened areas of red skin, often with silvery scales (psoriasis)
• Hives (urticaria)

• Muscle weakness, not caused by exercise (myopathy), bone damage in the jaw, painful tearing or abnormal connection in body tissues (fistula)

• Inflammation of the kidney
• Lung collapse with air leaking into the space between the lung and the chest wall, which often causes difficulty breathing (pneumothorax)

Frequency not known (proportion of people affected not known)

• Inflammation of the blood vessels in the skin (cutaneous vasculitis)
• Progressive destruction and loss of the intrahepatic bile ducts and jaundice

Reporting of adverse effects

If you experience any kind of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of CABOMETYX

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the blister pack and the label on the bottle and the box after EXP. The expiration date is the last day of the month indicated.

This medicine does not require special storage conditions.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package contents and additional information

Composition of CABOMETYX

The active ingredient is (S)-malate of cabozantinib.

CABOMETYX 20 mg film-coated tablets: each tablet contains (S)-malate of cabozantinib, equivalent to 20 mg of cabozantinib.

CABOMETYX 40 mg film-coated tablets: each tablet contains (S)-malate of cabozantinib, equivalent to 40 mg of cabozantinib.

CABOMETYX 60 mg film-coated tablets: each tablet contains (S)-malate of cabozantinib, equivalent to 60 mg of cabozantinib.

The other ingredients are:

• Tablet core:microcrystalline cellulose, anhydrous lactose, hydroxypropylcellulose, sodium croscarmellose, anhydrous colloidal silica, magnesium stearate. (see section 2 for lactose content)
• Film coating:hypromellose 2910, titanium dioxide (E171), triacetin, yellow iron oxide (E172)

Appearance of CABOMETYX and package contents

The CABOMETYX 20 mg film-coated tablets are yellow, round, and without a score, and have the inscription "XL" on one side and "20" on the other.

The CABOMETYX 40 mg film-coated tablets are yellow, triangular, and without a score, and have the inscription "XL" on one side and "40" on the other.

The CABOMETYX 60 mg film-coated tablets are yellow, oval, and without a score, and have the inscription "XL" on one side and "60" on the other.

CABOMETYX is available in packages containing a plastic bottle with 30 film-coated tablets.

The bottle contains three desiccant containers of silica gel and a polyester plug to prevent damage to the film-coated tablets. Keep these desiccant containers and the polyester plug in the bottle and do not swallow them.

Marketing Authorization Holder

Ipsen Pharma

70 rue Balard

75015 Paris

France

Manufacturer

Patheon France

40 Boulevard de Champaret

38300 Bourgoin Jallieu, France

Tjoapack Netherlands B.V.

Nieuwe Donk 9

4879 AC Etten-Leur

Netherlands

Rottendorf Pharma GmbH

Ostenfelderstrasse 51 – 61

D-59320 Ennigerloh, Germany

You can request more information about this medicine by contacting the local representative of the marketing authorization holder.

Date of the last revision of this prospectus:

Other sources of information

Detailed information about this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu.