CABOMETYX 40 mg FILM-COATED TABLETS

Introduction

Patient Information: Summary of Product Characteristics

CABOMETYX 20mg film-coated tablets

CABOMETYX 40mg film-coated tablets

CABOMETYX 60mg film-coated tablets

cabozantinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What is CABOMETYX and what is it used for
2. What you need to know before you take CABOMETYX
3. How to take CABOMETYX
4. Possible side effects
5. Storage of CABOMETYX
6. Contents of the pack and other information

1. What is CABOMETYX and what is it used for

What is CABOMETYX

CABOMETYX is a cancer medicine 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 anti-cancer medicine (sorafenib) is no longer able to stop the disease from getting worse.
• advanced neuroendocrine tumours: tumours that originate in the pancreas, stomach, intestines, lung or other organs. It is given when patients with these tumours no longer respond to a previous treatment option.

CABOMETYX is also used to treat differentiated thyroid cancer that is locally advanced or has spread to other parts of the body, a type of cancer in the thyroid gland, in adults when treatments with radioactive iodine and anti-cancer medicines are no longer able to stop the disease from getting worse.

CABOMETYX can be given in combination with nivolumab for advanced kidney cancer. It is important that you also read the leaflet for nivolumab. If you have any questions about these medicines, ask your doctor.

How does CABOMETYX work

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

2. What you need to know before you take CABOMETYX

Do not take CABOMETYX

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

Warnings and precautions

Talk to your doctor or pharmacist before you start taking CABOMETYX:

• if you have high blood pressure.
• if you have or have had an aneurysm (a bulge and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel
• if you have diarrhoea.
• if you have recently had significant bleeding.
• if you have had surgery in the last month (or if you have any planned), including dental surgery.
• if you have inflammatory bowel disease (such as Crohn's disease, ulcerative colitis, diverticulitis, or appendicitis).
• if you have recently had a blood clot in your leg, a stroke, or a heart attack.
• if you have thyroid problems. Tell your doctor if you get more tired easily, if you feel colder than other people, or if your voice becomes deeper while you are taking this medicine.
• if you have liver or kidney disease.

Talk to your doctor if you have any of the above.

You may need treatment, or your doctor may decide to change your dose of CABOMETYX or stop treatment altogether. Also, read section 4 “Possible side effects”.

You should also tell your dentist that you are taking this medicine. It is important for you to have good dental care during treatment.

Children and adolescents

CABOMETYX is not recommended for use in children and adolescents. The effects of this medicine in people under 18 years of age are not known.

Other medicines and CABOMETYX

Tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including those obtained without a prescription. This is because CABOMETYX may affect the way other medicines work. Also, some medicines may affect the way CABOMETYX works. This may require your doctor to change the dose(s) you are taking. You should tell your doctor about all medicines, but especially if you are taking:

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

CABOMETYX with food

Avoid taking products that contain grapefruit juice while you are taking this medicine, as they may increase the levels of this medicine in your blood.

Pregnancy, breast-feeding and fertility

Pregnancy should be avoided during treatment with CABOMETYX.If you or your partner can become pregnant, you must use effective contraception during treatment and for at least four months after finishing treatment. Talk to your doctor about what contraceptive methods are appropriate while you are taking this medicine (see also “Other medicines and CABOMETYX”).

Talk to your doctor if you or your partner become pregnant, or if you or your partner plan to become pregnant, during treatment with this medicine.

Talk to your doctor BEFORE you start taking this medicineif you or your partner are planning to have a child after finishing treatment. There is a possibility that treatment with this medicine could affect your fertility.

Women who take this medicine must stop breast-feeding during treatment and for at least four months after treatment has finished, as cabozantinib and/or its metabolites may be excreted in breast milk and be harmful to the baby.

If you take this medicine while using oral contraceptives, the oral contraceptive may not be effective. You should also use a barrier method of contraception (e.g. condom or diaphragm) while you are taking this medicine and for a minimum of 4 months after treatment has finished.

Driving and using machines

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

CABOMETYX contains lactose

This medicine contains lactose (a type of sugar). If your doctor has told you that you have an intolerance to some sugars, talk to them before taking this medicine.

CABOMETYX contains sodium

This medicine contains less than 1 mmol (23 mg of sodium) per tablet; this is essentially “sodium-free”.

3. How to take CABOMETYX

Always take this medicine exactly as your doctor or pharmacist has told you. If you are not sure, check with your doctor or pharmacist.

Keep taking this medicine until your doctor tells you to stop. If you experience serious side effects, your doctor may decide to change your dose or stop treatment earlier than planned. Your doctor will tell you if you need to adjust your dose.

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

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

Do nottake CABOMETYX with food.

Do not eat any food for at least 2 hours before and 1 hour after taking this medicine.

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 medicine than you should, talk to a doctor or go to hospital immediately with the tablets and this leaflet.

If you forget to take CABOMETYX

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

If you stop taking CABOMETYX

Stopping your treatment may stop the effect of your medicine. Do not stop taking this medicine unless you have talked to your doctor.

When this medicine is given in combination with nivolumab, you will first be given nivolumab followed by CABOMETYX.

Read the leaflet for nivolumab to understand how to use this medicine. If you have any further questions about the use of this medicine, 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 may 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 may 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 may 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 sores in the mouth, numbness or feeling of heaviness in the jaw, or noticing a loose tooth. These may 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(may 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 may include fatigue, weight gain, constipation, feeling of 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
• Stomach disorders, such as diarrhea, nausea, vomiting, constipation, indigestion, and abdominal pain
• Redness, swelling, or pain in the mouth or throat (stomatitis)
• Skin rash, sometimes with blisters, itching, pain in the hands or soles of the feet, rash
• 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(may 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) in blood sugar levels
• 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(may 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(may affect more than 1 in 10 people)

• Infections in the upper respiratory tract
• Reduced thyroid activity; symptoms may include fatigue, weight gain, constipation, feeling of cold, and dry skin
• Increased thyroid activity; symptoms may include rapid heart rate, sweating, and weight loss
• Decreased appetite, altered sense of taste
• Headache, dizziness
• High blood pressure (hypertension)
• Difficulty speaking, hoarseness (dysphonia), cough, and difficulty breathing
• Stomach upset, including diarrhea, nausea, vomiting, indigestion, abdominal pain, and constipation
• Redness, swelling, or pain in the mouth or throat (stomatitis)
• Skin 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) blood sugar levels
• 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(may 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 heart rate
• 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(may affect 1 in 100 people)

• Allergic reactions related to the infusion of the nivolumab medicine
• 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 (itchy rash)

• Muscle weakness, not caused by exercise (myopathy), bone damage in the jaw, painful tearing or abnormal connection in the 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 leaflet. 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 and the label of 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 that 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 leaflet:

Other sources of information

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