cabozantinib: package leaflet

What CABOMETYX is

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 anticancer medicine (sorafenib) is no longer stopping the disease from progressing.
- Advanced neuroendocrine tumours – tumours that originate from the pancreas, stomach, bowels, 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 locally advanced or metastatic differentiated thyroid cancer, a type of cancer in the thyroid gland, in adults when radioactive iodine and anticancer medicine treatments are no longer stopping the disease from progressing.

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

How CABOMETYX works

CABOMETYX blocks 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 this medicine can

slow down the rate at which the tumour grows and help to cut off the blood supply that the cancer needs.

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 taking CABOMETYX if you:
- 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 heart failure (can include symptoms like shortness of breath, feeling tired, fainting, swollen ankles and legs)
- have thyroid problems. Tell your doctor if you get tired more easily, generally feel colder than other people, or your voice deepens whilst taking this medicine.
- have liver or kidney disease.

Tell your doctor if any of these affect you.

You may need treatment for them, or your doctor may decide to change your dose of CABOMETYX or stop treatment altogether. See also section 4 “Possible side effects”.
You should also tell your dentist that you are taking this medicine. It is important for you to practice good mouth care during treatment.

Children and adolescents

CABOMETYX is not recommended for children or adolescents. The effects of this medicine in people younger than 18 years old are not known.

Other medicines and CABOMETYX

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because CABOMETYX can affect the way some other medicines work. Also, some medicines can affect the way CABOMETYX works. This could mean that your doctor needs to change the dose(s) that you take. You should tell your doctor about every medicine, but in particular if 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 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 aliskiren, ambrisentan, digoxin, talinolol, 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

CABOMETYX with food

Avoid consuming grapefruit-containing products for as long as you are using this medicine, as they may increase the levels of CABOMETYX in your blood.

Pregnancy, breast-feeding and fertility

Avoid becoming pregnant while being treated with CABOMETYX. If you or your partner could become pregnant, use adequate contraception during treatment and for at least 4 months after treatment has finished. Talk to your doctor about which methods of contraception are appropriate while you are taking this medicine (see also under Other medicines and CABOMETYX, above).

Tell your doctor if you or your partner become pregnant or plan to become pregnant while you are being treated with this medicine.

Talk to your doctor BEFORE taking this medicine if you or your partner are considering or planning to have a baby after your treatment has finished. There is a possibility your fertility could be affected by treatment with this medicine.

Women taking this medicine should not breast-feed during treatment 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 take this medicine whilst using oral contraceptives, the oral contraceptives may be ineffective.
You should also use a barrier contraceptive (e.g. condom or diaphragm) whilst taking this medicine and for at least 4 months after treatment has finished.

Driving and using machines

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

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

CABOMETYX contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium- free”.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

You should continue to take this medicine until your doctor decides to stop your treatment. If you get serious side effects, your doctor may decide to change your dose or stop treatment earlier than originally planned. Your doctor will tell you if you need your dose adjusted.

CABOMETYX should be taken once a day. The usual dose is 60 mg, however your doctor will decide on the right dose 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 a day.

You should not take CABOMETYX with food. You should not eat anything for at least 2 hours before and for 1 hour after taking the 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 have been instructed to, talk to a doctor or go to the hospital with the tablets and this leaflet straight away.

If you forget to take CABOMETYX

- If there are still 12 hours or more before your next dose is due, then take the missed dose as soon as you remember. Take the next dose at the normal time.
- If your next dose is due in less than 12 hours, then do not take the dose that you have missed.
Take your next dose at the normal time.

If you stop using CABOMETYX
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with this medicine unless you have discussed this with your doctor.

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

Please refer to the package leaflet of nivolumab in order to understand the use of this medicine. If you have any further questions on the use of this medicine, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get side effects, your doctor may tell you to take CABOMETYX at a lower dose. Your doctor may also prescribe other medicines to help control your side effects.

Tell your doctor straight away if you notice any of the following side effects – you may need urgent medical treatment:

• Symptoms including pain in the abdomen, nausea (feeling sick), vomiting, constipation, or fever. These may be signs of a gastrointestinal perforation, a hole that develops in your stomach or intestine that could be life-threatening. Gastrointestinal perforation is common (it may affect up to 1 in 10 people).

• Severe or uncontrollable bleeding with symptoms such as: vomiting blood, black stools, bloody urine, headache, coughing up blood. It is common (it may affect up to 1 in 10 people)
• Feeling drowsy, confused or loss of consciousness. This may be due to liver problems which are common (they may affect up to 1 in 10 people).
• Swelling, or shortness of breath. These are very common (they may affect more than 1 in 10 people).
• A wound that does not heal. It is uncommon (it may affect 1 in 100 people)
• Fits, headaches, confusion, or finding it difficult to concentrate. These may be signs of a condition called posterior reversible encephalopathy syndrome (PRES). PRES is uncommon (it may affect 1 in 100 people).
• Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could be signs of bone damage in the jaw (osteonecrosis). It is uncommon (it may affect 1 in 100 people).

Other side effects with CABOMETYX alone include:

Very common side effects (may affect more than 1 in 10 people)

• Anaemia (low levels of red blood cells which carry oxygen), low levels of platelets (cells which help the blood to clot)
• Reduced thyroid activity; symptoms can include tiredness, weight gain, constipation, feeling cold and dry skin
• Decreased appetite, altered sense of taste
• Decreased amount of magnesium, potassium or calcium in the blood
• Decreased amount of protein albumin in blood (which carries substances such as hormones, medicines, and enzymes throughout your body)
• Headache, dizziness
• High blood pressure (hypertension)
• Bleeding
• Difficulty in speaking, hoarseness (dysphonia), cough and shortness of breath
• Stomach upset, including diarrhoea, nausea, vomiting, constipation, indigestion and abdominal pain
• Redness, swelling or pain in the mouth or throat (stomatitis)
• Skin rash sometimes with blisters, itching, pain of the hands or soles of the feet, rash
• Pain in the arms, hands, legs or feet, pain in joints
• Feeling tired or weak, inflammation of the oral and gastrointestinal mucosa, swelling in your legs and arms
• Weight loss
• Abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase)

Common side effects (may affect up to 1 in 10 people)

• Abscess (collection of pus, with swelling and inflammation)
• Dehydration
• Decreased amount of phosphate and sodium in the blood
• Increased amount of potassium in the blood
• Increased amount of the waste product bilirubin in the blood (which may result in jaundice/yellow skin or eyes)
• High (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood
• Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and legs)
• Ringing in ears (tinnitus)
• Blood clots in the veins, low blood pressure (hypotension)

• Blood clots in the lungs, inflammation of the lining of the nose (allergic rhinitis)
• Inflammation of the pancreas, a painful tear or abnormal connection of the tissues in your body (fistula), gastro-oesophageal reflux disease (bringing up stomach acid), haemorrhoids (piles), dry mouth and pain in the mouth, difficulty in swallowing, flatulence
• Severe itching of skin, alopecia (hair loss and thinning), dry skin, acne, hair colour change, thickening of the skin outer layer, redness of the skin
• Muscle spasms
• Protein in urine (seen in tests)
• Abnormal liver function tests (increased amounts of the liver enzyme gamma-glutamyl transferase in your blood)
• Abnormal kidney function tests (increased amounts of creatinine in your blood)
• Increased level of the enzyme that breaks down fats (lipase) and of 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 in fighting infection)
• Lung infection (pneumonia)

Uncommon side effects (may affect 1 in 100 people)

• Fits, stroke
• Severe high blood pressure
• Blood clots in the arteries
• Decrease in bile flow from the liver
• A burning or painful sensation in the tongue (glossodynia)
• Heart attack
• Heart failure (can include symptoms like shortness of breath, feeling tired, fainting, swollen ankles and legs)
• Clot/embolus that travelled through your arteries and become stuck
• Collapsed lung with air trapped in the space between the lung and chest, often causing shortness of breath (pneumothorax)

Not known (proportion of people affected not known)

• An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
• Inflammation of the blood vessels in the skin (cutaneous vasculitis)

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

Very common side effects (may affect more than 1 in 10 people)

• Infections of the upper respiratory tract
• 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
• Decreased appetite, altered sense of taste
• Headache, dizziness
• High blood pressure (hypertension)
• Difficulty in speaking, hoarseness (dysphonia), cough and shortness of breath
• Stomach upset, including diarrhoea, nausea, vomiting, indigestion, abdominal pain and constipation
• Redness, swelling or pain in the mouth or throat (stomatitis)
• Skin rash sometimes with blisters, itching, pain of the hands or soles of the feet, rash or severe itching of skin

• Pain in joints (arthralgia), muscle spasm, muscle weakness and aching muscles
• Protein in the urine (seen in test)
• Feeling tired or weak, fever and oedema (swelling)
• Abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase in your blood, higher blood levels of the waste product bilirubin)
• Abnormal kidney function tests (increased amounts of creatinine in your blood)
• High (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood
• Anaemia (low levels of red blood cells which carry oxygen), low levels of white blood cells (which are important in fighting infection), low levels of platelets (cells which help the blood to clot)
• An increased level of the enzyme that breaks down fats (lipase) and of the enzyme that breaks down starch (amylase)
• Decreased amount of phosphate
• Increased or decreased amount of potassium
• Decreased or increased blood levels of calcium, magnesium, or sodium
• Decrease in body weight

Common side effects (may affect up to 1 in 10 people)

• Serious lung infection (pneumonia)
• Increase in some white blood cells called eosinophils
• Allergic reaction (including anaphylactic reaction)
• Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys)
• Dehydration
• Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and legs)
• Ringing in ears (tinnitus)
• Dry eyes and blurred vision
• Changes in the rhythm or rate of the heartbeat, fast heart rate
• Blood clots in the blood vessels
• Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing), blood clots in the lung, fluid around the lungs
• Nose bleeding
• Inflammation of the colon (colitis), dry mouth, pain in the mouth, inflammation of the stomach (gastritis) and haemorrhoids (piles)
• Inflammation of the liver (hepatitis)
• Dry skin and redness of the skin
• Alopecia (hair loss and thinning), hair colour change
• Inflammation of the joints (arthritis)
• Kidney failure (including abrupt loss of kidney function)
• Pain, chest pain
• Increase in triglyceride levels in the blood
• Increase in cholesterol levels in the blood

Uncommon side effects (may affect 1 in 100 people)

• Allergic reactions related to the infusion of the medicine nivolumab
• Inflammation of the pituitary gland situated at the base of the brain (hypophysitis), swelling of the thyroid gland (thyroiditis)
• A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain Barré syndrome); muscle weakness and tiredness without atrophy (myasthenic syndrome)

• Inflammation of the brain
• Inflammation of the eye (which causes pain and redness)
• Inflammation of the heart muscle
• Clot/embolus that travelled through your arteries and become stuck
• Inflammation of the pancreas (pancreatitis), intestinal perforation, burning or painful sensation in the tongue (glossodynia)
• Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
• Hives (itchy rash)
• Muscle tenderness of weakness, not caused by exercise (myopathy), bone damage in the jaw, painful tear or abnormal connection of the tissues in your body (fistula)
• Inflammation of the kidney
• Collapsed lung with air trapped in the space between the lung and chest, often causing shortness of breath (pneumothorax)

Not known (proportion of people affected not known)

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

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

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

Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP.
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What CABOMETYX contains

The active substance is cabozantinib (S)-malate.

CABOMETYX 20 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 20 mg of cabozantinib.
CABOMETYX 40 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 40 mg of cabozantinib.
CABOMETYX 60 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 60 mg of cabozantinib.

The other ingredients are:

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

What CABOMETYX looks like and contents of the pack

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.
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.
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.

CABOMETYX is available in packs containing one plastic bottle with 30 film-coated tablets. The bottle contains three silica gel desiccant canisters and a polyester coil to prevent damage to the film- coated tablets. Keep the canisters and the polyester coil in the bottle and do not swallow the desiccant canisters.

Marketing Authorisation 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, The Netherlands

Rottendorf Pharma GmbH
Ostenfelderstrasse 51 – 61
D-59320 Ennigerloh, Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien, Luxembourg/Luxemburg
Italia
Ipsen NV
België /Belgique/Belgien
Tél/Tel: + 32 9 243 96 00
Ipsen SpA
Tel: + 39 02 39 22 41

България
Latvija
PharmaSwiss EOOD
Тел.: +359 2 8952 110
Ipsen Pharma representative office
Tel: +371 67622233

Česká republika
Lietuva

Ipsen Pharma, s.r.o.
Tel: + 420 242 481 821
Ipsen Pharma SAS Lietuvos filialas
Tel. +370 700 33305

Danmark, Norge, Suomi/Finland, Sverige, Ísland
Magyarország
Institut Produits Synthèse (IPSEN) AB
Sverige/Ruotsi/Svíþjóð
Tlf/Puh/Tel/Sími: +46 8 451 60 00
IPSEN Pharma Hungary Kft.
Tel.: +36 1 555 5930

Deutschland, Österreich
Nederland
Ipsen Pharma GmbH
Deutschland
Tel.: +49 89 2620 432 89
Ipsen Farmaceutica B.V.
Tel: + 31 (0) 23 554 1600

Eesti
Polska
Centralpharma Communications OÜ
Tel: +372 60 15 540
Ipsen Poland Sp. z o.o.
Tel.: + 48 22 653 68 00

Ελλάδα, Κύπρος, Malta
Portugal
Ipsen Μονοπρόσωπη EΠΕ
Ελλάδα
Τηλ: + 30 210 984 3324
Ipsen Portugal - Produtos Farmacêuticos S.A.
Tel: + 351 21 412 3550

España
România
Ipsen Pharma, S.A.U.
Tel: + 34 936 858 100
Ipsen Pharma România SRL
Tel: + 40 21 231 27 20

France
Slovenija
Ipsen Pharma
Tél: + 33 1 58 33 50 00
PharmaSwiss d.o.o.
Tel: + 386 1 236 47 00

Hrvatska
Slovenská republika
Bausch Health Poland sp. z o.o. podružnica Zagreb
Tel: +385 1 6700 750
Ipsen Pharma, organizačná zložka
Tel: + 420 242 481 821

Ireland

Ipsen Pharmaceuticals Limited
Tel: + 44 (0)1753 62 77 77

This leaflet was last revised in

Other sources of information

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

COMETRIQ should not be taken with food. You should not eat anything for at least 2 hours before taking COMETRIQ and for 1 hour after taking the medicine. Swallow the capsules one at a time with water. Do not open them.
If you take more COMETRIQ than you should
If you have taken more COMETRIQ than you have been instructed to, talk to a doctor or go to the hospital with the capsules and this leaflet straight away.
If you forget to take COMETRIQ
- If there are still 12 hours or more before your next dose is due, then take the missed dose as soon as you remember. Take the next dose at the normal time.
- If your next dose is due in less than 12 hours, then do not take the dose that you have missed. Take your next dose at the normal time.
If you stop using COMETRIQ
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with COMETRIQ unless you have discussed this with your doctor. If you have any further questions on the use of this medicine, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get side effects, your doctor may tell you to take COMETRIQ at a lower dose. Your doctor may also prescribe other medicines to help control your side effects.
Tell your doctor straight away if you notice any of the following side effects – you may need urgent medical treatment:
- Symptoms including pain in the abdomen, nausea, vomiting, constipation, or fever. These may be signs of a gastrointestinal perforation, a hole that develops in your stomach or intestine that could be life-threatening.
- Swelling, pain in your hands and feet, or shortness of breath.
- A wound that does not heal.
- Vomiting or coughing up blood, which may be bright red or look like coffee grounds.
- Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could be signs of bone damage in the jaw (osteonecrosis).
- Seizures, headaches, confusion, or finding it difficult to concentrate. These may be signs of a condition called posterior reversible encephalopathy syndrome (PRES). PRES is uncommon (it affects less than 1 in 100 people).
- Diarrhoea that is severe and does not seem to be settling.

Other side effects include:

Very common side effects (may affect more than 1 in 10 people)

• Stomach upset, including diarrhoea, nausea, vomiting, constipation, indigestion, and abdominal pain
• Difficulty in swallowing
• Blister, pain of the hands or soles of the feet, rash or redness of the skin, dry skin
• Decreased appetite, weight loss, altered sense of taste
• Fatigue, weakness, headache, dizziness
• Hair colour changes (lightening), hair loss
• Hypertension (increase in blood pressure)
• Redness, swelling or pain in the mouth or throat, difficulty in speaking, hoarseness
• Changes in blood tests used to monitor general health and the liver, low levels of electrolytes (like magnesium, calcium or potassium)
• Low level of platelets
• Joint pain, muscle spasms
• Swollen lymph glands
• Pain in the arms, hands, legs or feet

Common side effects (may affect up to 1 in 10 people)

• Anxiety, depression, confusion
• Generalised pain, chest or muscle pain, ear pain, ringing in ears
• Weakness or reduced sensation or tingling in the limbs
• Chills, tremors
• Dehydration
• Inflammation of the abdomen or pancreas
• Inflammation of the lips and corners of the mouth
• Inflammation at the root of your hair, acne, blisters (on parts of your body other than the hands or feet)
• Swelling in the face and in other parts of the body
• Loss or change of taste
• Hypotension (decrease in blood pressure)
• Atrial fibrillation (a fast and erratic heartbeat)
• Lightening of skin, flakey skin, unusual pale skin
• Abnormal hair growth
• Haemorrhoids
• Pneumonia (lung infection)
• Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth
• Reduced thyroid activity; symptoms can include: tiredness, weight gain, constipation, feeling cold and dry skin
• Low level of white blood cells
• Decrease in level of phosphate in the blood
• Tear or hole or bleeding in your stomach or intestine, inflammation or tear of anus, bleeding in lungs or trachea (airway)
• An abnormal connection of the tissue in your digestive system; symptoms can include severe or persistent stomach ache
• Abnormal connection of the tissue in your trachea (airway), oesophagus, or lungs
• Abscess (collection of pus, with swelling and inflammation) in the abdomen or pelvis area or in your teeth/gums
• Blood clots in the blood vessels and the lungs
• Stroke
• Heart failure (can include symptoms like shortness of breath, feeling tired, fainting, swollen ankles and legs)

• Fungal infection that can be in the skin, mouth, or genitals
• Wounds that have difficulties healing
• Protein or blood in the urine, gallstones, painful urination
• Blurred vision
• Increase in the level of bilirubin in your blood (which may result in jaundice/yellow skin or eyes)
• Decrease in the levels of protein in your blood (albumin)
• Abnormal kidney function tests (increased amounts of creatinine in your blood)
• Increased level of the serum protein known as lipase.

Uncommon side effects (may affect 1 in 100 people)

- Inflammation of the oesophagus; symptoms can include heartburn, chest pain, feeling sick, altered taste, bloating, belching and indigestion
- Infection and inflammation in the lung, collapse of lung
- Skin ulcers, cysts, red spots on the face or thighs
- Facial pain
- Changes in test results that measure blood clotting or blood cells
- Loss of coordination in your muscles, damage to skeletal muscles
- Loss of attention, loss of consciousness, changes in speech, delirium, abnormal dreams
- Chest pain due to blockage in arteries, rapid heartbeat
- Liver damage, kidney failure
- Impaired hearing
- Inflammation in the eye, cataracts
• Clot/ embolus that travelled through your arteries and become stuck
- Stopping menstruation, vaginal bleeding
- A condition called posterior reversible encephalopathy syndrome (PRES) which has symptoms such as seizures, headaches, confusion, or finding it difficult to concentrate.
- Severe increase in blood pressure (hypertensive crisis).
- Collapsed lung with air trapped in the space between the lung and chest, often causing shortness of breath (pneumothorax)

Not Known (side effects with unknown frequency)
- Heart attack
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- Inflammation of the blood vessels in the skin (cutaneous vasculitis)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

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

Do not use this medicine after the expiry date which is stated on the blister cards and carton after EXP. The expiry date refers to the last day of that month.

Do not store above 25ºC. Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What COMETRIQ contains

The active substance is cabozantinib (S)-malate.

The COMETRIQ 20 mg hard capsules contain cabozantinib (S)-malate equivalent to 20 mg of cabozantinib.
The COMETRIQ 80 mg hard capsules contain cabozantinib (S)-malate equivalent to 80 mg of cabozantinib.

The other ingredients are:

• Capsule contents: microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, silica colloidal anhydrous, and stearic acid (see section 2 “COMETRIQ contains sodium”)
• Capsule shell: gelatin, and titanium dioxide (E171)
• The 20 mg capsules also contain black iron oxide (E172)
• The 80 mg capsules also contain red iron oxide (E172)
• Printing ink: shellac glaze, black iron oxide (E172), and propylene glycol

What COMETRIQ looks like and contents of the pack
COMETRIQ 20 mg hard capsules are grey and have “XL184 20mg” printed on one side.
COMETRIQ 80 mg hard capsules are orange and have “XL184 80mg” printed on one side.

COMETRIQ hard capsules are packaged in blister cards organised by prescribed dose. Each blister card contains enough medicine for 7 days. Each row of the blister card contains the daily dose.

The 60 mg daily dose blister card contains twenty-one 20 mg capsules as 7 daily doses in total. Each daily dose is given in one row and contains three 20 mg capsules:

three grey 20 mg

The 100 mg daily dose blister card contains seven 80 mg capsules and seven 20 mg capsules as 7 daily doses in total. Each daily dose is provided in one row and contains one 80 mg capsule and one 20 mg capsule:

one orange 80 mg + one grey 20 mg

The 140 mg daily dose blister card contains seven 80 mg capsules and twenty one 20 mg capsules as 7 doses in total. Each daily dose is provided in one row and contains one 80 mg capsule and three 20 mg capsules:

one orange 80 mg + three grey 20 mg
= 60 mg
= 100 mg
= 140 mg

COMETRIQ hard capsules are also available in 28 day packs:

84 capsules (4 blister cards of 21 x 20 mg) (60 mg/day dose)

56 capsules (4 blister cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose)

112 capsules (4 blister cards of 21 x 20 mg and 7 x 80 mg) (140 mg/day dose)

Each 28 day pack contains enough medicine for 28 days.

Marketing Authorisation Holder

Ipsen Pharma
70 rue Balard
75015 Paris
France

Manufacturer

Catalent Germany Schorndorf GmbH
Steinbeisstr. 1 und 2
73614 Schorndorf
Germany

Tjoapack Netherlands B.V.
Nieuwe Donk 9
4879 AC Etten-Leur
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien, Luxembourg/Luxemburg
Italia
Ipsen NV
Ipsen SpA
België /Belgique/Belgien
Tel: + 39 02 39 22 41
Tél/Tel: + 32 9 243 96 00

France
Latvija
Ipsen Pharma
Ipsen Pharma representative office
Tél: + 33 1 58 33 50 00
Tel: +371 67622233

България, Slovenija
Hrvatska
Biomapas UAB
Biomapas Zagreb d.o.o.
Литва, Litva
Tel: +385 17 757 094
Tel: +370 37 366307

Česká republika
Lietuva
Ipsen Pharma, s.r.o.
Ipsen Pharma SAS Lietuvos filialas
Tel: + 420 242 481 821
Tel. + 370 700 33305

Danmark, Norge, Suomi/Finland, Sverige, Ísland
Magyarország
Institut Produits Synthèse (IPSEN) AB
IPSEN Pharma Hungary Kft.
Sverige/Ruotsi/Svíþjóð
Tel.: +361 555 5930
Tlf/Puh/Tel/Sími: +46 8 451 60 00

Deutschland, Österreich
Nederland
Ipsen Pharma GmbH
Ipsen Farmaceutica B.V.
Deutschland
Tel: + 31 (0) 23 554 1600

Tel.: +49 89 2620 432 89

Eesti
Polska
Centralpharma Communications OÜ
Ipsen Poland Sp. z o.o.
Tel: +372 60 15 540
Tel.: + 48 (0) 22 653 68 00

Ελλάδα, Κύπρος, Malta
Portugal
Ipsen Μονοπρόσωπη EΠΕ
Ipsen Portugal - Produtos Farmacêuticos S.A.

Tel: + 351 21 412 3550

Ελλάδα/Greece
România
Τηλ: + 30 210 984 3324
Ipsen Pharma România SRL

Tel: + 40 21 231 27 20

España
Slovenská republika
Ipsen Pharma, S.A.
Ipsen Pharma
Tel: + 34 936 858 100
Tel: + 420 242 481 821

Ireland, United Kingdom (Northern Ireland)

Ipsen Pharmaceuticals Limited

Tel: + 44 (0)1753 62 77 77

This leaflet was last revised in

Other sources of information

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