Cabometyx

Package leaflet: Information for the patient

CABOMETYX 20 mg film-coated tablets, 40 mg film-coated tablets, 60 mg film-coated tablets

cabozantinib
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor. See section 4.

Contents of this leaflet

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

1. What CABOMETYX is and what it is used for

What CABOMETYX is
CABOMETYX is an anticancer medicine that contains the active substance cabozantinib.
It is used in adults to treat:

• an advanced kidney cancer called advanced renal cell carcinoma
• hepatocellular carcinoma when a specific anticancer medicine (sorafenib) is no longer controlling the progression of the disease.
• Advanced neuroendocrine tumours – tumours originating from the pancreas, stomach, intestine, lungs or other organs. Treatment is given when patients with these tumours no longer respond to a previous therapy.

CABOMETYX is also used in adults to treat locally advanced or metastatic differentiated thyroid carcinoma, a type of tumour of the thyroid gland, when treatments with radioactive iodine and anticancer medicines are no longer controlling the progression of the disease.
CABOMETYX may be given in combination with nivolumab for advanced renal cell carcinoma.
It is important to also read the package leaflet for nivolumab. If you have any questions about these medicines, please ask your doctor.
How CABOMETYX works
CABOMETYX blocks the action of proteins called tyrosine kinase receptors (RTKs), which are involved in cell growth and the development of new blood vessels that supply them. These proteins may be present in high levels in cancer cells, and by blocking their activity, this medicine can slow down the rate of tumour growth and help block the blood supply that the tumour needs.

2. What you should know before taking CABOMETYX

Do not take CABOMETYX

• if you are allergic to cabozantinib or to 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
• 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
• you have diarrhoea
• you have recently experienced significant bleeding episodes
• you have had surgery within the last month (or have planned surgical procedures), including dental procedures
• you suffer from an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis, diverticulitis or appendicitis)
• you have recently had a blood clot in your leg, a stroke, or a heart attack
• you have thyroid problems. Inform your doctor if you feel more tired than usual, if you generally feel colder than other people, or if your voice becomes deeper while taking this medicine.
• you have liver or kidney disease

Inform your doctor if you have any of these conditions.
You may require treatment for these conditions, or your doctor may decide to adjust your dose of CABOMETYX or stop treatment altogether. See also section 4 "Possible side effects".
Also inform your dentist that you are taking this medicine. It is important to maintain good oral hygiene during treatment.
Children and adolescents
CABOMETYX is not recommended for children and adolescents. The effects of this medicine in individuals under 18 years of age are unknown.
Other medicines and CABOMETYX
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription, because CABOMETYX may affect how other medicines work. In addition, some medicines may affect how CABOMETYX works. Therefore, your doctor may need to adjust the dose(s) of the medicines you are taking.
Tell your doctor about any medicines you are taking, but especially if you are taking:

• Medicines for the treatment of fungal infections, such as itraconazole, ketoconazole, and posaconazole
• Medicines used to treat bacterial infections (antibiotics), such as erythromycin, clarithromycin, and rifampicin
• Antiallergic medicines, such as fexofenadine
• Medicines for the treatment of angina pectoris (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 preparations containing St John’s wort (Hypericum perforatum), sometimes used for the treatment of depression or related conditions such as anxiety
• Anticoagulant medicines, such as warfarin and dabigatran etexilate
• Medicines for the treatment of 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 (cyclosporine) and cyclosporine-based treatment regimens for rheumatoid arthritis and psoriasis

CABOMETYX with food
Avoid consuming grapefruit-containing foods throughout your treatment with this medicine, as this could lead to increased levels of CABOMETYX in the blood.
Pregnancy, breastfeeding and fertility
Avoid becoming pregnant during treatment with CABOMETYX. Women of childbearing potential and men whose partners are of childbearing potential must use effective contraception during treatment and for at least 4 months after completion of treatment. Consult your doctor for advice on appropriate contraceptive methods during treatment with this medicine (see section above Other medicines and CABOMETYX).
Inform your doctor if you or your partner becomes pregnant or is planning a pregnancy during treatment with this medicine.
Talk to your doctor BEFORE taking this medicine if you or your partner is considering or planning to have a child after completing treatment. Treatment with this medicine may affect your fertility.
Women taking this medicine must not breastfeed during treatment and for at least 4 months after completion of treatment, as cabozantinib and/or its metabolites may be excreted in breast milk and could harm the baby.
If you take this medicine while using oral contraceptives, they may not be effective. You must also use a barrier contraceptive method (e.g., condom or diaphragm) during treatment with this medicine and for at least 4 months after completion of treatment.
Driving and using machines
Exercise caution when driving or operating machinery. Be aware that treatment with CABOMETYX may cause fatigue or weakness and may affect your ability to drive or operate machinery.
CABOMETYX contains lactose
This medicine contains lactose (a type of sugar). If your doctor has diagnosed you with an intolerance to certain sugars, consult him before taking this medicine.
CABOMETYX contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially "sodium-free".

3. How to take CABOMETYX

Take this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
You must continue taking this medicine until your doctor decides to stop the treatment. If serious side effects occur, your doctor may decide to adjust the dose or stop treatment earlier than originally planned. Your doctor will inform you if your dose needs to be changed.
CABOMETYX should be taken once daily. The usual dose is 60 mg, but your doctor will determine the appropriate dose for you.
When this medicine is administered in combination with nivolumab for the treatment of advanced renal cell carcinoma, the recommended dose of CABOMETYX is 40 mg once daily.
You should not take CABOMETYX with food. Do not eat for at least 2 hours before and for 1 hour after taking this medicine. Swallow the tablet whole with a glass of water; do not crush it.

If you take more CABOMETYX than you should
If you have taken more medicine than prescribed, contact your doctor immediately or go to the hospital, remembering to bring the tablets and this patient information leaflet with you.

If you forget to take CABOMETYX

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

If you stop taking CABOMETYX
Stopping treatment may interrupt the medicine's effect. Do not stop treatment with this medicine unless you have discussed it with your doctor.
When this medicine is administered in combination with nivolumab, nivolumab will be administered first, followed by CABOMETYX.
Refer to the nivolumab package leaflet for information on how to use that medicine. If you have further questions about the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If you experience side effects, your doctor may advise you to take CABOMETYX at a lower dose. Your doctor may also prescribe other medicines to help you manage the side effects.
Contact your doctor immediately if you experience any of the side effects listed below, as you may require urgent medical treatment:
Symptoms such as abdominal pain, nausea (feeling unwell), vomiting, constipation, or fever. These symptoms may indicate gastrointestinal perforation, a hole forming in the stomach or intestine, which could be life-threatening. Gastrointestinal perforation is common (may affect up to 1 in 10 people).
Severe or uncontrollable bleeding with symptoms such as: vomiting blood, black stools, blood in the urine, headache, coughing up blood. This is common (may affect up to 1 in 10 people).
Feeling drowsy, confused, or losing consciousness. This may be due to liver problems, which are common (may affect up to 1 in 10 people).
Swelling or shortness of breath. These are very common (may affect more than 1 in 10 people).
Wounds that do not heal. This is uncommon (may affect 1 in 100 people).
Seizures, headache, confusion, or difficulty concentrating. These symptoms may indicate a condition called reversible posterior encephalopathy syndrome (PRES). PRES is an uncommon side effect (may affect 1 in 100 people).
Pain in the mouth, teeth, and/or jaw, swelling or sores inside the mouth, numbness or heaviness in the jaw, or loose teeth. These may be signs of bone damage in the jaw (osteonecrosis). This is uncommon (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 that carry oxygen), low platelet levels (cells that help blood to clot)
Reduced thyroid activity; symptoms may include fatigue, weight gain, constipation, feeling cold, and dry skin
Loss of appetite, altered sense of taste
Decreased levels of magnesium, potassium, or calcium in the blood
Decreased levels of albumin in the blood (a protein that transports substances such as hormones, drugs, and enzymes throughout the body)
Headache, dizziness
High blood pressure (hypertension)
Bleeding
Difficulty speaking, hoarseness (dysphonia), cough, and shortness of breath
Stomach problems, 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 in hands or soles of feet, erythema
Pain in arms, hands, legs, or feet, joint pain
Feeling tired or weak, inflammation of the oral and gastrointestinal mucosa, swelling in arms and legs
Weight loss
Abnormal liver function laboratory tests (increased levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase)

Common side effects (may affect up to 1 in 10 people)
Abscess (collection of pus accompanied by swelling and inflammation)
Dehydration
Decreased levels of phosphate and sodium in the blood
Increased levels of potassium in the blood
Increased levels of bilirubin, a waste product, in the blood (which may cause jaundice/yellowing of skin or eyes)
High (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
Nerve inflammation (causing numbness, weakness, tingling, or burning sensations in arms and legs)
Ringing in the ears (tinnitus)
Blood clots in veins, low blood pressure (hypotension)
Blood clots in the lungs, inflammation of the nasal mucosa (allergic rhinitis)
Pancreatitis (inflammation of the pancreas), painful wound or abnormal connection between body tissues (fistula), gastro-oesophageal reflux disease (acid from the stomach rising up), haemorrhoids, dry mouth, mouth pain, difficulty swallowing, flatulence
Severe skin itching, alopecia (hair loss and thinning), dry skin, acne, change in hair colour, thickening of the outer skin layer, skin redness
Muscle spasms
Protein in the urine (detected in laboratory tests)
Abnormal liver function laboratory tests (increased levels of the liver enzyme gamma-glutamyl transferase in the blood)
Abnormal kidney function laboratory tests (increased levels of creatinine in the blood)
Increased levels of the enzyme that breaks down fats (lipase) and the enzyme that breaks down starch (amylase)
Increased levels of cholesterol or triglycerides in the blood
Low levels of white blood cells (important for fighting infections)
Lung infection (pulmonary infection)

Uncommon side effects (may affect up to 1 in 100 people)

• Seizures, stroke
• High blood pressure
• Blood clots in arteries
• Reduced bile flow from the liver
• Burning or painful sensation on the tongue (glossodynia)
• Heart attack
• Blood clot/embolus that has travelled through the arteries and become blocked
• Collapsed lung with trapped air in the space between the lung and chest wall, often causing shortness of breath (pneumothorax)

Not known (frequency cannot be estimated from available data)

• Dilation and weakening of the wall of a blood vessel or a tear in the blood vessel wall (aneurysms and arterial dissections)
• Inflammation of 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)

• Upper respiratory tract infections
• Reduced thyroid activity; symptoms may include fatigue, weight gain, constipation, feeling cold, and dry skin
• Increased thyroid activity; symptoms may 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 shortness of breath
• Stomach problems, 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 in hands or soles of feet, erythema, or intense skin itching
• Joint pain (arthralgia), muscle spasms, muscle weakness, and muscle pain
• Protein in the urine (detected in testing)
• Feeling tired or weak, fever, and oedema (swelling)
• Abnormal liver function laboratory tests (increased levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase in the blood, increased blood levels of the waste product bilirubin)
• Abnormal kidney function laboratory tests (increased levels of creatinine in the blood)
• High (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
• Anaemia (low levels of red blood cells that carry oxygen), low levels of white blood cells (important for fighting infections), low platelet levels (cells that help blood to clot)
• Increased levels of the enzyme that breaks down fats (lipase) and the enzyme that breaks down starch (amylase)
• Decreased phosphate levels
• Increased or decreased potassium levels
• Decreased or increased levels of calcium, magnesium, or sodium in the blood
• Decreased body weight

Common side 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)
• Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys)
• Dehydration
• Nerve inflammation (causing numbness, weakness, tingling, or burning sensations in arms and legs)
• Ringing in the ears (tinnitus)
• Dry eyes and blurred vision
• Changes in heart rhythm or rate, rapid heartbeat
• Blood clots in blood vessels
• Lung inflammation (pneumonitis, characterized by cough and breathing difficulties), blood clots in the lungs, fluid around the lungs
• Nosebleeds
• Inflammation of the colon (colitis), dry mouth, mouth pain, inflammation of the stomach (gastritis), and haemorrhoids
• Liver inflammation (hepatitis)
• Dry skin and skin redness
• Alopecia (hair loss and thinning), change in hair colour
• Joint inflammation (arthritis)
• Kidney failure (including sudden loss of kidney function)
• Pain, chest pain
• Increased levels of triglycerides in the blood
• Increased levels of cholesterol in the blood

Uncommon side effects (may affect 1 in 100 people)

• Allergic reactions related to the infusion of nivolumab
• Inflammation of the pituitary gland at the base of the brain (hypophysitis), swelling of the thyroid gland (thyroiditis)
• Temporary nerve inflammation causing pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); muscle weakness and fatigue without atrophy (myasthenic syndrome)
• Brain inflammation
• Eye inflammation (causing pain and redness)
• Inflammation of the heart muscle
• Blood clot/embolus that has travelled through the arteries and become blocked
• Pancreatitis (inflammation of the pancreas), intestinal perforation, burning or painful sensation on the tongue (glossodynia)
• Skin disease with thickened red patches, often with silvery scales (psoriasis)
• Hives (itchy rash)
• Muscle weakness due to muscle tenderness not caused by physical exercise (myopathy), bone damage in the jaw, painful wound or abnormal connection between body tissues (fistula)
• Kidney inflammation
• Collapsed lung with trapped air in the space between the lung and chest wall, often causing shortness of breath (pneumothorax)

Not known (frequency cannot be estimated from available data)

• Inflammation of 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 side effects not listed in this leaflet. You can also report side effects directly via the national adverse reactions reporting system.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store CABOMETYX

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister, on the vial label, and on the
carton after Exp. The expiry date refers to the last day of that month.
This medicine requires no special storage conditions.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

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 components are:

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

Description of the appearance of CABOMETYX and pack contents
CABOMETYX 20 mg film-coated tablets are yellow, round, and without score lines, with the code "XL" engraved on one side and the number "20" on the other.
CABOMETYX 40 mg film-coated tablets are yellow, triangular in shape, and without score lines, with the code "XL" engraved on one side and the number "40" on the other.
CABOMETYX 60 mg film-coated tablets are yellow, oval in shape, and without score lines, with the code "XL" engraved on one side and the number "60" on the other.
CABOMETYX is available in packs containing a plastic bottle with 30 film-coated tablets. The bottle contains three silica gel desiccant filters and a polyester spiral to prevent damage to the film-coated tablets. Keep the desiccant filters and the polyester spiral inside the bottle and do not ingest the desiccant filters.

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

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

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

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

Česká republika, Lietuva
Ipsen Pharma, s.r.o. Olbrachtova 2006/9, Ipsen Pharma SAS Lietuvos filialas
Tel: +370 700 33305
Tel: +420 242 481 821

Danmark, Norge, Suomi/Finland, Sverige, Ísland
Institut Produits Synthèse (IPSEN) AB
Sverige/Ruotsi/Svíþjóð Tel: +46 8 451 60 00

Magyarország
IPSEN Pharma Hungary Kft.
Tel: +36 1 555 5930

Deutschland, Österreich
Ipsen Pharma GmbH
Tel.: +49 89 2620 432 89

Nederland
Ipsen Farmaceutica B.V.
Tel: +31 (0) 23 554 1600

Eesti
Centralpharma Communications OÜ
Tel: +372 60 15 540

Polska
Ipsen Poland Sp. z o.o. Al. Jana Pawła II 29
Tel.: +48 22 653 68 00

Ελλάδα, Κύπρος, Malta
Ipsen Μονοπρόσωπη EΠΕ
Τηλ: +30 210 984 3324

Portugal
Ipsen Portugal - Produtos Farmacêuticos S.A.
Tel: +351 21 412 3550

España
Ipsen Pharma, S.A.U.
Tel: +34 936 858 100

România
Ipsen Pharma România SRL
Tel: +40 21 231 27 20

France
Ipsen Pharma
Tél: +33 1 58 33 50 00

Slovenija
PharmaSwiss d.o.o.
Tel: +386 1 236 47 00

Hrvatska
Bausch Health Poland sp. z.o.o. podružnica Zagreb
Tel: +385 1 6700 750

Slovenská republika
Ipsen Pharma, organizačná zložka
Tel: +420 242 481 821

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

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.