Cabometyx - Patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

CABOMETYX 20 mg film-coated tablets CABOMETYX 40 mg film-coated tablets CABOMETYX 60 mg 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 get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What CABOMETYX is and what it is used for

• 2. What you need to know before you take 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 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.

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 CABOMETYX can slow down the rate at which the tumour grows and help to 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 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 thyroid problems. Your thyroid function should be checked before you take CABOMETYX and regularly while you are taking it. Tell your doctor if you get tired more easily, generally feel colder than other people, or your voice deepens whilst taking this medicine. If your thyroid gland is not producing enough thyroid hormone, you may be treated with thyroid hormone replacement

• – 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 CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX.

Children and adolescents

CABOMETYX is not recommended for children or adolescents. The effects of CABOMETYX 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 CABOMETYX (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 CABOMETYX.

Talk to your doctor BEFORE taking CABOMETYX 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 CABOMETYX.

Women taking CABOMETYX 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 CABOMETYX whilst using oral contraceptives, the oral contraceptives may be ineffective. You should also use a barrier contraceptive (e.g. condom or diaphragm) whilst taking CABOMETYX 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

CABOMETYX 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”.

3. How to take CABOMETYX

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 CABOMETYX is given in combination with nivolumab for the treatment of advanced kidney cancer, the recommended dose of CABOMETYX is 40 mg once a day.

You should not take CABOMETYX with food. You should not eat anything for at least 2 hours before taking CABOMETYX 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 CABOMETYX 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 CABOMETYX unless you have discussed this with your doctor.

When CABOMETYX 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.

4. Possible side effects

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.
• Severe or uncontrollable bleeding with symptoms such as: vomiting blood, black stools, bloody urine, headache, coughing up blood.
• Swelling, pain in your hands and feet, or shortness of breath.
• A wound that does not heal.
• Fits, headaches, confusion, or finding it difficult to concentrate. These may be signs of a condition called posterior reversible encephalopathy syndrome (PRES). PRES is rare (it affects less than 1 in 1000 people).
• Feeling drowsy, confused or loss of consciousness. This may be due to liver problems.
• 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).

Other side effects with CABOMETYX alone include:

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

• Stomach upset, including diarrhoea, nausea, vomiting, constipation, indigestion and abdominal pain,
• Blisters, pain of the hands or soles of the feet, rash or redness of the skin
• Decreased appetite, weight loss, altered sense of taste
• Fatigue, weakness, headache, dizziness
• Hypertension (high blood pressure)
• Anaemia (low levels of red blood cells)
• Low level of platelets
• Redness, swelling or pain in the mouth or throat, difficulty in speaking, hoarseness, cough
• Changes in blood tests used to monitor general health and function of your organs (including the liver, and kidney), low levels of electrolytes (like magnesium, or potassium)
• Shortness of breath
• Reduced thyroid activity; symptoms can include tiredness, weight gain, constipation, feeling cold and dry skin
• Swelling in your legs and arms
• Pain in the arms, hands, legs or feet
• Low level of albumin in blood

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

• Abscess (collection of pus, with swelling and inflammation)
• Dehydration
• Difficulty in swallowing
• Ringing in ears (tinnitus)
• Blood clots in the blood vessels and lungs
• Low level of white blood cells
• Increased or decreased blood sugar level
• Decrease in levels of calcium, sodium and phosphate in the blood
• Increase in level of potassium in the blood
• Increase in the level of bilirubin in the blood (which may result in jaundice/yellow skin or eyes)
• Increase in amylase levels in the blood
• Increase in lipase levels in the blood
• Increase in cholesterol or triglyceride levels in the blood
• Numbness, tingling, burning sensation or pain in the limbs
• 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
• Feeling drowsy, confused or loss of consciousness due to liver problems
• Dry skin, severe itching of skin, acne
• Thickening of the skin outer layer
• Alopecia (hair loss and thinning), hair colour change
• Pain in joints, muscle spasms
• Protein in urine (seen in tests)
• A burning or stinging sensation of the tongue

Uncommon side effects (may affect 1 in 100 people)

• Fits
• Inflammation of the pancreas
• Decrease in bile flow from the liver
• Bone damage in the jaw
• Wound complications

Not known (proportion of people affected not known)

• Stroke
• Heart attack
• An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)

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
• Hypertension (high blood pressure)
• 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 redness of the 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)

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 severe itching of 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

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
• 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

Changes in test results

CABOMETYX in combination with nivolumab may cause changes in the results of tests carried out by your doctor. These include:

• 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
• A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
• An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch
• Decrease in levels of amount of phosphate
• Increased or decreased amount of calcium or potassium
• Increased or decreased blood levels of magnesium or sodium
• Decrease in body weight
• Increase in triglyceride levels in the blood
• Increase in cholesterol levels in the blood

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.

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 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.

6. Contents of the pack 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 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. Keep the canisters in the bottle and do not swallow the desiccant canisters.

Marketing Authorisation Holder

Ipsen Pharma

65 quai Georges Gorse

92100 Boulogne-Billancourt

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 Ipsen NV België /Belgique/Belgien

Italia Ipsen SpA Tel: + 39 02 39 22 41

Tél/Tel: + 32 9 243 96 00

Efcnrapua PharmaSwiss EOOD Ten.: +359 2 8952 110	Latvija Ipsen Pharma representative office Tel: +371 67622233
Česká republika Ipsen Pharma, s.r.o. Tel: + 420 242 481 821	Lietuva Ipsen Pharma SAS Lietuvos filialas Tel. +370 700 33305
Danmark, Norge, Suomi/Finland, Sverige, Ísland Institut Produits Synthèse (IPSEN) AB Sverige/Ruotsi/Sví^jóó	Magyarorszag IPSEN Pharma Hungary Kft. Tel.: +36 1 555 5930

Tlf/Puh/Tel/Sími: +46 8 451 60 00

Deutschland, Österreich Ipsen Pharma GmbH Deutschland

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

Tel.: +49 89 2620 432 89

Eesti Centralpharma Communications OÜ Tel: +372 60 15 540	Polska Ipsen Poland Sp. z o.o. Tel.: + 48 22 653 68 00
EXÀàôa, Kùnpoç, Malta Ipsen Movonpôoœnn EnE EXXàSa	Portugal Ipsen Portugal – Produtos Farmacéuticos S.A. Tel: + 351 21 412 3550

Tql: + 30 210 984 3324

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

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

Slovenska republika

Ipsen Pharma, organizacna zlozka

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:.

59

2-sided stratified log-rank test with aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region (Asia, other regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data)

estimated using the Cox proportional-hazard model

as assessed by investigator per RECIST 1.1

stratified Cochran-Mantel-Haenszel (CMH) test