Stivarga

Package leaflet: Information for the user

Stivarga 40 mg film-coated tablets

regorafenib
Read this leaflet carefully before you start taking this medicine as 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 pass it on to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Stivarga is and what it is used for

Stivarga contains the active substance regorafenib. It is a medicine used to treat cancer, which slows down the growth and spread of cancer cells and blocks the blood supply that allows cancer cells to grow.
Stivarga is used to treat:

• colorectal cancer that has spread to other parts of the body in adult patients previously treated or who cannot be treated with other medicines (fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy)
• gastrointestinal stromal tumours (GIST), a type of stomach and intestinal tumour that has spread to other parts of the body or cannot be surgically removed, in adult patients previously treated with other anticancer medicines (imatinib and sunitinib)
• liver cancer in adult patients previously treated with another anticancer medicine (sorafenib).

For any questions about how Stivarga works or why this medicine has been prescribed for you, please consult your doctor.

2. What you should know before taking Stivarga

Do not take Stivarga

• if you are allergic to regorafenib 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 Stivarga.
Be especially careful with Stivarga

• if you have liver problems, including Gilbert’s syndrome, with signs such as yellowing of the skin and whites of the eyes, dark urine, and confusion and/or disorientation. Treatment with Stivarga may increase the risk of liver problems. Before and during treatment with Stivarga, your doctor will perform certain blood tests to monitor liver function. You must not be treated with Stivarga if liver function is severely impaired, as there are no data available on the use of Stivarga in patients with severe liver impairment.
• if you have an infection with symptoms such as high fever, severe cough with or without increased mucus production (sputum), severe sore throat, shortness of breath, burning and/or pain during urination, unusual vaginal discharge or irritation, redness, swelling or pain anywhere in the body. Your doctor may temporarily suspend your treatment.
• if you have had or have bleeding problems and are taking warfarin, phenprocoumon or another anticoagulant medicine to prevent blood clots. Treatment with Stivarga may increase the risk of bleeding. Before starting treatment with Stivarga, your doctor may perform certain blood tests. Stivarga can cause severe bleeding in the gastrointestinal tract, for example in the stomach, throat, rectum or intestine, or in the lungs, kidneys, mouth, vagina and/or brain. Contact your doctor immediately if you experience any of the following symptoms: blood in the stool or black stools, blood in the urine, stomach pain, coughing up blood or vomiting blood.
• if you develop severe stomach or intestinal problems (gastrointestinal perforation or fistula), your doctor must stop treatment with Stivarga. Contact your doctor immediately if you experience any of the following symptoms: severe or persistent stomach pain, vomiting blood, red or black stools.
• if you experience chest pain or have heart problems. Before starting treatment with Stivarga and during treatment, your doctor will monitor heart function. Contact your doctor immediately if you experience any of the following symptoms, which may indicate a heart attack or reduced blood flow to the heart: discomfort or pain in the chest that may spread to the shoulders, arms, back, neck, jaw, teeth or stomach and may be intermittent; shortness of breath; sudden sweating with cold, clammy skin; dizziness or fainting.
• if you develop severe and persistent headache, vision problems, seizures or mental disturbances (such as confusion, memory loss or disorientation), contact your doctor immediately.
• if you have high blood pressure. Stivarga may increase blood pressure. Your doctor will monitor your blood pressure before and during treatment and may prescribe medication to treat high blood pressure.
• if you have or have had an aneurysm (a weakened and bulging blood vessel wall) or a tear in the wall of a blood vessel.
• if you have or have had damage to small blood vessels (thrombotic microangiopathy, TMA). Inform your doctor if you develop fever, fatigue, weakness, bruising, bleeding, swelling, confusion, vision loss or seizures.
• if you have recently undergone or are scheduled to undergo surgery. Stivarga may affect wound healing, and treatment may need to be interrupted until the wound has healed.
• if you develop skin problems. Stivarga may cause redness, pain, swelling or blisters on the palms of the hands or soles of the feet. If you notice any changes, contact your doctor. To manage symptoms, your doctor may recommend using creams and/or shoe pads or wearing gloves. If this side effect occurs, your doctor may adjust the dose or interrupt treatment until symptoms improve.

Before taking Stivarga, inform your doctor if any of these conditions apply to you. You may require additional treatment and further tests (see also section 4, “Possible side effects”).

Children and adolescents
There is no specific indication for the use of Stivarga in children and adolescents for the indication of metastatic colorectal cancer.
The safety and efficacy of Stivarga in children and adolescents for the indication gastrointestinal stromal tumours (GIST) have not been established. No data are available.
There is no specific indication for the use of Stivarga in children and adolescents for the indication hepatocellular carcinoma.

Other medicines and Stivarga
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription or over-the-counter medicines, such as vitamins, dietary supplements or herbal remedies. Some medicines may alter the effect of Stivarga or Stivarga may alter the effect of other medicines, leading to serious side effects. In particular, inform your doctor if you are taking any of the following medicines or any other medicine:

• certain antifungal medicines (e.g. ketoconazole, itraconazole, posaconazole and voriconazole)
• certain pain medicines (e.g. mefenamic acid, diflunisal and niflumic acid)
• certain antibiotics (e.g. rifampicin, clarithromycin, telithromycin)
• medicines used to treat epilepsy (seizures) (e.g. phenytoin, carbamazepine or phenobarbital)
• methotrexate, a medicine used to treat cancer
• rosuvastatin, fluvastatin, atorvastatin, medicines typically used to treat hypercholesterolemia
• warfarin or phenprocoumon, medicines used to thin the blood
• St. John’s wort (also available without prescription), an herbal remedy for depression.

Ask your doctor or pharmacist for advice before taking any medicine.

Stivarga with food and drink
Avoid drinking grapefruit juice while taking Stivarga. Grapefruit juice may alter the effect of Stivarga.

Pregnancy, breast-feeding and fertility
Inform your doctor if you suspect you are pregnant or are planning a pregnancy, because Stivarga must not be used during pregnancy unless absolutely necessary. Your doctor will discuss with you the potential risks associated with taking Stivarga during pregnancy.
Avoid becoming pregnant during treatment with Stivarga, because this medicine may harm the unborn child.
Both women of childbearing potential and men must use effective contraception during treatment and for at least eight weeks after the end of treatment.
You must not breast-feed during treatment with Stivarga, because this medicine may interfere with the child’s growth and development. Inform your doctor if you are breast-feeding or intend to breast-feed.
Stivarga may reduce fertility in both men and women. Consult your doctor before taking Stivarga.

Driving and using machines
It is unknown whether Stivarga affects the ability to drive or use machines. Do not drive or operate tools or machinery if you experience treatment-related symptoms that impair your ability to concentrate or react.

Important information about some excipients in Stivarga
This medicine contains 56.06 mg of sodium (a key component of table salt) per daily dose (4 tablets). This corresponds to 3% of the maximum daily dietary intake recommended for an adult.
This medicine contains 1.68 mg of lecithin (derived from soy) per daily dose (4 tablets).

3. How to take Stivarga

Take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
The recommended daily dose for adults is 4 Stivarga 40 mg tablets (160 mg of regorafenib). Your doctor may adjust the dose. Take the dose of Stivarga prescribed by your doctor.
Usually, your doctor will instruct you to take Stivarga for 3 weeks, followed by a 1-week break: this period constitutes 1 treatment cycle.
Take Stivarga every day at the same time, after a low-fat meal (containing less than 30% fat). Swallow the tablet whole with a glass of water after a light meal containing less than 30% fat. An example of a light (low-fat) meal includes 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat). Do not take Stivarga with grapefruit juice (see also section “Taking Stivarga with food and drink”).
If you vomit after taking regorafenib, do not take additional tablets and inform your doctor.
Your doctor may reduce the dose or decide to interrupt or permanently discontinue treatment, if necessary. Generally, you will continue taking Stivarga for as long as you benefit from it and do not experience unacceptable side effects.
No dose adjustment is required if you have mild impairment of liver function. If you have mild or moderate impairment of liver function during treatment with Stivarga, your doctor should monitor you closely. You must not be treated with Stivarga if you have severe impairment of liver function, as there is no available data on the use of Stivarga in patients with severe liver impairment.
No dose adjustment is required if you have mild, moderate, or severe impairment of kidney function.

If you take more Stivarga than you should
Inform your doctor immediately if you have taken more than the prescribed dose. You may need medical treatment, and your doctor may instruct you to stop taking Stivarga.
Taking an excessive amount of Stivarga may make certain side effects more likely or more severe, especially:

• skin reactions (rash, blisters, redness, pain, swelling, itching, or peeling of the skin)
• voice changes or hoarseness ( dysphonia )
• frequent bowel movements or watery stools ( diarrhea )
• mouth ulcers ( mucositis )
• dry mouth
• loss of appetite
• high blood pressure ( hypertension )
• excessive tiredness ( fatigue ).

If you forget to take Stivarga
If you forget a dose, take it as soon as you remember, on the same day. Do not take a double dose of Stivarga on the same day to make up for a forgotten dose taken the previous day. Inform your doctor each time you miss a dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them. This medicine may also alter the results of certain blood tests.
The most serious side effects, which have been associated with fatal outcomes, are:

• severe liver problems (including liver failure), bleeding, intestinal perforation, and infection.

Contact your doctor immediately if you notice any of the following symptoms:
Liver problems
Treatment with Stivarga may increase the risk of severe liver problems. Contact your doctor immediately if you experience any of the following symptoms:

• yellowing of the skin or whites of the eyes
• dark urine
• confusion and/or disorientation
  These may be signs of severe liver damage.

Bleeding
Stivarga may cause severe bleeding in the digestive tract, for example in the stomach, throat, rectum, or intestine, or in the lungs, kidneys, mouth, vagina, and/or brain. Contact your doctor immediately if you experience any of the following symptoms:

• blood in the stool or black stools
• blood in the urine
• abdominal pain
• coughing up blood or vomiting blood
  These may be signs of bleeding.

Severe abdominal problems (gastrointestinal perforation or fistula)
Contact your doctor immediately if you experience any of the following symptoms:

• severe abdominal pain or persistent abdominal pain
• vomiting blood
• red or black stools
  These may be signs of serious stomach or intestinal problems.

Infection
Treatment with Stivarga may increase the risk of infection, particularly of the urinary tract, nose, throat, and lungs. Treatment with Stivarga may also increase the risk of fungal infections of the mucous membranes, skin, or body. Seek immediate medical attention if you experience any of the following symptoms:

• high fever
• severe cough with or without increased mucus production (sputum)
• severe sore throat
• shortness of breath
• burning/pain during urination
• unusual vaginal discharge or irritation in that area
• redness, swelling, or pain in any part of the body
  These may be signs of infection.

Other side effects with Stivarga, listed by frequency:
Very common side effects (may affect more than 1 in 10 users)

• reduced number of platelets in the blood, leading to increased bruising or bleeding ( thrombocytopenia )
• reduced number of red blood cells ( anemia )
• reduced appetite and food intake
• high blood pressure ( hypertension )
• voice changes or hoarseness ( dysphonia )
• frequent bowel movements or loose stools ( diarrhea )
• mouth dryness or soreness, tongue pain, mouth ulcers ( stomatitis and/or mucosal inflammation )
• nausea
• vomiting
• elevated levels of bilirubin in the blood, a substance produced by the liver ( hyperbilirubinemia )
• changes in liver enzymes, which may indicate liver problems ( increased transaminases )
• redness, pain, blisters, and swelling of the palms of the hands and soles of the feet ( hand-foot skin reaction )
• skin rash
• weakness, lack of strength and energy, excessive tiredness or unusual drowsiness ( asthenia/fatigue )
• pain (including abdominal pain and back pain)
• constipation
• fever
• weight loss

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

• reduced number of white blood cells ( leukopenia )
• reduced activity of the thyroid gland ( hypothyroidism )
• low levels of potassium, phosphate, calcium, sodium, or magnesium in the blood ( hypokalemia, hypophosphatemia, hypocalcemia, hyponatremia, and hypomagnesemia )
• elevated levels of uric acid in the blood ( hyperuricemia )
• loss of body fluids ( dehydration )
• headache
• tremor
• nerve damage causing altered sensation, such as numbness, tingling, weakness, or pain ( peripheral neuropathy )
• altered taste
• dry mouth
• heartburn ( gastroesophageal reflux )
• infection or irritation of the stomach and intestine ( gastroenteritis )
• hair loss ( alopecia )
• dry skin
• exfoliative skin rash
• sudden, involuntary muscle contractions ( muscle spasms )
• presence of protein in the urine ( proteinuria )
• elevated levels of certain enzymes involved in digestion ( increased amylase and lipase )
• blood clotting abnormalities ( abnormal INR )

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

• signs/symptoms of an allergic reaction, which may include widespread severe rash, feeling unwell, fever, difficulty breathing, jaundice, changes in liver chemical values ( hypersensitivity reaction )
• heart attack, chest pain ( myocardial infarction and myocardial ischemia )
• very high blood pressure causing headache, confusion, blurred vision, nausea, vomiting, and seizures ( hypertensive crisis )
• inflammation of the pancreas, characterized by stomach-area pain, nausea, vomiting, and fever ( pancreatitis )
• nail disorders (nail changes such as cracked and/or brittle nails)
• multiple skin rashes ( erythema multiforme )

Rare side effects (may affect up to 1 in 1,000 users)

• blood clots in small blood vessels ( thrombotic microangiopathy )
• certain types of skin tumors ( keratoacanthoma/squamous cell skin carcinoma )
• headache, confusion, seizures, and vision loss, with or without high blood pressure ( Reversible Posterior Encephalopathy Syndrome/RPES )
• severe skin and/or mucosal reactions, which may include painful blisters and fever, with extensive skin peeling ( Stevens-Johnson syndrome and toxic epidermal necrolysis )

Not known (frequency cannot be estimated from the available data)

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

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Stivarga

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and label of the bottle after "EXP". The expiry date refers to the last day of that month.
Store in the original packaging to protect from moisture.
Keep the bottle tightly closed.
After opening the bottle, the medicine must be discarded after 7 weeks.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Stivarga contains

• The active substance is regorafenib. Each film-coated tablet contains 40 mg of regorafenib.
• The other components are: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, povidone (K-25), colloidal anhydrous silica, red iron oxide (E172), yellow iron oxide (E172), lecithin (derived from soy), macrogol 3350, polyvinyl alcohol (partially hydrolysed), talc and titanium dioxide (E171) (see also section “Important information on some of the excipients of Stivarga”).

Description of the appearance of Stivarga and the contents of the pack
The 40 mg Stivarga tablets are light pink, oval-shaped, film-coated tablets marked with “BAYER” on one side and “40” on the other side.
Each bottle contains 28 film-coated tablets.
Stivarga 40 mg tablets are available in packs containing one bottle or 3 bottles.
Not all pack sizes may be marketed.
Leave the desiccant inside the bottle. The desiccant is a moisture-absorbing material contained in a small container to protect the tablets from moisture.

Marketing Authorisation Holder
Bayer AG
51368 Leverkusen
Germany

Manufacturer
Bayer AG
Kaiser-Wilhelm-Allee 51368 Leverkusen
Germany

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

België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11

Lietuva
UAB Bayer
Tel. +370 5 23 36 868

България
Байер България ЕООД
Тел. +359 (0)2-424 72 80

Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11

Česká republika
Bayer s.r.o.
Tel: +420 266 101 111

Magyarország
Bayer Hungária Kft.
Tel.: +36-14 87-41 00

Danmark
Bayer A/S
Tlf: +45-45 23 50 00

Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05

Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48

Nederland
Bayer B.V.
Tel: +31-(0)23 799 1000

Eesti
Bayer OÜ
Tel: +372 655 85 65

Norge
Bayer AS
Tlf. +47 23 13 05 00

Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30 210 618 75 00

Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 46-0

España
Bayer Hispania S.L.
Tel: +34-93-495 65 00

Polska
Bayer Sp. z o.o.
Tel.: +48-22-572 35 00

France
Bayer HealthCare
Tél: +33-(0)800 87 54 54

Portugal
Bayer Portugal, Lda.
Tel: +351-21-416 42 00

Hrvatska
Bayer d.o.o.
Tel: +385-(0)1-6599 900

România
SC Bayer SRL
Tel: +40 21 529 59 00

Ireland
Bayer Limited
Tel: +353 1 216 3300

Slovenija
Bayer d. o. o.
Tel.: +386-(0)1-58 14 400

Ísland
Icepharma hf.
Sími: +354 540 80 00

Slovenská republika
Bayer, spol. s r.o.
Tel: +421 2 59 21 31 11

Italia
Bayer S.p.A.
Tel: +39-02-397 81

Suomi/Finland
Bayer Oy
Puh/Tel: +358-20 785 21

Κύπρος
NOVAGEM Limited
Τηλ: +357 22 48 38 58

Sverige
Bayer AB
Tel: +46-(0)8-580 223 00

Latvija
SIA Bayer
Tel: +371 67 84 55 63

United Kingdom (Northern Ireland)
Bayer AG
Tel: +44-(0) 118 206 3000

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