Prescribing Information for the User

Stivarga 40 mg Film-Coated Tablets

regorafenib

Read this entire prescribing information carefully before starting to take this medicine, as it contains important information for you.

• Keep this prescribing information, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this prescribing information. See section 4.

Stivarga contains the active ingredient regorafenib. It is a medication used to treat cancer and acts by slowing down the growth and spread of cancer cells and cutting off the blood supply that allows them to continue growing.

Stivarga is used to treat:

• colorectal cancer that has spread to other parts of the body in adult patients who have received other treatments or who cannot receive treatment with other medications (fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy)

• gastrointestinal stromal tumors (GIST), a type of stomach and intestine cancer, that has spread to other parts of the body or cannot be treated with surgery, in adult patients who have received previous cancer treatment (imatinib and sunitinib)

• adult patients with liver cancer who have been previously treated with another cancer medication (sorafenib)

If you have any doubts about how Stivarga works or why you have been prescribed this medication, consult your doctor.

Do not take Stivarga

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

Warnings and precautions

Consult your doctor or pharmacist before starting to take Stivarga.

Be especially careful with Stivarga

• if you have any liver problems,including Gilbert's syndrome, with signs such as:yellowing of the skin and the white of the eyes, dark urine, and confusion and/or disorientation. Treatment with Stivarga may increase the risk of liver problems. Your doctor will perform blood tests to monitor your liver function before and during treatment with Stivarga. If you have severe liver damage, you should not receive treatment with Stivarga, as there is no data on the use of Stivarga in patients with severe liver damage.

• if you have an infectionwith signs such as high fever, severe cough with or without increased mucus production (sputum), severe sore throat, difficulty breathing, burning or painful urination, unusual vaginal discharge, redness, swelling, and/or pain in any part of the body. Your doctor may interrupt your treatment temporarily.

• if you have or have had any bleeding problemsand are taking warfarin,fenprocumon, or another medicine that makes the blood less likely to clot. Treatment with Stivarga may increase the risk of bleeding. Your doctor may decide that you need to have a blood test before starting to take Stivarga. Stivarga may cause severe bleeding in the digestive tract, such as in the stomach, throat, rectum, or intestines, or in the lungs, kidneys, mouth, vagina, and/or brain. Seek medical help immediately if you experience the following symptoms: blood in the stool or black stools, blood in the urine, stomach pain, coughing/vomiting with blood.

• if you have severe stomach or intestinal problems(gastrointestinal perforation orfistulas), your doctor will decide whether to interrupt treatment with Stivarga. Seek medical help immediately if you experience the following symptoms: severe stomach pain or stomach pain that does not go away, vomiting with blood, bloody or black stools.

• if you have chest pain or any heart problems.Your doctor will check thefunctioning of your heart before starting to take Stivarga and during treatment. Seek medical help immediately if you experience the following symptoms, as they may be signs of a heart attack or reduced blood flow to the heart: chest pain that may radiate to the shoulders, arms, back, neck, teeth, jaw, or stomach, and may come and go; shortness of breath; sudden onset of sweating with cold and clammy skin, dizziness, or fainting.

• if you experience severe and persistent headache, visual disturbances, seizures, or mental status changes(such as confusion, memory loss, ordisorientation), contact your doctor immediately.

• if you have high blood pressure.Stivarga may increase blood pressure. Your doctor will monitoryour blood pressure before and during treatment and may prescribe a medicine to treat high blood pressure.

• if you have or have had an aneurysm(enlargement and weakening of the wall of a bloodvessel)or a tear in the wall of a blood vessel.

• if you have or have had damage to smaller blood vessels (microangiopathic thrombotic [MAT]).Inform your doctor if you experience fever, fatigue, lethargy, hematomas, hemorrhage, swelling, confusion, vision loss, and seizures.

• if you have recently undergone or are about to undergo a surgical procedure.Stivargamay affect the healing of your wounds, and you may need to stop treatment until your wound has healed.

• if you have skin problems.Stivarga may cause redness, pain, swelling, orblistering on the palms of your hands or the soles of your feet. If you notice any changes, contact your doctor. To treat the symptoms, your doctor may recommend using creams and/or shoe inserts and socks. If you experience this side effect, your doctor may change your dose or interrupt treatment until your condition improves.

If you are in any of these circumstances,,inform your doctorbefore taking Stivarga. It may be necessary to treat them, as well as perform additional tests (see also section 4 "Possible side effects").

Children and adolescents

The use of Stivarga in children and adolescents for the indication of colorectal cancer that has spread to other parts of the body is not relevant.

The safety and efficacy of Stivarga in children and adolescents for the indication of gastrointestinal stromal tumors (GIST) have not been established. There are no available data.

The use of Stivarga in children and adolescents for the indication of liver cancer is not relevant.

Other medicines and Stivarga

Inform your doctor or pharmacistif you are taking, have taken recently, or may need to take any other medicine. This includes those obtained without a prescription or over-the-counter, such as vitamins, dietary supplements, or herbal medicines. Some medicines may affect how Stivarga works or Stivarga may affect how these medicines work and cause serious side effects. Inform your doctor in particular if you are taking any of the following or any other medicine:

• some medicines to treat fungal infections (e.g., ketoconazole, itraconazole, posaconazole, and voriconazole)
• some medicines to treat pain (e.g., mefenamic acid, diflunisal, and niflumic acid)
• some medicines to treat bacterial infections (e.g., rifampicin, clarithromycin, telithromycin)
• medicines commonly used to treat epilepsy (seizures) (e.g., phenytoin, carbamazepine, or phenobarbital)
• methotrexate, a medicine commonly used to treat cancer
• rosuvastatin, fluvastatin, atorvastatin, medicines commonly used to treat high cholesterol
• warfarin or fenprocumon, medicines commonly used to make the blood less likely to clot
• St. John's Wort (medicine also obtained without a prescription), a herbal treatment for depression

Consult your doctor or pharmacist before using any medicine.

Taking Stivarga with food and drinks

Avoid drinking grapefruit juice while taking Stivarga, as it may affect how Stivarga works.

Pregnancy, breastfeeding, and fertility

Inform your doctor if you think you are pregnant, may be pregnant, or plan to become pregnant,as Stivarga should not be used during pregnancy unless clearly necessary. Your doctor will discuss the possible risks of taking Stivarga during pregnancy with you.

Avoid becoming pregnant during treatment with Stivarga,as this medicine mayharm the fetus.

Both women and men of childbearing ageshould use effective contraception duringtreatment and for at least eight weeks after treatment is completed.

Do not breastfeed your baby during treatment with Stivarga,as this medicine mayinterfere with the baby's growth and development.Inform your doctor if you are breastfeeding or plan to do so.

Stivarga may reduce fertility in both men and women. Consult your doctor before taking Stivarga.

Driving and operating machines

The effect of Stivarga on the ability to drive and operate machines is unknown. Do not drive or use tools or machines if you experience symptoms related to treatment that affect your ability to concentrate and react.

Important information about some of the components of Stivarga

This medicine contains 56.06 mg of sodium (main component of table salt/for cooking) in each daily dose (4 tablets). This is equivalent to 3% of the maximum daily sodium intake recommended for an adult.

This medicine contains 1.68 mg oflecithin(derived from soy) per daily dose (4 tablets).

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again..

The recommended daily dosein adults is 4 tablets of Stivarga 40 mg (160 mg ofregorafenib). Your doctor may change your dose. Take the dose of Stivarga prescribed by your doctor. In general, your doctor will ask you to take Stivarga for 3 weeks and then stop taking it for 1 week. This is 1 treatment cycle.

Take Stivarga at the same time every day, after a light meal (low in fat). Take the tablet whole with water after a light meal with a fat content of less than 30%. An example of a light meal (low in fat) would include 1 serving of cereal (around 30 g), 1 glass of skim milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g of fat). Do not take Stivarga with grapefruit juice (see also the section "Taking Stivarga with food and drinks").

If you experience vomiting after taking regorafenib, do not take additional tablets and inform your doctor.

Your doctor may need to reduce your dose or decide to interrupt or permanently discontinue treatment if necessary. In general, you will take Stivarga as long as you benefit from treatment and do not experience unacceptable side effects.

No dose adjustment is necessary if you have a mild impairment of liver function. If you have a mild or moderate impairment of liver function while on treatment with Stivarga, your doctor should closely monitor you. If you have a severe impairment of liver function, you should not receive treatment with Stivarga, as there is no data on the use of Stivarga in patients with severe liver impairment.

No dose adjustment is necessary if you have a mild, moderate, or severe impairment of renal function.

If you take more Stivarga than you should

Inform your doctor immediately if you have taken a dose greater than the one prescribed. You may need medical attention and your doctor may tell you to stop taking Stivarga.

Taking too much Stivarga may increase the likelihood of certain side effects or make them more severe, especially:

• skin reactions (rash, blisters, redness, pain, swelling, itching, or peeling of the skin)
• voice changes or hoarseness (hoarseness)
• increased frequency or loose stools (diarrhea)
• mouth sores (inflammation of the mucosa)
• dry mouth
• loss of appetite
• high blood pressure (hypertension)
• excessive fatigue (fatigue)

If you forget to take Stivarga

If you forget a dose, take it as soon as you remember that day. Do not take a double dose on the same day to make up for the missed dose the previous day. Inform your doctor of any dose you have missed.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. This medicine may also affect the results of some blood tests.

The most serious side effects,for which a fatal outcome has been observed, are:

• Severe liver problems (including liver failure), bleeding, gastrointestinal perforation, and infection.

Inform your doctor immediatelyif you experience any of the following symptoms:

Liver problems

Treatment with Stivarga may increase the risk of severe liver problems. Seek medical attention immediately if you experience any of the following symptoms:

• Yellowing of the skin and the white 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, such as in the stomach, throat, rectum, or intestines, or in the lungs, kidneys, mouth, vagina, and/or brain. Seek medical attention immediately if you experience any of the following symptoms:

• Blood in the stool or black stools
• Blood in the urine

• Abdominal pain
• Coughing or vomiting with blood

These may be signs of bleeding.

Severe gastrointestinal and intestinal problems (gastrointestinal perforation or fistula)

Seek medical attention immediately if you experience any of the following symptoms:

• Severe abdominal pain or abdominal pain that does not go away
• Vomiting with blood
• Red or black stools

These may be signs of severe gastrointestinal or intestinal problems.

Infection

Treatment with Stivarga may increase the risk of infections, especially urinary tract infections, nose, throat, and lung infections. Treatment with Stivarga may also increase the risk of fungal infections in the mucous membrane, skin, or body. You should seek medical attention immediately if you experience any of the following symptoms:

• High fever
• Severe cough with or without increased mucus production (sputum)
• Severe sore throat
• Difficulty breathing
• Unusual burning or pain while urinating
• Unusual vaginal discharge
• Redness, swelling, and/or pain in any part of the body.

These may be signs of an infection.

Other side effects of Stivarga indicated by frequency:

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

• Reduction in the number of platelets in the blood, characterized by easy bruising or bleeding (thrombocytopenia)
• Reduction in the number of red blood cells in the blood (anemia)
• Decreased appetite and food intake
• Elevated blood pressure (hypertension)
• Changes in voice or hoarseness (hoarseness)
• Frequent bowel movements or loose stools (diarrhea)
• Dryness or pain in the mouth, tongue pain, mouth sores (stomatitis and/or mucosal inflammation)
• Sensation of dizziness (nausea)
• Vomiting
• Elevated blood bilirubin concentrations, a substance produced by the liver (hyperbilirubinemia)
• • Changes in liver enzymes, which may indicate liver damage (elevated transaminases).

• Redness, pain, blisters, and swelling of the palms of the hands or soles of the feet (hand-foot syndrome)

• Rash
• Weakness, lack of strength and energy, excessive fatigue, and 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)

• Reduction in the number of white blood cells (leucopenia)
• Decreased activity of the thyroid gland (hypothyroidism)
• Low blood concentrations of potassium, phosphate, calcium, sodium, or magnesium (hypokalemia,hypophosphatemia, hypocalcemia, hyponatremia, and hypomagnesemia)
• Elevated blood concentrations of uric acid (hyperuricemia)
• Fluid loss from the body (dehydration)
• Headache
• Tremor
• Alteration of nerves that may cause a change in sensitivity, such as numbness, tingling, weakness, or pain (peripheral neuropathy)
• Disorders of taste
• Dry mouth
• Burning (gastroesophageal reflux)
• Infection or irritation of the stomach and intestines (gastroenteritis)
• Hair loss(alopecia)
• Dry skin
• Rash with scaling or peeling of the skin (exfoliative rash)
• Sudden, involuntary muscle contractions (muscle spasms)
• Protein in the urine (proteinuria)
• Elevated concentrations of certain enzymes involved in digestion (increased amylase and lipase)
• Abnormal coagulation of the blood (abnormal INR)

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

• Signs/symptoms of an allergic reaction that could include a severe generalized rash, dizziness, fever, shortness of breath, jaundice, changes in liver enzymes (hypersensitivity reaction).
• Heart attack, chest pain (myocardial infarction and ischemic heart disease)
• Severely elevated blood pressure that causes headache, confusion, blurred vision, nausea, vomiting, and fainting (hypertensive crisis)
• Inflammation of the pancreas characterized by abdominal pain, nausea, vomiting, and fever (pancreatitis)
• Disorders of the nails (changes in the nails such as ridges and/or brittle nails)
• Multiple skin rashes (erythema multiforme)

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

• Clots in small blood vessels (microangiopathy)
• Certain skin cancers (keratoacanthoma/squamous cell carcinoma)
• Headache, confusion, convulsions, and vision loss associated with or without high blood pressure (posterior reversible encephalopathy syndrome/PRES)

• Severe skin and/or mucous membrane reactions, including painful blisters and fever, including extensive skin detachment (Stevens-Johnson syndrome and toxic epidermal necrolysis)

Unknown frequency(frequency cannot be estimated from available data)

• Increased and weakened wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections).

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V..By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the box and the bottle label after “EXP or CAD”. The expiration date is the last day of the month indicated.

Store in the original packaging to protect it from moisture.

Store the bottle perfectly closed.

Once the bottle is opened, the medication must be discarded after 7 weeks.

Medicines should not be thrown down the drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This way, you will help protect the environment.

Composition of Stivarga

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

Appearance of the product and contents of the package

The Stivarga 40 mg tablets are light pink in color and oval in shape, marked with "BAYER" on one side and "40" on the other.

Each bottle contains 28 film-coated tablets.

The Stivarga 40 mg tablets are presented in bottles or three bottles.

Only some package sizes may be marketed.

Keep the desiccant in the bottle. The desiccant is a moisture-absorbing material introduced into a small container that protects the tablets from moisture.

Marketing Authorization Holder

Bayer AG

51368 Leverkusen

Germany

Responsible for manufacturing

Bayer AG

Kaiser-Wilhelm-Allee

51368 Leverkusen

Germany

To obtain more information about this medicinal product, please contact the local representative of the marketing authorization holder:

Last update of the summary of product characteristics:

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA): http://www.ema.europa.eu