STIVARGA 40 mg FILM-COATED TABLETS

2. What you need to know before you take Stivarga

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

Talk to your doctor or pharmacist before taking Stivarga.

Be careful with Stivarga

• 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. Your doctor will perform blood tests to monitor your liver function before and during treatment with Stivarga. If you have severe liver impairment, you should not receive treatment with Stivarga, as there is no data available on the use of Stivarga in patients with severe liver impairment.

• with signs such as high fever, severe cough with or without increased mucus production, severe sore throat, difficulty breathing, burning sensation/pain when urinating, unusual vaginal irritation/discharge, redness, swelling, and/or pain in any part of the body. Your doctor may temporarily interrupt your treatment.

• and if you are taking warfarin, phenprocoumon, or other medicines that make your blood thinner to prevent blood clots. Treatment with Stivarga may increase the risk of bleeding. Your doctor may decide to perform a blood test before you start taking Stivarga. Stivarga may cause serious bleeding in the digestive tract, such as in the stomach, throat, rectum, or intestine, or in the lungs, kidneys, mouth, vagina, and/or brain. Seek medical help immediately if you experience any of the following symptoms: blood in your stools or black stools, blood in your urine, stomach pain, coughing up/vomiting blood.

• (gastrointestinal perforation or fistula), your doctor should decide whether to interrupt treatment with Stivarga. Seek medical help immediately if you experience any of the following symptoms: severe stomach pain or stomach pain that does not go away, vomiting blood, red or black stools.

• Your doctor will check your heart function before you start taking Stivarga and during treatment. Seek medical help immediately if you experience any of the following symptoms, as they may be signs of a heart attack or reduced blood flow to the heart: chest pain or discomfort that may spread to your arms, back, neck, jaw, or stomach; shortness of breath; sudden sweating with cool, moist skin; feeling of fainting or dizziness.

• (such as confusion, memory loss, or disorientation), contact your doctor immediately.

• Stivarga may increase your blood pressure. Your doctor will monitor your blood pressure before and during treatment and may give you a medicine to treat high blood pressure.

• (enlargement and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.

• (thrombotic microangiopathy [TMA]). Tell your doctor if you experience fever, fatigue, tiredness, bruising, bleeding, swelling, confusion, vision loss, and seizures.

• Stivarga may affect the healing process of your wounds, and it may be necessary to stop treatment until the wound has healed.

• Stivarga may cause redness, pain, swelling, or blisters on the palms of your hands or soles of your feet. If you notice any changes, contact your doctor. To treat the symptoms, your doctor may recommend using creams and/or pads on your shoes and gloves. 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 situations, tell 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 colon or rectal 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. No data are available.

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

Other medicines and Stivarga

Tell your doctor or pharmacistif you are taking, have recently taken, or might take any other medicines. This includes medicines obtained without a prescription, 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. Tell your doctor in particular if you are taking any of the following medicines or any other medicine:

• certain medicines for treating fungal infections (e.g., ketoconazole, itraconazole, posaconazole, and voriconazole)
• certain medicines for treating pain (e.g., mefenamic acid, diflunisal, and nifluramic acid)
• certain medicines for treating 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 phenprocoumon, medicines commonly used to make your blood thinner
• St. John's Wort (also obtained without a prescription), a herbal treatment for depression

Talk to your doctor or pharmacist before taking any medicine.

Taking Stivarga with food and drinks

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

Pregnancy, breast-feeding, and fertility

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

Avoid becoming pregnant while taking Stivarga, as this medicine may harm your unborn baby.

Both men and women of childbearing ageshould use effective contraception during treatment and for at least 8 weeks after finishing treatment.

Do not breast-feed your baby while taking Stivarga, as this medicine may interfere with your baby's growth and development. Tell your doctor if you are breast-feeding or plan to breast-feed.

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

Driving and using machines

It is not known whether Stivarga affects the ability to drive and use machines. 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 ingredients of Stivarga

This medicine contains 56.06 mg of sodium (main component of cooking/table salt) in each daily dose (4 tablets). This is equivalent to 3% of the maximum recommended daily intake of sodium 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 not sure, ask your doctor or pharmacist.

The recommended daily dosein adults is 4 tablets of Stivarga 40 mg (160 mg of regorafenib). Your doctor may change your dose. Take the dose of Stivarga that your doctor has prescribed for you. 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 low-fat meal. Take the tablet whole with water after a low-fat meal with less than 30% fat content. An example of a low-fat meal includes 1 serving of cereal (about 30 g), 1 glass of skimmed milk, 1 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 vomit after taking regorafenib, do not take an additional tablet and inform your doctor.

Your doctor may need to reduce your dose or decide to interrupt or permanently stop treatment, if necessary. In general, you will take Stivarga as long as you are benefiting from treatment and not experiencing unacceptable side effects.

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

No dose adjustment is necessary if you have mild, moderate, or severe kidney impairment.

If you take more Stivarga than you should

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

Taking too much Stivarga may increase the chance of getting some side effects or make them more severe, especially:

• skin reactions (rash, blisters, redness, pain, swelling, itching, or peeling of the skin)
• changes in your voice or hoarseness (dysphonia)
• frequent or loose bowel movements (diarrhea)
• mouth sores (mucositis)
• dry mouth
• decreased 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 on the same day to make up for forgotten doses the day before. Inform your doctor of any dose you have missed.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. This medicine can also alter the results of some blood tests.

The most serious adverse 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 help immediately if you experience the following symptoms:

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

• Presence of blood in the stool or black stool
• Presence of blood in the urine

• Stomach pain
• Coughing up/vomiting blood

These may be signs of bleeding.

Severe gastric and intestinal problems (perforation or gastrointestinal fistula)

Seek medical help immediately if you experience the following symptoms:

• Severe stomach (abdominal) pain or stomach pain that does not disappear
• Vomiting blood
• Red or black stool

These may be signs of severe gastric or intestinal problems.

Infection

Treatment with Stivarga may increase the risk of infections, especially of the urinary tract, nose, throat, and lung. 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 these symptoms:

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

These may be signs of an infection.

Other adverse effects of Stivarga indicated by frequency:

Very common adverse 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
• High blood pressure (hypertension)
• Changes in voice or hoarseness (dysphonia)
• Frequent or loose bowel movements (diarrhea)
• Dryness or pain in the mouth, pain in the tongue, mouth sores (stomatitis and/or mucositis)
• Feeling of dizziness (nausea)
• Vomiting
• Elevated blood levels of bilirubin, a substance produced by the liver (hyperbilirubinemia)
• • Changes in liver enzymes, which may indicate liver damage (increased transaminases).

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

• Rash
• Weakness, lack of strength and energy, excessive fatigue, and unusual sleepiness (asthenia/fatigue)
• Pain (including abdominal pain and back pain)
• Constipation
• Fever
• Weight loss

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

• Decrease in the number of white blood cells (leukopenia)
• Decreased activity of the thyroid gland (hypothyroidism)
• Low blood levels of potassium, phosphate, calcium, sodium, or magnesium (hypokalemia, hypophosphatemia, hypocalcemia, hyponatremia, and hypomagnesemia)
• Elevated blood levels of uric acid (hyperuricemia)
• Loss of body fluids (dehydration)
• Headache
• Tremor
• Nerve damage that can cause a change in sensitivity, such as numbness, tingling, weakness, or pain (peripheral neuropathy)
• Taste disorders
• Dry mouth
• Heartburn (gastroesophageal reflux)
• Infection or irritation of the stomach and intestines (gastroenteritis)
• Hair loss (alopecia)
• Dry skin
• Scaly or flaky skin rash (exfoliative rash)
• Sudden, involuntary muscle contractions (muscle spasms)
• Protein in the urine (proteinuria)
• Elevated levels of certain digestive enzymes (increased amylase and lipase)
• Abnormal blood clotting (abnormal INR)

Uncommon adverse 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 chemicals (hypersensitivity reaction).
• Heart attack, chest pain (myocardial infarction and myocardial ischemia)
• Severely elevated blood pressure that causes headache, confusion, blurred vision, nausea, vomiting, and fainting (hypertensive crisis)
• Pancreatitis, characterized by stomach pain, nausea, vomiting, and fever
• Nail disorders (changes in nails such as ridging and/or brittle nails)
• Multiple skin rashes (erythema multiforme)

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

• Blood clots in small blood vessels (thrombotic microangiopathy)
• Certain skin cancers (keratoacanthoma/squamous cell carcinoma)
• Headache, confusion, seizures, 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 widespread skin peeling (Stevens-Johnson syndrome and toxic epidermal necrolysis)

Frequency not known(frequency cannot be estimated from available data)

• Increased and weakened blood vessel wall or tear in the blood vessel wall (aneurysms and arterial dissections).
• Lack of energy, confusion, sleepiness, tremors, altered consciousness: these symptoms may be signs of brain toxicity caused by high levels of ammonia in the blood (hyperammonemic encephalopathy).

Reporting adverse effects

If you experience any adverse effects, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Stivarga

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

Do not use this medicine after the expiration date stated on the carton and label of the bottle after "EXP" or "CAD". The expiration date is the last day of the month indicated.

Store in the original packaging to protect from moisture.

Keep the bottle tightly closed.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package contents and additional information

Composition of Stivarga

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

Appearance and package contents

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

Each bottle contains 28 film-coated tablets.

Stivarga 40 mg film-coated tablets are available in packs of one bottle or three bottles.

Not all pack 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

Manufacturer

Bayer AG

Kaiser-Wilhelm-Allee

51368 Leverkusen

Germany

You can obtain further information on this medicine by contacting the local representative of the marketing authorization holder:

Date of last revision of this leaflet:

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency (EMA) website: https://www.ema.europa.eu