Stivarga 40 mg film-coated tablets

Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

Stivarga 40 mg film-coated tablets

regorafenib

Read the entire leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet, as 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, and you should not give it to others, even if they have the same symptoms as you, because it could harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are adverse effects not listed in this leaflet. See section 4.

Contents of the 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 and works by slowing the growth and spread of cancer cells and by cutting off their blood supply, which they need to continue growing.

Stivarga is used to treat:

• metastatic colorectal cancer in adult patients who have previously received other treatments or who cannot be treated with other anticancer medicines (fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy)

• gastrointestinal stromal tumours (GIST), a type of stomach and intestinal cancer, that have spread to other parts of the body or cannot be surgically removed, in adult patients who have previously been treated with other anticancer medicines (imatinib and sunitinib)

• hepatocellular carcinoma (liver cancer) in adult patients who have previously been treated with another anticancer medicine (sorafenib)

If you have any questions about how Stivarga works or why it has been prescribed for you, please consult your doctor.

2. What you need to know before taking 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 especially careful with Stivarga

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

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

• if you have or have had any bleeding problems and if you are taking warfarin, phenprocoumon, or another medicine that thins the blood to prevent blood clots. Treatment with Stivarga may increase the risk of bleeding. Your doctor may decide that a blood test is necessary before starting Stivarga. Stivarga may cause serious bleeding in the gastrointestinal tract, such as in the stomach, throat, rectum, or intestine, or in the lungs, kidneys, mouth, vagina, and/or brain. Seek immediate medical help if you experience any of the following symptoms: blood in your stools or black stools, blood in your urine, stomach pain, coughing or vomiting blood.

• if you have severe stomach or intestinal problems (gastrointestinal perforation or fistulas), your doctor will need to decide whether to discontinue treatment with Stivarga. Seek immediate medical help 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.

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

• if you have a severe and persistent headache, visual disturbances, seizures, lack of energy, drowsiness, altered consciousness, or changes in mental status (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 it before and during treatment and may prescribe medication to treat high blood pressure.

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

• if you have or have had damage to the smallest blood vessels (thrombotic microangiopathy [TMA]). Inform your doctor if you experience fever, fatigue, tiredness, bruising, bleeding, swelling, confusion, vision loss, or seizures.

• if you have recently undergone or are scheduled to undergo a surgical procedure. Stivarga may affect wound healing, and treatment may need to be stopped until the wound has healed.

• if you have 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 and gloves. If you experience this adverse effect, your doctor may adjust your dose or interrupt treatment until your condition improves.

If you are in any of these situations, inform your doctor before taking Stivarga. These conditions may need to be treated, and additional tests may be required (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 pharmacist if you are taking, have recently taken, or might need to take any other medicines. This includes medicines obtained without a prescription or over-the-counter products, such as vitamins, dietary supplements, or herbal medicines. Some medicines may affect how Stivarga works, or Stivarga may affect how these medicines work, causing serious adverse effects. Inform your doctor especially if you are taking any of the following or any other medicine:

• certain medicines for fungal infections (e.g., ketoconazole, itraconazole, posaconazole, and voriconazole)
• certain pain medicines (e.g., mefenamic acid, diflunisal, and niflumic acid)
• certain medicines for 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 levels
• warfarin or phenprocoumon, medicines commonly used to thin the blood
• St. John’s wort (also available without a prescription), a herbal treatment for depression

Consult your doctor or pharmacist before using any medicine.

Taking Stivarga with food and drink

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, could 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 during treatment with Stivarga, as this medicine may harm the unborn baby.

Both women and men of reproductive age should use effective contraception during treatment and for at least eight weeks after treatment has ended.

You must not breastfeed during treatment with Stivarga, as this medicine may interfere with the baby's growth and development. Inform your doctor if you are breastfeeding or plan to breastfeed.

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 and use machines. Do not drive or operate tools or machinery if you experience treatment-related symptoms 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 (a main component of table/cooking salt) 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 of lecithin (derived from soy) per daily dose (4 tablets).

3. How to take Stivarga

Follow exactly the instructions given by your doctor for taking this medicine. If you are unsure, consult your doctor or pharmacist again.

The recommended daily dose in adults is 4 Stivarga 40 mg tablets (160 mg of regorafenib). Your doctor may change your dose. Take the dose of Stivarga prescribed by your doctor. Generally, your doctor will ask you to take Stivarga for 3 weeks, followed by a 1-week break. This constitutes 1 treatment cycle.

Take Stivarga at the same time each day, after a low-fat meal (containing less than 30% fat). Swallow the tablet whole with water after a light meal low in fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 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). You must 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 need to reduce your dose or decide to interrupt or permanently discontinue treatment, if necessary. Generally, you will continue taking Stivarga for as long as you are benefiting from treatment and do not experience unacceptable side effects.

Dose adjustment is not required if you have mild impairment of liver function. If you develop mild or moderate impairment of liver function while being treated with Stivarga, your doctor should monitor you closely. You must not receive Stivarga treatment if you have severe impairment of liver function, as there are no data available on the use of Stivarga in patients with severe hepatic impairment.

Dose adjustment is not 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 require medical attention, and your doctor may instruct you to stop taking Stivarga.

Taking too much Stivarga may increase the likelihood or severity of certain side effects, especially:

• skin reactions (rash, blistering, redness, pain, swelling, itching, or peeling of the skin)
• changes in voice or hoarseness (dysphonia)
• frequent or loose bowel movements (diarrhea)
• mouth sores (inflammation of the mucosa)
• dry mouth
• decreased appetite
• high blood pressure (hypertension)
• excessive tiredness (fatigue)

If you forget to take Stivarga

If you miss 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 a missed dose taken the previous day. Inform your doctor of any dose you have missed.

4. Possible adverse effects

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

The most serious adverse effects, for which fatal outcomes have been observed, are:

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

Immediately inform your doctor if you experience any of the following symptoms:

Liver problems

Treatment with Stivarga may increase the risk of serious liver problems. Seek immediate medical help 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 serious liver damage.

Bleeding

Stivarga may cause serious bleeding in the gastrointestinal tract, such as in the stomach, throat, rectum, or intestine, or in the lungs, kidneys, mouth, vagina, and/or brain. Seek immediate medical help if you experience any of the following symptoms:

• blood in the stool or black stools
• blood in the urine
• stomach pain
• coughing up or vomiting blood

These may be signs of bleeding.

Serious stomach and intestinal problems (gastrointestinal perforation or fistula)

Seek immediate medical help if you experience any of the following symptoms:

• severe stomach (abdominal) pain or persistent stomach 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 infections, especially 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. You should seek immediate medical attention if you experience any of these symptoms:

• high fever
• severe cough with or without increased mucus (sputum) production
• severe sore throat
• difficulty breathing
• burning or pain when urinating
• unusual vaginal irritation or discharge
• redness, swelling, and/or pain in any part of the body

These may be signs of infection.

Other adverse effects of Stivarga, listed according to their frequency:

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

• reduced number of platelets in the blood, leading to easy bruising or bleeding (thrombocytopenia)

• reduced 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, tongue pain, mouth ulcers (stomatitis and/or mucosal inflammation)

• feeling of dizziness (nausea)

• vomiting

• elevated blood levels of bilirubin, a substance produced by the liver (hyperbilirubinemia)

  • changes in liver-produced enzymes, which may indicate liver dysfunction (elevated transaminases)

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

• rash

• weakness, lack of strength and energy, excessive tiredness, and unusual drowsiness (asthenia/fatigue)

• pain (including abdominal pain and back pain)

• constipation

• fever

• weight loss

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

• decreased number of white blood cells (leukopenia)
• reduced 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 may cause changes in sensation, such as numbness, tingling, weakness, or pain (peripheral neuropathy)
• taste disturbances
• dry mouth
• burning sensations (gastroesophageal reflux)
• infection or irritation of the stomach and intestines (gastroenteritis)
• hair loss (alopecia)
• dry skin
• skin rash with scaling or peeling of the skin (exfoliative rash)
• sudden, involuntary muscle contractions (muscle spasms)
• protein in the urine (proteinuria)
• elevated levels of certain enzymes involved in digestion (increased amylase and lipase)
• abnormal blood clotting situation (abnormal INR)

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

• signs/symptoms of an allergic reaction, which may include widespread severe rash, dizziness, fever, shortness of breath, jaundice, changes in liver-produced chemicals (hypersensitivity reaction)
• heart attack, chest pain (myocardial infarction and myocardial ischemia)
• severely elevated blood pressure causing headache, confusion, blurred vision, nausea, vomiting, and fainting (hypertensive crisis)
• inflammation of the pancreas, characterized by stomach-area pain, nausea, vomiting, and fever (pancreatitis)
• nail disorders (nail changes such as grooves and/or brittle nails)
• multiple skin rashes (erythema multiforme)

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

• blood clots in small blood vessels (thrombotic microangiopathy)
• certain types of skin cancer (keratoacanthoma/squamous cell carcinoma of the skin)
• headache, confusion, seizures, and visual loss, with or without high blood pressure (reversible posterior encephalopathy syndrome / PRES)
• severe skin and/or mucous membrane reactions, including painful blisters and fever, with extensive skin peeling (Stevens-Johnson syndrome and toxic epidermal necrolysis)

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

• enlargement and weakening of a blood vessel wall or tearing of a blood vessel wall (aneurysms and arterial dissections)
• lack of energy, confusion, drowsiness, tremors, altered consciousness: these symptoms may be signs of brain toxicity caused by high levels of ammonia in the blood (hyperammonaemic encephalopathy)

Reporting of adverse effects

If you experience any adverse effect, talk to 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 listed 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 expiry date stated on the carton and label of the bottle after “EXP” or “CAD”. The expiry date refers to the last day of the month indicated.

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.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Stivarga

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

What Stivarga looks like and contents of the pack

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

Each bottle contains 28 film-coated tablets.

Stivarga 40 mg tablets are available in packs containing one bottle or three bottles.

Only certain pack sizes may be marketed.

Keep the desiccant in the bottle. The desiccant is a moisture-absorbing material contained in a small container which protects the tablets from moisture.

Marketing Authorization Holder

Bayer AG
51368 Leverkusen
Germany

Manufacturer

Bayer AG
Kaiser-Wilhelm-Allee
51368 Leverkusen
Germany

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

Date of the most recent review of this leaflet:

Other sources of information

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