Subinit

Package leaflet: Information for the user

Subinit, 12.5 mg, hard capsules
Subinit, 25 mg, hard capsules
Subinit, 50 mg, hard capsules
Sunitinib
Please read all of this leaflet carefully before 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 further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor. See section 4.

Contents of the leaflet

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

1. What Subinit is and what it is used for

Subinit contains sunitinib as the active substance, which is a protein kinase inhibitor. Subinit
is used in the treatment of certain cancers. It inhibits the activity of a specific group of proteins
known to be involved in the growth and spread of cancer cells.
Subinit is used to treat the following types of cancer in adults:

• Gastrointestinal stromal tumours (GIST), a type of stomach and intestinal tumour, when imatinib (another anticancer medicine) is no longer effective or cannot be used;
• Metastatic renal cell carcinoma (MRCC), a type of kidney cancer that has spread to other parts of the body;
• Pancreatic neuroendocrine tumours (pNET) (tumours arising from hormone-producing cells in the pancreas), which are progressing and cannot be surgically removed.

If you have any questions about how Subinit works or why this medicine has been prescribed,
please consult your doctor.

2. Important information before taking Subinit

When not to take Subinit

• If the patient is allergic to sunitinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Before starting treatment with Subinit, discuss the following with your doctor:

• If high blood pressure is present. Subinit may increase blood pressure. Your doctor may monitor your blood pressure during treatment with Subinit, and you may require treatment with blood pressure-lowering medicines if necessary.

• If you have or have previously had blood disorders, bleeding or bruising. Treatment with Subinit may increase the risk of bleeding or may cause changes in the number of certain blood cells, which may lead to anaemia or affect the blood’s ability to clot. If you are taking warfarin or acenocoumarol, anticoagulant medicines used to prevent blood clots, your risk of bleeding may be higher. Inform your doctor of any bleeding events during treatment with Subinit.

• If you have heart conditions. Subinit may cause heart problems. Inform your doctor if you experience severe fatigue, shortness of breath, or swelling in your feet or ankles.

• If you have heart rhythm disorders. Subinit may cause irregular heart rhythms. During treatment with Subinit, your doctor may perform an electrocardiogram (ECG) to monitor for such disturbances. Inform your doctor if you experience dizziness, fainting, or irregular heartbeat while taking Subinit.

• If you have recently had blood clots in veins and/or arteries (types of blood vessels), including stroke, heart attack, embolism, or thrombosis. Contact your doctor immediately if, during treatment with Subinit, you experience symptoms such as chest pain or pressure, arm, back, neck or jaw pain, shortness of breath, numbness or weakness on one side of the body, difficulty speaking, headache, or dizziness.

• If you have or have previously 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 previously had damage to the smallest blood vessels, called thrombotic microangiopathy. Inform your doctor if you develop fever, fatigue, weakness, bruising, bleeding, swelling, confusion, vision loss, or seizures while taking Subinit.

• If you have thyroid disorders. Subinit may cause thyroid problems. Inform your doctor if you feel unusually tired, feel colder than usual, or have a hoarse voice during treatment with Subinit. Your doctor should check thyroid function before starting Subinit and regularly during treatment. If your thyroid does not produce enough thyroid hormone, you may require thyroid hormone replacement therapy.

• If you have or have previously had pancreatic or gallbladder disorders. Inform your doctor if you experience any of the following symptoms: stomach pain (upper abdomen), nausea, vomiting, or fever. These may be signs of pancreatitis or gallbladder inflammation.

• If you have or have previously had liver problems. Inform your doctor if, during treatment with Subinit, you experience any of the following signs of liver dysfunction: itching, yellowing of the eyes or skin (jaundice), dark urine, or pain or discomfort in the upper right abdomen. Your doctor should order blood tests to monitor liver function before starting Subinit, during treatment, and whenever clinically indicated.

• If you have or have previously had kidney problems. Your doctor will monitor kidney function.

• If you are scheduled for surgery or have recently undergone surgery. Subinit may affect wound healing. The medicine is usually discontinued before surgery. Your doctor will decide when to restart Subinit.

• A dental examination is recommended before starting treatment with Subinit.

• If you experience pain in the mouth, tooth or jaw pain, swelling or ulceration in the mouth, numbness or a feeling of heaviness in the jaw, or loose teeth, inform your oncologist and dentist immediately.

• If you require invasive dental treatment or oral surgery, inform your dentist that you are taking Subinit, especially if you are currently or have previously received intravenous bisphosphonates. Bisphosphonates are medicines used to prevent bone disorders and may be taken for other conditions.

• If you have or have previously had skin and subcutaneous tissue disorders. While taking this medicine, pyoderma gangrenosum (painful skin ulceration) or necrotizing fasciitis (a rapidly spreading infection of the skin and/or soft tissues, which may be life-threatening) may occur. Contact your doctor immediately if you develop signs of infection around a skin lesion, including fever, pain, redness, swelling, or discharge of pus or blood. These conditions usually resolve after discontinuation of Subinit. Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) have been observed during treatment with this medicine. These initially appear as red, target-like or circular spots, often with central blisters. The rash may progress to extensive blistering or skin peeling and may be life-threatening. If you develop a rash or any of the above skin symptoms, seek immediate medical attention.

• If you have or have previously had seizures. Inform your doctor as soon as possible if you develop high blood pressure, headache, or vision loss.

• If you have diabetes. Blood glucose levels should be monitored regularly in diabetic patients to determine whether adjustment of antidiabetic medication is needed to minimize the risk of hypoglycaemia. Inform your doctor promptly if you experience symptoms of low blood sugar (fatigue, palpitations, excessive sweating, hunger, or loss of consciousness).

Children and adolescents
Subinit is not recommended for patients under 18 years of age.
Subinit with other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those obtained without a prescription, as well as any medicines you plan to take.
Some medicines may affect the concentration of Subinit in the body. Inform your doctor if you are taking medicines containing any of the following active substances:

• ketoconazole, itraconazole – used to treat fungal infections,
• erythromycin, clarithromycin, rifampicin – used to treat infections,
• ritonavir – used to treat HIV infection,
• dexamethasone – a corticosteroid used in various diseases (such as allergic and/or respiratory disorders or skin conditions),
• phenytoin, carbamazepine, phenobarbital – used to treat epilepsy and other neurological conditions,
• herbal products containing St John’s wort (Hypericum perforatum) – used to treat depression and anxiety.

Taking Subinit with food and drink
Do not drink grapefruit juice while taking Subinit.
Pregnancy and breastfeeding
If you are pregnant, breastfeeding, think you may be pregnant, or are planning to have a child, consult your doctor or pharmacist before using this medicine.
Women of childbearing potential should use an effective method of contraception during treatment with Subinit.
Women who are breastfeeding should inform their doctor. Breastfeeding is not recommended during treatment with Subinit.
Driving and operating machinery
If you experience dizziness or significant fatigue, exercise caution when driving or operating machinery.
Subinit contains sodium
Subinit contains less than 1 mmol of sodium (23 mg) per capsule, i.e. the medicine is considered "sodium-free".

3. How to take Subinit

This medicine should always be taken exactly as prescribed by the doctor. In case of doubt,
consult the doctor.
The doctor will prescribe the dose appropriate for the individual patient, depending on the type of tumour.
For patients being treated for:

• GIST or mRCC, the usual dose is 50 mg taken once daily for 28 days (4 weeks), followed by a 14-day (2-week) treatment-free break, in 6-week treatment cycles.
• pNET, the usual dose is 37.5 mg taken once daily continuously.

The doctor will determine the appropriate dose for the individual patient and the time when
treatment with Subinit should end.
Subinit may be taken with or without food.
Taking more Subinit than prescribed
If an excessive number of capsules has been taken, contact the doctor immediately.
Medical intervention may be necessary.
Missing a dose of Subinit
Do not take a double dose to make up for a missed dose.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Contact a doctor immediately if the patient experiences any of the following adverse reactions (see also Important information before taking the medicine Subinit):
Heart problems. Tell the doctor if the patient feels very tired, has shortness of breath or swelling of the feet and ankles. These may be symptoms of heart disease, which may include heart failure and heart muscle disease (cardiomyopathy).
Lung problems or breathing disorders. Tell the doctor if the patient develops cough, chest pain, sudden onset of shortness of breath, or coughs up blood. These may be symptoms of a condition called pulmonary embolism, which occurs when blood clots travel to the lungs.
Kidney function disorders. Tell the doctor if the patient experiences changes in frequency or absence of urination, which may be symptoms of kidney failure.
Bleeding. Tell the doctor if the patient experiences any of the following symptoms or severe bleeding during treatment with Subinit: stomach (abdominal) pain and swelling; vomiting blood; black, tarry stools; blood in the urine; headache or changes in consciousness; coughing up blood or bloody sputum from the lungs or airways.
Tumour rupture leading to intestinal perforation. Tell the doctor if the patient experiences severe abdominal pain, fever, nausea, vomiting, blood in the stool, or changes in bowel function.

Other adverse reactions associated with Subinit may include:
Very common (may occur in more than 1 in 10 people):

• Decreased number of platelets, red blood cells, and/or white blood cells (e.g. neutrophils).
• Shortness of breath.
• Hypertension.
• Extreme fatigue, loss of strength.
• Swelling due to fluid accumulation under the skin and around the eyes, deep allergic rash.
• Pain and/or irritation in the mouth, painful ulceration and/or inflammation, and/or dryness of the mouth, taste disturbances, gastrointestinal disturbances, nausea, vomiting, diarrhoea, constipation, abdominal pain and/or swelling, loss of and/or reduced appetite.
• Decreased thyroid activity (hypothyroidism).
• Dizziness.
• Headache.
• Nosebleeds.
• Back pain, joint pain.
• Pain in arms and legs.
• Yellowing of the skin and/or skin discoloration, excessive skin pigmentation, change in hair colour, rash on palms and soles, rash, dry skin.
• Cough.
• Fever.
• Difficulty sleeping.

Common (may occur in up to 1 in 10 people):

• Blood clots in blood vessels.
• Inadequate blood supply to the heart due to embolism or narrowing of the coronary arteries.
• Chest pain.
• Reduced amount of blood pumped by the heart.
• Fluid retention, including in the lung area.
• Infections.
• Complication following severe infection (blood infection), which may lead to tissue damage, organ failure, and death.
• Decreased blood sugar level (see section 2).
• Protein loss in urine, sometimes causing swelling.
• Pseudoinfluenza syndrome.
• Abnormal blood test results, including pancreatic and liver enzymes.
• High levels of uric acid in the blood.
• Haemorrhoids, rectal pain, bleeding gums, difficulty swallowing or loss of swallowing ability.
• Burning or painful sensation of the tongue, inflammation of the gastrointestinal mucosa, excessive gas in the stomach or intestines.
• Weight loss.
• Musculoskeletal pain (muscle and bone pain), muscle weakness, muscle fatigue, muscle pain, muscle cramps.
• Dryness of the nasal mucosa, sensation of nasal congestion.
• Excessive tearing.
• Skin sensation disturbances, itching, skin peeling and inflammation, blisters, acne, nail discoloration, hair loss.
• Sensory disturbances in limbs.
• Disorders related to increased or decreased sensitivity, especially to touch.
• Heartburn.
• Dehydration.
• Hot flushes.
• Abnormal urine colour.
• Depression.
• Chills.

Uncommon (may occur in up to 1 in 100 people):

• Life-threatening soft tissue infections, including the anogenital area (see section 2).
• Stroke.
• Myocardial infarction caused by interruption or reduction of blood supply to the heart.
• Changes in electrical function or rhythm disturbances of the heart.
• Presence of fluid around the heart (pericardial effusion).
• Liver failure.
• Abdominal (stomach) pain caused by inflammation of the pancreas.
• Tumour rupture leading to intestinal perforation.
• Inflammation (swelling or redness) of the gallbladder, with or without gallstones.
• Formation of abnormal connections between one body cavity and another or to the skin.
• Oral pain, tooth and/or jaw pain, swelling or ulceration of the mouth, numbness or heaviness in the jaw, or loose teeth. These may be symptoms of jaw bone damage (osteonecrosis), see section 2.
• Excessive production of thyroid hormones leading to increased resting metabolism.
• Impaired wound healing after surgical procedures.
• Increased activity of muscle enzyme (creatine phosphokinase) in blood.
• Excessive reaction to allergens, including hay fever, skin rash, itching, urticaria, swelling of any body part, and breathing difficulties.
• Inflammatory condition of the large intestine (colitis, ischemic colitis).

Rare (may occur in up to 1 in 1000 people):

• Severe reaction affecting the skin and/or mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).
• Tumour lysis syndrome, a group of metabolic complications that may occur during cancer treatment. These complications are caused by products released from dying tumour cells and may include: nausea, shortness of breath, irregular heartbeat, muscle cramps, seizures, cloudy urine, and fatigue associated with abnormal laboratory test results (high levels of potassium, uric acid, and phosphate, and low levels of calcium in the blood), which may lead to kidney changes and acute kidney failure.
• Abnormal muscle breakdown that may cause kidney disease (rhabdomyolysis).
• Abnormal changes in the brain that may cause a syndrome of symptoms including headache, confusion, seizures, and vision loss (reversible posterior leukoencephalopathy syndrome).
• Painful skin ulceration (pyoderma gangrenosum).
• Hepatitis.
• Inflammation of the thyroid gland.
• Damage to the smallest blood vessels called thrombotic microangiopathy.

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

• Enlargement and weakening of the blood vessel wall or rupture of the blood vessel wall (aneurysm and arterial dissection).

Reporting of adverse reactions
If any adverse symptoms occur, including any possible adverse reactions not listed in this leaflet, inform a doctor, pharmacist, or nurse.
Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store the medicine Subinit

• Keep the medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date stated on the carton and blister after: EXP. The expiry date refers to the last day of the stated month.
• Store below 30°C. Store in the original packaging to protect from light.
• Do not use this medicine if you notice that the packaging is damaged or if there are signs of prior opening.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Subinit contains
Subinit 12.5 mg hard capsules
The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to
12.5 mg of sunitinib. The other components are:

• Capsule contents: mannitol (E 421), sodium croscarmellose, povidone K-25, hypromellose 4 mPas, and magnesium stearate.
• Capsule shell - cap: erythrosine (E 127), titanium dioxide (E 171), indigo carmine (E 132), gelatin.
• Capsule shell - body: indigo carmine (E 132), erythrosine (E 127), titanium dioxide (E 171), gelatin.

Subinit 25 mg hard capsules
The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to
25 mg of sunitinib. The other components are:

• Capsule contents: mannitol (E 421), sodium croscarmellose, povidone K-25, hypromellose 4 mPas, and magnesium stearate.
• Capsule shell - cap: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.
• Capsule shell - body: indigo carmine (E 132), erythrosine (E 127), titanium dioxide (E 171), gelatin.

Subinit 50 mg hard capsules
The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to
50 mg of sunitinib. The other components are:

• Capsule contents: mannitol (E 421), sodium croscarmellose, povidone K-25, hypromellose 4 mPas, and magnesium stearate.
• Capsule shell - cap: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.
• Capsule shell - body: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.

What Subinit looks like and contents of the pack
Subinit 12.5 mg is available as hard, opaque gelatin capsules (size 4) with a red cap and red body, containing yellow to orange granules.
Subinit 25 mg is available as hard, opaque gelatin capsules (size 2) with a yellow cap and red body, containing yellow to orange granules.
Subinit 50 mg is available as hard, opaque gelatin capsules (size 1) with a yellow cap and yellow body, containing yellow to orange granules.
The medicine is available in PVC/Aclar(PCTFE)/PVC/Aluminium blisters.
The cardboard box contains 28 capsules.

Marketing Authorisation Holder
MT Pharma - Healthcare Sp. z o.o.
ul. Józefa Piłsudskiego 25
16-500 Sejny, Poland
tel.: +48 603 400 858

Manufacturer
Przedsiębiorstwo Farmaceutyczne LEK-AM sp. z o.o.
ul. Ostrzykowizna 14A
05-170 Zakroczym