Daruph

Package leaflet: Information for the user

Daruph, 16 mg, coated tablets
Daruph, 40 mg, coated tablets
Daruph, 55 mg, coated tablets
Daruph, 63 mg, coated tablets
Daruph, 79 mg, coated tablets
Daruph, 111 mg, coated tablets
Dasatinib
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, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

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

1. What Daruph is and what it is used for

Daruph contains the active substance dasatinib. This medicine is used to treat chronic myeloid
leukaemia (CML) in adults, adolescents and children aged at least 1 year. Leukaemia is a cancer
of the white blood cells. Normally, white blood cells help the body fight infections. In people
with CML, white blood cells called granulocytes grow uncontrollably. Daruph inhibits the growth
of these leukaemic cells.
Daruph is also used to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia
(Ph+ ALL) in adults, adolescents and children aged at least 1 year, and for the lymphoblastic
blast phase of CML in adults who have not responded to prior therapy. In people with acute
lymphoblastic leukaemia, white blood cells called lymphocytes multiply too quickly and live too
long. Daruph inhibits the growth of these leukaemic cells.
If you have any questions about how Daruph works or why it has been prescribed for you, please
consult your doctor.

2. Important information before taking Daruph

When not to take Daruph

• if the patient is allergic to dazatinib or any of the other ingredients of this medicine (listed in section 6). Consult a doctor if an allergic reaction is suspected.

Warnings and precautions
Before starting treatment with Daruph, discuss this with your doctor or pharmacist.

• if you are taking blood-thinning medicines or medicines that prevent blood clots (see section "Daruph and other medicines").
• if you have previously or currently have liver or heart function disorders.
• if you experience difficulty breathing, chest pain, or cough while taking Daruph: these may be symptoms of fluid accumulation in the lungs or chest cavity (which may occur more frequently in patients aged 65 years and older) or caused by changes in blood vessels supplying blood to the lungs.
• if you have ever had or may currently have hepatitis B virus infection; this is because dazatinib may cause reactivation of hepatitis B virus, which in some cases may lead to death. Patients will be closely monitored by their doctor for signs of this infection before starting treatment.
• if you develop bruising, bleeding, fever, fatigue, or confusion while taking Daruph, contact your doctor. These may indicate damage to blood vessels known as thrombotic microangiopathy (TMA).
• if your doctor has informed you that you have reduced stomach acidity (achlorhydria/hypochlorhydria). The dosage of Daruph may be adjusted. Your treating physician will perform periodic monitoring during treatment to assess whether Daruph is achieving the intended effect. Regular blood tests will also be performed during treatment with Daruph.

Children and adolescents
Daruph should not be used in children under one year of age. Data on the use of dazatinib in this age group are limited. Growth and bone development should be closely monitored in children taking Daruph.

Daruph and other medicines
Inform your doctor about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
Dazatinib is mainly metabolized in the liver. Certain medicines may affect the action of Daruph when used simultaneously.
The following medicines should not be used with Daruph:

• Ketoconazole, itraconazole – antifungal medicines.
• Erythromycin, clarithromycin, telithromycin – antibiotics.
• Ritonavir – an antiviral medicine.
• Phenytoin, carbamazepine, phenobarbital – medicines used in epilepsy.
• Rifampicin – a medicine used in tuberculosis.
• St. John’s wort – a herbal remedy available without prescription, used in the treatment of depression and other conditions (also known as Hypericum perforatum).

Do not take medicines that neutralize stomach acid (such as aluminium hydroxide or magnesium hydroxide) within 2 hours before or 2 hours after taking Daruph.
If you are taking medicines that reduce stomach acid secretion, such as omeprazole, for optimal results, take this medicine 2 hours after taking Daruph.

Inform your doctor if you are taking medicines that thin the blood or prevent blood clots.

Taking Daruph with food and drink
Do not take Daruph with grapefruit or grapefruit juice.

Pregnancy and breastfeeding
Women who are pregnant or suspect they may be pregnant should inform their doctor. Daruph should not be given to pregnant women unless absolutely necessary. Your doctor will discuss potential risks associated with taking Daruph during pregnancy.
It is recommended that both men and women use effective contraception during treatment with Daruph.
Inform your doctor if you are breastfeeding. Breastfeeding is not recommended while taking Daruph.

Driving and operating machinery
Exercise particular caution when driving or operating machinery if you experience adverse effects such as dizziness or visual disturbances.

Daruph contains lactose and sodium
If you have previously been diagnosed with intolerance to certain sugars, inform your doctor before taking this medicine.
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning the medicine is considered "sodium-free".

3. How to take Daruph

Do not switch from taking Daruph tablets to other tablets containing dazatynib without consulting your doctor. The strength of Daruph tablets differs from other medications containing dazatynib.
Daruph will only be prescribed by a physician experienced in the treatment of leukemia. This medicine must always be taken exactly as recommended by the doctor. If in doubt, consult your doctor or pharmacist. Daruph is intended for adults and children aged at least 1 year.

The recommended initial dose of the medicine for adult patients in the chronic phase of CML is 79 mg once daily.
The recommended initial dose of the medicine for adult patients in the accelerated phase or blast phase of CML, or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), is 111 mg taken once daily.

Dosing in children with chronic phase CML or Ph+ ALL is based on body weight. Dazatynib is administered orally once daily in the form of coated tablets or oral suspension powder. The use of coated Daruph tablets is not recommended in patients with body weight below 10 kg. In patients with body weight below 10 kg and in patients unable to swallow tablets, the oral suspension powder should be used. When switching between formulations (i.e. tablets and oral suspension powder), a change in dose may occur; therefore, switching from one formulation to another should not be done without medical advice. Based on the patient's body weight, adverse reactions, and response to treatment, the doctor will determine the appropriate formulation and dosage. The initial dose of Daruph in children is calculated according to body weight, as indicated below:

There are no dosage recommendations for Daruph in children under 1 year of age.
Depending on the response to treatment, the doctor may decide to increase or decrease the dose, or even temporarily interrupt treatment. To achieve higher or lower doses, it may be necessary to use a combination of tablets of different strengths.

How to take Daruph
Tablets should be taken at the same time each day. Tablets must be swallowed whole. Do not crush, split, or chew them. Do not take fragmented tablets. If tablets are crushed, split, chewed, or fragmented, there is no certainty that the patient has received the correct dose. Daruph tablets may be taken with or without food.

Special handling instructions for Daruph
It is unlikely that Daruph tablets will be damaged. However, if such a situation occurs, individuals handling Daruph should wear protective gloves.

How long to take Daruph
Daruph should be taken daily until the doctor decides that treatment should be discontinued. Ensure that Daruph is taken for as long as recommended by the doctor.

If more Daruph has been taken than recommended
If the patient accidentally takes more tablets than recommended, contact the doctor immediately, as the patient may require medical attention.

If a dose of Daruph is missed
Do not take a double dose to make up for a missed tablet. Take the next dose at the usual time.

If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although they do not occur in everyone.
The symptoms listed below may indicate serious adverse reactions:

• if chest pain, difficulty breathing, cough, or fainting occur.
• if unexpected bleeding or bruising occurs without prior injury.
• if blood is present in vomit, stool, or urine, or if the stool appears black.
• if signs of infection such as fever or severe chills occur.
• if fever, mouth or throat pain, development of blisters, or peeling of skin and (or) mucous membranes occur. You should contact your doctor immediately if any of the above symptoms occur.

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

• Infections (including bacterial, viral, and fungal infections).
• Heart and lungs: shortness of breath.
• Gastrointestinal disorders: diarrhea, nausea, or vomiting.
• Skin, hair, eyes, general symptoms: skin rash, fever, facial swelling, swelling of hands and feet, headache, feeling of fatigue or weakness, bleeding.
• Pain: muscle pain (during or after treatment), abdominal pain.
• Laboratory tests may show: low platelet count, low white blood cell count (neutropenia), anemia, presence of fluid around the lungs.

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

• Infections: pneumonia, herpes virus infection (including cytomegalovirus - CMV), upper respiratory tract infections, severe blood or tissue infection (including not uncommon cases resulting in death).
• Heart and lungs: palpitations, irregular heartbeat, congestive heart failure, weakening of the heart muscle, high blood pressure, increased blood pressure in the lungs, cough.
• Gastrointestinal disorders: appetite disturbances, taste disturbances, bloated or enlarged abdomen, inflammation of the large intestine, constipation, heartburn, oral ulcers, weight gain, weight loss, inflammation of the stomach.
• Skin, hair, eyes, general symptoms: tingling, skin itching, dry skin, acne, skin inflammation, continuous ringing in the ears (tinnitus), hair loss, excessive sweating, vision disturbances (including blurred or impaired vision), dry eyes, bruising, depression, insomnia, sudden skin redness, dizziness, injuries (bruises), loss of appetite, drowsiness, generalized swelling.
• Pain: joint pain, muscle weakness, chest pain, pain in hands and feet, chills, muscle and joint stiffness, muscle cramps.
• Laboratory tests may show: presence of fluid around the heart, presence of fluid in the lungs, heart rhythm disturbances, decreased white blood cell count (neutropia) with fever, gastrointestinal bleeding, high levels of uric acid in the blood.

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

• Heart and lungs: heart attack (including fatal cases), inflammation of the lining (fibrous sac) around the heart, irregular heartbeat, chest pain due to reduced blood flow to the heart (angina), low blood pressure, narrowing of the airways causing breathing difficulties, asthma, increased blood pressure in the arteries (blood vessels) of the lungs.
• Gastrointestinal disorders: pancreatitis, peptic ulcer disease, esophagitis, abdominal swelling (ascites), anal fissure, difficulty swallowing, gallbladder inflammation, biliary tract obstruction, gastroesophageal reflux (a condition in which acid and other stomach contents flow back into the throat).
• Skin, hair, eyes, general symptoms: allergic reactions, including formation of tender, red nodules on the skin (erythema nodosum), anxiety, disorientation, mood changes, decreased libido, fainting, tremor, eye inflammation causing redness or pain, skin disease characterized by tender, red, well-defined erythematous patches with sudden onset of fever and increased white blood cell count (neutrophilic dermatosis), hearing loss, light sensitivity, visual disturbances, excessive tearing of the eyes, skin pigmentation disorders, inflammation of subcutaneous fat tissue, skin ulceration, blistering of the skin, nail disorders, hair disorders, disorders of hands and feet, kidney failure, frequent urination, breast enlargement in men, menstrual disorders, general weakness and discomfort, reduced thyroid function, loss of balance while walking, bone necrosis (a condition involving reduced blood flow to bones leading to loss of bone mass and bone death), joint inflammation, skin swelling anywhere on the body.
• Pain: vein inflammation (phlebitis), which may cause redness, pain, and swelling, tendon inflammation (tendinitis).
• Brain: memory loss.
• Laboratory tests may show: abnormal blood test results and possible kidney dysfunction due to tumor breakdown products (tumor lysis syndrome), low albumin levels in the blood, low lymphocyte count (a type of white blood cells) in the blood, high cholesterol levels in the blood, enlarged lymph nodes, bleeding into the brain, abnormalities in the heart's electrical activity, heart enlargement, liver inflammation, presence of protein in the urine, increased creatine kinase activity (an enzyme mainly present in the heart, brain, and skeletal muscles), increased troponin activity (an enzyme mainly present in the heart and skeletal muscles), increased gamma-glutamyl transferase activity (an enzyme mainly present in the liver), milky-appearing fluid around the lungs (chylothorax).

Rare adverse reactions (may affect up to 1 in 1000 people):

• Heart and lungs: enlargement of the right ventricle of the heart, myocarditis (inflammation of the heart muscle), symptoms resulting from blocked blood flow to the heart muscle (acute coronary syndrome), cardiac arrest (cessation of blood ejection from the heart), coronary artery disease (heart), inflammation of the tissue covering the heart and lungs, blood clots, pulmonary embolism (blood clots in the lungs).
• Gastrointestinal disorders: loss of essential nutrients from the gastrointestinal tract such as proteins, intestinal obstruction, anal fistula (abnormal formation of a channel between the anus and the surrounding skin), kidney dysfunction, diabetes.
• Skin, hair, eyes, general symptoms: seizures, optic neuritis (which may cause complete or partial vision loss), blue-violet skin spots, hyperthyroidism, thyroid gland inflammation, ataxia (a condition related to lack of muscular coordination), difficulty walking, miscarriage, skin vasculitis (inflammation of blood vessels in the skin), skin fibrosis.
• Brain: stroke, transient neurological deficits due to impaired blood flow, facial nerve paralysis, dementia.
• Immune system: severe allergic reaction.
• Musculoskeletal and connective tissue: delayed healing of the rounded ends of bones (epiphyses) forming joints; slowed or delayed growth.

Other observed adverse reactions with unknown frequency (frequency cannot be estimated from available data):

• Pneumonitis.
• Bleeding in the stomach or intestines, which may lead to death.
• Reactivation of hepatitis B virus infection in patients with a history of prior infection.
• Reaction with fever, skin blistering, and mucosal ulceration.
• Symptoms of kidney disease, including swelling and abnormal laboratory test results such as protein in the urine and low blood protein levels.
• Damage to blood vessels known as thrombotic microangiopathy (TMA), including reduced number of red blood cells, reduced platelet count, and formation of blood clots.

During treatment, your doctor will monitor for the occurrence of the adverse reactions listed above.
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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 authorization holder or its representative.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store the medicine Daruph

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister pack or carton after the word "EXP". The expiry date refers to the last day of the stated month.
No special storage instructions apply for this medicine.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What Daruph contains

• The active substance is dazatinib. Each coated tablet contains 15.8 mg, 39.5 mg, 55.3 mg, 63.2 mg, 79.0 mg or 110.6 mg of dazatinib.
• The other ingredients are: Tablet core: monohydrate lactose, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, magnesium stearate. Tablet coating: hypromellose, propylene glycol, titanium dioxide (E171), yellow iron oxide (E172) (only for Daruph 55 mg coated tablets).

What Daruph looks like and contents of the pack
Daruph 16 mg coated tablets:
The coated tablet is white or almost white, round, with engraved marking “15.8” on one side and 5.5 mm in diameter.
Daruph 40 mg coated tablets:
The coated tablet is white or almost white, round, with engraved marking “39.5” on one side and 7 mm in diameter.
Daruph 55 mg coated tablets:
The coated tablet is slightly yellow or yellow, round, with engraved marking “55.3” on one side and 7 mm in diameter.
Daruph 63 mg coated tablets:
The coated tablet is white or almost white, round, with engraved marking “63.2” on one side and 8.5 mm in diameter.
Daruph 79 mg coated tablets:
The coated tablet is white or almost white, round, with engraved marking “79.0” on one side and 9.5 mm in diameter.
Daruph 111 mg coated tablets:
The coated tablet is white or almost white, round, with engraved marking “110.6” on one side and 11 mm in diameter.
Daruph is packed in OPA/Aluminium/PVC/Aluminium blisters.
Pack sizes: Daruph 16 mg, 40 mg, 55 mg coated tablets: 56 and 60 coated tablets.
Pack sizes: Daruph 63 mg, 79 mg, 111 mg coated tablets: 28 and 30 coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37 Prague 10
Czech Republic

Manufacturer
Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37 Prague 10
Czech Republic
Pharmacare Premium Ltd.
HHF003 Hal Far Industrial Estate
Hal Far Birzebbugia
BBG 3000, Malta

For further information, please contact the local representative of the Marketing Authorisation Holder:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel.: +48 22 375 92 00

This medicinal product is authorised in the European Economic Area under the following names:
Germany, Hungary, Italy, Poland, Romania, Slovakia, Sweden: Daruph