Cazacombi

Package leaflet: Information for the patient

Cazacombi, 5 mg + 12.5 mg, film-coated tablets
cilazapril + hydrochlorothiazide
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 questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm other people, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

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

1. What Cazacombi is and what it is used for

Cazacombi is a combination of two active substances called cilazapril and
hydrochlorothiazide.
Cazacombi is used to treat high blood pressure. The two active substances work together to lower blood pressure. They are used in combination when treatment with either substance alone is insufficient.
Cilazapril belongs to a group of medicines called ACE inhibitors (angiotensin-converting enzyme inhibitors). It works by relaxing and widening blood vessels. This helps lower blood pressure and also makes it easier for the heart to pump blood to all parts of the body.
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics or water pills. It works by increasing the amount of urine produced. This helps lower blood pressure.

2. Important information before using Cazacombi

When not to use Cazacombi:

• if the patient is allergic to cilazapril or hydrochlorothiazide, or any of the other ingredients of this medicine (listed in section 6);
• if the patient is allergic to medicines similar to Cazacombi, such as: other ACE inhibitors, thiazide diuretics, or sulfonamides;
• if the patient has previously experienced a severe adverse reaction called angioedema after taking other ACE inhibitors, or if the patient has hereditary angioedema or angioedema of unknown cause. Symptoms include swelling of the face, lips, mouth or tongue;
• if the patient has severe kidney disease (creatinine clearance less than 30 ml/min) or anuria (absence of urine output);
• after 3 months of pregnancy (Cazacombi should also be avoided in early pregnancy - see section "Pregnancy and breastfeeding");
• if the patient has diabetes or kidney dysfunction and is being treated with a blood pressure-lowering medicine containing aliskiren;
• if the patient has taken or is currently taking sacubitril with valsartan, a medicine used to treat certain types of chronic heart failure in adults, because the risk of angioedema (rapid swelling of tissues beneath the skin, such as in the throat) increases.

If any of the above situations apply, Cazacombi must not be taken.
In case of doubt, consult a doctor or pharmacist before using Cazacombi.

Warnings and precautions

Before starting Cazacombi, discuss with your doctor or pharmacist if:

• the patient has heart disease – Cazacombi should not be used in patients with certain heart conditions;
• the patient has previously had a stroke or impaired blood flow to the brain;
• the patient has severe liver disease or jaundice;
• the patient has kidney disease or impaired blood flow to the kidneys, known as renal artery stenosis;
• the patient is undergoing dialysis;
• the patient has recently experienced vomiting or diarrhoea;
• the patient is on a low-salt (low-sodium) diet;
• the patient is undergoing desensitisation to bee or wasp venom;
• the patient is scheduled for surgery (including dental surgery) – certain anaesthetics may lower blood pressure, potentially causing it to drop too low;
• the patient has fluid in the abdominal cavity (ascites);
• the patient has diabetes;
• the patient has collagenosis;
• the patient is undergoing low-density lipoprotein (LDL) apheresis using dextran sulfate;
• the patient has gout;
• the patient has porphyria;
• if the patient has previously had skin cancer or if unexpected skin changes occur during treatment. Treatment with hydrochlorothiazide, especially at high doses over a long period, may increase the risk of certain types of non-melanoma skin cancer and lip cancer. During treatment with Cazacombi, protect the skin from sunlight and UV radiation;
• if the patient has previously experienced breathing or lung problems (including pneumonia or fluid accumulation in the lungs) after taking hydrochlorothiazide. If the patient develops severe shortness of breath or breathing difficulties after taking Cazacombi, seek immediate medical help;
• if the patient experiences visual disturbances or eye pain. These may be symptoms of fluid accumulation in the vascular layer surrounding the eye (excessive fluid accumulation between choroid and sclera) or increased intraocular pressure – these may occur from several hours to weeks after taking Cazacombi. If left untreated, they may lead to permanent vision loss. Patients with prior allergy to penicillin or sulfonamides may be at higher risk of developing this condition;
• the patient is taking any of the following medicines, which increase the risk of angioedema (rapid swelling under the skin, e.g. in the throat):
  • racecadotril, a medicine used to treat diarrhoea;
  • temsirolimus, sirolimus, everolimus, and other medicines belonging to the mTOR inhibitor class (used to prevent organ transplant rejection and in cancer treatment);
  • vildagliptin, a medicine used to treat diabetes;
• the patient is taking any of the following medicines used to treat high blood pressure:
  • an angiotensin II receptor antagonist (ARB) (also known as sartans – e.g. valsartan, telmisartan, irbesartan), especially if the patient has kidney dysfunction related to diabetes;
  • aliskiren.

Your doctor may monitor kidney function, blood pressure, and blood electrolyte levels (e.g. potassium) at regular intervals.
See also information under the heading "When not to use Cazacombi".

Inform your doctor if you are pregnant, suspect you may be pregnant, or are planning pregnancy. Cazacombi is not recommended during early pregnancy and must not be used after 3 months of pregnancy, as it may seriously harm the unborn child (see section "Pregnancy and breastfeeding").

Children and adolescents

Cazacombi is not recommended for use in children and adolescents under 18 years of age.

Cazacombi and other medicines

Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken, or plan to take. This includes medicines without a prescription and herbal medicines. This is because Cazacombi may affect the action of other medicines, and some medicines may affect the action of Cazacombi.

In particular, inform your doctor or pharmacist if you are taking any of the following medicines:

• all medicines used to treat high blood pressure;
• non-steroidal anti-inflammatory drugs (NSAIDs) – including acetylsalicylic acid, indomethacin, and ibuprofen;
• insulin or other medicines used to treat diabetes;
• lithium (used to treat depression);
• corticosteroids (such as hydrocortisone, prednisolone, and dexamethasone) or other medicines that suppress the immune system;
• potassium supplements or salt substitutes containing potassium, potassium-sparing diuretics (water tablets, especially those that conserve potassium), and other medicines that may increase potassium levels in the body (such as trimethoprim and co-trimoxazole, also known as trimethoprim with sulfamethoxazole, used for bacterial infections; cyclosporine, an immunosuppressive medicine used to prevent organ transplant rejection; and heparin, a medicine used to thin the blood to prevent clots);
• diuretics;
• sympathomimetics;
• anaesthetics, opioids;
• tricyclic antidepressants, antipsychotics;
• gold compounds (used to treat rheumatoid arthritis);
• medicines used for heart failure or heart rhythm disorders;
• calcium supplements and vitamin D;
• cholestyramine/colestipol (used to lower blood fat levels);
• anticholinergic medicines;
• cytotoxic medicines (e.g. methotrexate, cyclophosphamide);
• iodine-containing contrast agents (given before certain radiological examinations);
• certain muscle relaxants;
• amantadine;
• medicines often used to prevent organ transplant rejection (sirolimus, everolimus, and other mTOR inhibitors). See section "Warnings and precautions".

Your doctor may need to adjust the dose and/or take additional precautions:

• if the patient is taking an angiotensin II receptor antagonist (ARB) or aliskiren (see also information under "When not to use Cazacombi" and "Warnings and precautions").

Cazacombi with food and drink

Cazacombi can be taken during or independent of meals.
Inform your doctor or pharmacist if you are taking potassium supplements.

Pregnancy and breastfeeding

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a baby, she should consult a doctor or pharmacist before using this medicine.

Pregnancy

Inform your doctor if you suspect (or are planning) pregnancy. Your doctor will usually recommend discontinuing Cazacombi before a planned pregnancy or immediately after pregnancy is confirmed, and will recommend an alternative medicine. Cazacombi is not recommended during early pregnancy and must not be used after 3 months of pregnancy, as it may seriously harm the unborn child.

Breastfeeding

Inform your doctor if you are breastfeeding or intend to breastfeed. Cazacombi is not recommended during breastfeeding, especially when breastfeeding a newborn or premature infant. Your doctor may recommend an alternative medicine.

Driving and using machines

Dizziness may occur while taking Cazacombi. This is more likely at the beginning of treatment. If the patient experiences dizziness, driving, using tools, or operating machinery should be avoided.

Cazacombi contains lactose monohydrate and sodium

If the patient has been informed by a doctor that they have an intolerance to certain sugars, they should consult their doctor before taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially "sodium-free".

3. How to take Cazacombi

This medicine should always be taken as directed by a doctor or pharmacist. If in doubt,
consult a doctor or pharmacist.
The recommended dose is 1 tablet per day, taken daily.
Taking the medicine
The tablet should be swallowed whole with water.
The time of day when Cazacombi is taken does not matter. However, this medicine should be taken
every day at approximately the same time.
Cazacombi may be taken before or after food.
Tablets must not be crushed or chewed.
Taking more Cazacombi than recommended
If you take more Cazacombi than recommended or if someone else takes the medicine,
contact a doctor immediately or go to the nearest hospital.
Bring the medicine packaging with you. The following symptoms may occur: dizziness, feeling of
"emptiness" in the head, shallow breathing, cold and clammy skin, inability to move or speak,
and slow or irregular heartbeat.
Missing a dose of Cazacombi

• If you miss a dose, skip the missed dose. Then take the next dose at your usual time.
• Do not take a double dose to make up for a missed dose.

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

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Serious adverse reactions:
If a serious reaction called angioedema occurs, stop using Cazacombi and seek medical advice immediately. Symptoms include:

• sudden swelling of the face, throat, lips or mouth, which may cause difficulty breathing or swallowing.

Blood disorders reported during treatment with ACE inhibitors and thiazide diuretics include:

• Low number of red blood cells (anaemia). Symptoms include tiredness, paleness, fast or irregular heartbeat (palpitations), and shortness of breath.
• Low number of all types of white blood cells. Symptoms include increased number of infections, for example in the mouth, gums, throat and lungs.
• Low number of platelets. Symptoms include easy bruising and nosebleeds.

Other possible adverse reactions:
Common (may affect up to 1 in 10 patients):

• dizziness
• cough
• nausea
• fatigue
• headache

Uncommon (may affect up to 1 in 100 patients):

• low blood pressure. This may cause weakness, dizziness or a feeling of "emptiness" in the head, blurred vision and fainting. Excessive lowering of blood pressure in some patients may increase the risk of myocardial infarction or stroke.
• rapid heartbeat, palpitations
• weakness
• chest pain
• breathing difficulties, including shortness of breath and chest tightness
• nasal leakage or congestion and sneezing (rhinitis)
• dryness or swelling of the oral mucosa, mouth pain
• loss of appetite
• altered taste
• diarrhoea and vomiting
• rash (which may be severe)
• muscle cramps or muscle or joint pain
• impotence
• excessive sweating
• sudden flushing (especially of the face)
• sleep disturbances
• decreased number of red blood cells, white blood cells or platelets, detected in blood tests (anaemia, neutropenia, agranulocytosis and thrombocytopenia)
• abnormal electrolyte levels (sodium, potassium, chloride, magnesium, calcium, bicarbonate) or increased glucose, uric acid, cholesterol and triglyceride levels, detected in blood tests
• a type of severe allergic reaction (anaphylaxis)
• cerebral ischaemia, transient ischaemic attack, ischaemic stroke (may occur when blood pressure is too low)
• myocardial infarction (may occur when blood pressure is too low)
• heart rhythm disorders
• interstitial lung disease
• pulmonary oedema
• lupus-like disorder
• tingling or numbness of hands or feet
• wheezing
• bronchitis
• feeling of fullness or pulsating pain behind the nose, cheeks and eyes (sinusitis)
• irritation of the tongue
• pancreatitis – symptoms include severe upper abdominal pain radiating to the back
• liver or kidney function disorders (detected in blood and urine tests)
• kidney disorders
• liver disorders, such as hepatitis or liver damage
• severe skin reactions, including blisters or skin peeling
• increased sensitivity to light
• hair loss (which may be temporary)
• loosening or separation of the nail from the nail bed
• breast enlargement in men
• depression
• confusion
• dry eyes
• yellow vision

Very rare (may affect up to 1 in 10,000 patients):

• acute respiratory failure (symptoms include severe shortness of breath, fever, weakness and confusion).

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

• malignant skin and lip tumours (non-melanoma skin cancer)
• visual impairment or eye pain due to increased pressure (possible symptoms of fluid accumulation in the uvea, the vascular layer surrounding the eye – excessive fluid accumulation between choroid and sclera – or acute angle-closure glaucoma)

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 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 this medicine.

5. How to store Cazacombi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging (after the abbreviation
EXP). The expiry date refers to the last day of the stated month.
This medicine should be stored in its original packaging to protect it from moisture.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Cazacombi contains

• The active substances are cilazapril and hydrochlorothiazide. Each coated tablet contains 5 mg of cilazapril (in the form of cilazapril monohydrate) and 12.5 mg of hydrochlorothiazide.
• The other components are sodium stearyl fumarate, talc, lactose monohydrate, hypromellose, and corn starch in the tablet core; and hypromellose, talc, titanium dioxide (E 171), and iron oxide red (E 172) in the tablet coating. See section 2, "Cazacombi contains lactose monohydrate and sodium".

What Cazacombi looks like and contents of the pack
Pink, oval, biconvex coated tablets measuring 10.5 mm x 5.5 mm.
Packaging: 28 or 30 coated tablets in blisters, packed in a cardboard box.
Marketing Authorisation Holder and Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia