Zinadiur

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

ZINADIUR 5 mg +6.25 mg film-coated tablets, 10 mg +12.5 mg film-coated tablets, 20 mg +25 mg film-coated tablets

Benazepril hydrochloride + Hydrochlorothiazide
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. 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. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What ZINADIUR is and what it is used for

ZINADIUR is a combination of two medicines called benazepril hydrochloride and hydrochlorothiazide.
Benazepril hydrochloride belongs to a group of medicines known as “ACE inhibitors” (Angiotensin-Converting Enzyme inhibitors). It works by:

• Reducing the body's production of substances that may cause an increase in blood pressure
• Relaxing and dilating blood vessels, thereby lowering blood pressure and increasing blood flow from the heart

Hydrochlorothiazide belongs to a group of medicines called “thiazide diuretics”. It works by promoting the formation and elimination of urine, which leads to a reduction in blood pressure.
ZINADIUR is used to treat hypertension (i.e. high blood pressure). The two active ingredients work together to lower blood pressure. They are used in combination when treatment with either component alone is not sufficient.

2. What you should know before taking ZINADIUR

DO NOT take ZINADIUR:

• If you are allergic to benazepril, hydrochlorothiazide, or any of the excipients of this medicine (see section 6)
• If you are allergic to medicines similar to ZINADIUR (other ACE inhibitors or sulfonamide-derived medicines). Signs of an allergic reaction may include hoarseness (change in normal voice), swelling of the lips, face, throat, hands or feet, difficulty swallowing or breathing
• If you have previously had a severe allergic reaction (angioedema) with swelling of the face, eyelids, lips or tongue after taking ACE inhibitor medicines
• If you have severe liver problems
• If you have severe kidney problems (creatinine clearance < 30 ml/min)
• If you have low levels of salts (potassium, sodium) in the blood
• If you have or have had high levels of uric acid in the blood (gout or history of gout)
• During the second and third trimesters of pregnancy, i.e. after the third month (see section below “Pregnancy and breastfeeding”)
• If you have diabetes or impaired kidney function and are being treated with a blood pressure-lowering medicine containing aliskiren
• If you have taken or are taking sacubitril/valsartan, a medicine used to treat chronic heart failure in adults, as this increases the risk of angioedema (rapid swelling under the skin, for example in the throat)

Talk to your doctor or pharmacist before taking ZINADIUR.
Warnings and precautions
Talk to your doctor or pharmacist before taking ZINADIUR:

• If you have high levels of calcium in the blood (shown by a blood test)
• If you have low levels of phosphates or magnesium in the blood (shown by a blood test)
• If you have diabetes, gout or high cholesterol, as thiazide diuretics, at high doses, may reduce glucose tolerance and increase levels of cholesterol, triglycerides and uric acid in the blood
• If you are taking potassium-containing salt substitutes or potassium-sparing diuretics
• If you have a cough
• If you are about to undergo general anaesthesia for surgery or dental procedures. You may need to stop treatment with ZINADIUR the day before; consult your doctor
• If a doctor has told you that you have narrowing of the heart's aortic valve (aortic stenosis) or of the heart's mitral valve (mitral stenosis)
• If you have undergone, or are about to undergo, desensitisation therapy for allergy to bee or wasp stings
• If you require haemodialysis (a procedure to purify the blood by filtration) with certain high-flux membranes, as reactions to the type of membrane used may occur
• If you have lost significant amounts of salts or body fluids (due to illness such as vomiting, diarrhoea, following a low-salt diet, long-term use of oral diuretics, dialysis, or heart failure). In such circumstances, treatment should be started under strict medical supervision
• If you have low blood pressure. A brief period of low blood pressure does not constitute a contraindication to continuing treatment
• If you experience a decrease in vision (acute transient myopia) or eye pain. These may be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or increased pressure in the eye (secondary angle-closure glaucoma), and may occur from a few hours to weeks after taking ZINADIUR. If untreated, these may lead to permanent vision damage. If you previously had an allergic reaction to penicillin or sulfonamides, you may be more likely to develop these symptoms
• If a doctor has told you that you have narrowing of the renal artery or if you have reduced kidney function, as this may cause an increase in blood urea. In this case, your doctor will perform tests to monitor blood urea levels both during the first weeks of treatment and subsequently at regular intervals. Therefore, your doctor may decide to reduce your dose of ZINADIUR
• If you have a "collagen disease" such as systemic lupus erythematosus, especially if associated with reduced kidney function
• If you have reduced liver function, which could lead to hepatic coma. If jaundice occurs (yellowing of the skin and whites of the eyes), stop treatment and contact your doctor immediately
• If you have reduced tolerance to sugars
• If you are taking any of the following medicines used to treat high blood pressure:
• an "angiotensin II receptor antagonist" (AIIRA) (also known as sartans – for example valsartan, telmisartan, irbesartan), especially if you have kidney problems related to diabetes
• Aliskiren
  • If you are taking any of the following medicines, the risk of angioedema may be increased:
• Racecadotril, a medicine used to treat diarrhoea
• Medicines used to prevent rejection of transplanted organs and to treat cancer (such as temsirolimus, sirolimus, everolimus)
• Vildagliptin, a medicine used to treat diabetes
  • If you have previously had skin cancer or if you develop an unexpected skin lesion during treatment. Treatment with hydrochlorothiazide, particularly long-term use at high doses, may increase the risk of certain types of non-melanoma skin cancer and lip cancer. Protect your skin from sun and UV exposure while taking ZINADIUR.
  • If you have had respiratory or lung problems (including inflammation or fluid in the lungs) after taking hydrochlorothiazide in the past. If you develop shortness of breath or severe breathing difficulty after taking ZINADIUR, consult a doctor immediately.

Your doctor may check your kidney function, blood pressure, and levels of electrolytes (e.g. potassium) in your blood at regular intervals.
See also the section "DO NOT take ZINADIUR".
Due to the diuretic present in ZINADIUR, levels of sodium and potassium in the blood may decrease.
This may cause dry mouth, thirst, weakness, drowsiness, irritability, fatigue or muscle pain, hypotension, nausea, or rapid heartbeat. Low potassium levels in the blood may exaggerate the cardiac response to digitalis and are more likely to occur in patients with hepatic cirrhosis and in those concurrently treated with corticosteroids or ACTH. Therefore, blood tests should be performed at the beginning and periodically during treatment.
Treatment with thiazide diuretics may activate systemic lupus erythematosus.
Other metabolic disturbances
Thiazide diuretics such as hydrochlorothiazide may reduce glucose tolerance in diabetic patients.
Adjustments in insulin or oral hypoglycaemic agent dosage may be required. Latent diabetes mellitus may become apparent during treatment with thiazide diuretics.
Close monitoring of patients with diabetes mellitus is required: avoid large fluctuations in blood glucose levels. Symptoms of hypoglycaemia may be masked.
Black patients
It has been observed that the incidence of angioedema (characterised by swelling of the face, lips, tongue, throat or sudden breathing difficulty) during ACE inhibitor therapy is higher in black patients of African origin than in those of other races.
For athletes
Use of the drug without therapeutic need constitutes doping and may lead to a positive result in anti-doping tests.
Other medicines and ZINADIUR
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicine, as it may be necessary to adjust doses or, in some cases, discontinue one of the medicines.
In particular, inform your doctor or pharmacist if you are taking:

• Other medicines to lower blood pressure, called "antihypertensives" (e.g. alpha-blockers, beta-blockers, calcium antagonists);
• Medicines to reduce cholesterol levels in the blood;
• Potassium supplements (including salt substitutes), potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), and other medicines that may increase potassium levels in the blood (such as trimethoprim and cotrimoxazole for treating bacterial infections; cyclosporine, an immunosuppressant used to prevent rejection of transplanted organs; and heparin, a medicine used to thin the blood and prevent clotting);
• Lithium (a medicine for psychiatric conditions);
• Corticosteroids (medicines to treat inflammation);
• Medicines for diabetes such as oral hypoglycaemics (medicines to reduce blood sugar levels) and insulin;
• Medicines used to relieve pain and inflammation, e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs);
• Digoxin (a medicine for heart problems, including heart rhythm disorders);
• Curare derivatives (medicines used for general anaesthesia and intensive care);
• Vitamin D;
• Cytotoxic medicines (anticancer medicines);
• Allopurinol (a medicine for treating gout);
• Amantadine (a medicine used for Parkinson's disease);
• Carbamazepine (for the treatment of epilepsy);
• Anticholinergic medicines (medicines for treating allergies and respiratory diseases);
• Neprilysin inhibitors (NEP) such as sacubitril (available in fixed-dose combination with valsartan), used to treat chronic heart failure in adults (see section “Do not take ZINADIUR”);
• Vildagliptin (a medicine used to treat diabetes) (see section “Warnings and precautions”);
• Medicines used to prevent rejection of transplanted organs and to treat cancer (e.g. temsirolimus, sirolimus, everolimus) (see section “Warnings and precautions”);
• Racecadotril (used to treat diarrhoea) (see section “Warnings and precautions”).

Concomitant administration of ZINADIUR and non-steroidal anti-inflammatory drugs (NSAIDs) (concomitant therapy) may reduce the antihypertensive effect and increase the risk of worsening kidney function, including possible acute kidney failure and elevated potassium levels in the blood, especially in patients with pre-existing kidney impairment. This combination should be used with caution, particularly in the elderly. Patients should be adequately hydrated and kidney function should be monitored at the start of concomitant therapy.
Your doctor may consider it necessary to adjust the dose and/or take other precautions.
If you are taking an angiotensin II receptor antagonist (AIIRA) or aliskiren (see sections "Do not take ZINADIUR" and "Warnings and precautions").
ZINADIUR with food, drinks and alcohol

• Drinking alcohol together with ZINADIUR may reduce the effectiveness of ZINADIUR and cause dizziness or lightheadedness. Discuss with your doctor how much alcohol you may drink while taking ZINADIUR. Alcohol increases the effects of blood pressure medicines.
• ZINADIUR may be taken before, during or after meals.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before using this medicine.
Pregnancy
The use of ZINADIUR is not recommended during the first trimester of pregnancy.
Do not take ZINADIUR during the second and third trimesters (see section “Do not take ZINADIUR”).
You must inform your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant).
Treatment with ZINADIUR should not be started during pregnancy.
Your doctor will usually advise you to stop taking ZINADIUR before becoming pregnant or as soon as pregnancy is confirmed, and will recommend an alternative medicine unless continuing treatment with an ACE inhibitor is considered essential. ZINADIUR is not recommended in early pregnancy, as there may be a slight increased risk of teratogenicity. ZINADIUR must not be taken if you are more than three months pregnant, as it may cause serious harm to the unborn child if taken after the third month of pregnancy (see section “Do not use ZINADIUR”).
If exposure to an ACE inhibitor occurs after the first trimester of pregnancy, your doctor will recommend an ultrasound examination to assess fetal renal and cranial function, and will subsequently monitor the newborn for risk of hypotension (low blood pressure).
Breastfeeding
Inform your doctor if you are breastfeeding or planning to breastfeed.
Breastfeeding of newborns (first weeks after birth), and especially premature infants, is not recommended while taking ZINADIUR. Your doctor will evaluate the benefits to you and the risks to the newborn associated with taking ZINADIUR during breastfeeding, and may recommend an alternative treatment if you wish to breastfeed.
Driving and using machines
You may experience dizziness while taking ZINADIUR. If this occurs, do not drive or operate tools or machinery.
ZINADIUR contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.
ZINADIUR contains castor oil
It may cause gastrointestinal disturbances and diarrhoea.

3. How to take ZINADIUR

Take this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor or pharmacist.
Taking this medicine

• Take the tablets by mouth at the same time each day (before, during, or after meals).
• Swallow the tablets with a liquid.
• The tablets may be swallowed whole or split in half (for divisible tablets).

How much to take
Your doctor may adjust your dose until your blood pressure is under control. The usual initial dose of ZINADIUR recommended for patients with mild to moderate hypertension is 5 mg + 6.25 mg once daily.
Most patients respond to a daily dose of 10 mg + 12.5 mg.
To achieve further blood pressure reduction, after 3 or 4 weeks, the dose may be increased up to 20 mg + 25 mg once daily.
The maximum recommended daily dose is 40 mg + 50 mg of ZINADIUR, divided into two administrations.
Another antihypertensive medicine may be added, but not a diuretic.
In patients already treated with diuretics who are to switch to ZINADIUR, diuretic therapy should be discontinued at least 3 days before starting ZINADIUR.
High blood pressure often does not cause specific symptoms. Therefore, carefully follow your doctor's instructions and do not change the dose or the way you take the medicine without consulting your doctor.
Children and adolescents
ZINADIUR is not recommended for children and adolescents under 18 years of age, as this medicine has not been studied in this age group.
If you take more ZINADIUR than you should
If very high doses of ZINADIUR are taken, severe dizziness and/or fainting may occur; severe or persistent nausea, vomiting or diarrhoea; unusual tiredness, weakness, muscle cramps; cardiac arrhythmias.
Contact your doctor immediately. While waiting for medical help, it is advisable to induce vomiting and then lie down with your legs raised.
If you forget to take ZINADIUR

• If you forget a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and continue with your regular schedule.
• Do not take a double dose to make up for the missed tablet.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Most of the side effects observed in clinical studies were mild to moderate in intensity, non-serious, and resolved without discontinuing treatment.
Stop taking ZINADIUR and contact your doctor immediately if you notice any severe side effect – you may need urgent medical treatment:

• Swelling of the face, eyes, lips, or throat causing difficulty in swallowing or breathing. This could be a sign of a severe allergic reaction to ZINADIUR
• Yellowing of the skin (jaundice) and whites of the eyes

Inform your doctor as soon as possible if you experience:

• Dizziness, lightheadedness (especially during the first days of treatment) or fainting
• Sore throat, fever, or chills. These may be symptoms of changes in blood composition
• Abdominal pain with nausea, vomiting, and fever. These could be signs of pancreatitis (inflammation of the pancreas)
• Numbness or tingling in hands, feet, or lips; skin rashes with or without itching
• Chest pain
• Skin reactions (e.g., blisters), sometimes painful
• Haemolytic anaemia (low haemoglobin concentration in the blood)

Other side effects include:
Common (affects less than 1 in 10 people)

• Dry and persistent cough (especially at night)
• Stomach upset
• Fast heartbeat
• Skin flushing
• Hives
• Itching
• Flu-like symptoms
• Headache
• Fatigue
• Frequent need to urinate
• Increased sensitivity of the skin to sunlight
• Loss of appetite
• Erectile dysfunction
• Orthostatic hypotension (sudden drop in blood pressure when standing up from a sitting or lying position), which may be worsened by concomitant intake of alcohol, anaesthetics, or sedatives

Uncommon (affects less than 1 in 100 people)

• Acute renal failure (kidney problems)

Rare (affects less than 1 in 1000 people treated)

• Diarrhoea, nausea
• Nervousness
• Sleep disturbances
• Loss of taste
• Ringing in the ears
• Joint pain
• Muscle pain
• Blurred vision
• Hypokalaemia
• Somnolence
• Dizziness
• Anxiety
• Constipation
• Increased uric acid, blood urea nitrogen, and serum creatinine levels
• Angina pectoris
• Arrhythmias
• Hepatitis
• Pemphigus (an autoimmune disorder affecting skin and mucous membranes)
• Decreased platelet count (sometimes with purpura)
• Depression
• Visual disturbances
• Intrahepatic cholestasis

Very rare (affects less than 1 in 10,000 people treated)

• Hyponatraemia
• Tinnitus
• Dysgeusia
• Myocardial infarction
• Stevens-Johnson syndrome
• Worsening of kidney function
• Decreased white blood cell count
• Bone marrow depression
• Necrotizing vasculitis
• Breathing difficulties, including pneumonia and pulmonary oedema
• Toxic epidermal necrolysis, cutaneous lupus erythematosus-like skin reactions, reactivation of cutaneous lupus erythematosus
• Acute respiratory distress (signs include severe shortness of breath, fever, weakness, and confusion)

Not known (frequency cannot be estimated from available data)

• Renal failure and worsening of kidney function (kidney problems)
• Severe skin reactions (erythema multiforme)
• Fever
• Muscle cramps
• Decreased vision (acute myopia) and eye pain due to increased intraocular pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma)
• Weakness
• Decreased production of all blood cells (aplastic anaemia)
• Increased blood sugar levels (hyperglycaemia)
• Glucose excretion in urine
• Worsening metabolic status in diabetic patients
• Hyperkalaemia
• Decreased count of certain types of white blood cells (agranulocytosis, neutropenia)
• Angioedema of the small intestine
• Skin and lip cancer (non-melanoma skin cancer)
• Worsening of psoriasis (a skin disease causing red, itchy, scaly patches, most commonly on knees, elbows, trunk, and scalp)

Hydrochlorothiazide may cause metabolic disturbances, especially at high doses. It may increase blood sugar levels and cause glucose excretion in urine in diabetic patients and other susceptible individuals.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store ZINADIUR

Do not store above 25 °C.
Keep in the original packaging.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the container after "Exp.". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What ZINADIUR contains
ZINADIUR 5 mg + 6.25 mg film-coated tablets
Active substances: benazepril hydrochloride 5 mg + hydrochlorothiazide 6.25 mg;
Other components: hydrogenated castor oil (see section 2 "ZINADIUR contains castor oil"); lactose (see section 2 "ZINADIUR contains lactose"); crospovidone, hypromellose; macrogol; talc; titanium dioxide.
ZINADIUR 10 mg + 12.5 mg film-coated tablets
Active substances: benazepril hydrochloride 10 mg + hydrochlorothiazide 12.5 mg;
Other components: hydrogenated castor oil (see section 2 "ZINADIUR contains castor oil"); lactose (see section 2 "ZINADIUR contains lactose"); crospovidone, hypromellose, red iron oxide (E172); macrogol; talc; titanium dioxide.
ZINADIUR 20 mg + 25 mg film-coated tablets
Active substances: benazepril hydrochloride 20 mg + hydrochlorothiazide 25 mg;
Other components: hydrogenated castor oil (see section 2 "ZINADIUR contains castor oil"); lactose (see section 2 "ZINADIUR contains lactose"); crospovidone, hypromellose, red iron oxide (E172); macrogol; talc; titanium dioxide.

Description of the appearance of ZINADIUR and package contents
PVC blisters with aluminium foil lidding, sealed onto an aluminium backing; or aluminium blisters; or PVC/PE/PVDC blisters sealed onto an aluminium backing.
ZINADIUR 5 mg + 6.25 mg film-coated tablets are white, oval-shaped, film-coated tablets. Pack size: 14 film-coated tablets.
ZINADIUR 10 mg + 12.5 mg film-coated tablets are light pink, oval-shaped, film-coated tablets. Pack sizes: 14 and 28 film-coated tablets.
ZINADIUR 20 mg + 25 mg film-coated tablets are red, oval-shaped, film-coated tablets. Pack size: 14 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Errekappa Euroterapici S.p.A. – Via Ciro Menotti 1/A – 20129 Milan – Italy
Under licence from: Meda Pharma S.p.A.

Manufacturer
FAMAR ITALIA S.p.A. – Via Zambeletti, 25 – Baranzate (MI) – Italy
Special Product’s Line S.p.A., Via Fratta Rotonda Vado Largo 1 – 03012 Anagni (FR), Italy