Acediur

OK for variation N1B/2017/965 and N1B/2015/4623

Package leaflet: Information for the user

ACEDIUR 50 mg + 25 mg tablets, 50 mg + 15 mg tablets

Captopril + 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 others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. WHAT ACEDIUR IS AND WHAT IT IS USED FOR

ACEDIUR contains the active substances captopril (belonging to the pharmacological class of ACE inhibitors, medicines used to lower blood pressure) and hydrochlorothiazide (a diuretic medicine belonging to the sulfonamides, which increases urine production, resulting in lowering of blood pressure).
ACEDIUR is used in adults for the treatment of essential hypertension (elevated blood pressure due to causes not yet identified).
The combination of captopril/hydrochlorothiazide is indicated for patients whose blood pressure is not adequately controlled with captopril alone or with hydrochlorothiazide alone.

2. WHAT YOU NEED TO KNOW BEFORE TAKING ACEDIUR

Do not take ACEDIUR

• if you are allergic to captopril or any other ACE inhibitor; if you are allergic to hydrochlorothiazide or other sulfonamide-derived drugs, or to any of the other ingredients of this medicine (listed in section 6);
• if you have previously experienced angioedema (sudden swelling of subcutaneous and submucosal tissues) associated with prior therapy with ACE inhibitors;
• if you have hereditary/idiopathic angioedema (of unknown origin);
• if you suffer from severe renal impairment (reduced kidney function with creatinine clearance less than 30 ml/min);
• if you suffer from severe hepatic impairment (reduced liver function);
• if you have diabetes or impaired renal function and are being treated with a blood pressure-lowering medicine containing the active substance aliskiren;
• if you are in the second or third trimester of pregnancy (see "Pregnancy, breastfeeding and fertility").

Warnings and precautions
Talk to your doctor or pharmacist before taking ACEDIUR if any of the following apply to you:

• 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 (see “Do not take ACEDIUR”);

• if you are taking any of the following medicines, the risk of angioedema (rapid subcutaneous swelling in areas such as the throat) is increased: sirolimus, everolimus, and other medicines belonging to the class of mTOR inhibitors (used to prevent rejection of transplanted organs);

• if you have arterial hypertension due to reduced blood flow to one or both kidneys, if you have pathological narrowing of a renal artery (in case of a single functioning kidney) or of both renal arteries; in these cases, treatment should be initiated under strict medical supervision with low doses, cautious dose adjustment, and monitoring of renal function;

• if you have had aortic and mitral stenosis (pathological narrowing of the aorta and one of the four valves inside the heart), obstructive hypertrophic cardiomyopathy (marked thickening of the heart walls, causing obstruction to normal blood flow), or cardiogenic shock (shock following heart failure);

• if you are undergoing desensitization therapy (administration of increasing doses of a substance causing allergic reactions until the body no longer reacts); allergic reactions, sometimes severe, have been reported in people treated with medicines like Acediur who underwent such desensitization; talk to your doctor before undergoing such desensitization procedures;

• if you have diabetes and have previously been treated with oral antidiabetics or insulin, Acediur may affect the action of insulin or other anti-diabetic medicines; consult your doctor;

• if you are scheduled for major surgery or treatments with anesthetics known to cause a drop in blood pressure;

• if you suffer from any liver disorder; thiazide diuretics should be used with caution in case of hepatic dysfunction or progressive liver disease, as even minor changes in fluid or electrolyte balance may lead to hepatic coma; discontinue treatment with ACEDIUR and seek specific medical evaluation if you develop jaundice (yellowing of the skin, sclerae, and mucous membranes) or marked increases in liver enzymes during treatment;

• if you suffer from any kidney disorder; in patients with kidney disease, thiazide diuretics (such as hydrochlorothiazide) may cause hyperazotemia; accumulation of the drug may also occur; if you have previously had kidney disease, urinary protein levels (dip-stick test on first morning urine) should be assessed before treatment and periodically thereafter; proteinuria (presence of proteins in urine) may occur, particularly if you have pre-existing renal dysfunction or are on relatively high doses of Acediur;

• if you are undergoing dialysis; allergic-type reactions have been reported in hemodialyzed patients using high-flux dialysis membranes (i.e., capable of removing medium-sized toxins), undergoing dextran-sulfate adsorption apheresis (removal of low-density lipoproteins), who are taking medicines like Acediur;

• if you experience reduced vision (transient myopia) or eye pain in one or both eyes while taking Acediur; this could be a sign that you are developing glaucoma (increased pressure in one or both eyes); in this case, stop treatment and consult a doctor;

• if you suffer from allergies, bronchial asthma, systemic lupus erythematosus (a chronic disease that can affect various organs and tissues of the body, in which the immune system produces responses directed against the body's own components) or lupus-like disorders;

• if you are taking potassium supplements, potassium-containing salt substitutes, potassium-sparing diuretics, or other medicines associated with increased potassium levels (e.g., heparin); in some patients treated with ACE inhibitors, including captopril, increased blood potassium levels have been observed;

• if hypotension (low blood pressure) occurs; hypotension has rarely been observed in patients with uncomplicated hypertension; symptomatic hypotension is more likely if you have hypertension and reduced volume (i.e., reduced amount of water in the body) and/or sodium due to intensive diuretic therapy, dietary salt restriction, diarrhea, vomiting, or hemodialysis; volume and/or sodium depletion should be corrected before administering an ACE inhibitor, and a lower initial dose should be considered; as with other antihypertensives, excessive blood pressure reduction in patients with cardiovascular ischemic disease may increase the risk of myocardial infarction or stroke;

• if angioedema (sudden swelling of subcutaneous or submucosal tissues in extremities, face, lips, tongue, glottis, or larynx) develops; in this case, you must stop treatment immediately;

• if cough develops; persistent dry cough has been reported with the use of Acediur, which resolves upon discontinuation of therapy;

• if neutropenia (decreased number of neutrophils, a type of white blood cell), agranulocytosis (severe decrease in granulocyte count), thrombocytopenia (decreased platelet count), or anemia (reduced hemoglobin level) occur. Use captopril with extreme caution if:

• you have collagen diseases (structural protein fundamental to connective tissue);

• you are on immunosuppressants (medicines that reduce or block immune response), allopurinol (a medicine that reduces uric acid formation), or procainamide (a medicine used to treat cardiac rhythm abnormalities);

• if you have a combination of these risk factors, especially in the presence of pre-existing renal dysfunction (see “Other medicines and ACEDIUR”).

In these cases, severe infections may develop, which sometimes do not respond to intensive antibiotic therapy.
In such situations, if you take captopril, it is recommended to perform white blood cell count and differential leukocyte count before starting therapy, every two weeks during the first three months of captopril therapy, and then periodically.
Thiazide diuretics, including hydrochlorothiazide, may cause water-electrolyte imbalance: hypokalemia (i.e., decreased potassium levels in blood), hyponatremia (i.e., decreased sodium levels in blood), and hypochloremic alkalosis (i.e., decreased blood acidity due to reduced chloride levels). Warning signs of water-electrolyte imbalance include dry mouth (area from mouth to throat), thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, fatigue, hypotension, oliguria (reduced urine output), tachycardia (increased heart rate), and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalemia may occur with thiazide diuretics, concomitant therapy with captopril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis (severe liver disease), polyuric patients (producing large amounts of urine), patients receiving inadequate electrolyte intake (i.e., insufficient intake of minerals such as calcium, magnesium, potassium, sodium), and patients receiving concomitant corticosteroids or ACTH (see “Other medicines and ACEDIUR”).
Dilutional hypokalemia may occur in patients with edema (fluid accumulation) during very hot weather. Chloride deficiency is usually mild and normally does not require treatment.
Thiazide diuretics may reduce urinary calcium excretion and cause intermittent and mild elevation of serum calcium levels in the absence of confirmed calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism (increased parathyroid function). Thiazide treatment should be discontinued before performing parathyroid function tests.
Thiazide diuretics have been shown to increase urinary magnesium excretion, which may result in hypomagnesemia (decreased magnesium levels in blood).
Your doctor may monitor your kidney function, blood pressure, and blood electrolyte levels (e.g., potassium) at regular intervals. See also information under “Do not take ACEDIUR”.
Medicines containing lithium should not be taken with Acediur without careful medical monitoring.
If you experience any of the following problems, contact your doctor immediately

• severe dizziness or fainting, which could be symptoms due to excessive lowering of blood pressure;
• swelling of arms, legs, ankles, face, lips, tongue, and/or throat, with difficulty swallowing or breathing;
• cough;
• jaundice (yellowing of skin/eyes);
• increased levels of cholesterol, triglycerides (fats), and uric acid in blood;
• decreased number of white blood cells, platelets, or reduced hemoglobin level;
• any signs of infection (such as sore throat or fever) that do not respond promptly to usual treatment;
• dry mouth (area from mouth to throat);
• thirst;
• weakness;
• lethargy;
• drowsiness;
• restlessness;
• muscle pain or cramps;
• fatigue;
• reduced urine output (oliguria);
• gastrointestinal disturbances such as nausea or vomiting;
• rapid heartbeat (tachycardia).

Captopril may cause false positive results in urine tests for acetone.
It may also interfere with tests for diagnosing pancreatic diseases (bentiromide test) and may reduce serum levels of proteins that bind iodinated thyroid hormones without signs of thyroid dysfunction.
Inform the following people that you are taking Acediur:

• medical staff if hospitalized, especially the anesthetist (if undergoing surgery);
• your dentist before dental anesthesia.

Children and adolescents
The safety and efficacy of ACEDIUR in children have not been established.
For those engaged in sports activities: using the drug without therapeutic need constitutes doping and may result in a positive outcome in anti-doping tests.
Other medicines and ACEDIUR
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
This is particularly important if you are also taking:

• medicines usually used to prevent rejection of transplanted organs (sirolimus, everolimus, and other medicines belonging to the class of mTOR inhibitors). See section “Warnings and precautions”;
• potassium supplements or potassium-containing salt substitutes, diuretics (tablets that promote urination, particularly so-called potassium-sparing diuretics), other medicines that may increase potassium levels in the body (including heparin and co-trimoxazole, also known as trimethoprim/sulfamethoxazole).

If concomitant use is indicated due to evident hypokalemia, they should be used cautiously with frequent monitoring of blood potassium levels (see “Warnings and precautions”).

• other diuretics; prior treatment with high doses of diuretics may lead to volume depletion (i.e., reduced water and sodium) and risk of hypotension (excessive drop in blood pressure) when starting captopril therapy; hypotensive effects may be reduced by discontinuing the diuretic, increasing volume or salt intake, or starting therapy with low doses of captopril; however, in specific studies conducted with hydrochlorothiazide or furosemide (molecules belonging to the diuretic category), no clinically significant pharmacological interactions were observed;
• medicines used to treat acute myocardial infarction; captopril may be used together with acetylsalicylic acid (at cardiologic doses), thrombolytics (a category of medicines capable of dissolving pathological blood clots), beta-blockers and/or nitrates (medicines used for heart and vascular conditions) in patients with myocardial infarction;
• antihypertensive medicines; concomitant use may increase the hypotensive effects of Acediur; 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 also “Do not take ACEDIUR” and “Warnings and precautions”);
• nitroglycerin and other nitrates or other vasodilators;
• medicines used to treat psychiatric conditions and some antidepressants; ACE inhibitors may enhance the hypotensive effects of certain tricyclic antidepressants and antipsychotics, leading to postural hypotension;
• allopurinol (a medicine that reduces uric acid formation), procainamide (a medicine used to treat cardiac rhythm abnormalities), cytostatics (anti-neoplastic medicines that inhibit and combat tumor development), or immunosuppressive agents (medicines that reduce or block immune response); concomitant administration of ACE inhibitors may increase the risk of leukopenia (decreased white blood cell count), especially when these are used at higher than normally recommended doses (see “Warnings and precautions”);
• sympathomimetic medicines (medicines that stimulate the autonomic nervous system), which may reduce the antihypertensive effects of ACE inhibitors;
• medicines used for diabetes; ACE inhibitors, including captopril, may enhance the hypoglycemic effects of insulin and antidiabetic medicines;
• parenteral amphotericin B (antifungal), carbenoxolone (anti-ulcer), corticosteroids (anti-inflammatory), corticotropin (or ACTH, a hormone important for cortisol synthesis), or stimulant laxatives (medicines capable of increasing intestinal motility and secretion); hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalemia;
• calcium salts; when administered concomitantly with thiazide diuretics, increased serum calcium concentration may occur due to reduced calcium excretion;
• cardiac glycosides (digitalis, medicines that increase heart function); diuretic-induced hypokalemia increases the risk of digitalis toxicity;
• cholestyramine and colestipol (medicines that reduce blood cholesterol); these medicines may delay or reduce absorption of hydrochlorothiazide. Take ACEDIUR at least one hour before or four to six hours after these medicines;
• muscle relaxants (used to relieve muscle spasms, e.g., tubocurarine chloride);
• medicines associated with torsade de pointes (a severe form of cardiac arrhythmia); due to the risk of reduced potassium levels in blood, caution should be exercised when administering ACEDIUR together with medicines associated with torsade de pointes, such as certain antiarrhythmics, antipsychotics, and other medicines known to induce torsade de pointes.
• Lithium: The combination of captopril and hydrochlorothiazide with lithium is not recommended. Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and potentiate the already elevated risk of lithium toxicity with ACE inhibitors. Careful monitoring of serum lithium levels should be performed if the combination is necessary.
• Non-steroidal anti-inflammatory drugs (NSAIDs): When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (e.g., selective COX-2 inhibitors such as celecoxib or valdecoxib, acetylsalicylic acid at doses ≥325 mg/day, and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, and increased blood potassium levels, especially in patients with pre-existing impaired renal function.
Use ACEDIUR with caution, especially if you are elderly. You should be adequately hydrated, and monitoring of renal function should be considered at the start of concomitant therapy.
ACEDIUR and alcohol
As with other antihypertensives, the ability to drive vehicles and operate machinery may be reduced when ACEDIUR is used in combination with alcohol, but these effects depend on individual susceptibility.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Do not take ACEDIUR during pregnancy. Exposure to ACE inhibitors during the second and third trimesters of pregnancy
causes fetal toxicity (reduced renal function, reduced amniotic fluid volume, delayed skull ossification) and neonatal effects (renal failure, hypotension, increased blood potassium levels).
If exposure to an ACE inhibitor occurs from the second trimester of pregnancy, an ultrasound assessment of renal function and skull development is recommended.
If you are planning a pregnancy, you should switch to alternative antihypertensive treatments with a proven safety profile in pregnancy, unless continuation of ACE inhibitor therapy is considered essential.
Breastfeeding
Inform your doctor if you are breastfeeding or planning to breastfeed. The use of ACEDIUR during breastfeeding is not recommended. If ACEDIUR is taken during breastfeeding, doses should be kept as low as possible.
Driving and using machines
As with other antihypertensives, the ability to drive vehicles and use machines may be reduced, for example at the beginning of treatment, when dosage is changed, and also when used in combination with alcohol, but these effects depend on individual susceptibility.
ACEDIUR 50 mg + 25 mg tablets and ACEDIUR 50 mg + 15 mg tablets contain lactose. If your doctor has diagnosed you with an intolerance to certain sugars, contact him/her before taking this medicine.
ACEDIUR 50 mg + 25 mg tablets contain the colorant E110, which may cause allergic reactions.

3. HOW TO TAKE ACEDIUR

Take this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
In patients whose blood pressure is not adequately controlled with captopril alone or hydrochlorothiazide alone, ACEDIUR may be taken before or after meals, either as a single daily dose or divided into two doses.
Do not exceed the maximum daily dose of 100 mg captopril/30 mg hydrochlorothiazide, equivalent to 1 tablet of ACEDIUR 50/25 mg or 2 tablets of ACEDIUR 50/15 mg per day.
If satisfactory reduction in blood pressure is not achieved, additional antihypertensive treatment may be added (see “Other medicines and ACEDIUR”).

Adults
Administration of ACEDIUR is usually recommended after gradual dose titration of the individual components.
The usual maintenance dose is 50/25 mg (1 tablet of ACEDIUR 50/25 mg) once daily in the morning.
When clinically appropriate, a direct switch from monotherapy (treatment with a single medicine) to fixed-dose combination (ACEDIUR) may be considered.
The 25/25 mg dose may be administered once daily in patients whose blood pressure is not adequately controlled with hydrochlorothiazide 25 mg monotherapy, and prior to titration (dose adjustment) of captopril.
The 50/25 mg and 25/25 mg doses should be taken as a single tablet daily, since taking two tablets would result in an inappropriate overdose of hydrochlorothiazide (50 mg/day).
The 50/15 mg dose may be used at the start of fixed-combination therapy in patients whose blood pressure is not adequately controlled with captopril 50 mg monotherapy and/or when a lower dose of hydrochlorothiazide is preferred.

Renal impairment
In case of reduced renal function (creatinine clearance between 30 and 80 ml/min), the usual initial dose is 25/12.5 mg (half a tablet of ACEDIUR 50/25 mg) once daily in the morning.
The combination of captopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Special populations
In patients with salt or volume depletion (reduced levels of salts or of water and sodium), elderly patients, and diabetic patients, the usual initial dose is 25/12.5 mg (half a tablet of ACEDIUR 50/25 mg) once daily.

Children and adolescents
The safety and efficacy of ACEDIUR in children have not been established.

Duration of treatment
As prescribed by the physician.

If you take more ACEDIUR than you should
If you take too much medicine, contact your doctor immediately or go to the nearest hospital.
In case of overdose with ACEDIUR, symptoms may include increased diuresis, electrolyte imbalance, severe hypotension, decreased level of consciousness (including coma), seizures, paresis (partial loss of muscle movement), cardiac arrhythmias (irregular heart rhythm), bradycardia (slow heart rate), and renal failure.
If ingestion was recent, measures to prevent absorption should be taken, such as gastric lavage (stomach emptying and washing), administration of adsorbents, and sodium sulfate within thirty minutes of ingestion, and elimination should be accelerated.
If hypotension occurs, the patient should be placed in Trendelenburg position (supine with the bed tilted 20–30° so that the head is lower than the pelvis and lower limbs) and fluids and sodium chloride should be administered rapidly. Treatment with angiotensin II may be considered.
Marked bradycardia and severe vagal reactions should be treated with atropine. Pacemaker use may be considered. Continuous monitoring of fluid balance, electrolytes, acid-base balance, and blood glucose is essential. In case of hypokalemia, potassium supplementation is required.
Captopril can be removed from the circulation by dialysis. The extent of hydrochlorothiazide removal by hemodialysis has not been established.

If you forget to take ACEDIUR
Do not take a double dose to make up for the missed dose.
If you have any questions about how to use this medicine, consult your doctor or pharmacist.

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
CAPTOPRIL
Adverse reactions reported with captopril and/or ACE inhibitor therapy include:

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

• Sleep disturbances;
• Altered taste, dizziness;
• Itching with or without redness, skin rash (sudden reddening of the skin), and alopecia (hair loss);
• Dry, irritating (non-productive) cough (see "Warnings and precautions") and dyspnea (difficulty breathing);
• Nausea, vomiting, gastric irritation, abdominal pain, diarrhea, constipation, dry mouth.

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

• Tachycardia (rapid heartbeat) or tachyarrhythmia, angina pectoris (chest pain caused by insufficient oxygenation of the heart muscle due to a temporary reduction in blood flow), palpitations;
• Chest pain, fatigue, malaise;
• Angioedema (see "Warnings and precautions");
• Hypotension (see "Warnings and precautions"), Raynaud's syndrome (characterized by excessive constriction of blood vessels), flushing, pallor.

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

• Anorexia (loss or reduced appetite);
• Drowsiness, headache, and paresthesia (altered sensation in limbs or other body parts);
• Renal dysfunction including renal failure, polyuria, oliguria, pollakiuria (frequent urination of small amounts of urine);
• Stomatitis (inflammation of the mucous membrane of the oral cavity), aphthous ulcerations (painful mouth ulcers).

Very rare adverse reactions (may affect up to 1 in 10,000 people)

• Hyperkalemia, hypoglycemia (decreased blood glucose concentration) (see "Warnings and precautions");
• Proteinuria, hyponatremia, hyperazotemia (see "Warnings and precautions"), eosinophilia (elevated concentration of eosinophil white blood cells in the blood), hypercreatininemia (elevated blood creatinine concentration), hyperbilirubinemia (elevated blood bilirubin concentration);
• Confusion, depression;
• Cerebrovascular events, including stroke and syncope (transient, rapidly onset loss of consciousness caused by reduced blood flow to the brain, short in duration and resolving spontaneously);
• Blurred vision;
• Cardiac arrest, cardiogenic shock;
• Urticaria (more or less itchy skin rash characterized by the appearance of roundish skin elevations, pinkish or sometimes pale in color, which disappear more or less rapidly), Stevens-Johnson syndrome (severe acute hypersensitivity reaction in which the skin and mucous membranes react to a medicine or infection), erythema multiforme (skin condition characterized by inflammation of blood vessels due to white blood cells), photosensitivity (excessive reaction to light), erythroderma (skin condition characterized by widespread and uniform redness associated with scaling or appearance of blisters), pemphigoid reactions (skin disease with appearance of large blisters), and exfoliative dermatitis (skin inflammation with peeling);
• Myalgia (muscle pain), arthralgia (joint pain);
• Nephrotic syndrome (see "Warnings and precautions");
• Impotence, gynecomastia (development of breast tissue in men);
• Fever;
• Decreased hemoglobin, hematocrit (blood test indicating the percentage of blood volume occupied by blood cells), leukocytes (white blood cells), platelets, positive antinuclear antibodies (a broad category of autoantibodies, i.e., antibodies produced by the body against itself, associated with numerous autoimmune diseases such as Lupus), elevated ESR (blood test analyzing the sedimentation rate of red blood cells);
• Glossitis (inflammation of the tongue), peptic ulcer (erosion of the inner lining of the stomach or intestine), pancreatitis (inflammation of the pancreas);
• Hepatic dysfunction and cholestasis (including jaundice), hepatitis including necrosis, increased liver enzymes and bilirubin;
• Bronchospasm, rhinitis (irritation and inflammation of nasal mucosa), allergic alveolitis (lung disease with cough and breathing difficulty originating from inhalation of an antigen to which the subject has been previously sensitized), eosinophilic pneumonia (inflammation of interstitial lung tissue);
• Neutropenia/agranulocytosis (see "Warnings and precautions"), pancytopenia (reduction in the number of all blood cells), especially in patients with renal dysfunction (see "Warnings and precautions"), anemia (including aplastic and hemolytic anemia), thrombocytopenia, lymphadenopathy, eosinophilia, autoimmune diseases and/or positive antinuclear antibodies.

HYDROCHLOROTHIAZIDE
Adverse reactions with unknown frequency (frequency cannot be estimated from available data)

• Sialadenitis (inflammation of the salivary glands);
• Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic and hemolytic anemia, bone marrow depression;
• Anorexia, hyperglycemia (elevated blood glucose concentration), glycosuria (loss of glucose in urine), hyperuricemia (high concentration of uric acid in blood), electrolyte imbalance (including hyponatremia and hypokalemia), increased cholesterol and triglycerides (fats);
• Restlessness, depression, sleep disturbances;
• Loss of appetite, paresthesias, sensation of light-headedness;
• Xanthopsia (visual disturbance involving yellow vision of white objects), transient blurred vision, acute myopia (visual defect causing observed objects to appear blurred), and acute secondary angle-closure glaucoma (eye disease caused by other eye or general conditions, characterized by reduced angle between cornea and iris leading to obstruction of aqueous humor outflow, i.e., the fluid between cornea and lens);
• Dizziness;
• Postural hypotension, cardiac arrhythmias;
• Necrotizing vasculitis (inflammation of blood vessels, cutaneous vasculitis);
• Respiratory disorders (including pneumonia and pulmonary edema);
• Gastric irritation, diarrhea, constipation, pancreatitis;
• Jaundice (intrahepatic cholestatic jaundice);
• Photosensitivity reactions, redness, lupus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions (severe, rapidly occurring allergic reactions), epidermotoxic necrolysis (serious skin disease induced by an allergy to certain medicines, characterized by destruction of skin epithelium and mucous membranes) (see "Warnings and precautions");
• Muscle spasms;
• Renal dysfunction, interstitial nephritis;
• Fever, weakness.

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

5. HOW TO STORE ACEDIUR

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of that month.
Do not store above 30°C.
Do not dispose of any medicine 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 PACKAGE AND OTHER INFORMATION

What ACEDIUR contains
ACEDIUR 50 mg + 25 mg tablets
Each tablet contains:
Active substances: captopril 50 mg + hydrochlorothiazide 25 mg.
Other components: microcrystalline cellulose, pregelatinized starch, lactose monohydrate, magnesium stearate, stearic acid and colour E 110.

ACEDIUR 50 mg + 15 mg tablets
Each tablet contains:
Active substances: captopril 50 mg + hydrochlorothiazide 15 mg.
Other components: microcrystalline cellulose, pregelatinized starch, lactose monohydrate, magnesium stearate, stearic acid.

Description of the appearance of ACEDIUR and contents of the pack
ACEDIUR 50 mg + 25 mg tablets
Tablets, oval, biconvex, pink in colour with a break line on one side. The tablet can be divided into two equal doses.
Pack containing 12 tablets in a blister.

ACEDIUR 50 mg + 15 mg tablets
Tablets, oval, biconvex, white in colour.
Pack containing 12 tablets in a blister.

Marketing Authorisation Holder
A. Menarini Industrie Farmaceutiche Riunite s.r.l., Via Sette Santi, 3 – Florence, Italy.

Manufacturer
A. Menarini Manufacturing Logistics and Services s.r.l., Campo di Pile - L'Aquila, Italy.
Menarini Von Heyden GmbH, Leipziger Strasse 7-13, Dresden, Germany.

This leaflet was last updated on