ACESISTEM - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Acesistem - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Enalapril (Enalapril maleate), Hydrochlorothiazide

Acesistem 20 mg / 12.5 mg tablets

Indications Why is Acesistem used? What is it for?

Acesistem contains the active substances enalapril and hydrochlorothiazide.

Enalapril belongs to a group of medicines called angiotensin converting enzyme inhibitors (ACE inhibitors), and it works by widening blood vessels to make it easier for the heart to pump blood to all parts of the body.

Hydrochlorothiazide belongs to the group of medicines called diuretics and works by promoting the elimination of a greater amount of water and salts through the kidneys, with consequent lowering of blood pressure. Together, enalapril and hydrochlorothiazide help reduce high blood pressure.

Acesistem is indicated for the treatment of high blood pressure (hypertension) in those patients whose blood pressure is not adequately controlled with enalapril alone.

Contraindications When Acesistem should not be used

Do not take Acesistem:

if you are allergic to enalapril, hydrochlorothiazide or any of the other ingredients of this medicine;
if you have ever had allergic reactions, with swelling of the face, lips, tongue and / or throat, with difficulty in swallowing and breathing, after previous treatment with other angiotensin converting enzyme inhibitors (ACE inhibitors);
if you have hereditary or idiopathic angioedema (ie without an apparent cause);
if you are allergic to any sulphonamide-derived medicines (ask your doctor if you are not sure what sulphonamide-derived medicines are);
if you do not urinate (anuria);
if you have severely impaired kidney function;
if you are more than three months pregnant (It is better to avoid ACESISTEM even in the early phase of pregnancy, see sections "Warnings and precautions" and "Pregnancy and breastfeeding");
if you have severe liver impairment; if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren (see section "Other medicines and ACESISTEM").

Precautions for use What you need to know before taking Acesistem

Talk to your doctor or pharmacist before taking Acesistem.

Tell your doctor:

if you are over 70 years of age;
if you think you are pregnant or are planning to become pregnant because he will prescribe another medicine instead of Acesistem. Acesistem is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that stage (see sections "Do not take Acesistem" and "Pregnancy and breastfeeding");
if you have or have had vomiting and / or diarrhea;
if you are being treated with diuretics (medicines that increase the amount of water and salts excreted by the kidneys);
if you are taking a special type of diuretics called potassium-sparing diuretics, if you are using potassium supplements, medicines that increase potassium levels in your blood or potassium-containing salt substitutes (see section "Other medicines and Acesistem");
if you are on a low sodium diet;
if you have or have ever had liver problems (see section 2 "Do not take Acesistem");
if you have "kidney failure or are undergoing hemodialysis (see section 2" Do not take Acesistem ");
if you have a narrowing or blockage of the blood vessels that carry blood to the kidneys (bilateral renal artery stenosis or artery stenosis of the only functioning kidney);
if you have kidney problems due to diabetes (diabetic nephropathy);
if you have recently had a kidney transplant;
if you urinate frequently;
if you are using corticosteroids, adrenocorticotropic hormone (hormone medicines);
if you have a collagen disease affecting your blood vessels (e.g. lupus erythematosus, rheumatoid arthritis), if you are being treated with medicines that suppress the immune response, if you are taking the medicines allopurinol or procainamide, or any combination of these conditions ;
if you have or have had an allergic condition, asthma or a condition that causes joint pain, redness of the skin and fever (systemic lupus erythematosus);
if you have ever had allergic reactions which may occur for example with swelling of the face, lips, mouth or throat (angioedema);
if you have heart or brain problems, especially:
- a "heart failure.
- a disease caused by reduced blood flow in the blood vessels of the heart (ischemic cardiovascular disease) or a disease caused by impaired blood circulation in the brain (cerebrovascular disease).
- a narrowing of the valves of the heart (aortic stenosis) or a condition causing thickening of the heart muscle (hypertrophic cardiomyopathy).
- acute heart failure.
if your doctor has told you that your blood acidity is higher than normal (metabolic acidosis);
if you have diabetes;
if you are dehydrated;
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 - eg valsartan, telmisartan, irbesartan,), particularly if you have diabetes-related kidney problems.
- aliskiren

Your doctor may check your kidney function, blood pressure and the amount of electrolytes (for example potassium) in your blood at regular intervals. See also information under the heading "Do not take Acesistem". - if you are to undergo treatment to reduce the effects of an "allergy to bee or wasp stings (desensitization treatment);

if you are to undergo treatment to remove cholesterol from your blood by means of machinery (low density lipoprotein apheresis - LDL);
if you are due to have surgery or anesthesia. The anesthetist should be informed that you are being treated with Acesistem;
if you are due to undergo an examination to evaluate the function of the parathyroid glands (parathyroid function), because treatment with Acesistem must be stopped before this examination;

Tell your doctor during treatment with Acesistem:

if you have diabetes and notice hypoglycaemia.
if you develop allergic reactions which may occur for example with swelling of the face, lips, mouth or throat. Black patients have a higher risk of developing these reactions.
has a dry and persistent cough because it could be due to one of the active ingredients contained in Acesistem.
if you have symptoms of altered salt levels eg. dry mouth, thirst, muscle weakness and pain, muscle cramps, tiredness, drowsiness, restlessness, low blood pressure, increased heart rate, decreased urine output and stomach or bowel upset such as nausea and vomiting.
if you have any signs of infection.

If you are a black patient it is important that you know that medicines like Acesistem may be less effective in lowering your blood pressure. Children and adolescents Acesistem should not be given to children and adolescents.

Interactions Which drugs or foods can modify the effect of Acesistem

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Tell your doctor if you are using or should use the following medicines:

other medicines to lower blood pressure as they can further reduce blood pressure
diuretics (medicines that increase the amount of water and salts excreted by the kidneys) eg. furosemide
nitroglycerin, other nitrates and medicines that work by widening blood vessels (vasodilating agents)
medicine used to treat changes in the rhythm of the heart, for example:
- quinidine
- procainamide
- amiodarone
- sotalol
medicines for depression (antidepressants)
medicines used in severe psychiatric disorders (antipsychotics)
medicines used for anesthesia
barbiturates (medicine for epilepsy)
medicines for diabetes eg. insulin and other oral medicines
medicines that retain potassium or that can increase potassium levels:
- potassium supplements
- salt substitutes containing potassium
- medicines to lower blood pressure called potassium sparing eg. amiloride, eplerenone, triamterene, spironolactone
lithium (medicine for mood disorders)
non-steroidal anti-inflammatory drugs eg. l "acetylsalicylic acid
cholestyramine and colestipol (medicines to lower blood cholesterol)
corticosteroids, adrenocorticotropic hormone (hormone medicines)
noradrenaline
medicines that relax the muscles e.g. tubocurarine
medicines against cancer eg. cyclophosphamide, methotrexate
medicines that affect the heart (digitalis glycosides e.g. digitalis)
laxatives
carbenoxolone (ulcer medicine)
sodium aurothiomalate, used in gold therapy and given by injection
opioid analgesics (medicines used to reduce pain)

Your doctor may need to change your dose and / or take other precautions:

if you are taking an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also information under "Do not take Acesistem and" Warnings and precautions ")

Acesistem with food, drink and alcohol

Do not drink alcohol while taking Acesistem, as a sharp fall in blood pressure can occur, particularly when standing up (orthostatic hypotension).

Most people take Acesistem with a glass of water.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Acesistem is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that time. Tell your doctor if you think you are pregnant. o you are planning to become pregnant because you will be prescribed another medicine instead of Acesistem.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. Acesistem is not recommended during breastfeeding unless your doctor considers it strictly necessary.

If you wish to breastfeed, your doctor may prescribe another treatment instead of Acesistem.

Driving and using machines

Acesistem can cause dizziness and tiredness, take special care if you have to drive or use machines.

Acesistem contains lactose (a milk sugar)

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

For those who carry out sports activities

The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

Dose, Method and Time of Administration How to use Acesistem: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Your doctor will work out the appropriate dose of Acesistem, based on your disease and the other medicines you are taking. It is very important that you continue to take Acesistem for as long as your doctor has told you as this will keep your blood pressure under control. Do not take more tablets than your doctor has told you.

The recommended starting dose of treatment is half a tablet per day.

The usual dose is 1 tablet per day, if necessary your doctor can then tell you to increase the dose to 2 tablets per day, in a single dose.

Most people take this medicine with a glass of water.

If you are being treated with a diuretic, your doctor will tell you to stop it a few days before starting treatment with Acesistem. If this is not possible, the doctor will decide whether to start therapy with Acesistem with lower doses.

Use in patients with kidney problems

The use of Acesistem is not recommended for patients with kidney problems (renal failure).

If you forget to take Acesistem

Do not take a double dose to make up for a forgotten tablet.

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

If you stop taking Acesistem

Do not stop taking this medicine unless your doctor tells you to.

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

Overdose What to do if you have taken an overdose of Acesistem

In case of accidental ingestion of an overdose of Acesistem, notify your doctor immediately or go to the nearest hospital.

If you (or someone else) have taken too much of this medicine, the following symptoms may occur:

excessive lowering of blood pressure (marked hypotension, associated with blockade of the renin-angiotensin system);
daze;
severe circulation problems (circulatory shock);
altered blood salt levels (electrolyte disturbances such as hypokalaemia, hypochloremia, hyponatremia);
severe kidney problems (kidney failure);
increased breathing rate (hyperventilation);
increased or decreased heart rate (tachycardia, bradycardia);
increased perception of heartbeat (palpitations);
dizziness
anxiety;
cough;
fluid loss (dehydration), due to excessive passing of urine (diuresis).

Side Effects What are the side effects of Acesistem

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Acesistem and contact your doctor immediately if you develop:

swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing or swallowing
swelling of the hands, feet or ankles • hives

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

Blurred vision
Dizziness
Cough
Nausea
Muscle weakness

Common (may affect up to 1 in 10 people)

Diarrhea, abdominal pain
Muscle cramps
Headache
Tiredness
Depression
Fainting
Reduction or increase in potassium levels in the blood
Increase in cholesterol and fats (triglycerides) in the blood
Increases in blood uric acid levels
Changes in taste
Reduction in blood pressure, particularly when standing up
Heart rhythm disturbances
Chest pain (angina pectoris
Chest pain
Difficulty in breathing
Rashes on the skin, allergic reactions
Swelling of the face, tongue, lips and extremities
Increase in blood creatinine levels

Uncommon (may affect up to 1 in 100 people)

Anemia
Reduction in magnesium levels in the blood
Flushes
Gout
Pain in the joints
Whistling and ringing in the ears
Reduction in blood sugar levels
Nervousness, confusion, insomnia, sleepiness
Changes in the sensation of the limbs or other parts of the body (paraesthesia)
Dizziness
Heart attack, palpitations
Cerebrovascular accident (TIA, "mini-stroke")
Sore throat, voice change (hoarseness), runny nose, asthma
Inflammation of the pancreas (pancreatitis), vomiting, difficult digestion, constipation, loss of appetite, stomach irritation, dry mouth, stomach injury (peptic ulcer), excess gas in the stomach or intestines (flatulence)
Alteration of intestinal motility (ileus)
Hives, itching, sweating
Hair loss
Impaired kidney function, including kidney failure, accumulation of substances in the blood that should be excreted via the kidneys (uremia), presence of proteins in the urine
Reduction of sodium levels in the blood
Decreased sexual desire, impotence
General feeling of not feeling well (malaise), fever

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

Reduction of white blood cells
Reduction in the number of platelets in the blood
Reduction in the number of all blood cells (pancytopenia)
Bone marrow depression - a decrease in the number of blood cells caused by a malfunction in the system that produces blood cells
Enlarged lymph nodes
Diseases of the immune system (autoimmune diseases)
Decrease in blood cell levels (hematocrit) and hemoglobin levels
Increased blood sugar levels
Abnormality of dreams, sleep disturbances
Partial loss of voluntary muscle motility and sensation
Poor blood circulation in the limbs (Raynaud's phenomenon)
Lung problems, including pneumonia, water in the lungs (which causes difficulty in breathing), alveolitis caused by allergy, cold
Inflammation of the mucous membrane of the mouth, mouth ulcers and canker sores, inflammation of the tongue
Liver problems including liver failure, inflammation of the liver (hepatitis), yellowing of the skin, mucous membranes and eyes (jaundice), inflammation of the gallbladder and death of liver cells which can be potentially fatal
Increase in liver enzyme levels (sign of liver damage)
Increase in bilirubin levels
Severe allergic reactions with high fever, red patches on the skin (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, purpura), severe skin rash with loss of skin and hair (exfoliative dermatitis), lupus erythematosus, rash on peeling skin (erythroderma), appearance of small fluid-filled blisters on the skin (pemphigus) • Reduced urine output (oliguria) • Acute inflammation of the kidney (interstitial nephritis)
Breast enlargement in males (gynecomastia)

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

Increased calcium levels (hypercalcemia)
Swelling from fluid accumulation of the intestine (intestinal angioedema).

Not known (frequency cannot be estimated from the available data)

Syndrome due to abnormal secretion of antidiuretic hormone (SIADH)

Other possible side effects

A symptom complex which may include:

fever
inflammation of a particular type of membrane that lines some organs (serositis)
inflammation of blood vessels
pain in muscles, joints and bones
Elevated ESR (visible in blood tests)
increase in the number of particular types of white blood cells in the blood (eosinophilia, leukocytosis)
Skin reactions including skin reactions to sunlight

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at "www.agenziafarmaco.it/it/responsabili". By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

This medicine does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What Acesistem contains

The active ingredients are enalapril maleate and hydrochlorothiazide. Each tablet contains 20 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide.
The other ingredients are sodium bicarbonate, lactose monohydrate, yellow iron oxide, maize starch, pregelatinised starch, magnesium stearate.

Description of the appearance of Acesistem and contents of the package

Each pack contains a blister of 14 or 28 tablets.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Acesistem is available in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ACESISTEM 20 MG + 12.5 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide.

Excipient with known effects:

One tablet contains 141.3 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of hypertension in patients for whom the therapeutic combination is indicated.

04.2 Posology and method of administration

ACESISTEM contains 20 mg enalapril maleate, and 12.5 mg hydrochlorothiazide.

Dosage

Hypertension

It is advisable to start therapy with ½ tablet a day.

In hypertension the usual dosage is 1 tablet, given once a day. If necessary, the dosage can be increased to 2 tablets, given once a day.

Previous diuretic therapy

In patients already being treated with diuretics, the use of enalapril may lead to marked hypotensive responses. In these patients, if the combination is necessary, it is important if possible to stop the diuretic a few days before administering enalapril. If this is not possible, it is essential to start therapy with enalapril at low doses (usually 2.5 mg). In these circumstances, a fixed dose combination is not appropriate; it can be used later when the titration of the individual components has demonstrated the need for dosages present in the ACESISTEM tablet.

Dosages in renal insufficiency

Thiazides may be inappropriate diuretics for use in patients with renal impairment and are ineffective with creatinine clearance values of 30 ml / min or less (ie in the presence of moderate or severe renal impairment).

In patients with creatinine clearance> 30 e

Pediatric population

Safety and efficacy in children have not been established.

Therefore, the use of the product is not recommended in pediatric age.

Elderly patients

In clinical studies, the efficacy and tolerability of enalapril maleate and hydrochlorothiazide administered concomitantly were similar in elderly and younger patients.

04.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

• Severe renal insufficiency (creatinine clearance ≤ 30 ml / min).

• Anuria.

• History of angioneurotic edema associated with previous treatment with an ACE inhibitor.

• Hereditary or idiopathic angioedema.

• Hypersensitivity to sulfonamide-derived drugs.

• Second and third trimester of pregnancy (see sections 4.4 and 4.6).

• Severe hepatic insufficiency.

• The concomitant use of ACESISTEM with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR 2) (see sections 4.5 and 5.1).

04.4 Special warnings and appropriate precautions for use

Enalapril maleate-Hydrochlorothiazide

Hypotension and hydroelectrolytic imbalance

Symptomatic hypotension is rarely observed in hypertensive patients without complications. In hypertensive patients treated with ACESISTEM, symptomatic hypotension is more likely to occur in case of depletion of the patient's blood volume, eg following therapy with diuretics, low-sodium diet, diarrhea or vomiting (see sections 4.5 and 4.8). Regular measurement of serum electrolytes should be performed at appropriate intervals in these patients. Particular attention should be paid to patients with ischemic cardiac or cerebrovascular disease in whom excessive hypotension may result in myocardial infarction or a cerebrovascular accident. Symptomatic hypotension has been observed in hypertensive patients with heart failure with or without associated renal failure.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, be given intravenous infusion with saline. A transient hypotensive response is not a contraindication to the administration of further doses, which can usually be given without difficulty after an increase in blood pressure due to volume expansion.

Impaired renal function

ACESISTEM should not be administered to patients with renal insufficiency (creatinine clearance 30 ml / min) until titration of enalapril has shown the need for the dose present in this formulation (see section 4.2).

Some hypertensive patients with no apparent pre-existing renal disease have developed elevations in BUN and serum creatinine when enalapril was given concomitantly with a diuretic (see Special warnings and precautions for use, Enalapril Maleate, Impaired renal function; Hydrochlorothiazide, Impaired renal function in paragraph 4.4). If this occurs, ACESISTEM therapy should be discontinued. This circumstance should suggest the possibility of a stenosis of the basic renal artery (see Special warnings and precautions for use, Enalapril Maleate, Renovascular hypertension in paragraph 4.4).

Hyperkalemia

The combination of enalapril with a low-dose diuretic cannot exclude the possibility of hyperkalaemia (see Special warnings and precautions for use, Enalapril maleate, Hyperkalaemia in paragraph 4.4).

Lithium

The combination of lithium with enalapril and diuretics is generally not recommended (see section 4.5).

Lactose

ACESISTEM contains 141.3 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Enalapril maleate

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Aortic stenosis / Hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be administered with caution to patients with left ventricular outflow tract obstruction and should be avoided in case of cardiogenic shock and hemodynamically significant obstruction.

Impaired renal function

Renal failure has been reported in association with enalapril and has mainly occurred in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognized promptly and adequately treated, associated renal failure to enalapril therapy is usually reversible (see section 4.2 and Special warnings and precautions for use, Enalapril maleate-Hydrochlorothiazide, Impaired renal function; Hydrochlorothiazide, Impaired renal function in paragraph 4.4).

Renovascular hypertension

In patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney treated with ACE inhibitors, there is an increased risk of hypotension and renal failure. Loss of renal function can occur with only minor changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision and monitoring of renal function.

Kidney transplant

There is no experience with the administration of enalapril in patients with a recent kidney transplant. Treatment with enalapril is therefore not recommended.

Patients on hemodialysis

The use of enalapril is not indicated in patients requiring dialysis for renal insufficiency.

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (eg AN 69) and treated at the same time with an ACE inhibitor. For such patients, the use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered.

Hepatic insufficiency

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients taking ACE inhibitors and developing jaundice or marked elevations in liver enzymes should discontinue the ACE inhibitor and undergo appropriate medical follow-up (see Special warnings and precautions for use, Hydrochlorothiazide, Hepatopathy in paragraph 4.4).

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Enalapril should be used with extreme caution in patients with vascular collagen disease, immunosuppressive therapy, allopurinol or procainamide treatments or a combination of these complicating factors, especially if there is pre-existing renal impairment. Some of these patients have developed serious infections which in some cases have not responded to intensive antibiotic therapy.When enalapril is used in these patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any signs of infection.

Hyperkalemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalaemia include renal failure, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, particularly dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes; or taking other drugs associated with increases in serum potassium (eg, heparin). Particularly in patients with impaired renal function, the use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes can lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of enalapril and any of the above drugs is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see Special warnings and precautions for use, Enalapril maleate-Hydrochlorothiazide, Hyperkalaemia; Hydrochlorothiazide, metabolic and endocrine effects section 4.4 and section 4.5).

Diabetic patients

Diabetic patients treated with oral antidiabetics or insulin starting therapy with an ACE inhibitor should be advised to monitor closely for hypoglycaemia, especially during the first month of concomitant use (see Special warnings and precautions for use, Hydrochlorothiazide, Metabolic and endocrine effects section 4.4 and section 4.5).

Hypersensitivity / angioneurotic edema

Angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. This can occur at any time. during treatment. In such cases, ACESISTEM should be promptly discontinued and appropriate monitoring instituted to ensure complete resolution of symptoms before the patient is discharged. Even in cases where swelling is confined to the tongue alone, without respiratory distress, Patients may require prolonged observation as treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, deaths have been reported due to angioedema associated with laryngeal edema or tongue edema. In patients involving the tongue, glottis o the larynx is likely to experience airway obstruction, especially in those with a history of airway surgery.If there is involvement of the tongue, glottis or larynx, which is likely to cause an "airway obstruction, appropriate therapy such as epinephrine 1: 1000 subcutaneously (0.3 to 0.5 ml) should be promptly administered and / or the maintenance of a patent airway must be ensured.

In black patients treated with ACE inhibitors, a higher incidence of angioedema has been reported than in white patients. However, black patients generally appear to have an increased risk of angioedema.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema during treatment with an ACE inhibitor (see also section 4.3).

Anaphylactoid reactions during desensitization to hymenoptera

Rarely, patients on ACE inhibitor therapy have reported life-threatening anaphylactoid reactions during desensitization with hymenoptera venom. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.

Anaphylactoid reactions in the course of LDL apheresis

Rarely, patients on ACE inhibitor therapy have reported life-threatening anaphylactic reactions during low-density lipoprotein (LDL) apheresis with dextran sulfate. These reactions were avoided by temporarily interrupting ACE inhibitor therapy prior to each apheresis session.

Cough

Cough has been reported with the use of ACE inhibitors. Typically the cough is nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery / Anesthesia

Enalapril blocks the formation of angiotensin II and, therefore, impairs the ability to compensate through the renin-angiotensin system of patients undergoing major surgery or anesthesia with agents that cause hypotension. The hypotension that occurs due to this mechanism can be corrected by volume expansion (see section 4.5).

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy.

For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor therapy is considered essential. When pregnancy is diagnosed. , treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

The use of enalapril is not recommended during breastfeeding.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, enalapril is apparently less effective in lowering blood pressure in blacks than in non-blacks, possibly due to a higher prevalence of low-renin condition in the black hypertensive population. .

Hydrochlorothiazide

Impaired renal function

Thiazides may not be the appropriate diuretics for the treatment of patients with renal impairment and are ineffective at creatinine clearance values of 30 ml / min or less (i.e., moderate or severe renal impairment) (see section 4.2 and Special warnings and precautions for use, Enalapril maleate-Hydrochlorothiazide, Impaired renal function; Enalapril maleate, Impaired renal function in paragraph 4.4).

Hepatopathy

Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as slight changes in the water and electrolyte balance can precipitate hepatic coma (see Special warnings and precautions for use, Enalapril maleate, Hepatic impairment in section 4.4).

Metabolic and endocrine effects

Thiazide therapy can impair glucose tolerance. The dose of antidiabetic drugs, including insulin, may need to be adjusted (see Special warnings and precautions for use, Enalapril maleate, Diabetic patients in paragraph 4.4).

Therapy with thiazide diuretics may be associated with an increase in cholesterol and triglyceride levels; however, at the 12.5 mg dose of hydrochlorothiazide, minimal or no effects were reported. In addition, no clinically significant effects on glucose, cholesterol, triglycerides, sodium, magnesium or potassium were reported in clinical trials with 6 mg hydrochlorothiazide.

In some patients, thiazide therapy may be associated with the development of hyperuricaemia and / or gout. This hyperuricaemic effect appears to be dose related and is not clinically significant at the 6 mg dose of hydrochlorothiazide contained in NEOPREX. Furthermore, enalapril may increase the urinary excretion of uric acid and, therefore, attenuate the hyperuricaemic effect of hydrochlorothiazide.

Periodic measurement of serum electrolytes should be performed at appropriate intervals, as is the case for any patient treated with diuretics.

Thiazides (including hydrochlorothiazide) can cause electrolyte imbalance (hypokalaemia, hyponatremia, and hypochloraemic alkalosis). Warning signs of electrolyte imbalance are xerostomia, thirst, muscle fatigue, lethargy, drowsiness, restlessness, muscle pain or cramps oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.

Although hypokalaemia may occur during use of thiazide diuretics, concomitant therapy with enalapril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients with marked diuresis, in patients with inadequate oral intake of electrolytes, and in patients treated with concomitant therapy with corticosteroids or ACTH (see section 4.5).

Hyponatremia may occur in oedematous patients in climatic conditions of high temperature. Chloride deficiency is usually mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight increase in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be a sign of latent hyperparathyroidism. Thiazide treatment should be stopped before testing for parathyroid function.

Thiazides have been shown to increase urinary excretion of magnesium, which can result in hypomagnesaemia.

Anti-doping test

The hydrochlorothiazide contained in this medicinal product may give a positive result in anti-doping tests.

Hypersensitivity

In patients taking thiazides, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

04.5 Interactions with other medicinal products and other forms of interaction

Enalapril maleate-Hydrochlorothiazide

Other antihypertensive drugs

Concomitant use of these drugs may increase the hypotensive effects of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

Lithium

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 further increase lithium levels and increase the risk of lithium toxicity with ACE inhibitors.

The use of ACESISTEM with lithium is not recommended, but if the combination is necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Non-steroidal anti-inflammatory drugs

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor or may decrease the diuretic, natriuretic and antihypertensive effect of diuretics.

Concomitant administration of NSAIDs (including COX-2 inhibitors) and ACE inhibitors has an additive effect on the increase in serum potassium, and may result in deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur. , especially in patients with impaired renal function (such as the elderly or patients who are volume depleted, including those on diuretic therapy).

Enalapril maleate

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Potassium-sparing diuretics or potassium supplements

ACE inhibitors attenuate diuretic induced potassium loss. Potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated due to demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Diuretics (thiazides or loop diuretics)

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see sections 4.2 and 4.4). The hypotensive effects can be reduced by the discontinuation of diuretics, by the increase of the blood volume or by the intake of salts.

Tricyclic Antidepressants / Antipsychotics / Anesthetics

The concomitant use of some anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a further reduction in blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetic

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycemic drugs) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This effect appeared to occur more likely during the first weeks of combined treatment. and in patients with impaired renal function (see section 4.8).

Alcohol

Alcohol increases the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and beta-blockers

Enalapril can be safely administered concomitantly with acetylsalicylic acid (at cardiological doses), thrombolytics and beta-blockers.

Aurotherapy

Nitritoid reactions (symptoms of which include flushing of the face, nausea, vomiting and hypotension) have been reported rarely in patients receiving injectable gold (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including enalapril.

Hydrochlorothiazide

Non-depolarizing muscle relaxants

Thiazides can increase sensitivity to tubocurarine.

Alcohol, barbiturates, or opioid analgesics

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral and insulin)

Dose adjustment of the antidiabetic drug may be required (see section 4.8).

Resins of cholestyramine and colestipol

The presence of anionic exchange resins interferes with the absorption of hydrochlorothiazide. Single doses of cholestyramine or colestipol resins bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Drugs that cause a lengthening of the QT interval (eg quinidine, procainamide, amiodarone, sotalol)

Increased risk of torsade de pointes.

Digitalis glycosides

Hypokalaemia may sensitize or increase the heart's response to the toxic effects of digitalis (eg, increased ventricular irritability).

Corticosteroids, ACTH

Increased electrolyte depletion, especially hypokalaemia.

Kaliuretic diuretics (e.g. furosemide), carbenoxolone, or laxative abuse

Hydrochlorothiazide may increase the loss of potassium and / or magnesium.

Pressor amines (e.g., norepinephrine)

The effect of the pressor amines can be diminished.

Cytostatic drugs (e.g., cyclophosphamide, methotrexate)

Thiazides can reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

04.6 Pregnancy and breastfeeding

Pregnancy

ACE inhibitors

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded.

For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor therapy is considered essential.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitors during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women (see section 5.3).

Should exposure to an ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Neonates whose mothers have taken ACE inhibitors should be closely monitored for hypotension ( see sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on its mechanism of action, the use of hydrochlorothiazide during the second and third trimester of pregnancy can compromise fetal placental perfusion and can cause fetal and neonatal effects such as jaundice, electrolyte disturbances and thrombocytopenia.

Hydrochlorothiazide should not be used for the treatment of gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for the treatment of hypertension in pregnant women except in rare situations where no other treatment could be used.

Feeding time

Enalapril

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2).

Although these concentrations appear to be clinically irrelevant, the use of ACESISTEM in breastfeeding is not recommended for preterm infants and in the first few weeks after delivery, due to the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In older infants, if deemed necessary for the mother, ACESISTEM can be taken during breastfeeding, but in this case the infant must be followed for the possible occurrence of adverse effects.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in breast milk in small quantities. High-dose thiazide diuretics cause intense diuresis which can inhibit milk production. The use of ACESISTEM while breastfeeding is not recommended. If ACESISTEM is taken during breastfeeding, doses should be kept as low as possible.

04.7 Effects on ability to drive and use machines

When driving vehicles or using machines it should be taken into account that occasionally dizziness or tiredness may occur (see section 4.8).

04.8 Undesirable effects

Undesirable effects reported in clinical trials and post-marketing experience with ACESISTEM, enalapril alone or hydrochlorothiazide alone, include:

Very common (> 1/10); Common (> 1/100, 1 / 1,000, 1 / 10,000,

Disorders of the blood and lymphatic system

Uncommon: anemia (including aplastic and haemolytic anemia).

Rare: neutropenia, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy.

Disorders of the immune system

Common: hypersensitivity, angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx have been reported (see section 4.4).

Rare: autoimmune diseases.

Endocrine pathologies

Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Common: hypokalaemia, hyperuricaemia.

Uncommon: hypoglycaemia (see section 4.4), hypomagnesaemia, gout *.

Very rare: hypercalcaemia (see section 4.4).

Psychiatric disorders

Common: depression.

Uncommon: confusion, insomnia, nervousness, decreased libido *.

Rare: changes in dream activity, sleep disturbances.

Nervous system disorders

Common: headache, syncope, taste disturbance.

Uncommon: somnolence, paraesthesia.

Rare: paresis (due to hypokalaemia).

Eye disorders

Very common: blurred vision.

Ear and labyrinth disorders

Uncommon: dizziness, tinnitus.

Cardiac pathologies

Common: arrhythmia (heart rhythm disturbances), angina pectoris, tachycardia.

Uncommon: palpitations, myocardial infarction.

Vascular pathologies

Very common: dizziness.

Common: hypotension, orthostatic hypotension.

Uncommon: cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), flushing.

Rare: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders

Very common: cough.

Common: dyspnoea.

Uncommon: rhinorrhea, laryngodynia and hoarseness, bronchospasm / asthma.

Rare: pulmonary infiltrates, respiratory distress syndrome (including pneumonia and pulmonary edema), rhinitis, allergic alveolitis / eosinophilic pneumonia.

Gastrointestinal disorders

Very common: nausea.

Common: diarrhea, abdominal pain.

Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer, flatulence *.

Rare: stomatitis, aphthous ulcers, glossitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Rare: hepatic failure, hepatic necrosis (potentially fatal), hepatitis - hepatocellular or cholestatic, jaundice, cholecystitis (particularly in patients with pre-existing cholelithiasis).

Skin and subcutaneous tissue disorders

Common: rash (exanthema).

Uncommon: diaphoresis, pruritus, urticaria, alopecia.

Rare: Erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus.

A symptom complex has been reported which may include some or all of the following conditions: fever, serositis, vasculitis, myalgia / myositis, arthralgia / arthritis, antinuclear antibody (ANA) positivity, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity, or other dermatological manifestations may occur.

Musculoskeletal and connective tissue disorders

Common: muscle cramps †.

Uncommon: arthralgia *.

Renal and urinary disorders

Uncommon: renal dysfunction, renal failure, proteinuria.

Rare: oliguria, interstitial nephritis.

Diseases of the reproductive system and breast

Uncommon: impotence.

Rare: gynecomastia.

General disorders and administration site conditions

Very common: asthenia.

Common: chest pain, fatigue.

Uncommon: malaise, fever.

Diagnostic tests

Common: hyperkalaemia, increases in serum creatinine, increases in cholesterol, increases in triglycerides.

Uncommon: increased uremia, hyponatremia.

Rare: blood glucose increased, liver enzyme increases, blood bilirubin increases, hemoglobin decreased, hematocrit decreased.

* Observed only with doses of 12.5 and 25 mg of hydrochlorothiazide, as the dose present in ACESISTEM.

† The frequency of muscle cramps defined as common refers to doses of 12.5 and 25 mg of hydrochlorothiazide, as the dose present in ACESISTEM, while the frequency of the event is defined as uncommon when it refers to the dose of 6 mg of hydrochlorothiazide present in the NEOPREX.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

No specific information is available on the treatment of ACESISTEM overdose. Treatment is symptomatic and supportive. Treatment with ACESISTEM should be discontinued and the patient kept under close observation. Suggested measures include induction of vomiting, administration of activated charcoal and a laxative if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension according to established procedures.

Enalapril maleate

The most relevant effects of overdose reported to date are marked hypotension, which occurs approximately six hours after ingestion of the tablets, concomitant with blockade of the renin-angiotensin system, and lightheadedness. Symptoms associated with ACE inhibitor overdose may include circulatory shock, electrolyte disturbances, renal insufficiency, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. After ingestion of 300 mg and 440 mg of enalapril maleate, serum levels of enalaprilat 100 and 200 times higher, respectively, have been reported. those typically seen after therapeutic doses.

Intravenous infusion of saline is the recommended treatment for overdose. In case of hypotension the patient should be placed in an anti-shock position. If available, treatment with angiotensin II and / or catecholamines infusion may also be considered. In case of recent ingestion, take measures to eliminate enalapril maleate (eg, emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from the general circulation by hemodialysis (see paragraph 4.4). For therapy-refractory bradycardia, pacemaker treatment is indicated. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Hydrochlorothiazide

The most commonly observed signs and symptoms are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatremia) and dehydration, as a result of "excessive diuresis. If digitalis has also been given, hypokalaemia may accentuate a" cardiac arrhythmia.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors (ACE inhibitors) and diuretics.

ATC code: C09BA02.

ACESISTEM (enalapril maleate / hydrochlorothiazide, MSD) is the combination of an angiotensin converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide); this combination gives ACESISTEM antihypertensive and diuretic properties.

Enalapril maleate is chemically referred to as (S) -1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline maleate (1: 1), while hydrochlorothiazide is 6 -chloro-7-sulfamoyl-3,4-dihydro- (2H) -1,2,4-benzothiadiazine-1,1-dioxide.

Enalapril maleate and hydrochlorothiazide have been used alone or concomitantly for the treatment of hypertension.

The antihypertensive effects of these two agents are additive and are maintained for at least 24 hours.

The enalapril maleate component of ACESISTEM has been shown to attenuate the potassium loss associated with hydrochlorothiazide.

Enalapril maleate and hydrochlorothiazide have a similar dosing schedule. ACESISTEM presents a convenient formulation for concomitant administration of enalapril maleate and hydrochlorothiazide.

Mechanism of action

Enalapril maleate

The angiotensin converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II, a pressure-acting substance. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits it. ACE. Inhibition of ACE results in a decrease in plasma angiotensin II levels, leading to an increase in plasma renin activity (due to the interruption of the negative feedback exerted on renin release) and a decreased secretion of aldosterone. ACE is identical to kininase II; consequently, enalapril can also block the breakdown of bradykinin, a potent peptide vasodepressor. However, the role of the latter in the therapeutic effects of enalapril is still to be elucidated. The mechanism by which enalapril lowers blood pressure appears to be mainly consisting of the suppression of the renin-angiotensin-aldosterone system, which plays a very important role in blood pressure regulation. Enalapril has an antihypertensive action even in patients with low-renin hypertension.

Enalapril maleate - Hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive agent which increases plasma renin activity. Although enalapril alone has antihypertensive activity even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide in these patients leads to a greater reduction in blood pressure.

Enalapril maleate

Administration of enalapril maleate to patients with hypertension resulted in a reduction in both supine and standing blood pressure without a significant increase in heart rate. Symptomatic postural hypotension is rare. In some patients, achieving optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril maleate is not associated with a rapid rise in blood pressure.

Effective inhibition of ACE activity usually occurs 2-4 hours after oral administration of a single dose of enalapril. Onset of antihypertensive activity is usually seen after one hour and maximal activity is reached 4 -6 hours after administration. The duration of the effect is dose-related. It has been shown, however, that at the recommended doses the antihypertensive and haemodynamic effects are maintained for at least 24 hours.

In haemodynamic studies in patients with essential hypertension, the reduction in blood pressure is accompanied by a reduction in peripheral arterial resistance with a slight increase in cardiac output and little or no change in heart rate. Following the administration of enalapril maleate there was an increase in renal blood flow, while the glomerular filtration rate remained unchanged. In patients who already had a low glomerular filtration rate prior to treatment, this usually increased.

Antihypertensive treatment with enalapril leads to a significant reduction in left ventricular hypertrophy, while maintaining the systolic performance of the left ventricle.

Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA Nephron-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.

These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group, and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Enalapril maleate - Hydrochlorothiazide

In clinical studies, the magnitude of blood pressure reduction observed with the combination of enalapril maleate and hydrochlorothiazide was greater than that observed with either component used alone. Furthermore, the antihypertensive effect of ACESISTEM was maintained for at least 24 hours.

05.2 Pharmacokinetic properties

Enalapril maleate

Orally administered enalapril maleate is rapidly absorbed, reaching peak serum concentrations within one hour of administration. Based on urinary recovery, the percentage of enalapril absorbed after oral administration is approximately 60%. Once absorbed, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur 3-4 hours after an oral dose of enalapril maleate. The excretion of enalapril is primarily renal. The major compounds present in the urine are enalaprilat, which accounts for 40% of the dose, and unchanged enalapril. Apart from conversion to enalaprilat, there has been no evidence of significant metabolism of enalapril. .

The serum concentration profile of enalaprilat shows a prolonged terminal phase, clearly associated with binding to ACE. In subjects with normal renal function, the equilibrium state of serum concentrations is reached on the fourth day of therapy with enalapril maleate. The half-life. effective accumulation of enalaprilat after multiple oral doses of enalapril maleate is 11 hours. Oral absorption of enalapril maleate is not affected by the presence of food in the gastrointestinal tract.

The extent of absorption and hydrolysis of enalapril are similar for all doses within the recommended therapeutic range.

Feeding time

After a single 20 mg oral dose in 5 postpartum women, the mean peak enalapril milk value was 1.7 mcg / L (range 0.54 to 5.9 mcg / L) 4 to 6 hours after postpartum. dose. The mean peak enalaprilat was 1.7 mcg / L (range 1.2 to 2.3 mcg / L); the peaks occurred at different times over the 24-hour period. Using the peak milk level data, the maximum estimated amount ingested by an exclusively breastfed infant would be approximately 0.16% of the maternal weight-adjusted dose.

A woman who had taken an oral dose of 10 mg per day of enalapril for 11 months had peak enalapril milk levels of 2 mcg / L 4 hours post dose and peak enalaprilat levels of approximately 0.75 mcg / L. 9 hours after the dose. The total amount of enalapril and enalaprilat dosed in milk during the 24 hour period was 1.44 mcg / L and 0.63 mcg / L, respectively. The levels of enalaprilat in milk were undetectable (

Hydrochlorothiazide

Hydrochlorothiazide is not metabolised but is rapidly eliminated by the kidney. With plasma levels monitoring for at least 24 hours, the plasma half-life was observed to vary over a range of 5.6-14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but not the blood brain barrier.

Enalapril maleate - Hydrochlorothiazide

Multiple concomitant doses of enalapril maleate and hydrochlorothiazide have little or no effect on the bioavailability of each of these drugs. The combination tablet is bioequivalent to the concomitant administration of the two separate components.

05.3 Preclinical safety data

Enalapril maleate

The safety of enalapril has been extensively studied in mice, rats, dogs and monkeys to establish its general toxicity.

Acute toxicity

Oral LD50 about 2,000 mg / kg in mice and rats.

Subacute and chronic toxicity

Rats: in rats treated for up to 1 year with 10-30-90 mg / kg / day there was a slight reduction in mean weight gain at all dose levels; azotemia values increased in rats treated with 30 or 90 mg / kg / day, however, no drug-dependent renal histological changes were found.

Dogs: Dogs treated for up to 1 year with 15 mg / kg / day showed no drug-dependent changes.

Monkeys: monkeys treated for one month with 30 mg / kg / day showed no drug-dependent changes.

Teratogenic studies were performed in rats and rabbits and the effects of enalapril on reproduction and postnatal development in rats were evaluated. Enalapril was administered to pregnant rats at doses up to 1,200 mg / kg / day (2,000 times the maximum human dose) from day 6 to day 17 of gestation and no evidence of embryo-lethality or teratogenicity was found.

No adverse effects on reproductive activity were found in male and female rats treated with doses of 10 to 90 mg / kg / day of enalapril. Neither enalapril, nor enalaprilat, nor enalapril associated with hydrochlorothiazide was mutagenic. in the Ames microbial mutagen test with or without metabolic activation. The combination of enalapril and hydrochlorothiazide was negative in an in vitro alkaline elution assay in rat hepatocytes and an in vitro chromosomal aberration assay. No carcinogenic effects were seen after 106 weeks of enalapril administration in the rat, with doses up to 90 mg / kg / day (150 times the maximum daily dose for humans).

Enalapril was also administered for 94 weeks to male and female mice at doses up to 90 and 180 mg / kg / day respectively (150 and 300 times the maximum daily human dose) and no evidence of carcinogenicity was found. .

Hydrochlorothiazide

In acute and chronic toxicology studies, hydrochlorothiazide has been shown to have relatively low toxicity.In acute animal toxicology studies, the LD50 in mice is greater than 10,000 mg / kg in suspension per os and 884 mg / kg intravenously. In rats, the acute LD50 is greater than 10,000 mg / kg in suspension orally and 3,130 mg / kg in suspension intraperitoneally. In rabbits the acute intravenous LD50 is 461 mg / kg and in dogs about 1,000 mg / kg. Dogs tolerate up to 2,000 mg / kg orally with no signs of toxicity. In chronic oral toxicology studies in rats using doses up to 2,000 mg / kg / day for 5 days a week for 26 weeks, no signs of drug effect or post-mortem drug-related changes were observed. Hydrochlorothiazide was administered to rats in a two-litter study, to mice in a 2-generation study, and to rabbits with a positive pregnancy test. None of these studies showed teratogenic effects of hydrochlorothiazide. Offspring raised to weaning or maturity showed no signs of treatment-related effects.

Enalapril maleate - Hydrochlorothiazide

The acute LD50 of hydrochlorothiazide administered intraperitoneally to mice was lower when enalapril was administered orally one hour prior to treatment. This change, however, was slight and at doses that would not be clinically significant. None were observed. sign of acute oral toxicity of enalapril in mice pretreated with oral hydrochlorothiazide.