Vasoretic - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Enalapril (Enalapril maleate), Hydrochlorothiazide

VASORETIC 20 mg + 12.5 mg tablets

Indications Why is Vasoretic used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

VASORETIC is an antihypertensive, a combination of an angiotensin converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

THERAPEUTIC INDICATIONS

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

Contraindications When Vasoretic should not be used

  • Hypersensitivity to enalapril maleate, hydrochlorothiazide or any of the excipients of VASORETIC.
  • 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 sulphonamide-derived medicinal products.
  • If you have been pregnant for more than 3 months. (It is also preferable to avoid using Vasoretic in early pregnancy - see PREGNANCY AND LACTATION section).
  • Severe hepatic insufficiency.
  • The concomitant use of VASORETIC with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate VFG

Precautions for use What you need to know before taking Vasoretic

Enalapril maleate-Hydrochlorothiazide

Hypotension and hydroelectrolytic imbalance

Symptomatic hypotension is rarely observed in hypertensive patients without complications. In hypertensive patients treated with VASORETIC, 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 INTERACTIONS and UNDESIRABLE EFFECTS). In these patients, regular measurement of serum electrolytes should be performed at appropriate intervals. Particular attention should be paid to patients with ischemic cardiac or cerebrovascular disease in whom excessive hypotension can lead myocardium 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

VASORETIC should not be administered to patients with renal insufficiency (creatinine clearance 30 ml / min) until enalapril titration has shown the need for the dose present in this formulation (see section DOSE, METHOD AND TIME OF ADMINISTRATION).

Some hypertensive patients with no apparent pre-existing renal disease have developed elevations in BUN and serum creatinine when enalapril was administered concomitantly with a diuretic (see section PRECAUTIONS FOR USE, Enalapril maleate, Impaired renal function, Hydrochlorothiazide , Impaired renal function). If this occurs, VASORETIC therapy should be discontinued. This circumstance should suggest the possibility of a stenosis of the basic renal artery (see section PRECAUTIONS FOR USE, Enalapril maleate, Renovascular hypertension).

Double 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 RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. 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.

Hyperkalemia

The combination of enalapril with a low dose diuretic cannot exclude the possibility of hyperkalaemia (see section PRECAUTIONS FOR USE, Enalapril maleate, Hyperkalaemia).

Lithium

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

Lactose

VASORETIC contains less than 200 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Enalapril maleate

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.Renal failure associated with enalapril therapy is usually reversible if recognized promptly and adequately treated (see sections DOSE, METHOD AND TIME OF ADMINISTRATION and PRECAUTIONS FOR USE, Enalapril maleate-Hydrochlorothiazide, Impaired renal function; Hydrochlorothiazide, Impaired kidney function).

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 section PRECAUTIONS FOR USE, Hydrochlorothiazide, Hepatopathy).

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; o taking other medicines associated with increases in serum potassium (e.g., 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 medicinal products is deemed adequate, they should be used with caution and with frequent monitoring of serum potassium (see sections PRECAUTIONS FOR USE, Enalapril Maleate-Hydrochlorothiazide, Hyperkalaemia; Hydrochlorothiazide, Metabolic Effects and endocrine and INTERACTIONS).

Diabetic patients

Diabetic patients treated with oral antidiabetic or insulin starting therapy with an ACE inhibitor should be advised to monitor carefully for hypoglycaemia, especially during the first month of concomitant use (see sections PRECAUTIONS FOR USE, Hydrochlorothiazide, Metabolic Effects and endocrine and INTERACTIONS).

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, Vasoretic 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 due to angioedema associated with laryngeal edema or tongue edema have been reported.

Airway obstruction is likely to occur in patients with involvement of the tongue, glottis or larynx, 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, it appears that in general black patients have a risk increased 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 CONTRAINDICATIONS section).

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 thus 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 INTERACTIONS section).

Pregnancy

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Vasoretic is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at this stage (see PREGNANCY AND LACTATION).

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 sections DOSE, METHOD AND TIME OF ADMINISTRATION and PRECAUTIONS FOR USE, Enalapril maleate-Hydrochlorothiazide, Renal impairment; Enalapril maleate, Renal impairment).

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 section PRECAUTIONS FOR USE, Enalapril maleate, Hepatic insufficiency).

Metabolic and endocrine effects

Thiazide therapy can impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be necessary (see section PRECAUTIONS FOR USE, Enalapril maleate, Diabetic patients).

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 SINERTEC. 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 INTERACTIONS).

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 medicine may give a positive result in the analysis of 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.

Interactions Which drugs or foods can modify the effect of Vasoretic

Tell your doctor or pharmacist you are taking, have recently taken or might take any other medicines.

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 "Contraindications" and "Precautions for use".

Enalapril maleate-Hydrochlorothiazide

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 "Contraindications" and "Precautions for use").

Other antihypertensive medicines

Concomitant use of these medicinal products 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 VASORETIC with lithium is not recommended, but if the combination is necessary, it should be perform careful monitoring of serum lithium levels (see section PRECAUTIONS FOR USE).

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

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 PRECAUTIONS FOR USE).

Diuretics (thiazides or loop diuretics)

Prior treatment with high dose diuretics may result in volume depletion and risk of hypotension when initiating therapy with enalapril (see sections DOSE, METHOD AND PRECAUTIONS FOR USE). The hypotensive effects may be reduced by discontinuation of drugs. diuretics, from increased blood volume or from the intake of salts.

Tricyclic Antidepressants / Antipsychotics / Anesthetics

The concomitant use of some anesthetic drugs, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a further reduction in blood pressure (see section PRECAUTIONS FOR USE).

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 medicinal products) may cause an increase in the blood glucose lowering effect with risk of hypoglycaemia. This effect appeared to be more likely to occur during the first weeks of combined treatment. and in patients with renal impairment (see section UNDESIRABLE EFFECTS).

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 medicines (oral and insulin)

Dose adjustment of the antidiabetic medicinal product may be required (see section UNDESIRABLE EFFECTS).

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.

Medicines 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 (eg, norepinephrine) The effect of pressor amines may be diminished.

Cytostatics (e.g., cyclophosphamide, methotrexate)

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

Pediatric population

Interaction studies have only been performed in adults.

Warnings It is important to know that:

Pregnancy

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Your doctor will usually advise you to stop taking Vasoretic before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Vasoretic. Vasoretic is not recommended during pregnancy. , and should not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if taken after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or if you need to start breastfeeding. Vasoretic is not recommended for mothers who are breastfeeding.

Effects on ability to drive and use machines

When driving vehicles or using machines it should be borne in mind that occasionally dizziness or tiredness may occur (see section UNDESIRABLE EFFECTS).

Dosage and method of use How to use Vasoretic: Dosage

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

Hypertension

It is advisable to start therapy with ½ tablet per 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 VASORETIC tablet.

Dosage 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 and <80 ml / min VASORETIC should only be used after titration of the individual components. When used alone, the recommended starting dose of enalapril maleate in mild renal impairment is 5-10 mg.

Pediatric use

Safety and efficacy in children have not been established. Therefore, the use of the product is not recommended in pediatric age.

Use in the elderly

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

Do not stop taking the medicine unless your doctor tells you to. If you have any questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Vasoretic

No specific information is available on the treatment of VASORETIC overdose. Treatment is symptomatic and supportive. Treatment with VASORETIC should be discontinued and the patient monitored closely. 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 failure, 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 the event 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 PRECAUTIONS FOR USE). Pacemaker treatment is indicated for bradycardia refractory to therapy. 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.

If you have any questions about the use of VASORETIC, ask your doctor or pharmacist.

Side Effects What are the side effects of Vasoretic

Undesirable effects reported in clinical trials and post-marketing experience with VASORETIC, 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, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine pathologies

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

Metabolism and nutrition disorders

Common: hypokalaemia, cholesterol increased, triglycerides increased, hyperuricaemia.

Uncommon: hypoglycaemia (see section PRECAUTIONS FOR USE), hypomagnesaemia, gout **.

Rare: blood glucose increased.

Very rare: hypercalcaemia (see section PRECAUTIONS FOR USE).

Nervous system disorders and psychiatric disorders

Common: headache, depression, syncope, taste disturbance.

Uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, dizziness, libido decreased **.

Rare: changes in dream activity, sleep disturbances, paresis (due to hypokalaemia).

Eye disorders

Very common: blurred vision.

Ear and labyrinth disorders

Uncommon: tinnitus.

Cardiac and vascular disorders

Very common: dizziness.

Common: hypotension, orthostatic hypotension, heart rhythm disturbances, angina pectoris, tachycardia.

Uncommon: flushing, palpitations, myocardial infarction or cerebrovascular accident *, possibly secondary to excessive hypotension in high-risk patients (see section PRECAUTIONS FOR USE).

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). Hypersensitivity / angioneurotic edema: Angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx has been reported (see section PRECAUTIONS FOR USE).

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 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.

Uncommon: increased uremia, hyponatremia.

Rare: increases in liver enzymes, increases in bilirubin.

* In clinical trials, the incidence rates in the placebo and active control groups were comparable.

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

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

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. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine

Expiry and Retention

Expiry: see the expiry date indicated on the package.

Warning: do not use the medicine after the expiry date indicated on the package.

The expiry date indicated refers to the product in intact packaging, correctly stored.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

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

Composition and pharmaceutical form

COMPOSITION

One VASORETIC tablet contains:

Active principles:

enalapril maleate 20 mg

hydrochlorothiazide 12.5 mg.

Excipients: sodium bicarbonate, lactose monohydrate, yellow iron oxide, corn starch, pregelatinised starch, magnesium stearate.

PHARMACEUTICAL FORM AND CONTENT

Tablets.

Pack of 14 tablets of 20 mg of enalapril maleate + 12.5 mg of hydrochlorothiazide, in aluminum blisters.

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 Vasoretic can be found 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 interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 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 HOLDER 08.0 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 RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

VASORETIC 20 MG + 12.5 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Active principles:

enalapril maleate 20 mg; hydrochlorothiazide 12.5 mg.

Excipients with known effects: 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

Dosage

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

Hypertension

It is advisable to start therapy with ½ tablet per 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 can lead to marked hypotensive responses.

In these patients, if the combination is necessary, it is important if possible to discontinue 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 VASORETIC 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 use

Safety and efficacy in children have not been established.

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

Use in the elderly

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

Method of administration

Oral use.


04.3 Contraindications

- Hypersensitivity to the active substance 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 sulphonamide-derived drugs.

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

- Severe hepatic insufficiency.

The concomitant use of VASORETIC with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (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 VASORETIC, 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

VASORETIC should not be administered to patients with renal insufficiency (creatinine clearance 80 ml / min and> 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 administered concomitantly with a diuretic (see Special warnings and precautions for use, Enalapril Maleate, Impaired renal function; Hydrochlorothiazide , Renal impairment in section 4.4). If this occurs, VASORETIC therapy should be discontinued. This should suggest the possibility of underlying renal artery stenosis (see Special warnings and precautions for use, Enalapril Maleate , Renovascular hypertension in section 4.4).

Double 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.

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

VASORETIC contains less than 200 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Enalapril maleate

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 therapy with enalapril is usually reversible (see section 4.2 and Special warnings and precautions for use, Enalapril maleate-Hydrochlorothiazide, Renal impairment; Hydrochlorothiazide, Renal impairment in section 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 e precautions for use, hydrochlorothiazide, liver disease 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; o taking other medicines associated with increases in serum potassium (e.g., 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 medicinal products is deemed adequate, 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 effects and endocrines in section 4.4 and section 4.5).

Diabetic patients

Diabetic patients treated with oral antidiabetic or insulin starting therapy with an ACE inhibitor should be advised to monitor carefully for hypoglycaemia, especially during the first month of concomitant use (see Special warnings and precautions for use, Hydrochlorothiazide, Metabolic effects and endocrines in 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, Vasoretic 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. Airway obstruction is likely to occur in patients with involvement of the tongue, glottis or larynx, 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).

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 use, Enalapril maleate-Hydrochlorothiazide, Impaired renal function; Enalapril maleate, Impaired renal function in section 4.4).

Hepatopathy

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as slight changes in water and electrolyte balance may 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. Dose adjustment of antidiabetic medicinal products, including insulin, may be necessary (see Special warnings and precautions for use, Enalapril maleate, Diabetic patients in section 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 SINERTEC. 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

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).

Other antihypertensive medicines

Concomitant use of these medicinal products may increase the hypotensive effects of enalapril and hydrochlorothiazide.

Concomitant use with nitroglycerin and other nitrates, or other vasodilators, can 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 VASORETIC 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.Acute renal failure may occur rarely, especially in patients with impaired renal function (such as the elderly or patients who are volume depleted, including those on diuretic therapy).

Enalapril maleate

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 medicinal products) may cause an increase in the blood glucose lowering effect with risk of hypoglycaemia. This effect appeared to be more likely to occur during the first weeks of combined treatment. and in patients with renal impairment (see sections 4.4 and 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 medicines (oral and insulin)

Dose adjustment of the antidiabetic medicinal product may be required (see sections 4.4 and 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.

Medicines 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.

Cytostatics (e.g., cyclophosphamide, methotrexate)

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

Pediatric population

Interaction studies have only been performed in adults.


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 trimesters 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 ). Maternal oligohydramnios occurred, presumably indicating decreased fetal renal function, and which can result in limb contractures, craniofacial deformations, and development of pulmonary hypoplasia.

Should exposure to an ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for the development of 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 not enough. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can compromise fetal-placental perfusion and can cause fetal and neonatal effects such as jaundice, balance disturbances. electrolyte and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or pre-eclampsia 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 essential hypertension in pregnant women except in rare situations where no other treatment can 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 VASORETIC during lactation is not recommended in preterm infants and in the first weeks after delivery due to the hypothetical risk of cardiovascular and renal effects and because there is insufficient clinical experience. . In the case of older infants, the use of VASORETIC in nursing mothers may be considered if this treatment is necessary for the mother and if the infant is followed up for possible adverse effects.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small quantities. Thiazides in high doses that cause intense diuresis can inhibit milk production. The use of VASORETIC is not recommended during breastfeeding. If VASORETIC is used 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

VASORETIC is generally well tolerated. In clinical trials, adverse reactions were generally mild and transient in nature and, in many cases, did not require discontinuation of therapy.

The most common adverse reactions reported with VASORETIC during clinical trials were headache and cough.

The following side effects have been reported with VASORETIC, enalapril alone or hydrochlorothiazide alone, both during clinical trials and with marketing of the medicine:

Table 1. Undesirable effects of VASORETIC

System and organ classification Very common (≥ 1/10) Common (≥1 / 100 to Uncommon (≥1 / 1,000 to Rare (≥1 / 10,000 to Very rare ( Not known (frequency cannot be estimated from the available data) Disorders of the blood and lymphatic system Anemia (including aplastic and haemolytic anemia) Neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases Endocrine pathologies Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Metabolism and nutrition disorders Hypokalaemia, increased cholesterol, increased triglycerides, hyperuricaemia Hypoglycaemia (see section 4.4), hypomagnesaemia, gout ** Increased blood glucose Hypercalcaemia (see section 4.4) Nervous system disorders and psychiatric disorders Headache, depression, syncope, taste disturbance Confusion, somnolence, insomnia, nervousness, paraesthesia, dizziness, decreased libido ** Changes in dream activity, sleep disturbances, paresis (due to hypokalaemia) Eye disorders Blurred vision Ear and labyrinth disorders Tinnitus Cardiac and vascular disorders Dizziness Hypotension, orthostatic hypotension, heart rhythm disturbances, angina pectoris, tachycardia Flushing, palpitations, myocardial infarction or cerebrovascular accident *, possibly secondary to excessive hypotension in high-risk patients (see section 4.4) Raynaud's phenomenon Respiratory, thoracic and mediastinal disorders Cough Dyspnea Rhinorrhea, laryngodynia and hoarseness, bronchospasm / asthma Lung infiltrates, respiratory distress syndrome (including pneumonia and pulmonary edema), rhinitis, allergic alveolitis / eosinophilic lungs Gastrointestinal disorders Nausea Diarrhea, abdominal pain Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer, flatulence ** Stomatitis / aphthous ulcers, glossitis Intestinal angioedema Hepatobiliary disorders Hepatic failure, hepatic necrosis (potentially fatal), hepatitis - hepatocellular or cholestatic, jaundice, cholecystitis (particularly in patients with pre-existing cholelithiasis) Skin and subcutaneous tissue disorders Skin rash (rash). Hypersensitivity / angioneurotic edema: Angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx has been reported (see section 4.4). Diaphoresis, itching, urticaria, alopecia 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 / myosis, arthralgia / arthritis, antinuclear antibody positivity, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity, or other dermatological manifestations may occur Musculoskeletal and connective tissue disorders Muscle cramps ** * Arthralgia ** Renal and urinary disorders Renal dysfunction, renal failure, proteinuria Oliguria, interstitial nephritis Diseases of the reproductive system and breast Impotence Gynecomastia General disorders and administration site conditions Asthenia Chest pain, fatigue Malaise, fever Diagnostic tests Hyperkalaemia, increases in serum creatinine Increases in uremia, hyponatremia Increases in liver enzymes, increases in bilirubin

* In clinical trials, the incidence rates in the placebo and active control groups were comparable.

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

*** The frequency of muscle cramps defined as common refers to doses of 12.5 and 25 mg of hydrochlorothiazide, as the dose present in VASORETIC, while the frequency of the event is defined as uncommon when it refers to the dose of 6 mg of hydrochlorothiazide present in SINERTEC 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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.


04.9 Overdose

No specific information is available on the treatment of VASORETIC overdose. Treatment is symptomatic and supportive. Treatment with VASORETIC should be discontinued and the patient monitored closely. 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 failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

After ingestion of 300 mg and 440 mg of enalapril maleate, serum levels of enalaprilat were reported to be 100 and 200 times higher, respectively, than those typically observed 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.

VASORETIC (enalapril maleate / hydrochlorothiazide, MSD) is the combination of an angiotensin converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide); this combination gives VASORETIC 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 VASORETIC has been shown to attenuate the potassium loss associated with hydrochlorothiazide.

Enalapril maleate and hydrochlorothiazide have a similar dosing schedule. VASORETIC 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. However, it has been shown that antihypertensive and haemodynamic effects are maintained for at least 24 hours at recommended doses.

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.

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 VASORETIC was maintained for at least 24 hours.

Double block

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 adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.


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 are observed 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.

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 medicinal products. The combination tablet is bioequivalent to the concomitant administration of the two separate components.

Feeding time

After a single 20 mg oral dose in 5 women in the postpartum period the mean peak level of enalapril in milk was 1.7 mcg / L (range 0.54 to 5.9 mcg / L) 4 to 6 hours after the dose. The mean peak level of 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 data from peak milk levels, the estimated maximum intake of an exclusively breastfed infant would be approximately 0.16% of the maternal weight-adjusted dosage. A woman who had taken oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 mcg / L 4 hours after a dose and peak enalaprilat levels of 0.75 mcg / L approximately 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24-hour period was 1.44 mcg / L and 0.63 mcg / L, respectively.

Levels of enalaprilat in milk were not measurable (

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 observed to have relatively low toxicity. In acute animal toxicology studies the LD 50 in mice is greater than 10,000 mg / kg in suspension orally and 884 mg / kg intravenously. In rats, the acute LD 50 is greater than 10,000 mg / kg in suspension orally and 3,130 mg / kg in suspension intraperitoneally. In rabbits the acute IV LD 50 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 the effect were observed. drug, nor drug-related changes at autopsy. 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.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Sodium bicarbonate, lactose monohydrate, yellow iron oxide, corn starch, pregelatinised starch, magnesium stearate.


06.2 Incompatibility

Not relevant.


06.3 Period of validity

3 years.


06.4 Special precautions for storage

This medicine does not require any special storage conditions.


06.5 Nature of the immediate packaging and contents of the package

The tablets are contained in aluminum blisters.

14 tablets of 20 mg + 12.5 mg

28 tablets of 20 mg + 12.5 mg

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

MERCK SHARP & DOHME LIMITED Hertford Road, Hoddesdon Hertfordshire, Great Britain

08.0 MARKETING AUTHORIZATION NUMBER

14 tablets 20 mg + 12.5 mg AIC: 027056011

28 tablets 20 mg + 12.5 mg AIC: 027056023

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

December 1989 / June 2005

10.0 DATE OF REVISION OF THE TEXT

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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