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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide Excipient with known effect:

Each tablet contains 122.16 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Round, white, flat tablet, scored on one side and with bevelled edge. Diameter 8mm. The tablet can be divided into equal doses.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential hypertension.

The fixed-dose combination in Enalapril Maleate and hydrochlorothiazide 20 mg/12.5mg tablets is not suitable for initial therapy. It is intended to replace the combination of 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide in patients who have been stabilised on the individual active substances given in the same proportions as separate medications.

4.2 Posology and method of administration

Route of administration: Oral use.

Dose of Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets should be determined primarily by the response to the enalapril maleate component of the combination.

Individual dose titration with both active substances can be recommended.

The fixed-dose combination should replace monotherapy with the individual active substances.

Essential hypertension Usual dose is one tablet a day.

The tablets can be taken irrespective of food intake.

Prior diuretic therapy

Treatment with diuretics should be discontinued 2 to 3 days before the start of the treatment with Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets. See section 4.4.

Dosage in renal insufficiency

Thiazide diuretics may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency). See section 4.3.

The dose of enalapril should be titrated in patients with renal impairment whose creatinine clearance is > 30 ml/min before switching to Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets. Loop diuretics are preferred to thiazides in this population. The dose of enalapril maleate and hydrochlorothiazide should be kept as low as possible (see section 4.4). During the use of Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets monitoring of the renal function is required.

Paediatric population

Safety and effectiveness in children have not been established.

Use in elderly patients

The efficacy and tolerability of concomitant use of enalapril maleate and hydrochlorothiazide has been shown in clinical studies to be as good in elderly as in younger patients. In case of physiological renal impairment the recommended initial dose is half a tablet once daily.

4.3 Contraindications

-    hypersensitivity to enalapril maleate, hydrochlorothiazide, or any of the excipients

-    severe renal impairment (creatinine clearance < 30 ml/min)

-    anuria

-    history of angioneurotic oedema linked to previous ACE-inhibitor therapy

-    hereditary or idiopathic angiooedema

-    hypersensitivity to sulfonamide-derived drugs

-    second and third trimesters of pregnancy (see sections 4.4 and 4.6)

-    severe hepatic impairment

-    Enalapril/hydrochlorothiazide should not be administered with aliskiren containing products in patients with diabetes or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.4)

4.4 Special warnings and precautions for use

Enalapril Maleate-Hydrochlorothiazide

Hypotension and Electrolyte Fluid Imbalance

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets, symptomatic hypotension is more likely to occur if the patient has been volume - depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (see sections 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. Special attention should be paid to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. In hypertensive patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed.

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

Renal Function Impairment

Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets 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 increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic (see section 4.4). If this occurs, therapy with Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets should be discontinued. In this situation, the possibility of underlying renal artery stenosis should be considered (see section 4.4).

The use of enalapril/hydrochlorothiazide in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see section 4.3).

Monitoring of renal function is desired during use of Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets.

Hyperkalaemia

The combination of enalapril and a low-dose diuretic cannot exclude the possibility of hyperkalaemia to occur (see section 4.4).

Lithium

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

Paediatric population

There is limited efficacy and safety experience in hypertensive children, especially for the combination of enalapril and hydrochlorothiazide.

Lactose

Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets contains less than 200 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 medicinal product.

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators ACE-inhibitors should be given with caution in patients with left ventricular valvular or aortic outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Renal Function Impairment

Renal failure has been reported in association with enalapril and has been mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible (see sections 4.2 and 4.4).

Renovascular Hypertension

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision and monitoring of renal function.

Kidney Transplantation

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

Haemodialysis Patients

The use of enalapril is not indicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. AN 69®) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see section 4.4).

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving 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 collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is preexisting impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If enalapril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Hyperkalaemia

Elevations in serum potassium have been observed in patients treated with an ACE inhibitor, including enalapril. Risk factors for the development of hyperkalemia include renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events in particular dehydration, acute cardiac decompensation, metabolic acidosis and

concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or using other drugs associated with increases in serum potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see sections 4.4 and 4.5).

Primary hyperaldosteronism

The use of Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets is not recommended, as patients with primary hyperaldosteronism will not respond to antihypertensive medicinal products acting through inhibition of the RAS system.

Diabetic Patients

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of treatment with an ACE inhibitor (see section 4.5)

Hypersensitivity/Angioneurotic Oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients with angiotensin-converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases, Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to discharging the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angiooedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to Whites. However, in general it appears that Blacks have an increased risk for angioedema.

Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor. (See section 4.3.)

Anaphylactoid Reactions during Hymenoptera Desensitisation

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

Anaphylactoid Reactions during LDL-Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Cough

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

Surgery/Anaesthesia

Enalapril blocks angiotensin II formation and therefore impairs the ability of patients undergoing major surgery or during anaesthesia with agents that produce hypotension to compensate via the renin-angiotensin system. Hypotension which occurs due to this mechanism can be corrected by volume expansion (see section 4.5).

Pregnancy

ACE-inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. 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 black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Hydrochlorothiazide

Renal Function Impairment

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency) (see section 4.2, section 4.3 and section 4.4, Enalapril/Hydrochlorothiazide, Renal Function Impairment; Enalapril, Renal Function Impairment).

In patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the active substance may develop in patients with renal renal insufficiency. If progressive renal dysfunction develops characterized by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy (see section 4.3).

Hepatic Disease

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alternations in fluid and electrolyte balances may precipitate hepatic coma (see sections 4.3 and 4.4).

Metabolic and Endocrine effects

Thiazide therapy may impair glucose tolerance. Dosage adjustments of antidiabetic agents, including insulin may be required (see section 4.4 Enalapril, Diabetic Patients). Latent diabetes mellitus may become manifest during thiazide therapy (see section 4.5).

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, at a 12.5 mg dose of hydrochlorothiazide, minimal or no effect was reported. In addition, in clinical studies with 6 mg of hydrochlorothiazide no clinically significant effect on glucose, cholesterol, triglycerides, sodium, magnesium or potassium was reported.

Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. This effect on hyperuricemia appears to be dose-related, and is not clinically significant at a 6 mg dose of hydrochlorothiazide. In addition, enalapril may increase urinary uric acid and thus attenuate the hyperuricaemic effect of hydrochlorothiazide.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

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

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

Hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and does usually not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of latent hyperparathyroidism. Thiazides should be discontinued before testing parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result is hypomagnesaemia.

Anti-doping test

Hydrochlorothiazide contained in this medicinal product can produce a positive analytic result in an anti-doping test.

Hypersensitivity

In patients receiving thiazides, sensitivity 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.

4.5 Interaction with other medicinal products and other forms of interaction

Enalayril-Hvdrochloroth iazide

Other Antihypertensive Agents

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

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors.

Use of Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets 20 mg/12.5 mg tablets with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4.)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

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

NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors exert an additive effect on the increase in serum potassium, and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function (such as the elderly or patients who are volume depleted, including those on diuretic therapy). Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Dual Blockade of the Renin-angiotensin-aldosterone System

It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher frequency of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g., by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function.

Iodinated contrast media

There is an increased risk of acute renal insufficiency especially with high doses of iodinated contrast media.

Enalapril

Potassium-sparing Diuretics and Potassium Supplements

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

Diuretics (thiazide 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 effect can be reduced by discontinuation of the diuretic or by increasing volume or salt intake.

Tricyclic Antidepressants/Antipsychotics/Anaesthetics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of the blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetics

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

Cyclosporine

Cyclosporine increases the risk of hyperkalaemia with ACE inhibitiors.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic Acid, Thrombolytics andfi-blockers

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

Trimetoprim

Trimethoprim with its amiloride like action in the distal tubule may predispose the patient using enalapril to hyperkalaemia.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

Hydrochlorothiazide

Nondepolarising Muscle Relaxants

Thiazides may increase the responsiveness to tubocurarine.

Alcohol, Barbiturates, or Opioid Analgesics Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (Oral Agents and Insulin)

Dosage adjustment of the antidiabetic drug may be required (see sections 4.4 and 4.8).

Cholestyramine and Colestipol Resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 %, respectively Sulphonamide diuretics should be taken at least 1 hour prior to or 4 to 6 hours after these medicinal products.

Medicinal Products Increasing the QT Interval (e.g., quinidine, procainamide, amiodarone, sotalol)

Increased risk of torsade de pointes.

Calcium salts and vitamine D

Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.

Digitalis Glycosides

Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalaemia.

Kaliuretic Diuretics (e.g., Furosemide), Carbenoxolone, or Laxative Abuse Hydrochlorothiazide may increase the loss of potassium and/or magnesium.

Pressor amines (e.g. Norardrenaline Epinephrine)

The effect of pressor amines may be decreased.

Cytostatics (e.g. Cyclophosphamide, Fluorouracil, Methotrexate)

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

Prostaglandin synthetase inhibitors

In some patients the administration of a prostaglandin synthetase inhibitor may reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

Immunosuppressants, systemic corticoids, procainamid Decrease in blood leukocyte count, leukopenia

Antigout medication (e.g. allopurinol, brenzbromarone)

Medication for gout may need to be increased as hydrochlorothiazide tends to increase the level of uric acid

Clinical chemistry

Hydrochlorothiazide may cause diagnostic interference of the bentiromide test. Thiazides may decrease serum PBI (Protein Bound Iodine) levels without signs of thyroid disturbance.

4.6 Pregnancy and lactation

Epidemiological evidence regarding 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. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to ACE inhibitors 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 hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animals studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, 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 essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Lactation

Enalapril:

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

Although these concentrations seem to be clinically irrelevant, the use of enalapril/hydrochlorothiazide in breast feeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In the case of an older infant, the use of enalapril/hydrochlorothiazide in a breast feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effects.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of enalapril/hydrochlorothiazide during breast feeding is not recommended. If enalapril/hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible.

4.7    Effects on ability to drive and use machines

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur. (See section 4.8.)

4.8    Undesirable effects

The most frequently reported adverse reactions were vertigo and fatigue. These were usually light in nature and did generally not lead to discontinuation of therapy.

Side effects reported with Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets, enalapril alone or hydrochlorothiazide alone either during clinical studies or after the drug was marketed are listed in the table below.:

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: Very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10.000, <

1/1000), very rare (< 10.000), not known (cannot be estimated from the available data)

	very common	common	uncommon	rare	very rare	not known
Infections and Infestations						Sialadenit
Blood and Lymphatic System Disorders			anaemia (including aplastic and haemolytic)	neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytop enia, agranulocytos is, bone marrow depression, leukopenia, pancytopenia, lymphadenop athy, autoimmune diseases
Immune system disorders						anaphylac reactions
Endocrine Disorders						syndrome inappropri antidiureti hormone secretion (SIADH)
Metabolism and Nutrition Disorders		hypokalemia, increase of cholesterol, increase of triglycerides, hyperuricemia	hypoglycemia (see section 4.4), hypomagnese mia, gout	increase in blood glucose	hypercalcemi a (see section 4.4)	glycosuria
Nervous System and Psychiatric Disorders		headache, depression, syncope, taste alteration	confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, decreased libido	dream abnormality, sleep disorders, paresis (due to hypokalaemia )		restlessnes light- headednes
Eye Disorders	blurred vision					Xanthopsi
Ear and Labyrinth Disorders			tinnitus
Cardiac and Vascular	dizziness	hypotension, orthostatic	flushing, palpitations,	Raynaud's phenomenon		necrotisin angiitis

Disorders:		hypotension, , rhythm disturbances, angina pectoris, tachycardia	myocardial infarction or cerebrovascul ar accident, possibly secondary to excessive hypotension in risk patients (see section 4.4)			(vasculitis cutaneous vasculitis)
Respiratory, Thoracic and Mediastinal Disorders	cough	dyspnoea	rhinorrhoea, sore throat and hoarseness, bronchospasm /asthma	pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosi nophilic pneumonia
Gastrointestin al Disorders	nausea	diarrhoea, abdominal pain, dysgeusia	ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence	stomatitis/aph thous ulcerations, glossitis	intestinal angioedema
Hepatobiliary Disorders				hepatic failure, hepatic necrosis (may be fatal), hepatitis -either hepatocellular or cholestatic, jaundice, cholecystitis (in particular in patients with preexisting cholelithiasis)
Skin and Subcutaneous		rash (exanthema),	diaphoresis, pruritus,	erythema multiforme,

Tissue Disorders		hypersensitivi ty/angioneuro tic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4).	urticaria, alopecia	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: fever, serositis, vasculitis, myalgia/myos itis, arthralgia/arth ritis, positive ANA, elevated ESR, eosinophilia, and leukocytosis. Exanthema, photosensitivi ty or other dermatologic symptoms may occur.
Musculoskelet al, Connective Tissue and Bone Disorders		muscle cramps	arthralgia
Renal and Urinary Disorders			renal dysfunction, renal failure, proteinuria	oliguria, interstitial nephritis
Reproductive System and Breast Disorders			impotence	gynaecomasti a

General Disorders and Administratio n Site Conditions	asthenia	fatigue	malaise, fever
Investigations		hyperkalaemi a, increases in serum creatinine	increases in blood urea content, hyponatraemi a	elevations of liver enzymes, elevations of serum bilirubin

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard.

4.9 Overdose

No specific information is available on the treatment of overdosage with Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets.. Treatment is symptomatic and supportive. Therapy with Enalapril Maleate and Hydrochlorothiazide 20mg/12.5mg tablets should be discontinued and the patient observed closely. Suggested measures include induction of emesis, administration of activated charcoal, and administration of a laxative if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Enalapril Maleate

The most prominent features of overdosage reported to date are marked hypotension, beginning some 6 hours after ingestion of tablets, concomitant with blockade of the renin angiotensin system, and stupor.

Symptoms associated with overdosage of ACE inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizzyness, anxiety and cough. Serum enalaprilat levels 100-and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg enalapril maleate, respectively.

The recommended treatment of overdosage is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures aimed at eliminating enalapril maleate (e.g., emesis, gastric lavage, administration of absorbents, and sodium sulphate). Enalaprilat may be removed from the general circulation by hemodialysis. (See section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Hydrochlorothiazide

The most common objective and subjective symptoms are resulting from electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) as well as dehydration as a result of excessive diuresis. If digitalis is given as well, hypokalaemia may accentuate arrhythmias.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, combinations.

ATC-code: C09BA02

Enalapril Maleate and hydrochlorothiazide 20 mg/12.5mg tablets is a combination of an angiotensin-converting enzyme inhibitor (enalapril) and a diuretic (hydrochlorothiazide).

The angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I into the vasopressor angiotensin II. Following absorption, enalapril is hydrolysed to enalaprilat which inhibits ACE. As a result of the inhibition of ACE, the plasma levels of angiotensin II drop and this, in turn, leads to an increase in plasma renin activity (by inhibition of the negative feedback of renin release) and to a decrease in aldosterone secretion.

ACE is identical to kininase II. That is why enalapril can also block the degradation of bradykinin, a powerful vasodepressor peptide. The role of this in the therapeutic effect of enalapril, however, still needs to be clarified. Although the view is that enalapril lowers the blood pressure primarily by the mechanism of inhibiting the rennin/angiotensin/aldosterone system, which plays an important role in regulating blood pressure, it is also the case that enalapril can lower blood pressure in hypertensive patients with low renin levels.

Hydrochlorothiazide is a fluid-expelling and blood pressure-lowering agent which increases plasma renin activity. The blood pressure-lowering effects of the two active substances are additive and usually last for 24 hours. The percentage of hypertensive patients which has a satisfactory reaction to Enalapril Maleate and hydrochlorothiazide 20 mg/12.5mg tablets, is greater than the percentage which has a satisfactory reaction to one of the active substances separately.

The enalapril component of Enalapril Maleate and hydrochlorothiazide 20 mg/12.5mg tablets usually reduces the potassium loss associated with hydrochlorothiazide.

5.2 Pharmacokinetic properties

Enalapril

Absorption

Enalapril maleate is absorbed rapidly when taken orally with maximum serum levels of enalapril achieved within one hour. Judging from the amounts recovered from urine, absorption of oral enalapril is 60-70%.

The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.

Following absorption, enalapril is rapidly and largely hydrolysed to enalaprilat, a potent ACE inhibitor. Maximum serum concentrations of enalaprilat are achieved within three to four hours after an oral dose of enalapril. The extent of absorption and hydrolysis of enalapril is the same for various doses within the recommended therapeutic dosing range.

Elimination

Enalapril is primarily excreted via the kidneys. The main components in urine are enalaprilat - about 40% of the dose - and intact enalapril. There are no indications for major metabolic conversions of enalapril other than the conversion to enalaprilat. The profile of the serum concentration of enalaprilat shows an extended terminal phase which appears to be associated with the binding to ACE. In individuals with normal renal function, steady-state serum concentrations of enalaprilat were achieved on the fourth day of once daily administration of enalapril. After multiple doses of enalapril, the effective half-life (after accumulation) is 11 hours.

Special populations

The hydrolysis of enalapril into its active metabolite may be delayed in cirrhotic patients.

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with creatinine clearance 40-60 ml/min, steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance <30 ml/min), AUC was increased approximately 8-fold, and the effective half-life of enalaprilat following multiple doses was prolonged. Enalaprilat may be removed from the general circulation by hemodialysis.

Lactation:

After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level

was 1.7 pg/L (range 0.54 to 5.9 pg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 pg/L (range 1.2 to 2.3 pg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16 % of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 pg/L 4 hours after a dose and peak enalaprilat levels of 0.75 pg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 pg/L and 0.63 pg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2 pg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10 mg in two mothers; enalapril levels were not determined.

Hydrochlorothiazide

Absorption

The bioavailability of hydrochlorothiadize is 60-80%. Simultaneous food intake increases the absorption somewhat (about 15%).

Distribution

Hydrochlorothiazide passes the placental barrier, but not the blood/liquor barrier.

Biotransformation/elimination

The plasma half-life varies between 5.6 and 14.8 hours. Hydrochlorothiazide is not metabolized, but rapidly excreted via the kidneys. At least 61 % of the oral dose is excreted unchanged within 24 hours.

Special populations :

The half-life is prolonged in patients with impaired renal function.

Enalapril/Hydrochlorothiazide

Absorption

Co-administration of enalapril maleate and hydrochlorothiazide in various doses has little or no effect on the bioavailability of these two substances. The combination tablet is biologically equivalent to co-administration of the two separate substances.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril has no effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin system and partly due to ischemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Maize starch Starch pregelatinised Sodium hydrogen carbonate Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

Shelf life

08/01/2014