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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Enalapril Maleate Tablets 5mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Enalapril Maleate 5mg

Each tablet contains 157.3 mg of lactose monohydrate For a full list of excipients, see 6.1

3    PHARMACEUTICAL FORM

Tablets

Circular white tablets with a score on one side and marked E5 on the other side. Diameter 8mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension: Treatment of all grades of essential hypertension, also renovascular hypertension.

Congestive heart failure: Enalapril tablets should be used as an adjunctive therapy with digitalis and/ or non potassium-sparing diuretics as appropriate. Enalapril has been shown to improve symptoms, retard the progression of the disease, and reduce mortality and hospitalisation.

Prevention of symptomatic heart failure: When used in asymptomatic patients with left ventricular dysfunction, enalapril retards the development of symptomatic heart failure, and reduces hospitalisation for heart failure.

Prevention of coronary ischaemic events in patients with left ventricular dysfunction: Enalapril reduces the incidence of myocardial infarction and reduces hospitalisation for unstable angina pectoris.

4.2 Posology and method of administration

The dose should be individualized according to patient profile (see section 4.4) and blood pressure response.

For oral use.

The maximum daily dose is 40mg. Absorption is not affected by food.

Essential and renovascular hypertension:

A starting dose of 5mg to maximally 20mg once a day is recommended depending on the degree of hypertension and the condition of the patient. In mild hypertension, the recommended initial dose is 5 to 10 mg.

Patients with a strongly activated renin-angiotensinaldosterone system (e.g., renovascular hypertension, salt and/or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. The dose should be titrated to give optimum control of blood pressure. A starting dose of 5 mg or lower is recommended in such patients and the initiation of treatment should take place under medical supervision.

The dosage of other antihypertensive agents being used together with enalapril may need to be adjusted (see sections 4.3, 4.4, 4.5 and 5.1). Where enalapril replaces a beta-blocking drug in the therapeutic regime, the beta-blocking agent should not be discontinued abruptly; the dosage should be titrated down after commencing therapy with enalapril (see Manufacturer's recommendations).

With concomitant diuretic therapy: The recommended initial dose of enalapril is 5mg or lower. Symptomatic hypotension can occur following the initial dose of enalapril; this is more likely when enalapril is added to previous diuretic therapy. Caution is recommended, therefore, since these patients may be volume or salt-depleted. If possible, the diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with enalapril. Enalapril minimises the development of thiazide-induced hypokalaemia and hyperuricaemia. Renal function and serum potassium should be monitored.

The usual maintenance dose is 10-20mg given once daily. In severe hypertension the dosage may be increased incrementally to a maximum of 40mg once daily.

Heart failure/asymptomatic left ventricular dysfunction:

In the management of symptomatic heart failure, Enalapril Tablets are used in addition to diuretics and, where appropriate, digitalis or beta-blockers. The recommended starting dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5mg once daily initiated under close medical supervision to determine the initial effect on the blood pressure. For patients with severe heart failure, therapy should be initiated in hospital. Evidence of systolic left ventricular dysfunction should be obtained by relevant techniques (e.g. radionuclide ventriculography or echocardiography or equivalent) prior to initiation of preventative treatment; however, a repeated measurement may not be necessary in patients with one or more myocardial infarctions and documented reduction in cardiac function.

In patients with symptomatic heart failure, this dosage schedule has been shown to improve survival.

In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with Enalapril Tablets in heart failure, the dose should be increased gradually to the usual maintenance dose of 20 mg, given in a single dose or two divided doses, as tolerated by the patient. The dose should be titrated gradually over a two to four week period. The maximum dose is 40 mg daily given in two divided doses.

Suggested Dosage Titration of Enalapril Tablets in Patients with Heart Failure/Asymptomatic Left Ventricular Dysfunction

Week Dose	mg/day
Week 1	Days 1 to 3: 2.5 mg/day* in a single dose Days 4 to 7: 5 mg/day in two divided doses
Week 2	10 mg/day in a single dose or in two divided doses
Weeks 3 and 4	20 mg/day in a single dose or in two divided doses

*Special precautions should be followed in patients with impaired renal function or taking diuretics (See section 4.4).

Blood pressure and renal function should be monitored closely both before and during treatment with enalapril (see section 4.4) because hypotension and (more rarely) consequent renal failure have been reported. Serum potassium and renal function should also be monitored.

In order to decrease the possibility of symptomatic hypotension, patients on previous high dose diuretics should have the diuretic dose reduced before introducing enalapril. The appearance of hypotension after the initial dose of enalapril does not preclude subsequent careful dose titration with the drug, following effective treatment of the hypotension.

Some patients are considered to be at higher risk when started on an ACE inhibitor and are recommended for initiation of therapy in hospital. Research data have shown such patients to be: those with severe heart failure; those on multiple or high-dose diuretics (e.g. > 80mg frusemide); patients with hypovolaemia; hyponatraemia (serum sodium < 130mmol/l); pre-existing hypotension (systolic blood pressure < 90mm Hg); patients with unstable cardiac failure; renal impairment (serum creatinine > 150uml/l); those on high-dose vasodilator therapy; patients aged 70 years or over (see 'Precautions').

Use in impaired renal function:

Excretion is primarily by the renal route. Enalapril should therefore be used with caution in patients with renal impairment.

Generally, the intervals between the administration of enalapril should be prolonged and/or the dosage reduced.The dose should be titrated against the response, and should be kept as low as possible to maintain adequate control of blood pressure or heart failure.

Creatinine Clearance (CrCL) mL/min	Initial Dose mg/day
30<CrCL<80 ml/min.	5 - 10 mg
10<CrCL 30 ml/min.	2.5 mg
CrCL 10 ml/min.	2.5 mg on dialysis days*

* See section 4.4.

Enalapril is dialysable. Dialysis patients may be given the usual dose of enalapril on dialysis days. A high incidence of anaphylactoid reactions have been reported in patient dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided. On the days when patients are not on dialysis the dosage should be tailored to the blood pressure response.

Use in the elderly (over 65 years):

The dose should be in line with the renal function of the elderly patient (see section 4.4).

Enalapril has been shown to be effective in the treatment of hypertension in the elderly, and some elderly patients may be more responsive to enalapril than younger patients.

The dose should be titrated according to need for the control of blood pressure. Children:

There is limited clinical trial experience of the use of Enalapril Tablets in hypertensive paediatric patients (see sections 4.4, 5.1 and 5.2).

For patients who can swallow tablets, the dose should be individualized according to patient profile and blood pressure response. The recommended initial dose is 2.5 mg in patients 20 to <50 kg and 5 mg in patients >50 kg. Enalapril is given once daily. The dosage should be adjusted according to the needs of the patient to a maximum of 20 mg daily in patients 20 to <50 kg and 40 mg in patients >50 kg. (See section 4.4.)

Enalapril is not recommended in neonates and in paediatric patients with glomerular filtration rate <30 ml/min/1.73 m2, as no data are available.

4.3 Contraindications

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

•    Hypersensitivity to the product, any of its components or any other ACE inhibitor

•    History of angioneurotic oedema relating to previous treatment with an ACE inhibitor.

•    Hereditary or idiopathic angioedema

•    The concomitant use of Enalapril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Pregnancy and lactation:

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).

Use of enalapril is not recommended during breast feeding (see sections 4.6 and 5.2). Symptomatic hypotension

Symptomatic hypotension has been seen only rarely in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see sections 4.4 and 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment (see Dosage and administration for management of these patients.) In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of Enalapril and/or diuretic is adjusted.

Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension develops, the patient should be placed in a supine position. Volume repletion with oral fluids or intravenous normal saline may be required. Intravenous atropine may be necessary if there is associated bradycardia. A transient hypotensive response is not a contra-indication to further doses, which can usually be given without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with enalapril. This effect is anticipated, and usually is not a reason to discontinue treatment. If such hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or enalapril may become necessary.

The appearance of hypotension after the initial dose of enalapril does not preclude subsequent careful dose titration with the drug after effective management of the hypotension.

Aortic or Mitral Valve Stenosis/Hypertrophic Cardiomyopathy As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Impaired renal function

Pre-treatment assessment of renal function: Evaluation of the patient should include assessment of renal function prior to initiation of therapy, and during treatment where appropriate.

In cases of renal impairment (creatinine clearance <80 ml/min) the initial enalapril dosage should be adjusted according to the patient’s creatinine clearance (see section 4.2) and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients. 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.

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. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis (see 'Renovascular hypertension').

Renovascular hypertension

Enalapril can be used when surgery is not indicated, or prior to surgery. In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and creatinine, reversible upon discontinuation of therapy, have been seen. This is especially likely in patients treated with diuretics and/or those with renal insufficiency. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Kidney Transplantation

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

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis 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.

Neutropenia/Agranulocvtosis

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 pre-existing 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.

Hypersensitivity/Angioneurotic oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases, enalapril should be discontinued immediately and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. 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.

Where there is involvement of the tongue, glottis or larynx, patients are likely to experience airway obstruction, appropriate therapy such as subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Afro-Caribbean patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Afro-Caribbean.

Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also 'Contraindications').

Other hypersensitivity reactions, including urticaria, have been reported.

Anaphylactic reactions during hymenoptera desensitisation Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp venom) have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitisation.

Haemodialysis patients

A high incidence of anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (AN 69®) and treated concomitantly with and ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid reactions during LDL apheresis

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

Hypoglycaemia

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use. (See section 4.5.)

Cough

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

Surgery/anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks angiotensin-II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalaemia include those with 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 those patients taking 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. Hyperkalaemia 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 section 4.5)

Lithium

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

Lactose

Enalapril Tablets contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Enalapril Tablets contains less than 200 mg of lactose per tablet.

Paediatric Use

There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications. Limited pharmacokinetic data are available in children above

2 months of age. (Also see sections 4.2, 5.1, and 5.2.) Enalapril Tablets is not recommended in children in other indications than hypertension.

Enalapril Tablets is not recommended in neonates and in paediatric patients with glomerular filtration rate <30 ml/min/1.73 m2, as no data are available. (See section 4.2.)

Ethnic differences

Where enalapril has been used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response, possibly because of a higher prevalence of low-renin states in the Afro-Caribbean hypertensive population.

Enalapril should not be used in patients with aortic stenosis or outflow obstruction.

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

There is evidence that the 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 (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

4.5 Interaction with other medicinal products and other forms of interaction

Potassium sparing diuretics or potassium supplements Plasma potassium usually remains within normal limits, although cases of hyperkalaemia have been reported. If enalapril is given with a potassium-losing diuretic, the likelihood of diuretic-induced hypokalaemia may be lessened. Enalapril may elevate plasma potassium levels in patients with renal failure. Potassium supplements, potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride) and potassium-containing salt substitutes are not recommended, particularly in patients with impaired renal function, since they may lead to significant increases in plasma potassium. However, if the concomitant use of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of plasma potassium.

Clinical trial data has 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 RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

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 section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of enalapril.

Other antihypertensive agents

Concomitant use of these agents may increase the hypotensive effects of enalapril. 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 with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (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. Long-term controlled clinical trials with enalapril have not confirmed these findings and do not preclude the use in diabetic patients. It is advised, however, that these patients be monitored.

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

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroiods and procainamide

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Including Cyclooxygenase-2 (COX-2) Inhibitors

The administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of an ACE inhibitor. However, in a clinical pharmacology study, indometacin or sulindac was administered to hypertensive patients receiving enalapril and there was no evidence of a blunting of the antihypertensive action of enalapril. Furthermore, it has been described that NSAIDs (including COX-2 inhibitors) and ACE inhibitors exert an addictive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and 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.

Antacids

Induce decreased bioavailability of ACE inhibitors.

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.

Sympathomimetics

May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored, to confirm that the desired effect is being obtained.

Alcohol

Enhances the hypotensive effect with ACE inhibitors.

Ciclosporin

Increases the risk of hyperkalaemia with ACE inhibitors.

Acetyl salicylic acid, thrombolytics and -blockers

Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and -blockers.

4.6 Pregnancy and lactation

Pregnancy:

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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to 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 hypotension (see sections 4.3 and 4.4).

Lactation:

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 in breastfeeding 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 in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

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.

4.8    Undesirable effects

Undesirable effects reported for enalapril include:

[Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).]

Blood and the lymphatic system disorders:

uncommon: anaemia (including aplastic and hemolytic)

rare: neutropenia, decreases in hemoglobin, decreases in hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders: not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders:

uncommon: hypoglycaemia (see 4.4 'Special warnings and precautions for use', Hypoglycemia)

Nervous system and psychiatric disorders: common: headache, depression

uncommon: confusion, somnolence, insomnia, nervousness, paresthaesia, vertigo

rare: dream abnormality, sleep disorders Eye disorders:

very common: blurred vision Cardiac and vascular disorders: very common: dizziness

common: hypotension (including orthostatic hypotension), syncope, chest pain, rhythm disturbances, angina pectoris, tachycardia

uncommon: orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular accident^*, possibly secondary to excessive hypotension in high risk patients (see 4.4 'Special warnings and precautions for use')

rare: Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders:

very common: cough

common: dyspnea

uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/asthma rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia Gastrointestinal disorders: very common: nausea, common: diarrhoea, abdominal pain, taste alteration uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer rare: stomatitis/aphthous ulcerations, glossitis very rare: intestinal angioedema Hepatobiliary disorders:

rare: hepatic failure, hepatitis - either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)

Skin and subcutaneous tissue disorders:

common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see 4.4 'Special warnings and precautions for use')

uncommon: diaphoresis, pruritus, urticaria, alopecia

rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Renal and urinary disorders:

uncommon: renal dysfunction, renal failure, proteinuria rare: oliguria

Reproductive system and breast disorders: uncommon: impotence rare: gynecomastia

General disorders and administration site conditions: very common: asthenia common: fatigue

uncommon: muscle cramps, flushing, tinnitus, malaise, fever Investigations: common: hyperkalemia, increases in serum creatinine

uncommon: increases in blood urea, hyponatremia

rare: elevations of liver enzymes, elevations of serum bilirubin

Incidence rates were comparable to those in the placebo and active control groups in the clinical trials

4.9 Overdose

Limited data are available for overdosage in humans. The most prominent features of overdosage reported to date are marked hypotension, beginning some six 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, dizziness, anxiety, and cough. Serum enalaprilat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300mg and 440mg of enalapril, 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). Enalapril can be removed from the general circulation by haemodialysis. (See section 4.4.) Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Following oral administration, enalapril is rapidly absorbed and hydrolysed to enalaprilat, a highly specific, long-acting, non-sulphydryl angiotensinconverting enzyme inhibitor. Enalaprilat modulates a specific physiological mechanism, the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure. Onset of action begins smoothly and gradually within one hour and the effects continue usually for 24 hours after a single daily dose.

Data indicate no loss of effect during long term therapy. Rebound hypertension does not occur following abrupt cessation of therapy.

Congestive heart failure patients benefit particularly from reduction in preload and after-load of the heart, with an increase in cardiac output, without reflex tachycardia.

Two large randomised, 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 angiotensin II receptor blocker.

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

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. 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 more frequently reported in the aliskiren group than in the placebo group.

5.2. Pharmacokinetic Properties

Following oral administration, peak serum concentrations occur within one hour. Based on urinary recovery, the extent of absorption is approximately 60%. The absorption of enalapril is not affected by food. Peak serum concentrations occur three to four hours after an oral dose. Excretion is primary renal. Approximately 94% of the dose is recovered in the urine and faeces as enalaprilat or enalapril. Enalaprilat is 50% to 60% bound to plasma proteins, its elimination is multiphasic with a half life of 11 hours after multiple doses to patients with normal renal function.

Lactation: After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7frg/L (range 0.54 to 5.9pg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7pg/L (range 1.2 to 2.3pg/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 2pg/L 4 hours after a dose and peak enalaprilat levels of 0.75pg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44pg/L and 0.63pg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2pg/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.

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 does not have serious adverse effects on fertility and reproductive performance in rats, and it is not teratogenic. It crosses the placenta and has been shown to be foetotoxic in rabbits during middle and late pregnancy.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinised maize starch, sodium hydrogen carbonate.

6.2    Incompatibilities

Not Applicable

6.3    Shelf life

30 months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PP container (Securitainer) with desiccant.

Al/Al blisters in cardboard outer container.

Pack sizes: 28 tablets (blister), 50 tablets (securitainer).

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd,

115 Narborough Road,

Leicester,

LE3 0PA,

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0083

14/04/2005

10 DATE OF REVISION OF THE TEXT

27/01/2015