Angiotension Converting Enzyme (ACE) inhibitor – ATC Code: C09AA02

enalapril maleate

One tablet contains 5 mg enalapril maleate. Excipients: Each tablet contains 184.2mg lactose monohydrate

Tablet. White or off-white oblong biconvex tablet with bevelled edge, breakline engraved on one face

• Treatment of hypertension

• Treatment of symptomatic heart failure

• Prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction 35%).

The absorption of enalapril is not affected by food.

The dose should be individualised according to patient profile and blood pressure response.

Hypertension

The initial dose is 5 to maximally 20 mg, depending on the degree of hypertension and the condition of the patient (see below). Enalapril is given once daily. In mild hypertension, the recommended initial dose is 5 to 10 mg. Patients with a strongly activated renin-angiotensin-aldosterone 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. A starting dose of 5 mg or lower is recommended in such patients and the initiation of treatment should take place under medical supervision.

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril. A starting dose of 5 mg or lower is recommended in such patients. If possible, diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with enalapril. Renal function and serum potassium should be monitored.

The usual maintenance dose is 20 mg daily. The maximum maintenance dose is 40 mg daily.

Heart failure/Asymptomatic left ventricular dysfunction

In the management of symptomatic heart failure, enalapril is used in addition to diuretics and, where appropriate, digitalis or beta-blockers. The initial dose of enalapril in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and it should be administered under close medical supervision to determine the initial effect on the blood pressure. In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with enalapril 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. This dose titration is recommended to be performed over a 2 to 4 week period. The maximum dose is 40 mg daily given in two divided doses.

Suggested dosage titration of enalapril in patients with heart failure/asymptomatic left ventricular dysfunction

*Special precautions should be followed in patients with impaired renal function or taking diuretics.

Blood pressure and renal function should be monitored closely both before and after starting treatment with enalapril because hypotension and (more rarely) consequent renal failure have been reported. In patients treated with diuretics, the dose should be reduced if possible before beginning treatment with enalapril. The appearance of hypotension after the initial dose of enalapril does not imply that hypotension will recur during chronic therapy with enalapril and does not preclude continued use of the drug. Serum potassium and renal function also should be monitored.

Dosage in renal insufficiency

Generally, the intervals between the administration of enalapril should be prolonged and/or the dosage reduced.

* See Precautions.

Enalaprilat is dialysable. Dosage on non-dialysis days should be adjusted depending on the blood pressure response.

There is limited clinical trial experience of the use of enalapril in hypertensive paediatric patients.

For patients who can swallow tablets, the dose should be individualised 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.

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.

The dose should be in line with the renal function of the elderly patient.

• Hypersensitivity to enalapril, to any of the excipients or any other ACE inhibitor

• History of angioedema associated with previous ACE-inhibitor therapy

• Hereditary or idiopathic angioedema

• Second and third trimesters of pregnancy

Symptomatic hypotension

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, symptomatic 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. 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. 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 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 contra-indication to further doses, which can be given usually 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 hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or enalapril may be necessary.

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.

Renal function impairment

In cases of renal impairment (creatinine clearance <80 ml/min) the initial enalapril dosage should be adjusted according to the patient's creatinine clearance 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.

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 with low doses, careful titration, 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.

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.

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 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 promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of the tongue only 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 angioedema 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 adrenaline (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 non-blacks.

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

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 desensitisation.

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.

Haemodialysis patients

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.

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.

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 diagnosis 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. If hypotension occurs and is considered to be due to this mechanism, it 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, inter-current events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (eg. 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). 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.

Lithium

The combination of lithium and enalapril is generally not recommended.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

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. Enalapril is not recommended in children in other indications than hypertension.

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.

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.

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 anti-hypertensive 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.

Potassium-sparing diuretics or 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 increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.

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. 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.

Tricyclic antidepressants/Antipsychotics/Anaesthetics/Narcotics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor.

NSAIDs including COX-2 inhibitors) and 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.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

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.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetyl salicylic acid, thrombolytics and β - blockers

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

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.

Undesirable effects reported for enalapril include:

Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <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 haemolytic).

Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.

Metabolism and nutrition disorders:

Uncommon: hypoglycaemia.

Nervous system and psychiatric disorders:

Common: depression, headache.

Uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, 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.

Rare: Raynaud's phenomenon.

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

Respiratory, thoracic and mediastinal disorders:

Very common: cough.

Common: dyspnoea.

Uncommon: bronchospasm/asthma, rhinorrhoea, sore throat and hoarseness.

Rare: allergic alveolitis/eosinophilic pneumonia, pulmonary infiltrates, rhinitis.

Gastro-intestinal disorders:

Very common: nausea.

Common: diarrhoea, abdominal pain, taste alteration.

Uncommon: ileus, pancreatitis, peptic ulcer, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth.

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: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported, rash.

Uncommon: diaphoresis, pruritus, urticaria, alopecia.

Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, pemphigus, erythema multiforme, 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 failure, renal dysfunction, 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: hyperkalaemia, increases in serum creatinine.

Uncommon: increases in blood urea, hyponatraemia.

Rare: elevations of liver enzymes, elevations of serum bilirubin.

Endocrine disorders

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

Zentiva

(POM)

29 March 2012