Each tablet contains 20mg Enalapril (as maleate).

Tablet. White circular biplaner uncoated tablets with 20 embossed on one face and score line on the other.

Treatment of hypertension:

All grades of essential hypertension and renovascular hypertension.

Treatment of heart failure:

In heart failure, Enalapril 20mg, tablets should be used as an adjunctive therapy with non-potassium-sparing diuretics and, where appropriate, digitalis. Enalapril 20mg, tablets have 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 20mg, tablets retard the development of symptomatic heart failure, and reduce hospitalisation for heart failure.

Prevention of coronary ischaemic events in patients with left ventricular dysfunction:

Enalapril 20mg, tablets reduce both the incidence of myocardial infarction and hospitalisation for unstable angina pectoris.

The maximum daily dose is 40 mg.

The absorption of Enalapril 20mg, tablets is not affected by food intake.

Essential and renovascular hypertension:

Treatment should be initiated with 5 mg once a day. Where concomitant therapy is a diuretic, the recommended initial dose of Enalapril 20mg, tablets is 2.5 mg (see “With concomitant diuretic therapy”). The dose should be titrated to give optimum control of blood pressure. The usual maintenance dose is 10-20 mg given once daily. In severe hypertension, the dosage may be increased incrementally to a maximum of 40 mg once daily.

The dosage of other antihypertensive agents being used together with Enalapril 20 mg, tablets may need to be adjusted. Where Enalapril 20 mg, tablets replace 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 20 mg, tablets.

With concomitant diuretic therapy:

The recommended initial dose of Enalapril tablets is 2.5 mg. Symptomatic hypotension can occur following the initial dose of Enalapril tablets; this is more likely to occur when Enalapril tablets are 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 20 mg, tablets.

Enalapril 20 mg, tablets minimise the development of thiazide-induced hypokalaemia and hyperuricaemia.

Use in the elderly (over 65 years):

The starting dose should be 2.5 mg. Enalapril 20 mg, tablets are effective in the treatment of hypertension in the elderly. Some elderly patients may be more responsive to Enalapril 20 mg, tablets than younger patients.

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

Heart failure / Asymptomatic left ventricular dysfunction:

The recommended starting dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg once daily initiated under close medical supervision. 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 preventive treatment; however, a repeated measurement may not be necessary in patients with one or more myocardial infarctions and documented reduction in cardiac function.

Following initiation of therapy, the dose should be titrated gradually to the usual maintenance dose of 20 mg, given as a single dose or two divided doses, according to the tolerability of the patient. In patients with symptomatic heart failure, this dosage schedule has been shown to improve survival.

The dose titration of Enalapril 20 mg, tablets may be performed over a two- to four-week period or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. Blood pressure and renal function should be monitored closely both before and during treatment with Enalapril 20 mg, tablets. Serum potassium should also be monitored.

Some patients, other than those with severe heart failure, 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 on multiple or high-dose diuretics (e.g.> 80 mg frusemide); patients with hypovolaemia; hyponatraemia (serum sodium < 130 mmol/l); pre-existing hypotension (systolic blood pressure < 90 mmHg); patients with unstable cardiac failure; renal impairment (serum creatinine> 150 mmol/l); those on high-dose vasodilator therapy; patients aged 70 years or over.

In order to decrease the possibility of symptomatic hypotension, patients on previous high-dose diuretics should have the diuretic dose reduced before introducing Enalapril 20 mg, tablets. The appearance of hypotension after the initial dose of Enalapril 20 mg, tablets does not preclude subsequent careful dose titration with the drug, following effective treatment of the hypotension.

Use in impaired renal function:

Enalapril 20 mg, tablets are excreted by the kidney. It should be used with caution in patients with renal impairment. The recommended starting dose is 2.5 mg. 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.

Enalapril 20 mg, tablets are dialysable. Dialysis patients may be given the usual dose of Enalapril 20 mg, tablets on dialysis days (see “Special warnings and special precautions for use”–“Haemodialysis patients”). On the days patients are not on dialysis, the dosage should be tailored to the bloodpressure response.

Children:

The paediatric use of Enalapril 20 mg, tablets has not been studied.

Pregnancy: Second and third trimesters of pregnancy

Hypersensitivity:

Hypersensitivity to the product or any of the components, and in patients with a history of angioneurotic oedema following previous treatment with an ACE inhibitor.

Pretreatment assessment of renal function:

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

Symptomatic hypotension:

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Enalapril 20 mg, tablets, 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 (see “Posology and method of administration” for management of these patients).

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 20 mg, tablets. 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 20 mg, tablets may become necessary.

Impaired renal function:

Enalapril 20 mg, tablets should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses.

Close monitoring of renal function before and during therapy should be performed as deemed appropriate in those with renal insufficiency. In the majority, renal function will not be altered, or may improve.

Renal failure has been reported in association with Enalapril 20 mg, tablets and has been occurring 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 20 mg, tablets is usually reversible.

Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine when Enalapril 20 mg, tablets have been given concurrently with a diuretic. Dosage reduction of Enalapril 20 mg, tablets and/or discontinuation of the diuretic may be required.

This situation should raise the possibility of an underlying renal artery stenosis (see comment below).

Renovascular hypertension:

Enalapril 20 mg, tablets 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 to occur in patients treated with diuretics and/or those with renal insufficiency.

Angioneurotic oedema:

Angioneurotic oedema has been reported with angiotensin-converting enzyme inhibitors, including Enalapril 20 mg, tablets. This may occur at any time during treatment. In such cases, Enalapril 20 mg, tablets 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 monitored carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, appropriate therapy such as subcutaneous adrenaline (0.5 ml, 1:1000) should be administered promptly.

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”). In particular, black or Afro-Caribbean patients receiving ACE inhibitors have been reported to have a higher incidence of Angioedema compared to nonblacks.

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 has been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided.

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.

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-inhibitorinduced cough should be considered as part of the differential diagnosis of cough.

Surgery / Anesthesia:

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Enalapril 20 mg, tablets block angiotensin-II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.

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

General:

Where Enalapril 20 mg, tablets have been used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.

Enalapril 20 mg, tablets should not be used in patients with aortic stenosis or outflow tract obstruction.

Drug interactions:

Combination with other antihypertensive agents such as beta-blockers, methyldopa, calcium antagonists, and diuretics may increase the antihypertensive efficacy.

Adrenergic-blocking drugs should only be combined with Enalapril 20 mg, tablets under careful supervision. Concomitant propranolol may reduce the bioavailability of Enalapril 20 mg, tablets, but this does not appear to be of any clinical significance.

Concomitant therapy with lithium may increase the serum lithium concentration.

Plasma potassium:

Plasma potassium usually remains within normal limits, although cases of hyperkalaemia have been reported. If Enalapril 20 mg, tablets are given with a potassium-losing diuretic, the likelihood of diuretic-induced hypokalaemia may be lessened. Enalapril 20 mg, tablets may elevate plasma potassium levels in patients with renal failure. Potassium supplements, potassium-sparing diuretics and potassiumcontaining 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.

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 of enalapril in diabetic patients. It is advised however, that caution should be exercised in this patient population.

Narcotic drugs / Antipsychotics:

Postural hypotension may occur with ACE inhibitors.

Allopurinol, cytostatic or immunosuppressive agents, systematic corticosteroids or procainamide:

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

Non-steroidal anti-inflammatory drugs:

The administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of an ACE inhibitor. However, in a clinical pharmacology study indomethacin or sulindac was administered to hypertensive patients receiving Enalapril 20 mg, tablets and there was no evidence of a blunting of the antihypertensive action of Enalapril 20 mg, tablets. Furthermore, it has been described that NSAIDS and ACE inhibitors exert an additive 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.

Antacids:

Induce decreased bioavailability of ACE inhibitors.

Sympathomimetics:

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

Alcohol:

Alcohol enhances the hypotensive effect of ACE inhibitors.

Cyclosporin:

Cyclosporin increases the risk of hyperkalaemia with ACE inhibitors.

Severe hypotension and renal failure have occurred in association with therapy with Enalapril 20 mg, tablets. These appear to occur in certain specific sub-groups. 

Other adverse reactions:

Dizziness and headaches are the most commonly reported side effects. Less frequently, fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, and cough have been reported. Even less frequently, renal dysfunction, renal failure, and oliguria have been reported.

Rarely reported side effects include:

Cardiovascular: myocardial infarction or cerebrovascular accident, possibly secondary to severe hypotension in high-risk patients (see “Special warnings and special precautions for use”), chest pain, palpitations, rhythm disturbances, angina pectoris.

Gastro-intestinal: ileus, pancreatitis, hepatic failure, hepatitis - either hepatocellular or cholestatic, jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.

Nervous system / Psychiatric: depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo.

Respiratory: pulmonary infiltrates, bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat, and hoarseness.

Skin: diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.

Other: impotence, flushing, taste alteration, tinnitus, glossitis, blurred vision.

A complex of symptoms has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Hypersensitivity / Angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely.

Laboratory test findings: increases in blood urea and plasma creatinine, reversible on discontinuation of Enalapril 20 mg, tablets, are most likely to occur in the presence of severe heart failure or bilateral renal artery stenosis, especially in patients with renal insufficiency (see “Special warnings and special precautions for use”). However, increases in blood urea and plasma creatinine may occur without evidence of preexisting renal impairment, especially in patients taking diuretics. In this event, undiagnosed renal artery stenosis should be suspected. Dosage reduction of Enalapril 20 mg, tablets and/or discontinuation of the diuretic should be considered.

Hyperkalaemia and hyponatraemia have also been reported in a few cases (for further information see “Interactions with other medicaments and other forms of interaction – Plasma potassium”).

Decreases in haemoglobin and haematocrit as well as elevation of liver enzymes and/or serum bilirubin have been reported in a few patients, and are usually reversible upon discontinuation of Enalapril 20 mg, tablets.

Decreases in platelets and white cell count, and rare cases of neutropenia, thrombocytopenia, bone-marrow depression, and agranulocytosis have been reported, but a causal relationship to Enalapril 20 mg, tablets has not been established.

IPG Pharma Ltd.

POM- Prescription Only Medicine

05 November 2010