Enalapril 20 Mg/2,5 mg/5 mg/10 mg Tablets

ENALAPRIL UNIMED is indicated in:

• Hypertension: All degrees of essential hypertension. Renovascular hypertension.
• Heart failure: Enalapril maleate can improve existing symptoms and prognosis and diminish the mortality rate and need for hospitalisation, generally with non-potassium-sparing diuretics for heart failure and digitalis for severe heart failure. (section 5.1)
• Asymptomatic Left Ventricular Dysfunction: In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction u2264 35 %) enalapril maleate decreases the rate of development of overt heart failure and decreases the incidence of hospitalisation for heart failure (see section 5.1)

Posology

Essential hypertension: The usual initial dose for mild hypertension is 10 mg once daily. For other degrees of hypertension, 20 mg once a day is recommended. If required, the dosage may be increased gradually over a period of 2 to 4 weeks (or quicker if symptoms so require) to a maintenance dose adjusted according to the needs of the patient. The usual maintenance dose is one 20 mg tablet daily.

Renovascular hypertension: Therapy should be initiated with a lower starting dose (e.g., 5 mg or less) once a day and then be adjusted according to the needs of the patient. Most patients usually respond to one 20 mg tablet, once daily. Caution is recommended for patients recently treated with diuretics.

Asymptomatic left ventricular dysfunction: Therapy should be under close medical supervision to determine the initial effect on blood pressure. The usual initial dose is 2,5 mg once a day, increased gradually over 2 to 4 weeks following management of any symptomatic hypotension, to a daily maintenance dose of usually 20 mg either once a day or in two divided doses as required by the patient response. Initiation of preventative treatment may be considered straightforward for patients with a history of myocardial infarction and whose cardiac function tests have been shown to necessitate it; in other cases, systolic left ventricular dysfunction ought to be shown, e.g., by echocardiography or equivalent technique.

Heart failure: (Co-administration with non-potassium-sparing diuretic or digitalis). Therapy should be started under close medical supervision or (for severe heart failure) in hospital. The usual initial dose is 2,5 mg once a day, increased gradually over a period of 2 to 4 weeks (or quicker, if signs and symptoms of heart failure are present) to the daily maintenance dose of usually 20 mg either once a day or in two divided doses. Hypotension and consequent renal failure have been reported following initiation of therapy. If hypotension is caused by the initial dose and is managed appropriately it need not necessitate cessation of enalapril maleate therapy. If it cannot be managed and becomes symptomatic, revision of the therapeutic regimen is required. Serum potassium should also be monitored (see section 4.5).

Concomitant Therapy: Dosage adjustment of additional antihypertensive agents in the therapeutic regimen may be necessary. Gradual reduction of the dosage of any beta-blocker in the therapeutic regimen is required, as the dosage of enalapril is titrated up. There is an increased likelihood of hypotension when enalapril is added to current diuretic therapy. If it is possible, the dose of the diuretic should be decreased or discontinued 2 - 3 days prior to the start of enalapril therapy, especially as these patients may be volume or salt depleted. If this is not possible, the initial dose of ENALAPRIL UNIMED should be low (5 mg or less) to determine the initial effect on the blood pressure. Dosages should then be adjusted according to patient needs.

Special populations

Dosage in Renal Insufficiency: The minimum maintenance dose that controls symptoms is desirable.

Renal Status

Method of administration

Oral use. ENALAPRIL UNIMED may be taken at any time irrespective of meals, as its absorption is not affected by food.

Enalapril maleate tablets are contraindicated in patients who are hypersensitive to the medicine or any of the excipients in the tablets. Enalapril tablets are also contraindicated in patients who have:

• had previous treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB) that resulted in angioneurotic oedema. These patients must never again be given these medicines.
• hereditary or idiopathic angioedema
• hypertrophic obstructive cardiomyopathy (HOCM)
• severe renal function impairment (creatinine clearance less than 30 mL/min)
• bilateral renal artery stenosis
• renal artery stenosis in patients with a single kidney
• aortic stenosis.
• concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, amiloride
• porphyria
• lithium therapy: Concomitant administration with ENALAPRIL UNIMED may lead to toxic blood concentration of lithium.
• Pregnancy and lactation (see section 4.6)

Should a woman become pregnant while receiving an ACE inhibitor, the treatment must be stopped promptly and the patient switched to a different medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication. (see section 4.2 and 4.6).

u2022 ACE-inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the 2nd and 3rd trimesters. ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydraminosis, which may result in limb contractures, craniofacial deformities and hypoplastic lung development, as well as hypotension, hyperkalaemia, oliguria and anuria in newborns, have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.

Infants whose mothers have taken ENALAPRIL UNIMED should be closely observed for hypotension, oliguria and hyperkalaemia. These adverse effects to the embryo and foetus, do not appear to have resulted from intra-uterine ACE-inhibitor exposure, limited to the first trimester. Enalapril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit.

Symptomatic Hypotension:

• In some uncomplicated hypertensive patients receiving ENALAPRIL UNIMED, 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 section 4.5 and 4.8).
• Symptomatic hypotension has been observed in patients with heart failure, who may also have associated renal insufficiency. 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.
• An excessive fall in blood pressure in ischaemic heart or cerebrovascular diseased patients could result in myocardial infarction or cerebrovascular accident. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of ENALAPRIL UNIMED and/or diuretic is adjusted.
• 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. In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with ENALAPRIL UNIMED.

This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of ENALAPRIL UNIMED may be necessary.

Renal function Impairment:

• Renal insufficiency results in decreased dose requirements. (see sections 4.2 and 4.3). In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and serum creatinine, reversible upon discontinuation of therapy, have been seen. (see section 4.3). This is especially likely in patients with renal insufficiency. Some patients with no apparent pre-existing renal disease have developed minor and usually transient increases in blood urea and serum creatinine when ENALAPRIL UNIMED has been given concomitantly with a diuretic. Dosage reduction of ENALAPRIL UNIMED and/or discontinuation of the diuretic may be required.

Hypersensitivity/Angioneurotic Oedema:

• Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with angiotensin-converting enzyme inhibitors, including ENALAPRIL UNIMED. In such cases, ENALAPRIL UNIMED should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
• Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy such as subcutaneous adrenaline (epinephrine) solution 1:1 000 (0,3 ml to 0,5 ml) should be administered promptly. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. These patients should never receive any ENALAPRIL UNIMED or any other ACE inhibitor or angiotensin receptor blockers again.
• 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 desensitisation.

Haemodialysis Patients:

• Anaphylactoid reactions have been reported in patients exposed to high-flux membranes dialysis (e.g., AN 69u00ae) or low-density lipoprotein apheresis with dextran sulfate while treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or methods of LDL apheresis; or a different class of antihypertensive agent.

Cough:

• A non-productive, persistent cough has been reported with the use of ACE-inhibitors. The cough resolves after therapy discontinuation. 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 maleate 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.

Severe autoimmune disease, especially systemic lupus erythematosus, other collagen vascular disease or scleroderma: Increased risk for development of neutropenia or agranulocytosis.

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 UNIMED 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 UNIMED 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.

In acute myocardial infarction, treatment with ENALAPRIL UNIMED should not be initiated in patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 u03bcmol/L or proteinuria exceeding 500 mg/24 hours). If renal dysfunction develops during treatment (serum creatinine concentrations exceeding 177 u03bcmol/L or doubling of the pre-treatment value) then ENALAPRIL UNIMED may need to be withdrawn (see section 4.3).

Hypotension in acute myocardial infarction - treatment with ENALAPRIL UNIMED must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These include patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2,5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then ENALAPRIL UNIMED should be withdrawn.

Bone marrow depression u2013 Increased risk of agranulocytosis and neutropenia.

Diabetes mellitus u2013 Increased risk of hyperkalaemia, as well as hypoglycaemia may occur.

Hyperkalaemia u2013 ENALAPRIL UNIMED may cause an increase in serum potassium levels.

ENALAPRIL UNIMED causes a higher rate of angioedema in black patients than in non-black patients.

Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, amiloride may lead to hyperkalaemia, which may be severe and lead to cardiac conduction abnormalities, dysrhythmias and cardiac arrest. (see section 4.5).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) - There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ENALAPRIL UNIMED and aliskiren is therefore contraindicated (see section 4.3). ENALAPRIL UNIMED should not be used concomitantly with aliskiren. (see section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients. (See section 4.3). Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolones or ACE inhibitors/renin-angiotensin receptor blockers.

ENALAPRIL UNIMED contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take ENALAPRIL UNIMED.

ENALAPRIL 2,5 mg/ 5 mg / 10 mg/ 20 mg UNIMED contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium-freeu2019.

Paediatric population

There is limited documentation of use in children. Use of enalapril in children is not recommended since safety and efficacy has not been completely established.

Antihypertensive Therapy:

• The combination of ENALAPRIL UNIMED with other antihypertensive medicines, may increase the antihypertensive effect, especially in combination with diuretics. Dosage adjustments may be necessary during concurrent use or when one medicine is discontinued.
• The combination of ENALAPRIL UNIMED with beta-adrenergic blocking agents and methyldopa or calcium entry blockers may potentiate the hypotensive effects of ENALAPRIL UNIMED.
• Ganglionic blocking agents or adrenergic blocking agents, combined with ENALAPRIL UNIMED, should be administered with careful observation of the patient.
• Because of lack of experience, concomitant treatment of ENALAPRIL UNIMED with calcium antagonists is not recommended.

Serum Potassium:

Risk factors for the development of hyperkalaemia of ENALAPRIL UNIMED include renal insufficiency, diabetes mellitus and concomitant use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes. In patients with renal failure, the administration of ENALAPRIL UNIMED may lead to elevation of serum potassium. The use of potassium supplements, potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Serum Lithium:

Lithium elimination may be reduced. Therefore, the serum lithium levels should be carefully compared if lithium salts are to be administered.

Antidiabetics:

Epidemiological studies have suggested that concomitant administration of ACE inhibitors as in ENALAPRIL UNIMED 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. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia.

Non-steroidal anti-inflammatory agents including Selective Cyclooxygenase-2 Inhibitors:

Non-steroidal anti-inflammatory medicines (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) u2013 reduce the antihypertensive effects of ENALAPRIL UNIMED. Blood pressure monitoring should be increased when any NSAID (including a selective COX-2 inhibitor) is added or discontinued in a patient treated with ENALAPRIL UNIMED. In patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co-administration of ENALAPRIL UNIMED may result in a further deterioration of renal function. These effects are usually reversible.

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 as in ENALAPRIL UNIMED therapy including enalapril.

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren:

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 (see sections 4.3, 4.4).

Fluoroquinolones:

Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3). This may lead to renal impairment due to altered renal haemodynamics in particular clinical situations.

Pregnancy

The use of ENALAPRIL UNIMED is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ENALAPRIL UNIMED during pregnancy (see section 4.3). 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 ENALAPRIL UNIMED should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE inhibitors as in ENALAPRIL UNIMED during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations. ENALAPRIL UNIMED passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of ENALAPRIL UNIMED during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see section 4.3).

Breastfeeding mothers:

Caution should be exercised when enalapril is prescribed for lactating mothers as enalapril and enalaprilat are secreted in human milk. Therefore, the use of ENALAPRIL UNIMED is not recommended in women breastfeeding their babies (see section 4.3).

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

Tabulated list of adverse reactions

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with Enalapril Maleate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of ENALAPRIL UNIMED is important. It allows continued monitoring of the benefit/risk balance of ENALAPRIL UNIMED. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Limited data are available for overdosage in humans.

Symptoms

The most prominent feature of overdosage reported to date, is marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, electrolyte disturbances, renal failure and stupor.

Treatment

Treatment is symptomatic and supportive. If ingestion is recent, induce emesis. Activated charcoal may be given in severe overdosage if the patient presents within 1 hour of ingestion. Treatment consists of volume expansion by intravenous infusion of 0,9 % sodium chloride solution to correct hypotension and treating dehydration and electrolyte imbalances. Enalapril maleate may be removed from the general circulation by haemodialysis.