ALAPREN Tablet Ref.[50543] Active ingredients: Enalapril

Should a woman become pregnant while receiving ALAPREN TABLETS, the treatment must be stopped promptly and switched to a different class of medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication. (See Section 4.3 and 4.6).

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 ALAPREN TABLETS and aliskiren is therefore contraindicated (see Section 4.3). ALAPREN TABLETS should not be used concomitantly with aliskiren. (see Section 4.3).

ALAPREN TABLETS can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the 2nd and 3rd trimesters (see Section 4.3 and 4.4).

Assessment of renal function prior to initiation of ALAPREN TABLETS and during treatment with ALAPREN TABLETS should be included in the evaluation of patient, where appropriate.

Symptomatic hypotension: Symptomatic hypotension can occur especially in patients who are volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see Section 4.5 and 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension is most likely to occur in those with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment (see Section 4.2) for management of these patients). In these patients, therapy should be started under medical supervision and the patient should be monitored closely whenever the dose of ALAPREN TABLETS and/or diuretic is adjusted. Similarly, patients with ischaemic heart or cerebrovascular disease may develop an excessive fall in blood pressure which could result in a myocardial infarction or cerebrovascular accident.

If hypotension develops, suitable management including placing the patient in a supine position and, if necessary, an intravenous infusion of normal saline may be required. A transient hypotensive response is not a contraindication to further doses, which can be given with monitoring once the blood pressure is increased after volume expansion.

Some patients with heart failure who have normal or low blood pressure could develop additional lowering of systemic blood pressure following ALAPREN TABLETS administration. If symptomatic hypotension occurs, a reduction of dose of ALAPREN TABLETS and/or discontinuation of the diuretic may be necessary (see Section 4.2).

Impaired Renal Function: Caution should be exercised when using ALAPREN TABLETS in patients with renal insufficiency. Such patients may require reduced or less frequent doses (see Section 4.2). The renal function should be monitored before and during therapy in those with renal insufficiency.

Renovascular hypertension: ALAPREN TABLETS is contraindicated in renovascular hypertension (see Section 4.3).

Kidney Transplantation: There is no experience regarding the administration of ALAPREN TABLETS in patients with recent kidney transplantation. Treatment with ALAPREN TABLETS is therefore not recommended.

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/reninangiotensin receptor blockers.

Hepatic failure: Patients receiving ALAPREN TABLETS who develop jaundice or marked elevations of hepatic enzymes should discontinue ALAPREN TABLETS and receive appropriate medical follow-up.

Neutropenia/Agranulocytosis: Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors including ALAPREN TABLETS. ALAPREN TABLETS 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.

Hypersensitivity/Angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been seen to occur following treatment with ALAPREN TABLETS. This may occur at any time during treatment. In such cases, ALAPREN TABLETS should be discontinued immediately and appropriate monitoring should be taken to ensure complete resolution of symptoms prior to discharging the patient. Angioneurotic oedema associated with laryngeal oedema may be fatal. Involvement of the tongue, glottis or larynx, likely to cause airways obstruction, necessitates emergency measures such as prompt administration of subcutaneous adrenaline (0,3-0,5 ml, 1:1000).

Black patients receiving ALAPREN TABLETS have been reported to have a higher incidence of angioedema compared with non-black patients.

Patients with a history of angioedema unrelated to ALAPREN TABLETS should be considered to be at increased risk of angioedema while receiving ALAPREN TABLETS (see also Section 4.3).

Anaphylactic reactions during hymenoptera desensitisation: Patients receiving ALAPREN TABLETS during desensitisation with hymenoptera venom (e.g. bee or wasp venom) have been found to experience life threatening hypersensitivity reactions. Temporarily withholding ALAPREN TABLETS therapy prior to each desensitisation can help avert such reactions.

Hypersensitivity reactions during LDL apheresis: Less frequently, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening hypersensitivity reactions. These reactions may be avoided by withholding ALAPREN TABLETS therapy prior to each apheresis.

Haemodialysis patients: In patients dialysed with high-flux membranes and treated concomitantly with ALAPREN TABLETS a high incidence of anaphylactoid reactions have been reported. It is recommended that in such patients a different type of dialysis membrane or a different class of antihypertensive agent should be used.

Hypoglycaemia: Diabetic patients treated with oral antidiabetic agents or insulin starting ALAPREN TABLETS, should be told to closely monitor for hypoglycaemia, especially during the first month of combined use.

Surgery/Anaesthesia: ALAPREN TABLETS blocks the formation of angiotensin-II secondary to compensatory renin release in patients undergoing major surgery or during anaesthesia with agents that cause hypotension. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Serum potassium: See Section 4.5.

Excipients

ALAPREN TABLETS contain lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

ALAPREN TABLETS contain soodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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 Section 4.3 and 4.4).

Antihypertensive Therapy

The combination of ALAPREN TABLETS with other antihypertensive medicines may increase the antihypertensive effect, especially in combination with diuretics.

The combination of ALAPREN TABLETS with ß-adrenergic blocking agents and methyldopa or calcium entry blockers potentiates the hypotensive effects of ALAPREN TABLETS. Ganglionic blocking agents or adrenergic blocking agents, combined with ALAPREN TABLETS, should only be administered with careful observation of the patient.

Because of lack of experience, concomitant treatment of ALAPREN TABLETS with calcium antagonists is not recommended.

Concomitant use with nitroglycerine and other nitrates, or other vasodilators, may increase the risk of hypotension.

Serum Lithium

Lithium elimination may be reduced. See Section 4.3.

Serum Potassium

Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium containing salt substitutes. ALAPREN TABLETS may elevate serum potassium levels in patients with renal impairment. 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. See Section 4.3.

Non-steroidal anti-inflammatory medicines including selective cyclooxygenase-2 inhibitors

Non-steroidal anti-inflammatory medicines (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the antihypertensive effect of ALAPREN TABLETS. The co-administration of NSAIDs (including COX-2 inhibitors) with ALAPREN TABLETS exert an additive effect on the increase in serum potassium, and may result in a deterioration of renal function, including acute renal failure, especially in patients with compromised renal function (such as the elderly or patients who are volume-depleted, including those on diuretic therapy).

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ALAPREN TABLETS therapy.

Antidiabetics

Concomitant administration of ALAPREN TABLETS 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.

Others

Concomitant use of general anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ALAPREN TABLETS may result in further reduction of blood pressure.

Concomitant administration of allopurinol, cytostatic or immuno-suppressive agents, systemic corticosteroids or procainamide with ALAPREN TABLETS may increase the risk for leucopenia (see Section 4.4. Neutropenia/Agranlocytosis).

Concomitantly administered cyclosporin increases the risk of hyperkalaemia with ALAPREN TABLETS.

Since sympathomimetics may reduce the antihypertensive effects of ALAPREN TABLETS, careful monitoring of blood pressure should occur when these medicines are used concomitantly with ALAPREN TABLETS.

Alcohol enhances the hypotensive effect of concomitantly administered ALAPREN TABLETS.

Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury. See Section 4.3.

A case series of 16 reports of acute kidney injury (AKI) associated with enalapril and ciprofloxacin as co-suspect or interacting medicines was identified in VigiBase, the WHO global database of individual case safety reports. Analysis of 11 cases indicated that in most patients although clinical conditions and a number of medicines were likely to have increased their risk of AKI, including ACE inhibitor-related AKI, the event did not occur until after a ciprofloxacin prescription, lending weight to ciprofloxacin being the cause or a combined action of ciprofloxacin and enalapril. Furthermore, the interaction between ACE inhibitors and fluoroquinolones to precipitate acute kidney injury is a class effect for all ACE inhibitors and not just enalapril, and also a class effect of all the fluroquinolones not just with ciprofloxacin. Thus, concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury. See Section 4.3.

Pregnancy

The use of ALAPREN TABLETS is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ALAPREN TABLETS during pregnancy (see Section 4.3). 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 ALAPREN TABLETS should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE inhibitors 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. ALAPREN TABLETS 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 ALAPREN TABLETS 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).

Lactation

Enalapril and enalaprilat are secreted into the breast milk.

ALAPREN TABLETS is contraindicated in women breastfeeding their babies.

ALAPREN TABLETS may cause dizziness or weariness. Patients should be warned not to drive or use machines, until their individual susceptibility to the effects of ALAPREN TABLETS is known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/

Not applicable.