Zestril 5 mg, 10 mg and 20 mg Tablet

Hypertension: ZESTRIL is indicated in the treatment of mild to moderate hypertension. It may be used alone or concomitantly with other classes of antihypertensive medicines.

Congestive heart failure: ZESTRIL is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis.

Acute myocardial infarction: ZESTRIL is indicated for the treatment of haemodynamically stable patients, within 24 hours after acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. Administration is by the oral route.

Posology ZESTRIL should be administered in a single daily dose. ZESTRIL should be taken at approximately the same time each day. Absorption of ZESTRIL tablets is not affected by food, and tablets may be administered before, during or after meals. Dosage should be adjusted according to blood pressure response.

Mild to moderate hypertension: The recommended starting dose is 10 mg. The usual effective maintenance dosage is 20 mg administered in a single daily dose. A maximum dose of 40 mg a day in hypertension is recommended. If the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks on a certain dose level, the dose can further be increased.

Diuretic-treated patients: Symptomatic hypotension may occur following initiation of therapy with ZESTRIL; this is more likely in patients who are being treated currently with diuretics. Caution is recommended in all patients who may be volume- and/or salt-depleted. The diuretic should be discontinued 2 to 3 days before beginning therapy with ZESTRIL (see section 4.4). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with ZESTRIL should be initiated with a 5 mg dose. The subsequent dosage of ZESTRIL should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

Dosage adjustment in renal impairment: A lower dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued and in patients who are volume- and/or salt-depleted for any reason. Dosage in patients with renal impairment should be based on creatinine clearance as outlined below:

Creatinine clearance (ml/min) Starting dose (mg/day) 31-80 5-10 The dosage may be titrated upward until blood pressure is controlled or to a maximum of 20 mg daily.

Renovascular hypertension: Special care to be exercised in some patients with renovascular hypertension because of the possibility of exaggerated response. The dosage should be lowered to 2,5 mg or 5 mg and the patient should be monitored.

Congestive heart failure: In patients not adequately controlled by digitalis and/or diuretics, ZESTRIL may be added in a starting dose of 2,5 mg once a day. Dose adjustment should be based on the clinical response of the individual patients. The dose of ZESTRIL should be increased:

• by increments of no greater than 10 mg
• at intervals of no less than 2 weeks
• to the highest dose tolerated by the patient up to a maximum of 35 mg once daily.

Patients at high risk of symptomatic hypotension, e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, prior to therapy with ZESTRIL. The effect of the starting dosage of ZESTRIL on blood pressure should be monitored carefully.

Acute myocardial infarction: Treatment with ZESTRIL may be started within 24 hours of the onset of symptoms. The first dose of ZESTRIL is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Patients with a low systolic blood pressure (120 mm Hg or less) when treatment is started or during the first 3 days after the infarct should be given a lower dose - 2,5 mg orally (see section 4.4). If hypotension occurs (systolic blood pressure less than or equal to 100 mm Hg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2,5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mm Hg for more than 1 hour), ZESTRIL should be withdrawn. Dosing should continue for 6 weeks. The benefit appears to be greatest in patients with large myocardial infarctions and evidence of impaired left ventricular function. Patients who develop symptoms of heart failure should continue with ZESTRIL (see section 4.2 for congestive heart failure). ZESTRIL is compatible with intravenous or transdermal glyceryl trinitrate.

Special Populations Use in the elderly: There are no age-related changes in the efficacy or safety profile of the agent. When advanced age is associated with a decrease in renal function, however, the guidelines set out in the dose adjustment table (see renal impairment above) should be used to determine the starting dose of ZESTRIL. Thereafter, the dosage should be adjusted according to the blood pressure response. Paediatric use: Safety and effectiveness of ZESTRIL in children has not been established.

Nursing mothers: The safety of ZESTRIL has not been established in nursing mothers. ZESTRIL is contraindicated:

• Hypersensitivity to any of the components of ZESTRIL
• A history of angioedema related therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema (see section 4.4).
• Severe renal function impairment (creatinine clearance less than 30 ml/min).
• Hypertrophic obstructive cardiomyopathy (HOCM).
• 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 (see section 4.5).
• Porphyria.
• Lithium therapy: Concomitant administration with ZESTRIL may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of ZESTRIL with aliskiren-containing products is contraindicated (see section 4.4)
• Concomitant use of fluoroquinolones with ACE inhibitors/Renin-Angiotensin blockers is contraindicated in patients with moderate to severe renal impairment (see section 4.5).

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

The adverse effects to the embryo and foetus do not appear to have resulted from intra- uterine ACE inhibitor exposure limited to the first trimester. Should a woman become pregnant while receiving ZESTRIL, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Infants whose mothers may have taken ZESTRIL should be closely observed for hypotension, oliguria and hyperkalaemia. Lisinopril crosses the human placenta. Limited experience indicates that peritoneal dialysis may be of some benefit in the clearance of lisinopril from the neonatal circulation. Lisinopril can theoretically be removed from the neonatal circulation by exchange transfusion.

Symptomatic hypotension: Symptomatic hypotension may occur in uncomplicated hypertensive patients. In hypertensive patients receiving ZESTRIL, 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 congestive 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, initiation of therapy and dose adjustment should be monitored under close medical supervision.

Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom 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 congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with ZESTRIL. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of ZESTRIL may be necessary.

Hypotension in acute myocardial infarction: Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mm Hg 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 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2,5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then ZESTRIL should be withdrawn.

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 increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ZESTRIL or aliskiren is therefore contraindicated (see section 4.3). ZESTRIL should not be used concomitantly with aliskiren (see section 4.3). ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ZESTRIL may block 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.

Renal function impairment: In patients with congestive heart failure, hypotension following the initiation of therapy with ZESTRIL may lead to some further impairment in renal function. Acute renal failure, has been reported in this situation. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, especially when ZESTRIL has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ZESTRIL and/or discontinuation of the diuretic and/or ZESTRIL may be required.

In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/litre and/or proteinuria exceeding 500 mg/24 hours. If renal dysfunction develops during treatment with ZESTRIL (serum creatinine concentration exceeding 265 micromol/litre or a doubling from the pre-treatment value) then the physician should consider withdrawal of ZESTRIL.

Hypersensitivity/Angio-oedema: Angio-oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ZESTRIL. This may occur at any time during therapy. In such cases, ZESTRIL should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with anti-histamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angio-oedema 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. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. These patients should never receive any ACE inhibitor again. ZESTRIL causes a higher rate of angio-oedema in black patients than in non-black patients. Patients with a history of angio-oedema unrelated to ACE inhibitor therapy may be at increased risk of angio-oedema while receiving an ACE inhibitor (see section 4.3).

Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) or tissue plasminogen activator may increase the risk of angioedema (see section 4.5).

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 ZESTRIL (see section 4.5).

Haemodialysis patients: Anaphylactoid reactions have been reported in patients undergoing certain haemodialysis procedures (e.g. with the high flux membrane AN 69 and during low-density lipoproteins (LDL) apheresis with dextran sulphate) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Desensitisation: Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent rechallenge.

Cough: Cough has been reported with the use of ZESTRIL. 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.

Serum potassium: See section 4.5. 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.

Antihypertensive medicines: When combined with other antihypertensive medicines, additive falls in blood pressure may occur. 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 and 4.4).

Medicines that may increase the risk of angioedema: Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) or tissue plasminogen activator may increase the risk of angioedema.

Diuretics: When a diuretic is added to the therapy of a patient receiving ZESTRIL, the antihypertensive effect is additive. Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may experience an excessive reduction of blood pressure when ZESTRIL is added. The possibility of symptomatic hypotension with ZESTRIL can be minimised by discontinuing the diuretic prior to initiation of treatment with ZESTRIL.

Antidiabetics: 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.

Lithium: Lithium elimination may be reduced (see section 4.3).

Potassium supplements, potassium-sparing agents or potassium-containing salt substitutes and other medicines that may increase serum potassium levels: Serum potassium tends to rise but usually remains within normal limits, however hyperkalaemia may occur. 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 and other medicines that may increase serum potassium levels (e.g., heparin, cotrimoxazole). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes and other medicines that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Concomitant use of ZESTRIL and any of the above-mentioned agents is contraindicated (see 4.3).

Other agents: Indomethacin may diminish the antihypertensive efficacy of concomitantly administered ZESTRIL. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDs), the co-administration of lisinopril may result in further deterioration in renal function.

Fluoroquinolones: Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blocker may precipitate acute kidney injury (see section 4.3). The interaction between ACE inhibitors and fluoroquinolones to precipitate acute kidney injury is a class effect for all ACE inhibitors and class effect of all the fluoroquinolones. Thus, concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury. See Section 4.3. ZESTRIL has been used concomitantly with nitrates without evidence of clinically significant adverse interactions.

The use of ZESTRIL is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ZESTRIL during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatment which have an established safety profile for use in pregnancy. When pregnancy is detected, treatment with ZESTRIL 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. ZESTRIL 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-born, have been reported after administration of ZESTRIL 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).

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

a. Summary of the safety profile Clinical Trials: Common clinical side-effects of ZESTRIL are: dizziness, headache, diarrhoea, fatigue, cough and nausea. Other side-effects: orthostatic effects (including hypotension), rash and asthenia. In patients with congestive heart failure, high doses of ZESTRIL may predispose to symptoms related to hypotension (dizziness, syncope) and to biochemical changes related to impaired renal function (hyperkalaemia and increased serum creatinine) as would be expected with ACE inhibitor therapy.

b. Tabulated summary of adverse reactions Post-marketing: The following undesirable effects have been observed and reported during treatment with ZESTRIL with the following frequencies: Very common (> 1/10), common (> 1/100, 1/1000, 1/10000, < 1/1000), very rare (< 1/10000) including isolated reports.

Blood and the lymphatic system disorders: very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia

Immune system disorders: not known: anaphylactic/anaphylactoid reaction

Metabolism and nutrition disorders: uncommon: hyperkalaemia rare: hyponatraemia very rare: hypoglycaemia

Nervous system and psychiatric disorders: common: dizziness, headache uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances rare: mental confusion

Cardiac and vascular disorders: common: orthostatic effects (including hypotension) uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: common: cough uncommon: rhinitis rare: bronchospasm, sinusitis

Gastrointestinal disorders: common: diarrhoea, vomiting uncommon: nausea, abdominal pain and indigestion rare: dry mouth very rare: pancreatitis, intestinal angio-oedema

Hepato-biliary disorders: very rare: hepatitis- either hepatocellular or cholestatic, jaundice. Hepatic failure. Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving ZESTRIL who develop jaundice or marked elevation of hepatic enzymes should discontinue ZESTRIL and receive appropriate medical follow up.

Skin and subcutaneous tissue disorders: uncommon: rash, pruritus rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, which may be fatal, extremities, lips, tongue, glottis, and/or larynx (see section 4.4), urticaria, alopecia, psoriasis. very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme. A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Renal and urinary disorders: common: renal dysfunction rare: uraemia, acute renal failure very rare: oliguria/anuria

Reproductive system and breast disorders: uncommon: impotence

General disorders and administration site conditions: uncommon: fatigue, asthenia

Investigations: uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes. rare: decreases in haemoglobin, decreases in haematocrit, increases in serum bilirubin.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

The symptoms of overdosage may include severe hypotension, electrolyte disturbances and renal failure. Treatment is symptomatic and supportive.