Zofaril 7,5 Mg & 30 Mg Tablet

Hypertension

ZOFARIL is indicated for the treatment of mild to moderate essential hypertension.

Acute myocardial infarction

ZOFARIL is indicated for the treatment initiated within the first 24 hours of patients with acute myocardial infarction with or without signs and symptoms of heart failure, who are haemodynamically stable and have not received thrombolytic therapy.

Posology

Hypertension

Adults

The need for dosage titration should be determined by measurement of blood pressure just before the next dose. The dose should be increased at an interval of four weeks.

Patients without volume or salt depletion

Treatment should be started with 15 mg once daily and titrated upwards to achieve optimal blood pressure control. The usual effective dose is 30 mg once daily. The maximum dose is 60 mg per day administered in a single or two divided doses. In case of inadequate response, other antihypertensives such as diuretics may be added (see sections 4.3, 4.4 and 4.5).

Patients suspected of volume or salt depletion

First-dose hypotension may occur in high-risk patients (see section 4.4). Initiation of therapy with ACE inhibitors requires correction of salt and/or volume deficiencies, discontinuation of an existing diuretic therapy for two to three days before ACE inhibition and a starting dose of 15 mg daily. If this is not possible, the initial dose should be 7,5 mg daily. Patients at high risk for severe acute hypotension should be monitored closely preferably in hospital, for as long as the maximal effect is expected after administration of the first dose and whenever the dose of ACE inhibitor and/or diuretic is increased. This also applies to patients with angina pectoris or cerebrovascular disease in whom excessive hypotension could result in a myocardial infarction or cerebrovascular accident.

Renal impairment and dialysis

In hypertensive patients with mild renal impairment (creatinine clearance > 45 mL/min) the same dose level and once-daily regimen for ZOFARIL can be employed as for patients with normal renal function. Patients with moderate to severe impairment (creatinine clearance < 45 mL/min) should be given one-half the therapeutic dose of ZOFARIL; the once-daily dosage regimen does not require modification. The starting dose and the dosage regimen of ZOFARIL for hypertensive patients maintained on dialysis should be one-quarter the dose used for patients with normal renal function. Recent clinical observations have shown a high incidence of anaphylactoid-like reactions in patients on ACE inhibitors during haemodialysis with high-flux dialysis membranes or during LDL apheresis (see section 4.4).

Elderly patients (over 65 years)

In elderly patients with normal creatinine clearance no adjustment is necessary. In elderly patients with reduced creatinine clearance (< 45 mL/min) half of the daily dose is recommended. Creatinine clearance may be estimated from serum creatinine by the following formula: (140 - age) x mass (kg) x 0,85 (if female) CrCl (mL/min) = ________________________________ serum Cr (u03bcmol/L)

Hepatic impairment

In hypertensive patients with mild to moderate hepatic impairment (Child-Pugh A and B), the starting dose of ZOFARIL is half of the dose for patients with normal hepatic function. In hypertensive patients with severe liver impairment (Child-Pugh C) ZOFARIL is contraindicated.

Paediatric population

ZOFARIL should not be given to children under the age of 18 years as safety and efficacy of ZOFARIL have not been established.

Acute myocardial infarction

Adults

Treatment with ZOFARIL should begin within 24 hours after the onset of symptoms of acute myocardial infarction and continued for six weeks. The posology should be as follows:

• 1st and 2nd day: 7,5 mg every 12 hours
• 3rd and 4th day: 15 mg every 12 hours
• from 5th day and onwards: 30 mg every 12 hours.

In the event of low systolic blood pressure ( u2264 120 mmHg) at the start of treatment or during the first three days following myocardial infarction, the daily dose should not be increased. In the event of hypotension ( u2264 100 mmHg), the treatment can be continued with the dose that was previously tolerated. In the event of severe hypotension (systolic blood pressure lower than 90 mmHg in two consecutive measurements at least one hour apart), ZOFARIL should be discontinued. After 6 weeksu2019 treatment patients must be re-evaluated and the treatment should be discontinued in patients without signs of left ventricular dysfunction or cardiac failure. If these signs are present, treatment might be continued long term.

Patients should also receive, as appropriate, the standard treatment such as nitrates, aspirin or u03b2-blockers.

Elderly patients (over 65 years)

ZOFARIL should be used with caution in myocardial infarction patients who are more than 75 years of age.

Renal impairment and dialysis

The efficacy and safety of ZOFARIL in myocardial infarction patients with renal impairment or who are undergoing dialysis have not been established. Therefore, ZOFARIL should not be used in these patients.

Hepatic impairment

The efficacy and safety of ZOFARIL in myocardial infarction patients with hepatic impairment have not been established. Therefore, it should not be used in these patients.

Method of administration

ZOFARIL can be taken before, during or after meals. Dosage must be titrated according to the therapeutic response of the patient.

• Hypersensitivity to zofenopril calcium, other angiotensin-converting enzyme (ACE) inhibitors or any of the excipients listed in section 6.1.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Concomitant use with sacubitril/valsartan treatment. ZOFARIL must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Aortic stenosis.
• Severe hepatic impairment.
• Pregnancy and lactation (see sections 4.4 and 4.6).
• Women of child-bearing potential unless protected by effective contraception.
• Bilateral renal artery stenosis or unilateral renal artery stenosis in patients with a single kidney.
• The concomitant use of ZOFARIL with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73 mu00b2) (see sections 4.5).
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria.
• Lithium therapy: Concomitant administration with ZOFARIL may lead to toxic blood concentrations of lithium (see section 4.5).
• Concomitant use of fluoroquinolones with ZOFARIL is contraindicated in patients with moderate to severe renal impairment (creatinine clearance u2264 30 mL/min) and in elderly patients.

Hypotension: ZOFARIL may cause a profound fall in blood pressure especially after the first dose, although symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. It is more likely to occur in patients who have been volume and electrolyte depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see section 4.5 and section 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is more 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 patients at increased risk of symptomatic hypotension, treatment should be started under close medical supervision preferably in the hospital, with low doses and careful dose titration. If possible, diuretic treatment should be discontinued temporarily when therapy with ZOFARIL is initiated. Such considerations apply also to patients with angina pectoris or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular incident. If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with medicine after effective management. In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with ZOFARIL. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of ZOFARIL may be necessary.

Hypotension in acute myocardial infarction: Treatment with ZOFARIL must not be initiated in acute myocardial infarction patients if there is a risk of additional serious haemodynamic depression following treatment with a vasodilator. These are patients with a systolic blood pressure of < 100 mmHg or with cardiogenic shock. Treatment with ZOFARIL in acute myocardial infarction patients may lead to severe hypotension. In the case of persistent hypotension (systolic blood pressure < 90 mmHg for more than one hour), ZOFARIL should be discontinued. In patients with severe heart failure following an acute myocardial infarction ZOFARIL should only be administered if the patient is haemodynamically stable.

Myocardial infarction patients with impaired hepatic function: The efficacy and safety of ZOFARIL in myocardial infarction patients with hepatic impairment has not been established. Therefore, it should not be used in these patients.

Elderly patients: ZOFARIL should be used with caution in myocardial infarction patients u2265 75 years of age.

Patients with renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors, as in ZOFARIL. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis. If considered absolutely necessary, treatment with ZOFARIL should be started in hospital under close medical supervision with low doses and careful dose titration. Diuretic treatment should be discontinued temporarily when therapy with ZOFARIL is initiated and renal function be closely monitored during the first few weeks of therapy.

Patients with renal insufficiency: ZOFARIL should be used with caution in patients with renal insufficiency as they require reduced doses. Close monitoring of renal function during therapy should be performed as deemed appropriate. Renal failure has been reported in association with ZOFARIL, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine concentrations, particularly when a diuretic is given concomitantly. Dosage reduction of ZOFARIL and/or discontinuation of the diuretic may be required. It is recommended that the renal function be monitored closely during the first few weeks of therapy. The efficacy and safety of ZOFARIL in myocardial infarction patients with renal impairment have not been established. Therefore, in the presence of renal impairment (serum creatinine u2265 2,1 mg/dL and proteinuria u2265 500 mg/day) and myocardial infarction ZOFARIL should not be used.

Patients who are dialysed: Patients who are dialysed using high-flux polyacrylonitrile membranes (e.g. AN 69) and treated with ACE inhibitors, as in ZOFARIL are likely to experience anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within a few minutes of commencing haemodialysis. It is recommended to use an alternative membrane or an alternative antihypertensive medicinal product. The efficacy and safety of ZOFARIL in myocardial infarction patients undergoing haemodialysis have not been established. Therefore, it should not be used in these patients.

Patients on LDL apheresis: Patients treated with an ACE inhibitor, as in ZOFARIL undergoing LDL apheresis with dextrane sulphate may experience anaphylactoid reactions similar to those seen in patients undergoing haemodialysis with high-flux membranes (see above). It is recommended that a medicine from another class of antihypertensive medicines is used in these patients.

Anaphylactic reactions during desensitisation or after insect bites: Patients receiving ACE inhibitors, as in ZOFARIL during desensitisation treatment (e.g. hymenoptera venom) or after insect bites have experienced life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicine. Therefore, caution should be used in patients treated with ZOFARIL undergoing such desensitisation procedures.

Kidney transplantation: There is no experience regarding the administration of ZOFARIL in patients with a recent kidney transplantation.

Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore the use of ZOFARIL is not recommended.

Hypersensitivity/angioedema: Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with ZOFARIL, which occurs most frequently during the first weeks of treatment. However, in rare cases severe angioedema may develop after long-term treatment with an angiotensin-converting enzyme inhibitor. Treatment with ZOFARIL should promptly be discontinued and replaced by an agent belonging to another class of medicines. Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous epinephrine (adrenaline) solution 1:1 000 (0,3 to 0,5 mL) or slow intravenous epinephrine (adrenaline) 1 mg/mL (which should be diluted as instructed) with close monitoring of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred. Even in such instances where swelling of only the tongue is involved, without respiratory distress, patients may require observation since treatment with antihistamines and corticosteroids may not be sufficient. Angiotensin-converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving ZOFARIL (see section 4.3). Concomitant use of ZOFARIL with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of ZOFARIL. Treatment with ZOFARIL must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ZOFARIL with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

Cough: During treatment with ZOFARIL a dry and non-productive cough may occur which disappears after discontinuation of ZOFARIL. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Hepatic failure: ACE inhibitors, as in ZOFARIL 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 ZOFARIL who develop jaundice or marked elevations of hepatic enzymes should discontinue ZOFARIL and receive appropriate medical follow-up.

Serum potassium: ACE inhibitors, as in ZOFARIL can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalaemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ZOFARIL, and serum potassium and renal function should be monitored (see section 4.5).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE inhibitors (as in ZOFARIL), angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors (as in ZOFARIL), angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ZOFARIL and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Surgery/anaesthesia: ZOFARIL may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anaesthesia, since they may block angiotensin II formation secondary to compensatory renin release. If it is not possible to withhold ZOFARIL, intravascular and plasma volumes should be carefully monitored.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy: ZOFARIL should be used with caution in patients with mitral valve stenosis and obstruction in the outflow of the left ventricle.

Neutropenia/agranulocytosis: Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ZOFARIL. The risk of neutropenia appears to be dose- and type-related and is dependent on the patient's clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment, especially when it is associated with collagen vascular disease e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive medicines, treatment with allopurinol or procainamide or a combination of these complicating factors. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If ZOFARIL is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of ZOFARIL therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count should be performed. ZOFARIL and other concomitant medicine (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1 000/mmu00b3) is detected or suspected. It is reversible after discontinuation of ZOFARIL.

Psoriasis: ZOFARIL should be used with caution in patients with psoriasis.

Proteinuria: Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ZOFARIL. Patients with prior renal disease should have urinary protein estimation (dip-stick on first morning urine) prior to treatment, and periodically thereafter.

Diabetic patients: The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic medicines or insulin, during the first month of treatment with ZOFARIL (see section 4.5).

Lithium: The combination of lithium and ZOFARIL is generally not recommended (see section 4.5).

Fluoroquinolones: Concomitant use of fluoroquinolones and ZOFARIL may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3).

Medicines increasing the risk of angioedema: Concomitant use of ZOFARIL with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Concomitant use of ZOFARIL with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

Concomitant use not recommended

Potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other agents that increase serum potassium. Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with ZOFARIL. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when ZOFARIL is co-administered with other medicines that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of ZOFARIL with the above-mentioned medicines is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

ACE inhibitors, angiotensin II receptor blockers or aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors (as in ZOFARIL), 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 medicine (see sections 4.3 and 4.4).

Fluoroquinolones: Concomitant use of fluoroquinolones and ZOFARIL may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Concomitant use requiring caution

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 ZOFARIL (see section 4.4). 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 ZOFARIL.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ZOFARIL. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ZOFARIL. Therefore, ZOFARIL is not recommended in association with lithium and careful monitoring of serum lithium levels should be performed if the concomitant use proves necessary.

Gold: Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving therapy with ZOFARIL.

Anaesthetics: ZOFARIL may enhance the hypotensive effects of certain anaesthetics.

Narcotic medicines, tricyclic antidepressants, antipsychotics or barbiturates: Postural hypotension may occur.

Other antihypertensives (e.g. beta-blockers, alpha-blockers, calcium antagonists): There may be additive hypotensive effect or potentiation. Treatment with nitroglycerin and other nitrates or other vasodilators, should be used with caution.

Cimetidine: May enhance the risk of hypotensive effect.

Ciclosporin: Hyperkalaemia may occur during concomitant use of ZOFARIL with cyclosporin. Monitoring of serum potassium is recommended.

Heparin: Hyperkalaemia may occur during concomitant use of ZOFARIL with heparin. Monitoring of serum potassium is recommended.

Allopurinol, cytostatic or immunosuppressives, systemic corticosteroids or procainamide: Increased risk of hypersensitivity reactions when ZOFARIL is used concurrently. Concomitant administration with ZOFARIL may lead to an increased risk of leucopenia.

Antidiabetics: ZOFARIL can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics like sulphonylurea, in diabetics. In such cases it may be necessary to reduce the dose of the antidiabetic medicine during simultaneous treatment with ZOFARIL.

Haemodialysis with high-flux dialysis membranes: Increased risk of anaphylactoid reactions when ZOFARIL is used concurrently.

To be taken into account with concomitant use

Nonsteroidal anti-inflammatory medicines (including ASA u2265 3 g/day): The administration of nonsteroidal anti-inflammatory medicines may reduce the antihypertensive effect of ZOFARIL. Furthermore, it has been described that NSAIDs and ACE inhibitors, as in ZOFARIL 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. Acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated patients.

Antacids: Reduce the bioavailability of ZOFARIL.

Sympathomimetics: May reduce the antihypertensive effects of ZOFARIL; patients should be carefully monitored to confirm that the desired effect is being obtained.

Food: May reduce the rate but not the extent of absorption of zofenopril calcium.

Additional information: Direct clinical data on the interaction of zofenopril with other medicines which are metabolised by CYP enzymes are not available. However, in vitro metabolic studies with zofenopril demonstrated no potential interaction with medicines that are metabolised by CYP enzymes.

Pregnancy

ZOFARIL should not be used in pregnancy. Women of childbearing age should ensure effective contraception if on ZOFARIL treatment. The use of ZOFARIL is not recommended during the first trimester of pregnancy (see section 4.4). The use of ZOFARIL is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4). 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 ZOFARIL should be stopped immediately and, if appropriate, alternative therapy should be started.

Breastfeeding

ZOFARIL should not be used while breastfeeding.

There are no studies on the effect of ZOFARIL on the ability to drive. When driving vehicles or operating machines it should be remembered that occasionally drowsiness, dizziness or weariness may occur.

The table below shows all the adverse reactions that have been reported during clinical practice in patients treated with ZOFARIL. They are listed by body-system and ranked under headings of frequency using the following convention: very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, u2264 1/100); rare (u2265 1/10 000, u2264 1/1 000); very rare (u22641/10 000).

MedDRA System Organ Class Adverse reactions Frequency

Nervous system disorders Dizziness Common Headache Common

Respiratory, thoracic and mediastinal disorders Cough Common

Gastrointestinal disorders Nausea Common Vomiting Common

Skin and subcutaneous tissue disorders Rash Uncommon Angioedema Rare

Musculoskeletal and connective tissue disorders Muscle cramp Uncommon

General disorders and administration site conditions Fatigue Common Asthenia Uncommon

The following adverse reactions have been observed associated with ACE inhibitor therapy:

Blood and lymphatic system disorders In a few patients, agranulocytosis and pancytopenia may occur. There were reports of haemolytic anaemia in patients with glucose 6-phosphate dehydrogenase deficiency.

Metabolism and nutrition disorders Very rare hypoglycaemia.

Endocrine disorders Not known, inappropriate antidiuretic hormone secretion.

Psychiatric disorders Rarely, depression, altered mood, sleep disorders, confusional state.

Nervous system disorders Occasionally paraesthesia, dysgeusia, balance disorder.

Eye disorders Rarely, blurred vision.

Ear and labyrinth disorders Rarely, tinnitus.

Cardiac disorders Individual cases of tachycardia, palpitations, dysrhythmias, angina pectoris, and myocardial infarction have been reported for ACE inhibitors in association with hypotension.

Vascular disorders Severe hypotension has occurred after initiation or increase of therapy. This occurs especially in certain risk groups (see section 4.4). In association with hypotension, symptoms like dizziness, feeling of weakness, impaired vision, rarely with disturbance of consciousness (syncope) have been reported. Rarely, flushing occurs.

Respiratory, thoracic and mediastinal disorders Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been reported. ACE inhibitors have been associated with the onset of angioneurotic oedema in a small subset of patients, involving the face and oropharyngeal tissues. In isolated cases angioneurotic oedema involving the upper airways has caused fatal airway obstruction.

Gastrointestinal disorders Occasionally, abdominal pain, diarrhoea, constipation and dry mouth can occur. Individual cases of pancreatitis and ileus have been described in association with ACE inhibitors. Very rare small bowel angioedema.

Hepatobiliary disorders Individual cases of cholestatic jaundice and hepatitis have been described in association with ACE inhibitors.

Skin and subcutaneous tissue disorders Occasionally allergic and hypersensitivity reactions can occur like pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescences, alopecia. This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA-titers.

Rarely hyperhidrosis occurs.

Musculoskeletal and connective tissue disorders Occasionally, myalgia can occur.

Renal and urinary disorders Renal insufficiency may occur or be intensified. Acute renal failure has been reported (see section 4.4). Rarely micturition disorders occur.

Reproductive system and breast disorders Rarely erectile dysfunction.

General disorders and administration site conditions Very rarely peripheral oedema and chest pain.

Investigations Increases in blood urea and creatinine, reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. In a few patients, decreases in haemoglobin, haematocrit, platelets and white cell count have been reported. Increases in serum levels of hepatic enzymes and bilirubin have also been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of ZOFARIL is important. It allows continued monitoring of the benefit/risk balance of ZOFARIL. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure. After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently. Therapeutic measures depend on the nature and severity of the symptoms. If the ingestion is recent, measures to prevent absorption such as administration of adsorbents and sodium sulphate may be implemented. If hypotension occurs, the patient should be placed in shock position and the judicious use of volume expanders and/or treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. ACE inhibitors may be removed from the circulation by haemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.