SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
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SUMMARY OF PRODUCT CHARACTERISTICS
Page 2 of 36 1. NAME OF THE MEDICINAL PRODUCT
Zofenopril Mylan 30 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 30 mg of zofenopril calcium, equivalent to 28.7 mg of zofenopril
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet)
White, film-coated, capsule shaped, biconvex tablets of 5.5 mm x 10.0 mm with “ZP break-line 1” on one side and “M” on other side.
The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
Zofenopril is indicated for the treatment of mild to moderate essential hypertension.
Acute Myocardial Infarction
Zofenopril 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.
4.2 Posology and method of administration
NOTE! Please be aware that not all recommended dosages can be administered with this product, since the lowest dose achievable with this product is 15 mg (half a tablet).
Posology Dosage must be titrated according to the therapeutic response of the patient.
Hypertension 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.
Page 3 of 36 In case of inadequate response, other antihypertensive agents such as diuretics may be added (see sections 4.3, 4.4, 4.5 and 5.1).
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 zofenopril 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 zofenopril; the once-daily dosage regimen does not require modification.
The starting dose and the dosage regimen of zofenopril 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 In the elderly with normal creatinine clearance no adjustment is necessary.
In the elderly with reduced creatinine clearance (less than 45 ml/min) half of the daily dose is recommended.
Creatinine clearance may be estimated from serum creatinine by the following formula:
Clearance Creatinine (ml/min) = (140 – age) x weight (kg) Serum Cr. (mg/dl) x 72
The above method provides creatinine clearance in males. For females the value obtained should be multiplied by 0.85.
Hepatic impairment In hypertensive patients with mild to moderate hepatic impairment, the starting dose of zofenopril is half of the dose for patients with normal hepatic function.
In hypertensive patients with severe liver impairment zofenopril is contraindicated.
Acute myocardial infarction Treatment with zofenopril 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
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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 (≤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 (≤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), zofenopril should be discontinued.
After 6 weeks 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 β-blockers.
Elderly Zofenopril 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 zofenopril in myocardial infarction patients with renal impairment or who are undergoing dialysis has not been established. Therefore, zofenopril should not be used in these patients.
Hepatic impairment The efficacy and safety of zofenopril in myocardial infarction patients with hepatic impairment has not been established. Therefore, it should not be used in these patients.
All indications
Paediatric population The safe or effective use of zofenopril in children and adolescents below the age of 18 years has not been established. Therefore, it should not be used in children.
Method of administration
For oral use. Zofenopril can be taken before, during or after meals.
4.3 Contraindications
Hypersensitivity to the active substance, any other ACE inhibitor or to any of the excipients listed in section 6.1.
History of angioneurotic oedema associated with previous ACE inhibitor therapy.
Hereditary/idiopathic angioneurotic oedema.
Severe hepatic impairment.
2nd and 3rd trimester of pregnancy (see sections 4.4. and 4.6).
Women of child-bearing potential unless protected by effective contraception.
Page 5 of 36 Bilateral renal artery stenosis or unilateral renal artery stenosis in cases of a solitary single kidney.
The concomitant use of Zofenopril Mylan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).
Concomitant use with sacubitril/valsartan therapy. Zofenopril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).
4.4 Special warnings and precautions for use
Hypotension As with other ACE inhibitors, zofenopril 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 sections 4.5 and 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 zofenopril 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 a myocardial infarction or cerebrovascular accident.
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 drug 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 zofenopril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of zofenopril may be necessary.
Pregnancy ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatment which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Hypotension in acute myocardial infarction Treatment with zofenopril must not be initiated in acute myocardial infarction patients if there is a risk of additional serious heamodynamic depression following treatment with a vasodilator. These are patients with a systolic blood pressure of <100 mmHg or with cardiogenic shock. Treatment with zofenopril 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), zofenopril should be discontinued. In patients with severe heart failure
Page 6 of 36 following an acute myocardial infarction zofenopril should only be administered if the patient is haemodynamically stable.
Page 7 of 36 Myocardial infarction patients with impaired hepatic function The efficacy and safety of zofenopril in myocardial infarction patients with hepatic impairment has not been established. Therefore, it should not be used in these patients
Elderly Zofenopril should be used with caution in myocardial infarction patients >75 years of age.
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. 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 zofenopril 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 zofenopril is initiated and renal function should be closely monitored during the first few weeks of therapy.
Renal insufficiency Zofenopril 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 ACE inhibitors, 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 the ACE inhibitor 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 zofenopril in myocardial infarction patients with renal impairment has not been established. Therefore, in presence of renal impairment (serum creatinine ≥ 2.1 mg/dl and proteinuria 500 mg/day) and myocardial infarction zofenopril should not be used.
Renal dialysis Patients who are dialysed using high-flux polyacrylonitrile membranes (e.g. AN 69) and treated with ACE inhibitors 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 zofenopril in myocardial infarction patients undergoing haemodialysis has not been established. Therefore, it should not be used in these patients.
LDL apheresis Patients treated with an ACE inhibitor undergoing LDL apheresis with dextrane sulfate may experience anaphylactoid reactions similar to those seen in patients undergoing haemodialysis with high-flux membranes (see above). It is recommended that an agent from another class of antihypertensive drugs is used in these patients.
Anaphylactic reactions during desensitisation or after insect bites Rarely, patients receiving ACE inhibitors 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 medicinal product. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.
Page 8 of 36 Kidney transplantation There is no experience regarding the administration of zofenopril 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 this product is not recommended.
Hypersensitivity/angioedema Concomitant use of ACE inhibitors 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 zofenopril. Treatment with zofenopril 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 ACE inhibitors 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). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with ACE inhibitors 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 ACE inhibitors should promptly be discontinued and replaced by an agent belonging to another class of drugs.
Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) or slow intravenous 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 an ACE inhibitor (see section 4.3).
Cough During treatment with zofenopril a dry and non-productive cough may occur which disappears after discontinuation of zofenopril.
ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Hepatic failure Rarely, ACE inhibitors 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 ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
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Serum potassium ACE inhibitors 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 ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).
Surgery/Anaesthesia ACE inhibitors 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 the ACE inhibitor, intravascular and plasma volumes should be carefully monitored.
Aortic and mitral valve stenosis/Hypertrophic cardiomyopathy ACE inhibitors 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 ACE inhibitors. The risk of neutropenia appears to be dose- and type-related and is dependent on 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 agents, 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 zofenopril 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 zofenopril 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. Zofenopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1000/mm3) is detected or suspected.
It is reversible after discontinuation of the ACE inhibitor.
Psoriasis ACE inhibitors 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 ACE inhibitors. 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 products or insulin, during the first month of treatment with an ACE inhibitor (see section 4.5).
Lithium The combination of lithium and zofenopril is generally not recommended (see section 4.5).
Page 10 of 36 Ethnic differences As with other angiotensin converting enzyme inhibitors, zofenopril may be less effective in lowering blood pressure in black people than in non-blacks. Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) There is evidence that the concomitant use of ACE-inhibitors, 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, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). 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.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use not recommended Medicines increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).
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 zofenopril. 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 zofenopril is co-administered with other agents 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 zofenopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.
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 zofenopril (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 zofenopril.
Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors.
Therefore, zofenopril is not recommended in association with lithium and careful monitoring of serum lithium levels should be performed if the concomitant use proves necessary.
Gold
Page 11 of 36 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 ACE inhibitor therapy.
Anaesthetic medicinal products ACE inhibitors may enhance the hypotensive effects of certain anaesthetic medicinal products.
Narcotic drugs/Tricyclic antidepressants/Antipsychotics/Barbiturates Postural hypotension may occur.
Other antihypertensive substances (e.g. Beta-blockers, alpha-blockers, calcium antagonists) There may be additive hypotensive effect or potentiation. Treatment with glyceryl trinitrate and other nitrates, or other vasodilators, should be used with caution.
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, 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, 4.4 and 5.1).
Cimetidine May enhance the risk of hypotensive effect.
Ciclosporin Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Heparin. Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide Increased risk of hypersensitivity reactions when ACE inhibitors are used concurrently. Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.
Antidiabetics Rarely ACE inhibitors can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics like sulfonylurea, in diabetics. In such cases it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE inhibitors.
Haemodialysis with high-flux dialysis membranes Increased risk of anaphylactoid reactions when ACE inhibitors are used concurrently.
To be taken into account with concomitant use Non-Steroidal Anti-inflammatory medicinal products (including ASA 3g/day) The administration of non-steroidal anti-inflammatory agents may reduce the antihypertensive effect of an ACE inhibitor. Furthermore, it has been described that NSAIDS and ACE inhibitors exert an additive effect on the increase in serum potassium whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated.
Antacids Reduce the bioavailability of ACE inhibitors.
Sympathomimetics
Page 12 of 36 May reduce the antihypertensive effects of ACE inhibitors; 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 drugs which are metabolised by CYP enzymes are not available. However, in vitro metabolic studies with zofenopril demonstrated no potential interaction with drug that are metabolised by CYP enzymes.
4.6 Fertility, pregnancy and lactation
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor is considered essential, patients planning pregnancy should be changes to alternative anti-hypertensive treatment which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
ACE inhibitor therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Breast-feeding Because no information is available regarding the use of zofenopril during breast-feeding, Zofenopril Mylan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects on ability to drive and use machines
There are no studies on the effect of zofenopril on the ability to drive. When driving vehicles or operating machines it should be remembered that occasionally drowsiness, dizziness or weariness may occur.
4.8 Undesirable effects
Tabulated list of adverse reactions
The table below shows all the adverse reactions that have been reported during clinical practice in patients treated with zofenopril. They are listed by body-system and ranked under headings of frequency using the following convention: Very common (>1/10), Common (>1/100 to ˂1/10), Uncommon (>1/1,000 to ˂1/100), Rare (>1/10,000 to ˂1/1,000), Very rare (˂1/10,000), Not known (cannot be estimated from the available data).
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MedDRA Adverse reactions Frequency System Organ Class (SOC) 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 Fatigue Common conditions
Asthenia Uncommon
The following adverse reactions have been observed associated with ACE inhibitors therapy:
Blood and lymphatic system disorders In a few patients agranulocytosis and pancytopenia may occur. There are 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, mood altered, sleep disorders, confusional state.
Nervous system disorders Occasionally paraesthesia, dysgeusia, balance disorder.
Eye disorders Rarely, vision blurred.
Ear and labyrinth disorders Rarely, tinnitus.
Cardiac disorders
Page 14 of 36 Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, 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).
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 oedema peripheral 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.
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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 the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via [To be completed nationally].
4.9 Overdose
Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.
After ingestion of an overdose, the patients 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 gastric lavage and administration of adsorbents and sodium sulfate 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 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 hemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors plain, ATC code: C09AA15.
Mechanism of action The beneficial effects of zofenopril in hypertension and acute myocardial infarction appear to result primarily from the suppression of the plasma renin-angiotensin aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lung for arginine salt of zofenoprilat) results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity. The plasma ACE activity is suppressed by 53.4% and 74.4% at 24 hours after administration of single oral doses of 30 mg and 60 mg zofenopril calcium respectively.
Inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin- system, which contributes to peripheral vasodilatation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of zofenopril calcium and is responsible for certain side effects.
Clinical efficacy and safety In patients with hypertension, administration of zofenopril results in a reduction of supine and standing blood pressure to about the same extent, with no compensatory increase of the heart rate. Mean systemic vascular resistance tends to decline after zofenopril administration.
Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy.
Page 16 of 36 Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure. Currently there are no data regarding the effects of zofenopril on morbidity and mortality in hypertensive patients.
Although antihypertensive effects have been found in all races studied, black hypertensive patients (usually a low-renin hypertensive population) has a smaller average response to ACE inhibitor monotherapy than non-black patients. This difference disappears when a diuretic is added.
The clinical effect resulting from the early use of zofenopril following myocardial infarction may be linked to many factors such as the reduction in plasma levels of angiotensin II (in this way limiting the process of ventricular remodelling which can negatively influence the quod vitam prognosis of the infarction patient), and the increase in plasma/tissue concentrations of vasodilator substances (prostaglandins-kinin system)
A randomised, placebo-controlled clinical trial of zofenopril was performed in 1,556 patients with anterior myocardial infarction who had not received thrombolytic therapy. Treatment was begun within 24 hours and continued for 6 weeks. The incidence of the primary combined endpoint (severe heart failure and/or death at 6 weeks) was reduced in zofenopril-treated patients (zofenopril 7.1%, placebo 10.6%). At one year, the survival rate was improved in the zofenopril group.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE- inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
Page 17 of 36 5.2 Pharmacokinetic properties
Zofenopril calcium is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from thio-ester hydrolysis.
Absorption Zofenopril calcium is rapidly and completely absorbed by the oral route and undergoes nearly complete conversion to zofenoprilat, which reaches peak blood levels after 1.5 h following an oral dose of zofenopril. Single dose kinetics are linear over a dose-range of 10-80 mg of zofenopril calcium and no accumulation occurs after the administration of 15-60 mg of zofenopril calcium for 3 weeks. The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption and the AUCs of zofenoprilat are nearly identical in the fasted or fed state.
Distribution Approximately 88% of the circulating radioactivity measured ex-vivo following a radiolabelled dose of zofenopril calcium is bound to plasma protein and the steady state volume of distribution is 96 litres.
Biotransformation Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in human urine following a radiolabelled dose of zofenopril calcium. The main metabolite is zofenoprilat (22%), which is then metabolised through several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and S- methylation of the thiol group (8%). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1300 ml/min following oral zofenopril calcium.
Elimination Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%) and faeces (16%) while following an oral dose of radiolabelled zofenopril calcium, 69% and 26% of the radioactivity is recovered in urine and faeces respectively, indicating a dual route of elimination (kidney and liver).
Other special populations
Pharmacokinetics in the elderly In the elderly, no dose adjustment is required when the renal function is normal.
Pharmacokinetics in renal dysfunction Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled zofenopril calcium, patients with mild renal impairment (creatinine clearance >45 and <90 ml/min) eliminate zofenopril from the body at the same rate as normal subjects (creatinine clearance > 90 ml/min).
In patients with moderate to severe renal impairment (7- 44 ml/min), the rate of elimination is reduced to about 50% of normal. This indicates that these patients should be given half the usual starting dose of zofenopril.
In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the rate of elimination is reduced to 25% of normal. This indicates that these patients should be given a quarter of the usual starting dose of zofenopril.
Pharmacokinetics in hepatic dysfunction In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril calcium, the Cmax and Tmax values for zofenoprilat were similar to those in normal subjects. However, AUC values in cirrhotic patients were about twice those obtained for
Page 18 of 36 normal subjects, indicating that the initial dose of zofenopril for patients with mild to moderate hepatic dysfunction should be half of that for patients with normal hepatic function.
There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.
5.3 Preclinical safety data
In repeat oral dose toxicity studies conducted in three mammalian species most of the treatment related effects where those usually reported for ACE inhibitors. These changes included a decrease in erythrocytic parameters, an increase in serum urea nitrogen, a decrease in heart weight and hyperplasia of the juxta-glomerular cells which occurred at dose levels much higher than the maximum recommended human dose. In a repeat dose oral toxicity study in the dog, species-specific immunologically-mediated blood dyscrasias occurred at high dose levels.
No significant changes in cytochrome P450 enzyme activities have been observed in a 1 year repeated oral toxicity study in the monkey.
In reproductive toxicity studies, zofenopril caused a dose related reduction in growth rate in offspring and also nephrotoxicity and reduced postnatal viability at dose levels of 90 and 270 mg/kg in the F1 generation. Treatment with zofenopril during pregnancy caused foetal and developmental toxicity in offspring in the rat and also embryo- and feto-toxicity in the rabbit but only at maternally toxic dose levels.
Genotoxicity studies showed that zofenopril was not mutagenic or clastogenic.
Carcinogenicity studies conducted in mice and rats revealed no evidence of carcinogenicity. An increased incidence of testicular atrophy occurred only in the mouse study, the clinical significance of which is unknown.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core Microcrystalline cellulose Pregelatinised starch (maize) Magnesium stearate
Film-coat Hypromellose (E464) Titanium dioxide (E171) Macrogol 400 Polysorbate 80
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
After first opening (HDPE bottle with PP cap only): 30 days
Page 19 of 36 6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
HDPE bottle with Polypropylene cap containing 500 tablets (hospital pack).
PVC/Aclar/ Aluminium foil blisters in cartons of 7, 12, 14, 28, 30, 56, 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
[To be completed nationally]
Page 20 of 36
LABELLING
Page 21 of 36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON (FOR BLISTER/BOTTLE)
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril Mylan 30 mg film-coated tablets zofenopril calcium
2. STATEMENT OF ACTIVE SUBSTANCE
Each tablet contains 30 mg of zofenopril calcium, equivalent to 28.7 mg of zofenopril.
3. LIST OF EXCIPIENTS
4. PHARMACEUTICAL FORM AND CONTENTS
Film-coated tablet
Blister: 7 film-coated tablets 12 film-coated tablets 14 film-coated tablets 28 film-coated tablets 30 film-coated tablets 56 film-coated tablets 90 film-coated tablets
Bottle: 500 film-coated tablets (hospital pack)
5. METHOD AND ROUTE OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Page 22 of 36 8. EXPIRY DATE
EXP
Bottle only: Discard 30 days after first opening.
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
Batch/Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zofenopril Mylan 30 mg tablets
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC: SN:
Page 23 of 36 NN:
Page 24 of 36 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE (LABEL)
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril Mylan 30 mg film-coated tablets zofenopril calcium
2. STATEMENT OF ACTIVE SUBSTANCE
Each tablet contains 30 mg of zofenopril calcium, equivalent to 28.7 mg of zofenopril.
3. LIST OF EXCIPIENTS
4. PHARMACEUTICAL FORM AND CONTENTS
Film-coated tablet
500 film-coated tablets
5. METHOD AND ROUTE OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Discard 30 days after first opening. First opened:………..
9. SPECIAL STORAGE CONDITIONS
Page 25 of 36 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
Batch/Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zofenopril Mylan 30 mg tablets
Page 26 of 36
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril Mylan 30 mg film-coated tablets zofenopril calcium
2. NAME OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Batch/Lot:
5. OTHER
Page 27 of 36
PACKAGE LEAFLET
Page 28 of 36 Package leaflet: Information for the patient
Zofenopril Mylan 30 mg film-coated tablets zofenopril calcium
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet 1. What Zofenopril Mylan is and what it is used for 2. What you need to know before you take Zofenopril Mylan 3. How to take Zofenopril Mylan 4. Possible side effects 5. How to store Zofenopril Mylan 6. Contents of the pack and other information
1. What Zofenopril Mylan is and what it is used for
Zofenopril Mylan contains zofenopril, which belongs to a group of medicines known as ACE inhibitors (Angiotensin Converting Enzyme Inhibitors). Zofenopril works by making your blood vessels wider. This helps your blood pressure to fall. It also makes it easier for your heart to pump blood around your body.
Zofenopril Mylan can be used - To treat high blood pressure – also called hypertension - After a heart attack (acute myocardial infarction) in people who may or may not show signs and symptoms of heart failure, and who have not received treatment that helps dissolve blood clots (thrombolytic therapy).
2. What you need to know before you take Zofenopril Mylan
Do not take Zofenopril Mylan:
- if you are allergic to zofenopril or any of the other ingredients of this medicine listed in section 6. - if you have had any previous allergic reaction to any other ACE inhibitor such as captopril or enalapril - if you have a history of severe swelling of the face, tongue and throat (angioneurotic oedema) associated with previous ACE inhibitor therapy, or if you have ever got these symptoms without any known reason (hereditary/idiopathic angioneurotic oedema) - if you are more than 3 months pregnant. (It is also better to avoid Zofenopril Mylan in early pregnancy – see pregnancy breast-feeding section) - if you are a woman of child bearing age, unless you use a proper contraceptive. - if you suffer from narrowing of the blood vessels (arteries) to both kidneys (or to your kidney if you only have one kidney) - if you suffer from severe liver impairment. - if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.
Page 29 of 36 - If you have taken or are currently taking sacubitril/valsartan, a medicine used to treat a type of long-term (chronic) heart failure in adults, as the risk of angioedema (rapid swelling under the skin in an area such as the throat) is increased.
Warnings and precautions
Talk to your doctor or pharmacist before taking Zofenopril Mylan if:
- you have diabetes - you have psoriasis - you have liver problems - you have been told to limit the amount of salt in your diet or have had severe diarrhoea or sickness, because zofenopril may cause your blood pressure to fall - you have low amounts of fluid and salt in your body due to diuretic treatment - you have kidney problems, including narrowed blood vessels (arteries) to one kidney (renal artery stenosis) or have had a recent kidney transplant. Your doctor may need to reduce your dose - you are having treatment to reduce your reaction to insect bites, are undergoing dialysis, or if you are having treatment of your blood by a machine to lower cholesterol (LDL apheresis) as there is a risk of suffering an allergic reaction to zofenopril - you take potassium-sparing diuretics, extra potassium in your diet or a salt substitute that contains potassium because zofenopril may increase your blood salt (potassium) levels - you suffer from low blood pressure as zofenopril may cause your blood pressure to fall further - you have heart failure (a weakness of the heart muscle), thickening of the heart walls resulting in obstruction of the blood flow from the left side of the heart (hypertrophic cardiomyopathy) or a narrowing of the heart valve (aortic and mitral valve stenosis) - you have reduced blood flow to the heart (angina) or brain, or you have had a stroke or mini- stroke (also known as transient ischaemic attack (TIA)) - you suffer from a collagen vascular disease e.g. scleroderma, System Lupus Erythematosus (or lupus, an allergic condition causing e.g. joint pain, skin rashes and fever) - you have abnormally high levels of the hormone aldosterone in your blood (primary aldosteronism) - you are over 75 years of age; zofenopril should be used with caution - you are black. You may be at more risk of angioneurotic oedema or this medicine may be less effective than in non-black patients - you are taking any of the following medicines, the risk of angioedema (rapid swelling under the skin in area such as the throat) may be increased: - Racecadotril, a medicine used to treat diarrhoea - Medicines used to prevent organ transplant rejection and for cancer (e.g., temsirolimus, sirolimus, everolimus) - Vildagliptin, a medicine used to treat diabetes - you are taking any of the following medicines used to treat high blood pressure: - an angiotensin II receptor blocker (ARB) (also known as sartans - for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems. - aliskiren
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.
See also information under the heading “Do not take Zofenopril Mylan”
- you must tell your doctor if you think you are (or might become) pregnant. Zofenopril is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy breast-feeding section).’
During treatment
Page 30 of 36 - Tell your doctor, dentist or hospital staff that you are taking this medicine if you are being anaesthetised (for an operation). This will help the anaesthetist to control your blood pressure and heart rate during the procedure - Tell your doctor if you develop a dry cough whilst taking this medicine, you may need to change to an alternative treatment.
Other medicines and Zofenopril Mylan
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines: - Potassium supplements (including salt substitutes), potassium-sparing diuretics and other medicines that can increase the amount of potassium in your blood (e.g. trimethoprim and co- trimoxazole for infections caused by bacteria; ciclosporin, an immunosuppressant medicine used to prevent organ transplant rejection; and heparin, a medicine used to thin blood to prevent clots). Racecadotril (a medicine used to treat diarrhoea), medicines used to prevent organ transplant rejection and for cancer (e.g., temsirolimus, sirolimus, everolimus), and vildagliptin (a medicine used to treat diabetes). The risk of angioedema may be increased. - Water tablets (diuretics) such as spironolactone, triamterene or amiloride are not recommended because these may increase the levels of potassium in your blood. Also other kinds of water tablets may cause your blood pressure to fall. - Lithium (for some types of mental illness) because zofenopril may cause the level of lithium in your blood to increase. - Medicines for serious mental illness (psychosis), barbiturate medicines (normally used for epilepsy), anaesthetics or narcotics (e.g. strong painkillers) because taking these medicines at the same time as zofenopril my cause low blood pressure. - Other medicines for high blood pressure, including calcium channel blockers, ß-blockers and α- blockers; if taken with zofenopril may cause your blood pressure to fall. - Cimetidine may increase the risk of low blood pressure. - Allopurinol (used to treat gout and kidney stones), procainamide (used to treat heart beat problems), corticosteroids and medicines to suppress your immune system may increase the risk of low white cell count. - Ciclosporin (used to suppress your immune system) because there is a risk of kidney problems when taken with zofenopril. - Non-steroidal anti-inflammatory drugs (NSAIDs), (for pain or inflammation) may reduce the effectiveness of zofenopril. - Medicines for diabetes taken by mouth or insulin, because zofenopril may cause your blood sugar levels to drop even further when taken with these medicines. - Antacids (used to treat heartburn and stomach ulcer), because they reduce the effectiveness of zofenopril. - Medicines that affect your nervous system (known as sympathomimetics) may reduce the effectiveness of zofenopril. Your doctor will tell you if this affects you. - Glyceryl trinitrate and other nitrates (used to help with chest pain (angina) or improve blood flow). - Cytostatic agents (used in the treatment of cancer). - Tricyclic antidepressants (normally used for depression). - Gold injections for arthritis because it may lower blood pressure.
Your doctor may need to change your dose and/or to take other precautions: - If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings “Do not take Zofenopril Mylan” and “Warnings and precautions”).
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking zofenopril before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Zofenopril Mylan. Zofenopril is not
Page 31 of 36 recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Zofenopril is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is new born, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
When driving vehicles or operating machines it should be remembered that occasionally drowsiness, dizziness or weariness may occur.
3. How to take Zofenopril Mylan
Dosage Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
Swallow tablets whole, or divided into halves, with water. You can take them before, during or after meals.
Your doctor or pharmacist should tell you the frequency and duration of the treatment.
Adults with high blood pressure (hypertension) The recommended starting dose is 15 mg each day (half a tablet).
Your doctor may increase your dosage to find the dose that suits you best. The usual effective dose is 30 mg each day. The maximum dose is 60 mg each day in one single or 2 divided doses.
Adults with high blood pressure suffering from volume or salt depletion The first zofenopril tablets you take may make your blood pressure fall. If you are concerned talk to your doctor or pharmacist. If you are taking water tablets (diuretics) then you will need to stop taking them for two to three days before starting to take zofenopril. The recommended starting dose is 15 mg each day but your doctor may start you on 7.5 mg each day if they feel this is more suitable for you. With this product not all recommended dosages can be administered.
Adults with high blood pressure and liver problems If you have mild to moderate liver problems, the doctor will alter the amount of zofenopril you take depending on how well your liver is working.
Adults with high blood pressure and kidney problems If you have kidney problems, the doctor will alter the amount of zofenopril you take depending on how well your kidneys are working.
Elderly Your dose depends on how well your kidneys are working. Your doctor will tell you how much Zofenopril Mylan to take.
Adults after a heart attack It is recommended to start taking this medicine within 24 hours of the heart attack and continue taking for at least six weeks.
Page 32 of 36 The recommended starting dose is 7.5 mg twice a day (every 12 hours). On day 3, the dose may be increased to 15 mg twice a day (every 12 hours). From day 5, the dose may be increased to 30 mg twice a day (every 12 hours). With this product not all recommended dosages can be administered.
Use in children and adolescents Zofenopril Mylan is not recommended for use in children.
If you take more Zofenopril Mylan than you should
Contact your doctor or go to the nearest hospital emergency department immediately. Take the container and any remaining tablets with you. Signs and symptoms of overdose include: Extremely low blood pressure, shock, stupor, abnormally slow heart beat, electrolyte disturbances and kidney failure.
If you forget to take Zofenopril Mylan
If you miss a dose do not worry. Take your normal dose when it is next due. Do not take a double dose to make up for a forgotten dose.
If you stop taking Zofenopril Mylan
If you suddenly stop taking Zofenopril Mylan you may suffer from side effects. If you need to stop taking this medicine talk to your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any of the following side effects, contact your doctor immediately or go to the nearest hospital casualty department straight away. It is important to inform medical personnel about your medication:
Rare (may affect up to 1 in 1,000 people) Serious allergic reaction which causes swelling of the face, tongue or throat, difficulty swallowing, hives and difficulty in breathing.
Very rare (may affect up to 1 in 10,000 people) Swelling of the gut, which may cause stomach pain which may become severe.
Not known (frequency cannot be estimated from the available data) Severe skin reaction, which may cause blistering of the skin, mouth, eyes and genitals or a more severe form causing extensive skin damage (separation of the top layer of skin from lower layers of skin) and flu-like symptoms (fever, muscle pain, joint pain and changes in blood cells, which may be seen in blood tests). Severe reduction in blood cells which can cause weakness, bruising or bleeding, or make infections more likely. This may be seen in blood tests. Fever with a severely deteriorated general state of health or a fever with local infection symptoms such as sore throat/mouth ulcers or difficulty urinating (agranulocytosis). Irregular heart rhythms or chest pain, particularly at rest, which may be a sign of reduced blood flow to the heart (angina pectoris). Heart attack. You may feel clammy, short of breath, or have severe chest pain and pain moving into the jaw and arms. This may occur if your blood pressure is very low. Inflammation of the pancreas which causes severe pain in the abdomen and back.
Page 33 of 36 Lack of bowel movement, which may cause a distended belly, stomach pain, feeling sick/vomiting, and no passage of gas and stool. Yellowing of the skin or whites of the eyes, which may be cause by a blockage in the bile duct or inflammation of the liver. You may also notice dark urine, pale stools, or fever.
Stroke, which may be caused by bleeding in the brain. You may have slurred speech, sudden weakness or numbness on one side of the face or body, vision problems or a sudden severe headache.
Other side effects which have been seen with this medicine:
Common (may affect up to 1 in 10 people) Feeling unusually tired Feeling or being sick Dizziness Headache Cough. This medicine may cause a persistent dry (no phlegm being produced) cough. If this occurs, talk to your doctor as you may need an alternate medicine.
Uncommon (may affect up to 1 in 100 people) Rash Weakness, muscle cramp
The following side effects have been seen with other ACE inhibitors and therefore could occur whilst taking this medicine.
Rare (may affect up to 1 in 1,000 people) Muscle pain Shortness of breath, bronchitis Inflamed and swollen sinuses causing pain, high temperature and tenderness An itchy runny nose Swollen sore tongue Abdominal pain Diarrhoea Constipation Dry mouth Depression Mood changes Sleeping problems Impotence Confusion Ringing in the ears Increased sweating Flushing Difficulty passing urine Blurred vision
Very rare (may affect up to 1 in 10,000 people) Chest pain Swelling of hands, ankles or feet Low blood sugar
Not known (frequency cannot be estimated from the available data)
Page 34 of 36 Reduction in red blood cells which can make the skin pale or yellow and cause weakness or breathlessness. This is more likely in people with another medical condition (known as glucose-6-phosphate dehydrogenase deficiency). Severe low blood pressure, which may cause dizziness, feeling of weakness, impaired vision or rarely fainting or loss of consciousness. This is more likely to occur when you first start taking this medicine or when you increase the dose. Serious kidney problems. You may have lower back pain, pass little or no urine, or urine that is passed may be cloudy or have blood in it. Tingling, pins and needles Balance disorder Taste disturbance Faster heart beat, or awareness of the chest beating (palpitations) Itchy skin, hives, a psoriasis like skin reaction or a red, raised ‘measles’ like rash Hair loss Changes in blood counts and tests for activity of the liver, which may be seen in blood tests . Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via [To be completed nationally]. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Zofenopril Mylan
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date, which is stated on the blister, carton, label or bottle after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Zofenopril Mylan supplied in bottles should be used for no longer than 30 days after the bottle has first been opened.
Do not use this medicine if you notice any discoloration of the tablets.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Zofenopril Mylan contains
The active substance is zofenopril calcium. Each tablet contains 30 mg of zofenopril calcium. The other ingredients are microcrystalline cellulose, pregelatinised starch (maize), magnesium stearate, hypromellose (E464), titanium dioxide (E171), macrogol 400 and polysorbate 80.
What Zofenopril Mylan looks like and contents of the pack
Zofenopril Mylan 30 mg film coated tablets are white, film-coated, capsule shaped tablets with “ZP break-line 1” on one side and “M” on other side. The tablet can be divided into equal doses.
Zofenopril Mylan is available in plastic bottles containing 500 tablets (hospital pack) or blister packs of 7, 12 14, 28, 30, 56, 90 tablets. Not all pack sizes may be marketed.
Page 35 of 36
Marketing Authorisation Holder
[To be completed nationally]
Manufacturers
McDermott Laboratories Limited trading as Gerard Laboratories 35/36 Baldoyle Industrial Estate, Grange Road, Dublin 13 Ireland
Mylan Hungary Kft. Mylan utca 1., Komárom, 2900 Hungary
This medicinal product is authorised in Member States of the EEA under the following names:
France ZOFENOPRIL MYLAN 30 mg, comprimé pelliculé sécable Italy Zofenopril Mylan Generics Netherlands Zofenoprilcalcium Mylan 30 mg, filmomhulde tabletten Portugal Zofenopril Mylan Romania Zofenopril Mylan 30 mg comprimate filmate
This leaflet was last revised in [To be completed nationally].
Page 36 of 36