Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Menarini International Operations Luxembourg S.A., 1 Avenue de la Gare, 1611 Luxembourg
As with other ACE inhibitors, ZOFENIL 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 ZOFENIL 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 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 ZOFENIL. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of ZOFENIL may be necessary.
Treatment with ZOFENIL 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 <100mmHg or with cardiogenic shock. Treatment with ZOFENIL in acute myocardial infarction patients may lead to severe hypotension. In the case of persistent hypotension (systolic blood pressure <90mmHg for more than one hour), ZOFENIL should be discontinued. In patients with severe heart failure following an acute myocardial infarction ZOFENIL should only be administered if the patient is haemodynamically stable.
The efficacy and safety of ZOFENIL in myocardial infarction patients with hepatic impairment has not been established. Therefore, it should not be used in these patients
ZOFENIL should be used with caution in myocardial infarction patients ≥75 years of age
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 ZOFENIL 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 ZOFENIL is initiated and renal function be closely monitored during the first few weeks of therapy.
ZOFENIL 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 ZOFENIL 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 ZOFENIL should not be used.
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 ZOFENIL in myocardial infarction patients undergoing haemodialysis has not been established. Therefore, it should not be used in these patients.
Patients treated with an ACE inhibitor 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 an agent from another class of antihypertensive drugs is used in these patients.
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.
There is no experience regarding the administration of ZOFENIL in patients with a recent kidney transplantation.
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.
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 4.3 Contraindication).
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 Zofenil. Treatment with Zofenil 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.
During treatment with ZOFENIL a dry and non-productive cough may occur which disappears after discontinuation of ZOFENIL. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
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 enzymesshould discontinue the ACE inhibitor and receive appropriate medical follow-up.
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).
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 Section 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.
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.
ACE inhibitors should be used with caution in patients with mitral valve stenosis and obstruction in the outflow of the left ventricule.
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.
ACE inhibitors should be used with caution in patients with psoriasis.
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.
The glycaemia levels should be closely monitored in diabetic patientspreviously treated with oral antidiabeticproductsor insulin, during the first month of treatment with an ACE inhibitor (see section 4.5).
The combination of Lithium and ZOFENIL is generally not recommended (see section 4.5).
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.
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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).
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.
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).
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with zofenopril (see 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.
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, Zofenil is not recommended in association with lithium and careful monitoring of serum lithium levels should be performed if the concomitant use proves necessary.
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.
ACE inhibitors may enhance the hypotensive effects of certain anaesthetic medicinal products.
Postural hypotension may occur.
There may be additive hypotensive effect or potentiation. Treatment with nitroglycerine and other nitrates, or other vasodilators, should be used with caution.
May enhance the risk of hypotensive effect.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with cyclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Increased risk of hypersensitivity reactions when ACE inhibitors are used concurrently. Concomitant administration with ACE inhibitors may lead to an increased risk of leukopenia.
Rarely ACE inhibitors 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 during simultaneous treatment with ACE inhibitors.
Increased risk of anaphylactoid reactions when ACE inhibitors are used concurrently.
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.
Reduce the bioavailability of ACE inhibitors.
May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
May reduce the rate but not the extent of absorption of zofenopril calcium.
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.
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated 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 therapy is considered essential, 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (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).
Because no information is available regarding the use of ZOFENIL during breastfeeding, ZOFENIL is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
There are no studies on the effect of ZOFENIL 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 ZOFENIL. They are listed by body-system and ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, ≤1/100); rare (≥1/10,000, ≤1/1,000); very rare (≤1/10,000).
| 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 inhibitors therapy.
In a few patients agranulocytosis and pancytopenia may occur. There are reports of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Very rare hypoglycaemia
Not known, inappropriate antidiuretic hormone secretion.
Rarely, depression, mood altered, sleep disorders, confusional state.
Occasionally paraesthesia, dysgeusia, balance disorder.
Rarely, vision blurred.
Rarely, tinnitus.
Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction have been reported for ACE inhibitors in association with hypotension.
Severe hypotension has occurred after initiation or increase of therapy. This occurs especially in certain risk groups (see Special warnings and precautions for use). In association with hypotension, symptoms like dizziness, feeling of weakness, impaired vision, rarely with disturbance of consciousness (syncope).
Rarely flushing occurs.
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.
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
Individual cases of cholestatic jaundice and hepatitis have been described in association with ACE inhibitors.
Occasionally allergic and hypersensitivity reactions can occur like pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermic necrolysis, psoriasis-like efflorescences, alopecia.
This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA-titers.
Rarely hyperhidrosis occurs.
Occasionally, myalgia can occur.
Renal insufficiency may occur or be intensified. Acute renal failure has been reported (see Special warnings and precautions for use).
Rarely micturition disorders occur.
Rarely, erectile dysfunction.
Very rarely oedema peripheral and chest pain.
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 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Not applicable.
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