Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
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.
Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Dapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has 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 most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Dapril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Dapril may be necessary.
Treatment with Dapril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mm Hg or lower or those in cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then Dapril should be withdrawn.
As with other ACE inhibitors, Dapril should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.
In cases of renal impairment (creatinine clearance < 80 ml/min) the initial Dapril dosage should be adjusted according to the patient’s creatinine clearance (see Table 1 in section 4.2) and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.
In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or with stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Dapril therapy.
Some hypertensive patients with no apparent pre–existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Dapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre–existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Dapril may be required.
In acute myocardial infarction, treatment with Dapril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with Dapril (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre–treatment value) then the physician should consider withdrawal of Dapril.
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This may occur at any time during therapy. In such cases, Dapril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
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).
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 lisinopril. Treatment with lisinopril 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.
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re–administration of the medicinal product.
Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving Dapril who develop jaundice or marked elevations of hepatic enzymes should discontinue Dapril and receive appropriate medical follow–up.
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Dapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Dapril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non–black patients.
As with other ACE inhibitors, Dapril may be less effective in lowering blood pressure in black patients than in non–blacks, possibly because of a higher prevalence of low–renin states in the black hypertensive population.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non–productive, persistent and resolves after discontinuation of therapy. ACE inhibitor–induced cough should be considered as part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Dapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
ACE inhibitors can cause hyperkalemia 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, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia 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).
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).
The combination of lithium and lisinopril is generally not recommended (see section 4.5).
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).
When lisinopril is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
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 treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), vildagliptin or tissue plasminogen activator may increase the risk of angioedema (see section 4.4).
When a diuretic is added to the therapy of a patient receiving lisinopril the antihypertensive effect is usually additive.
Patients already on diuretics and especially those, in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction in blood pressure when lisinopril is added. The possibility of symptomatic hypotension with lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with lisinopril (see sections 4.2 and 4.4).
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with lisinopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in serum potassium. Care should also be taken when lisinopril 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 lisinopril 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.
If lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
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 lithium toxicity with ACE inhibitors. Use of lisinopril with lithium is not recommendedAntihypertensive agents
When lisinopril is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
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 treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), vildagliptin or tissue plasminogen activator may increase the risk of angioedema (see section 4.4).
When a diuretic is added to the therapy of a patient receiving lisinopril the antihypertensive effect is usually additive.
Patients already on diuretics and especially those, in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction in blood pressure when lisinopril is added. The possibility of symptomatic hypotension with lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with lisinopril (see sections 4.2 and 4.4).
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with lisinopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in serum potassium. Care should also be taken when lisinopril 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 lisinopril 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.
If lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Lithium, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).
When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. These effects are usually reversible. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
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.
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and / or nitrates.
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 trimesters 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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, and hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitors 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 Dapril during breastfeeding, Dapril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially whilst nursing a newborn or preterm infant.
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.
The following undesirable effects have been observed and reported during treatment with lisinopril and other ACE inhibitors with the following frequencies: Very common 1/10, Common 1/100 to <1/10, Uncommon 1/1000 to <1/100, Rare 1/10,000 to <1/1000, Very rare <1/10,000, Not known (cannot be estimated from the available data).
Rare: decreases in haemoglobin, decreases in haematocrit.
Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopoenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease.
Not known: anaphylactic/anaphylactoid reaction.
Very rare: hypoglycaemia.
Uncommon: mood alterations, sleep disturbances, hallucinations.
Rare: mental confusion.
Not known: depressive symptoms.
Common: dizziness, headache.
Uncommon: paresthesia, vertigo, taste disturbance.
Rare: olfactory disturbance.
Not known: syncope.
Common: orthostatic effects (including hypotension).
Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see section 4.4), palpitations, tachycardia, Raynaud’s phenomenon.
Common: cough.
Uncommon: rhinitis.
Very rare: bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.
Common: diarrhoea, vomiting.
Uncommon: nausea, abdominal pain and indigestion.
Rare: dry mouth.
Very rare: pancreatitis, intestinal angioedema.
Very rare: hepatitis – either hepatocellular or cholestatic, jaundice and hepatic failure (see section 4.4).
Uncommon: rash, pruritus.
Rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4), urticaria, alopecia, psoriasis.
Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma.
A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Common: renal dysfunction.
Rare: uraemia, acute renal failure.
Very rare: oliguria/anuria.
Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Uncommon: impotence.
Rare: gynecomastia.
Uncommon: fatigue, asthenia.
Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia.
Rare: increases in serum bilirubin, hyponatraemia.
Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive paediatric patients and that the safety profile in this age group is comparable to that seen in adults.
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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
None known.
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