Instructions Pramilet tablets 5 mg/10 mg blister No. 30
Composition
active ingredients: amlodipine, lisinopril;
5 mg/10 mg tablets: each tablet contains amlodipine besylate equivalent to 5 mg amlodipine and lisinopril dihydrate equivalent to 10 mg lisinopril;
5 mg/20 mg tablets: each tablet contains amlodipine besylate equivalent to 5 mg amlodipine and lisinopril dihydrate equivalent to 20 mg lisinopril;
10 mg/20 mg tablets: each tablet contains amlodipine besylate equivalent to 10 mg amlodipine and lisinopril dihydrate equivalent to 20 mg lisinopril;
Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
for 5 mg/10 mg dosage: white or almost white, round, flat tablets, engraved with "K" on one side and plain on the other side;
for 5 mg/20 mg dosage: white or almost white, round, flat tablets, engraved with "5" and "20", separated by a score on one side, and plain on the other side;
for 10 mg/20 mg dosage: white or almost white, round, flat tablets, engraved with "10" and "20" separated by a score on one side, and plain on the other side.
Pharmacotherapeutic group: Angiotensin-converting enzyme (ACE) inhibitors, combinations. ACE inhibitors in combination with calcium antagonists. Lisinopril and amlodipine. ATC code: C09B B03.
Pharmacological properties
Pramilet® is a combination drug with a fixed combination of doses of the active ingredients - lisinopril and amlodipine.
Lisinopril
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE leads to a decrease in angiotensin II concentrations, which in turn reduces vasopressor activity and aldosterone secretion. The decrease in aldosterone may lead to an increase in serum potassium.
Because the mechanism by which lisinopril lowers blood pressure is through inhibition of the renin-angiotensin-aldosterone system, lisinopril lowers blood pressure even in hypertensive patients with low-renin status. ACE is identical to kininase II, the enzyme that degrades bradykinin. Whether elevated concentrations of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be determined.
Amlodipine
Amlodipine is a dihydropyridine calcium ion entry inhibitor (slow calcium channel blocker, or calcium ion antagonist) that blocks their entry through membranes into myocardial and vascular muscle cells.
The mechanism of hypotensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle.
The reduction in total ischemic load occurs due to two mechanisms of action:
- Amlodipine causes peripheral arteriole dilation and thus reduces total peripheral vascular resistance (afterload). Since the heart rate remains stable, the reduced workload on the heart leads to a decrease in energy consumption and myocardial oxygen demand.
- The mechanism of action of amlodipine may also involve dilation of coronary arteries and arterioles in intact and ischemic areas of the myocardium. This leads to increased myocardial oxygen supply in patients with vasospastic angina (Prinzmetal's angina or variant angina).
Once-daily administration of amlodipine produces clinically significant reductions in blood pressure in both the supine and standing positions in hypertensive patients over 24 hours. Due to the slow onset of action, a rapid antihypertensive effect is not achieved.
In patients with angina pectoris, a single daily dose of amlodipine increases exercise tolerance, increases the duration of the interval to an angina attack, delays the development of ST segment depression (by 1 mm), and also reduces the frequency of angina attacks and the frequency of nitroglycerin intake.
Amlodipine does not exhibit any adverse effects on metabolism or plasma lipid concentrations and can be used to treat patients with bronchial asthma, type 2 diabetes mellitus, and gout.
Pharmacokinetics.
Lisinopril
Lisinopril is an oral ACE inhibitor that does not contain a sulfhydryl group.
Absorption
After oral administration, peak plasma concentrations are reached after 7 hours, although a slight delay in the time to peak serum concentrations was observed in patients with acute myocardial infarction. Based on urinary excretion data, the mean extent of absorption of lisinopril is approximately 25%, with interpatient variability ranging from 6% to 60% over the dose range studied (5 to 80 mg). In patients with heart failure, the absolute bioavailability of lisinopril is reduced to approximately 16%. The absorption of lisinopril is independent of food intake.
Lisinopril does not bind to serum proteins, with the exception of circulating ACE. In preclinical studies, it has been demonstrated that the penetration of lisinopril through the blood-brain barrier is negligible.
Breeding
Lisinopril is not metabolized in the body and is excreted unchanged in the urine. With repeated administration, the effective half-life of lisinopril is 12.6 hours. Renal clearance of lisinopril in healthy volunteers is approximately 50 ml/min. The concentration of lisinopril in the blood serum decreases with a long terminal half-life, which does not contribute to the accumulation of the active substance in the body. Presumably, this terminal half-life represents saturable binding to ACE and is not dose-dependent.
Pharmacokinetic characteristics in special patient groups
Liver failure
Impaired liver function in patients with cirrhosis resulted in reduced absorption of lisinopril (approximately 30% based on urinary excretion data), but increased exposure (approximately 50%) compared to healthy volunteers due to reduced clearance.
Kidney failure
Impaired renal function reduces the clearance of lisinopril, which is excreted by them, but this decrease becomes clinically significant only at a glomerular filtration rate of less than 30 ml/min. In mild and moderate renal failure (creatinine clearance from 30 to 80 ml/min), the mean area under the concentration-time curve (AUC) increases by only 13%, while in severe renal failure (creatinine clearance from 5 to 30 ml/min) there is a 4.5-fold increase in the mean AUC. Lisinopril can be removed from the body by hemodialysis. After 4 hours of hemodialysis, the concentration of lisinopril in the blood plasma decreases by an average of 60%, and the dialysis clearance is from 40 to 55 ml/min.
Heart failure
Patients with heart failure have higher plasma concentrations of lisinopril compared to healthy volunteers (average increase in AUC of 125%), but based on urinary excretion data, absorption of lisinopril is reduced by approximately 16% compared to healthy subjects.
Elderly patients
Elderly patients have higher lisinopril blood concentrations and higher (approximately 60%) AUC values compared to young patients.
Amlodipine
Absorption, distribution, plasma protein binding
After administration of therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentrations 6–12 hours after administration. Absolute bioavailability is estimated to be 64 to 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Food intake does not affect the bioavailability of amlodipine.
Biotransformation and excretion
The terminal plasma half-life is approximately 35–50 hours and corresponds to once-daily dosing. Amlodipine is extensively metabolized in the liver to an inactive metabolite, with only 10% of the parent compound and 60% of the metabolites excreted in the urine.
Pharmacokinetic characteristics in special patient groups
Liver failure
Clinical data on the use of amlodipine in patients with hepatic impairment are very limited. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in half-life and AUC by approximately 40-60%.
Elderly patients
The time to reach maximum plasma concentrations is almost the same in elderly and younger patients. Elderly patients tend to have a decreased clearance of amlodipine, which results in an increase in AUC and half-life.
The increase in AUC and half-life in patients with congestive heart failure was consistent with expectations for this age group.
Fixed-dose combination drug
No pharmacokinetic interactions between the active components of Pramilet® tablets have been described. Pharmacokinetic parameters (AUC, Cmax, tmax, t1/2) did not differ from those after administration of the active components separately.
Food intake does not affect the absorption of Pramilette® tablets in the gastrointestinal tract.
Indication
Essential hypertension in adults.
Pramilast® is used in patients whose blood pressure is adequately controlled by concomitant administration of lisinopril and amlodipine in appropriate doses.
Contraindication
Related to lisinopril:
• hypersensitivity to lisinopril or any other ACE inhibitor;
• history of angioedema associated with the use of an ACE inhibitor;
• hereditary or idiopathic angioedema;
• pregnancy or planning to become pregnant, breastfeeding (see section "Use during pregnancy or breastfeeding");
• simultaneous use with sacubitril/valsartan; it is not recommended to start taking Pramilet® earlier than 36 hours after taking the last dose of sacubitril/valsartan (see sections “Interaction with other medicinal products and other types of interactions” and “Special instructions for use”).
Related to amlodipine:
• hypersensitivity to amlodipine or to any other dihydropyridine derivatives;
• severe arterial hypotension;
• shock (especially cardiogenic);
• obstruction of the left ventricular outflow tract (severe aortic valve stenosis);
• hemodynamically unstable heart failure after acute myocardial infarction.
Related to the drug Pramilet®:
• all of the above contraindications associated with the use of individual components also apply to the combined medicinal product Pramilet®;
• hypersensitivity to any of the excipients of the drug Pramilet® (see section "Composition").
Interaction with other medicinal products and other types of interactions
Interactions related to lisinopril
Antihypertensives
Concomitant use of lisinopril with other antihypertensive drugs (e.g. nitroglycerin and other nitrates or other vasodilators) may lead to an additional decrease in blood pressure.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Dual blockade of the RAAS with the simultaneous use of ACE inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren is known to be associated with an increased risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy (see sections "Contraindications", "Special warnings and precautions for use").
Drugs that may increase the risk of developing angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections 4.3 and 4.4).
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (such as temsirolimus, sirolimus, everolimus) or neutral endopeptidase inhibitors (including racecadotril), or tissue plasminogen activator, or vildagliptin may lead to an increased risk of angioedema (see section 4.4).
Diuretics
When a diuretic is added to lisinopril therapy, the antihypertensive effect is usually enhanced. In patients already receiving diuretics, and especially in those who have recently been prescribed diuretic therapy, excessive reduction in blood pressure may occasionally occur when lisinopril is added to therapy. The risk of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic before starting treatment with lisinopril (see sections 4.4 and 4.2).
Potassium-containing food supplements or salt substitutes, potassium-sparing diuretics, and other medications that may increase serum potassium levels
Although serum potassium is usually within normal limits, hyperkalaemia may occur in some patients treated with lisinopril. Potassium-sparing diuretics (such as spironolactone, triamterene or amiloride), dietary supplements or salt substitutes containing potassium may lead to significant increases in serum potassium, especially in patients with impaired renal function. Caution should be exercised when lisinopril is administered concomitantly with other drugs that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to have a similar effect to potassium-sparing diuretics such as amiloride. Therefore, concomitant administration of lisinopril with the above-mentioned drugs is not recommended. If concomitant use is necessary, the drugs should be used with caution and with periodic monitoring of serum potassium (see section "Special warnings and precautions for use").
Cyclosporine
Concomitant use of ACE inhibitors and cyclosporine may lead to hyperkalemia. Monitoring of serum potassium is recommended.
Heparin.
Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium is recommended.
If lisinopril is administered concomitantly with a potassium-sparing diuretic, diuretic-induced hypokalemia may be attenuated.
Lithium preparations
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and may potentiate the already increased lithium toxicity associated with ACE inhibitors. Concomitant use of lisinopril and lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels is recommended (see section 4.4).
The simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose that has an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the development of acute renal failure, and to an increase in serum potassium, especially in patients with reduced renal function. These effects are reversible. Caution should be exercised when using combination therapy, especially in elderly patients. Patients should receive an adequate amount of fluid, it is recommended to carefully monitor renal function both at the beginning of combination therapy and during treatment.
Gold
Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) following the administration of injectable gold (e.g. sodium aurothiomalate) have been reported more frequently in patients treated with ACE inhibitors.
Tricyclic antidepressants/antipsychotics/anesthetics
Concomitant use of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may lead to a further decrease in blood pressure (see section "Special warnings and precautions for use").
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Hypoglycemic drugs
It is known that the concomitant use of ACE inhibitors and medicinal hypoglycaemic agents (insulin, oral hypoglycaemic agents) may lead to an increased hypoglycaemic effect with the risk of hypoglycaemia. This phenomenon occurs most frequently during the first weeks of combination therapy and in the presence of renal insufficiency.
Drugs that suppress bone marrow function (immunosuppressants, allopurinol, procainamide)
Concomitant use with lisinopril increases the risk of neutropenia and/or agranulocytosis (see section "Special warnings and precautions for use").
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Lisinopril can be used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, beta-blockers and/or nitrates.
Interactions related to amlodipine
Effects of other drugs on amlodipine
CYP3A4 isoenzyme inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole fungicides, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine concentrations, which increases the risk of hypotension. The clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, medical supervision of patients is recommended, as well as dose adjustment of amlodipine, if necessary.
Clarithromycin is a CYP3A4 inhibitor. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close medical supervision of patients is recommended when amlodipine is used concomitantly with clarithromycin.
CYP3A4 isoenzyme inducers
When used simultaneously with known inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in the blood may change. Therefore, it is necessary to monitor blood pressure and, if necessary, adjust the doses of drugs during and after combined treatment, especially when using strong inducers of the CYP3A4 isoenzyme (such as rifampicin, Hypericum perforatum).
Taking amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this may lead to an increase in the bioavailability of amlodipine, resulting in an increase in its hypotensive effect.
Dantrolene (infusion)
In animal studies, ventricular fibrillation and cardiovascular failure with concomitant hyperkalemia and subsequent fatal outcome were observed after verapamil and intravenous dantrolene administration. Due to the risk of hyperkalemia, it is recommended to avoid the concomitant use of calcium channel blockers such as amlodipine in patients predisposed to malignant hyperthermia and for the treatment of malignant hyperthermia.
Effect of amlodipine on other medicinal products
The hypotensive effect of amlodipine enhances the corresponding effect of other drugs that have antihypertensive properties.
Tacrolimus
Concomitant use of tacrolimus and amlodipine may lead to increased blood concentrations of tacrolimus; the mechanism of this interaction is not fully understood. To avoid toxic effects of tacrolimus, blood concentrations of tacrolimus should be monitored during amlodipine therapy and the dose of tacrolimus adjusted if necessary.
Mammalian target of rapamycin (mTOR) inhibitors
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Concomitant use of amlodipine with mTOR inhibitors may increase the effects of the latter.
To date, no studies of the interaction of cyclosporine and amlodipine have been conducted in healthy volunteers or in other populations, with the exception of renal transplant patients, in whom an increase in cyclosporine blood concentrations (on average by 0-40%) was observed. Therefore, in such patients, cyclosporine blood concentrations should be monitored during amlodipine therapy and, if necessary, the cyclosporine dose should be reduced.
Simvastatin
Coadministration of multiple doses of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin concentrations compared to simvastatin alone. The dose of simvastatin should be limited to 20 mg daily in patients receiving amlodipine.
It is known that in clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Application features
All of the following application features associated with the use of individual components also apply to the combined medicinal product Pramilet®.
Application features associated with lisinopril
Symptomatic hypotension
Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension.
A significant decrease in blood pressure may occur in patients with a decrease in circulating blood volume due to diuretics, a strict salt-free diet, dialysis, diarrhea, vomiting, as well as in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").
Symptomatic hypotension has been reported in patients with heart failure with or without renal insufficiency. Such cases are most likely to occur in patients with more severe heart failure due to high doses of loop diuretics, hyponatremia or functional renal insufficiency. In patients at increased risk of symptomatic hypotension, the parameters of the antihypertensive effect should be monitored after taking the initial dose. These recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure could lead to myocardial infarction or stroke. In the event of hypotension, the patient should be placed in the supine position with the lower extremities elevated and fluid loss should be replaced (intravenous infusion of saline) if necessary. Transient hypotension is not a contraindication to the use of the drug, and continued use usually does not cause problems after the increase in blood pressure as a result of an increase in circulating blood volume.
In some heart failure patients with normal or low blood pressure, lisinopril may cause an additional decrease in systemic blood pressure. This is a known effect and is not usually a reason for discontinuation of therapy. If hypotension becomes symptomatic, a reduction in dose or discontinuation of lisinopril may be necessary.
Arterial hypotension in acute myocardial infarction
Lisinopril should not be initiated in patients with acute myocardial infarction who are likely to develop further serious haemodynamic deterioration after treatment with vasodilators. These include patients with a systolic blood pressure of 100 mm Hg or less or with cardiogenic shock. During the first 3 days after myocardial infarction, the dose should be reduced if the systolic blood pressure is 120 mm Hg or less. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if the systolic blood pressure is 100 mm Hg or less. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour), lisinopril should be discontinued.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy
As with all ACE inhibitors, lisinopril should be administered with caution to patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.
Kidney failure
In case of impaired renal function (creatinine clearance
In patients with heart failure, hypotension after initiation of treatment with ACE inhibitors may lead to further deterioration of renal function. In such cases, acute renal failure, usually reversible, has been reported.
Some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney who have been treated with ACE inhibitors may develop increases in blood urea and serum creatinine, usually reversible upon discontinuation of the drug. This is particularly likely in patients with renal insufficiency.
In some hypertensive patients without significant pre-existing renovascular hypertension, increases in blood urea and serum creatinine, usually minor and transient, have been observed, particularly when lisinopril has been administered concomitantly with a diuretic. This is particularly likely in patients with pre-existing renal insufficiency. Dosage reduction and/or discontinuation of the diuretic and/or lisinopril may be necessary.
In acute myocardial infarction, lisinopril should not be initiated in patients with evidence of renal insufficiency, as defined by serum creatinine concentration exceeding 177 μmol/l and/or proteinuria exceeding 500 mg/24 hours. If renal function deteriorates during treatment with lisinopril (serum creatinine concentration exceeding 265 μmol/l or twice the pre-treatment value), the physician should consider discontinuing lisinopril.
Proteinuria
Rare cases of proteinuria have been reported in patients, especially with reduced renal function or after high doses of lisinopril. In case of clinically significant proteinuria (more than 1 g/day), the drug should be prescribed only after assessing the benefits of treatment and the potential risks and under constant monitoring of the patient's clinical and biochemical parameters.
Hypersensitivity, angioedema
Isolated cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with ACE inhibitors, including lisinopril. Angioedema may occur at any time during treatment. In such cases, lisinopril should be discontinued immediately, appropriate treatment should be initiated, and medical supervision should be provided to ensure resolution of all symptoms before discharge. Even in cases of tongue swelling not associated with respiratory failure, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be inadequate.
Very rarely, deaths have been reported due to angioedema associated with laryngeal or tongue oedema. Patients with lesions of the tongue, glottis or larynx may develop airway obstruction, particularly in patients who have previously undergone airway surgery. In such cases, emergency medical treatment should be sought immediately. This may include the administration of adrenaline and/or maintenance of a patent airway. The patient should be closely monitored until complete and sustained resolution of symptoms.
ACE inhibitors cause angioedema more often in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be more likely to develop angioedema when treated with an ACE inhibitor (see section 4.3).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated until 36 hours after the last dose of lisinopril. Lisinopril should not be initiated until 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 (such as 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 distress) (see section 4.5). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors and vildagliptin in patients already taking ACE inhibitors.
Anaphylactoid reactions in patients undergoing hemodialysis
Anaphylactoid reactions have been reported in patients dialyzed with high-flux, high-permeability dialysis membranes (e.g. AN 69) and concomitantly treated with an ACE inhibitor. Consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive drug in such patients.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
In isolated cases, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by withholding ACE inhibitor therapy prior to each apheresis session.
Desensitization
Patients receiving ACE inhibitors during desensitization with hymenoptera venom (e.g., Hymenoptera venom) have developed persistent anaphylactoid reactions. In these patients, anaphylactoid reactions were avoided by temporary withdrawal of ACE inhibitors, but they developed again after accidental administration of the drug.
In rare cases, ACE inhibitors have been associated with a syndrome that began with cholestatic jaundice, progressed to fulminant necrosis, and sometimes resulted in death. The mechanism of this syndrome is unclear. Patients receiving lisinopril who develop jaundice or significantly elevated liver enzymes should discontinue lisinopril and receive appropriate medical attention.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis are reversible and resolve upon discontinuation of the ACE inhibitor.
Lisinopril should be administered with extreme caution to patients with systemic connective tissue diseases, immunosuppressants, allopurinol or procainamide, or a combination of these aggravating factors, especially in the presence of pre-existing renal impairment. Some of these patients have developed serious infections, which in several cases have not responded to intensive antibiotic therapy. Periodic laboratory tests (blood count with differential) are recommended in such patients during treatment with lisinopril, and they should be advised to report any signs of infection.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren increases the risk of hypotension, hyperkalaemia and renal impairment (including acute renal failure). For this reason, dual blockade of the RAAS through concomitant use with ACE inhibitors, ARBs or aliskiren is not recommended (see section 4.5).
If dual RAAS blockade is absolutely indicated, careful observation by a specialist and mandatory monitoring of kidney function, water and electrolyte balance, and blood pressure are necessary.
ACE inhibitors and ARBs II should not be used concomitantly in patients with diabetic nephropathy.
Race
ACE inhibitors cause angioedema more frequently in black patients than in non-black patients. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in non-black patients, probably because of a higher frequency of low-renin states in black patients with hypertension.
Cough
Cough has been reported with the use of ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/anesthesia
In patients undergoing major surgery or during general anesthesia with drugs that cause hypotension, lisinopril may block the formation of angiotensin II after compensatory renin release. If hypotension develops, presumably as a result of the above mechanism, it can be corrected by increasing the circulating blood volume.
