Instructions for Bi-prenelia tablets 8 mg/10 mg blister No. 30
Composition
active ingredients: perindopril tertbutylamine, amlodipine;
1 tablet of 8 mg/10 mg contains: perindopril tertbutylamine - 8.00 mg, corresponding to 6.68 mg of perindopril; amlodipine besylate - 13.87 mg, corresponding to 10.00 mg of amlodipine;
excipients: microcrystalline cellulose (type 200XLM), microcrystalline cellulose (type 112), sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white or almost white tablets, round, 9.5 mm in diameter, biconvex, embossed with "5" on one side.
Pharmacotherapeutic group
ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine.
ATX code C09B B04.
Pharmacological properties
Pharmacodynamics
Perindopril
Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I to the vasoconstrictor angiotensin II and also causes the breakdown of the vasodilator bradykinin to an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of plasma renin (by inhibiting the negative feedback on renin release) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also leads to an increase in the activity of the circulating and local kallikrein-kinin system (and thus also leads to the activation of the prostaglandin system). This mechanism of action is responsible for the blood pressure lowering effect of ACE inhibitors and is partly responsible for some of their side effects (e.g., cough).
Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.
Arterial hypertension.
Perindopril effectively lowers blood pressure in all degrees of arterial hypertension: mild, moderate and severe; a decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions.
Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.
Typically, renal blood flow also increases, while glomerular filtration rate (GFR) is usually unchanged.
The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for at least 24 hours: the T/P ratio (maximum efficacy/minimum efficacy during the day) of perindopril is 87–100%.
Blood pressure decreases rapidly. In patients who respond to treatment, blood pressure normalization occurs within a month and is maintained without the occurrence of tachyphylaxis.
There is no withdrawal effect when perindopril is discontinued.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have shown that perindopril has vasodilating properties. It improves the elasticity of large arteries and reduces the ratio of wall thickness to lumen for small arteries.
Prevention of cardiovascular complications in patients with documented stable ischemic heart disease (IHD).
In experimental studies, congestive heart failure was induced by coronary artery ligation and it was shown that perindopril reduces myocardial hypertrophy and excessive subendocardial collagen, restores the ratio of myosin and isoenzyme, and reduces the incidence of reperfusion arrhythmia.
Perindopril tert-butylamine facilitates the work of the heart by reducing pre- and afterload on the heart.
Studies in patients with heart failure have demonstrated:
reduction of right and left ventricular filling pressures; reduction of systemic peripheral resistance; increase in cardiac index and improvement of cardiac output; increase in regional muscle blood flow in the myocardium.
In comparative studies, the initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared with placebo.
Amlodipine
Amlodipine is a calcium ion flux inhibitor belonging to the dihydropyridine group (slow calcium channel blocker or calcium ion antagonist) and blocks the transmembrane flow of calcium ions into myocardial and vascular smooth muscle cells.
Amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). Since the heart rate is unchanged, the reduction in workload on the heart reduces myocardial energy consumption and oxygen demand. Amlodipine also partially contributes to the dilation of the main coronary arteries and coronary arterioles in both intact and ischemic areas of the myocardium. This dilation increases the supply of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina).
In patients with hypertension, once-daily administration of amlodipine provides clinically significant reductions in supine and standing blood pressure over 24 hours. Due to its slow onset of action, amlodipine does not cause acute hypotension.
In patients with angina, once-daily administration of amlodipine increases total exercise time, time to angina attack, and time to 1 mm ST-segment depression, reduces the frequency of angina attacks, and reduces the need for nitroglycerin.
Amlodipine is not associated with any negative metabolic effects or changes in plasma lipid levels, so it can be used in patients with asthma, diabetes, and gout.
Pharmacokinetics
The rate and extent of absorption of perindopril and amlodipine, both as monodrugs and as part of the fixed combination BI-PRENELIA®, do not significantly differ.
Perindopril
After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour.
Perindopril is a prodrug. 27% of the total amount of perindopril taken reaches the bloodstream in the form of the active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in the blood plasma is reached 3-4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thus reducing its bioavailability, therefore the daily dose of perindopril tert-butylamine is recommended to be taken once in the morning before meals.
There is a linear relationship between the dose of perindopril and its concentration in the blood plasma. The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg. The binding of perindoprilat to plasma proteins is 20%, mainly to angiotensin-converting enzyme, but this indicator is dose-dependent. Perindoprilat is excreted in the urine. The terminal half-life of the unbound fraction is approximately 17 hours. The equilibrium plasma concentration stage occurs 4 days after the start of treatment.
The elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal insufficiency (see section 4.4). Therefore, routine medical monitoring will include frequent monitoring of creatinine and potassium levels.
Dialysis clearance of perindoprilat is 70 ml/min.
The kinetics of perindopril are altered in patients with cirrhosis of the liver: the hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients (see section "Special warnings and precautions for use").
Amlodipine
After oral administration of therapeutic doses of amlodipine, it is well absorbed and reaches maximum blood concentrations 6–12 hours after administration. Absolute bioavailability is 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.
The plasma half-life is approximately 35–50 hours, which allows the drug to be administered once daily.
Amlodipine is mainly metabolized in the liver to form inactive metabolites. 60% of the metabolites are excreted in the urine, 10% in unchanged form.
Use in elderly patients: The time to reach maximum plasma concentrations of amlodipine is similar in elderly and younger patients. Elderly patients tend to have a lower clearance of amlodipine and, consequently, an increase in AUC and half-life. The increase in AUC and half-life in patients with congestive heart failure was consistent with the age of the patients studied.
Use in patients with hepatic impairment: There are very limited clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic insufficiency, the clearance of amlodipine is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.
Indication
Arterial hypertension and/or ischemic heart disease (if treatment with perindopril and amlodipine is necessary).
Contraindication
Hypersensitivity to perindopril (or to any other ACE inhibitor), to amlodipine (or to dihydropyridine derivatives) or to any of the excipients; history of angioedema associated with previous treatment with an ACE inhibitor; hereditary or idiopathic angioedema; severe hypotension; shock, including cardiogenic shock; significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney; obstruction of the outflow tract from the left ventricle (e.g. severe aortic stenosis); haemodynamically unstable heart failure after acute myocardial infarction; pregnancy or planning pregnancy (see section "Use during pregnancy and lactation"); extracorporeal treatment leading to contact of blood with negatively charged surfaces;
simultaneous use with drugs containing the active substance aliskiren in patients with diabetes mellitus or patients with renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”);
concomitant use with sacubitril/valsartan (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
All warnings regarding individual components of the drug also apply to the drug BI-PRENELIA®.
Perindopril
Clinical trial data suggest that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions 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 and 4.4).
Drugs causing hyperkalemia. Some drugs or therapeutic classes of drugs may cause hyperkalemia, such as: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim. Concomitant use of these drugs increases the risk of hyperkalemia.
Concomitant use is contraindicated (see section "Contraindications").
Aliskiren: In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, worsening of renal function, and cardiovascular morbidity and mortality is increased.
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g. polyacrylic membranes) and low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive drug.
Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated because concomitant neprilysin and ACE inhibition increases the risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant use is not recommended (see section "Special precautions for use").
Aliskiren: in all other patients, as well as in patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, worsening of renal function, cardiovascular morbidity and mortality is increased.
Concomitant use of an ACE inhibitor and an angiotensin receptor blocker
According to the scientific literature, in patients with atherosclerosis, heart failure or diabetes mellitus with target organ damage, the simultaneous use of ACE inhibitors and angiotensin receptor blockers was accompanied by an increased incidence of arterial hypotension, syncope, hyperkalemia and deterioration of renal function (including acute renal failure) compared with monotherapy with drugs that affect the renin-angiotensin-aldosterone system. The use of dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) is possible only in individual cases, subject to careful monitoring of renal function, potassium levels and blood pressure.
Estramustine: increased risk of adverse reactions such as angioedema.
Co-trimoxazole (trimethoprim/sulfamethoxazole).
Potassium-sparing diuretics (e.g. triamterene, amiloride and others), potassium salts: hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). These drugs are not recommended for simultaneous use with perindopril (see section "Special warnings and precautions for use"). However, if the simultaneous use of these substances is necessary, they should be used with caution and frequent monitoring of serum potassium levels is required. Regarding the use of spironolactone in heart failure, see the section "Concomitant use requiring special attention".
Lithium. Reversible increases in serum lithium concentrations and toxicity have been reported when ACE inhibitors are used with lithium preparations. The use of perindopril with lithium preparations is not recommended. If such a prescription is proven necessary, careful monitoring of serum lithium levels is mandatory (see section "Special instructions").
Concomitant use requiring special attention.
Antidiabetic agents (insulin, oral hypoglycemic agents).
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to an increased blood sugar lowering effect with a risk of hypoglycaemia. This is most likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Baclofen enhances the antihypertensive effect. Blood pressure should be monitored and the dose of the antihypertensive agent adjusted if necessary.
Diuretics. In patients taking diuretics, and especially in those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure may occur after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect can be reduced by canceling the diuretic, increasing the circulating blood volume or salt intake before starting perindopril therapy, which should be started at a low dose and gradually increased. In arterial hypertension, when the previously prescribed diuretic could cause water/electrolyte depletion, it should be canceled before starting treatment with an ACE inhibitor (in such cases, the diuretic can be resumed over time) or the ACE inhibitor should be prescribed at a low dose and gradually increased. In congestive heart failure on the background of taking a diuretic, the ACE inhibitor should be started at the minimum dose, possibly after reducing the dose of the diuretic. In any case, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day are used concomitantly with low-dose ACE inhibitors in patients with heart failure II-IV functional classes according to the New York Heart Association (NYHA) scale and an ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (potentially fatal), especially if the recommendations for the appointment of such a combination are not followed. Before starting this combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function. It is recommended to carefully monitor potassium and creatinine weekly during the first month of treatment and monthly thereafter.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. A reduction in the antihypertensive effect may occur when ACE inhibitors are used concomitantly with NSAIDs, such as: acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 (COX-2) inhibitors, non-selective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including acute renal failure, and increases in serum potassium, especially in patients with a history of impaired renal function. This combination should be administered with caution, particularly in elderly patients. Patients should be rehydrated and renal function monitored at the start of combination therapy and during subsequent treatment.
Racecadotril: ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk is increased when used concomitantly with racecadotril (a medicine used to treat acute diarrhoea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients receiving concomitant mTOR inhibitors are at increased risk of developing angioedema (see section 4.4).
Concurrent use requiring attention.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Patients who use a combination of a gliptin and an ACE inhibitor are at increased risk of angioedema due to the fact that the gliptin reduces the activity of dipeptidyl peptidase-IV (DPP-IV).
Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to a further decrease in blood pressure (see section "Special warnings and precautions for use").
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold: A nitrate-like reaction (symptoms include facial flushing, nausea, vomiting, and hypotension) has been reported rarely in patients receiving concomitant ACE inhibitors, including perindopril, and injectable gold (sodium aurothiomalate).
Amlodipine
Effect of other drugs on amlodipine.
There is no data on the safe use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Data obtained during in vitro studies with human blood plasma indicate that amlodipine has no effect on the binding of the studied drugs (digoxin, phenytoin, warfarin or indomethacin) to blood proteins.
CYP3A4 inhibitors.
Concomitant use of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine exposure, which also increases the risk of hypotension, especially in elderly patients. Clinical monitoring of the patient and dose adjustment may be necessary.
It is not recommended to use amlodipine and grapefruit or grapefruit juice simultaneously, since in some patients the bioavailability of amlodipine may increase, which, in turn, leads to increased hypotensive effect.
CYP3A4 inducers.
Plasma concentrations of amlodipine may be altered following concomitant use of known CYP3A4 inducers. Therefore, blood pressure should be monitored and the dose adjusted to take into account the concomitant use of these medicinal products both during and after concomitant treatment, especially with strong CYP3A4 inducers (e.g. rifampicin, St. John's wort).
Dantrolene (infusion).
Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
The effect of amlodipine on other drugs.
The hypotensive effect of amlodipine potentiates the hypotensive effect of other antihypertensive agents.
Tacrolimus.
There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. To avoid tacrolimus toxicity, patients taking tacrolimus should have their blood levels monitored regularly and the tacrolimus dose adjusted if necessary when amlodipine is co-administered with amlodipine.
mTOR (mammalian target of rapamycin) inhibitors.
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate the effects of the latter.
Cyclosporine.
Interaction studies between ciclosporin and amlodipine have not been performed in healthy volunteers or other populations, except in renal transplant patients, in whom variable increases in ciclosporin trough concentrations (mean 0-40%) were observed. In renal transplant patients receiving amlodipine, monitoring of ciclosporin concentrations should be considered and, if necessary, a reduction in the ciclosporin dose should be considered.
Simvastatin.
Co-administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.
Sildenafil.
A single dose of 100 mg of sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil were used simultaneously as combination therapy, each drug exhibited an independent hypotensive effect.
Other medicines.
Clinical drug interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Ethanol (alcohol).
Single and multiple doses of 10 mg amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.
Laboratory tests.
The effect on laboratory test results is unknown.
Combination of perindopril and amlodipine
Drugs that require special caution when used concomitantly
Baclofen enhances the antihypertensive effect. It is necessary to monitor blood pressure and kidney function, and if necessary, adjust the dose.
Drugs whose concomitant administration requires attention
Antihypertensives (such as beta-blockers) and vasodilators:
Concomitant use of these agents may enhance the hypotensive effect of perindopril and amlodipine.
Concomitant use with nitroglycerin and other nitrates or with other vasodilators may cause a further decrease in blood pressure and should therefore be administered with caution.
Corticosteroids, tetracosactide: reduction of antihypertensive effect (due to water and salt retention by corticosteroids). Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increase antihypertensive effect and increase risk of orthostatic hypotension. Amifostine: may increase antihypertensive effect of amlodipine. Tricyclic antidepressants/antipsychotics/anaesthetics: increase antihypertensive effect and increase risk of orthostatic hypotension.
Application features
All warnings regarding individual components of the drug also apply to the fixed combination BI-PRENELIA®.
Perindopril
Stable coronary artery disease: If an episode of unstable angina (of any severity) occurs during the first month of treatment with perindopril, the risk/benefit ratio should be carefully weighed before deciding whether to continue therapy.
Hypotension. ACE inhibitors may cause a decrease in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely to occur in patients who are volume-depleted, in those taking diuretics, on a salt-restricted diet, in patients on dialysis, in cases of diarrhoea or vomiting and in patients with severe renin-dependent hypertension (see sections 4.5 and 4.8). Symptomatic hypotension has been observed in patients with symptomatic heart failure, with or without concomitant renal insufficiency. Symptomatic hypotension is most likely to occur in patients with more severe heart failure, who are receiving high doses of loop diuretics, who have hyponatremia or functional renal insufficiency. Patients at increased risk of symptomatic hypotension should be closely monitored during initiation of therapy and during dose titration (see sections 4.2 and 4.8). These precautions also 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.
If hypotension occurs, the patient should be placed in the horizontal position and, if necessary, intravenously administered 0.9% (9 mg/ml) sodium chloride solution.
Transient hypotension is not a contraindication for further use of the drug, which can usually be used without any problems after restoration of blood volume and increase in blood pressure.
In some patients with congestive heart failure with normal or low blood pressure, perindopril may cause an additional decrease in systemic blood pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy: As with other ACE inhibitors, perindopril should be administered with caution to patients with mitral valve stenosis or left ventricular outflow obstruction (aortic stenosis or hypertrophic cardiomyopathy).
Kidney dysfunction.
In case of renal insufficiency (creatinine clearance < 60 ml/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section 4.2) and then according to the patient's response to treatment. Monitoring of potassium and creatinine levels is part of routine medical practice in such patients (see section 4.8).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in blood urea and plasma creatinine levels have been observed when using ACE inhibitors, which usually return to normal after discontinuation of treatment. This is especially true in patients with renal insufficiency. In the presence of concomitant renovascular hypertension, the risk of severe arterial hypotension and renal insufficiency increases. In such patients, treatment should be initiated under close medical supervision with low doses and with careful dose titration. Given the above, treatment with diuretics may contribute to the development of arterial hypotension, so they should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril.
In some hypertensive patients with no known renovascular disease prior to treatment, increases in blood urea and serum creatinine, usually minor and transient, have occurred, particularly when perindopril was administered concomitantly with a diuretic. However, this is more common in patients with pre-existing renal insufficiency. A dose reduction and/or discontinuation of the diuretic and/or perindopril may be necessary.
Patients undergoing hemodialysis: Anaphylactoid reactions have been reported in patients receiving ACE inhibitors while undergoing hemodialysis using high-flux membranes. Such patients should be switched to a different type of dialysis membrane or to a different class of antihypertensive agent.
Patients after kidney transplantation: There is no experience in prescribing perindopril to patients after a recent kidney transplantation.
Renovascular hypertension.
When ACE inhibitors are prescribed to patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, there is an increased risk of hypotension and renal failure (see section 4.3). Diuretic treatment may be a beneficial factor. Loss of renal function may be manifested by minimal changes in serum creatinine levels even in patients with stenosis of the artery to a single kidney.
Hypersensitivity/angioedema.
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported (see section 4.8). This may occur at any time during treatment. In such cases, the drug should be discontinued immediately and the patient should be monitored until symptoms resolve. In isolated cases where the swelling is limited to the face and lips, the patient usually improves without treatment. Antihistamines may be useful in reducing symptoms.
Angioedema associated with laryngeal oedema may be fatal. In cases where the oedema involves the tongue, glottis or larynx causing airway obstruction, urgent emergency treatment is required, which may include administration of adrenaline and/or maintenance of a patent airway. The patient should be closely monitored until symptoms resolve or the condition stabilizes. Patients with a history of angioedema unrelated to ACE inhibitors are at increased risk of developing angioedema while taking ACE inhibitors (see section 4.3).
Rare cases of intestinal angioedema have been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no previous history of facial angioedema and C1-esterase levels were normal. The diagnosis of intestinal angioedema was made by abdominal computed tomography or ultrasound, or at the time of surgery. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of patients with abdominal pain receiving ACE inhibitors.
Simultaneous application
