Instructions for Amlessa tablets 4 mg + 5 mg blister No. 30
Composition
active ingredients: perindopril tert-butylamine and amlodipine;
1 tablet contains 4 mg perindopril tert-butylamine (equivalent to 3.34 mg perindopril) and 5 mg amlodipine (equivalent to 6.935 mg amlodipine besylate) or
4 mg perindopril tert-butylamine (equivalent to 3.34 mg perindopril) and 10 mg amlodipine (equivalent to 13.870 mg amlodipine besylate), or
8 mg perindopril tert-butylamine (equivalent to 6.68 mg perindopril) and 5 mg amlodipine (equivalent to 6.935 mg amlodipine besylate), or
8 mg perindopril tert-butylamine (equivalent to 6.68 mg perindopril) and 10 mg amlodipine (equivalent to 13.870 mg amlodipine besylate);
Excipients: microcrystalline cellulose; pregelatinized starch; sodium starch glycolate; calcium chloride, hexahydrate; sodium bicarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
4 mg/5 mg: white or almost white, round, slightly biconvex tablets with beveled edges;
4 mg/10 mg: white or almost white, capsule-shaped, biconvex, with a score on one side of the tablet;
8 mg/5 mg: white or almost white, round, biconvex tablets with beveled edges;
8 mg/10 mg: white or almost white, round, biconvex tablets with beveled edges and a score line on one side.
Pharmacotherapeutic group
Combined preparations of angiotensin-converting enzyme inhibitors. ACE inhibitors in combination with calcium antagonists. ATC code C09B B04.
Pharmacological properties
Pharmacodynamics.
The rate and extent of absorption of perindopril and amlodipine as monodrugs in the composition of Amlessa do not differ significantly.
Perindopril
Perindopril is an inhibitor of angiotensin-converting enzyme (ACE), which converts ACE. The converting enzyme, or kinase, is an exopeptidase that converts angiotensin I to angiotensin II and also causes the breakdown of the vasodilator agent bradykinin to an inactive heptapeptide. Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by an increase in plasma renin activity (by inhibiting the negative feedback of renin release) and a decrease in aldosterone secretion. Since ACE blocks bradykinin, inhibition of the activity of this enzyme leads to an increase in the activity of the circulating and local kallikrein-kinin system and, thereby, to the activation of the prostaglandin system. This mechanism contributes to the blood pressure-lowering effect of ACE inhibitors and is partly responsible for the appearance of some side effects (e.g. cough).
Perindopril is converted in the body to the active metabolite perindoprilat. Other metabolites do not show inhibition of ACE activity in vitro.
Amlodipine
Amlodipine is a calcium ion antagonist that blocks the influx of calcium ions through the membranes into the smooth muscle cells of the myocardium and blood vessels. The mechanism of hypotensive action of amlodipine is due to a direct effect on the smooth muscle of the blood vessels. The exact mechanism of action of amlodipine in angina has not been established, but it is known that amlodipine reduces myocardial ischemia in two ways.
Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. The reduction in workload on the heart leads to a decrease in energy consumption and myocardial oxygen demand.
The mechanism of action of amlodipine also probably involves dilation of the main coronary arteries and coronary arterioles. This dilation increases the oxygen supply to the myocardium in patients with Prinzmetal's angina. In patients with hypertension, once-daily dosing provides clinically significant reductions in blood pressure (both standing and supine) over a 24-hour period.
In patients with angina, once-daily administration of amlodipine prolongs total active time, time to angina onset, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and the need for nitroglycerin tablets.
Pharmacokinetics.
Perindopril
After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations (Cmax) occurring within 1 hour. The plasma half-life (t1/2) of perindopril is 1 hour.
Perindopril is a prodrug. 27% of the administered dose of perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms 5 more inactive metabolites. Cmax of perindoprilat in blood plasma is reached after 3-4 hours.
Since food intake reduces the conversion of perindopril to perindoprilat, and therefore its bioavailability, it is recommended that perindopril tert-butylamine be taken orally in a single daily dose in the morning before meals.
There is a linear relationship between the dose of perindopril and its concentration in blood plasma.
The elimination of perindoprilat is reduced in elderly patients and in patients with heart or renal failure. Therefore, regular monitoring of potassium and creatinine levels is necessary.
The dialysis clearance of perindoprilat is 70 ml/min.
The kinetics of perindopril are altered in patients with cirrhosis: the hepatic clearance of the parent molecule is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients.
Amlodipine
After oral administration in therapeutic doses, amlodipine is well absorbed and reaches Cmax 6-12 hours after administration. Absolute bioavailability is from 64 to 80%. The volume of distribution is approximately 21 l/kg. Food intake does not affect the bioavailability of amlodipine. In vitro studies have shown that approximately 97.5% of circulating amlodipine binds to plasma proteins.
T1/2 is approximately 35-50 hours, which allows the drug to be administered once a day. Amlodipine is metabolized in the liver to form inactive metabolites. 60% of the dose is excreted in the urine, and 10% of the drug is excreted unchanged.
Use in elderly patients. The time required to reach Cmax of amlodipine is the same in both elderly and younger patients. In elderly people, there is a tendency for amlodipine clearance to decrease, resulting in an increase in AUC (area under the concentration-time curve) and t1/2. The recommended dosage regimen for elderly patients is similar, but dose increases should be made with caution.
Use in patients with renal insufficiency (see section "Method of administration and dosage").
Use in patients with impaired liver function. T1/2 of amlodipine, like all calcium antagonists, is increased in patients with impaired liver function.
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 inhibitors), to amlodipine (or to other dihydropyridines) or to any of the excipients of the drug;
history of angioedema after taking any ACE inhibitors;
idiopathic or hereditary angioedema;
severe arterial hypotension;
shock, including cardiogenic shock;
obstruction of the left ventricular outflow tract (for example, severe aortic stenosis);
unstable angina;
heart failure after acute myocardial infarction (within the first 28 days);
the second and third trimesters of pregnancy (see sections “Special precautions for use” and “Use during pregnancy or breastfeeding”);
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. Perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections “Interaction with other medicinal products and other forms of interaction” and “Special warnings and precautions for use”);
extracorporeal treatments that result in blood coming into contact with negatively charged surfaces (see section “Interaction with other medicinal products and other types of interactions”);
significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").
Interaction with other medicinal products and other types of interactions
All precautions regarding the separate use of perindopril and amlodipine also apply to the use of the drug Amlessa.
Perindopril
Drugs that increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as it increases the risk of angioedema (see sections 4.3 and 4.4). Sacubitril/valsartan therapy should be initiated no earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section 4.4).
Concomitant use is contraindicated.
Clinical trial data have 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 incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Extracorporeal therapies: Extracorporeal therapies that bring blood into contact with negatively charged surfaces, such as dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, due to an increased risk of severe anaphylactoid reactions (see section 4.3). If such treatments are necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated because concomitant inhibition of neprilysin and ACE may increase 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 of ACE inhibitors and angiotensin receptor blockers
Published data have shown that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, the concomitant use of ACE inhibitors and angiotensin receptor blockers was associated with an increased incidence of hypotension, syncope, hyperkalemia, and deterioration of renal function (including acute renal failure) compared with monotherapy with drugs that affect the renin-angiotensin-aldosterone system (RAAS). Dual blockade (i.e., the combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases and with careful monitoring of renal function, potassium levels, and blood pressure.
Estramustine
The risk of adverse reactions such as angioedema increases.
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts
The combination of perindopril with these drugs is not recommended due to the risk of hyperkalemia (potentially fatal), especially in case of impaired renal function (additive effect of hyperkalemia) (see "Special instructions"). If concomitant use is nevertheless indicated, they should be used with caution and serum potassium levels should be regularly monitored. For the use of spironolactone in heart failure, see below.
Lithium
When using ACE inhibitors with lithium preparations, a reversible increase in plasma lithium concentration is possible and, accordingly, an increase in the risk of its toxic effects. It is not recommended to use perindopril with lithium preparations. In case of proven need for such use, careful monitoring of lithium levels in the blood plasma is mandatory (see section "Special instructions").
Concomitant use requiring special attention
Drugs that cause hyperkalemia
Although serum potassium levels are usually within normal limits, hyperkalemia may occur in some patients taking Amlessa. Some drugs may increase the incidence of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, and trimethoprim and co-trimoxazole [trimethoprim/sulfamethoxazole] (trimethoprim acts as a potassium-sparing diuretic amiloride). The combination of Amlessa and the above drugs will increase the risk of hyperkalemia and is therefore not recommended. If concomitant use is necessary, caution and frequent monitoring of serum potassium levels are required.
Antidiabetic agents (insulin, oral hypoglycemic agents)
Epidemiological studies suggest that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may lead to an increased hypoglycemic effect with a risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combined treatment and in patients with renal insufficiency.
Baclofen
The antihypertensive effect is enhanced. If necessary, blood pressure should be monitored and the dose of antihypertensive drugs should be adapted.
In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
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)
In the case of simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of an ACE inhibitor, it should be borne in mind that:
If the recommendations for the use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during the treatment of patients with NYHA [New York Heart Association] class II–IV heart failure and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic;
before prescribing such a combination, one should make sure that there is no hyperkalemia and renal failure;
It is recommended to carefully monitor potassium and creatinine levels weekly during the first month of treatment and monthly thereafter.
NSAIDs, including acetylsalicylic acid ≥ 3 g/day
The antihypertensive effect may be reduced when ACE inhibitors are used concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the possibility of developing acute renal failure, an increase in plasma potassium levels, especially in patients with a history of impaired renal function. This combination should be administered with caution, especially in elderly patients. Patients should be rehydrated and attention should be paid to monitoring renal function immediately after the initiation of combination therapy and periodically thereafter.
Concomitant use requiring attention
Antihypertensives and vasodilators
Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.
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").
Diuretics
In patients taking diuretics, and especially in those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by discontinuing the diuretic, increasing the circulating blood volume or salt intake before starting therapy with perindopril. Treatment should be started with low doses and gradually increased.
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold: A nitrate-like reaction (symptoms: facial flushing, nausea, vomiting, and hypotension) has occurred rarely in patients receiving concomitant ACE inhibitors, including perindopril, and injectable gold (sodium aurothiomalate).
Amlodipine
Effects of other drugs on amlodipine
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 may also lead to an increased risk of hypotension. The clinical significance of such changes may be more pronounced 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 primarily leads to increased hypotensive effect.
CYP3A4 inducers
Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments considered both during and after concomitant medication, 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.
Effect of amlodipine on other medicinal products
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, regular monitoring of tacrolimus blood levels and, if necessary, dosage adjustment are required when amlodipine is co-administered.
No interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations, except in renal transplant patients, where a variable increase in ciclosporin trough concentrations (mean 0-40%) was 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.
Clinical drug interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Mechanistic target of rapamycin (mTOR) inhibitors
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When co-administered with mTOR inhibitors, amlodipine may increase the exposure of mTOR inhibitors.
Application features
All of the following warnings regarding individual components of the drug also apply to the drug Amlessa.
Perindopril
Hypersensitivity/angioedema
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (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's condition usually improves without treatment. Antihistamines may be useful in reducing symptoms.
Angioedema associated with laryngeal oedema can 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 airway management. Patients should be closely monitored until symptoms resolve and the condition stabilizes.
Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of developing angioedema while receiving an ACE inhibitor (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 C-1 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 excluded in the differential diagnosis of patients presenting with abdominal pain while taking ACE inhibitors (see section 4.8).
The combination of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section 4.4). Sacubitril/valsartan therapy should be initiated no earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan treatment is discontinued, perindopril therapy may be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the 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 (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already taking ACE inhibitors.
Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis
Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during plasmapheresis of LDL using dextran sulfate. The development of anaphylactoid reactions can be avoided by temporarily stopping ACE inhibitor treatment before each plasmapheresis.
Anaphylactoid reactions may occur in patients taking ACE inhibitors during desensitization treatment with bee venom-containing drugs. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but the reactions may recur if provocation tests are performed carelessly.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagen vascular diseases, immunosuppressants, allopurinol or procainamide or a combination of these aggravating factors, especially in the presence of pre-existing renal impairment. Serious infections may occasionally develop in these patients, which in rare cases may not respond to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of the white blood cell count is recommended and patients should be advised to report any signs of infection (sore throat, fever).
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney are at increased risk of hypotension and renal failure when treated with ACE inhibitors (see section 4.3). Diuretic therapy may be beneficial. Loss of renal function may occur with only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, it should only be done under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Primary aldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act through inhibition of the renin-angiotensin system. Therefore, the use of this drug is not recommended.
Pregnancy
ACE inhibitors should not be used during pregnancy. 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 possible, alternative therapy should be started (see sections 4.3 and 4.8).
Arterial hypotension
ACE inhibitors may cause a decrease in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely in patients who are hypovolemic, taking diuretics, on a salt-restricted diet, on dialysis, in patients with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients at high risk of developing symptomatic hypotension, blood pressure, renal function, and serum potassium should be closely monitored during treatment with Amlessa. This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure could lead to myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, intravenously administered 0.9% (9 mg/ml) sodium chloride solution. Transient hypotension is not a contraindication to further treatment with the drug, which can usually be used after volume repletion and blood pressure elevation.
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 failure
Some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney who have been treated with ACE inhibitors have experienced increases in blood urea and serum creatinine, which were usually reversible after discontinuation of therapy. These increases are more likely to occur in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In some patients with hypertension without overt renal vascular disease, increases in blood urea and serum creatinine, usually minor and transient, have been observed, especially when perindopril was given concomitantly with a diuretic. These increases are more likely to occur in patients with pre-existing renal insufficiency.
Liver failure
Cases of a syndrome that begins with cholestatic jaundice and progresses to transient hepatic necrosis and sometimes fatal outcome have been reported rarely during treatment with an ACE inhibitor. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevations of liver enzymes while taking an ACE inhibitor should discontinue the drug and receive appropriate medical evaluation and treatment (see section 4.8).
Racial factor
ACE inhibitors cause angioedema more often in black patients than in non-blacks. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients than in non-blacks, possibly because of lower renin levels in the blood of black hypertensive patients.
Cough
Cough has been reported with ACE inhibitor therapy. The cough is typically nonproductive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitors should be considered in the differential diagnosis of cough.
Surgery/anesthesia
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or during anesthesia with drugs that cause arterial hypotension. The drug should be discontinued 1 day before surgery. In the event of arterial hypotension, if it is believed that it is caused by this mechanism, the patient's condition can be normalized by increasing the volume of circulating blood.
Serum potassium
Some patients taking ACE inhibitors, including perindopril, have experienced increases in serum potassium. ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. This effect is usually minor in patients with normal renal function. Patients with renal insufficiency, with worsening renal function, patients > 70 years of age, patients with diabetes mellitus, with concomitant conditions such as dehydration, acute cardiac decompensation, metabolic acidosis, and patients taking concomitant potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium, other drugs that increase serum potassium levels (e.g. heparin, co-trimoxazole [trimethoprim/sulfamethoxazole]), especially aldosterone antagonists or angiotensin receptor blockers, are at increased risk of developing hyperkalemia. Use of
