Bis-Aliter capsules 5 mg + 4 mg blister No. 30

Instructions for Bis-Aliter capsules 5 mg + 4 mg blister No. 30

Composition

active ingredients: bisoprolol, perindopril;

1 capsule of 5 mg / 4 mg contains:

5 mg of bisoprolol fumarate, equivalent to 4.24 mg of bisoprolol, and 4 mg of perindopril tert-butylamine, equivalent to 3.34 mg of perindopril;

1 capsule of 5 mg / 8 mg contains:

5 mg of bisoprolol fumarate, equivalent to 4.24 mg of bisoprolol, and 8 mg of perindopril tert-butylamine, equivalent to 6.68 mg of perindopril;

1 capsule of 10 mg / 8 mg contains:

10 mg of bisoprolol fumarate, equivalent to 8.49 mg of bisoprolol, and 8 mg of perindopril tert-butylamine, equivalent to 6.68 mg of perindopril;

excipients:

for bisoprolol tablets: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; iron oxide (E 172);

for perindopril tablets: lactose monohydrate; microcrystalline cellulose; magnesium stearate; colloidal anhydrous silica;

capsule (body and cap): gelatin; water; titanium dioxide (E 171).

Dosage form

The capsules are hard.

Main physicochemical properties: opaque, hard gelatin capsules of white or almost white color, containing one tablet of white or almost white perindopril and two tablets of yellow to yellow-brown bisoprolol.

Pharmacotherapeutic group

Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors, combinations. ACE inhibitors, other combinations. Perindopril and bisoprolol. ATC code C09B X02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Bisoprolol

Bisoprolol is a highly selective β1-adrenoceptor blocker that does not have intrinsic sympathomimetic and pronounced membrane-stabilizing activity. It has low affinity for β2-receptors of bronchial and vascular smooth muscle, as well as for β2-receptors responsible for metabolic regulation. Therefore, bisoprolol should generally not affect airway resistance and β2-mediated metabolic effects. Its β1-selectivity extends beyond the therapeutic dosage range.

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 causes a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of plasma renin (by inhibiting the negative feedback of renin release) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also causes an increase in the activity of the circulating and local kallikrein-kinin systems (and, thus, activates the prostaglandin systems). This mechanism of action accounts for the blood pressure lowering effect of ACE inhibitors and is partly responsible for some of the side effects (e.g. cough). Perindopril acts through its active metabolite, perindoprilat. The other metabolites do not show activity in inhibiting ACE in vitro.

Pharmacodynamic effects

Bisoprolol

Bisoprolol does not exhibit a pronounced negative inotropic effect. The maximum effect of bisoprolol is achieved 3–4 hours after administration. Due to the half-life of 10–12 hours, bisoprolol retains its therapeutic effect for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved after two weeks of administration. With a single administration to patients with ischemic heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume and, thus, reduces cardiac output and oxygen consumption. With prolonged administration, the initially increased peripheral resistance decreases. A decrease in plasma renin activity probably causes the antihypertensive effect of β-blockers. Bisoprolol reduces the sympathoadrenergic response by blocking β-adrenoreceptors of the heart, which causes a decrease in heart rate and contractility. This, in turn, causes a decrease in myocardial oxygen consumption, which is necessary in the treatment of angina pectoris in ischemic heart disease.

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 in the patient both in the supine and standing positions. Perindopril reduces peripheral vascular resistance, which causes a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate. As a rule, renal blood flow also increases, while the 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 residual effect is about 87-100% of the peak effect. Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without the occurrence of tachyphylaxis. Discontinuation of treatment is not accompanied by a withdrawal effect. 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 of small arteries. Perindopril reduces cardiac work by reducing pre- and afterload on the heart: reduces left and right ventricular filling pressure, reduces total peripheral vascular resistance, increases cardiac output and improves cardiac index (according to studies).

Pharmacokinetics.

The rate and extent of absorption of bisoprolol and perindopril in the composition of the drug BIS-ALITER do not significantly differ from the rate and extent of absorption of bisoprolol and perindopril when used separately as monotherapy.

Bisoprolol

Absorption

Bisoprolol is almost completely (> 90%) absorbed from the gastrointestinal tract. The first-pass effect through the liver is insignificant (approximately 10%), which results in a high bioavailability (approximately 90%) after oral administration.

Distribution

The volume of distribution is 3.5 l/kg. The binding of bisoprolol to plasma proteins is about 30%.

Biotransformation and excretion

Bisoprolol is eliminated from the body in two ways. 50% is metabolized in the liver to inactive metabolites, which are then excreted by the kidneys, and the remaining 50% is excreted by the kidneys in an unmetabolized form. Total clearance is approximately 15 l/h. The plasma half-life is 10–12 hours, which provides a 24-hour effect after a once-daily dose.

Special patient groups

The kinetics of bisoprolol are linear and independent of age. Since bisoprolol is eliminated from the body to the same extent by the kidneys and liver, dose adjustment is not required in patients with impaired liver function or renal failure. Pharmacokinetics in patients with chronic heart failure and impaired liver or kidney function have not been studied. In patients with chronic heart failure (NYHA functional class III [New York Heart Association]), bisoprolol plasma levels are higher and the half-life is longer compared to healthy volunteers. At a daily dose of 10 mg, the maximum plasma concentration in the steady state is 64 ± 21 ng/ml and the half-life is 17 ± 5 h.

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour.

Distribution

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, and is dose-dependent.

Biotransformation

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. The maximum concentration of perindoprilat in the blood plasma is reached after 3-4 hours. Since food intake reduces the conversion of perindopril to perindoprilat, and therefore its bioavailability, perindopril tert-butylamine is recommended to be administered orally in a single daily dose in the morning before meals.

Breeding

Perindoprilat is excreted in the urine, with a terminal half-life of the unbound fraction of approximately 17 hours. Steady state is reached after 4 days.

Linearity

There is a linear relationship between the dose of perindopril and its concentration in blood plasma.

Special patient groups

The elimination of perindoprilat is slowed down in elderly patients and in patients with heart or renal failure. It is recommended to select the dose for patients with renal failure taking into account the degree of renal failure (creatinine clearance). The dialysis clearance of perindoprilat is 70 ml/min. The kinetics of perindopril are changed in patients with cirrhosis of the liver: the hepatic clearance of the parent molecule is halved. However, the amount of perindoprilat formed is not reduced. Therefore, such patients do not need to adjust the dose (see sections "Special instructions for use" and "Method of administration and dosage").

Indication

The drug BIS-ALITER in dosages of 5 mg / 8 mg and 10 mg / 8 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (with a history of myocardial infarction and/or revascularization) in adult patients who require therapy with bisoprolol and perindopril in doses available in a fixed combination.

The drug BIS-ALITER in a dosage of 5 mg / 4 mg is indicated for the treatment of arterial hypertension and/or stable ischemic heart disease (in the presence of a history of myocardial infarction and/or revascularization) and/or stable chronic heart failure with reduced left ventricular systolic function in adult patients who require therapy with bisoprolol and perindopril in doses available in a fixed combination.

Contraindication

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product, or to any other ACE inhibitors;
• acute heart failure or heart failure in the stage of decompensation requiring intravenous inotropic therapy;
• cardiogenic shock;
• atrioventricular block II or III degree (without an artificial pacemaker);
• sick sinus syndrome;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe form of bronchial asthma or severe chronic obstructive pulmonary disease;
• severe form of peripheral arterial occlusive disease or severe form of Raynaud's syndrome;
• untreated pheochromocytoma (see section "Special instructions for use");
• metabolic acidosis;
• history of angioedema associated with previous ACE inhibitor therapy (see section "Special warnings and precautions for use");
• hereditary or idiopathic angioedema;
• pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");
• simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”);
• simultaneous use with sacubitril/valsartan. BIS-ALITER should not be used 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 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

In an interaction study conducted in healthy volunteers, no interaction between bisoprolol and perindopril was found. Information on interactions with other medicinal products for each active substance is provided below.

Medicines that increase the risk of developing angioedema

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as 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 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).

Drugs that cause hyperkalemia

Serum potassium levels are usually within normal limits, but hyperkalemia may occur in some patients taking BIS-ALITER. Some medicinal products (therapeutic classes of medicinal products) increase the risk of hyperkalemia, including 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 cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic, similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of BIS-ALITER with the above-mentioned drugs is not recommended. If concomitant use of these substances is necessary, they should be used with caution and serum potassium should be monitored frequently.

Concomitant use is contraindicated (see Contraindications section).

Aliskiren

Extracorporeal treatment methods

Extracorporeal treatments that bring blood into contact with negatively charged surfaces, such as dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate, are contraindicated due to the 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.

Concomitant use is not recommended.

Interactions related to bisoprolol

Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonidine, rilmenidine)

Concomitant use with centrally acting antihypertensive drugs may lead to worsening of heart failure due to decreased central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt withdrawal of β-blocker therapy, particularly without prior dose reduction, increases the risk of rebound hypertension.

Class I antiarrhythmics (e.g., quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone)

Potentiation of the effect on atrioventricular conduction time and enhancement of the negative inotropic effect are possible.

Calcium antagonists of the verapamil group and, to a lesser extent, diltiazem

Negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil to patients taking β-blockers may result in significant hypotension and atrioventricular block.

Interactions related to perindopril

Aliskiren

In all other patients, as in patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function and cardiovascular morbidity and mortality is increased.

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of adverse reactions such as hypotension, hyperkalaemia and worsening of renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3 and 4.4). In patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker has been reported to be associated with an increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single RAAS-acting agent. Dual blockade (i.e., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) may be considered in individual cases with close monitoring of renal function, potassium levels, and blood pressure.

Estramustine

There is a risk of increased adverse reactions, in particular the occurrence of angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts

Hyperkalemia (possibly fatal), especially in patients with renal insufficiency (additive hyperkalemic effect). The above-mentioned drugs are not recommended for concomitant use with perindopril (see section "Special warnings and precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and serum potassium should be monitored frequently. For the use of spironolactone in heart failure, see below.

Lithium

Reversible increases in serum lithium concentrations and increased toxicity have been reported with concomitant use of ACE inhibitors. Concomitant use of perindopril and lithium is not recommended. However, if such a combination is warranted, serum lithium levels should be closely monitored (see section 4.4).

Concomitant use requiring special attention

Interactions related to bisoprolol and perindopril

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies suggest that the simultaneous use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to an increase in the blood sugar-lowering effect with the risk of hypoglycemia. This phenomenon is most likely to occur in the first weeks of combined treatment and in the presence of renal failure. The simultaneous use of bisoprolol with insulin and oral antidiabetic agents may lead to an increase in the blood sugar-lowering effect. Blockade of β-adrenoceptors may mask the symptoms of hypoglycemia.

With the simultaneous use of the drug BIS-ALITER with NSAIDs (such as acetylsalicylic acid in anti-inflammatory doses, cyclooxygenase COX-2 inhibitors and non-selective NSAIDs), a decrease in the antihypertensive effect of bisoprolol and perindopril is possible. In addition, the simultaneous use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including possible acute renal failure, and an increase in blood potassium levels, especially in patients with pre-existing impaired renal function. Such a combination should be prescribed with caution, especially in elderly patients. It is necessary to restore the patient's water balance and consider monitoring renal function after starting combination therapy and during further treatment.

Antihypertensive drugs and vasodilators

Concomitant use with antihypertensive drugs, vasodilators (e.g. nitroglycerin, other nitrates or other vasodilators) or with other drugs that may lower blood pressure (e.g. tricyclic antidepressants, barbiturates, phenothiazines) increases the risk of hypotensive effects of perindopril and bisoprolol.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of ACE inhibitors and certain anesthetics, tricyclic antidepressants and antipsychotics may lead to a further decrease in blood pressure. Concomitant use of bisoprolol with anesthetics may lead to attenuated reflex tachycardia and an increased risk of arterial hypotension.

Sympathomimetics

β-sympathomimetics (e.g. isoprenaline, dobutamine): Concomitant use with bisoprolol may reduce the effects of both drugs. Sympathomimetics that activate α- and β-adrenoceptors (e.g. norepinephrine, epinephrine): Combination with bisoprolol may potentiate the α-adrenoceptor-mediated vasoconstrictor effects of these drugs, leading to an increase in blood pressure and exacerbation of intermittent claudication. Such interactions are more likely with non-selective β-blockers. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Interactions related to bisoprolol

Dihydropyridine-type calcium antagonists, such as felodipine and amlodipine

Concomitant use increases the risk of arterial hypotension; increases the risk of further deterioration of ventricular pumping function in patients with heart failure.

Class III antiarrhythmic drugs (e.g. amiodarone)

Possible increased effect on atrioventricular conduction time.

Parasympathomimetic drugs

Concomitant use may increase atrioventricular conduction time and the risk of bradycardia.

Topical ß-blockers (e.g. eye drops for glaucoma)

Concomitant use may enhance the systemic effects of bisoprolol.

Digitalis glycosides

Decreased heart rate, increased atrioventricular conduction time.

Interactions related to perindopril

Baclofen

Enhances antihypertensive effect. Blood pressure should be monitored and dose adjusted if necessary.

Diuretics

In patients taking diuretics, especially in case of 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 if the diuretic is discontinued, the circulating blood volume is increased or salt intake is increased before starting therapy, which should be started at low doses with a gradual increase in the dose of perindopril. In arterial hypertension, when the previously prescribed diuretic could have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the use of the diuretic can be resumed over time) or treatment with an ACE inhibitor should be started at low doses with a gradual increase in the dose. In congestive heart failure on the background of taking a diuretic, the use of an ACE inhibitor should be started at a low dose, possibly after a reduction in the dose of the concomitant diuretic. In all cases, renal function (creatinine level) should be monitored during the first weeks of treatment with an ACE inhibitor.

Potassium-sparing diuretics (eplerenone, spironolactone)

Concomitant use of eplerenone or spironolactone at doses of 12.5 to 50 mg/day with low-dose ACE inhibitors: 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 class II-IV heart failure and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic. Before prescribing this combination, it is necessary to ensure that there is no hyperkalemia and renal insufficiency. It is recommended to carefully monitor serum potassium and creatinine weekly during the first month of treatment and monthly thereafter.

Concomitant use requiring attention

Interactions related to bisoprolol

Mefloquine

Increased risk of developing bradycardia.

Monoamine oxidase inhibitors (except MAO-B inhibitors)

Increased hypotensive effect of β-blockers and risk of hypertensive crisis.

Interactions related to perindopril

Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may rarely cause reactions similar to those seen with nitrates (symptoms: flushing, nausea, vomiting and hypotension).

Application features

All warnings regarding the use of individual components of the drug apply to the drug BIS-ALITER.

Arterial hypotension

ACE inhibitors may cause a sharp decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and is more likely in patients who are volume-depleted, such as those taking diuretics, those on a salt-restricted diet, those on dialysis, those with diarrhoea or vomiting, and those with severe renin-dependent hypertension (see sections 4.5 and 4.8). Symptomatic hypotension is more likely 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, those taking high doses of loop diuretics, those with hyponatraemia or functional renal insufficiency. Patients at increased risk of symptomatic hypotension should be closely monitored during initiation of therapy and during dose titration. These precautions also apply to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure may lead to myocardial infarction or stroke. In the event of hypotension, the patient should be placed in the supine position and, if necessary, intravenous sodium chloride 9 mg/ml (0.9%) solution should be administered. Transient hypotension is not a contraindication to continued use of the drug, which can usually be continued without any problems after volume expansion and blood pressure elevation. 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 treatment. If hypotension becomes symptomatic, it may be necessary to reduce the dose or gradually discontinue treatment with individual components.

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, BIS-Aliter should be discontinued immediately. β-blocker therapy should be continued. Appropriate monitoring of the patient's condition should be established until the symptoms have completely disappeared. In cases where the swelling is limited to the face and lips, the patient's condition usually improves without treatment, but antihistamines may be useful in reducing symptoms. Angioedema associated with laryngeal edema can be fatal. If the swelling extends to the tongue, glottis or larynx, which may lead to airway obstruction, emergency treatment should be initiated immediately, which may include the administration of adrenaline and/or maintenance of a patent airway. The patient should be kept under close medical supervision until complete and sustained resolution of symptoms. Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of developing angioedema (see section 4.3). Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients have presented with abdominal pain (with or without nausea and 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 computed tomography or ultrasound or during surgery. The symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section 4.3). Sacubitril/valsartan should not be started until 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril should not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) and ACE inhibitors also increases the risk of angioedema (see section 4.5). Therefore, a careful benefit-risk assessment should be made before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients taking perindopril. 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.

Liver dysfunction

Rarely, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice and progresses to rapid hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or significantly elevated liver enzymes while taking ACE inhibitors should discontinue the ACE inhibitor and receive appropriate medical evaluation and treatment (see section 4.8).

Racial characteristics

ACE inhibitors cause angioedema more frequently in black patients than in non-black patients. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black hypertensive patients than in non-black patients, possibly because of lower renin levels in these patients.

Cough

Cough has been reported with ACE inhibitors. This cough is non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Hyperkalemia

Some patients have experienced increases in serum potassium levels while taking ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting aldosterone release. This effect is usually minor in patients with normal renal function. Risk factors for hyperkalaemia include: renal insufficiency, worsening renal function, age > 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute cardiac decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes or other medicinal products that increase serum potassium levels (including heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), especially aldosterone antagonists and angiotensin receptor blockers. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be closely monitored. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, this should be done with caution and with frequent monitoring of serum potassium (see section 4.5).

Combinations with lithium

The concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").

Combinations with potassium-sparing drugs, potassium-containing food supplements, or potassium-containing salt substitutes

Concomitant use of perindopril with