Amlessa

INSTRUCTIONS for medical use of the medicinal product Amlessa (Amlessa®)

Composition:

Active substances: perindopril tert-butylamine and amlodipine;

One tablet contains 4 mg of perindopril tert-butylamine (equivalent to 3.34 mg of perindopril) and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besylate), or

4 mg of perindopril tert-butylamine (equivalent to 3.34 mg of perindopril) and 10 mg of amlodipine (equivalent to 13.870 mg of amlodipine besylate), or

8 mg of perindopril tert-butylamine (equivalent to 6.68 mg of perindopril) and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besylate), or

8 mg of perindopril tert-butylamine (equivalent to 6.68 mg of perindopril) and 10 mg of amlodipine (equivalent to 13.870 mg of amlodipine besylate);

Excipients: microcrystalline cellulose; pregelatinized starch; sodium starch glycolate; calcium chloride, hexahydrate; sodium hydrocarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

4 mg/5 mg: white or almost white, round, slightly biconvex tablets with bevelled edges;

4 mg/10 mg: white or almost white, capsule-shaped, biconvex tablets with a bevelled edge and a notch on one side;

8 mg/5 mg: white or almost white, round, biconvex tablets with bevelled edges;

8 mg/10 mg: white or almost white, round, biconvex tablets with bevelled edges and a score line on one side.

Pharmacotherapeutic group. Combined 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 individual components within the drug Amlessa do not differ significantly.

Perindopril

Perindopril is an angiotensin-converting enzyme (ACE) inhibitor. The converting enzyme, or kinase, is an exopeptidase that catalyzes the conversion of angiotensin I to angiotensin II, and also promotes the breakdown of the vasodilatory agent bradykinin into an inactive heptapeptide. Inhibition of ACE activity leads to reduced plasma concentrations of angiotensin II, accompanied by increased plasma renin activity (due to inhibition of the negative feedback on renin release) and decreased aldosterone secretion. Since ACE also degrades bradykinin, inhibition of this enzyme results in increased activity of circulating and local kallikrein-kinin systems, thereby promoting prostaglandin system activation. This mechanism contributes to the antihypertensive effect of ACE inhibitors and partially explains certain adverse effects (e.g., cough).

Perindopril is converted in the body into its active metabolite, perindoprilat. Other metabolites do not exhibit ACE-inhibitory activity in vitro.

Amlodipine

Amlodipine is a calcium ion antagonist that blocks calcium ion influx through cell membranes into vascular and cardiac smooth muscle cells. The antihypertensive mechanism of amlodipine is due to its direct effect on vascular smooth muscle. The exact mechanism of amlodipine in angina is not fully established, but it is known that amlodipine reduces myocardial ischemia via two pathways.

Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload) against which the heart must work. This reduction in cardiac workload leads to decreased myocardial energy consumption and oxygen demand.

The mechanism of amlodipine may also involve dilation of major coronary arteries and arterioles. This dilation increases oxygen delivery to the myocardium in patients with Prinzmetal's angina. In patients with arterial hypertension, once-daily dosing provides clinically significant reduction in blood pressure (both in supine and standing positions) over the entire 24-hour period.

In patients with angina, once-daily administration of amlodipine prolongs total exercise time, time to onset of angina, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and decreases the need for nitroglycerin tablets.

Pharmacokinetics.

Perindopril

After oral administration, perindopril is rapidly absorbed, with peak plasma concentration (Cmax) reached within 1 hour. The elimination half-life (t1/2) of perindopril in plasma is 1 hour.

Perindopril is a prodrug. Approximately 27% of the administered dose of perindopril reaches the systemic circulation as the active metabolite, perindoprilat. In addition to the active perindoprilat, perindopril forms five inactive metabolites. Cmax of perindoprilat in plasma is achieved within 3–4 hours.

Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril tert-butylamine is recommended to be taken orally as a single daily dose in the morning before meals.

There is a linear relationship between perindopril dose and its plasma concentration.

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is about 20%, primarily to ACE, and is dose-dependent. Perindoprilat is excreted in urine, and the terminal elimination half-life of unbound perindoprilat is approximately 17 hours. Steady-state levels are achieved within 4 days.

Elimination of perindoprilat is reduced in elderly patients and in patients with cardiac or renal insufficiency. Therefore, regular monitoring of potassium and creatinine levels is necessary.

The dialysis clearance of perindoprilat is 70 mL/min.

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of formed perindoprilat is not reduced. Therefore, dose adjustment is not required in these patients.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed and reaches Cmax within 6–12 hours after intake. Absolute bioavailability ranges from 64% to 80%. The volume of distribution is approximately 21 L/kg. Food intake does not affect amlodipine bioavailability. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The t1/2 is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is metabolized in the liver to inactive metabolites. About 60% of the administered dose is excreted in urine, and 10% is excreted unchanged.

Use in elderly patients. The time required to reach Cmax of amlodipine is similar in elderly and younger patients. In elderly individuals, there is a tendency toward reduced amlodipine clearance, resulting in increased AUC (area under the concentration-time curve) and t1/2. The recommended dosing regimen for elderly patients is the same; however, dose escalation should be performed cautiously.

Use in patients with renal impairment (see section "Administration and Dosage").

Use in patients with hepatic impairment. The t1/2 of amlodipine, as with all calcium antagonists, is prolonged in patients with impaired liver function.

Clinical characteristics.

Indications.

Arterial hypertension and/or ischemic heart disease (when treatment with perindopril and amlodipine is required).

Contraindications.

• Hypersensitivity to perindopril (or to any other angiotensin-converting enzyme (ACE) inhibitors), to amlodipine (or to other dihydropyridines), or to any excipient of the drug;
• history of angioedema after administration of any ACE inhibitors;
• idiopathic or hereditary angioedema;
• severe arterial hypotension;
• shock, including cardiogenic shock;
• obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
• unstable angina;
• heart failure following acute myocardial infarction (within the first 28 days);
• second and third trimesters of pregnancy (see sections «Special precautions for use» and «Use during pregnancy or breastfeeding»);
• concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (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 combination. Therapy with perindopril may be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections «Interaction with other medicinal products and other types of interactions» and «Special precautions for use»);
• extracorporeal treatment methods leading to blood 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 precautions for use»).

Interaction with other medicinal products and other types of interactions.

All precautions regarding individual use of perindopril and amlodipine also apply to the use of the medicinal product Amlessa.

Perindopril

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections «Contraindications», «Special precautions for use»). 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 «Contraindications», «Special precautions for use»).

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 development (see section «Special precautions for use»).

Concomitant use contraindicated

Aliskiren. In patients with diabetes or impaired renal function, the risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality increases.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to use of a single agent acting on the RAAS (see sections «Contraindications», «Special precautions for use», and «Pharmacological properties»).

Extracorporeal treatment methods. Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain highly permeable membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions (see section «Contraindications»). If such treatment is necessary, consider using a different type of dialysis membrane or another class of antihypertensive agents.

Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as simultaneous inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan therapy should occur 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 «Contraindications» and «Special precautions for use»).

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Published data indicate that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system (RAAS). Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases under strict monitoring of renal function, potassium levels, and blood pressure.

Estramustine

Increases the risk of adverse reactions such as angioedema.

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

Combination of perindopril with these agents is not recommended due to the risk of hyperkalemia (potentially fatal), especially in cases of renal impairment (additive hyperkalemic effect) (see «Special precautions for use»). If concomitant use is necessary, it should be done with caution and regular monitoring of serum potassium levels. For use of spironolactone in heart failure, see below.

Lithium

Concomitant use of ACE inhibitors with lithium preparations may lead to reversible increases in plasma lithium concentration and, consequently, increased risk of lithium toxicity. Concomitant use of perindopril with lithium preparations is not recommended. If such use is necessary, plasma lithium levels must be closely monitored (see section «Special precautions for use»).

Concomitant use requiring special attention

Medicinal products causing hyperkalemia

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients taking Amlessa. Some medicinal products may increase the frequency of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, as well as trimethoprim and co-trimoxazole [trimethoprim/sulfamethoxazole] (trimethoprim acts as a potassium-sparing diuretic similar to amiloride). Combination of Amlessa with the above-mentioned agents increases 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 concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment.

Baclofen

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

In arterial hypertension, if a previously prescribed diuretic may have caused fluid/electrolyte deficiency, it should be discontinued before initiating ACE inhibitor therapy (diuretic therapy may be resumed later) or the ACE inhibitor should be started at a low dose with gradual dose escalation.

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, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

When eplerenone or spironolactone is used concomitantly with low-dose ACE inhibitors, the following should be considered:

• In cases where recommendations for use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and loop diuretic;
• Before prescribing this combination, ensure absence of hyperkalemia and renal impairment;
• Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

NSAIDs, including acetylsalicylic acid ≥ 3 g/day

The antihypertensive effect of ACE inhibitors may be reduced when used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the likelihood of acute renal failure, and elevated plasma potassium levels, especially in patients with a history of renal impairment. This combination should be prescribed with caution, particularly in elderly patients. Patients should be adequately hydrated, and renal function should be monitored immediately after initiation of combination therapy and periodically thereafter.

Concomitant use requiring attention

Antihypertensive agents and vasodilators

Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional reduction in blood pressure.

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotic agents with ACE inhibitors may lead to further reduction in blood pressure (see section «Special precautions for use»).

Diuretics

In patients taking diuretics, particularly those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake before starting perindopril therapy. Treatment should begin with low doses and gradually increase.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold. Nitritoid reactions (symptoms: facial flushing, nausea, vomiting, and arterial hypotension) rarely occur in patients concurrently receiving ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate).

Amlodipine

Effect of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to significant increases in amlodipine exposure, potentially increasing the risk of arterial hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients, the bioavailability of amlodipine may increase, primarily enhancing its hypotensive effect.

CYP3A4 inducers

When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustments considered both during and after concomitant use of such drugs, especially those with strong CYP3A4 induction (e.g., rifampicin, St. John's wort).

Dantrolene (infusions)

In animals, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during 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 used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment are required when used concomitantly with amlodipine.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, except in kidney transplant patients, where variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

Simvastatin

Concomitant use of multiple 10 mg doses of amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients receiving amlodipine, the simvastatin dose should be limited to 20 mg daily.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

mTOR inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may increase exposure to mTOR inhibitors.

Special precautions for use.

All the warnings listed below regarding individual components of the medicinal product apply also to the medicinal product Amlissa.

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 angiotensin-converting enzyme (ACE) inhibitors, including perindopril (see section "Adverse reactions"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient's condition should be instituted until complete resolution of symptoms. In isolated cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamines may be helpful in relieving symptoms.

Angioedema associated with laryngeal swelling may be fatal. In cases where swelling involves the tongue, glottis or larynx, causing airway obstruction, emergency treatment is required, which may include administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until complete resolution of symptoms and stabilization of their condition.

Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, prior facial angioedema was not observed and C-1 esterase levels were within normal limits. Diagnosis of intestinal angioedema was established by abdominal computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be excluded during differential diagnosis in patients presenting with abdominal pain while receiving ACE inhibitors (see section "Adverse reactions").

Combination of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Special precautions for use"). Therapy with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy may be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction"). Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Anaphylactoid reactions may be avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.

Anaphylactoid reactions during desensitization therapy

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing products. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy, but reactions may recur upon inadvertent provocation testing.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with extreme caution to patients with collagen vascular diseases, during immunosuppressive therapy, allopurinol, or procainamide treatment, or when these risk factors are combined, especially in the presence of existing renal impairment. Serious infections, sometimes unresponsive to intensive antibiotic therapy, may occasionally develop in such patients. If perindopril is prescribed to these patients, periodic monitoring of white blood cell count is recommended, and patients should be informed to report any signs of infection (e.g., 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 impairment when treated with ACE inhibitors (see section "Contraindications"). Diuretic therapy may be a contributing factor. 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)

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade therapy is considered absolutely necessary, it should be performed only 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 hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting through inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended.

Pregnancy

ACE inhibitors should not be prescribed during pregnancy. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Arterial hypotension

ACE inhibitors may cause a reduction in arterial pressure. Symptomatic hypotension is less common in patients with uncomplicated arterial hypertension and is more likely in patients with hypovolemia who are receiving diuretics, on a low-salt diet, undergoing dialysis, or with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). In patients at high risk of symptomatic hypotension during treatment with Amlissa, careful monitoring of blood pressure, renal function, and serum potassium levels is required. This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or cerebrovascular accident.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication to further treatment, which can usually be resumed after restoration of blood volume and increase in blood pressure.

Stenosis of aortic and mitral valves / hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril should be administered with caution in patients with mitral valve stenosis or left ventricular outflow obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment

In patients with renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice in such patients (see section "Adverse reactions").

In some patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney receiving ACE inhibitors, increases in blood urea nitrogen and serum creatinine have been observed, which were usually reversible upon discontinuation of therapy. Such increases occur most frequently in patients with pre-existing renal impairment. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal failure. In some patients with arterial hypertension without evident renal vascular disease, increases in blood urea and serum creatinine have been observed, usually mild and transient, particularly when perindopril is used concomitantly with a diuretic. Such increases occur most frequently in patients with pre-existing renal impairment.

Hepatic impairment

Rare cases of a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes resulting in death, have been reported in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes while receiving an ACE inhibitor should discontinue the drug and undergo appropriate medical evaluation and treatment (see section "Adverse reactions").

Racial factor

ACE inhibitors cause angioedema more frequently in black patients than in other racial groups. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients than in patients of other races, possibly due to lower plasma renin levels in black patients with arterial hypertension.

Cough

Cough has been reported during therapy with ACE inhibitors. The 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.

Surgery/anesthesia

Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or anesthesia with agents causing arterial hypotension. The drug should be discontinued one day prior to surgery. If arterial hypotension occurs and is considered to be due to this mechanism, the patient's condition may be corrected by increasing circulating blood volume.

Serum potassium

Elevated serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. This effect is usually mild in patients with normal renal function. Patients at increased risk of hyperkalemia include those with renal impairment, worsening renal function, patients aged > 70 years, patients with diabetes mellitus, those with concomitant conditions such as dehydration, acute heart failure, metabolic acidosis, and patients receiving potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium (e.g., heparin, co-trimoxazole [trimethoprim/sulfamethoxazole]), particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to significant increases in serum potassium, especially in patients with impaired renal function. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be used cautiously in patients receiving ACE inhibitors, and serum potassium levels and renal function should be monitored. If concomitant use of perindopril and any of the above-mentioned drugs is considered appropriate, they should be used with caution and serum potassium levels should be monitored frequently (see section "Special precautions for use").

Patients with diabetes mellitus

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin require careful monitoring of blood glucose levels during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Amlodipine

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Use in patients with heart failure

Patients with heart failure should be treated with caution.

In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III-IV), the incidence of pulmonary edema was higher in the amlodipine treatment group than in the placebo group (see section "Pharmacological properties"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of serious cardiovascular complications and mortality.

Hepatic impairment

The elimination half-life of amlodipine is prolonged and AUC values are higher in patients with hepatic impairment; dosage recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lower end of the dose range, and caution should be exercised both at the start of treatment and during dose escalation. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.

Use in elderly patients

Dose escalation should be performed with caution in elderly patients (see sections "Dosage and administration" and "Pharmacokinetics").

Use in renal impairment

Amlodipine may be administered to such patients at usual doses. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not dialyzable.

Interactions

Concomitant use of Amlissa with lithium, potassium-sparing diuretics, potassium-containing dietary supplements, or dantrolene is not recommended.

Use during pregnancy or breastfeeding

Due to the effects of individual components of this medicinal product on pregnancy and lactation:

• Amlissa is not recommended during the first trimester of pregnancy. Amlissa is contraindicated during the second and third trimesters of pregnancy.
• Amlissa is not recommended during lactation. Therefore, a decision should be made to discontinue breastfeeding or discontinue Amlissa therapy, taking into account the importance of this therapy for the mother.

Pregnancy

Perindopril. Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated.

It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors are used during the second trimester of pregnancy, ultrasound assessment of fetal renal function and skull ossification is recommended.

Infants born to mothers who have taken ACE inhibitors should be closely monitored for arterial hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special precautions for use").

If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Amlodipine. The safety of amlodipine use during pregnancy has not been established.

Animal studies have shown reproductive toxicity at high doses. Use during pregnancy is recommended only when no safer alternative exists and when the disease itself poses a greater risk to the mother and fetus.

Breastfeeding period

Amlodipine passes into human breast milk. The infant's exposure, expressed as a fraction of the maternal dose, has been estimated at an interquartile range of 3–7%, with a maximum of 15%. As information on the use of Amlissa during breastfeeding is lacking, the product is not recommended for use during this period. Preference should be given to medicinal products with better safety profiles during breastfeeding, especially for newborns or preterm infants.

The effect of amlodipine on infants is unknown. The decision on whether to continue or discontinue breastfeeding or continue or discontinue amlodipine therapy should be made considering the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.

Fertility

Perindopril. No effect on reproductive capacity or fertility has been observed.

Amlodipine. Reversible biochemical changes in the head of spermatozoa have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in one rat study.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of Amlissa on the ability to drive or operate machinery have been conducted. Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea, reaction ability may be impaired. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage

Initiate treatment with 1 tablet once daily, preferably taken in the morning before food.

The tablets must not be divided. The dosage range of the medicinal product allows flexible adjustment of the component ratio according to clinical needs. The dose should be individually titrated for each patient depending on the indication, disease course, and blood pressure levels.

The use of a fixed-dose combination is not suitable for initial therapy.

Maximum daily dose – 1 tablet of Amlessa 8 mg/10 mg per day.

Patients with renal impairment and elderly patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

Elimination of perindoprilat is slowed in elderly patients and in patients with renal impairment. Therefore, frequent monitoring of creatinine and potassium levels is required during treatment. Amlessa can be prescribed to patients with creatinine clearance (CC) ≥ 60 mL/min. Amlessa is contraindicated in patients with CC < 60 mL/min in this dosage form. Such patients should receive individually adjusted doses of perindopril and amlodipine.

Changes in amlodipine plasma concentration do not correlate with the severity of renal impairment.

Patients with hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

Dosage recommendations for patients with mild to moderate hepatic dysfunction have not been established; therefore, dose selection should be cautious and initiated at the lower end of the dosage range (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). To determine the optimal initial and maintenance dose in patients with hepatic dysfunction, the dose should be individually titrated using separate formulations of amlodipine and perindopril. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic dysfunction. The use of amlodipine in patients with severe hepatic impairment should begin with the lowest dose and be slowly titrated.

Children

The medicinal product is not recommended for use in children (under 18 years of age) due to lack of studies in this patient group.

Overdose

There is no information available on overdose with Amlessa in human subjects.

Overdose (ingestion of large doses) of amlodipine may lead to excessive peripheral vasodilation and, consequently, to profound and possibly prolonged systemic arterial hypotension, including shock up to fatal outcome. Amlodipine is not removed by hemodialysis.

Rarely, non-cardiogenic pulmonary edema has been observed as a consequence of amlodipine overdose, which may not manifest immediately (within 24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (e.g., fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment

Clinically significant arterial hypotension caused by amlodipine overdose requires active measures to support cardiovascular function, including monitoring of cardiac and pulmonary parameters, positioning the patient supine with legs elevated, monitoring circulating blood volume, and diuresis.

Vasoconstrictors are indicated to restore vascular tone and normalize blood pressure. To counteract calcium channel blockade, intravenous calcium gluconate should be administered.

In some cases, gastric lavage may be beneficial.

Since amlodipine is highly protein-bound, dialysis is unlikely to be effective.

Data on perindopril overdose in humans are limited. Symptoms of angiotensin-converting enzyme (ACE) inhibitor overdose include arterial hypotension, shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Treatment should involve intravenous administration of physiological saline. In case of arterial hypotension, the patient should be placed in a supine position with low head elevation. Angiotensin II and/or catecholamines may also be administered intravenously. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In cases of refractory bradycardia, implantation of a pacemaker should be considered. Continuous monitoring of vital signs, serum electrolytes, and creatinine levels is required.

Adverse reactions.

The adverse effects listed below were observed during treatment with perindopril or amlodipine administered separately and are recorded according to MedDRA system organ classes and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity. Adverse events are generally mild and transient in most patients.

*The frequency was calculated from clinical trial data for adverse reactions identified from spontaneous reports.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture and light. Keep out of reach of children.

Packaging. 10 tablets in a blister; 3, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.