Parnavel Amlo (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C09BB04 (Perindopril and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Parnavel Amlo	Tablets 5 mg+4 mg: 10, 20, 30, 40, 50, 60, 80, 90, 100, 120, 150, 180, 200 or 300 pcs.
		Tablets 5 mg+8 mg: 10, 20, 30, 40, 50, 60, 80, 90, 100, 120, 150, 180, 200 or 300 pcs.
		Tablets 10 mg+4 mg: 10, 20, 30, 40, 50, 60, 80, 90, 100, 120, 150, 180, 200 or 300 pcs.
		Tablets 10 mg+8 mg: 10, 20, 30, 40, 50, 60, 80, 90, 100, 120, 150, 180, 200 or 300 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, with a score and a bevel.

	1 tab.
Amlodipine besylate	6.94 mg,
Equivalent to amlodipine content	5 mg
Perindopril erbumine	4 mg

Excipients: microcrystalline cellulose (MCC-102) – 84.06 mg, sodium carboxymethyl starch – 4 mg, magnesium stearate – 1 mg.

10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (4) – cardboard packs.
10 pcs. – contour cell blisters (5) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
10 pcs. – contour cell blisters (10) – cardboard packs.
20 pcs. – contour cell blisters (1) – cardboard packs.
20 pcs. – contour cell blisters (2) – cardboard packs.
20 pcs. – contour cell blisters (3) – cardboard packs.
20 pcs. – contour cell blisters (4) – cardboard packs.
20 pcs. – contour cell blisters (5) – cardboard packs.
20 pcs. – contour cell blisters (6) – cardboard packs.
20 pcs. – contour cell blisters (10) – cardboard packs.
30 pcs. – contour cell blisters (1) – cardboard packs.
30 pcs. – contour cell blisters (2) – cardboard packs.
30 pcs. – contour cell blisters (3) – cardboard packs.
30 pcs. – contour cell blisters (4) – cardboard packs.
30 pcs. – contour cell blisters (5) – cardboard packs.
30 pcs. – contour cell blisters (6) – cardboard packs.
30 pcs. – contour cell blisters (10) – cardboard packs.
30 pcs. – contour cell blisters (1) – cardboard packs (2) – cardboard packs.

Tablets white or almost white, round, flat, round, flat, with a cross score and a bevel.

	1 tab.
Amlodipine besylate	6.94 mg,
Equivalent to amlodipine content	5 mg
Perindopril erbumine	8 mg

Excipients: microcrystalline cellulose (MCC-102) – 175.06 mg, sodium carboxymethyl starch – 8 mg, magnesium stearate – 2 mg.

Tablets white or almost white, round, flat, with a score.

	1 tab.
Amlodipine besylate	13.88 mg,
Equivalent to amlodipine content	10 mg
Perindopril erbumine	4 mg

Excipients: microcrystalline cellulose (MCC-102) – 172.12 mg, sodium carboxymethyl starch – 8 mg, magnesium stearate – 2 mg.

Tablets white or almost white, round, flat, with a score and a bevel.

	1 tab.
Amlodipine besylate	13.88 mg,
Equivalent to amlodipine content	10 mg
Perindopril erbumine	8 mg

Excipients: microcrystalline cellulose (MCC-102) – 168.12 mg, sodium carboxymethyl starch – 8 mg, magnesium stearate – 2 mg.

Clinical-Pharmacological Group

Combined antihypertensive and antianginal drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Combined antihypertensive and antianginal drug containing perindopril erbumine (ACE inhibitor) and Amlodipine (calcium channel blocker).

Amlodipine is a calcium channel blocker, a dihydropyridine derivative. It has antianginal and antihypertensive effects. It blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more in vascular smooth muscle cells than in cardiomyocytes).

The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The antianginal effect is due to the expansion of coronary and peripheral arteries and arterioles: in angina pectoris, it reduces the severity of myocardial ischemia; by expanding peripheral arterioles, it reduces total peripheral vascular resistance, reduces afterload on the myocardium, reduces myocardial oxygen demand; by expanding coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents spasm of the coronary arteries (including that caused by smoking). In patients with stable angina pectoris, a single daily dose increases exercise tolerance, increases the time to onset of angina attack and ischemic depression of the ST segment on the ECG, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It has a long-term dose-dependent antihypertensive effect. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in the supine and standing position). Orthostatic hypotension is quite rare when prescribing amlodipine. It does not cause a decrease in the left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout.

A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Perindopril is an ACE inhibitor. ACE or kininase II is an exopeptidase that converts angiotensin I into the vasoconstrictor substance angiotensin II; in addition, ACE destroys bradykinin, which has a vasodilating effect, into an inactive heptapeptide. Suppression of ACE activity leads to a decrease in angiotensin II, an increase in plasma renin activity and a weakening of aldosterone secretion. Since ACE also destroys bradykinin, suppression of ACE also leads to an increase in the activity of the kallikrein-kinin system.

Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro. Perindopril has a therapeutic effect in any degree of arterial hypertension, reducing systolic and diastolic blood pressure in the supine and standing positions. It reduces total peripheral vascular resistance, resulting in an increase in peripheral blood flow without changes in heart rate. Renal blood flow is usually increased, while glomerular filtration rate does not change.

The hypotensive effect reaches its maximum 4-6 hours after a single oral dose of perindopril and persists for 24 hours. The hypotensive effect 24 hours after a single oral dose is about 87-100% of the maximum hypotensive effect. The decrease in blood pressure develops rapidly. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of therapy does not lead to the development of withdrawal syndrome.

Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

The effectiveness of the use of perindopril in patients with stable coronary artery disease without clinical symptoms of chronic heart failure led to a significant reduction in the absolute risk of complications in patients who had previously suffered a myocardial infarction or revascularization procedure.

Pharmacokinetics

The extent of absorption of amlodipine and perindopril when using this combination does not differ significantly from that when using the individual drugs.

Amlodipine

Amlodipine is well absorbed after oral administration at therapeutic doses. Food intake does not affect the bioavailability of amlodipine. C_max in plasma is reached after 6-12 hours. Absolute bioavailability is 64-80%. V_d is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Amlodipine is metabolized in the liver to form inactive metabolites. The final T_1/2 from plasma is 35-50 hours, which allows the drug to be taken once a day. Approximately 60% of the administered dose is excreted by the kidneys, 10% unchanged.

T_1/2 of amlodipine is prolonged in patients with impaired liver function.

Perindopril

After oral administration, Perindopril is rapidly absorbed and reaches C_max in plasma within 1 hour. Food intake reduces the bioavailability of perindopril, so the drug should be taken once a day, in the morning, before meals. There is a linear relationship between the plasma concentration of perindopril and its dose. The binding of perindoprilat to plasma proteins (mainly to ACE) is 20% and depends on its concentration. V_d of free perindoprilat is approximately 0.2 L/kg. C_ss is reached within 4 days after oral administration.

Perindopril does not have pharmacological activity and is a prodrug. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream in the form of an active metabolite – perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration.

T_1/2 of perindopril from plasma is approximately 1 hour. Perindoprilat is excreted by the kidneys, T_1/2 of the unbound fraction is approximately 17 hours.

The elimination of perindoprilat is slowed down in elderly patients and in patients with cardiac and renal failure, so monitoring of such patients should include regular monitoring of plasma creatinine and potassium concentrations. The dialysis clearance of perindoprilat is 70 ml/min.

Indications

Arterial hypertension and/or coronary artery disease: stable exertional angina in patients requiring therapy with perindopril and amlodipine.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension
I20	Angina pectoris

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified
BA40.Z	Angina pectoris, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

The drug is taken orally, 1 tablet once a day, preferably in the morning before meals.

The dose of the drug is selected after prior titration of the doses of the individual components of the drug: perindopril and amlodipine in patients with arterial hypertension and stable angina pectoris.

If necessary, the dose of the drug can be changed based on individual selection of doses of individual components: (Amlodipine 5 mg+Perindopril 4 mg) or (Amlodipine 10 mg+Perindopril 4 mg) or (Amlodipine 5 mg+Perindopril 8 mg) or (Amlodipine 10 mg+Perindopril 8 mg).

Maximum daily dose: Amlodipine 10 mg+Perindopril 8 mg.

This combination can be prescribed to patients with CrCl greater than 60 ml/min. The drug is contraindicated in patients with CrCl less than 60 ml/min. Such patients are recommended to individually select doses of perindopril and amlodipine. Changes in plasma amlodipine concentration do not correlate with the severity of renal failure.

Caution should be exercised when using the drug in patients with hepatic insufficiency, as there are no recommendations for the doses of the drug in such patients.

When using the drug in elderly patients, dose adjustment is not required.

The drug should not be prescribed to children and adolescents under 18 years of age, as there are no data on the efficacy and safety of the use of perindopril and amlodipine in these groups of patients, both in monotherapy and as part of combination therapy.

Adverse Reactions

Classification of the frequency of side effects (WHO): very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1000); very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

In each group, adverse effects are presented in order of decreasing severity.

From the hematopoietic system: very rare – leukopenia/neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency, decreased hemoglobin concentration and hematocrit.

From the immune system: uncommon – urticaria.

Metabolic disorders: very rare – hyperglycemia, frequency unknown – hypoglycemia.

From the nervous system: common – drowsiness, dizziness, headache, paresthesia, vertigo; uncommon – insomnia, mood lability, sleep disturbance, tremor, hypoesthesia; very rare – peripheral neuropathy, confusion.

From the senses: common – visual disturbances, tinnitus.

From the organ of vision common – visual disturbances.

From the organ of hearing and balance often – tinnitus.

From the cardiovascular system: often – palpitations, flushing, marked decrease in blood pressure; infrequently – syncope; rarely – chest pain; very rarely – angina pectoris, myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients, arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), stroke, possibly due to excessive blood pressure reduction in high-risk patients, vasculitis.

From the respiratory system: often – dyspnea, cough; infrequently – rhinitis, bronchospasm; very rarely – eosinophilic pneumonia.

From the digestive system: often – abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation; infrequently – dry mouth, taste disturbance, change in bowel habit; very rarely – pancreatitis, gingival hyperplasia, gastritis, hepatitis, cholestatic jaundice, cytolytic or cholestatic hepatitis.

From the skin often – skin itching, skin rash, alopecia, hemorrhagic rash, photosensitivity, increased sweating; very rarely – erythema multiforme, Stevens-Johnson syndrome.

Allergic reactions infrequently – angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx; very rarely – Quincke’s edema.

From the musculoskeletal system often – muscle cramps; infrequently – arthralgia, myalgia, back pain.

From the urinary system: infrequently – urination disorder, nocturia, frequent urination, renal failure; very rarely – acute renal failure.

From the reproductive system: infrequently – impotence, gynecomastia.

Other often – peripheral edema, asthenia, increased fatigue; infrequently – chest pain, malaise, weight gain, weight loss.

Laboratory parameters rarely – increased bilirubin concentration; very rarely – increased AST, ALT activity (most often in combination with cholestasis); frequency unknown – increased serum urea and creatinine concentration.

Additional data on amlodipine: isolated cases of extrapyramidal syndrome have been reported with the use of slow calcium channel blockers.

Contraindications

Amlodipine

Severe arterial hypotension (systolic BP less than 90 mm Hg);
Hemodynamically unstable heart failure after acute myocardial infarction;
Shock, including cardiogenic shock;
Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
Unstable angina (except for Prinzmetal’s angina);
Age under 18 years (efficacy and safety not established);
Hypersensitivity to amlodipine or other dihydropyridine derivatives.

Perindopril

History of angioedema (Quincke’s edema) (including while taking other ACE inhibitors);
Hereditary/idiopathic angioedema;
Age under 18 years (efficacy and safety not established);
Hypersensitivity to perindopril or other ACE inhibitors.

Amlodipine+Perindopril

Renal failure (creatinine clearance less than 60 ml/min);
Age under 18 years (efficacy and safety not established);
Hypersensitivity to the drug components.

With caution hepatic insufficiency; chronic heart failure; aortic and/or mitral stenosis; hypertrophic obstructive cardiomyopathy; bilateral renal artery stenosis, stenosis of the artery of a single functioning kidney; renal failure (creatinine clearance <60 ml/min); systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis); reduced blood volume (diuretic use, salt-restricted diet, vomiting, diarrhea); atherosclerosis; cerebrovascular diseases; renovascular hypertension; diabetes mellitus; use of inhibitors or inducers of the CYP4503A4 isoenzyme, potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium preparations; hyperkalemia; surgery/general anesthesia; hemodialysis using high-flux polyacrylonitrile membranes (risk of anaphylactoid reactions); LDL apheresis with dextran sulfate; simultaneous desensitizing therapy with allergens (e.g., hymenoptera venom); status after kidney transplantation (lack of clinical data); elderly age; use in patients of Black race.

Use in Pregnancy and Lactation

Use of this combination drug is contraindicated during pregnancy.

The Amlodipine+Perindopril combination is not recommended during lactation due to the lack of relevant clinical experience with perindopril and amlodipine both in monotherapy and as part of combination therapy.

Use in Hepatic Impairment

The drug should be prescribed with caution in hepatic insufficiency.

Use in Renal Impairment

This combination is contraindicated in renal failure (creatinine clearance less than 60 ml/min).

The drug should be prescribed with caution in bilateral renal artery stenosis, stenosis of the artery of a single functioning kidney; renal failure (creatinine clearance <60 ml/min).

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age due to the lack of data on the drug’s efficacy and safety in this age group.

Geriatric Use

The drug should be prescribed with caution in elderly patients.

Special Precautions

In patients with impaired liver function, the T_1/2 of amlodipine is prolonged. When prescribing the drug to such patients, caution should be exercised and liver enzyme activity should be regularly monitored.

In patients with chronic heart failure (NYHA class III and IV), treatment should be carried out with caution due to the possibility of pulmonary edema.

When using ACE inhibitors, including perindopril, in rare cases, angioedema of the face, lips, tongue, vocal folds, and/or larynx may occur. If these symptoms appear, the drug should be discontinued immediately; the patient should be under observation until the signs of edema completely disappear.

If angioedema involves only the face and lips, its manifestations usually resolve on their own or antihistamines may be used to treat its symptoms. Angioedema involving swelling of the tongue or larynx can lead to airway obstruction and death. If such symptoms appear, epinephrine (adrenaline) 1:1000 dilution (0.3 or 0.5 ml) should be administered subcutaneously immediately and/or airway patency should be ensured. The patient should be under medical supervision until the symptoms completely and permanently disappear.

In patients with a history of Quincke’s edema not associated with the use of ACE inhibitors, the risk of its development while taking drugs of this group may be increased.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is established by abdominal CT, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

There are isolated reports of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom. ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescribing an ACE inhibitor to patients receiving immunotherapy with hymenoptera venom should be avoided. However, anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

In rare cases, life-threatening anaphylactoid reactions may develop in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.

In patients receiving ACE inhibitors, anaphylactoid reactions have been observed during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is advisable to use a different type of membrane and use an antihypertensive drug of a different pharmacotherapeutic group.

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia and anemia are possible. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves on its own after discontinuation of ACE inhibitors.

Perindopril should be used with great caution in patients with connective tissue diseases and simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, especially with existing renal impairment. Some patients may develop severe infections that do not respond to intensive antibiotic therapy. If perindopril is prescribed, monitoring of the white blood cell count in the blood plasma is recommended. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), they should consult a doctor.

In liver cirrhosis accompanied by edema and ascites, arterial hypotension, chronic heart failure, significant activation of the RAAS may be noted, especially with severe hypovolemia and decreased plasma electrolyte levels (against the background of a long-term salt-restricted diet, long-term diuretic use).

The use of an ACE inhibitor causes blockade of the RAAS, therefore a sharp decrease in blood pressure and/or an increase in plasma creatinine concentration, indicating the development of acute renal failure, may occur, which is more often observed when taking the first dose or during the first 2 weeks of therapy with the drug.

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely occurs in patients without concomitant diseases. The risk of excessive blood pressure reduction is increased in patients with reduced blood volume, which may occur during diuretic therapy, adherence to a strict salt-restricted diet, hemodialysis, diarrhea or vomiting, or in patients with severe arterial hypertension with high renin activity. In patients at high risk of developing symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with the drug. The same precautions apply to patients with angina or cerebrovascular diseases, in whom a pronounced decrease in blood pressure can lead to myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in a horizontal position with a low headboard. If necessary, restore blood volume by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of the drug. After restoration of blood volume and blood pressure, treatment with the drug can be continued.

Concomitant use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing salt substitutes is not recommended.

During therapy with an ACE inhibitor, a dry non-productive cough may occur, which disappears after discontinuation of drugs of this group. If a dry cough appears, a possible connection of this symptom with the use of an ACE inhibitor should be remembered.

In case of impaired renal function (creatinine clearance less than 60 ml/min), individual dose selection of perindopril and amlodipine is recommended. Regular monitoring of plasma potassium and creatinine levels is a necessary condition in the treatment of such patients. In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney taking ACE inhibitors, an increase in plasma urea and creatinine concentrations was noted, which was reversible after discontinuation of therapy. These changes are more likely in patients with renal failure. In patients with renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure. In some patients with arterial hypertension without obvious signs of pre-existing kidney disease who took Perindopril simultaneously with a diuretic, a slight and temporary increase in serum urea and creatinine concentrations was noted. These changes develop more often in patients with pre-existing renal impairment.

Rarely, the use of ACE inhibitors is accompanied by a syndrome that begins with cholestatic jaundice and then progresses to fulminant hepatic necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice appears or liver transaminase activity increases during the use of an ACE inhibitor, the ACE inhibitor should be discontinued immediately and the patient should remain under appropriate medical supervision.

Patients of Black race develop angioedema while taking ACE inhibitors more often than patients of other races. Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of Black race compared to patients of other races. Perhaps this difference is due to the fact that Black patients with arterial hypertension more often have low plasma renin activity.

The use of ACE inhibitors in patients undergoing major surgery and/or general anesthesia may lead to a marked decrease in blood pressure if general anesthetics with hypotensive action are used. This is due to the blockade of angiotensin II formation against the background of compensatory increased renin activity. If the development of arterial hypotension is associated with the described mechanism, the blood volume should be increased. It is recommended to discontinue the drug 24 hours before surgery.

During therapy with ACE inhibitors, including Perindopril, some patients may experience an increase in plasma potassium levels. Risk factors for the development of hyperkalemia are renal failure, impaired renal function, elderly age (over 70 years), diabetes mellitus, intercurrent conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis, simultaneous use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), drugs or supplements containing potassium, potassium-containing salt substitutes or simultaneous use of other drugs that increase plasma potassium levels (e.g., heparin). Hyperkalemia can cause serious, sometimes life-threatening arrhythmias. If simultaneous use of perindopril and one of the above agents is necessary, caution should be exercised and plasma potassium levels should be regularly monitored.

In patients with diabetes mellitus taking oral hypoglycemic agents and/or insulin, enhanced monitoring of blood glucose concentration is necessary during the first few months of therapy with ACE inhibitors.

Use in pediatrics

The drug is contraindicated in children and adolescents under 18 years of age due to the lack of data on the drug’s efficacy and safety in this age group.

Effect on ability to drive vehicles and operate machinery

Due to the possibility of dizziness and other side effects while using this combination, caution should be exercised when driving vehicles and working with other technical devices requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Amlodipine

In animal studies, after intravenous administration of verapamil and dantrolene, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed. Given the risk of hyperkalemia, simultaneous use of slow calcium channel blockers, including amlodipine, and dantrolene should be avoided.

With simultaneous use of CYP3A4 inducers (rifampicin, St. John’s wort preparations, anticonvulsants such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), a decrease in the plasma concentration of amlodipine is possible due to increased metabolism in the liver. Caution should be exercised when using amlodipine simultaneously with inducers of microsomal oxidation and, if necessary, the dose of amlodipine should be adjusted.

With simultaneous use of strong and moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, antifungal drugs from the azole group (itraconazole and ketoconazole), antibiotics from the macrolide group such as erythromycin and clarithromycin, as well as verapamil and diltiazem), an increase in the plasma concentration of amlodipine and an increased risk of side effects are possible, especially in elderly patients. Caution should be exercised during simultaneous use and, if necessary, the dose of amlodipine should be adjusted.

Simultaneous use of beta-blockers (bisoprolol, metoprolol) and the alpha- and beta-blocker carvedilol, used in chronic heart failure, increases the risk of arterial hypotension and worsening of chronic heart failure in patients with uncontrolled or latent chronic heart failure (enhancement of inotropic effect). In addition, beta-blockers may reduce excessive reflex cardiac sympathetic activation in the setting of concomitant chronic heart failure.

Perindopril

Potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium preparations or potassium-containing salt substitutes may lead to a significant increase in plasma potassium levels, so their use simultaneously with ACE inhibitors is not recommended. If concomitant therapy is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be carried out.

When lithium preparations and ACE inhibitors were used simultaneously, cases of reversible increase in serum lithium concentration and associated toxic effects were reported. Concomitant therapy with perindopril and lithium preparations is not recommended. If combination therapy is necessary, it should be carried out under regular monitoring of plasma lithium concentration.

Simultaneous use with estramustine is accompanied by an increased risk of angioedema.

The use of NSAIDs, including COX-2 inhibitors, acetylsalicylic acid in high doses (more than 3 g/day) and non-selective NSAIDs, may lead to a reduction in the diuretic, natriuretic, and hypotensive effects of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure and an increase in serum potassium levels, especially in patients with pre-existing reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. In this case, patients must compensate for fluid loss and carefully monitor renal function, both at the beginning of treatment and during the treatment process.

The use of ACE inhibitors may enhance the hypoglycemic effect of insulin or sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemic episodes has been reported very rarely (possibly due to an increase in glucose tolerance, leading to a reduced need for insulin).

In patients taking diuretics, especially with excessive fluid and/or electrolyte loss, a significant decrease in blood pressure may be observed at the start of ACE inhibitor use. The risk of developing arterial hypotension can be reduced by discontinuing the diuretic, increasing fluid and/or salt intake before starting therapy, and initiating therapy with low doses of perindopril with their subsequent gradual increase.

Sympathomimetics may reduce the hypotensive effect of ACE inhibitors.

In patients receiving simultaneous injectable therapy with gold preparations (sodium aurothiomalate) and ACE inhibitors, including Perindopril, nitritoid-like reactions (flushing of the facial skin, nausea, vomiting, decreased blood pressure) have been rarely observed.

Concomitant use of ACE inhibitors with allopurinol, cytostatic and immunosuppressive agents, corticosteroids (for systemic use), and procainamide may be associated with an increased risk of leukopenia.

Concomitant use of ACE inhibitors and agents for general anesthesia may lead to an enhancement of the hypotensive effect.

Amlodipine+Perindopril

With simultaneous use of baclofen, potentiation of the hypotensive effect is possible. Blood pressure and renal function should be monitored, and the dose of amlodipine should be adjusted.

With simultaneous use of antihypertensive drugs (for example, beta-blockers) and vasodilators, an enhancement of the hypotensive effect of perindopril and amlodipine is possible.

Caution should be exercised with simultaneous use of nitroglycerin, other nitrates, or other vasodilators, as this may cause an additional decrease in blood pressure.

Concomitant use of corticosteroids (mineralo- and glucocorticoids), tetracosactide reduces the hypotensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance the hypotensive effect and increase the risk of orthostatic hypotension.

Amifostine may potentiate the hypotensive effect of amlodipine.

Tricyclic antidepressants/antipsychotics/general anesthetics enhance the hypotensive effect and increase the risk of orthostatic hypotension.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

Medixlife (Author)

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