Ampliton (Tablet kit) Instructions for Use

Marketing Authorization Holder

Makiz-Pharma, LLC (Russia)

ATC Code

C09BB (ACE inhibitors in combination with calcium channel blockers)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Cilazapril (Rec.INN registered by WHO)

Dosage Forms

	Ampliton	Tablet kit: 10 pcs. in a blister, 3 or 6 blisters in a pack; tab. 5 mg: 5 pcs.; tab., coated, 2.5 mg: 5 pcs.
		Tablet kit: 14 pcs. in a blister, 2 or 4 blisters in a pack; tab. 5 mg: 7 pcs.; tab., coated, 2.5 mg: 7 pcs.

Dosage Form, Packaging, and Composition

Tablet kit

Excipients: lactose, microcrystalline cellulose, calcium stearate, sodium croscarmellose (primellose), colloidal silicon dioxide (aerosil).

Excipients: lactose, corn starch, hypromellose 3 cPz, talc (sodium hydrosilicate), sodium stearyl fumarate.

Coating composition hypromellose 6 cPz, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Tablet kit

Excipients: lactose, microcrystalline cellulose, calcium stearate, sodium croscarmellose (primellose), colloidal silicon dioxide (aerosil).

Excipients: lactose, corn starch, hypromellose 3 cPz, talc (sodium hydrosilicate), sodium stearyl fumarate.

Coating composition hypromellose 6 cPz, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171).

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Amlodipine is a second-generation calcium channel blocker, a dihydropyridine derivative. It has antianginal and antihypertensive effects. By binding to dihydropyridine receptors, it blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more in vascular smooth muscle cells than in cardiomyocytes). The antianginal effect is due to the expansion of coronary vessels and peripheral arteries and arterioles: in angina, it reduces the severity of myocardial ischemia; by expanding peripheral arterioles, it reduces total peripheral resistance, reduces cardiac preload, and reduces myocardial oxygen demand.

By expanding the main coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents the development of coronary artery constriction (including that caused by smoking).

In patients with angina, a single daily dose increases exercise tolerance time, slows the development of angina and ischemic ST-segment depression, and reduces the frequency of angina attacks and nitroglycerin consumption.

It has a long-term dose-dependent antihypertensive effect. The antihypertensive effect is due to a direct vasodilating effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (in lying and standing positions). It does not cause a sharp decrease in blood pressure, a decrease in exercise tolerance, or left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy, has an antiatherosclerotic and cardioprotective effect in coronary artery disease. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases the glomerular filtration rate, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have an adverse effect on metabolism and plasma lipids.

Time to onset of effect is 2-4 hours, duration of effect is 24 hours.

Cilazapril is a prodrug that is rapidly converted in the body into an active form – cilazaprilat – a specific long-acting ACE inhibitor that blocks the conversion of inactive angiotensin I to angiotensin II, which has a pronounced vasoconstrictive effect.

In recommended doses, the effect of cilazapril in patients with arterial hypertension and in patients with chronic heart failure lasts for 24 hours. In patients with normal renal function during treatment with cilazapril, the serum potassium concentration usually remains within normal limits. In patients simultaneously taking potassium-sparing diuretics, an increase in potassium content is possible.

In arterial hypertension, it reduces systolic and diastolic blood pressure, both in the “standing” and “lying” positions, usually without orthostatic reactions. Cilazapril is effective at all stages of arterial hypertension, as well as in renal hypertension. Reflex tachycardia does not occur, although slight changes in heart rate may be observed, which are not clinically significant. In some patients, the decrease in blood pressure may decrease by the time of the next dose. With long-term treatment, the antihypertensive effect of cilazapril persists. After sudden withdrawal of the drug, a rapid increase in blood pressure does not occur.

In patients with arterial hypertension with concomitant moderate or severe renal failure, the glomerular filtration rate and renal blood flow during treatment with cilazapril, as a rule, do not change, despite a clinically significant decrease in blood pressure.

The antihypertensive effect of cilazapril (as with the use of other ACE inhibitors) in patients of the Black race may be less pronounced than in patients of other races. However, if Cilazapril is used in combination with hydrochlorothiazide, no differences in the effect of the drug are observed in patients of different races.

In recommended doses, the antihypertensive effect in patients with arterial hypertension and in patients with chronic heart failure lasts up to 24 hours. After oral administration, the antihypertensive effect of cilazapril usually appears within the first hour and reaches a maximum after 3-7 hours.

Indications

• Arterial hypertension.

ICD codes

Dosage Regimen

Take orally in the morning. Administer simultaneously one 5 mg Amlodipine tablet and one-half to one 2.5 mg Cilazapril tablet (providing 1.25-2.5 mg cilazapril).

Take tablets with water. Adhere to a consistent daily schedule.

Based on blood pressure control, the frequency for both components may be increased to twice daily.

Do not exceed the maximum daily dose of 10 mg for amlodipine and 5 mg for cilazapril.

For patients with renal impairment, adjust the dose based on creatinine clearance. Monitor renal function during initial therapy.

In elderly patients, use the standard regimen but exercise caution when titrating the dose.

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose. Do not double the dose.

Adverse Reactions

Amlodipine

From the cardiovascular system palpitations, shortness of breath, marked decrease in blood pressure, fainting, vasculitis, edema (ankle and foot swelling), facial flushing; rarely – heart rhythm disturbances (bradycardia, ventricular tachycardia, atrial flutter), chest pain, orthostatic hypotension; in some cases – development or worsening of heart failure, extrasystole, migraine.

From the central and peripheral nervous system headache, dizziness, fatigue, drowsiness, mood changes, convulsions; rarely – loss of consciousness, hypoesthesia, nervousness, paresthesia, tremor, vertigo, asthenia, malaise, insomnia, depression, unusual dreams; in some cases – ataxia, apathy, agitation, amnesia.

From the digestive system: nausea, vomiting, epigastric pain; rarely – increased activity of liver transaminases and jaundice (due to cholestasis), pancreatitis, dry mouth, flatulence, gingival hyperplasia, constipation or diarrhea; in some cases – gastritis, increased appetite.

From the urinary system rarely – pollakiuria, painful urge to urinate, nocturia; in some cases – dysuria, polyuria.

From the reproductive system rarely – sexual dysfunction (including decreased potency), gynecomastia.

Dermatological reactions in some cases – xeroderma, alopecia, dermatitis, purpura, skin discoloration.

Allergic reactions skin itching, rash (including erythematous, maculopapular rash, urticaria, angioedema).

From the musculoskeletal system rarely – arthralgia, arthrosis, myalgia (with long-term use), back pain; in some cases – myasthenia.

From the respiratory system: rarely – dyspnea, nosebleed; in some cases – cough, rhinitis.

From metabolism: rarely – polyuricemia, increase/decrease in body weight, hyperglycemia, increased sweating, thirst.

From the hematopoietic system rarely – thrombocytopenia, leukopenia.

From the sensory organs: rarely – visual disturbances, diplopia, conjunctivitis, eye pain, tinnitus, in some cases – parosmia, taste disturbance, accommodation disturbance, xerophthalmia.

Other in some cases – cold clammy sweat.

Cilazapril

From the cardiovascular system less than 2% – marked decrease in blood pressure, weakness. When using ACE inhibitors in some cases – symptomatic arterial hypotension, especially in patients with hyponatremia and hypovolemia caused by vomiting, diarrhea, previous treatment with diuretics, salt-free diet or dialysis.

From the central and peripheral nervous system: often – headache, dizziness.

From the digestive system: less than 2% – dyspeptic phenomena; in some cases – pancreatitis, sometimes with a fatal outcome.

From the urinary system rarely – a slight, mainly reversible increase in the content of creatinine and blood urea nitrogen (mainly in patients with renal artery stenosis or with renal failure, but they are also observed in patients with normal renal function, especially in those who simultaneously receive diuretics). In patients whose renal function depends mainly on the renin-angiotensin-aldosterone system, for example, in severe circulatory failure, renal artery stenosis and other kidney diseases, treatment with cilazapril (like other ACE inhibitors) may lead to an increase in blood urea nitrogen and serum creatinine concentrations. Although after discontinuation of cilazapril and/or diuretics these changes are usually reversible, cases of severe renal impairment and, rarely, acute renal failure have been described.

Dermatological reactions less than 2% – rash.

Allergic reactions : rarely – angioedema spreading to the face, lips, tongue, glottis and/or larynx (requires immediate discontinuation of the drug and appropriate therapy).

From the respiratory system: less than 2% – cough.

From the hematopoietic system a decrease in hemoglobin, hematocrit and/or leukocyte levels is possible. A causal relationship of these disorders with cilazapril intake has not been established.

Contraindications

Amlodipine

• Severe arterial hypotension;
• Collapse;
• Cardiogenic shock;
• Pregnancy;
• Lactation period;
• Children and adolescents under 18 years of age (efficacy and safety not established);
• Hypersensitivity to amlodipine and other dihydropyridine derivatives.

Use with caution in case of impaired liver function, sick sinus syndrome (severe bradycardia, tachycardia), chronic heart failure in the stage of decompensation, with mild or moderate arterial hypotension, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after it), with diabetes mellitus, impaired lipid profile, in elderly patients.

Cilazapril

• History of angioedema (including hereditary, idiopathic, as well as angioedema caused by previous use of other ACE inhibitors);
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Hyperkalemia;
• Porphyria;
• Pregnancy;
• Lactation period;
• Hemodialysis using high-performance polyacrylonitrile methallyl sulfate membranes (e.g., AN69), hemofiltration, LDL apheresis.

Use with caution in chronic renal failure (proteinuria more than 1 g/day), severe circulatory failure, arterial hypotension, mitral stenosis, aortic stenosis, coronary artery disease, with bone marrow depression, condition after kidney transplantation, in patients on hemodialysis, with diabetes mellitus, gout, hyperuricemia, salt-restricted diet, with liver cirrhosis, conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), with COPD, in patients under 18 years of age (safety and efficacy of use not established).

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in case of impaired liver function.

Use in Renal Impairment

Patients with renal failure may require a dose reduction depending on creatinine clearance. In renal failure, renal function should be monitored during the first weeks of therapy.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Prescribe with caution to elderly patients.

Special Precautions

Amlodipine

During treatment, it is necessary to monitor body weight, sodium intake, and prescribe an appropriate diet.

Maintaining dental hygiene and frequent visits to the dentist are necessary (to prevent soreness, bleeding and gingival hyperplasia).

The dosage regimen for elderly patients is the same as for patients of other age groups. When increasing the dose, careful monitoring of elderly patients is necessary.

Although calcium channel blockers do not have a withdrawal syndrome, a gradual dose reduction is recommended before discontinuing treatment.

Amlodipine does not affect plasma concentrations of potassium, glucose, triglycerides, total cholesterol, LDL, uric acid, creatinine and blood urea nitrogen.

Effect on ability to drive vehicles and mechanisms

No effect of amlodipine on the ability to drive a car or operate machinery has been reported. Nevertheless, some patients, mainly at the beginning of treatment, may experience drowsiness and dizziness. If they occur, the patient should take special precautions when driving a car and operating machinery.

Cilazapril

Cilazapril (like other ACE inhibitors) should be prescribed with caution to patients with aortic stenosis.

In case of acute arterial hypotension, the patient should be placed horizontally; in this case, infusion of saline or a drug that increases circulating blood volume may be required. After replenishment of circulating blood volume, treatment with cilazapril can be continued. However, if symptoms do not disappear, the dose should be reduced or the drug discontinued.

Blood pressure may decrease significantly in patients with chronic circulatory failure receiving ACE inhibitors. However, in clinical studies in which patients with chronic circulatory failure took Cilazapril at a dose of 500 mcg, symptoms of arterial hypotension did not occur. Arterial hypotension can be caused by the use of ACE inhibitors during surgical interventions in combination with anesthetics that also have a hypotensive effect. In such cases, an increase in circulating blood volume by intravenous infusion or – if this measure is ineffective – infusion of angiotensin II may be indicated.

Patients with renal failure may require a dose reduction depending on creatinine clearance. In renal failure, as well as in severe heart failure, renal function should be monitored during the first weeks of therapy.

Concomitant use of potassium-sparing diuretics may cause an increase in serum potassium levels, especially in patients with renal failure. Therefore, if concomitant use of these drugs is indicated, their dose should be reduced at the beginning of treatment with cilazapril, carefully monitoring serum potassium concentration and renal function.

Hemodialysis using high-performance polyacrylonitrile methallyl sulfate membranes (e.g., AN69), hemofiltration or LDL apheresis can cause anaphylaxis or anaphylactoid reactions in patients taking ACE inhibitors, including Cilazapril, including life-threatening shock.

The mechanism of this phenomenon is not precisely known. The above procedures should be avoided in these patients.

Anaphylactic reactions may occur in patients undergoing hyposensitization with wasp or bee venom and simultaneously receiving an ACE inhibitor. For this reason, Cilazapril should be discontinued before starting hyposensitization. In addition, in this situation, Cilazapril should not be replaced with beta-blockers.

The use of ACE inhibitors in patients with diabetes mellitus may potentiate the effect of oral hypoglycemic drugs.

Overdose

Amlodipine

Symptoms pronounced decrease in blood pressure, tachycardia, excessive peripheral vasodilation.

Treatment gastric lavage, administration of activated charcoal, maintenance of cardiovascular function, monitoring of heart and lung function parameters, elevated position of the limbs, control of circulating blood volume and diuresis to restore vascular tone – use of vasoconstrictor drugs (if there are no contraindications to their use); to eliminate the consequences of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Cilazapril

Data on overdose are limited. In healthy volunteers who took Cilazapril in single doses up to 160 mg, no undesirable effect on blood pressure was noted.

Symptoms the most likely is a significant decrease in blood pressure.

Treatment increase in circulating blood volume. If indicated, cilazaprilat can be partially removed from the body by hemodialysis.

Drug Interactions

Amlodipine

Inhibitors of microsomal oxidation increase the plasma concentration of amlodipine, increasing the risk of side effects, while inducers of hepatic microsomal enzymes decrease it.

The hypotensive effect is reduced with simultaneous use with NSAIDs, especially with indomethacin (sodium retention and blockade of prostaglandin synthesis in the kidneys), alpha-adrenergic stimulants, estrogens (sodium retention), and sympathomimetics.

Thiazide and loop diuretics, beta-blockers, verapamil, ACE inhibitors and nitrates enhance the antianginal and hypotensive effects.

Amiodarone, quinidine, alpha₁-blockers, antipsychotics and slow calcium channel blockers may enhance the hypotensive effect.

It does not affect the pharmacokinetic parameters of digoxin and warfarin.

Cimetidine does not affect the pharmacokinetics of amlodipine.

When used concomitantly with lithium preparations, manifestations of neurotoxicity may be enhanced (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Calcium preparations may reduce the effectiveness of slow calcium channel blockers.

Procainamide, quinidine and other drugs that cause QT interval prolongation enhance the negative inotropic effect and may increase the risk of significant QT interval prolongation.

Grapefruit juice may reduce the plasma concentration of amlodipine, but this reduction is so small that it does not have a significant effect on the action of amlodipine.

Cilazapril

When used in combination with other antihypertensive agents, an additive effect and an increased risk of arterial hypotension are possible.

Cilazapril is used concomitantly with digoxin, nitrates, furosemide, thiazides, coumarin anticoagulants and histamine H₂-receptor blockers. No increase in plasma digoxin concentration or other clinically significant or pharmacokinetic interaction was observed. Combined use of potassium-sparing diuretics with cilazapril may lead to an increase in serum potassium, especially in patients with renal failure.

Use of cilazapril, like other ACE inhibitors, together with NSAIDs may reduce the hypotensive effect of the drug. This is not observed in patients who received Cilazapril before the prescription of NSAIDs.

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.