Amprilan^® (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

C09AA05 (Ramipril)

Active Substance

Ramipril

Dosage Forms

	Amprilan®	Tablets 1.25 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.
		Tablets 2.5 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.
		Tablets 5 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.
		Tablets 10 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, oval, flat, with a beveled edge.

Excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate.

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Tablets light yellow, oval, flat, with a beveled edge.

Excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate, dye mixture PB22886 yellow (contains lactose monohydrate, iron oxide yellow dye (E172)).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Tablets pink, oval, flat, with a beveled edge, with visible inclusions.

Excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate, dye mixture PB24899 pink (contains lactose monohydrate, iron oxide red dye (E172), iron oxide yellow dye (E172)).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Tablets white or almost white, oval, flat, with a beveled edge.

Excipients: sodium carbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate.

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

ACE inhibitor. It is a prodrug from which the active metabolite ramiprilat is formed in the body. It is believed that the mechanism of the antihypertensive action is associated with competitive inhibition of ACE activity, which leads to a decrease in the rate of conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor substance.

As a result of the decrease in angiotensin II concentration, a secondary increase in plasma renin activity occurs due to the elimination of the negative feedback during renin release and a direct decrease in aldosterone secretion. Due to its vasodilating action, it reduces total peripheral vascular resistance (afterload), pulmonary capillary wedge pressure (preload) and resistance in the pulmonary vessels; increases cardiac output and exercise tolerance.

In patients with signs of chronic heart failure after myocardial infarction, Ramipril reduces the risk of sudden death, the progression of heart failure to severe/resistant failure and reduces the number of hospitalizations for heart failure.

It is known that Ramipril significantly reduces the incidence of myocardial infarction, stroke and cardiovascular death in patients with increased cardiovascular risk due to vascular diseases (coronary artery disease, previous stroke or peripheral vascular disease) or diabetes mellitus, who have at least one additional risk factor (microalbuminuria, arterial hypertension, increased total cholesterol levels, low HDL levels, smoking). It reduces overall mortality and the need for revascularization procedures, slows the onset and progression of chronic heart failure.

In both diabetic and non-diabetic patients, Ramipril significantly reduces existing microalbuminuria and the risk of developing nephropathy. These effects are observed in patients with both elevated and normal blood pressure.

The hypotensive effect of ramipril develops in about 1-2 hours, reaches a maximum within 3-6 hours, and lasts for at least 24 hours.

Pharmacokinetics

When taken orally, absorption is 50-60%, food does not affect the extent of absorption but slows down absorption. C_max is reached in 2-4 hours. It is metabolized in the liver to form the active metabolite ramiprilat (6 times more potent in inhibiting ACE than Ramipril), inactive diketopiperazine, and is glucuronidated. All formed metabolites, except for ramiprilat, have no pharmacological activity. Plasma protein binding for ramipril is 73%, for ramiprilat is 56%. Bioavailability after oral administration of 2.5-5 mg ramipril is 15-28%; for ramiprilat is 45%. After daily administration of ramipril at a dose of 5 mg/day, the steady-state plasma concentration of ramiprilat is reached by the 4th day.

T_1/2 for ramipril is 5.1 hours; in the distribution and elimination phase, the decrease in serum concentration of ramiprilat occurs with T_1/2 of 3 hours, followed by a transitional phase with T_1/2 of 15 hours, and a long terminal phase with very low plasma concentrations of ramiprilat and T_1/2 of 4-5 days. T_1/2 increases in chronic renal failure. V_d of ramipril is 90 L, of ramiprilat is 500 L. 60% is excreted by the kidneys, 40% through the intestines (mainly in the form of metabolites). In case of impaired renal function, the excretion of ramipril and its metabolites slows down in proportion to the decrease in creatinine clearance; in case of impaired liver function, the conversion to ramiprilat slows down; in heart failure, the concentration of ramiprilat increases by 1.5-1.8 times.

Indications

Arterial hypertension; chronic heart failure; heart failure developing within the first few days after acute myocardial infarction; diabetic and non-diabetic nephropathy; reduction of the risk of myocardial infarction, stroke and cardiovascular mortality in patients with high cardiovascular risk, including patients with confirmed coronary artery disease (with or without a history of myocardial infarction), patients who have undergone percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, with a history of stroke and patients with occlusive lesions of peripheral arteries.

ICD codes

Dosage Regimen

Take orally, once or twice daily, with or without food. Swallow the tablet whole with a sufficient amount of liquid.

For arterial hypertension, initiate therapy at 1.25 mg to 2.5 mg once daily. Adjust the dose at intervals of 2 to 3 weeks based on therapeutic response. The usual maintenance dose is 2.5 mg to 5 mg daily. The maximum daily dose is 10 mg.

For chronic heart failure, start with 1.25 mg once daily. Double the dose every 1 to 2 weeks if tolerated. The target maintenance dose is 5 mg twice daily.

For post- myocardial infarction, begin with 2.5 mg twice daily. If hypotension occurs, reduce to 1.25 mg twice daily. Increase to a target dose of 5 mg twice daily as tolerated.

For nephropathy or cardiovascular risk reduction, the initial dose is 1.25 mg to 2.5 mg once daily. The maintenance dose is typically 5 mg to 10 mg once daily.

For patients with impaired renal function (creatinine clearance less than 40 mL/min), initiate treatment at 1.25 mg once daily. The maximum daily dose is 5 mg. Titrate upward cautiously.

For elderly patients or those with volume depletion, start at the lower end of the dosing range ( 1.25 mg daily). Monitor blood pressure closely after the initial dose and with each dosage increase.

Do not abruptly discontinue therapy. Regularly monitor renal function and serum potassium levels during treatment.

Adverse Reactions

From the cardiovascular system arterial hypotension; rarely – chest pain, tachycardia.

From the CNS dizziness, weakness, headache; rarely – sleep disorders, mood disorders.

From the digestive system diarrhea, constipation, loss of appetite; rarely – stomatitis, abdominal pain, pancreatitis, cholestatic jaundice.

From the respiratory system dry cough, bronchitis, sinusitis.

From the urinary system rarely – proteinuria, increased concentration of creatinine and urea in the blood (mainly in patients with impaired renal function).

From the hematopoietic system rarely – neutropenia, agranulocytosis, thrombocytopenia, anemia.

From laboratory parameters hyperkalemia, hyponatremia.

Allergic reactions skin rash, angioedema and other hypersensitivity reactions.

Other rarely – muscle cramps, impotence, alopecia.

Contraindications

Severe impairment of renal and liver function, bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation; primary hyperaldosteronism, hyperkalemia, aortic stenosis, pregnancy, lactation (breastfeeding), children and adolescents under 18 years of age, hypersensitivity to ramipril and other ACE inhibitors.

Use in Pregnancy and Lactation

Ramipril is contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe impairment of liver function.

Use in Renal Impairment

Contraindicated in severe impairment of renal function, condition after kidney transplantation. In patients with concomitant renal impairment, doses are selected individually according to creatinine clearance values. Before starting treatment, all patients should have their renal function examined.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

In patients with concomitant renal impairment, doses are selected individually according to creatinine clearance values. Before starting treatment, all patients should have their renal function examined. During treatment with ramipril, regular monitoring of renal function, blood electrolyte composition, blood levels of liver enzymes, and peripheral blood picture (especially in patients with diffuse connective tissue diseases, in patients receiving immunosuppressants, allopurinol) is carried out.

In patients who have a deficiency of fluid and/or sodium, correction of water and electrolyte disturbances must be carried out before starting treatment. During treatment with ramipril, hemodialysis using polyacrylonitrile membranes should not be performed (increased risk of anaphylactic reactions).

Drug Interactions

With simultaneous use of potassium-sparing diuretics (including spironolactone, triamterene, amiloride), potassium preparations, salt substitutes and dietary supplements containing potassium, the development of hyperkalemia is possible (especially in patients with impaired renal function), because ACE inhibitors reduce aldosterone content, which leads to potassium retention in the body against the background of limited potassium excretion or its additional intake into the body.

With simultaneous use with NSAIDs, a decrease in the hypotensive effect of ramipril, impaired renal function is possible.

With simultaneous use with “loop” or thiazide diuretics, the antihypertensive effect is enhanced. Marked arterial hypotension, especially after taking the first dose of a diuretic, apparently occurs due to hypovolemia, which leads to a transient increase in the hypotensive effect of ramipril. There is a risk of developing hypokalemia. The risk of impaired renal function increases.

With simultaneous use with agents that have a hypotensive effect, an enhancement of the hypotensive effect is possible.

With simultaneous use with insulin, hypoglycemic agents derivatives of sulfonylurea, metformin, the development of hypoglycemia is possible.

With simultaneous use with allopurinol, cytostatics, immunosuppressants, procainamide, an increased risk of developing leukopenia is possible.

With simultaneous use with lithium carbonate, an increase in the concentration of lithium in the blood serum is possible.

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.