Ramipril-Teva tablets 5 mg blister No. 30

Instructions for Ramipril-Teva tablets 5 mg blister No. 30

Composition

active ingredient: ramipril;

1 tablet contains 5 mg of ramipril;

excipients: lactose monohydrate, pregelatinized starch, croscarmellose sodium, sodium bicarbonate, sodium stearyl fumarate; 2.5 mg tablets – iron oxide yellow (E 172); 5 mg tablets – iron oxide red (E 172), iron oxide yellow (E 172).

Dosage form

Tablet.

Main physicochemical properties:

5 mg tablets: pink, oblong, biplane tablets with two break lines on the sides; upper punch: parallel break line, embossed R/3, with bevel; lower punch: with bevel; 8.8 mm x 4.4 mm.

Pharmacotherapeutic group

Angiotensin-converting enzyme (ACE) inhibitors. Monocomponent ACE inhibitors. Ramipril. ATC code C09A A05.

Pharmacological properties

Pharmacodynamics

Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms: ACE, kinase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II (the active vasoconstrictor) and the cleavage of the active vasodilator bradykinin. The reduction in the formation of angiotensin II and the inhibition of the cleavage of bradykinin lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a decrease in aldosterone secretion. The response to monotherapy with ACE inhibitors was on average less pronounced in black (Afro-Caribbean) hypertensive patients (a population characterized by low-renin levels in hypertension) than in patients of other races.

Antihypertensive properties. Administration of ramipril leads to a significant decrease in peripheral arterial resistance. As a rule, there are no significant changes in renal plasma flow or glomerular filtration rate. Administration of ramipril to patients with arterial hypertension leads to a decrease in blood pressure in both the horizontal and vertical positions of the patient, which is not accompanied by a compensatory increase in heart rate.

In most patients, the antihypertensive effect occurs 1-2 hours after a single oral dose of the drug. The maximum effect after a single oral dose usually occurs after 3-6 hours. The antihypertensive effect after a single dose is usually maintained for 24 hours.

With long-term treatment with ramipril, the maximum antihypertensive effect develops after 3-4 weeks. It has been proven that with long-term therapy, the antihypertensive effect persists for 2 years.

Abrupt discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure (rebound phenomenon).

Heart failure. Ramipril has been shown to be effective in patients with heart failure of NYHA functional classes II-IV, when used as an adjunct to conventional diuretic therapy and, if necessary, cardiac glycosides. The drug has a beneficial effect on cardiac hemodynamics (reduction of left and right ventricular filling pressures, total peripheral vascular resistance, increase in cardiac output and improvement of cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular disease prevention/nephroprotection

A placebo-controlled preventive study (the HOPE study) was conducted in over 9200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of cardiovascular disease after a history of atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol, low-density lipoprotein cholesterol, or smoking).

This study demonstrated that ramipril statistically significantly reduced the incidence of myocardial infarction, cardiovascular death, and stroke, both individually and in combination (primary composite endpoint).

HOPE study: main results

The MICRO-HOPE study, which was previously planned as part of the HOPE study, examined the effect of adding ramipril 10 mg to existing treatment compared with placebo in 3,577 patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes and at least one CV risk factor.

The primary analysis showed that 117 (6.5%) of the study participants treated with ramipril and 149 (8.4%) of the study participants treated with placebo developed significant nephropathy, corresponding to a relative risk reduction of 24%; 95% CI [3-40], p=0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, was conducted to evaluate the effect of ramipril treatment on the magnitude of the decline in glomerular filtration rate (GFR) in 352 normotensive or hypertensive patients (aged 18-70 years) with mild (mean urinary protein excretion >1 and <3 g/day) or severe proteinuria (≥3 g/day) due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The results of the primary analysis among patients with the most severe proteinuria (the subgroup that discontinued early because of evidence of benefit in the ramipril group) showed that the mean rate of decline in GFR per month was lower with ramipril than with placebo: −0.54 (0.66) vs −0.88 (1.03) mL/min/month, p=0.038. Thus, the between-group difference was 0.34 [0.03-0.65] per month and approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint of doubling of plasma creatinine and/or end-stage renal disease (requiring hemodialysis or kidney transplantation) compared with 45.5% in the placebo group (p=0.02).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Two large randomized controlled trials [ONTARGET (Telmisartan Monotherapy and Ramipril Combination Trial on the Overall Endpoint) and VA NEPHRON-D (Veterans Diabetic Nephropathy Trial)] have investigated the combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus with concomitant signs of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a significant benefit of combination therapy with respect to renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute renal failure and/or hypotension compared with monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren in Patients with Type 2 Diabetes with Cardiovascular and Renal Endpoints) was designed to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse clinical outcomes. There was a higher incidence of cardiovascular death and stroke in the aliskiren group compared with the placebo group, as well as an increased incidence of serious adverse events of interest (hyperkalemia, hypotension, and renal dysfunction).

Children. A randomized, double-blind, placebo-controlled clinical trial enrolled 244 pediatric patients with hypertension (73% of whom had primary hypertension) aged 6 to 16 years. Participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25 mg, 5 mg, and 20 mg/kg body weight. After 4 weeks, ramipril was ineffective in reducing the primary endpoint of systolic blood pressure, but it did reduce diastolic blood pressure at the highest dose of the range studied. Both medium and high doses of ramipril were shown to reduce systolic and diastolic blood pressure to a statistically significant extent in children with established hypertension.

This effect was not observed in a 4-week, randomized, double-blind, dose-escalation study evaluating the effect of drug withdrawal in 218 pediatric patients aged 6 to 16 years (75% of whom had primary hypertension). In this study, a modest rebound increase in both diastolic and systolic blood pressure was observed after drug withdrawal, but it was not statistically significant for the return to baseline pressure in all dose groups of the studied ramipril range [low dose (0.625 mg–2.5 mg), medium dose (2.5 mg–10 mg), or high dose (5 mg–20 mg)] based on body weight. Ramipril did not show a linear dose-dependent effect in the pediatric group studied.

Pharmacokinetics

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 hour. Based on the amount of substance recovered in the urine, the extent of absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at a dose of 2.5 mg and 5 mg is 45%.

Peak plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached 2-4 hours after administration of ramipril. After the use of usual doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are reached by approximately the 4th day of treatment.

Distribution: The plasma protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.

Metabolism: Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

Elimination. Elimination of metabolites occurs mainly by renal excretion. The decline in plasma concentrations of ramiprilat is multiphasic. Due to the strong saturable binding to ACE and the slow dissociation from the enzyme, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations.

After repeated doses of ramipril once daily, the effective half-life is 13-17 hours for doses of 5-10 mg and longer for lower doses (1.25-2.5 mg). The difference is due to the saturable capacity of the enzyme to bind ramiprilat.

Neither ramipril nor its metabolite has been detected in breast milk following a single oral dose. However, the effect of repeated doses is unknown.

Patients with impaired renal function (see section "Method of administration and dosage").

In patients with impaired renal function, renal excretion of ramiprilat is reduced and renal clearance of ramiprilat is proportional to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Patients with impaired liver function (see section "Method of administration and dosage").

In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat was slowed down due to a decrease in the activity of hepatic esterases, and the plasma levels of ramipril were increased in these patients. However, the maximum concentrations of ramiprilat in these patients did not differ from those in subjects with normal hepatic function.

Breastfeeding: After a single oral dose of ramipril, its levels in breast milk were below the detection limit. However, the effect of multiple doses is unknown.

Preclinical safety data. When the drug was administered orally to rodents and dogs, it was found that ramipril did not cause acute toxic effects. Studies with long-term oral administration of the drug were conducted in rats, dogs and monkeys. In all three species of animals, changes in electrolyte balance and blood picture were observed. In dogs and monkeys receiving the drug at a dose of 250 mg/kg body weight per day, a significant increase in the juxtaglomerular apparatus was observed, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs and monkeys tolerated daily doses of the drug, which were 2; 2.5 and 8 mg/kg body weight per day, respectively. At the same time, they did not experience undesirable effects.

Reproductive toxicity studies conducted in rats, rabbits and monkeys did not reveal any teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to female rats during pregnancy and lactation resulted in irreversible renal damage (dilation of the renal pelvis) in the offspring at doses of 50 mg/kg body weight per day and above.

Numerous mutagenicity tests using various test systems have not revealed any mutagenic or genotoxic properties of ramipril.

Indication

Treatment of arterial hypertension

Prevention of cardiovascular disease: reduction of cardiovascular morbidity and mortality in patients with:

severe cardiovascular disease of atherothrombotic origin (history of ischemic heart disease or stroke or peripheral vascular disease); diabetes with at least one cardiovascular risk factor (see section "Pharmacodynamics").

Treatment of kidney disease:

initial glomerular diabetic nephropathy as evidenced by microalbuminuria; severe glomerular diabetic nephropathy as evidenced by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1); severe non-diabetic glomerular nephropathy as evidenced by macroproteinuria ≥3 g/day (see section 5.1).

Treatment of symptomatic heart failure

Secondary prevention after acute myocardial infarction: reduction of mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is started more than 48 hours after the onset of acute myocardial infarction.

Contraindication

Hypersensitivity to the active substance or to any of the excipients included in the formulation or to other ACE inhibitors. History of angioedema (hereditary, idiopathic or previously treated with ACE inhibitors or angiotensin II receptor antagonists). Significant bilateral renal artery stenosis or stenosis of the renal artery to a single functioning kidney. Pregnant women and women planning to become pregnant (see section "Use during pregnancy and lactation"). Arterial hypotension or hemodynamically unstable conditions.

The simultaneous use of Ramipril-Teva with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR less than 60 ml/min/1.73 m2) (see sections “Pharmacodynamics” and “Interaction with other medicinal products and other types of interactions”).

Concomitant use with sacubitril/valsartan: Treatment with Ramipril should only be initiated 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).

The concomitant use of ACE inhibitors and extracorporeal therapies that result in contact of blood with negatively charged surfaces should be avoided (see section 4.5).

Interaction with other medicinal products and other types of interactions

Extracorporeal therapies that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate, are contraindicated due to the increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different dialysis membrane or a different class of antihypertensive agent.

Potassium-sparing diuretics, potassium-containing food supplements or salt substitutes containing potassium. Although serum potassium levels usually remain within normal limits, hyperkalaemia may occur in some patients taking this medicine. Potassium-sparing diuretics (such as spironolactone, triamterene or amiloride), food supplements containing potassium or salt substitutes containing potassium may lead to significant increases in serum potassium. Caution should also be exercised when Ramipril-Teva is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole) since trimethoprim is known to act as a potassium-sparing diuretic, as is amiloride. Therefore, the combination of Ramipril-Teva with the above-mentioned medicinal products is not recommended. If concomitant use of such drugs is indicated, treatment should be carried out with caution and serum potassium levels should be monitored frequently (see section "Special warnings and precautions for use").

Cyclosporine: Concomitant use of ACE inhibitors with cyclosporine may cause hyperkalemia. Monitoring of serum potassium is recommended.

Heparin: Concomitant use of ACE inhibitors with heparin may lead to hyperkalemia. Monitoring of serum potassium is recommended.

Tacrolimus: Hyperkalemia may occur, therefore plasma potassium levels should be carefully monitored.

Antihypertensive drugs (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be expected (see section "Method of administration and dosage" for diuretics).

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) which may reduce the antihypertensive effect of Ramipril-Teva. Close monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may cause changes in the blood picture. Increased likelihood of hematological reactions (see section "Special instructions").

Lithium salts: ACE inhibitors may reduce lithium excretion, which may lead to increased lithium toxicity. Lithium levels should be carefully monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of Ramipril-Teva is expected to be reduced. Also, the simultaneous use of ACE inhibitors and NSAIDs may be accompanied by an increased risk of deterioration of renal function and an increase in blood potassium levels.

Dual blockade of the renin-angiotensin-aldosterone system: Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalaemia and worsening renal function (including acute renal failure) compared with the use of a single agent affecting the RAAS (see sections 5.1, 5.3 and 4.4).

Application features

Special patient groups

Pregnancy: ACE inhibitors or angiotensin II receptor antagonists should be used during pregnancy only if clearly needed. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).

Patients at particular risk of hypotension

Patients with significantly increased RAAS activity

In patients with significantly increased RAAS activity, there is a risk of a sudden significant decrease in blood pressure and deterioration of renal function due to ACE inhibition, especially if an ACE inhibitor or concomitant diuretic is prescribed for the first time or the dose is increased for the first time.

A significant increase in RAAS activity, which requires medical supervision, including constant monitoring of blood pressure, can be expected, for example, in patients:

It is generally recommended that dehydration, hypovolemia, or electrolyte depletion be corrected before initiating treatment (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Dual blockade of RAAS

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren has been shown to increase the risk of hypotension, hyperkalaemia and deterioration of renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 5.1 and 5.5).

If such dual blockade therapy is considered absolutely necessary, it should only be used under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Transient or persistent heart failure after myocardial infarction

Patients at risk of cardiac or cerebral ischemia in the event of acute hypotension

In the initial phase of treatment, special medical supervision is required.

Elderly patients

See the section "Method of administration and dosage".

Surgical intervention

If possible, ramipril treatment should be discontinued 1 day before surgery.

Monitoring kidney function

Renal function should be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. Patients with impaired renal function should be monitored particularly closely (see section 4.2). There is a risk of worsening renal function, especially in patients with congestive heart failure or after kidney transplantation, and in patients with renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Hypersensitivity/angioedema

Angioedema has been reported in patients receiving ramipril (see section 4.8). If angioedema develops, Ramipril should be discontinued and emergency treatment should be initiated immediately. The patient should be kept under medical observation for at least 12-24 hours and may be discharged after complete resolution of symptoms. Intestinal angioedema has been reported in patients receiving ACE inhibitors, including ramipril (see section 4.8). Patients have complained of abdominal pain (with or without nausea/vomiting).

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

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) or vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue with or without respiratory distress) (see section 4.5).

Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in patients already taking an ACE inhibitor.

Anaphylactic reactions during desensitization

When using the drug, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increases. Therefore, before desensitization, Ramipril-Teva should be temporarily discontinued.

Monitoring electrolyte balance: serum potassium level

ACE inhibitors may cause hyperkalaemia because they inhibit the release of aldosterone. This effect is usually insignificant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, other drugs that increase serum potassium (e.g. heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or angiotensin receptor antagonists, hyperkalaemia may occur. Caution should be exercised when potassium-sparing diuretics and angiotensin receptor antagonists are used in patients taking ACE inhibitors. Serum potassium and renal function should be monitored in such patients (see section 4.5).

If concomitant use of the above-mentioned drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section “Interaction with other medicinal products and other types of interactions”).

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow suppression has also been reported. Monitoring of the white blood cell count is recommended to detect possible leukopenia. More frequent monitoring is advisable in patients at the beginning of treatment and in cases of impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or in those taking other medicinal products that may cause changes in the blood picture (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).

Ethnic differences

The drug causes angioedema more often in patients of the Negroid race than in representatives of other races. The hypotensive effect of ramipril, as with other ACE inhibitors, may be less pronounced in patients of the Negroid race than in representatives of other races. This may be due to the fact that in patients of the Negroid race with arterial hypertension, arterial hypertension with low renin activity is more often observed.

Cough

Cough has been reported with the use of the drug. It is characteristic that the cough is unproductive, prolonged and disappears after discontinuation of therapy. In the differential diagnosis of cough, the possibility of cough due to ramipril should be borne in mind.

Ramipril-Teva contains lactose monohydrate, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some side effects (for example, symptoms of low blood pressure, such as dizziness) may impair the patient's ability to concentrate and reduce the speed of their reactions, which is risky in situations where these qualities are particularly important (for example, when driving vehicles or working with other mechanisms).

This is usually possible at the beginning of treatment or when switching from other drugs to treatment with Ramipril-Teva. After taking the first dose or a subsequent increase in dose, it is advisable not to drive or operate other machinery for several hours.

Use during pregnancy or breastfeeding

Pregnancy. The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is detected during therapy, the drug should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women (see section "Contraindications").

Breastfeeding: Due to the lack of information regarding the use of ramipril during breastfeeding (see section 5.1), this drug is not recommended for use in breastfeeding women; alternative drugs with better established safety profiles during lactation are preferable, especially in breast-feeding mothers.