Trinomy® [Atorvastatin, Acetylsalicylic Acid, Ramipril]

Pharmacological properties

acetylsalicylic acid. acetylsalicylic acid irreversibly inhibits platelet aggregation. this effect on platelets is due to cog acetylation. this irreversibly inhibits the synthesis of thromboxane a2 (which stimulates platelet aggregation and has a vasoconstrictor effect) in platelets. this effect is permanent and usually manifests itself throughout the 8-day platelet life span.

Acetylsalicylic acid also inhibits the synthesis of prostacyclin (prostaglandin, inhibits platelet aggregation, but has a vasodilating effect) in the endothelial cells of blood vessels. This effect is temporary. After acetylsalicylic acid is removed from the blood, nucleated endothelial cells again begin to synthesize prostacyclin. As a result, one low daily dose of acetylsalicylic acid (100 mg / day) causes inhibition of thromboxane A₂ in platelets without a significant effect on prostacyclin synthesis.

Acetylsalicylic acid belongs to the group of acid-forming NSAIDs with analgesic, antipyretic and anti-inflammatory properties. The mechanism of their action is the irreversible inhibition of COX enzymes that are involved in the synthesis of prostaglandins. Higher doses of acetylsalicylic acid are used to treat mild to moderate pain, fever, and also for the treatment of acute and chronic inflammatory diseases such as rheumatoid arthritis.

Experimental data have shown that when used simultaneously with low doses of acetylsalicylic acid, ibuprofen can inhibit platelet aggregation. In a study that compared the effect of a single dose of ibuprofen 400 mg 8 hours before or 30 minutes before taking 81 mg of acetylsalicylic acid (in the form of an immediate release tablet), a decrease in the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation was observed. However, this data is limited because there is uncertainty regarding the extrapolation of this data to clinical practice. Therefore, there is no corresponding conclusion on the regular use of ibuprofen, and there are no data on the corresponding clinical effect, which may be considered related to the episodic use of ibuprofen.

Atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the conversion rate of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, which is a precursor to sterols, in particular cholesterol. TG and cholesterol in the liver are embedded in VLDL molecules, enter the blood plasma and are transported to peripheral tissues. LDL is formed from VLDL and is catabolized mainly by interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces plasma cholesterol and plasma lipoprotein concentrations by inhibiting HMG-CoA reductase, and subsequently cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and LDL catabolism.

Atorvastatin reduces the formation of LDL and the number of particles of LDL. Atorvastatin causes a pronounced and lasting increase in LDL receptor activity in combination with a favorable change in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol in patients with homozygous familial hypercholesterolemia (a group that did not always respond to hypolipidemic drug therapy).

Atorvastatin demonstrated the ability to reduce the concentration of total cholesterol (30–46%), LDL cholesterol (41–61%), apolipoprotein B (34–50%) and TG (14–33%), while simultaneously causing a variable increase in the concentration of HDL cholesterol and apolipoprotein A1 in a study in which the dose dependence of such an effect was studied. These results are consistent with data from patients with heterozygous familial hypercholesterolemia, unrelated forms of hypercholesterolemia and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus. It has been proven that lower levels of total cholesterol, LDL cholesterol, and apolipoprotein B reduce the risk of developing cardiovascular disease and mortality from these diseases.

Ramipril. Ramiprilat, an active metabolite of the ramipril prodrug, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: ACE; kinase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into the active substance of the vasoconstrictor action of angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone secretion. In patients of a Negroid race (Afro-Caribbean origin) with hypertension (usually patients with hypertension with a low level of renin), the average response to monotherapy with an ACE inhibitor was lower than in patients of a different race.

Antihypertensive properties. The use of ramipril causes a marked decrease in peripheral arterial resistance. Typically, renal plasma flow and glomerular filtration rate do not change. The use of ramipril in patients with hypertension leads to a decrease in blood pressure in a standing and lying position, without a compensatory increase in heart rate. In most patients, after taking a single dose, the antihypertensive effect appears after 1-2 hours, and the maximum effect after 3-6 hours and usually lasts 24 hours. With continued use of ramipril, the maximum antihypertensive effect is usually achieved after 3-4 weeks. It was found that with long-term therapy, the antihypertensive effect is maintained for 2 years. The sudden cessation of treatment with ramipril does not cause a rapid and excessive ricochet increase in blood pressure.

Heart failure. As an adjunct to diuretic and cardiac glycoside therapy, ramipril has been shown to be effective in patients with heart failure of functional classes II – IV according to NYHA classification. The drug has a beneficial effect on cardiac hemodynamics (lowering the filling pressure of the left and right ventricles, decreasing the heart rate, increasing cardiac output and improving the cardiac index). He also reduced neuroendocrine activation.

Pharmacokinetics Acetylsalicylic acid. Acetylsalicylic acid is metabolized to its main active metabolite, salicylic acid, before, during and after absorption. Metabolites are excreted mainly by the kidneys. In addition to salicylic acid, the main metabolites of acetylsalicylic acid are salicylic acid glycine conjugate (salicylic uric acid), glucuronide ester and salicylic acid ester (salicylphenol glucuronide and salicylacyl glucuronide), as well as gentibenzoic acid and gentisic acid;

The absorption of acetylsalicylic acid after administration is fast, complete and independent of galenic preparations. The hydrolysis of the acetylsalicylic acid acetyl residue to a certain extent occurs when passing through the gastrointestinal mucosa. C_max in blood plasma is achieved 10–20 minutes after administration (acetylsalicylic acid), or after 0.3–2 hours (total salicylate).

The kinetics of salicylic acid excretion is largely dose-dependent, since the ability to metabolize salicylic acid is limited (T_½ ranges from 2 to 30 hours).

T_½ acetylsalicylic acid is only a few minutes, T_½ salicylic acid is 2 hours after taking a dose of 0.5 g of acetylsalicylic acid, 4 hours after taking 1 g and increases to 20 hours after taking a single dose of 5 g.

Binding to plasma proteins in humans depends on concentration; a value ranging from 49 to more than 70% (acetylsalicylic acid) and from 66 to 98% (salicylic acid) was recorded. Salicylic acid is in the cerebrospinal fluid and synovial fluid after taking acetylsalicylic acid. Salicylic acid crosses the placenta and passes into breast milk.

Atorvastatin. Absorption. Atorvastatin is rapidly absorbed after administration; C_max in blood plasma is achieved within 1-2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. After administration, the bioavailability of atorvastatin in the form of coated tablets and in the form of a solution is 95 and 99%, respectively.

The bioavailability of atorvastatin is about 12%, and the systemic availability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic availability is due to presystemic clearance in the gastrointestinal mucosa and / or hepatic presystemic metabolism.

Distribution. The average volume of distribution of atorvastatin is about 381 liters. Binding to blood plasma proteins - ≥98%.

Metabolism. Atorvastatin is metabolized by the action of cytochrome P450 3A4 to ortho- and para-hydroxylated derivatives and other products of beta oxidation. In addition to other metabolic pathways, these products are further subject to glucuronidation. Under in vitro conditions, ortho- and para-hydroxylated metabolites cause inhibition of HMG-CoA reductase, equivalent to its inhibition by atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is almost 70% determined by the activity of circulating metabolites.

Breeding. Atorvastatin is excreted mainly with bile after hepatic and / or extrahepatic metabolism. However, atorvastatin is not subject to significant hepatic recirculation. Medium T_½ atorvastatin from human blood plasma is about 14 hours. The half-cycle of inhibitory activity against HMG-CoA reductase is about 20-30 hours due to the presence of active metabolites.

Ramipril. Absorption. After taking ramipril, it is rapidly absorbed in the digestive tract: C_max ramipril in plasma is reached within 1 hour. Taking into account excretion in the urine, the degree of absorption is at least 56% and does not significantly depend on the presence of food in the digestive tract. The bioavailability of the active metabolite of ramiprilat after oral administration of 2.5 and 5 mg of ramipril is 45%.

C_max ramiprilat, the only active metabolite of ramipril, is reached 2–4 hours after taking ramipril. After applying the usual doses of ramipril once a day, the equilibrium concentration of ramiprilat in plasma is reached after 4 days of treatment.

Distribution. The binding to plasma proteins of ramipril is about 73% and ramiprilat is about 56%.

Metabolism. Ramipril is almost completely metabolized to ramiprilat and diketopiperazinovoy ether, diketopiperazinovoy acid, as well as glucuronides ramipril and ramiprilat.

Breeding. Excretion of metabolites occurs mainly by renal excretion. A decrease in the concentration of ramiprilat in plasma is multiphase. Through powerful saturated binding with ACE and slow dissociation due to the enzyme, ramiprilat exhibits a prolonged terminal excretion phase even at very low plasma concentrations.

Effective T_½ ramiprilat after taking repeated doses of 5-10 mg of ramipril once a day is 13-17 hours and longer with low doses (1.25-2.5 mg).The difference is due to the fact that the ability of the enzyme to bind to ramiprilat is saturating.

After taking a single dose, neither ramipril nor its metabolite was detected in breast milk. However, it is not known what effect the administration of repeated doses causes.

Indications

Secondary prophylaxis of cardiovascular complications in adult patients as replacement therapy, when adequate control is provided during therapy with monocomponent agents in equivalent therapeutic doses.

Application

The drug is trinomy, hard capsules, intended for oral use. the drug should be taken 1 time per day, preferably after a meal. the capsule should be swallowed whole with a sufficient amount of water. the capsule should not be chewed, crushed and opened. the capsule clogging system ensures the preservation of the pharmacological properties of the active substances.

During treatment with Trinomy, grapefruit juice is not recommended.

Adults Patients who are provided with adequate control during therapy with acetylsalicylic acid, atorvastatin and ramipril in equivalent therapeutic doses can switch to Trinomy therapy, hard capsules.

Treatment should be initiated under medical supervision (see SPECIAL INSTRUCTIONS).

To prevent complications from the cardiovascular system, the maintenance dose of ramipril should be 10 mg 1 time per day.

Special patient groups. Patients with renal failure. Creatinine clearance should be considered when determining the daily dose for patients with renal failure:

• if creatinine clearance is ≥60 ml / min, the maximum daily dose of ramipril should be 10 mg;
• if creatinine clearance is 30–60 ml / min, the maximum daily dose of ramipril should be 5 mg.

Trinomy is contraindicated in patients undergoing hemodialysis and / or with severe renal failure (creatinine clearance 30 ml / min) (see CONTRAINDICATIONS).

Patients with liver failure. Caution is advised when using Trinomy in patients with liver failure. It is necessary to carry out functional liver tests before starting and periodically during treatment. Patients who develop symptoms or signs of liver damage should undergo functional liver tests. It is necessary to observe patients in whom an increase in the level of transaminases was detected until the deviations are eliminated. In the case when the level of transaminases is 3 times higher than the upper limit of the norm, the use of Trinomy should be discontinued (see ADVERSE EFFECTS).

In addition, the maximum daily dose of ramipril for this category of patients should be 2.5 mg.

Trinomy is contraindicated in patients with severe or acute liver failure (see CONTRAINDICATIONS).

Elderly patients. Due to the high risk of adverse reactions, treatment of elderly patients and very weak patients should be started with caution.

Contraindications

Hypersensitivity to active substances or other components of the drug, other salicylates, NSAIDs, other inhibitors of apf or tartrazine;

• hypersensitivity to soy or peanuts;
• history of asthma or other allergic reactions caused by the use of acetylsalicylic acid or other non-steroidal analgesics / anti-inflammatory drugs;
• acute peptic ulcers (see SPECIAL INSTRUCTIONS);
• hemophilia and other bleeding disorders (thrombocytopenia, hemorrhagic diathesis);
• severe renal and hepatic insufficiency (see APPLICATION);
• contraindicated in patients on hemodialysis (see APPLICATION);
• severe heart failure, arterial hypotension, hemodynamically unstable conditions;
• combined use with methotrexate at a dose of 15 mg / week or higher (see INTERACTIONS);
• nasal polyps associated with asthma, which is caused or exacerbated by the use of acetylsalicylic acid;
• liver disease or a constant increase in the level of transaminases in blood plasma by more than 3 times compared with the norm, which has no explanation (see SPECIAL INSTRUCTIONS);
• During pregnancy and breastfeeding. It is contraindicated for women of reproductive age who do not use effective methods of contraception (see Use during pregnancy and lactation);
• concomitant use with tipranavir or ritonavir (due to the risk of rhabdomyolysis) (see SPECIAL INSTRUCTIONS and INTERACTIONS);
• concomitant use with cyclosporine (due to the risk of rhabdomyolysis) (see SPECIAL INSTRUCTIONS and INTERACTIONS);
• combination with methotrexate;
• a history of angioedema (hereditary, idiopathic, or caused by the use of ACE inhibitors or angiotensin II receptor antagonists);
• extracorporeal treatments that result in blood contact with negatively charged surfaces (see INTERACTIONS);
• severe bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney;
• ramipril should not be used in patients with hypotensive or hemodynamically unstable conditions;
• children and adolescents under the age of 18 years. Children under 16 years of age with fever, flu, or chickenpox have a risk of developing Reyes syndrome;
• recent injuries, surgical interventions.

Side effects

Side effects by frequency of occurrence are classified into the following categories: very often (≥10), often (≥1 / 100 and 1/10), infrequently (≥1 / 1000 and 1/100), rarely (≥1 / 10,000 and 1 / 1000), very rarely (1/10 000), unknown (frequency not determined by available data).

The following are side effects that may occur as a result of monotherapy with one of the active substances.

Acetylsalicylic acid

On the part of the blood and lymphatic system: rarely / very rarely - heavy bleeding has been reported, which in some cases can be life-threatening, for example, brain hemorrhage, especially in patients with uncontrolled hypertension and / or with the use of anticoagulants.

The following types of bleeding were observed with a possible prolongation of blood coagulation time: nasal, skin bleeding, bleeding from the gums, bleeding from the urogenital tract (see SPECIAL INSTRUCTIONS). This effect can last from 4 to 8 days after administration.

From the digestive tract: very often - disorders of the digestive tract, such as heartburn, nausea, vomiting, stomach pain and diarrhea. Small bleeding in the gastrointestinal tract (microbleeding); infrequently - peptic ulcers, gastrointestinal bleeding, iron deficiency anemia due to latent bleeding in the gastrointestinal tract after prolonged use, inflammatory processes in the gastrointestinal tract; very rarely - perforation of peptic ulcer. You should immediately inform your doctor if you have melena or vomiting of blood (signs of severe stomach bleeding).

On the part of the respiratory system: often - paroxysmal bronchospasm, severe shortness of breath, rhinitis, nasal congestion.

From the side of the nervous system: headache, dizziness, hearing impairment or tinnitus (tinnitus) and confusion can be symptoms of an overdose (see OVERDOSAGE).

On the part of the skin and subcutaneous tissues: infrequently - skin reactions; very rarely - erythema multiforme.

From the immune system: rarely - hypersensitivity reactions of the skin, respiratory tract, gastrointestinal tract, cardiovascular system, especially in patients with asthma (with the following possible symptoms: decreased blood pressure, shortness of breath, rhinitis, nasal congestion, anaphylactic shock, Quinckes edema).

On the part of the liver and biliary tract: very rarely - increased liver function tests.

From the kidneys and urinary system: very rarely - renal failure.

Metabolism and eating disorders: very rarely - hypoglycemia. Acetylsalicylic acid in low doses reduces uric acid excretion. In susceptible patients, this can cause gout attacks.

Atorvastatin. During a placebo-controlled clinical trial using atorvastatin involving 16,066 patients (8755 took atorvastatin, 7311 took placebo) who were treated for an average of 53 weeks, 5.2% of patients taking atorvastatin discontinued treatment due to the development of adverse events. reactions compared with 4% of patients in the placebo group.

As with other HMG-CoA reductase inhibitors, an increase in plasma transaminases has been reported in patients taking atorvastatin. These changes were mainly mild, short-term and did not require discontinuation of treatment. A clinically significant increase in plasma transaminases (3 times higher than the upper limit of normal) was observed in 0.8% of patients taking atorvastatin. This increase was dose-dependent and reversible in all patients.

An increase in creatinine clearance of more than 3 times from the upper limit of normal was usually observed in 2.5% of patients taking atorvastatin, as with other HMG-CoA reductase inhibitors in clinical trials. An increase of more than 10 times the upper limit of normal was observed in 0.4% of patients taking atorvastatin (see SPECIAL INSTRUCTIONS).

The development of such adverse reactions has been reported with the use of certain statins:

• sexual dysfunction;
• depression;
• exceptional cases of the development of interstitial lung diseases, especially with prolonged treatment (see SPECIAL INSTRUCTIONS);
• diabetes mellitus: the frequency of adverse reactions depends on the presence or absence of risk factors (fasting glucose ≥5.6 mmol / l, body mass index 30 kg / m², an increased level of TG, AH in history).

Infectious and parasitic diseases: often - nasopharyngitis.

From the blood and lymphatic system: rarely - thrombocytopenia.

From the immune system: often - allergic reactions; very rarely - anaphylaxis.

Metabolism and eating disorders: often - hyperglycemia; infrequently - hypoglycemia, weight gain, anorexia.

From the psyche: infrequently - nightmares, insomnia.

From the nervous system: often - headache; infrequently - dizziness, paresthesia, hypesthesia, dysgeusia, amnesia; rarely - peripheral neuropathy.

From the side of the organ of vision: infrequently - blurred vision; rarely - visual impairment.

From the side of the hearing organ: infrequently - tinnitus; very rarely - hearing loss.

On the part of the respiratory system: often - pharyngolaryngeal pain, epistaxis.

From the digestive system: often - constipation, flatulence, dyspepsia, nausea, diarrhea; infrequently: vomiting, pain in the upper and lower abdomen, belching, pancreatitis.

On the part of the liver and biliary tract: infrequently - hepatitis; rarely - cholestasis; very rarely - liver failure.

On the part of the skin and subcutaneous tissues: infrequently - urticaria, rash, itching, alopecia; rarely, angioedema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

On the part of the musculoskeletal system and connective tissue: often - myalgia, arthralgia, pain in the limbs, muscle cramps, swelling of the joints, back pain; infrequently - neck pain, muscle fatigue; rarely - myopathy, myositis, rhabdomyolysis, tendinopathy (sometimes complicated by a tendon rupture).

From the reproductive system and mammary glands: very rarely - gynecomastia.

General disorders: infrequently - malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia.

Laboratory indicators: often - deviations of liver function tests, increased creatinine clearance in the blood; infrequently - the presence of white blood cells in the urine.

Ramipril. When ramipril is used, a persistent dry cough and adverse reactions associated with arterial hypotension may occur. Serious adverse reactions include angioedema, hyperkalemia, renal or hepatic failure, pancreatitis, skin reactions, and neutropenia / agranulocytosis.

From the cardiovascular system: infrequently - myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, tachycardia, peripheral edema.

On the part of the blood and lymphatic system: infrequently - eosinophilia; rarely - a decrease in the number of leukocytes (including neutropenia or agranulocytosis), a decrease in the number of red blood cells, hemoglobin, platelets (thrombocytopenia); unknown - bone marrow damage, pancytopenia, hemolytic anemia.

From the nervous system: often - headache, dizziness; infrequently - vertigo, paresthesia, ageusia, dysgeusia; rarely - tremor, imbalance; unknown - cerebral ischemia, including ischemic stroke and transient ischemic attacks, deterioration of psychomotor skills, burning sensation, parosmia.

From the side of the organ of vision: infrequently - impaired vision, including blurred vision; rarely conjunctivitis.

On the part of the hearing organ: rarely - hearing loss, tinnitus.

From the respiratory system: often - unproductive annoying cough, bronchitis, sinusitis, shortness of breath; infrequently - bronchospasm, including exacerbation of asthma, nasal congestion.

From the digestive system: often - inflammation of the digestive tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequently - pancreatitis (in exceptional cases, with the use of ACE inhibitors, fatal consequences were reported), increased levels of pancreatic enzymes, angioedema of the small intestine, pain in the upper abdomen, including gastritis, constipation, dry mouth; rarely - glossitis; unknown - stomatitis.

On the part of the kidneys and urinary system: infrequently - disorders of the kidneys, including acute renal failure, increased urine production, increased existing proteinuria, increased levels of urea in the blood, increased levels of creatinine in the blood.

From the skin and subcutaneous tissues: often - a rash, including maculopapular; infrequently - angioedema, in exceptional cases, fatal consequences were observed due to airway obstruction; itching, hyperhidrosis; rarely - exfoliative dermatitis, urticaria, onycholysis; very rarely - photosensitivity; unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis with complications, psoriasiform dermatitis, pemphigoid or lichenoid rash or enanthema, alopecia.

From the musculoskeletal system and connective tissue: often - muscle spasms, myalgia; infrequently - arthralgia.

Metabolism and eating disorders: often - increased levels of potassium in the blood; infrequently - anorexia, loss of appetite; unknown - decreased sodium levels in the blood.

From the vascular system: often - arterial hypotension, orthostatic decrease in blood pressure, loss of consciousness; infrequently - tides; rarely - vascular stenosis, hypoperfusion, vasculitis; unknown - Raynauds syndrome.

General disorders: often - chest pain, fatigue; infrequently - pyrexia; rarely - asthenia.

From the side of the immune system: unknown - anaphylactic or anaphylactoid reactions, increased level of antinuclear antibodies.

On the part of the liver and biliary tract: infrequently - an increase in the number of liver enzymes and / or conjugated bilirubin; rarely - cholestatic jaundice, hepatocellular disorders; unknown - acute liver failure, cholestatic or cytolytic hepatitis (in exceptional cases, fatal consequences were observed).

From the reproductive system and mammary glands: infrequently - temporary erectile dysfunction, decreased libido; unknown - gynecomastia.

From the psyche: infrequently - depressed mood, anxiety, nervousness, anxiety, sleep disturbances, including insomnia; rarely - confusion; unknown - impaired attention.

special instructions

Caution for special patient groups. Particularly careful medical monitoring is recommended in the following cases:

• hypersensitivity to other analgesics / anti-inflammatory / antipyretic / antirheumatic agents or other allergens (see CONTRAINDICATIONS);
• allergic reactions (eg, skin reactions, itching, urticaria), asthma, pollinosis, swelling of the nasal mucosa (adenoid vegetation) or other chronic diseases of the respiratory system (see CONTRAINDICATIONS);
• a peptic ulcer or a history of gastrointestinal bleeding (see CONTRAINDICATIONS);
• decreased liver and / or kidney function (see APPLICATION);
• risk of arterial hypotension: in patients with increased activity of the renin-angiotensin-aldosterone system, transient or persistent heart failure after myocardial infarction, in patients at risk of cardiac or cerebral ischemia, in the case of acute arterial hypotension, blood pressure monitoring should be performed to reduce the risk of acute a marked decrease in blood pressure and impaired renal function due to the use of ACE inhibitors (see CONTRAINDICATIONS);
• circulatory disorders (vasorenal hypertension, congestive heart failure, dehydration, major surgery, sepsis, or serious hemorrhagic complications);
• glucose-6-phosphate dehydrogenase deficiency;
• the risk of increased uric acid levels;
• large amounts of alcohol and / or a history of liver disease;
• period of pregnancy: you should immediately stop treatment with the drug and, if necessary, start alternative therapy (see CONTRAINDICATIONS and Use during pregnancy and lactation).

ACE inhibitors are more likely to cause angioneurotic edema in patients of the Negroid race than in patients of other races.

Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in patients of the Negroid race due to the high prevalence of hypertension with low levels of renin in representatives of this race.

It is necessary to monitor the patients condition during treatment in case of:

• combined use with NSAIDs, corticosteroids, selective serotonin reuptake inhibitors, antiplatelet agents, anticoagulants;
• combined use with ibuprofen;
• the development of signs or symptoms of liver damage.

Surgical intervention: treatment with Trinomy should be temporarily suspended a few days before a major surgical intervention or in the event of a serious medical or surgical condition. With minor interventions, such as tooth extraction, taking the drug can affect the length of the bleeding time.

Especially careful monitoring of the condition of patients with renal failure is necessary (see APPLICATION). There is a risk of impaired renal function, especially in patients with congestive heart failure or after kidney transplantation.

In patients at risk of developing hyperkalemia, i.e., renal failure at the age of 70, patients with uncontrolled diabetes mellitus, patients with conditions such as dehydration, acute heart failure, metabolic acidosis, in patients who use potassium salts, potassium-sparing diuretics, or others substances that increase the level of potassium in the blood plasma, it is recommended to regularly monitor the level of potassium in the blood plasma (see INTERACTIONS).

Special Side Effects Warning

From the liver. Functional liver tests should be performed periodically.

From the skeletal muscle. Atorvastatin, as well as other inhibitors of HMG-CoA reductase, in rare cases can affect skeletal muscles and cause myalgia, myositis and myopathy, which can progress to rhabdomyolysis, a potentially life-threatening condition characterized by a significantly increased creatinine clearance (CC) ( 10 times higher than the upper limit of normal), myogemoglobinemia and myoglobinuria, which can lead to the development of renal failure. If at the beginning of treatment the level of QC is significantly increased (5 times higher than the upper limit of the norm), treatment should not be started. The use of Trinomy should be discontinued in the case of a clinically significant increase in the level of CC (10 times higher than the upper limit of the norm) or in the case of diagnosis or suspicion of rhabdomyolysis. QC should not be measured after physical exertion or in the presence of any possible alternative reason for the increase in QC level, as this complicates the interpretation of indicators. If at the beginning of treatment the level of QC is significantly increased (5 times higher than the upper limit of normal),