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Ekvamer® International Nonproprietary Name Lisinopril / Amlodipine / Rosuvastatin Dosage Form: Capsules Composition Each capsule contains: Capsule 10 mg/5 mg/10 mg Active substances: Lisinopril – 10.00 mg (as 10.88 mg lisinopril dihydrate) Amlodipine – 5.00 mg (as 6.94 mg amlodipine besylate) Rosuvastatin - 10.00 mg (as 10.40 mg rosuvastatin calcium) Excipients: Microcrystalline cellulose, type 12; Microcrystalline cellulose, type 101; Lactose monohydrate, Sodium starch glycolate (type A); Magnesium hydroxide; Magnesium stearate; Opadry II 85F32410 Yellow (contains: Polyvinyl alcohol, Titanium dioxide (E 171), Macrogol 3350, Talc, Iron oxide yellow (E 172)). Hard gelatin capsule contains: Patent Blue V (E 131), Azorubine, Carmoisine (E 122), Sunset Yellow (E 110), Titanium dioxide (E 171), Gelatin. Capsule 10 mg/5 mg/20 mg Active substances: Lisinopril – 10.00 mg (as 10.88 mg lisinopril dihydrate) Amlodipine – 5.00 mg (as 6.94 mg amlodipine besylate) Rosuvastatin - 20.00 mg (as 20.80 mg rosuvastatin calcium) Excipients: Microcrystalline cellulose, type 12; Microcrystalline cellulose, type 101; Lactose monohydrate, Sodium starch glycolate (type A); Magnesium hydroxide; Magnesium stearate; Opadry II 85F32410 Yellow (contains: Polyvinyl alcohol, Titanium dioxide (E 171), Macrogol 3350, Talc, Iron oxide yellow (E 172)). Hard gelatin capsule contains: Azorubine, Carmoisine (E 122), Titanium dioxide (E 171), Gelatin. Capsule 20 mg/10 mg/10 mg Active substances: Lisinopril – 20.00 mg (as 21.76 mg lisinopril dihydrate) Amlodipine – 10.00 mg (as 13.88 mg amlodipine besylate) Rosuvastatin - 10.00 mg (as 10.40 mg rosuvastatin calcium) Excipients: Microcrystalline cellulose, type 12; Microcrystalline cellulose, type 101; Lactose monohydrate, Sodium starch glycolate (type A); Magnesium hydroxide; Magnesium stearate; Opadry II 85F32410 Yellow (contains: Polyvinyl alcohol, Titanium dioxide (E 171), Macrogol 3350, Talc, Iron oxide yellow (E 172)). Hard gelatin capsule contains: Azorubine, Carmoisine (E 122), Indigotine (E 132), Titanium dioxide (E 171), Gelatin. Capsule 20 mg/10 mg/20 mg Active substances: Lisinopril – 20.00 mg (as 21.76 mg lisinopril dihydrate) Amlodipine – 10.00 mg (as 13.88 mg amlodipine besylate) Rosuvastatin - 20.00 mg (as 20.80 mg rosuvastatin calcium) Excipients: Microcrystalline cellulose, type 12; Microcrystalline cellulose, type 101; Lactose monohydrate, Sodium starch glycolate (type A); Magnesium hydroxide; Magnesium stearate; Opadry II 85F32410 Yellow (contains: Polyvinyl alcohol, Titanium dioxide (E 171), Macrogol 3350, Talc, Iron oxide yellow (E 172)). Hard gelatin capsule contains: Patent Blue V (E 131), Azorubine, Carmoisine (E 122), Sunset Yellow (E 110), Titanium dioxide (E 171), Gelatin. Description Capsule 10 mg/5 mg/10 mg: Light pink hard gelatin capsules, size #1. Capsule contents – 1 round, biconvex white tablet (containing lisinopril and amlodipine) and 1 round, biconvex film-coated yellow tablet (containing rosuvastatin). Capsule 10 mg/5 mg/20 mg: Pink hard gelatin capsules, size #1. Capsule contents – 1 round, biconvex white tablet (containing lisinopril and amlodipine) and 2 round, biconvex film-coated yellow tablets (containing rosuvastatin). Capsule 20 mg/10 mg/10 mg: Lilac hard gelatin capsules, size #1. Capsule contents – 2 round, biconvex white tablets (containing lisinopril and amlodipine) and 1 round, biconvex film-coated yellow tablet (containing rosuvastatin). Capsule 20 mg/10 mg/20 mg: Dark lilac hard gelatin capsules, size #0. Capsule contents – 2 round, biconvex white tablets (containing lisinopril and amlodipine) and 2 round, biconvex film-coated yellow tablets (containing rosuvastatin). Also, see other dosage of Ekvamer: Ekvamer - Ekvamer 10/5/10mg 30 capsules Pharmacotherapeutic group: HMG-CoA reductase inhibitors, other combinations. Rosuvastatin, amlodipine and lisinopril. Pharmacological properties Pharmacodynamics Ekvamer® is a combined antihypertensive and hypolipidemic drug. Ekvamer® contains three active substances – amlodipine, lisinopril, and rosuvastatin. The mechanism of action of Ekvamer® is based on the pharmacological properties of its active substances. Amlodipine A dihydropyridine derivative – a "slow" calcium channel blocker, exhibits antihypertensive and antianginal effects. It blocks "slow" calcium channels, reducing the transmembrane passage of calcium ions into cells. The antianginal effect is due to the dilation of coronary and peripheral arteries and arterioles: - In angina pectoris, it reduces the severity of myocardial ischemia; by dilating peripheral arterioles, it reduces total peripheral vascular resistance, reduces cardiac afterload, and decreases myocardial oxygen demand; - By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina). In patients with stable angina pectoris, a single daily dose increases tolerance to physical exertion, slows the development of angina attacks and ST segment ischemic depression, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in both supine and standing positions). Due to its slow onset of action, amlodipine does not cause a sharp drop in blood pressure. In patients with cardiovascular diseases, amlodipine use reduces mortality from myocardial infarction and stroke, and hospitalizations due to progression of unstable angina and chronic heart failure; it reduces the incidence of interventions aimed at restoring coronary blood flow. It does not increase the risk of mortality or complications and fatal outcomes in patients with chronic heart failure (NYHA functional class III-IV) receiving digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In patients with chronic heart failure of non-ischemic etiology (NYHA functional class III-IV) receiving amlodipine, there is a risk of developing pulmonary edema. Amlodipine does not adversely affect metabolism and serum lipid profile, therefore, it can be used in patients with bronchial asthma, diabetes mellitus, and gout. Lisinopril Lisinopril is a peptide dipeptidyl peptidase enzyme inhibitor. It inhibits ACE, which catalyzes the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE leads to a decrease in angiotensin II concentration, resulting in reduced vasopressor activity and aldosterone secretion. The latter reduction may lead to an increase in serum potassium levels. It is believed that the mechanism of blood pressure lowering by lisinopril is primarily based on the suppression of the renin-angiotensin-aldosterone system, and therefore, lisinopril lowers blood pressure even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether the increased concentration of the potent vasodilator peptide bradykinin contributes to the therapeutic effects of lisinopril is not yet established. ACE inhibitors prolong survival in patients with chronic heart failure and in patients who have had a myocardial infarction without clinical manifestations of heart failure. The antihypertensive effect and ACE-inhibiting action of lisinopril also reduced microalbuminuria as a direct effect on kidney tissues. Lisinopril treatment does not affect glycemic control, as evidenced by the absence of a significant effect on glycosylated hemoglobin (HbA1c) levels. Rosuvastatin Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary target of rosuvastatin is the liver, where cholesterol (CH) synthesis and low-density lipoprotein (LDL) catabolism occur. Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, thereby increasing LDL catabolism and binding, which in turn inhibits the synthesis of very low-density lipoproteins (VLDL) and reduces the total amount of LDL and VLDL. Rosuvastatin reduces elevated concentrations of LDL cholesterol (LDL-CH), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-CH) concentration, as well as reduces the concentrations of apolipoprotein B (Apo B), non-HDL-CH, TG-VLDL, and increases apolipoprotein A-I (Apo A-I) concentration (see Table 1), and reduces the ratios of CH-LDL/CH-HDL, total CH/CH-HDL, non-HDL-CH/CH-HDL, and ApoB/ApoA-I. The therapeutic effect is observed within the first week of starting rosuvastatin therapy and reaches 90% of the maximum possible after 2 weeks of treatment. The maximum therapeutic effect is usually achieved by the 4th week and is maintained with regular intake. Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (Fredrickson classification type IIa and IIb) (mean adjusted percentage change from baseline) Dose | Number of patients | CH-LDL | Total CH | CH-HDL | TG | Non-HDL-CH | Apo B | Apo A-I Placebo | 13 | -7 | -5 | 3 | -3 | -7 | -3 | 0 5 mg | 17 | -45 | -33 | 13 | -35 | -44 | -38 | 4 10 mg | 17 | -52 | -36 | 14 | -10 | -48 | -42 | 4 20 mg | 17 | -55 | -40 | 8 | -23 | -51 | -46 | 5 40 mg | 18 | -63 | -46 | 10 | -28 | -60 | -54 | 0 Clinical efficacy Rosuvastatin is effective in adult patients with hypercholesterolemia, with or without hypertriglyceridemia, regardless of race, sex, or age, including patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with Fredrickson classification type IIa and IIb hypercholesterolemia (mean baseline LDL-CH concentration approximately 4.8 mmol/L), LDL-CH concentration reaches less than 3 mmol/L with rosuvastatin 10 mg. In patients with homozygous familial hypercholesterolemia receiving rosuvastatin 20 mg and 40 mg, the mean reduction in LDL-CH concentration is 22%. An additive effect is observed with the combination of rosuvastatin and fenofibrate in reducing triglyceride concentration and with nicotinic acid in increasing HDL-CH concentration (see "Precautions"). Pharmacokinetics Amlodipine Absorption: After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Maximum serum concentration (Cmax) is reached 6-12 hours after administration. Mean absolute bioavailability is 64-80%. Concomitant food intake does not affect amlodipine absorption. Distribution and protein binding: The volume of distribution is 21 L/kg body weight, indicating that a large proportion of amlodipine is in the tissues and a small proportion is in the blood. A large proportion of amlodipine in the blood (97.5%) is bound to serum proteins. Metabolism: Amlodipine is extensively metabolized in the liver. Metabolites have no significant pharmacological activity. Elimination: The terminal elimination half-life (t1/2) is approximately 35-50 hours, allowing for once-daily dosing. Amlodipine is excreted in urine as unchanged drug (10%) and metabolites (60%). Amlodipine is not removed by hemodialysis. Pharmacokinetics in specific patient groups: Patients with liver failure: Prolongation of t1/2 in patients with liver failure indicates that amlodipine accumulation in the body will be higher with prolonged use (increases up to 60 hours). Patients with renal failure: Renal failure does not significantly affect amlodipine pharmacokinetics. Elderly patients (over 65 years): The time to reach maximum serum concentration of amlodipine is the same in young and elderly patients. However, amlodipine clearance is reduced in elderly patients, leading to an increase in the area under the concentration-time curve (AUC) and a prolonged elimination half-life compared to young individuals. An increase in AUC and elimination half-life was also observed in patients with congestive heart failure. Lisinopril Absorption: Data on urinary excretion indicate that the mean absorption of lisinopril is approximately 25%, with variations from 6% to 60% in different patients within the administered dose range (5 to 80 mg). In patients with heart failure, the absolute bioavailability of lisinopril is reduced to approximately 16%. Lisinopril absorption is not affected by food intake. Distribution and protein binding: After oral administration, maximum serum concentration of lisinopril is observed approximately 7 hours later, with a slight increase in the time to reach maximum concentration in patients with acute myocardial infarction. Lisinopril is not bound to serum proteins, except for circulating ACE. Animal studies have shown that lisinopril does not significantly cross the blood-brain barrier. Metabolism: Lisinopril is not biotransformed in the body. Elimination: With multiple doses of lisinopril, the effective elimination half-life is 12.6 hours. Lisinopril clearance in healthy volunteers is approximately 50 ml/min. The decrease in serum concentration has a prolonged terminal phase, which does not lead to drug accumulation in the body. This terminal phase may represent saturated binding to ACE and is not dose-proportional. Pharmacokinetics in specific patient groups: Hepatic impairment: Hepatic impairment in patients with liver cirrhosis led to reduced absorption of lisinopril (approximately 30% based on urinary excretion data), however, compared to healthy volunteers, the drug concentration increased (approximately 50%) due to reduced clearance. Renal impairment: Lisinopril excretion is reduced in renal impairment, but this reduction becomes clinically significant only when the glomerular filtration rate is less than 30 ml/min/1.73m². In mild to moderate renal impairment (creatinine clearance (CC) 30 to 80 ml/min), the mean AUC increases by only 13%, whereas in severe renal impairment (CC 5 to 30 ml/min), the mean AUC increases 4.5-fold. Lisinopril can be removed from the body by hemodialysis. After 4 hours of hemodialysis, serum lisinopril concentration decreased by an average of 60%, and dialyzer clearance was 40 to 55 ml/min. Heart failure: Compared to healthy volunteers, serum lisinopril concentration is higher in patients with heart failure (mean AUC increase of 125%), but based on urinary excretion data, lisinopril absorption is reduced by approximately 16% in these patients compared to healthy volunteers. Elderly patients: Compared to younger individuals in the study, elderly patients showed higher serum lisinopril concentrations and AUC values (increase up to 60%). Rosuvastatin Absorption: Cmax of rosuvastatin in serum is reached approximately 5 hours after oral administration. Distribution and protein binding: The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to serum proteins, primarily albumin. Metabolism: Rosuvastatin is primarily metabolized in the liver, which is the main site of cholesterol synthesis and LDL-CH metabolism. It is metabolized to a limited extent (approximately 10%). Rosuvastatin is not a substrate for CYP450 isoenzymes. The main isoenzyme involved in rosuvastatin metabolism is CYP2C9. CYP2C19, CYP3A4, and CYP2D6 isoenzymes are involved to a lesser extent. The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. Compared to rosuvastatin, N-desmethyl is about 50% less active, and lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting HMG-CoA reductase is provided by rosuvastatin. Elimination: Approximately 90% of the dose is excreted unchanged in the feces (including absorbed and unabsorbed rosuvastatin). The remaining portion is excreted by the kidneys. Approximately 5% is excreted unchanged by the kidneys. The elimination half-life from serum is approximately 19 hours. The elimination half-life does not change with increasing doses of the drug. The mean geometric serum clearance is approximately 50 L/h (coefficient of variation 21.7%). Like other HMG-CoA reductase inhibitors, rosuvastatin hepatic uptake involves a membrane transporter that participates in rosuvastatin hepatic elimination. Linearity: Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with daily dosing. Pharmacokinetics in specific patient groups: Sex and age: Sex and age do not have a clinically significant effect on rosuvastatin pharmacokinetics. Race: Compared to Caucasian patients, pharmacokinetic studies have shown approximately a twofold increase in median rosuvastatin AUC and Cmax in Mongoloid race patients (Japanese, Chinese, Filipinos, Vietnamese, and Koreans); studies in Indian nationals have shown a 1.3-fold increase in median AUC and Cmax. Pharmacokinetic analysis has not revealed clinically significant differences in pharmacokinetics between Caucasians and Black individuals. Patients with renal impairment: In patients with mild to moderate renal impairment, serum concentrations of rosuvastatin or N-desmethyl do not change significantly. Compared to healthy volunteers, rosuvastatin concentration in serum is 3 times higher, and N-desmethyl concentration is 9 times higher in patients with severe renal impairment (CC less than 30 ml/min). Compared to healthy volunteers, rosuvastatin concentration in serum was approximately 50% higher in patients on hemodialysis. Patients with liver impairment: In patients with various stages of liver impairment, no increase in rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. In two patients with Child-Pugh scores of 8 and 9, a slight twofold increase in t1/2 was observed. There is no experience with rosuvastatin in patients with Child-Pugh scores greater than 9. Genetic polymorphism: Certain types of genetic polymorphism can lead to increased rosuvastatin exposure (see "Pharmacokinetics"). In carriers of SLCO1B1 c.521CC and ABCG2 c.421AA genotypes, an increase in rosuvastatin exposure (AUC) of 1.6-fold and 2.4-fold, respectively, was observed compared to carriers of SLC01B1 c.521TT and ABCG2 c.421CC genotypes. Specific genotyping is not performed in clinical practice, however, it should be noted that a lower daily dose of rosuvastatin is recommended for patients with SLC01B1 c.521 TT and ABCG2 c.421 AA genotypes. Indications for use Ekvamer® is indicated as an alternative to the concomitant use of amlodipine, lisinopril, and rosuvastatin at the specified doses in adult patients whose condition is adequately controlled with the same doses of amlodipine, lisinopril, and rosuvastatin as contained in Ekvamer®, for the treatment of arterial hypertension and concomitant dyslipidemia: - Primary hypercholesterolemia (Fredrickson classification type IIa, excluding familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (Fredrickson classification type IIb), when diet and other non-drug methods (e.g., exercise, weight loss) are insufficient. - Familial homozygous hypercholesterolemia as an adjunct to diet therapy and other lipid-lowering measures, or when diet or other lipid-lowering therapies (e.g., LDL apheresis) are insufficiently effective; - Primary prevention of major cardiovascular events in patients at high risk, as an adjunct to correction of other risk factors. Contraindications - Hypersensitivity to amlodipine and other dihydropyridine derivatives. - Hypersensitivity to lisinopril or other ACE inhibitors. - Hypersensitivity to rosuvastatin. - Hypersensitivity to any other excipient of the drug. - History of angioedema, including that associated with ACE inhibitor use. - Hereditary or idiopathic angioedema. - Severe arterial hypotension (systolic blood pressure less than 90 mmHg). - Shock (including cardiogenic shock). - Obstruction of the left ventricular outflow tract (including severe aortic stenosis). - Hemodynamically unstable heart failure after acute myocardial infarction. - Concomitant use of Ekvamer® and aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (eGFR less than 60 ml/min/1.73m²). - Liver diseases in the active phase, including persistent elevation of serum transaminase activity, as well as any elevation of transaminase activity (more than 3 times the upper limit of normal). - Severe renal impairment (CC less than 30 ml/min). - Myopathy. - Concomitant use of cyclosporine. - Predisposition to the development of myotoxic complications. - In women: pregnancy, lactation, inadequate contraception. - Children under 18 years of age (efficacy and safety not established). - Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption. Patients with liver impairment: There is no experience with rosuvastatin in patients with Child-Pugh scores greater than 9 (see "Pharmacokinetics"). Use during pregnancy and lactation Pregnancy: Ekvamer® is contraindicated during pregnancy. Adequate, well-controlled clinical studies of Ekvamer® in pregnant women have not been conducted. ACE inhibitors used in the second and third trimesters of pregnancy can cause fetal and neonatal death. Fetal oligohydramnios, hypoplasia of cranial bones, deformities of cranial and facial bones, pulmonary hypoplasia, and renal developmental abnormalities in newborns may occur. Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibitors outweighs the benefit of rosuvastatin use during pregnancy. Women of reproductive potential should use adequate contraceptive measures. If pregnancy occurs during therapy, use of the drug should be immediately discontinued, and alternative treatment should be initiated if necessary. Ekvamer® therapy should not be initiated during pregnancy. Alternative therapy with an established safety profile during pregnancy should be considered when planning pregnancy. Lactation: Ekvamer® is contraindicated during lactation. It is unknown whether the active substances are excreted in breast milk. They are known to be excreted in the milk of lactating rats. If the drug is needed during lactation, breastfeeding should be discontinued. Fertility: Adequate, well-controlled clinical studies of the effect of Ekvamer® on fertility have not been conducted. Dosage and administration Method of administration: Ekvamer® can be taken independently of food intake. Dosage: As a rule, fixed-dose combination drugs are not used at the beginning of therapy. Ekvamer® is used as an alternative to the concomitant use of amlodipine, lisinopril, and rosuvastatin at the specified doses in adult patients who are already taking amlodipine, lisinopril, and rosuvastatin at the same doses contained in this drug, when the titrated optimal maintenance doses are: Titrated optimal maintenance doses | Ekvamer® dosage form Amlodipine-5 mg, Lisinopril-10 mg, and Rosuvastatin-10 mg | Capsule 10 mg/5 mg/10 mg Amlodipine-5 mg, Lisinopril-10 mg, and Rosuvastatin-20 mg | Capsule 10 mg/5 mg/20 mg Amlodipine-10 mg, Lisinopril-20 mg, and Rosuvastatin-10 mg | Capsule 20 mg/10 mg/10 mg Amlodipine-10 mg, Lisinopril-20 mg, and Rosuvastatin-20 mg | Capsule 20 mg/10 mg/20 mg The recommended dose of Ekvamer® is 1 capsule per day. The maximum daily dose is 1 capsule. If dose adjustment is necessary, titration should be done using individual components of amlodipine, lisinopril, and rosuvastatin. Special patient groups: Patients with renal impairment: During Ekvamer® therapy, renal function, serum potassium, and sodium levels should be monitored. If renal function deteriorates, Ekvamer® should be discontinued. Individual dose selection of separate active components is recommended for such patients. Ekvamer® is contraindicated at all doses in patients with severe renal impairment (see "Contraindications"). Patients with liver impairment: Ekvamer® is contraindicated in patients with liver diseases in the active phase and in patients with severe liver dysfunction (Child-Pugh score of 9) (see "Contraindications"). Recommended doses for patients with mild or moderate liver impairment have not been established. Dose selection should be done with caution, and treatment should be initiated at the lowest recommended dose. Children and adolescents (under 18 years): The efficacy and safety of Ekvamer® in children and adolescents have not been established. Elderly patients (over 65 years): Ekvamer® should be used with caution in elderly patients. Clinical studies have not provided sufficient data on age-related changes in the safety or efficacy profile of amlodipine and lisinopril. The recommended starting dose of rosuvastatin for patients over 70 years of age is 5 mg. Race: In pharmacokinetic studies of rosuvastatin in patients of different races, an increase in systemic rosuvastatin concentration in serum was observed in Mongoloid race patients (see "Precautions"). This fact should be considered when prescribing Ekvamer® to patients in this group. For rosuvastatin 10 mg and 20 mg, the recommended starting dose of rosuvastatin in Mongoloid race patients should be 5 mg. Genetic polymorphism: Certain types of genetic polymorphism are known to cause increased rosuvastatin exposure (see "Pharmacokinetics"). A lower daily dose of rosuvastatin is recommended for carriers of SLC01B1 c.521CC and ABCG2 c.421 AA genotypes. Concomitant therapy: Rosuvastatin is transported by various transporter proteins (mainly OATP1B1 and BCRP). Concomitant use of rosuvastatin with drugs (such as cyclosporine, certain human immunodeficiency virus (HIV) protease inhibitors, including ritonavir and atazanavir, lopinavir and/or tipranavir) that increase rosuvastatin concentration in serum due to interaction with transporter proteins may increase the risk of myopathy (including rhabdomyolysis) (see "Precautions" and "Interactions with other medicinal products"). In such cases, the possibility of alternative therapy or temporary discontinuation of rosuvastatin use should be assessed. If the use of the above-mentioned drugs is necessary, the benefit-risk ratio of concomitant rosuvastatin therapy should be evaluated, and dose adjustment should be considered (see "Interactions with other medicinal products"). Side effects Adverse reactions are listed by organ system class, according to MedDRA classification and frequency: Very common – 1/10 (≥10%) Common – 1/100 (≥1%, but <10%) Uncommon – 1/1000 (≥0.1%, but <1%) Rare – 1/10000 (≥0.01%, but <0.1%) Very rare – less than 1/10000 (<0.01%) Unknown frequency – frequency cannot be determined from available data. Within each frequency group, adverse reactions are listed in order of decreasing seriousness. The following adverse reactions have been described during monotherapy with amlodipine, lisinopril, and rosuvastatin: Amlodipine Blood and lymphatic system disorders Very rare: Leukopenia, thrombocytopenia. Immune system disorders Very rare: Allergic reactions. Metabolism and nutrition disorders Very rare: Hyperglycemia. Psychiatric disorders Uncommon: Labile mood, depression, anxiety, insomnia; Rare: Confusion. Nervous system disorders Common: Headache, dizziness, somnolence (especially at the beginning of treatment); Uncommon: Hypoesthesia, paresthesia, tremor, dysgeusia (altered taste sensation), syncope; Very rare: Hypertonia, peripheral neuropathy; Unknown frequency: Extrapyramidal syndrome. Eye disorders Common: Visual disturbances (including diplopia). Ear and labyrinth disorders Uncommon: Tinnitus. Cardiac disorders Common: Palpitations; Uncommon: Arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation). Very rare: Myocardial infarction. Vascular disorders Common: Flushing; Uncommon: Marked hypotension; Very rare: Vasculitis. Respiratory, thoracic and mediastinal disorders Common: Dyspnea; Uncommon: Cough, rhinitis. Gastrointestinal disorders Common: Nausea, abdominal pain, dyspepsia, disorders of defecation rhythm (including diarrhea and constipation); Uncommon: Vomiting, dry mouth; Very rare: Pancreatitis, gastritis, gingival hyperplasia. Hepatobiliary disorders Very rare: Jaundice, increased serum transaminase activity, hepatitis. Skin and subcutaneous tissue disorders Uncommon: Alopecia, purpura, change in skin color, hyperhidrosis, pruritus, rash, exanthema, urticaria; Very rare: Erythema multiforme, angioedema, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitization. Musculoskeletal and connective tissue disorders Common: Ankle edema, muscle cramps; Uncommon: Arthralgia, myalgia, back pain. Renal and urinary disorders Uncommon: Increased urinary frequency, painful urination, nocturia. Reproductive system and breast disorders Uncommon: Erectile dysfunction, gynecomastia. General disorders and administration site conditions Very common: Edema. Common: Increased fatigue, asthenia. Uncommon: Weight loss/gain, chest pain, pain, malaise. Lisinopril Blood and lymphatic system disorders Rare: Decreased hemoglobin and hematocrit; Very rare: Bone marrow suppression, lymphadenopathy, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, hemolytic anemia, anemia. Immune system disorders Very rare: Autoimmune disorders. Endocrine disorders Rare: Syndrome of inappropriate secretion of antidiuretic hormone. Metabolism and nutrition disorders Very rare: Hypoglycemia. Psychiatric disorders Uncommon: Labile mood, sleep disturbance, hallucinations; Rare: Confusion; Unknown frequency: Depression. Nervous system disorders Common: Dizziness, headache; Uncommon: Paresthesia, vertigo, dysgeusia; Rare: Parosmia (altered sense of taste); Unknown frequency: Syncope. Cardiac disorders Uncommon: Myocardial infarction (due to marked hypotension in patients at increased risk), palpitations, tachycardia. Vascular disorders Common: Orthostatic effects (including hypotension); Uncommon: Cerebrovascular accident (in patients at increased risk due to marked hypotension), Raynaud's syndrome. Respiratory, thoracic and mediastinal disorders Common: Dry cough; Uncommon: Rhinitis; Very rare: Bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia. Gastrointestinal disorders Common: Diarrhea, vomiting; Uncommon: Nausea, dyspepsia, abdominal pain; Rare: Dry mouth; Very rare: Pancreatitis, intestinal angioedema. Hepatobiliary disorders Very rare: Hepatocellular and cholestatic jaundice, hepatitis, liver failure. Skin and subcutaneous tissue disorders Uncommon: Rash, pruritus; Rare: Urticaria, alopecia, psoriasis, hypersensitivity/angioedema of the face, extremities, lips, tongue, glottis and/or larynx; Very rare: Increased sweating, bullous eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, cutaneous pseudolymphoma (a symptom complex that may include or be characterized by a combination of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody test, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis, skin rash, photosensitization or skin changes). Renal and urinary disorders Common: Renal impairment; Rare: Acute renal failure, uremia; Very rare: Oliguria, anuria. Reproductive system and breast disorders Uncommon: Decreased potency; Rare: Gynecomastia. Effects on laboratory and instrumental investigation results Uncommon: Hyperkalemia, increased serum urea and creatinine, increased serum liver enzyme activity; Rare: Hyponatremia, hyperbilirubinemia. Rosuvastatin Side effects observed during rosuvastatin intake are usually mild and resolve spontaneously. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mainly dose-dependent. Blood and lymphatic system disorders Rare: Thrombocytopenia. Immune system disorders Rare: Hypersensitivity reactions, including angioedema. Endocrine disorders Common: Type 2 diabetes mellitus (incidence will depend on the presence or absence of risk factors (fasting glucose concentration ≥ 5.6 mmol/L, body mass index > 30 kg/m², increased triglyceride concentration, history of arterial hypertension)). Psychiatric disorders Unknown frequency: Depression. Nervous system disorders Common: Headache, dizziness; Very rare: Polyneuropathy, memory loss or impairment; Unknown frequency: Peripheral neuropathy, sleep disturbances (including insomnia and nightmares). Respiratory, thoracic and mediastinal disorders Unknown frequency: Cough, dyspnea. Gastrointestinal disorders Common: Nausea, constipation, abdominal pain; Rare: Pancreatitis; Unknown frequency: Diarrhea. Hepatobiliary disorders Rare: Increased serum transaminase activity; Very rare: Jaundice, hepatitis. Skin and subcutaneous tissue disorders Uncommon: Pruritus, rash, urticaria; Unknown frequency: Stevens-Johnson syndrome. Musculoskeletal and connective tissue disorders Common: Myalgia; Rare: Myopathy (including myositis), rhabdomyolysis; Very rare: Arthralgia. Unknown frequency: Immune-mediated necrotizing myopathy, tendon disorders, in some cases complicated by tendon rupture. Renal and urinary disorders Very rare: Hematuria. Reproductive system and breast disorders Very rare: Gynecomastia. General disorders and administration site conditions Common: Asthenia; Unknown frequency: Peripheral edema. Effects on kidneys: In patients receiving rosuvastatin, proteinuria, mainly of tubular origin, was observed, detected by dipstick tests. Changes in urine protein content (from trace or negative to ++ and above) were found in less than 1% of patients receiving rosuvastatin 10 and 20 mg, and in approximately 3% of patients receiving 40 mg. In patients receiving 20 mg, a minimal quantitative change in urine protein was observed – from trace or negative to + level. In most cases, proteinuria decreased or disappeared spontaneously with continued treatment. Analysis of clinical trial data and post-marketing data did not reveal a causal relationship between proteinuria and acute or progressive kidney disease. Hematuria was also observed in patients receiving rosuvastatin, with a low incidence based on clinical data. Effects on skeletal muscles: In patients receiving any dose of rosuvastatin, especially doses >20 mg, effects on skeletal muscles were observed, such as myalgia, myopathy (including myositis), and in rare cases, rhabdomyolysis, with or without renal failure. In patients receiving rosuvastatin, dose-dependent increases in creatine kinase (CK) activity were observed; in most cases, these were mild, asymptomatic, and transient. If CK activity increases (above the upper limit of the normal range), treatment should be discontinued. Effects on liver: As with other HMG-CoA reductase inhibitors, increased liver transaminase activity was observed in some patients receiving rosuvastatin, dose-dependently; in most cases, this was mild, asymptomatic, and transient. The following side effects have been described with some HMG-CoA reductase inhibitors: - Sexual dysfunction; - In rare exceptional cases – interstitial lung disease, especially with long-term therapy (see "Precautions"). If any side effect indicated in the instructions is complicated, or if a side effect not described in these instructions develops, consult your doctor. Overdose There is no data on overdose with Ekvamer®. Amlodipine Symptoms: Marked hypotension with possible reflex tachycardia and excessive peripheral vasodilation (risk of developing marked and sustained hypotension, including shock and fatal outcome). Treatment: Gastric lavage, administration of activated charcoal (especially within the first 2 hours after overdose), maintenance of cardiovascular system function, elevation of lower extremities, monitoring of cardiovascular and respiratory system function, monitoring of circulating blood volume and diuresis. To restore vascular tone – use of vasoconstrictors (if no contraindications exist); to counteract the effects of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is ineffective. Lisinopril Symptoms: Marked hypotension, circulatory shock, cough, anxiety, renal failure, water-electrolyte imbalance, tachycardia, palpitations, bradycardia, pulmonary hyperventilation, dizziness. Treatment: If not much time has passed since administration, measures should be taken to remove lisinopril (e.g., induce vomiting, gastric lavage, administration of sorbents and sodium sulfate). Symptomatic therapy, intravenous infusion of 0.9% sodium chloride solution. Patients should be placed in a supine position with lower extremities elevated. Intravenous infusion of angiotensin II and/or catecholamines may also be possible. For persistent bradycardia, an artificial pacemaker may be implanted. Hemodialysis may be used (see "Patients on hemodialysis," "Precautions"). Continuous monitoring of vital signs, serum creatinine concentration, and electrolyte levels is necessary. Rosuvastatin There is no specific treatment for rosuvastatin overdose. In case of overdose, symptomatic treatment and maintenance of vital organ and system functions are recommended. Liver function and CK activity should be monitored. Hemodialysis is unlikely to be effective. Interactions with other medicinal products Amlodipine Effects of other drugs on amlodipine: CYP3A4 isoenzyme inhibitors: Concomitant use of amlodipine and strong or moderate inhibitors of CYP3A4 isoenzyme (protease inhibitors, azole antifungal drugs, macrolides, e.g., erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine concentration and an increased risk of hypotension. The clinical manifestation of this pharmacokinetic deviation may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary. CYP3A4 isoenzyme inducers: Data on the effects of CYP3A4 isoenzyme inducers on amlodipine are not available. Concomitant use of CYP3A4 isoenzyme inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]) may lead to a decrease in serum amlodipine concentration. Caution should be exercised when using amlodipine and CYP3A4 isoenzyme inducers concomitantly. Concomitant use of amlodipine and grapefruit or grapefruit juice is not recommended, as it may increase amlodipine bioavailability in some patients, which in turn increases the hypotensive effect. Dantrolene (infusion): In laboratory animals, ventricular fibrillation and cardiovascular failure were observed with intravenous administration of verapamil and dantrolene, accompanied by hyperkalemia, fatal outcome, and collapse. Due to the risk of hyperkalemia, concomitant use of dantrolene and slow calcium channel blockers, including amlodipine, should be avoided in patients predisposed to malignant hyperthermia, as well as during the treatment of malignant hyperthermia. Effects of amlodipine on other drugs: Amlodipine enhances the hypotensive effect of other drugs with antihypertensive activity used to lower blood pressure. Tacrolimus: Concomitant use of tacrolimus and amlodipine may lead to an increase in tacrolimus concentration in the blood; the mechanism of this interaction is not fully understood. To avoid toxic effects of tacrolimus, tacrolimus blood concentration should be monitored during amlodipine treatment, and tacrolimus dose adjustment should be made if necessary. Cyclosporine: Studies on the interaction between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except for patients who have undergone kidney transplantation. In these individuals, an increase in cyclosporine concentration in the blood (approximately 0%-40%) was observed. Therefore, during amlodipine treatment, cyclosporine blood concentration should be monitored, and cyclosporine dose reduction should be made if necessary. Simvastatin: Compared to simvastatin monotherapy, multiple concomitant administrations of amlodipine 10 mg with simvastatin 80 mg led to a 77% increase in simvastatin concentration. Therefore, in patients receiving up to 20 mg of amlodipine daily, simvastatin dose reduction is recommended. Rosuvastatin: Multiple concomitant administrations of amlodipine 10 mg and rosuvastatin 20 mg resulted in a 28% increase in rosuvastatin AUC and a 31% increase in Cmax. The exact mechanism of interaction is unknown. This effect is not expected to have clinical significance with daily use of Ekvamer®, as it is indicated only for patients already taking lisinopril, amlodipine, and rosuvastatin at the same doses as in the indicated combination. In a clinical trial, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin. Lisinopril Other antihypertensive drugs: Concomitant use of lisinopril with other antihypertensive drugs (e.g., nitroglycerin and other nitrates or other vasodilators) may cause marked hypotension (additive effect). Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse events such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to the use of a single drug acting on the RAAS. Diuretics: Concomitant use of diuretics and lisinopril usually results in an additional hypotensive effect. When lisinopril is prescribed to patients already taking diuretics or who have recently been prescribed diuretics, excessive hypotension may occur. The risk of symptomatic hypotension can be reduced by discontinuing diuretics before starting lisinopril treatment. Potassium-containing dietary supplements, potassium-sparing diuretics, or salt substitutes: Concomitant use of potassium-sparing diuretics (spironolactone, eplerenone (a derivative of spironolactone), triamterene, amiloride), potassium preparations, or salt substitutes increases the risk of hyperkalemia, especially in patients with renal impairment. If lisinopril is used with potassium-sparing diuretics, diuretic-induced hypokalemia may be reduced. Lithium preparations: Concomitant use of lisinopril and lithium preparations leads to slowed elimination of lithium from the body, increased serum lithium concentration, and development of toxic effects. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance already increased lithium toxicity with ACE inhibitors. Concomitant use of lisinopril and lithium preparations is not recommended, but if this combination is necessary, serum lithium concentration should be strictly monitored. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥3 g/day: Concomitant use of ACE inhibitors and NSAIDs (e.g., acetylsalicylic acid as an anti-inflammatory agent, cyclooxygenase-2 (COX-2) inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of renal impairment, including acute renal failure, and increase serum potassium levels, especially in patients with pre-existing renal impairment. These effects are usually reversible. These combinations should be prescribed with caution, especially in the elderly. Patients should receive adequate fluid intake. In addition, after initiating combination therapy, the need for renal function monitoring and its periodic performance should be decided. Gold: Nitritoid reactions (symptoms of vasodilation, including hyperemia, nausea, dizziness, and hypotension, which can be very severe) have been observed more frequently in patients receiving ACE inhibitors after intramuscular administration of gold-containing drugs (e.g., sodium aurothiomalate). Tricyclic antidepressants/antipsychotics/anesthetics: Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may cause marked hypotension (see "Precautions"). Sympathomimetics: Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. Hypoglycemic drugs: Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic drugs (insulin, oral hypoglycemic agents) may enhance hypoglycemic effects with a risk of hypoglycemia. This event is more likely to occur during the first few weeks of combination therapy, as well as in patients with renal impairment. Plasminogen tissue activators: Concomitant use with tissue plasminogen activators may increase the risk of angioedema. Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates: Lisinopril can be used with acetylsalicylic acid (at cardiological doses), thrombolytics, beta-blockers, and/or nitrates. Rosuvastatin Effects of other drugs on rosuvastatin: Transporter protein inhibitors: Rosuvastatin binds to certain transporter proteins, mainly OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transporter proteins may lead to increased serum rosuvastatin concentration and an increased risk of myopathy (see Table 2 and "Dosage and administration" and "Precautions"). Cyclosporine: In a study of concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC was on average 7 times higher than that observed in healthy volunteers (see "Contraindications"). It does not affect serum cyclosporine concentration. Rosuvastatin use is contraindicated in patients taking cyclosporine (see "Contraindications"). Human immunodeficiency virus protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant use of HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure (see Table 2). Concomitant use of rosuvastatin 20 mg and a combination drug containing two HIV protease inhibitors (atazanavir 300 mg/ritonavir 100 mg) in healthy volunteers resulted in approximately a threefold and sevenfold increase in rosuvastatin AUC(0-24) and Cmax, respectively. Therefore, concomitant use of rosuvastatin and certain combinations of protease inhibitors may only be possible after careful dose selection of rosuvastatin based on the expected increase in rosuvastatin exposure (see "Precautions" and Table 2). Gemfibrozil and other hypolipidemic agents: Concomitant use of rosuvastatin and gemfibrozil leads to a twofold increase in maximum serum rosuvastatin concentration and an increase in rosuvastatin AUC (see "Precautions"). Based on specific interaction data, no significant pharmacokinetic interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and nicotinic acid at lipid-lowering doses (≥1 g/day) increase the risk of myopathy with concomitant use of HMG-CoA reductase inhibitors, possibly because they can cause myopathy when used as monotherapy (see "Precautions"). Ezetimibe: Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg was associated with a 1.2-fold increase in rosuvastatin AUC in patients with hypercholesterolemia (see Table 2). The increased risk of adverse events due to pharmacodynamic interaction between rosuvastatin and ezetimibe should not be ruled out. Antacids: Concomitant use of rosuvastatin and an aluminum or magnesium hydroxide-containing antacid suspension leads to a decrease in serum rosuvastatin concentration by approximately 50%. This effect is less pronounced if antacids are taken 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied. Erythromycin: Concomitant use of rosuvastatin and erythromycin leads to a 20% decrease in rosuvastatin AUC(0-t) and a 30% decrease in rosuvastatin Cmax. This interaction may occur due to increased intestinal motility caused by erythromycin. CYP450 isoenzymes: In vitro and in vivo studies have shown that rosuvastatin is not an inducer or inhibitor of CYP450 isoenzymes. Furthermore, rosuvastatin is a weak substrate for these enzymes. Therefore, no drug interactions involving CYP450 isoenzymes are expected with rosuvastatin. No clinically significant interactions were observed between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 inhibitors) or ketoconazole (CYP2A6 and CYP3A4 inhibitors). Effects on drugs requiring rosuvastatin dose adjustment (see Table 2): Rosuvastatin dose adjustment should be made when used concomitantly with drugs that increase rosuvastatin exposure. If a twofold or greater increase in exposure is expected, the starting dose of rosuvastatin should be 5 mg once daily. The maximum daily dose of rosuvastatin should also be adjusted so that the expected exposure to rosuvastatin does not exceed that for a 40 mg dose taken without interacting drugs. For example, the maximum daily dose of rosuvastatin with concomitant gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure). Table 2. Effect of concomitant therapy on rosuvastatin exposure (AUC, data listed in descending order) – published clinical trial results Concomitant therapy regimen | Rosuvastatin regimen | Change in rosuvastatin AUC Cyclosporine 75-200 mg bid, 6 months | 10 mg qd, 10 days | 7.1-fold increase Atazanavir 300 mg/ritonavir 100 mg qd, 8 days | 10 mg single dose | 3.1-fold increase Simeprevir 150 mg qd, 7 days | 10 mg single dose | 2.8-fold increase Lopinavir 400 mg/ritonavir 100 mg bid, 17 days | 20 mg qd, 7 days | 2.1-fold increase Clopidogrel 300 mg loading dose, then 75 mg qd | 20 mg single dose | 2-fold increase Gemfibrozil 600 mg bid, 7 days | 80 mg single dose | 1.9-fold increase Eltrombopag 75 mg qd, 5 days | 10 mg single dose | 1.6-fold increase Darunavir 600 mg/ritonavir 100 mg bid, 7 days | 10 mg qd, 7 days | 1.5-fold increase Tipranavir 500 mg/ritonavir 200 mg bid, 11 days | 10 mg single dose | 1.4-fold increase Dronedarone 400 mg bid | Not available | 1.4-fold increase Itraconazole 200 mg qd, 5 days | 10 mg single dose | 1.4-fold increase Ezetimibe 10 mg qd, 14 days | 10 mg qd, 14 days | 1.2-fold increase Fosamprenavir 700 mg/ritonavir 100 mg bid, 8 days | 10 mg single dose | No change Aleglitazar 0.3 mg, 7 days | 40 mg, 7 days | No change Silymarin 140 mg tid, 5 days | 10 mg single dose | No change Fenofibrate 67 mg tid, 7 days | 10 mg, 7 days | No change Rifampin 450 mg qd, 7 days | 20 mg single dose | No change Ketoconazole 200 mg bid, 7 days | 80 mg single dose | No change Fluconazole 200 mg qd, 11 days | 80 mg single dose | No change Erythromycin 500 mg qid, 7 days | 80 mg single dose | 20% decrease Baikalin 50 mg tid, 14 days | 20 mg single dose | 47% decrease Effects of rosuvastatin on other drugs Vitamin K antagonists: Like other HMG-CoA reductase inhibitors, initiating rosuvastatin therapy or increasing the dose of rosuvastatin in patients concomitantly taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Decreasing or discontinuing rosuvastatin dose may lead to a decrease in INR. In such cases, INR monitoring is necessary. Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinylestradiol and the AUC of norgestrel by 26% and 34%, respectively. Such an increase in serum concentration should be considered when selecting the dose of oral contraceptives. Pharmacokinetic data on concomitant use of rosuvastatin and hormone replacement therapy are not available. A similar effect should not be ruled out with concomitant use of rosuvastatin and hormone replacement therapy. However, such combinations have been widely used in clinical trials and were well tolerated by patients. Other drugs: Digoxin: Based on data from specific interaction studies, no clinically significant interaction with digoxin is expected. Fusidic acid: The risk of developing myopathy, including rhabdomyolysis, may be increased with concomitant use of systemically administered statins and fusidic acid. The mechanism of this interaction (pharmacodynamic and/or pharmacokinetic) is unknown. Cases of rhabdomyolysis (including several fatal cases) have been reported with the use of this combination. If systemic fusidic acid is necessary, rosuvastatin treatment should be discontinued for the entire duration of fusidic acid treatment (see also "Precautions"). Precautions If a patient is hospitalized, they must inform the doctor that they are taking Ekvamer®. If you forget to take an Ekvamer® capsule, wait and take the next capsule at the usual time. Do not take a double dose to compensate for a missed dose. When using Ekvamer®, the recommendations described below for the use of individual components should be taken into account. Amlodipine Safety and efficacy of amlodipine in hypertensive crisis have not been established. Patients with heart failure: Amlodipine treatment in patients with heart failure should be carried out with caution. In long-term placebo-controlled clinical trials involving patients with severe heart failure (NYHA functional class III-IV), an increased incidence of pulmonary edema was observed compared to the placebo group. Slow calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they increase the risk of cardiovascular complications and mortality in this patient group. Patients with liver dysfunction: In patients with liver dysfunction, the elimination half-life and AUC of amlodipine increase; recommended doses for such patients have not been established. Amlodipine treatment should be initiated at the lowest dose. Caution should be exercised at the beginning of treatment and when increasing the dose. In patients with severe liver failure, dose titration should be slow and under medical supervision. Patients with renal impairment: In this patient group, amlodipine can be used at usual doses. Changes in amlodipine concentration in serum do not correlate with the severity of renal impairment. Amlodipine is not removed by hemodialysis. Elderly patients: Dose escalation in elderly patients should be done with caution (see "Dosage and administration" and "Pharmacokinetics"). Lisinopril Symptomatic arterial hypotension: Marked hypotension most often develops with reduced circulating blood volume due to diuretic therapy, dietary salt restriction, dialysis, diarrhea, and vomiting (see "Interactions with other medicinal products" and "Side effects") or in patients with severe renin-dependent hypertension. In patients with chronic heart failure, with or without renal impairment, symptomatic hypotension may develop. It occurs more frequently in patients with severe heart failure, as a result of high doses of loop diuretics, hyponatremia, or renal impairment. In such patients, therapy should be initiated under strict medical supervision (appropriate selection of lisinopril and diuretic doses). The same rule should be followed when prescribing lisinopril to patients with ischemic heart disease and cerebrovascular insufficiency, where a sharp drop in blood pressure may lead to myocardial infarction or stroke. In case of marked hypotension, patients should lie down and, if necessary, fluid replacement should be administered (intravenous infusion of 0.9% sodium chloride solution). Transient hypotensive response is not a contraindication for subsequent doses of lisinopril; treatment usually proceeds without complications after correction of hypovolemia and restoration of blood pressure levels. In some patients with chronic heart failure, with normal or reduced blood pressure, a decrease in blood pressure may occur during lisinopril treatment, which is usually not a reason to discontinue therapy. If hypotension becomes symptomatic, the dose should be reduced or lisinopril therapy discontinued. Aortic and mitral valve stenosis/hypertrophic obstructive cardiomyopathy: Like other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis and obstruction of the left ventricular outflow tract (aortic stenosis or hypertrophic obstructive cardiomyopathy). Acute myocardial infarction: Lisinopril therapy should not be initiated in patients with acute myocardial infarction who are at risk of serious hemodynamic deterioration after vasodilator use (patients with systolic blood pressure of 100 mmHg or less, patients in cardiogenic shock). Within the first 3 days after myocardial infarction, the dose of lisinopril should be reduced if systolic blood pressure is 120 mmHg or less. The maintenance dose of lisinopril should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mmHg or less. If hypotension persists (systolic blood pressure 90 mmHg for more than 1 hour), lisinopril use should be discontinued. Renal impairment: In renal impairment (CC <80 ml/min), the initial dose of lisinopril should be selected according to the CC level, followed by adjustment based on the patient's clinical response to therapy. Routine monitoring of serum potassium and creatinine levels is standard medical practice in the treatment of such patients. In patients with chronic heart failure, marked hypotension during ACE inhibitor therapy may lead to further deterioration of renal function. Cases of acute renal failure have been described, usually reversible. In patients with bilateral renal artery stenosis or stenosis of a single renal artery, an increase in serum urea and creatinine levels has been observed with ACE inhibitor use, usually reversible after discontinuation of treatment. This complication often occurs in patients with renal impairment. In the presence of concomitant renovascular hypertension, the risk of severe hypotension and renal failure increases. In such patients, treatment should be initiated under strict medical supervision, with low doses and careful dose titration. Since diuretics may worsen this condition, they should be discontinued and renal function monitored during the first few weeks of lisinopril therapy. Lisinopril is not used in acute myocardial infarction in patients with severe renal impairment, defined by serum creatinine levels exceeding 177 µmol/L and/or proteinuria exceeding 500 mg/day. If renal dysfunction develops during lisinopril therapy (serum creatinine level exceeds 265 µmol/L or doubles compared to baseline), discontinuation of lisinopril use should be considered. Hypersensitivity/angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx, which may occur at any time during therapy, has rarely occurred in patients treated with ACE inhibitors, including lisinopril. In such cases, immediate discontinuation of lisinopril is required, and the patient should receive appropriate treatment and be under medical supervision until symptoms completely resolve. Even when only tongue edema occurs without concomitant respiratory impairment, the patient requires prolonged observation, as treatment with antihistamines and corticosteroids may not be sufficient. Laryngeal or tongue angioedema can be fatal. Swelling of the tongue, larynx, or glottis can cause airway obstruction, especially in patients with a history of surgical intervention in the airway area, so appropriate therapy (0.3-0.5 mL of 1:1000 epinephrine solution (adrenaline) subcutaneously) and/or appropriate measures to ensure airway patency are immediately necessary. Strict patient monitoring is required until complete resolution of symptoms. Compared to patients of other races, angioedema occurred more frequently in Black patients treated with ACE inhibitors. In patients with a history of angioedema not related to prior ACE inhibitor treatment, the risk of its development may be increased during ACE inhibitor treatment (see also "Contraindications"). Anaphylactoid reactions: In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. Such reactions can be avoided by temporarily discontinuing ACE inhibitor intake before each apheresis procedure. Anaphylactic reactions: During desensitization procedures (e.g., to hymenopteran venom) in patients receiving ACE inhibitors, life-threatening anaphylactic reactions may occur. Such reactions can be avoided by temporarily discontinuing ACE inhibitors before each desensitization procedure, however, these reactions have recurred with accidental intake of these drugs. Liver dysfunction: In very rare cases, ACE inhibitor therapy may lead to cholestatic jaundice progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. Therefore, lisinopril should be discontinued if serum transaminase activity increases and cholestasis symptoms develop, and the patient should be under appropriate medical supervision. Patients on hemodialysis: Anaphylactic reactions have been observed in patients undergoing hemodialysis with high-flux membranes (e.g., AN69®) and concomitantly taking ACE inhibitors. If hemodialysis is necessary, a different type of membrane or another antihypertensive drug should be used. Neutropenia/agranulocytosis: Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other aggravating factors, neutropenia occurred less frequently. Neutropenia and agranulocytosis resolved after discontinuation of ACE inhibitor treatment. Lisinopril should be used with caution in patients with collagenoses, as well as in patients receiving immunosuppressive therapy, allopurinol, or procainamide, or a combination of these aggravating factors, especially in the presence of renal impairment. In some patients, severe infections developed, which in some cases did not respond to intensive antibiotic therapy. In such patients, periodic monitoring of leukocyte count is recommended when using lisinopril; patients should also be informed to consult a doctor if any signs of infection develop. Dual RAAS blockade: According to available data, concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual RAAS blockade resulting from concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see "Interactions with other medicinal products" and "Pharmacodynamics"). If dual RAAS blockade is necessary, treatment should be carried out under medical supervision with monitoring of renal function, electrolyte levels, and blood pressure. In patients with diabetic nephropathy, combined use of ACE inhibitors and angiotensin II receptor antagonists should not be done. Race: Compared to patients of other races, angioedema occurred more frequently in Black patients treated with ACE inhibitors. Like other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in Black patients, possibly due to a higher incidence of hyporeninemic hypertension. Cough: Dry, persistent cough has been reported with ACE inhibitor use, which resolves after discontinuation of ACE inhibitor treatment. Cough caused by ACE inhibitor use should be considered in the differential diagnosis of cough. Surgical intervention/general anesthesia: In patients requiring extensive surgical intervention or general anesthesia with drugs that cause hypotension, lisinopril may block angiotensin II formation during compensatory renin release. Marked hypotension, considered to be a result of this mechanism, can be reversed by increasing circulating blood volume. Before surgical intervention (including dental surgery), the surgeon/anesthesiologist should be informed that the patient is taking ACE inhibitors. Hyperkalemia: Cases of hyperkalemia have been reported. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, and concomitant use of potassium-sparing diuretics (spironolactone, eplerenone (a derivative of spironolactone), triamterene, and amiloride), potassium preparations, or salt substitutes containing potassium, and drugs that increase serum potassium levels (e.g., heparin). If concomitant use of lisinopril and the mentioned drugs is necessary, caution and regular monitoring of serum potassium levels are recommended. Diabetic patients: In diabetic patients using oral hypoglycemic agents or insulin, strict monitoring of serum glucose concentration is necessary during the first month of ACE inhibitor therapy. Lithium preparations: Concomitant use of lithium preparations and lisinopril is generally not recommended. Rosuvastatin In patients receiving high doses of rosuvastatin, especially 40 mg, proteinuria, mainly of tubular origin, has been described, which is usually transient or short-lived, detected by dipstick tests. Proteinuria is not a prognostic factor for acute or progressive kidney disease. The incidence of serious adverse renal events reported in the post-marketing period was higher with the 40 mg dose. Renal function assessment should be considered in the standard examination of patients receiving rosuvastatin 40 mg daily. Musculoskeletal system: With any dose of rosuvastatin, especially doses >20 mg, the following adverse reactions have been described: myalgia, myopathy (including myositis), and in rare cases, rhabdomyolysis. In very rare cases, rhabdomyolysis has been observed with the combined use of ezetimibe and HMG-CoA reductase inhibitors. Pharmacodynamic interactions should not be ruled out, and caution should be exercised when using these drugs concomitantly. As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis was higher in the post-marketing period with the 40 mg dose. Creatine phosphokinase (CK) activity determination: CK activity determination should not be performed after intense physical exertion or in the presence of other possible causes of increased CK activity that could lead to misinterpretation of the results. If CK activity is significantly elevated (more than 5 times the upper limit of normal), repeat determination should be performed after 5-7 days. Treatment should not be initiated if the repeat test confirms elevated baseline CK activity (more than 5 times the upper limit of normal). Before initiating therapy, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see "Precautions"). Accompanying factors include: - Renal impairment; - Hypothyroidism; - Hereditary muscle diseases in personal or family history; - Muscle toxicity in the history of using other HMG-CoA reductase inhibitors or fibrates; - Excessive alcohol consumption; - Age over 70 years; - Situations where serum rosuvastatin concentration may increase; - Concomitant use of fibrates. The benefit/risk ratio of therapy should be determined, and appropriate clinical monitoring should be performed. During therapy, patients should be informed to seek immediate medical attention in case of sudden onset of muscle pain, muscle weakness, or cramps, especially if accompanied by malaise and fever. CK activity should be determined in such patients. Therapy should be discontinued if CK activity is significantly elevated (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CK activity is less than 5 times the upper limit of normal). If symptoms resolve and CK activity returns to normal, the possibility of re-initiating rosuvastatin or other HMG-CoA reductase inhibitors at a lower dose and under strict patient supervision should be considered. Routine monitoring of CK activity in the absence of symptoms is not recommended. Rare cases of immune-mediated necrotizing myopathy have been described, clinically manifested by proximal muscle weakness and increased serum creatine kinase activity during or after statin therapy, including rosuvastatin. This condition persists despite discontinuation of statin therapy. No potentiation of effects on skeletal muscles was observed during rosuvastatin and concomitant therapy. However, an increased incidence of myositis and myopathy has been reported in patients receiving other HMG-CoA reductase inhibitors (statins) concomitantly with fibrate derivatives, gemfibrozil, cyclosporine, lipid-lowering doses of nicotinic acid (more than 1 g/day), azole antifungal agents, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy with concomitant use of certain HMG-CoA reductase inhibitors. Therefore, concomitant use of rosuvastatin and gemfibrozil is not recommended. The concomitant use of rosuvastatin and fibrates or lipid-lowering doses of nicotinic acid (more than 1 g/day) requires strict benefit/risk assessment. Concomitant use of rosuvastatin 40 mg with fibrates is contraindicated (see "Interactions with other medicinal products"). Rosuvastatin should not be used with systemically administered fusidic acid or within 7 days of discontinuation of fusidic acid treatment. If systemic fusidic acid is necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients concomitantly taking fusidic acid and statins (see "Interactions with other medicinal products"). Patients should be advised to seek immediate medical attention in case of muscle weakness, pain, or increased muscle sensitivity. Re-initiation of statin therapy may be considered 7 days after the last dose of fusidic acid. In exceptional cases, when long-term use of systemic fusidic acid preparations is necessary, for example, for the treatment of severe infections, the possibility of concomitant use of rosuvastatin and fusidic acid should be considered individually and under strict medical supervision. Rosuvastatin should not be used in acute, serious conditions that may predispose patients to myopathy or renal failure (due to rhabdomyolysis) (e.g., sepsis, hypotension, extensive surgical intervention, trauma, severe metabolic, endocrine, or electrolyte balance disorders; or uncontrolled convulsive seizures). Liver function control: As with other HMG-CoA reductase inhibitors, caution should be exercised when prescribing rosuvastatin in patients with a history of liver disease and/or patients who consume excessive alcohol. Liver function tests are recommended before starting therapy and 3 months after initiation. If serum liver transaminase activity exceeds 3 times the upper limit of normal, rosuvastatin intake should be discontinued or the dose reduced. In the post-marketing period, the incidence of serious liver complications (mainly increased liver transaminase activity) was higher in patients receiving rosuvastatin 40 mg. In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying diseases should be treated before starting rosuvastatin treatment. Race: In pharmacokinetic studies in patients of Mongoloid race, compared to Caucasian patients, systemic rosuvastatin concentration was observed to increase (see "Dosage and administration" and "Pharmacokinetics"). HIV protease inhibitors: With concomitant use of rosuvastatin and various HIV protease inhibitors in combination with ritonavir, systemic exposure to rosuvastatin increases. The benefit of reduced blood lipid concentration with rosuvastatin intake should be assessed, as well as the potential increase in serum rosuvastatin concentration when initiating rosuvastatin therapy, and when increasing the rosuvastatin dose in HIV-infected patients receiving HIV protease inhibitors. Concomitant use of rosuvastatin and HIV protease inhibitors without rosuvastatin dose adjustment is not recommended (see "Interactions with other medicinal products"). Interstitial lung diseases: Isolated cases of interstitial lung diseases have been reported with the use of some HMG-CoA reductase inhibitors (statins), especially with long-term use. The disease may manifest as dyspnea, non-productive cough, and general deterioration of condition (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued. Diabetes mellitus: Existing evidence suggests that statins cause an increase in blood glucose concentration and, in some patients with a high risk of developing diabetes mellitus, may provoke hyperglycemia to a level requiring standard diabetes mellitus treatment. However, the reduction in the risk of vascular complications with statin therapy outweighs the risk of hyperglycemia development and should not be a reason to discontinue statins. Clinical and biochemical parameters should be monitored in patients at risk of hyperglycemia (fasting glucose concentration 5.6 to 6.9 mmol/L, body mass index > 30 kg/m², increased triglyceride concentration, history of arterial hypertension) in accordance with national recommendations. Excipients Lactose: Ekvamer® capsules at doses of 10 mg/5 mg/10 mg and 20 mg/10 mg/10 mg contain 48.10 mg of lactose monohydrate per capsule. Ekvamer® capsules at doses of 10 mg/5 mg/20 mg and 20 mg/10 mg/20 mg contain 96.20 mg of lactose monohydrate per capsule. Patients with rare hereditary diseases such as lactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take Ekvamer®. Dyes: Azorubine: Ekvamer® contains the food dye azorubine. Azorubine may cause allergic reactions. Sunset Yellow: Ekvamer® capsules at doses of 10 mg/5 mg/10 mg and 20 mg/10 mg/20 mg contain the food dye Sunset Yellow. Sunset Yellow may cause allergic reactions. Effects on ability to drive and use machines: Data on the effect of the drug on the ability to drive and operate machinery are not provided. Given that excessive hypotension, dizziness, somnolence, and similar side effects may occur, caution should be exercised when performing potentially hazardous activities that require special attention and rapid reactions (driving and operating other vehicles, working with moving machinery, dispatcher and operator activities, etc.). Packaging Capsules, 10 mg/5 mg/10 mg, 10 mg/5 mg/20 mg, 20 mg/10 mg/10 mg, 20 mg/10 mg/20 mg. 5 capsules in a PA/Al/PVC and aluminum foil blister. 6 blisters with instructions for medical use in a cardboard box. Storage conditions: Store at a temperature not exceeding 25°C, in the original packaging to protect from moisture. Keep out of reach of children. Shelf life: 3 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions: Pharmaceutical product group II, dispensed with prescription form #3.