Equamer, 5 mg+10 mg+10 mg capsules 30 pcs

A combined antihypertensive and hypolipidemic drug. Three active substances – amlodipine, lisinopril and rosuvastatin – form part of the drug Equamer®. Mechanism of action of Equamer® is based on pharmacological properties of active ingredients.

Amlodipine

The dihydropyridine derivative is a slow calcium channel blocker (SCB) with hypotensive and antianginal effects. It blocks slow calcium channels, reduces transmembrane transition of calcium ions into the cell (more in vascular smooth muscle cells than in cardiomyocytes).

The antianginal action is due to the dilation of coronary and peripheral arteries and arterioles:

– in angina reduces the severity of myocardial ischemia; by dilating the peripheral arterioles, it reduces the RPS, reduces the afterload on the heart, reduces myocardial oxygen demand;
– By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases the flow of oxygen to the myocardium (especially in vasospastic angina); prevents spasm of coronary arteries (including those caused by smoking).caused by smoking).
In patients with stable angina a single daily dose increases exercise tolerance, delays the development of angina attacks and ischemic ST-segment depression, reduces the frequency of angina attacks and consumption of nitroglycerin and other nitrates.

It has a long-term dose-dependent antihypertensive effect. The antihypertensive effect is due to a direct vasodilatory effect on vascular smooth muscle. In arterial hypertension a single dose provides clinically significant reduction of BP during 24 hours (in patient’s supine and standing position).

Orthostatic hypotension with amlodipine is rare. Amlodipine does not cause a decrease in exercise tolerance and left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conduction, does not cause reflex increase in HR, inhibits platelet aggregation, increases FFR, has a weak natriuretic effect. In diabetic nephropathy it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and blood plasma lipid concentration and can be used for treatment of patients with bronchial asthma, diabetes and gout. Significant decrease in BP is observed after 6-10 hours, the duration of effect – 24 hours.
. In patients with cardiovascular diseases (including coronary atherosclerosis with lesions of one vessel and up to stenosis of 3 or more arteries, carotid atherosclerosis) who had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) or in patients with angina pectoris the use of amlodipine prevents an increase in the thickness of intima-media carotid artery complex, reduces mortality from myocardial infarction, stroke, PTCA, aortocoronary bypass surgery; leads to a decrease in the number of hospitalizations for unstable angina and progression of chronic heart failure (CHF); reduces the frequency of interventions to restore coronary blood flow.

Does not increase risk of death or complications and lethal outcomes in patients with CHF (NYHA functional class III-IV) during therapy with digoxin, diuretics and ACE inhibitors. In patients with CHF (functional class III-IV according to NYHA classification) of non-ischemic etiology during amlodipine use there is a possibility of pulmonary edema development.

Lisinopril

A ACE inhibitor, reduces angiotensin II formation from angiotensin I. Reducing the concentration of angiotensin II leads to a direct reduction in the release of aldosterone. Reduces bradykinin degradation and increases prostaglandin synthesis. Reduces RPS, BP, preload, pulmonary capillary pressure, causes an increase in the minute blood volume and increases myocardial tolerance to exercise in patients with CHF. Dilates arteries more than veins. Some effects are attributed to the effect on the tissue renin-angiotensin system. Long-term use reduces myocardial hypertrophy and resistive arterial wall hypertrophy.

It improves the blood supply to the ischemic myocardium.

The ACE inhibitors prolong life expectancy in patients with CHF and slow the progression of left ventricular dysfunction in patients who have had a myocardial infarction without clinical manifestations of heart failure.

The onset of action is within 1 hour after oral administration. Maximal hypotensive effect is determined after 6-7 hours and sustained for 24 hours. In arterial hypertension the effect is noted in the first days after the start of treatment, a stable effect develops after 1-2 months. When lisinopril is abruptly withdrawn, no marked increase in BP has been noted. In addition to BP reduction, lisinopril reduces albuminuria. In patients with hyperglycemia, it normalizes the function of damaged glomerular endothelium. Lisinopril does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to increased incidence of hypoglycemia.

Rosuvastatin

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 main target of rosuvastatin action is the liver, where cholesterol (Chs) synthesis and LDL catabolism take place.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, increasing the capture and catabolism of LDL, which in turn leads to the inhibition of LDL synthesis, thereby reducing the total amount of LDL and LDL-C.

. Rosuvastatin reduces elevated concentrations of LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) and increases the concentration of high-density lipoprotein cholesterol (HDL-C), and decreases the concentration of apolipoprotein B (ApoB), Chs-non-LDL, Chs-LDL, TG-LDL, and increases the concentration of apolipoprotein A-I (ApoA-I) (see Tables 1 and 2), decreases the ratio of hs-LDL/Hs-LDL, total hs/Hs-LDL, hs-non-LDL/Hs-LDL, and the apoB/apoA-I ratio.

Therapeutic effect appears within the first week after the start of therapy with rosuvastatin and after 2 weeks of treatment reaches 90% of the maximum possible. Maximum therapeutic effect is usually reached by 4 weeks and is maintained with regular administration.

Indications

Equamer® is indicated as replacement therapy in adult patients whose condition is already adequately controlled by taking amlodipine, lisinopril and rosuvastatin in the same doses as in Equamer® for the treatment of arterial hypertension and concomitant dyslipidemia:

Active ingredient

Composition

1 capsule contains:

Active ingredients:

amlodipine besylate 6.94 mg, which corresponds to the content of amlodipine5 mg

lisinopril dihydrate 10.88 mg, which corresponds to the content of lisinopril 10 mg,

rosuvastatin calcium 10.4 mg, which corresponds to the content of rosuvastatin 10 mg.

Supplementary substances:

microcrystalline cellulose,

type 12 – 60.41 mg,

microcrystalline cellulose,

Type 101 – 45.27 mg,

lactose monohydrate – 48.1 mg,

sodium carboxymethyl starch – 9.5 mg,

magnesium hydroxide – 7.5 mg,

magnesium stearate – 2 mg,

opadray II yellow – 2 mg (polyvinyl alcohol 40%, titanium dioxide 23.5%, macrogol-3350 20.2%, talc 14.8%, iron oxide yellow dye 1.5%), hard gelatin capsule – 76 mg (proprietary blue dye 0.00022%, azorubin dye 0.03684%, sunset yellow dye 0.0204%, titanium dioxide 3.7037%, gelatin to 100%).

How to take, the dosage

Equamer® can be taken regardless of the time of meals.
Doses
Generally, a fixed-dose combination drug is not suitable for initial therapy.
Equamer® is used as substitution therapy in adult patients who are already receiving amlodipine, lisinopril and rosuvastatin in the same doses as this drug.

The recommended dose of Equamer® is 1 capsule daily. The maximum daily dose is 1 capsule.
If correction of the drug dose is necessary the doses should be titrated using amlodipine, lisinopril and rosuvastatin separately.

Special patient groups

– Patients with renal insufficiency
During therapy with Equamer® renal function, plasma potassium and sodium levels should be monitored. In case of worsening of renal function, Equamer® should be discontinued. Individual selection of doses of individual active components is recommended for such patients. The use of the drug in patients with severe renal failure is contraindicated in all vines (see section “Contraindications”).

– Patients with hepatic failure
The drug Equamer® is contraindicated in patients with liver disease in the active phase and patients with severe liver function impairment (more than 9 points on the Child-Pugh scale) (see.

– Children and adolescents (under 18 years)
Safety and efficacy of Equamer® in children and adolescents has not been established.

– Elderly patients (over 65 years)
In elderly patients Equamer® should be used with caution.
No data on changes in the effectiveness or safety profile of amlodipine, lisinopril or rosuvastatin depending on age were obtained in clinical trials.

– Race
When studying pharmacokinetic parameters of rosuvastatin in patients belonging to different races, increased systemic concentration of rosuvastatin in blood plasma was noted among patients of mongoloid race. This fact should be taken into account when prescribing Equamer® in this group of patients. Recommended initial dose of rozuvastatin for Mongoloid patients should be 5 mg if prescribed in dose of 10 mg and 20 mg.

– Genetic polymorphism
Carriers of SLC01B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA had increased exposure (AUC) to rosuvastatin compared to carriers of SLC01B1 C.521T and ABCG2 C.421CC genotypes. The recommended maximum dose of rosuvastatin is 20 mg per day (see section “Pharmacokinetics”).

Concomitant therapy
Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When co-administration of rosuvastatin with drugs (such as cyclosporine, some human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase. In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of rosuvastatin should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with rosuvastatin should be assessed and the possibility of reducing its dose should be considered.

Interaction

Amlodipine

Amlodipine may be safely used for therapy of arterial hypertension together with thiazide diuretics, alpha-adrenoblockers, beta-adrenoblockers or ACE inhibitors. In patients with stable angina pectoris amlodipine may be combined with other antianginal agents, e.g. long- or short-acting nitrates, beta-adrenoblockers.

Unlike other PBMCs, no clinically significant interaction of amlodipine (generation III PBMCs) has been found when combined with nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin. Antianginal and antihypertensive effects of PBMCs may be enhanced when combined with thiazide and “loop” diuretics, ACE inhibitors, beta-adrenoblockers and nitrates, and their antihypertensive effects may be enhanced when combined with alpha-adrenoblockers and neuroleptics.

While no negative inotropic effects have generally been observed with amlodipine, some PBMCs can exacerbate the negative inotropic effects of antiarrhythmic agents that cause QT interval prolongation (e.g., amiodarone and quinidine).

Amlodipine may also be safely used concomitantly with oral antibiotics and typoglycemic agents.
A single administration of 100 mg sildenafil in patients with essential hypertension has no effect on the pharmacokinetic parameters of amlodipine.

Repeated use of amlodipine 10 mg and atorvastatin 80 mg is not associated with significant changes in the parameters of pharmacokinetics of etorvastatin.

Simvastatin: Simultaneous multiple use of amlodipine in dose of 10 mg and simvastatin in dose of 80 mg leads to 77% increase of simvastatin exposure. In such cases, the dose of simvastatin should be limited to 20 mg.

Rosuvastatin: In concomitant repeated use of amlodipine 10 mg and rosuvastatin 20 mg, an increase of approximately 28% in AUC and 31% in Cmax of rosuvastatin was observed. The exact mechanism of interaction is unknown. This effect is not expected to be clinically relevant with daily use of Equimer® because it is indicated only in patients already receiving lisinopril, amlodipine and rosuvastatin in the same doses as in this combination.

Ethanol (beverages containing alcohol): Amlodipine does not affect the pharmacokinetics of ethanol in single and repeated doses of 10 mg.

Antiviral agents (ritonavir): increases plasma concentrations of PBMCs. including amlodipine.
Neuroleptics and isoflurane: increase the antihypertensive effect of dihydropyridine derivatives.
Calcium preparations may decrease the effect of PBMCs.

When concomitant use of PBMCs with lithium preparations (no data available for amlodipine) an increase in their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) may occur.

There have been no studies of concomitant use of amlodipine and cyclosporine in healthy volunteers and all groups of patients, except for patients after kidney transplantation. Various studies on the interaction of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect, or increase the minimum concentration of cyclosporine to varying degrees up to 40%. These data should be taken into account and the concentration of cyclosporine in this group of patients should be monitored when concomitant use of cyclosporine and amlodipine. There is no effect on the serum concentration of digoxin and its renal clearance.

There is no significant effect on the effect of warfarin (prothrombin time).
Cimetidine does not affect the pharmacokinetics of amlodipine.

In in vitro studies amlodipine does not affect the binding to plasma proteins of digoxin, phenytoin, warfarin and indomethacin.
Grapefruit juice: simultaneous administration of 240 mg grapefruit juice and 10 mg amlodipine orally is not significantly altered amlodipine pharmacokinetics. However, it is not recommended to use grapefruit juice and amlodipine concomitantly, since a genetic polymorphism of CYP3A4 isoenzyme may increase the bioavailability of amlodipine and, consequently, increase the antihypertensive effect.

Aluminum- or magnesium-containing aptacids: their single administration has no significant effect on amlodipine pharmacokinetics.
CYP3A4 isoenzyme inhibitors: simultaneous use of diltiazem 180 mg and amlodipine 5 mg in elderly patients (from 69 to 87 years) with arterial hypertension shows 57% increase of systemic amlodipine exposure.

Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years) does not lead to significant changes in amlodipine exposure (increase in AUC by 22%). Although the clinical significance of these effects is not entirely clear, they may be more pronounced in older patients.

Powerful inhibitors of CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole) may lead to increased plasma concentrations of amlodipine to a greater extent than diltiazem. Caution should be exercised when using amlodipine and CYP3A4 isoenzyme inhibitors.
CYP3A4 isoenzyme inducers: no data on the effect of CYP3A4 isoenzyme inducers on amlodipine pharmacokinetics. BP should be carefully monitored when concomitant use of amlodipine and inducers of CYP3A4 isoenzyme.

Lysipopril
. Concomitant use with potassium-saving diuretics (spironolactone, eplerenone (spironolactone derivative), triamterene, amiloride), potassium preparations, potassium-containing salt substitutes increases the risk of hyperkalemia, especially in patients with impaired renal function.

In concomitant use with diuretics, pronounced BP reduction.

Concomitant use of lisinopril with beta-adrenoblockers, “slow” calcium channel blockers, diuretics, tricyclic antidepressants/neuroleptics increases the severity of antihypertensive effect.

In concomitant use with nonsteroidal anti-inflammatory drugs (indomethacin and others), including acetylsalicylic acid >3 g/day, estrogens, as well as adrenomimetics – reduction of the antihypertensive effect of lisinopril.
In concomitant use with lithium drugs – slowing of lithium excretion.

Simultaneous use with antacids and colestiramine slows absorption in the gastrointestinal tract.
Ethanol increases the effect of lisinopril.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of angiotensin-II receptor antagonists (ARA II), ACE inhibitors or aliskiren is associated with an increased incidence of arterial hypotension, hyperkalemia and renal function disorders (including renal failure) compared to use of one drug acting on RAAS.
Concomitant use with insulin and oral hypoglycemic agents increases the risk of hypoglycemia.
Concomitant use of ACE inhibitors and intravenous gold drugs (sodium aurothiomalate) has described a symptom complex including facial skin hyperemia, nausea, vomiting and BP decrease.

The simultaneous use of lisinopril with acetylsalicylic acid as an antiplatelet agent, thrombolytics, beta-adrenoblockers and/or nitrates is not contraindicated.

Concomitant use with selective serotonin reuptake inhibitors may lead to significant hyponatremia.
Concomitant use with allopurinol, procainamide, cytostatics may increase the risk of leukopenia.

Rosuvastatin

The effect of other drugs on rosuvastatin

Transport protein inhibitors: Rosuvastatin binds to some transport proteins, in particular to OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

Cyclosporine: in concomitant use of rosuvastatin and cyclosporine the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see section “Contraindications”). Does not affect the plasma concentration of cyclosporine. Rosuvastatin is contraindicated in patients taking cyclosporine.

Human immunodeficiency virus protease inhibitors: although the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure.

A pharmacokinetic study but concomitant administration of 20 mg rosuvastatin and a combination drug containing two HIV progease inhibitors (400 mg lopinavir/100 mg rigonavir) in healthy volunteers resulted in approximately twofold and fivefold increases in AUC(0-24) and Cmax of rosuvastatin respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors in patients with human immunodeficiency virus is not recommended.

Gemfibrozil and other hypolipidemic agents: co-administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in maximum plasma concentration of rosuvastatin and an increase in AUC of rosuvastatin. Based on the data on specific interaction, ts is expected pharmacokinetic significant interaction with fenofibrate, pharmacodynamic interaction is possible.

Hemfibrozil, fenofibrate, other fibrates and nicotinic acid at lipid-lowering doses (greater than 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can also cause myopathy when used in monotherapy.

Ezetimibe: concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe was accompanied by increased AUC of rosuvastatin in patients with hypercholesterolemia. An increased risk of side effects due to pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded.

Antacids: concomitant use of rosuvastatin and suspensions of antacids containing aluminum or magnesium hydroxide leads to a decrease in plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Eritromycin: Concomitant use of rosuvastatin and erythromycin decreases AUC(0-24) of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by taking erythromycin.

Fusidic acid: There have been no studies on the interaction between rosuvastatin and fusidic acid. As with other HMG-CoA reductase inhibitors, there have been post-marketing reports of cases of rhabdomyolysis when co-administering rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, temporary discontinuation of rosuvastatin is possible.

Cytochrome P450 isoenzymes: Results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes.

In addition, rosuvastatin is a weak substrate for these enzymes. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected. No clinically significant interaction between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor) was observed.

Drug interactions that require dose adjustment of rosuvastatin.

The dose of rosuvastatin should be adjusted if co-administration with drugs that increase exposure to rosuvastatin is necessary. If exposure is expected to increase by a factor of 2 or more, 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 of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of rosuvastatin when concomitantly used with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure).

The effect of using rosuvastatin on other drugs

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, starting rosuvastatin therapy or increasing the dose of rosuvastatin in patients receiving concurrent vitamin K antagonists (such as warfarin or other coumarin anticoagulants) may increase the international normalized ratio (MHO). Cancellation or reduction of the dose of rosuvastatin may cause a decrease in Ml 10. In such cases, MHO should be monitored.

Special Instructions

If you are hospitalized, tell your doctor that you are taking Equimer®.
If you also forget to take an Equimer® capsule, wait and take the next capsule at the usual time. Do not take a double dose to make up for the missed dose.

When using Equamer®, consider the recommendations for the individual components of the drug detailed below.

Amlodipine

It is necessary to maintain dental hygiene and see a dentist (to prevent soreness, bleeding and gum hyperplasia). In elderly patients, the T½ may increase and the clearance of amlodipine may decrease. No dose modification is required, but closer monitoring 5 is necessary in patients in this category.

The efficacy and safety of amlodipine in hypertensive crisis have not been established.

While there is no withdrawal syndrome with BMK, it is advisable to discontinue amlodipine treatment by gradually reducing the dose of the drug.

Amlodipine use in patients with nonischemic CHF of NYIIA functional class III and IV has been associated with increased incidence of pulmonary edema despite no signs of worsening heart failure.

Lisinopril

Symptomatic arterial hypotension
Most often, a pronounced decrease in BP occurs with a decrease in the BOD caused by diuretic therapy, reduction of dietary salt, dialysis, diarrhea and vomiting (see sections “Interaction of the Interaction of the Blood Pressure and Blood Pressure”). See sections “Interaction with other medicinal products” and “Side effects”). In patients with CHF, both with concomitant renal failure and without it, symptomatic arterial typotension may develop. It is more often found in patients with severe heart failure as a consequence of using high doses of diuretic, hyponatremia or impaired renal function. In these patients the therapy should be started under close medical supervision (with caution select the dose of lisinopril and diuretics).

The same rules should be observed when administering lisinopril to patients with coronary heart disease, cerebrovascular insufficiency, in which acute decrease of BP may lead to myocardial infarction or stroke.

In case of pronounced BP decrease, the patient should be laid down and, if necessary, the loss of fluid should be replenished (intravenous infusion of 0.9% sodium chloride solution). Transient hypotensive reaction is not a contraindication for taking the next dose of lisinopril.
When using lisinopril, some patients with CHF, but with normal or reduced BP, may have lower BP, which is usually not a reason for discontinuing therapy. If arterial hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril therapy is necessary.

In patients who are at risk of symptomatic arterial hypotension (those on a salt restricted or salt free diet) with or without hyponatremia, and also in patients who received high doses of diuretics, loss of fluids and salts should be compensated before initiating therapy.

The antihypertensive effect of the initial dose of lisinopril should be monitored.

Aortic and mitral valve stenosis/hypertrophic obstructive cardiomyopathy

. As with other ACE inhibitors, lisinopril should be prescribed with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction (aortic stenosis or hypertrophic obstructive cardiomyopathy).

Acute myocardial infarction

The use of standard therapy (thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-adrenoblockers) is indicated.

Lisinopril may be used in conjunction with intravenous nitroglycerin or with nitroglycerin transdermal systems.

Lisinopril therapy should not be initiated in patients with acute myocardial infarction who are at risk of further serious hemodynamic deterioration after vasodilator use (patients with a systolic BP of 100 mm Hg or lower, patients with cardiogenic shock). During the first 3 days after myocardial infarction, the dose of lisinopril should be reduced if systolic BP is 120 mm Hg or lower. Maintenance doses of lisinopril should be reduced to 5 mg or temporarily to 2.5 mg if systolic BP is 100 mm Hg or lower. If arterial hypotension persists (systolic BP less than 90 mm Hg for more than 1 hour), lisinopril should not be continued.

Kidney function impairment

In patients with CHF, a marked decrease in BP after initiation of ACE inhibitor treatment may lead to further impairment of renal function. Cases of acute renal failure have been reported.

In patients with bilateral renal artery stenosis or artery stenosis of the single kidney receiving ACE inhibitors, there have been increased serum urea and creatinine concentrations, usually reversible after treatment discontinuation and more common in patients with renal insufficiency.

Lisinoporil is not used in acute myocardial infarction in patients with severe renal dysfunction, established with changes in serum creatinine concentration exceeding 177 μmol/L and/or proteinuria exceeding :U0 mg/day. If renal dysfunction develops during therapy with lisinopril (a serum creatinine concentration exceeding 265 µmol/L, or a doubling of the value compared to the value before treatment), the physician should assess the need for further use of lisinopril.

Hypersensitivity/Angeoneurotic Edema

Angeoneurotic edema of the face, extremities, lips, tongue, epiglottis and/or larynx, which may occur at any time during therapy, has rarely been noted in patients treated with an ACE inhibitor, including lisinopril. In such a case, lisinopril therapy should be discontinued as soon as possible and the patient should be monitored until the symptoms have completely regressed. In cases where the swelling is limited to the face and lips, this condition usually resolves without treatment, but antihistamines may be used.

The angioedema with laryngeal edema can be fatal. Tongue, epiglottis or laryngeal edema may cause airway obstruction, so appropriate therapy (0.3-0.5 ml 1:1000 epinephrine (adrenaline) subcutaneously) and/or measures to ensure airway patency should be taken immediately. It has been noted that patients of the Negro race taking ACE inhibitors developed angioedema more frequently than patients of other races.

Patients taking ACE inhibitors rarely had intestinal angioedema. These patients complained of abdominal pain (with or without nausea and vomiting); in some cases there was no prior angioedema of the face and C-1 esterase activity was within normal limits. Intestinal angioedema was diagnosed by gastrointestinal computed tomography or ultrasound, or by surgery; symptoms disappeared after ACE inhibitor withdrawal. In the differential diagnosis of abdominal pain in patients taking ACE inhibitors, the development of intestinal angioedema should be considered.

Patients who have a history of angioedema not associated with previous treatment with ACE inhibitors may be at increased risk of developing it during treatment with an ACE inhibitor (see also section “Contraindications”).
Anaphylactic reactions during desensitization procedures

In patients receiving ACE inhibitors during desensitization treatment (e.g., with Hymenoptera venom), life-threatening anaphylactic reactions may occur in very rare cases. This can be avoided by temporarily withdrawing the ACE inhibitor before each desensitization procedure.

Hepatic dysfunction

The use of ACE inhibitors can lead to cholestatic jaundice with progression up to fulminant hepatic necrosis, therefore lisinopril should be stopped if hepatic transaminases are elevated and symptoms of cholestasis appear.

Patients on hemodialysis

Anaphylactic reactions have also been reported in patients on hemodialysis using high-flow membranes (e.g., AN69®) and receiving ACE inhibitors concomitantly. If hemodialysis is necessary, a different type of membrane or a different hypotensive drug should be used.

Cough

When using an ACE inhibitor, a “dry”, prolonged cough has been noted, which disappeared after discontinuation of ACE inhibitor treatment. In the differential diagnosis of cough, cough caused by ACE inhibitor use must be considered.

Surgery/General anesthesia

In patients whose condition requires extensive surgery or general anesthesia with drugs causing arterial hypotension, lisinopril may block angiotensin II formation with compensatory renin release.
A marked decrease in BP, which is believed to be a consequence of this mechanism, can be ) with a granular increase in circulating blood volume.
Before surgical intervention (including dental surgery I intervention), the surgeon/anesthesiologist should be informed about the use of an ACE inhibitor.

Hyperkalemia

Cases of hyperkalemia have been reported.

Risk factors for hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-saving diuretics (spironolactone, eplerenone (spironolactone derivative), triamterene and amiloride), potassium preparations or salt substitutes containing potassium, especially in patients with impaired renal function.

If there is a need to use lisinopril concomitantly with the above mentioned drugs it is recommended to take precautions and monitor serum potassium levels regularly.

Patients with diabetes mellitus

In diabetic patients taking oral hypoglycemic drugs or receiving insulin, careful monitoring of plasma glucose concentration should be performed during the first month of ACE inhibitor therapy.

Double blockade of the RAAS by angiotensin II receptor antagonists (ARA II), ACE inhibitors, or aliskiren

. It has been proved that simultaneous use of angiotensin receptor antagonists -ARA II), ACE inhibitors or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). For this reason, combined use of APA II, ACE inhibitors or aliskiren is not recommended.

If this therapy is necessary, it is recommended that renal function, BP and serum electrolytes be monitored closely by a specialist.

The ACE inhibitors, ARA II should not be used in patients with diabetic nephropathy.

Systemic connective tissue diseases
In patients with severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), lisinopril should be used with caution.

Patients in the elderly

In elderly patients the use of standard doses of lisinopril leads to higher concentration of lisinopril in blood, therefore special caution is required when determining the dose, although no differences in antihypertensive effect of lisinopril in elderly and young patients have been found.

Rosuvastatin

Patients receiving rosuvastatin may show proteinuria. Changes in the amount of protein in the urine (from no or trace amounts to ++ or more) are seen in less than 1% of patients receiving 10-20 mg rosuvastatin and about 3% of patients receiving 40 mg rosuvastatin. Little change in urinary protein was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing renal disease.

Musculoskeletal disorders

The following adverse reactions have been reported with rosuvastatin in all doses, and especially with doses greater than 20 mg: myalgia, myopathy, and in rare cases rhabdomyolysis.

Creatine phosphokinase activity determination

The determination of CPK activity should not be performed after strenuous physical activity or in the presence of other possible causes of increase in CPK activity, which may lead to misinterpretation of the results. If initially the CPK activity is significantly elevated (5 times higher than the upper limit of normal) the measurement should be repeated in 5-7 days. The therapy should not be started if the repeated test confirms the initial CPK activity (more than 5 times higher than the upper limit of normal).

Pre-therapy

Patients with existing risk factors for myopathy/rhabdomyolysis should be cautious when prescribing rosuvastatin, as well as other HMG-CoL reductase inhibitors (see section “Caution”).

The risk/benefit ratio of therapy should be considered and clinical monitoring should be performed.

At the time of therapy

The patient should be informed to immediately inform the physician if there is any sudden onset of muscle pain, muscle weakness, or cramping, especially if combined with malaise and fever. In such patients, CPK activity should be determined. Therapy should be stopped if CPK activity is significantly increased (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times lower than the upper limit of normal).

If symptoms disappear and CPK activity returns to normal, re-prescribing rosuvastatin or other HMG-CoA reductase inhibitors at lower doses with close patient monitoring should be considered.

Routine monitoring of CPK activity in the absence of symptoms is not advisable.

There is no evidence of increased skeletal muscle effects with rosuvastatin and concomitant therapy. However an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors (statins) in combination with fibrin acid derivatives, including emfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (over I g/day), azole antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with some HMG-CoA reductase inhibitors. Thus, concomitant use of rosuvastatin and gemfibrozil is not recommended. The risk/benefit ratio of co-administration of rosuvastatin and fibrates or nicotinic acid at lipid-lowering doses (more than 1 g/suc) should be carefully weighed. Rosuvastatin at a dose of 40 mg is contraindicated together with fibrates (see section “Interaction with other medicinal products”).

2-4 weeks after the start of treatment and/or increasing the dose of rosuvastatin it is necessary to control lipid metabolism parameters (if necessary, the dose of rosuvastatin should be adjusted).

Control of liver function

It is recommended to determine liver function parameters before the start of therapy and 3 months after the start of therapy. Rosuvastatin should be discontinued or the dose should be reduced if serum hepatic transaminase activity exceeds 3 times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for underlying diseases should be carried out before starting treatment with rosuvastatin.

Raciality

In studies of pharmacokinetic parameters in patients of mongoloid race an increase in systemic rosuvastatin concentration has been observed compared to that of Caucasian race patients (see sections “Administration and Doses” and “Pharmacokinetics”).

HIV protease inhibitors

The co-administration of rosuvastatin with HIV protease inhibitors is not recommended (see section “Interaction with other medicinal products”).

Interstitial lung disease

In the use of some HMG-CoA reductase inhibitors (statins), especially for a long time, sporadic cases of interstitial lung disease have been reported. Manifestations of the disease may include dyspnea, non-productive cough and deterioration of general well-being (weakness, weight loss and fever). If interstitial lung disease is suspected, patinum therapy should be discontinued.

Type 2 diabetes mellitus

In patients with fasting glucose concentrations between 5.6 and 6.9 mmol/L, rosuvastatin therapy has been associated with an increased risk of developing type 2 diabetes mellitus.

Excipients

Lactose
Equamer® dosage 5 mg + 10 mg + 10 mg and dosage 10 mg + 20 mg + 10 mg contain 48.10 mg of lactose monohydrate in each capsule. Equamer® doses of 5 mg + 10 mg + 20 mg and doses of 10 mg + 20 mg + 20 mg contain 96.20 mg of lactose monohydrate in each capsule.
Patients with rare inherited conditions such as lactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Equamer®.

The dye azorubin
The drug Equamer® contains the food dye azorubin.
Azorubia may cause allergic reactions.

Sunset Yellow Dye
Equamer® doses of 5 mg + 10 mg + 10 mg and 10 mg + 20 mg + 20 mg contain the food dye sunset yellow.
The food dye sunset yellow may cause allergic reactions.

Impact on ability to drive vehicles and mechanisms

There are no data on the effect of the drug on the ability to drive vehicles and mechanisms. Caution should be exercised when performing potentially dangerous activities requiring particular attention and quick reactions (driving a vehicle or other vehicles, operating moving machinery, operator’s work, etc.) due to possible excessive decrease of blood pressure, dizziness, somnolence, and similar side effects.

Contraindications

With caution
Aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, arterial hypotension, cerebrovascular disease (including Cerebrovascular diseases (including insufficiency of cerebral circulation), coronary heart disease, coronary insufficiency, CHF of non-ischemic etiology of III-IV functional class according to NYHA classification, acute myocardial infarction (and within 1 month after it), unstable angina pectoris, sinus node weakness syndrome (significant tachycardia or bradycardia), severe autoimmune systemic diseases of connective tissue including systemic lupus erythematosus.including systemic lupus erythematosus, scleroderma), suppression of medullary hematopoiesis, diabetes mellitus, hyperkalemia, bilateral renal artery stenosis, stenosis of the artery of the single kidney, conditions after renal transplantation, mild to moderate renal failure (CK 30-80 ml/min), azotemia, primary aldosteronism, diet with restriction of table salt, conditions accompanied with reduction of circulating blood volume (includingч. vomiting, diarrhea), advanced age, mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) liver failure, hypothyroidism, personal or family history of hereditary muscle disease and previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates alcohol abuse, conditions in which increased plasma concentrations of rosuvastatin have been noted, race (Mongoloid race), concomitant administration of fibrates, history of liver disease, sepsis, major surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorder, or uncontrolled seizures.

Side effects

Unwanted adverse reactions are presented by systemic organ class according to MedDRA classification and frequency of occurrence:
Very common – 1/10 appointments (>10%)
Frequent – 1/100 appointments (>1%, but <10%)
Infrequent – 1/1000 appointments (>0.1%, but <1%)
Rare – 1/10000 appointments (>0.01%, by < 0.1%)
Very rare – less than 1/10000 appointments (< 0.01%)
Frequency unknown – insufficient data to estimate incidence.
Within each group, adverse reactions are distributed in decreasing order of significance.
The following adverse reactions have been reported when amlodipine, lisinopril, and rosuvastatin were treated separately:

Amlodipine
– Blood and lymphatic system disorders
Very rare: thrombocytopenic purpura, leukopenia, thrombocytopenia.
– Immune system disorders
Infrequent: skin itching, rash (including erythematous and maculopapular rash, urticaria);
Very rare: angioedema, erythema multiforme.
– Metabolic and nutritional disorders
Very rarely: hyperglycemia.
– Psychiatric disorders
Infrequently: mood lability, unusual dreams, increased excitability, depression, anxiety;
Very rarely: apathy, agitation, amnesia.
– Nervous system disorders
Often: headache, dizziness, increased fatigue, drowsiness;
Infrequently: Asthenia, malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, muscle rigidity, insomnia, perversion of taste;
Rare: seizures;
Very rare: migraine, increased sweating, ataxia, parosmia.
– Visual organ disorders
Infrequent: diplopia, accommodation disorders, xerophthalmia, conjunctivitis, pain in the eyes, visual impairment.
– Hearing organ disorders and labyrinth disorders
Infrequent: tinnitus.
– Heart disorders
Often: palpitations;
Very rarely: development or worsening of chronic heart failure, heart rhythm disorders (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, pain in the chest.
– Vascular disorders
Often: peripheral edema (ankles and feet), “hot flashes”;
Infrequent: significant decrease in blood pressure;
Very rarely: syncope, vasculitis, orthostatic hypotension.
– Respiratory system, chest and mediastinal organs disorders
Infrequent: dyspnea, rhinitis, nasal bleeding;
Very rare: cough.
Disorders of the digestive system
Often: nausea, abdominal pain;
Infrequent: Vomiting, constipation, diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst;
Rarely: gum hyperplasia, increased appetite;
Very rare: pancreatitis, gastritis.
– Liver and biliary tract disorders
Very rarely: jaundice (usually cholestatic), hyperbilirubinemia, increased activity of liver transaminases, hepatitis.
Skin and subcutaneous tissue disorders
Rare: dermatitis;
Very rare: alopecia, xeroderma, “cold” sweat, impaired skin pigmentation.
– Disorders of the skeletal-muscular and connective tissue
Infrequent: arthralgia, muscle cramps, myalgia, back pain, arthrosis;
Rare: myasthenia.
Renal and urinary tract disorders
Infrequent: frequent urination, painful urination, nycturia;
Very rare: dysuria, polyuria.
Genital and mammary gland disorders
Infrequent: erectile dysfunction, gynecomastia.
– General disorders and disorders at the injection site
Infrequent: pain of unspecified localization, weight gain/loss.

Lisinopril
– Disorders of the blood and lymphatic system
Rare: decrease in hemoglobin and hematocrit;
Very rare: Inhibition of bone marrow function, lymphadenopathy, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, hemolytic anemia, anemia;
Frequently unknown: erythropenia.
– Immune system disorders
Infrequent: skin rash, itching;
Rare: angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx;
Very rare: Intestinal angioedema, autoimmune diseases, increased antinuclear antibody titer, increased erythrocyte sedimentation rate (ESR);
Frequency unknown: eosinophilia, leukocytosis, fever (there are reports of the development of lupus-like syndrome, which may include fever, myalgia, arthralgia/arthritis, increased antinuclear antibody titer, increased CRP, eosinophiligo, leukocytosis, and possible rash, photosensitivity reactions or other skin manifestations).
– Endocrine system disorders
Frequency is unknown: syndrome of inadequate secretion of antidiuretic hormone.
– Metabolism and nutrition disorders
Very rare: hypoglycemia.
– Psychiatric disorders
Often: sleep disturbance;
Infrequent: mood lability;
Rare: confusion;
Frequently unknown: confusion, depression.
– Nervous system disorders
Often: dizziness, headache;
Infrequent: paresthesia, somnolence;
Rarely: asthenic syndrome;
Frequently unknown: syncope, convulsive twitching of muscles of face and limbs.
– Cardiac disorders
Infrequent: chest pain, myocardial infarction (due to significant decrease in BP in high-risk patients);
Rare: tachycardia, bradycardia, worsening of chronic heart failure, atrioventricular conduction disturbances, palpitations.
– Vascular disorders
Often: marked BP decrease;
Infrequent: cerebral circulation disorders (due to marked BP decrease/risk patients), Raynaud’s syndrome;
Rare: orthostatic hypotension;
Frequency unknown: vasculitis.
– Respiratory system, thorax and mediastinum disorders
Often: “dry” cough, sinusitis, allergic alveolitis/eosinophilic pneumonia;
Infrequent: rhinitis;
Very rare: bronchospasm;
Often unknown: dyspnea.
– Digestive system disorders
Infrequent: dyspepsia, perversion of taste, abdominal pain;
Rare: dry mouth mucosa;
Very rare: pancreatitis;
Frequency unknown: anorexia.
– Disorders of the liver and biliary tract
Often: liver failure;
Very rare: hepatocellular and cholestatic jaundice, hepatitis.
– Skin and subcutaneous tissue disorders
Infrequent: skin rash, itching;
Rare: urticaria, alopecia, psoriasis, photosensitization;
Very rare: increased sweating, vesicles, Stevens-Johnson syndrome, toxic epidermal necrolysis, exudative erythema multiforme, skin pseudolymphoma.
– Musculoskeletal and connective tissue disorders
Frequency unknown: myalgia, arthralgia/arthritis.
– Renal and urinary tract disorders
Often: impaired renal function;
Rare: acute renal failure, uremia;
Very rare: oliguria, anuria;
Frequently unknown: proteinuria.
– Disorders of the genitals and breast
Infrequent: decreased potency;
Rare: gynecomastia.
Influence on the results of laboratory and instrumental studies
Infrequent: hyperkalemia, hyponatremia, increased concentration of urea and creatinine in serum;
Rare: increased activity of “liver” enzymes, hyperbilirubinemia.
Simultaneous use of LPF inhibitors and intravenous gold drugs (sodium aurothiomalate) described a symptom complex including facial hyperemia, nausea, vomiting and decrease in BP.

Rosuvastatin
Side effects observed when taking rosuvastatin are usually mild and go away on their own. As with the use of other HMG-CoA-reductase inhibitors, the incidence of side effects is mainly dose-dependent.
– Blood and lymphatic system disorders
Frequency is unknown: thrombocytopenia.
– Immune system disorders
Rare: hypersensitivity reactions, including angioedema.
– Endocrine system disorders
Often: diabetes of type 2 (frequency will depend on the presence or absence of risk factors (fasting glucose concentration >5.6 mmol/l, BMI >30 kg/m2, triglyceride hypertension in anamnesis).
– Mental disorders
Frequency unknown: depression.
– Nervous system disorders
Often: headache, dizziness;
Very rarely: polyneuropathy, memory loss or decrease;
Often unknown: peripheral neuropathy, sleep disorders (including insomnia and “nightmares” dreams).
– Respiratory system, chest and mediastinum organs disorders
Frequency unknown: cough, shortness of breath.
– Digestive system disorders
Often: constipation, nausea, abdominal pain;
Rare: pancreatitis;
Frequency unknown: diarrhea.
– Disorders of the liver and biliary tract
Rare: increased activity of “liver” transaminases;
Very rare: jaundice, hepatitis.
– Skin and subcutaneous tissue disorders
Infrequent: skin itching, rash, urticaria;
Frequency unknown: Stevens-Johnson syndrome.
– Musculoskeletal and connective tissue disorders
Often: myalgia;
Rare: myopathy (including myositis), rhabdomyolysis with or without the development of acute renal failure;
Very rare: Arthralgia;
Frequency unknown: immune-mediated necrotizing myopathy, tendon disease, in some cases complicated by rupture, temporary increase in creatine phosphokinase (CPK) activity. In case of increase of CPK activity (more than 5 times the upper limit of normal) the therapy should be suspended (see section “Indications”).
– Disorders of the kidneys and urinary tract
Very rare: hematuria;
Frequency unknown: proteinuria.
– Genital and mammary disorders
Frequently unknown: gynecomastia.
General disorders and disorders at the site of administration
Frequently: asthenia;
Frequently unknown: peripheral edema.
Effect on the results of laboratory and instrumental studies
Frequency unknown: increased concentration of bilirubin, blood glucose, increased concentration of glycosylated hemoglobin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid disorders.
When using some HMG-CoA reductase inhibitors the following adverse effects were reported:

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

There are no data on overdose of Equimer.

Amlodipine

Symptoms: pronounced BP decrease with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including development of shock and death).

The treatment: gastric lavage, administration of activated charcoal (especially in the first 2 hours after overdose), maintenance of cardiovascular function, elevated position of the lower extremities, control of cardiovascular and respiratory system functions, control of circulating blood volume (RBC) and diuresis. To restore vascular tone – use vasoconstrictors (if there are no contraindications for their use); to eliminate the effects of calcium channel blockade – intravenous injection of calcium gluconate. Hemodialysis is ineffective.

Lisinopril

Symptoms: marked decrease in BP, dry mouth, drowsiness, urinary retention, constipation, anxiety, increased irritability, impaired renal function, electrolyte-water balance, tachycardia, bradycardia, collapse, hyperventilation of the lungs, dizziness.

Treatment: symptomatic therapy, intravenous administration of 0.9% sodium chloride solution and, if possible, use of vasopressors, BP control, water and electrolyte balance. In stable bradycardia an artificial pacemaker may be used. Hemodialysis is possible (see instructions for patients on hemodialysis under “Cautions”).

Rosuvastatin

The pharmacokinetic parameters of rosuvastatin do not change when multiple daily doses are taken simultaneously.

There is no specific treatment for rosuvastatin overdose. In case of overdose it is recommended to perform symptomatic treatment and measures aimed at maintenance of functions of vital organs and systems. Control of liver function and CPK activity is necessary. Hemodialysis is unlikely to be effective.