Lipertans^® (Tablets) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Laboratories Industrie (France)

Packaging and Quality Control Release

Servier (Ireland) Industries, Ltd. (Ireland)

ATC Code

C10BX11 (Atorvastatin, amlodipine and perindopril)

Active Substances

Amlodipine (Rec.INN)

Atorvastatin (Rec.INN)

Perindopril (Rec.INN)

Dosage Forms

	Lipertans®	Film-coated tablets, 5 mg+10 mg+5 mg: 30 pcs.
		Film-coated tablets, 5 mg+20 mg+5 mg: 30 pcs.
		Film-coated tablets, 5 mg+20 mg+10 mg: 30 pcs.
		Film-coated tablets, 10 mg+20 mg+10 mg: 30 pcs.
		Film-coated tablets, 10 mg+40 mg+10 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, with engravings “1” on one side and ” on the other side.

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose (avicel PH-101), sodium carboxymethyl starch, hypromellose, maltodextrin, magnesium stearate.

Coating composition: sepifilm 3915 yellow (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171), iron oxide yellow dye (E172)).

30 pcs. – polypropylene bottles with a dispenser and a cap containing 2 g of silica gel (1) – cardboard packs with first opening control.

Film-coated tablets yellow, round, with engravings “2” on one side and ” on the other side.

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose (avicel PH-101), sodium carboxymethyl starch, hypromellose, maltodextrin, magnesium stearate.

Coating composition: sepifilm 3915 yellow (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171), iron oxide yellow dye (E172)).

30 pcs. – polypropylene bottles with a dispenser and a cap containing 2 g of silica gel (1) – cardboard packs with first opening control.

Film-coated tablets yellow, square with rounded corners, with engravings “3” on one side and ” on the other side.

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose (avicel PH-101), sodium carboxymethyl starch, hypromellose, maltodextrin, magnesium stearate.

Coating composition: sepifilm 3915 yellow (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171), iron oxide yellow dye (E172)).

30 pcs. – polypropylene bottles with a dispenser and a cap containing 2 g of silica gel (1) – cardboard packs with first opening control.

Film-coated tablets yellow, oblong, with engravings “4” on one side and ” on the other side.

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose (avicel PH-101), sodium carboxymethyl starch, hypromellose, maltodextrin, magnesium stearate.

Coating composition: sepifilm 3915 yellow (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171), iron oxide yellow dye (E172)).

30 pcs. – polypropylene bottles with a dispenser and a cap containing 2 g of silica gel (1) – cardboard packs with first opening control.

Film-coated tablets yellow, oblong, with engravings “5” on one side and ” on the other side.

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose (avicel PH-101), sodium carboxymethyl starch, hypromellose, maltodextrin, magnesium stearate.

Coating composition: sepifilm 3915 yellow (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171), iron oxide yellow dye (E172)).

30 pcs. – polypropylene bottles with a dispenser and a cap containing 2 g of silica gel (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Combined drug (ACE inhibitor + slow calcium channel blocker + cholesterol synthesis inhibitor)

Pharmacotherapeutic Group

Hypolipidemic agents; hypolipidemic agents, combinations; hypolipidemic agents in combination with other agents

Pharmacological Action

Combined drug with antihypertensive, antianginal and hypolipidemic action.

Amlodipine is a slow calcium channel blocker, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The detailed mechanism by which amlodipine exerts its antianginal action is not fully established, but it is known that amlodipine reduces the total ischemic load through a dual action

• Causes dilation of peripheral arterioles, reducing total peripheral vascular resistance (afterload). Since the heart rate does not change, the myocardial oxygen demand decreases;
• Causes dilation of coronary arteries and arterioles in both ischemic and intact areas. Their dilation increases oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal’s angina, or variant angina).

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in standing and lying positions for 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical.

In patients with angina, taking amlodipine once a day increases total exercise time, increases time to onset of angina attack and time to 1 mm ST segment depression, and reduces the frequency of angina attacks and sublingual nitroglycerin consumption.

Amlodipine has no adverse metabolic effects and does not affect plasma lipid concentrations. The drug can be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that both converts angiotensin I to the vasoconstrictor angiotensin II and breaks down bradykinin, which has a vasodilating effect, into an inactive heptapeptide.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both circulating and tissue kallikrein-kinin systems, and the prostaglandin system is also activated.

Perindopril exerts its therapeutic effect through an active metabolite, perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro.

Atorvastatin is a statin that reduces plasma cholesterol and lipoprotein concentrations by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, and increases the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL. Reduces the formation of LDL and the number of LDL particles. Atorvastatin causes a significant and persistent increase in LDL receptor activity combined with favorable qualitative changes in circulating LDL particles. Effectively reduces LDL cholesterol concentration in patients with homozygous hereditary hypercholesterolemia, usually resistant to therapy with other hypolipidemic agents.

Pharmacokinetics

The extent of absorption of amlodipine and perindopril when using this combination does not differ significantly from that when using single-component drugs.

Amlodipine

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine. C_max of amlodipine in plasma is reached 6-12 hours after oral administration of the drug. Absolute bioavailability is about 64-80%. V_d is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine is bound to plasma proteins.

The terminal T_1/2 of amlodipine from plasma is 35-50 hours. Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the administered dose excreted unchanged and 60% excreted by the kidneys as metabolites.

Perindopril arginine

When taken orally, perindopril is rapidly absorbed, C_max in plasma is reached within 1 hour. T_1/2 of perindopril from plasma is 1 hour. Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream in the form of the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals. There is a linear relationship between the plasma concentration of perindopril and its dose. V_d of free perindoprilat is approximately 0.2 L/kg. Binding of perindoprilat to plasma proteins, mainly to ACE, is about 20% and is dose-dependent. Perindoprilat is excreted from the body by the kidneys. The terminal T_1/2 of the free fraction is about 17 hours, so steady state is reached within 4 days.

Atorvastatin

Atorvastatin is rapidly absorbed after oral administration, C_max in plasma is reached in 1-2 hours. The extent of absorption of atorvastatin increases in proportion to the dose. The absolute bioavailability of atorvastatin is about 12%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and/or first-pass metabolism in the liver. The average V_d of atorvastatin is about 381 L. Binding to plasma proteins is at least 98%. Atorvastatin is metabolized by the CYP3A4 isoenzyme to ortho- and parahydroxylated derivatives and various beta-oxidation products. In addition to other metabolic pathways, these products are further metabolized by conjugation with glucuronic acid. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to its inhibition by atorvastatin. Approximately 70% of the reduction in HMG-CoA reductase activity is due to the action of active circulating metabolites. Atorvastatin is excreted mainly in the bile as a result of hepatic and/or extrahepatic metabolism. However, atorvastatin does not undergo significant enterohepatic recirculation. The average T_1/2 is about 14 hours, while the T_1/2 of inhibitory activity against HMG-CoA reductase due to the action of active metabolites is about 20-30 hours.

Indications

This fixed combination is intended for use in patients who require combination therapy with amlodipine, atorvastatin and perindopril in appropriate doses.

Arterial hypertension in adult patients with lipid metabolism disorders: primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant), or combined (mixed) hypercholesterolemia (type IIa and type IIb according to the Fredrickson classification, respectively), when the response to diet and other non-drug treatments is insufficient; homozygous familial hypercholesterolemia – as an adjunct to other hypolipidemic treatments (e.g., LDL apheresis) or if such treatments are not available.

Stable coronary artery disease in adult patients with lipid metabolism disorders: primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant), or combined (mixed) hypercholesterolemia (type IIa and type IIb according to the Fredrickson classification, respectively) when diet therapy and other non-drug methods are insufficiently effective; homozygous familial hypercholesterolemia – as an adjunct to other hypolipidemic treatments (e.g., LDL apheresis) or if such treatments are not available.

ICD codes

Dosage Regimen

Orally, once a day.

The dose of the fixed combination is selected after previously conducted titration of doses of single-component drugs containing the corresponding active substances. If a change in the dose of one of the active substances is required (for example, due to a newly diagnosed disease, a change in the patient’s condition, the development of arterial hypotension or a drug interaction), then an individual selection of doses of individual components is necessary.

Adverse Reactions

From the hematopoietic system very rarely – leukopenia, neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency, decreased hemoglobin concentration and hematocrit.

From the immune system infrequently – allergic reactions.

From metabolism very rarely – hyperglycemia; frequency not specified – hypoglycemia.

From the nervous system: frequently – drowsiness (especially at the beginning of treatment), dizziness (especially at the beginning of treatment), headache, paresthesia, vertigo; infrequently – insomnia, mood lability (including anxiety), sleep disturbance, tremor, hypoesthesia, depression, syncope; rarely – confusion; very rarely – peripheral neuropathy, hypertonia.

From the sensory organs: frequently – visual disturbances (including diplopia), tinnitus.

From the cardiovascular system: frequently – palpitations, flushing, marked decrease in blood pressure; very rarely – angina pectoris, myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients, arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), stroke, possibly due to excessive blood pressure reduction in high-risk patients, vasculitis.

From the respiratory system frequently – dyspnea, cough; infrequently – rhinitis, bronchospasm; very rarely – eosinophilic pneumonia.

From the digestive system: frequently – abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation; infrequently – change in bowel rhythm, dry mouth; very rarely – pancreatitis, gingival hyperplasia, gastritis, hepatitis, jaundice, increased activity of liver enzymes (most often in combination with cholestasis), cytolytic or cholestatic hepatitis.

From the skin and subcutaneous tissue frequently – skin itching, rash, exanthema; infrequently – angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx, alopecia, hemorrhagic rash, skin discoloration, increased sweating, urticaria; very rarely – Quincke’s edema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity.

From the musculoskeletal system: frequently – muscle cramps, leg edema; infrequently – arthralgia, myalgia, back pain, muscle fatigue; rarely – myositis, rhabdomyolysis, tendinopathy (sometimes accompanied by tendon rupture); frequency unknown – immune-mediated necrotizing myopathy.

From the urinary system: infrequently – urination disorder, nocturia, frequent urination, renal function impairment; very rarely – acute renal failure.

From the reproductive system and mammary gland infrequently – impotence, gynecomastia.

General reactions frequently – edema, asthenia, increased fatigue; infrequently – chest pain, malaise, pain.

Laboratory parameters often – increased CPK; infrequently – weight gain, weight loss; rarely – increased bilirubin concentration; frequency not specified – increased serum urea and creatinine concentration, hyperkalemia.

Additional data on amlodipine: isolated cases of extrapyramidal syndrome have been reported.

Contraindications

Hypersensitivity to amlodipine, perindopril, atorvastatin or to other ACE inhibitors, to other dihydropyridine derivatives, to other statins; active liver disease or unexplained persistent elevation of plasma hepatic transaminases more than 3 times the upper limit of normal; severe arterial hypotension; shock (including cardiogenic); left ventricular outflow tract obstruction (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction; history of angioedema (Quincke’s edema) while taking other ACE inhibitors; hereditary or idiopathic angioedema; concomitant use with aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (GFR < 60 ml/min/1.73 m² body surface area); concomitant use with angiotensin II receptor antagonists (ARBs) in patients with diabetic nephropathy; concomitant use with fusidic acid; concomitant use with the combination sacubitril/valsartan; extracorporeal treatments using certain negatively charged surface membranes; bilateral renal artery stenosis or stenosis of the artery to a single kidney; pregnancy, breastfeeding period, use in women of childbearing potential not using adequate contraceptive methods; children under 18 years of age.

With caution

Interstitial lung disease, diabetes mellitus, CHF, arterial hypotension, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, renal failure, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), hemodialysis using high-flux membranes, hypersensitivity/angioedema, anaphylactic reaction during LDL apheresis and desensitization, neutropenia, use in Black patients, surgery/general anesthesia, hyperkalemia, concomitant use of lithium preparations, potassium, potassium-sparing diuretics, potassium-containing salt substitutes, dual blockade of the RAAS, hepatic impairment, use in patients who abuse alcohol and/or have a history of liver disease, use in patients with risk factors for rhabdomyolysis, concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme, elderly age, acute myocardial infarction (and the period within 1 month after it), unstable angina, sick sinus syndrome.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: active liver disease or unexplained persistent elevation of plasma hepatic transaminases more than 3 times the upper limit of normal;

Use in Renal Impairment

This combination is contraindicated in renal failure (creatinine clearance less than 60 ml/min).

The drug should be prescribed with caution in bilateral renal artery stenosis, stenosis of the artery to a single functioning kidney; renal failure.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The elimination of perindoprilat is slowed in elderly patients. Therefore, in such patients, plasma creatinine and potassium concentrations should be regularly monitored.

Special Precautions

Amlodipine

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

Treatment of patients with heart failure should be carried out with caution. When using amlodipine in patients with chronic heart failure NYHA Class III and IV, pulmonary edema may develop. Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure due to a possible increased risk of cardiovascular adverse events and mortality.

In patients with impaired liver function, the T_1/2 and AUC of amlodipine increase. Dosing recommendations have not been established. Amlodipine should be started at the lowest doses and precautions should be taken, both at the start of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of clinical status.

In elderly patients, dose increases should be performed with caution.

Patients with renal impairment can take amlodipine at standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed from the body by dialysis.

Perindopril

When taking ACE inhibitors, including perindopril, the development of angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may occur in rare cases. This can occur at any time during therapy. If symptoms appear, the drug should be discontinued immediately and the patient should be observed until the signs of edema completely disappear. If the edema involves only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If such symptoms occur, epinephrine (adrenaline) should be administered subcutaneously immediately and/or airway patency should be ensured. The patient should be under medical supervision until the symptoms have completely and permanently resolved.

In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development when taking drugs of this group may be increased.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea or vomiting, in some cases, without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is made using computed tomography of the abdominal area, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

In rare cases, in patients receiving ACE inhibitors, life-threatening anaphylactoid reactions may develop during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

There are isolated reports of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy (e.g., with hymenoptera venom). In these same patients, an anaphylactoid reaction was avoided by temporarily discontinuing ACE inhibitors, and when the drug was accidentally taken, the anaphylactoid reaction recurred.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur during ACE inhibitor therapy. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with particular caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the white blood cell count. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Thus, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended. If therapy with dual blockade is considered absolutely necessary, it should be carried out only under strict medical supervision and with regular monitoring of renal function, blood electrolyte levels, and blood pressure.

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

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients without concomitant diseases. The risk of excessive blood pressure reduction is increased in patients with reduced blood volume, which may occur during diuretic therapy, while following a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity. In patients at increased risk of symptomatic arterial hypotension, blood pressure, renal function, and serum potassium levels should be carefully monitored during therapy with the combination drug.

A similar approach applies to patients with angina and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in a supine position with legs elevated. If necessary, blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further use of the drug. After restoration of blood volume and blood pressure, treatment can be continued.

Perindopril, like other ACE inhibitors, should be prescribed with caution to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as to patients with mitral stenosis. Amlodipine is contraindicated in patients with left ventricular outflow tract obstruction.

In patients with renal impairment (creatinine clearance less than 60 ml/min), individual selection of perindopril and amlodipine doses is recommended. Such patients require regular monitoring of serum potassium and creatinine levels.

In patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney, during therapy with ACE inhibitors, an increase in serum urea and creatinine may occur, which usually resolves upon discontinuation of therapy. This effect is more often observed in patients with renal impairment. The additional presence of renovascular hypertension causes an increased risk of severe arterial hypotension and renal failure in such patients.

In some patients with arterial hypertension without signs of renal vascular disease, an increase in serum urea and creatinine concentration may occur, especially with the simultaneous administration of perindopril with a diuretic, usually minor and transient. This effect is more often observed in patients with pre-existing renal impairment.

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs while taking ACE inhibitors, the drug should be discontinued and a doctor should be consulted.

Black patients develop angioedema while taking ACE inhibitors more often than patients of other races.

Perindopril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in Black patients compared to patients of other races. Perhaps this difference is due to the fact that Black patients with arterial hypertension more often have low renin activity.

A dry cough may occur during ACE inhibitor therapy. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. This should be taken into account when conducting a differential diagnosis of cough.

In patients scheduled for major surgery or the use of anesthetic agents that cause arterial hypotension, the use of perindopril may block the formation of angiotensin II against the background of compensatory renin release. Treatment should be discontinued one day before surgery. If arterial hypotension develops due to the specified mechanism, blood pressure should be maintained by replenishing blood volume.

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes, and the use of other drugs that contribute to an increase in plasma potassium levels (e.g., heparin). The use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function.

Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of perindopril and the above drugs is necessary, treatment should be carried out with caution while regularly monitoring serum potassium levels.

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be carefully monitored during the first month of therapy.

Atorvastatin

Liver function should be monitored before starting treatment with atorvastatin and periodically during treatment. If liver enzyme activity increases, exceeding the upper limit of normal by 3 times, it is recommended to reduce the dose or discontinue use. In patients with impaired liver function, the T_1/2 of amlodipine increases, so caution is required when using this combination..

The diagnosis of myopathy should be considered in patients taking HMG-CoA reductase inhibitors who have unexplained symptoms, such as muscle pain or tenderness, muscle weakness, or muscle cramps. In such cases, CPK activity monitoring is necessary. CPK activity should not be measured after intense physical exertion or if there is a likely alternative cause for increased CPK activity. If CPK activity is significantly above normal (more than 5 times the upper limit of normal), CPK activity should be determined regularly for 5-7 days to confirm the results.

CPK activity should be determined before starting treatment with atorvastatin in the following situations: impaired renal function; hypothyroidism; personal or family history of muscle diseases; history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates; history of liver disease and/or alcohol abuse; in elderly patients (> 65 years) in the presence of risk factors for rhabdomyolysis. The expected benefit and risk of treatment should be carefully weighed and patients should be regularly monitored. If CPK activity is increased more than 5 times compared to the upper limit of normal, treatment should not be started.

Patients should be informed of the need to immediately report to the doctor any cases of unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise or fever.

If muscle pain, weakness, or cramps occur during treatment, CPK activity should be monitored. If it is determined that CPK activity has exceeded the upper limit of normal by more than 5 times, treatment should be discontinued.

If muscle symptoms are severe and cause daily discomfort throughout the day, even if CPK activity is increased less than 5 times compared to the upper limit of normal, treatment should be discontinued.

Increased CPK activity should be taken into account in the differential diagnosis of chest pain when assessing the likelihood of myocardial infarction. When using atorvastatin, as with other drugs of this class, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described.

Concomitant use of this combination and dantrolene (infusion solution), gemfibrozil or other fibrates is not recommended.

When used concomitantly with cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), fibric acid derivatives, macrolide antibiotics, including erythromycin, clarithromycin, antifungal drugs belonging to the azoles (itraconazole, ketoconazole), nefazodone, as well as HIV protease inhibitors, the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors increases.

Effect on the ability to drive vehicles and mechanisms

Although no negative effect on the ability to drive vehicles or other complex mechanisms was observed while taking the drug, due to the possible excessive decrease in blood pressure, development of dizziness, drowsiness and other adverse reactions, caution should be exercised in the listed situations, especially at the beginning of treatment and when increasing the dose.

Drug Interactions

Amlodipine

Dantrolene (IV administration) in laboratory animals, cases of fatal ventricular fibrillation and collapse were noted against the background of verapamil use and IV administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers, including amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as when treating malignant hyperthermia.

Inducers of the CYP3A4 isoenzyme data on the effect of inducers of the CYP3A4 isoenzyme on amlodipine are lacking. Concomitant use of inducers of the CYP3A4 isoenzyme (e.g., rifampicin, St. John’s wort preparations) may lead to a decrease in the plasma concentration of amlodipine. Caution should be exercised when using amlodipine and inducers of microsomal oxidation concomitantly.

Inhibitors of the CYP3A4 isoenzyme concomitant use of amlodipine and potent or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, antifungal drugs of the azole group, macrolides, e.g., erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in the concentration of amlodipine. The clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients, therefore clinical monitoring and dose adjustment may be required.

Amlodipine enhances the hypotensive effect of drugs with antihypertensive action.

Perindopril

Clinical trial data show that dual blockade of the RAAS due to the simultaneous use of ACE inhibitors, ARBs, or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to situations where only one drug affecting the RAAS is used.

Potassium-sparing diuretics, potassium preparations, and potassium-containing salt substitutes despite serum potassium levels remaining within the normal range, some patients may develop hyperkalemia when using perindopril. Potassium-sparing diuretics (e.g., spironolactone, eplerenone (a spironolactone derivative), triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes can lead to a significant increase in serum potassium levels. Therefore, the simultaneous use of an ACE inhibitor and the aforementioned agents is not recommended. If concomitant use is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be performed.

Lithium preparations when lithium preparations and ACE inhibitors are used concomitantly, a reversible increase in plasma lithium levels and associated toxic effects may occur. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of plasma lithium levels is required.

Estramustine simultaneous use of estramustine with ACE inhibitors is associated with an increased risk of angioedema.

NSAIDs, including high doses of acetylsalicylic acid (≥3 g/day) simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect of ACE inhibitors. Concurrent use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium levels, especially in patients with pre-existing reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should have their fluid loss compensated and renal function carefully monitored both at the start of treatment and during the treatment process.

Hypoglycemic agents (insulin, sulfonylurea derivatives) ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is observed very rarely (probably due to increased glucose tolerance and reduced insulin requirement).

Diuretics (thiazide and “loop”) in patients receiving diuretics, especially with excessive fluid and/or electrolyte loss, a significant decrease in BP may be observed at the start of therapy with an ACE inhibitor; the risk of this can be reduced by discontinuing the diuretic, administering increased amounts of fluid and/or table salt, and by initiating perindopril at a low dose with subsequent gradual increase.

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Gold preparations when using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparations (sodium aurothiomalate), a symptom complex including facial flushing, nausea, vomiting, and arterial hypotension has been described.

Simultaneous use with ACE inhibitors allopurinol, immunosuppressive agents, corticosteroids (for systemic use), and procainamide may be associated with an increased risk of leukopenia, especially in patients with pre-existing renal impairment.

Concomitant use of ACE inhibitors and agents for general anesthesia may lead to a hypotensive effect.

Atorvastatin

Concomitant intake of amlodipine and consumption of grapefruit or grapefruit juice is not recommended, due to a possible increase in the bioavailability of amlodipine in some patients, which, in turn, may lead to an enhancement of the BP-lowering effects.

Itraconazole, ketoconazole: the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (due to reduced hepatic metabolism of atorvastatin).

Telithromycin: the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (due to reduced hepatic metabolism of atorvastatin).

Gemfibrozil and other fibric acid derivatives the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (due to reduced hepatic metabolism of atorvastatin).

CYP3A4 isoenzyme inhibitors: atorvastatin is metabolized by the CYP3A4 isoenzyme. Erythromycin, a CYP3A4 inhibitor, increased the plasma concentration of atorvastatin by 40%. Concomitant administration of atorvastatin and CYP3A4 inhibitors, certain macrolide antibiotics (e.g., erythromycin, clarithromycin), immunosuppressants (cyclosporine), antifungal agents belonging to the azole class (e.g., itraconazole, ketoconazole), amiodarone, protease inhibitors, or the antidepressant nefazodone, may lead to an interaction resulting in increased plasma concentrations of atorvastatin.

CYP3A4 isoenzyme inducers simultaneous use of atorvastatin and inducers of the CYP3A4 isoenzyme (e.g., phenytoin, rifampicin) may lead to a significant decrease in the plasma concentration of atorvastatin. Due to the dual mechanism of interaction of rifampicin (induction of the CYP3A4 isoenzyme and inhibition of the hepatocyte uptake transporter OATP1B1), co-administration of atorvastatin and rifampicin led to a mean increase in the C_max and AUC parameters of atorvastatin by 12% and 90%, respectively. In contrast, taking atorvastatin some time after rifampicin intake was accompanied by a significant decrease (approximately 80%) in the plasma concentration of atorvastatin.

Warfarin: taking atorvastatin concomitantly with warfarin may lead to an enhancement of the anticoagulant effect with a risk of bleeding. Patients receiving warfarin should be monitored by a physician, as adjustment of the anticoagulant dose may be required.

Nicotinic acid: lipid-lowering doses of nicotinic acid (more than 1 g/day) may increase the risk of myopathy when taken concomitantly with HMG-CoA reductase inhibitors. Rarely, renal failure may develop as a consequence of rhabdomyolysis and myoglobinuria. Therefore, the benefit/risk ratio of simultaneous use of atorvastatin and nicotinic acid in lipid-lowering doses should be considered.

Antacids: simultaneous oral intake of a suspension containing magnesium and aluminum hydroxides reduced the plasma concentration of atorvastatin by approximately 35%, however, the degree of LDL-C reduction did not change.

Grapefruit juice: grapefruit juice contains one or more components that inhibit CYP3A4, and therefore can lead to increased plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme. Consumption of one glass (240 ml) of grapefruit juice led to an increase in the AUC of atorvastatin by 37% and a decrease in the AUC of the active ortho-hydroxy metabolite of atorvastatin by 20.4%. However, larger quantities of grapefruit juice (more than 1.2 l/day for 5 days) increased the AUC of atorvastatin by 2.5 times and the AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) by 1.3 times. Simultaneous intake of large quantities of grapefruit juice and atorvastatin is not recommended.

Oral contraceptives: use of atorvastatin together with an oral contraceptive containing norethisterone and ethinyl estradiol led to increased plasma concentrations of norethisterone and ethinyl estradiol. This effect should be considered when selecting an oral contraceptive for a woman receiving atorvastatin.

Colestipol: the lipid-lowering effect of the combination with colestipol is superior to that of each drug individually, despite a 25% reduction in the concentration of atorvastatin when used simultaneously with colestipol.

Antipyrine (phenazone): simultaneous administration of multiple doses of atorvastatin and phenazone revealed a minor effect on the clearance of phenazone, or the absence of such an effect.

During long-term use of digoxin simultaneously with 10 mg of atorvastatin, a slight increase in the steady-state concentrations of digoxin was observed.

Assessment of the effect of amiodarone or verapamil on atorvastatin has not been conducted. It is known that both drugs – amiodarone and verapamil – inhibit the activity of the CYP3A4 isoenzyme, and their simultaneous use with atorvastatin may lead to an increase in the concentration of atorvastatin.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.