Roxatenz^®-inda (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

C10BX13 (Rosuvastatin, Perindopril and Indapamide)

Active Substances

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Rosuvastatin (Rec.INN registered by WHO)

Dosage Forms

	Roxatenz®-inda	Film-coated tablets, 1.25 mg+4 mg+10 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 1.25 mg+4 mg+20 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 2.5 mg+8 mg+10 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 2.5 mg+8 mg+20 mg: 30, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of a reddish-brown color, round, slightly biconvex, with an engraving “PIR1” on one side and a bevel.

Excipients: microcrystalline cellulose, type 200, low moisture, microcrystalline cellulose, type 112, crospovidone type A, colloidal silicon dioxide, magnesium stearate.

Film coating composition film-forming mixture 1: polyvinyl alcohol, macrogol-3350, titanium dioxide (E171), talc, iron oxide red (E172), iron oxide black (E172), iron oxide yellow (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets pink with a grayish tint, round, slightly biconvex, with an engraving “PIR2” on one side and a bevel.

Excipients: microcrystalline cellulose, type 200, low moisture, microcrystalline cellulose, type 112, crospovidone type A, colloidal silicon dioxide, magnesium stearate.

Film coating composition film-forming mixture 2: polyvinyl alcohol, macrogol-3350, titanium dioxide (E171), talc, iron oxide red (E172), iron oxide yellow (E172), iron oxide black (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets light pink in color, round, slightly biconvex, with an engraving “PIR3” on one side and a bevel.

Excipients: microcrystalline cellulose, type 200, low moisture, microcrystalline cellulose, type 112, crospovidone type A, colloidal silicon dioxide, magnesium stearate.

Film coating composition film-forming mixture 3: polyvinyl alcohol, macrogol-3350, titanium dioxide (E171), talc, iron oxide red (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets pale pinkish-brown in color, round, slightly biconvex, with an engraving “PIR4” on one side and a bevel.

Excipients: microcrystalline cellulose, type 200, low moisture, microcrystalline cellulose, type 112, crospovidone type A, colloidal silicon dioxide, magnesium stearate.

Film coating composition film-forming mixture 4: polyvinyl alcohol, macrogol-3350, titanium dioxide (E171), talc, iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive and hypolipidemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

A combined medicinal product containing perindopril – an ACE inhibitor, Indapamide – a thiazide-like diuretic, and rosuvastatin – a selective, competitive inhibitor of HMG-CoA reductase (statin).

Indapamide

Indapamide belongs to sulfonamide derivatives and is pharmacologically similar to thiazide diuretics.

Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increased excretion of sodium, chloride, and to a lesser extent potassium and magnesium ions by the kidneys, thereby enhancing diuresis and reducing blood pressure.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II, a vasoconstrictor substance; in addition, ACE stimulates the secretion of aldosterone and the breakdown of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide.

As a result, perindopril: reduces aldosterone secretion; increases plasma renin activity by negative feedback; with long-term use, reduces total peripheral resistance, which is mainly due to its effect on blood vessels in muscles and kidneys.

These effects are not accompanied by sodium or fluid retention, or the development of reflex tachycardia.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

Perindopril acts through its main active metabolite – perindoprilat. Its other metabolites are inactive.

The action of perindopril leads to: venous dilation (reduction of cardiac preload), due to changes in prostaglandin metabolism; reduction of total peripheral resistance (reduction of cardiac afterload).

When studying hemodynamic parameters in patients with chronic heart failure (CHF), the following was revealed: a decrease in filling pressure in the left and right ventricles of the heart; a decrease in total peripheral resistance; an increase in cardiac output and an increase in cardiac index; enhanced muscular peripheral blood flow.

As a result, exercise test results are significantly improved.

Rosuvastatin

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, a precursor of cholesterol.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn inhibits the synthesis of VLDL, thereby reducing the total amount of LDL and VLDL.

Pharmacokinetics

Indapamide

Rapidly and completely absorbed from the gastrointestinal tract. C_max in plasma is reached 1 hour after oral administration. The degree of binding to plasma proteins is 79%.

T_1/2 is 14-24 hours (average 18 hours). Repeated administration of indapamide does not lead to its accumulation in the body. It is excreted mainly by the kidneys (70% of the orally administered dose) and through the intestines (22%) in the form of inactive metabolites.

Perindopril

When taken orally, perindopril is rapidly absorbed. C_max in plasma is reached 1 hour after oral administration.

Perindopril is a prodrug, i.e., it does not possess pharmacological activity. About 27% of the orally administered dose of perindopril enters the bloodstream as the active metabolite – perindoprilat. In addition to the active metabolite – perindoprilat, 5 other metabolites are formed, which do not possess 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, perindopril should be taken once a day, in the morning, before meals.

V_d of free perindoprilat is approximately 0.2 L/kg. The degree of binding of perindoprilat to plasma proteins (mainly to ACE) depends on the concentration of perindopril and is about 20%.

T_1/2 of perindopril from plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The terminal T_1/2 of the free fraction is about 17 hours, and steady state is reached within 4 days.

There is a linear relationship between the plasma concentration of perindopril and the orally administered dose.

Rosuvastatin

C_max of rosuvastatin in plasma is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

It is metabolized mainly by the liver, which is the main organ synthesizing cholesterol and metabolizing LDL-C. V_d of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

It undergoes limited metabolism (about 10%). Rosuvastatin is a non-specific substrate of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. Isoenzymes CYP2C19, CYP3A4, CYP2D6 are involved to a lesser extent. The main identified metabolites are N-desmethylrosuvastatin and lactone metabolites.

N-desmethylrosuvastatin is approximately 50% less active than rosuvastatin; lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for inhibiting plasma HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

About 90% of the rosuvastatin dose is excreted unchanged through the intestines (including absorbed and unabsorbed rosuvastatin). The remainder is excreted by the kidneys. T_1/2 from plasma is approximately 19 hours (does not change with increasing drug dose). The geometric mean plasma clearance is 50 L/h (coefficient of variation – 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin.

The systemic exposure of rosuvastatin increases proportionally to the dose. Pharmacokinetic parameters do not change with daily use.

Indications

Treatment of arterial hypertension and concomitant dyslipidemia: primary hypercholesterolemia (type IIa according to the Fredrickson classification, including familial heterozygous hypercholesterolemia), mixed hypercholesterolemia (type IIb according to the Fredrickson classification) or familial homozygous hypercholesterolemia.

ICD codes

Dosage Regimen

Take orally, as a single daily dose once a day.

Swallow the tablet whole with water.

Take in the morning, before a meal.

The appropriate tablet strength must be determined by a physician based on the patient’s previous stable doses of the individual monocomponents.

Dose selection is critical for patients with renal impairment; use is contraindicated if creatinine clearance is less than 30 ml/min.

For patients with moderate renal impairment (CrCl 30-60 ml/min), initiate therapy with caution and consider individual titration of components.

Do not use in patients with severe hepatic impairment or active liver disease.

The recommended starting dose for the rosuvastatin component in specific populations (e.g., Asian patients, those with predisposing factors for myopathy) is 5 mg.

Do not exceed the maximum daily dose of 40 mg for the rosuvastatin component, except in rare cases under strict medical supervision.

Regular monitoring of renal function, electrolytes, and liver enzymes is required during treatment.

Discontinue therapy if a significant increase in creatine kinase (CK) levels or myopathy symptoms occur.

Adverse Reactions

Infections and infestations rhinitis.

Blood and lymphatic system disorders: eosinophilia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia, neutropenia, hemolytic anemia, thrombocytopenia.

Immune system disorders hypersensitivity reactions (especially skin reactions, in patients prone to allergic and asthmatic reactions).

Endocrine disorders type 2 diabetes mellitus.

Metabolism and nutrition disorders hypoglycemia, hyperkalemia, often transient, hyponatremia, hypercalcemia, decreased potassium levels with the development of hypokalemia, especially important for patients at high risk.

Psychiatric disorders mood disturbance, sleep disorder, confusion, depression.

Nervous system disorders dizziness, headache, paresthesia, dysgeusia, somnolence, syncope, peripheral neuropathy, polyneuropathy, memory loss, stroke, possibly due to excessive blood pressure reduction in high-risk patients, possible development of hepatic encephalopathy in case of hepatic insufficiency.

Eye disorders visual impairment, myopia, blurred vision.

Ear and labyrinth disorders vertigo, tinnitus.

Cardiac disorders palpitations, tachycardia, angina pectoris, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients.

Vascular disorders arterial hypotension (and effects associated with arterial hypotension), vasculitis, Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, bronchospasm, eosinophilic pneumonia.

Gastrointestinal disorders abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, dry oral mucosa, pancreatitis.

Hepatobiliary disorders hepatitis, impaired liver function, jaundice.

Skin and subcutaneous tissue disorders skin itching, skin rash, maculopapular rash, urticaria, angioedema of the face, lips, extremities, tongue mucosa, vocal folds and/or larynx, purpura, increased sweating, photosensitivity reactions, pemphigoid, exacerbation of psoriasis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders muscle cramps, possible exacerbation of pre-existing systemic lupus erythematosus, arthralgia, myalgia, myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture, tendon injury, immune-mediated necrotizing myopathy.

Renal and urinary disorders renal failure, acute renal failure, hematuria.

Reproductive system and breast disorders erectile dysfunction, gynecomastia.

General disorders and administration site conditions asthenia, back pain, malaise, peripheral edema, pyrexia, fatigue.

Investigations increased concentration of urea, uric acid, creatinine, bilirubin in plasma, increased activity of hepatic enzymes, decreased hemoglobin and decreased hematocrit, increased plasma glucose concentration, prolongation of the QT interval on the electrocardiogram.

Contraindications

History of angioedema (Quincke’s edema) associated with ACE inhibitor use; hereditary/idiopathic angioedema; severe renal failure (creatinine clearance less than 30 ml/min); severe hepatic insufficiency (including with hepatic encephalopathy); active liver disease (including persistent elevation of hepatic transaminases and elevation of serum hepatic transaminases more than 3 times the upper limit of normal); myopathy; patients predisposed to the development of myotoxic complications; hypokalemia; concomitant use with drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type; concomitant use of cyclosporine; concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area); concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy; concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema; extracorporeal treatments using certain negatively charged surface membranes; severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney; use in women of childbearing potential not using adequate contraceptive methods; pregnancy, breastfeeding period; under 18 years of age (efficacy and safety not established); due to insufficient clinical experience, it should not be used in patients on hemodialysis, as well as in patients with untreated decompensated heart failure.

With caution

Systemic connective tissue diseases (SLE, scleroderma), immunosuppressant therapy (risk of neutropenia, agranulocytosis), bone marrow depression, reduced blood volume (diuretic use, salt-restricted diet, vomiting, diarrhea), coronary artery disease, cerebrovascular diseases, impaired liver and kidney function, renovascular hypertension, diabetes mellitus, CHF (NYHA functional class IV), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), labile blood pressure, use in elderly patients, Black race, athletes (possible positive reaction in doping control), hemodialysis using high-flux polyacrylonitrile membranes (e.g., AN69), before LDL apheresis procedure, simultaneous desensitizing therapy with allergens (e.g., hymenoptera venom), status after kidney transplantation, stenosis of the aortic and/or mitral valve, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis, stenosis of the artery of a single kidney, concomitant use with lithium, gold, NSAIDs, baclofen, corticosteroids, drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type, presence of risk factors for myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption, conditions in which an increase in plasma concentration of rosuvastatin has been noted, racial affiliation (Mongoloid race – Japanese and Chinese), concomitant use with fibrates, history of liver disease, sepsis, arterial hypotension, major surgical interventions, trauma, severe metabolic, endocrine or electrolyte disturbances or uncontrolled seizures, concomitant use with ezetimibe.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in patients with severe hepatic insufficiency and in patients with active liver diseases.

Use in Renal Impairment

In patients with severe renal impairment (CrCl <30 ml/min), use is contraindicated.

Pediatric Use

Use is contraindicated for children and adolescents under 18 years of age.

Geriatric Use

Before starting the medication, renal functional activity and plasma potassium levels should be assessed. At the beginning of therapy, the dose is selected taking into account the degree of blood pressure reduction, especially in case of reduced blood volume and electrolyte loss, which helps to avoid a sharp decrease in blood pressure.

Special Precautions

Renal Impairment

In patients with severe renal impairment (CrCl <30 ml/min), use is contraindicated.

In patients with CrCl <60 ml/min, individual dose titration of the individual active components included in the medicinal product is recommended.

Elderly Patients

Before starting the drug, renal functional activity and plasma potassium levels should be assessed. At the beginning of therapy, the dose is selected taking into account the degree of blood pressure reduction, especially in case of reduced blood volume and electrolyte loss, which helps to avoid a sharp decrease in blood pressure.

Diabetes Mellitus

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentration is necessary during the first month of treatment with an ACE inhibitor.

Blood glucose levels should be monitored in patients with diabetes mellitus, especially with low plasma potassium levels.

Perindopril/Indapamide

Arterial Hypotension and Water-Electrolyte Balance Imbalance

In patients with hyponatremia (especially with renal artery stenosis, including bilateral), there is a risk of sudden onset of arterial hypotension. Therefore, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels. In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuing therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of the perindopril and indapamide combination, or only one of the drugs.

Renovascular Hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney, therapy with ACE inhibitors increases the risk of arterial hypotension and renal failure. Diuretic use may be an additional risk factor. Worsening of renal function may be observed even with a slight change in plasma creatinine concentration, even in patients with unilateral renal artery stenosis.

The treatment method for renovascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors may be effective in patients with renovascular hypertension, both those awaiting surgery and when surgery is not possible.

In patients with diagnosed or suspected renal artery stenosis, treatment with indapamide/perindopril should be initiated in a hospital setting.

Risk of Arterial Hypotension and/or Renal Failure (in patients with CHF, water-electrolyte imbalance, etc.)

In some pathological conditions, significant activation of the RAAS may be noted, especially in cases of marked hypovolemia and decreased plasma electrolyte levels (against the background of a salt-free diet or long-term diuretic use), in patients with initially low blood pressure, renal artery stenosis, CHF, or liver cirrhosis with edema and ascites.

The use of ACE inhibitors causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in plasma creatinine concentration, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely at other times during therapy. In such cases, when resuming therapy, it is recommended to use the perindopril and indapamide combination at a lower dose and then gradually increase the dose.

Heart Failure/Severe Heart Failure

In patients with CHF (NYHA functional class IV) and patients with type 1 diabetes (risk of spontaneous increase in potassium ions), treatment should be started with lower doses of the perindopril and indapamide combination and under close medical supervision.

Patients with hypertension and coronary artery disease should not stop taking beta-blockers; the perindopril and indapamide combination must be used concomitantly with beta-blockers.

Hepatic Impairment

In rare cases, cholestatic jaundice may occur during treatment with ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If a significant increase in liver enzymes or the appearance of jaundice occurs during treatment with ACE inhibitors, the drug should be discontinued and the patient should continue to be monitored.

In the presence of impaired liver function, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, the drug should be discontinued immediately.

Indapamide

Photosensitivity

Cases of photosensitivity reactions have been reported during treatment with thiazide and thiazide-like diuretics. If a photosensitivity reaction occurs, treatment should be discontinued. If diuretic therapy needs to be continued, it is recommended to protect the skin from exposure to sunlight or artificial UV rays.

Plasma Sodium Levels

Before starting treatment, plasma sodium levels should be determined. During treatment with this combination, this indicator should be regularly monitored. At the initial stage of therapy, a decrease in plasma sodium levels may be asymptomatic, so regular laboratory monitoring is necessary. Elderly patients and patients with liver cirrhosis require more frequent monitoring of plasma sodium levels.

Any diuretic drug can cause hyponatremia, sometimes leading to extremely serious consequences.

Hyponatremia combined with hypovolemia can cause dehydration and orthostatic hypotension.

A concomitant decrease in plasma chloride levels can lead to secondary compensatory metabolic alkalosis (the frequency and severity of this effect are insignificant).

Plasma Potassium Levels

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patient categories: elderly patients, debilitated patients (whether receiving or not receiving concomitant drug therapy), patients with liver cirrhosis, including those with edema and ascites, patients with coronary artery disease, CHF. In such patients, hypokalemia enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of other antihypertensive agents in combination with a diuretic, regular monitoring of plasma potassium levels is necessary.

QT Interval Prolongation

The high-risk group also includes patients with an increased QT interval, regardless of whether this increase is due to congenital causes or the action of drugs. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially polymorphic ventricular tachycardia of the “torsades de pointes” type, which can be fatal.

In all the cases described above, regular monitoring at the start of therapy is necessary.

If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma Calcium Levels

Thiazide and thiazide-like diuretics reduce the renal excretion of calcium, which can cause a slight temporary increase in plasma calcium levels. Marked hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases, it is necessary to investigate parathyroid function, having first discontinued diuretic medication.

Diuretics and Renal Function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentration in adult patients below 25 mg/L or 220 µmol/L). In elderly patients, the normative plasma creatinine concentration should be adjusted for age, weight, and sex, according to the Cockcroft formula.

CrCl = (140 – age) x weight / 0.814 x plasma creatinine concentration,

Where: age is in years, weight is in kg, creatinine concentration is in µmol/L.

For women, this formula should be adjusted by multiplying the result by a factor of 0.85.

At the beginning of treatment with diuretics, due to hypovolemia and hyponatremia, patients may experience a temporary decrease in GFR and an increase in plasma urea and creatinine concentrations. This transient functional renal failure is not dangerous for patients with unchanged renal function, but in patients with renal failure, its severity may increase.

Uric Acid

In patients with elevated plasma uric acid levels, the frequency of gout attacks may increase during therapy.

Athletes

Indapamide may give a positive reaction during doping control.

Acute Myopia and Secondary Acute Angle-Closure Glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction leading to the development of acute transient myopia and an acute attack of angle-closure glaucoma. If left untreated, an acute attack of angle-closure glaucoma can lead to permanent vision loss. First of all, the drug should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for developing an acute attack of angle-closure glaucoma include a history of allergic reactions to sulfonamide derivatives and penicillins.

Perindopril

Dual Blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) with the simultaneous use of ACE inhibitors with ARBs or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with an ARB or aliskiren is not recommended. If dual blockade is necessary, it should be performed under strict specialist supervision with regular monitoring of renal function, plasma potassium levels, and blood pressure. ACE inhibitors should not be used simultaneously with ARBs in patients with diabetic nephropathy.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur during treatment with ACE inhibitors. In patients with normal renal function and no other risk factors, neutropenia is rare. After discontinuation of the ACE inhibitor, neutropenia and agranulocytosis resolve on their own. Perindopril should be used with particular caution in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma) during therapy with immunosuppressants, allopurinol, or procainamide, especially in patients with impaired renal function.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril in such patients, it is recommended to periodically monitor the white blood cell count in the plasma. If any symptoms of infectious diseases appear (e.g., sore throat, fever), patients should consult a doctor.

Hypersensitivity/Angioedema

During treatment with ACE inhibitors, including perindopril, angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx may occur in rare cases. This can happen at any time during therapy. If symptoms appear, the drug should be discontinued immediately and the patient should be monitored until symptoms completely resolve. As a rule, swelling of the face and lips does not require treatment, although antihistamines may be used to relieve symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, appropriate therapy should be started immediately, for example, by subcutaneous injection of a 1:1000 solution of epinephrine (adrenaline) (0.3-0.5 ml) and/or ensuring airway patency.

A higher risk of angioedema has been reported in Black patients.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking drugs of this group.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. In this case, patients complain of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was established using CT, abdominal ultrasound, or during surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients complaining of abdominal pain who are taking ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

mTOR Inhibitors

In patients simultaneously taking mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), therapy may be accompanied by an increased risk of angioedema (e.g., edema of the upper airways or tongue with/without respiratory impairment).

Anaphylactoid Reactions during Desensitization

There are isolated reports of anaphylactoid reactions in patients taking ACE inhibitors during desensitizing therapy (e.g., with hymenoptera venom: bees, wasps). ACE inhibitors should be used with caution in patients with a burdened allergic history or a tendency to allergic reactions during desensitization. The use of ACE inhibitors should be avoided in patients receiving immunotherapy with hymenoptera venom. Such reactions can be avoided by temporarily discontinuing ACE inhibitors at least 24 hours before the start of the desensitization procedure.

Anaphylactoid Reactions during LDL Apheresis

In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent such reactions, ACE inhibitors should be temporarily discontinued before each apheresis procedure.

Hemodialysis

In rare cases, anaphylactoid reactions have developed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is recommended to use a different type of membrane or use an antihypertensive drug from a different pharmacotherapeutic group.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are generally not sensitive to antihypertensive drugs whose action is based on inhibition of the RAAS. Thus, the use of this drug is not recommended.

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy. Women planning pregnancy should be prescribed an alternative antihypertensive agent with an established safety profile for use during pregnancy. If pregnancy is detected, treatment with ACE inhibitors should be discontinued immediately, and alternative antihypertensive therapy should be prescribed if necessary.

Cough

A dry, persistent cough may occur during therapy with ACE inhibitors. The cough persists for a long time during treatment with drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, the possibility of its occurrence due to ACE inhibitor use should be considered. If it is necessary to use drugs of this group, the ACE inhibitor may be continued.

Surgery/General Anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may lead to a pronounced decrease in blood pressure, especially when using general anesthetic agents that have an antihypertensive effect. It is recommended to discontinue long-acting ACE inhibitors, including perindopril, 24 hours before surgery.

Aortic and Mitral Stenosis, HOCM

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but particular caution should be exercised in patients with coronary artery disease and cerebrovascular diseases. In such patients, treatment is started with low doses of the drug.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors. Risk factors for hyperkalemia are renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of CHF, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, as well as other agents that contribute to an increase in plasma potassium levels (e.g., heparin, trimethoprim or co-trimoxazole (sulfamethoxazole + trimethoprim) and especially aldosterone antagonists or ARBs, acetylsalicylic acid ≥3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus).

The use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in serum potassium levels, especially in patients with reduced renal function.

Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If simultaneous use of the drug with the above agents is necessary, caution should be exercised and plasma potassium levels should be regularly monitored.

Ethnic Differences

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

Rosuvastatin

Effect on the Musculoskeletal System

When using rosuvastatin at all doses, but especially at doses exceeding 20 mg/day, the following effects on the musculoskeletal system have been reported: myalgia, myopathy, and in rare cases, rhabdomyolysis. Very rare cases of rhabdomyolysis have been noted with the concomitant use of HMG-CoA reductase inhibitors and ezetimibe. This combination should be used with caution, as a pharmacodynamic interaction cannot be excluded.

As with other HMG-CoA reductase inhibitors, the frequency of rhabdomyolysis in the post-marketing use of rosuvastatin is higher when using a dose of 40 mg/day.

Determination of CK Activity

Serum CK activity should not be determined after intense physical exertion or in the presence of other possible reasons for its increase, as this may lead to incorrect interpretation of the results. If the baseline serum CK activity is significantly elevated (5 times above the upper limit of normal), a repeat test should be performed after 5-7 days. Therapy should not be initiated if the repeat test confirms the initial high serum CK activity (more than 5 times the upper limit of normal).

Interstitial Lung Disease

With the use of some HMG-CoA reductase inhibitors, especially over a long period, isolated cases of interstitial lung disease have been reported (see the “Adverse Reactions” section). Manifestations of the disease may include dyspnea, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever).

If interstitial lung disease is suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.

Before Starting Therapy

Depending on the daily dose, rosuvastatin should be prescribed with caution to patients with existing risk factors for myopathy/rhabdomyolysis or the use of the drug is contraindicated.

Such factors include

• impaired renal function,

• hypothyroidism,

• personal or family history of muscle disease,

• history of myotoxic phenomena when taking other HMG-CoA reductase inhibitors or fibrates,

• excessive alcohol consumption,

• age over 65 years,

• conditions in which the plasma concentration of rosuvastatin may increase,

• concomitant use of fibrates.

In such patients, the risk and potential benefit of therapy should be assessed. Clinical monitoring is also recommended. If the baseline serum CK activity is more than 5 times the upper limit of normal, therapy should not be initiated.

During Therapy

The patient should be informed of the need to immediately inform the doctor in case of unexpected muscle pain, muscle weakness, or cramps, especially in combination with malaise and fever. In such patients, serum CK activity should be determined. Therapy should be discontinued if serum CK 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 serum CK activity is not more than 5 times the upper limit of normal). If symptoms disappear and serum CK activity returns to normal, the possibility of resuming rosuvastatin or other HMG-CoA reductase inhibitors at lower doses under close medical supervision should be considered. Monitoring serum CK activity in the absence of symptoms is not advisable.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations of persistent proximal muscle weakness and increased serum CK activity during therapy or upon discontinuation of HMG-CoA reductase inhibitors, including rosuvastatin, have been noted.

According to clinical studies, no signs of increased effects on skeletal muscles were noted with the use of rosuvastatin and concomitant therapy. However, an increased number of cases of myositis and myopathy have been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives (e.g., gemfibrozil), cyclosporine, niacin in lipid-lowering doses (more than 1 g/day), azole-derived antifungal agents, HIV protease inhibitors, and macrolide antibiotics.

When used concomitantly with some HMG-CoA reductase inhibitors, gemfibrozil increases the risk of myopathy. Thus, the concomitant use of rosuvastatin and gemfibrozil is not recommended. The benefits of further modification of plasma lipid concentrations with the combined use of rosuvastatin with fibrates or niacin in lipid-lowering doses must be carefully weighed against the possible risk. Rosuvastatin at doses of 30 mg/day and 40 mg/day is contraindicated for combination therapy with fibrates.

Due to the increased risk of rhabdomyolysis, rosuvastatin should not be used in patients with acute conditions that may lead to myopathy or conditions predisposing to the development of renal failure (e.g., sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, or uncontrolled seizures).

Rosuvastatin should not be used concomitantly or within 7 days after stopping therapy with fusidic acid preparations. If concomitant use is necessary, rosuvastatin should be discontinued during therapy with fusidic acid. Reports of rhabdomyolysis (including fatal cases) have been received in patients receiving fusidic acid concomitantly with a statin. The patient should immediately consult a doctor if any symptoms of muscle weakness, tenderness, or pain appear.

Statin therapy can be resumed 7 days after taking the last dose of fusidic acid.

In exceptional cases where prolonged systemic therapy with fusidic acid is necessary, for example, for the treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and carried out under strict medical supervision.

Protease Inhibitors

In patients receiving rosuvastatin concomitantly with protease inhibitors and ritonavir, an increase in the systemic exposure of rosuvastatin was noted. The expected benefit from lowering lipid concentrations with the use of rosuvastatin in HIV-infected patients receiving protease inhibitors and the potential increase in rosuvastatin plasma concentration at the start of therapy and during rosuvastatin dose titration should be taken into account.

Concomitant use of rosuvastatin with protease inhibitors is not recommended until the rosuvastatin dose is adjusted.

Ethnic Differences

In pharmacokinetic studies, an increase in the plasma concentration of rosuvastatin was noted in Mongoloid subjects compared with Caucasoid subjects.

Effect on Driving and Operating Machinery

When driving vehicles or working with machinery, the possibility of dizziness during treatment should be taken into account.

As a result, the ability to drive vehicles or other mechanisms may be reduced.

Drug Interactions

For Perindopril and Indapamide

Concomitant use not recommended

Lithium preparations when lithium preparations and ACE inhibitors are used concomitantly, cases of reversible increase in plasma lithium levels and associated toxic effects have been registered. Concomitant use of thiazide diuretics may contribute to a further increase in plasma lithium levels and increase the risk of its toxic effects while taking an ACE inhibitor. Concomitant use of the perindopril and indapamide combination with lithium preparations is not recommended. If concomitant use is necessary, plasma lithium levels should be carefully monitored.

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) when used concomitantly with mTOR inhibitors, therapy may be accompanied by an increased risk of angioedema.

Concomitant use of drugs requiring special attention

Baclofen enhancement of the antihypertensive effect is possible. Blood pressure, renal function should be monitored, and, if necessary, the dose of antihypertensive agents should be adjusted.

NSAIDs, including high doses of acetylsalicylic acid (≥3 g/day) concomitant use of ACE inhibitors and NSAIDs (including acetylsalicylic acid in doses that have an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors, increases the risk of renal function impairment, up to the development of acute renal failure, increases serum potassium levels, especially in patients with initially reduced renal function.

Caution should be exercised when using this combination, especially in elderly patients. Before starting treatment, patients must compensate for fluid loss, and renal function should be regularly monitored both at the start of therapy and during treatment.

Concomitant use requiring attention

Tricyclic antidepressants, antipsychotic agents (neuroleptics) drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Corticosteroids, tetracosactide reduction of the antihypertensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Other antihypertensive agents enhancement of the antihypertensive effect is possible.

For Indapamide

Concomitant use requiring special attention

Drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type since there is a risk of hypokalemia, Indapamide should be used with caution concomitantly with drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type, such as class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, dofetilide, ibutilide, bretylium tosilate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), other drugs such as bepridil, cisapride, difemanil methyl sulfate, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine. Serum potassium levels should be monitored to avoid hypokalemia, and if it develops, it should be corrected, and the QT interval on the ECG should be monitored.

Drugs that can cause hypokalemia intravenous amphotericin B, glucocorticoids and mineralocorticoids (with systemic administration), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Plasma potassium levels should be monitored, and if necessary, corrected. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. Non-stimulant laxatives should be used.

Cardiac glycosides hypokalemia enhances the toxic effect of cardiac glycosides. When using indapamide and cardiac glycosides concomitantly, plasma potassium levels, ECG parameters should be monitored, and therapy should be adjusted if necessary.

Concomitant use requiring attention

Metformin functional renal failure while taking diuretics, especially “loop” diuretics, when used concomitantly with metformin increases the risk of lactic acidosis. Metformin should not be used if plasma creatinine concentration exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodinated contrast agents in patients with hypovolemia during diuretic therapy, there is an increased risk of acute renal failure, especially when using contrast agents containing high doses of iodine. Before using iodinated contrast agents, blood volume should be replenished.

Calcium salt preparations when used concomitantly, hypercalcemia may develop due to reduced renal excretion of calcium.

Cyclosporine an increase in plasma creatinine concentration may occur without changing the plasma concentration of cyclosporine, even in the absence of significant sodium ion loss and dehydration.

For Perindopril

Clinical trial data have shown that dual blockade of the RAAS as a result of simultaneous administration of ACE inhibitors, ARBs, or aliskiren leads to an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure) compared with the use of only one drug affecting the RAAS.

Concomitant use of ACE inhibitors with ARBs in patients with diabetic nephropathy is contraindicated and is not recommended in other patients.

Concomitant use contraindicated

Aliskiren and medicines containing aliskiren concomitant use of ACE inhibitors with aliskiren or preparations containing aliskiren in patients with diabetes and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m²) is contraindicated and is not recommended in other patients.

Neutral endopeptidase inhibitors an increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

When ACE inhibitors are used concomitantly with medicines containing sacubitril (a neprilysin inhibitor), the risk of angioedema increases, therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescribing drugs containing sacubitril to patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors, is contraindicated.

Extracorporeal treatments extracorporeal treatments using certain high-flux membranes with a negatively charged surface (e.g., polyacrylonitrile), such as hemodialysis or hemofiltration, as well as LDL apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions. If a patient requires extracorporeal treatments, the possibility of using another type of dialysis membrane or another class of antihypertensive drugs should be considered.

Concomitant use not recommended

Potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene, both in monotherapy and as part of combination therapy) and potassium preparations ACE inhibitors reduce potassium loss by the kidneys caused by the diuretic. When used concomitantly with ACE inhibitors, an increase in serum potassium levels up to a fatal outcome is possible. If concomitant use of an ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be carried out.

Estramustine concomitant use may lead to an increased risk of side effects such as angioedema.

Concomitant use requiring special attention

Oral hypoglycemic agents (sulfonylurea derivatives) and insulin the effects described below have been described for captopril and enalapril. The use of ACE inhibitors may enhance the hypoglycemic effect of sulfonylurea derivatives and insulin in patients with diabetes. The development of hypoglycemia is observed very rarely (due to increased glucose tolerance and reduced insulin requirement).

Concomitant use requiring attention

Antihypertensive agents and vasodilators concomitant use of these drugs may enhance the antihypertensive effect of perindopril. When prescribed concomitantly with nitroglycerin, other nitrates, or other vasodilators, an additional decrease in blood pressure is possible.

Allopurinol, cytotoxic and immunosuppressive agents, corticosteroids (with systemic use) and procainamide concomitant use with ACE inhibitors may increase the risk of leukopenia.

General anesthetics concomitant use of ACE inhibitors and general anesthetics may lead to an enhancement of the antihypertensive effect.

Diuretics (thiazide and “loop”) the use of diuretics in high doses can lead to hypovolemia (due to a decrease in blood volume), and the addition of perindopril to therapy can lead to a pronounced decrease in blood pressure.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin) when used concomitantly with ACE inhibitors, the risk of angioedema increases due to the suppression of DPP-4 activity by the gliptin.

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Gold preparations when ACE inhibitors, including perindopril, are used concomitantly with intravenous administration of a gold preparation (sodium aurothiomalate), a symptom complex including facial skin flushing, nausea, vomiting, and a pronounced decrease in blood pressure has been described.

Co-trimoxazole (sulfamethoxazole + trimethoprim) concomitant use with ACE inhibitors may increase the risk of hyperkalemia.

Tissue plasminogen activators observational studies have revealed an increased frequency of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

For Rosuvastatin

Effect of other drugs on rosuvastatin

Transporter protein inhibitors rosuvastatin is a substrate for some transporter proteins, in particular, OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transporter proteins may be accompanied by an increase in the plasma concentration of rosuvastatin and an increased risk of myopathy.

Cyclosporine when rosuvastatin and cyclosporine are used concomitantly, the AUC of rosuvastatin is on average 7 times higher than the value observed in healthy volunteers. Concomitant use with rosuvastatin does not affect the plasma concentration of cyclosporine. The use of rosuvastatin is contraindicated in patients taking cyclosporine. Concomitant use with rosuvastatin does not affect the plasma concentration of cyclosporine.

Protease inhibitors although the exact mechanism of interaction has not been established, concomitant use of protease inhibitors can significantly increase the exposure of rosuvastatin. Concomitant use in healthy volunteers of 10 mg rosuvastatin and a combination of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) is accompanied by an increase in the steady-state AUC(0-24 h) and Cmax of rosuvastatin by 3 and 7 times, respectively. Concomitant use of rosuvastatin and some combinations of protease inhibitors is possible only after careful adjustment of the rosuvastatin dose based on the expected increase in its exposure.

Gemfibrozil and other hypolipidemic agents The concomitant use of rosuvastatin and gemfibrozil leads to a twofold increase in the plasma C_max and AUC of rosuvastatin. Based on specific interaction data, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, as well as nicotinic acid in lipid-lowering doses (more than 1 g/day) increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can cause myopathy when used in monotherapy. In such patients, therapy should be initiated at a dose of 5 mg. Concomitant use of fibrates and rosuvastatin at daily doses of 30 mg and 40 mg is contraindicated.

Ezetimibe Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg was accompanied by a 1.2-fold increase in the AUC of rosuvastatin in patients with hypercholesterolemia. A pharmacodynamic interaction between rosuvastatin and ezetimibe, manifested as an increased risk of adverse reactions, cannot be ruled out.

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

Erythromycin The concomitant use of rosuvastatin and erythromycin leads to a 20% decrease in the AUC_(0-t) of rosuvastatin and a 30% decrease in its C_max. This interaction may occur as a result of increased intestinal motility caused by erythromycin.

Cytochrome P450 system isoenzymes Results from in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 system isoenzymes. Furthermore, rosuvastatin is a weak substrate for this isoenzyme system. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 system isoenzymes is expected.

No clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes) was noted.

Effect of rosuvastatin use on other drugs

Vitamin K antagonists As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in its dose in patients concomitantly taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in INR. Discontinuation of rosuvastatin or a decrease in its dose may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives/HRT

Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting the dose of hormonal contraceptives.

Pharmacokinetic data on the concomitant use of rosuvastatin and HRT are lacking; therefore, a similar effect with this combination cannot be ruled out. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other drugs

Digoxin No clinically significant interaction between rosuvastatin and digoxin is expected.

Fusidic acid The risk of myopathy, including rhabdomyolysis, may be increased with the concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) has not been established. Reports of rhabdomyolysis (including fatal cases) have been received in patients taking this combination.

If concomitant use is necessary, rosuvastatin should be discontinued during therapy with fusidic acid.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.