Tristanium^® (Tablets) Instructions for Use

Marketing Authorization Holder

Hanmi Pharm., Co. Ltd. (Republic of Korea)

Manufactured By

Hanmi Pharm., Co. Ltd. (Republic of Korea)

ATC Code

C10BX (HMG-CoA reductase inhibitors in other combinations)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Losartan (Rec.INN registered by WHO)

Rosuvastatin (Rec.INN registered by WHO)

Dosage Forms

	Tristanium®	Film-coated tablets, 5 mg+50 mg+10 mg: 30 or 100 pcs.
		Film-coated tablets, 5 mg+50 mg+20 mg: 30 or 100 pcs.
		Film-coated tablets, 5 mg+100 mg+10 mg: 30 or 100 pcs.
		Film-coated tablets, 5 mg+100 mg+20 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, oval, biconvex.

Excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate.

Shell composition film coating Opadry II white (Opadry II White) 85F18422 (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol-4000, talc).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles – cardboard packs.
100 pcs. – bottles – cardboard packs.

Film-coated tablets yellow, oval, biconvex.

Excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate.

Shell composition film coating Opadry II yellow (Opadry II Yellow) 85F12347 (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol-4000, talc, yellow iron oxide dye (E172)).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles – cardboard packs.
100 pcs. – bottles – cardboard packs.

Film-coated tablets light pink, oval, biconvex.

Excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate.

Shell composition film coating Opadry II pink (Opadry II Pink) 85F19452 (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol-4000, talc, red iron oxide dye (E172), black iron oxide dye (E172)).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles – cardboard packs.
100 pcs. – bottles – cardboard packs.

Film-coated tablets dark pink, oval, biconvex.

Excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate.

Shell composition film coating Opadry II pink (Opadry II Pink) 85F64726 (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol-4000, talc, red iron oxide dye (E172), sunset yellow dye (E110), indigo carmine dye (E132).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles – cardboard packs.
100 pcs. – bottles – cardboard packs.

Pharmacotherapeutic Group

Combined agent (slow calcium channel blocker + angiotensin II receptor antagonist + HMG-CoA reductase inhibitor)

Pharmacological Action

Antihypertensive combined medicinal product.

Amlodipine is a calcium channel blocker, a dihydropyridine derivative. It inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is associated with its vasodilating effect on vascular smooth muscles. The exact mechanism by which Amlodipine reduces the frequency and severity of angina attacks has not been fully established, but Amlodipine may reduce myocardial ischemia through the two effects described below.

1. Amlodipine dilates peripheral arterioles and thereby reduces total peripheral vascular resistance, the so-called afterload. Since the heart rate during amlodipine intake practically does not increase, this reduction in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand.

2. The mechanism of the antianginal action of amlodipine also appears to be associated with the dilation of the main coronary arteries and arterioles, both in areas of the myocardium with normal blood flow and in ischemic areas. This dilation increases oxygen delivery to the myocardium in patients with coronary artery spasm (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 the supine and standing positions for 24 hours. Orthostatic arterial hypotension is not typical during the use of amlodipine due to its slow onset of action.

In patients with arterial hypertension and normal renal function, Amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate and effective renal plasma flow without changes in filtration fraction or proteinuria.

Losartan is a highly effective angiotensin II receptor antagonist (type AT₁). Losartan and its pharmacologically active carboxylated metabolite, both in vitro and in vivo, block all physiological effects of angiotensin II, regardless of the source or pathway of synthesis. Losartan selectively binds to AT₁ receptors and does not bind to or block receptors of other hormones and ion channels that play an important role in the regulation of cardiovascular function. Furthermore, Losartan does not inhibit ACE (kininase II), which promotes the degradation of bradykinin. Consequently, effects not directly related to the blockade of AT₁ receptors, in particular, the enhancement of effects associated with the action of bradykinin or the development of edema, are not related to the action of losartan.

Losartan suppresses the increase in systolic and diastolic blood pressure observed during angiotensin II infusion. At the time of reaching C_max of losartan in plasma after taking losartan at a dose of 100 mg, the aforementioned effect is suppressed by approximately 85%, and 24 hours after single and multiple doses – by 26-39%.

During losartan intake, the elimination of the negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity. The increase in plasma renin activity is accompanied by an increase in the concentration of angiotensin II in plasma. After discontinuation of losartan, plasma renin activity and angiotensin II concentration decreased to baseline values. Since Losartan is a specific antagonist of angiotensin II AT₁ receptors, it does not inhibit ACE (kininase II) – the enzyme that inactivates bradykinin. The plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing drug dose. Since Losartan and its active metabolite are angiotensin II receptor antagonists, both contribute to the antihypertensive effect.

Rosuvastatin is a hypolipidemic agent from the statin group. A selective competitive inhibitor of HMG-CoA reductase – the enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, which leads to increased uptake and catabolism of LDL, inhibition of VLDL synthesis, reducing the total concentration of LDL and VLDL. It reduces the concentrations of LDL-C, non-HDL-C, VLDL-C, total cholesterol, TG, total VLDL, Apo-B, reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, Apo-B/apolipoprotein A1 (ApoA1), increases the concentrations of HDL-C and ApoA1. The therapeutic effect appears within 1 week after the start of therapy, reaches 90% of the maximum after 2 weeks, reaches a maximum by 4 weeks and thereafter remains constant.

Pharmacokinetics

Amlodipine

After oral administration of amlodipine in therapeutic doses, C_max in plasma is reached in 6-12 hours. The absolute bioavailability of the drug is 64-80%. Food intake does not affect the bioavailability of amlodipine. V_d is approximately 21 L/kg, indicating that most of the active substance is in the tissues, and a smaller part is in the blood. The binding of amlodipine to plasma proteins is about 97.5%. Amlodipine is largely (approximately 90%) subjected to slow but active metabolism in the liver to form inactive metabolites in the absence of a significant “first-pass” effect through the liver. T_1/2 of amlodipine from plasma is approximately 35-50 hours, which confirms the possibility of its use once a day. With repeated administration, T_1/2 of amlodipine is approximately 45 hours. The drug is excreted by the kidneys: 10% of the administered dose is excreted unchanged and 60% as metabolites, 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg; 0.42 L/h/kg). The elimination of amlodipine from plasma occurs in two phases.

Losartan

When taken orally, Losartan is well absorbed and undergoes metabolism during the “first pass” through the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan is approximately 33%. The mean C_max values of losartan and its active metabolite are reached at 1 hour and 3-4 hours, respectively. When taking losartan during a normal meal, no clinically significant effect on the plasma concentration profile of losartan was identified. Losartan and its active metabolite bind to plasma proteins (mainly albumin) by more than 99%. V_d of losartan is 34 L. It practically does not penetrate the BBB. Approximately 14% of the dose of losartan administered intravenously or orally is converted into its active metabolite. After oral administration and intravenous administration of radiolabeled carbon losartan (¹⁴C losartan), the radioactivity of circulating plasma is primarily associated with the presence of losartan and its active metabolite. Low conversion of losartan to its active metabolite was observed in approximately 1% of patients participating in the study. In addition to the active metabolite, biologically inactive metabolites are formed, including two main metabolites formed by hydroxylation of the butyl side chain and one minor one – N-2-tetrazole-glucuronide. The plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When taking losartan orally, about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as the active metabolite. Losartan and its active metabolite have linear pharmacokinetics when taken orally in doses up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal T_1/2 of approximately 2 and 6-9 hours, respectively. With a single dose of the drug at a dose of 100 mg, neither Losartan nor its active metabolite significantly accumulate in the body. Excretion of losartan and its metabolites occurs through the intestine with bile and by the kidneys. After oral administration of ¹⁴C-labeled losartan, about 35% of radioactivity is detected in urine and 58% in feces in men. After intravenous administration of ¹⁴C-labeled losartan, approximately 43% of radioactivity is detected in urine and 50% in feces in men.

Rosuvastatin

C_max of rosuvastatin in plasma is reached approximately 5 hours after taking the drug. Absolute bioavailability is 20%. V_d is 134 L. Binding to plasma proteins (mainly albumin) is approximately 90%. Penetrates the placental barrier. It is metabolized in the liver to a small extent (about 10%), being a non-profile substrate for cytochrome P450 isoenzymes. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. The CYP2C19, CYP3A4 and CYP2D6 isoenzymes are involved in the metabolism to a lesser extent. The main metabolites of rosuvastatin are N-desmethyl- Rosuvastatin and lactone metabolites. N-desmethyl- Rosuvastatin is approximately 50% less active than Rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for the inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

About 90% of the rosuvastatin dose is excreted unchanged through the intestine, the remainder by the kidneys. The plasma T_1/2 is approximately 19 hours and does not change with increasing drug dose. The mean geometric plasma clearance value is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, a specific membrane transporter, OATP1B1, is involved in the process of hepatic uptake of the active substance, playing an important role in its hepatic elimination.

Systemic exposure of rosuvastatin increases proportionally to the dose.

Indications

Arterial hypertension in adult patients suffering from such lipid metabolism disorders as: primary hypercholesterolemia according to the Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet, when diet and other non-drug treatments (e.g., exercise, weight loss) are insufficient; familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (e.g., LDL apheresis), or in cases where such therapy is not sufficiently effective; hypertriglyceridemia (type IV according to the Fredrickson classification) as an adjunct to diet.

The fixed combination is intended for use in patients who require combination therapy with amlodipine, losartan and rosuvastatin in appropriate doses.

ICD codes

Dosage Regimen

Take Tristanium^®orally, as a single dose once daily.

Select the appropriate tablet strength based on the individual therapeutic needs for amlodipine, losartan, and rosuvastatin.

This fixed-dose combination is indicated for patients whose condition is stabilized on the individual components given concurrently at the same doses present in the tablet.

The available dosage strengths are: 5 mg amlodipine / 50 mg losartan / 10 mg rosuvastatin; 5 mg amlodipine / 50 mg losartan / 20 mg rosuvastatin; 5 mg amlodipine / 100 mg losartan / 10 mg rosuvastatin; and 5 mg amlodipine / 100 mg losartan / 20 mg rosuvastatin.

Swallow the tablet whole with a glass of water; it can be taken with or without food.

For the rosuvastatin component, the usual starting dose is 5 mg, 10 mg, or 20 mg once daily.

The maximum recommended dose for rosuvastatin is 40 mg once daily; however, the 40 mg strength is not available in this fixed combination.

Initiate therapy with a rosuvastatin dose of 5 mg in specific patient populations, including those of Asian ancestry, patients with predisposing factors for myopathy, or when used concomitantly with certain interacting drugs like gemfibrozil.

Do not use the 40 mg rosuvastatin component concomitantly with fibrates.

For patients with severe renal impairment (CrCl < 30 mL/min), the use of this combination is contraindicated.

Dose adjustment is not required in elderly patients or those with mild to moderate renal impairment; however, use with caution in these populations.

Regularly monitor lipid levels to assess therapeutic response and adjust the dose if necessary, following established clinical guidelines.

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose; in that case, continue with the regular dosing schedule and do not double the dose.

Adverse Reactions

Blood and lymphatic system disorders very rarely – leukopenia; infrequently – anemia, Henoch-Schönlein disease, ecchymosis, hemolysis; rarely – thrombocytopenia.

Immune system disorders very rarely – allergic reactions; rarely – anaphylactic reactions, angioedema, including laryngeal and vocal fold edema with the development of airway obstruction and/or facial edema, lips, pharynx, and/or tongue.

Metabolism and nutrition disorders infrequently – weight loss, weight gain, anorexia, gout; very rarely – hyperglycemia.

Nervous system disorders frequently – drowsiness, dizziness, headache; infrequently – unusual dreams, sleep disturbances, tremor, dysgeusia, syncope, hypoesthesia, paresthesia.

Psychiatric disorders infrequently – mood changes (including anxiety), insomnia, depression, anxiety, anxiety disorder, panic disorder, memory impairment, peripheral neuropathy; rarely – confusion, increased excitability, migraine, fainting; very rarely – hypertonia; frequency unknown – extrapyramidal disorders.

Eye disorders frequently – visual disturbances (including diplopia); infrequently – blurred vision, burning sensation in the eyes, conjunctivitis, decreased visual acuity.

Ear and labyrinth disorders infrequently – tinnitus, vertigo, ringing in the ears.

Cardiac disorders frequently – palpitations, sensation of “flushing”; infrequently – arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), decreased blood pressure, vasculitis, orthostatic hypotension, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation), sternal pain, angina, second-degree AV block, cerebrovascular accident; frequency unknown – dose-dependent orthostatic effect; very rarely – myocardial infarction.

From the respiratory system frequently – dyspnea, upper respiratory tract infections, nasal congestion, sinusitis, cough; infrequently – throat discomfort, pharyngitis, laryngitis, dyspnea, bronchitis, epistaxis, airway obstruction, rhinitis.

From the digestive system frequently – abdominal pain, nausea, bowel habit rhythm disturbances (including diarrhea and constipation), diarrhea, dyspepsia; infrequently – vomiting, dry mouth, constipation, toothache, flatulence, intestinal obstruction; very rarely – pancreatitis, gastritis, gingival hyperplasia; frequency unknown – anorexia.

From the liver and biliary tract very rarely – hepatitis, jaundice, increased activity of liver enzymes (mostly in combination with cholestasis); frequency unknown – liver function disorders.

From the skin and subcutaneous tissues frequently – ankle and foot edema; infrequently – alopecia, purpura, skin pigmentation change (appearance of discolored skin areas), hyperhidrosis, pruritus, skin rash, exanthema, urticaria; very rarely – erythema, dermatitis, Stevens-Johnson syndrome, photosensitivity, toxic epidermal necrolysis, dry skin, hyperemia.

From the musculoskeletal system frequently – muscle spasms, myalgia, back pain, lower limb pain; infrequently – upper limb pain, arthralgia, joint swelling, knee pain, muscle and bone pain, shoulder pain, joint stiffness, arthritis, fibromyalgia, coxalgia, muscle weakness; rarely – myopathy (including myositis); frequency unknown – immune-mediated necrotizing myopathy, rhabdomyolysis.

From the urinary system frequently – renal function impairment, renal failure; infrequently – pollakiuria, dysuria, nocturia, proteinuria, urinary tract infections; very rarely – hematuria.

From the reproductive system and breast: infrequently – erectile dysfunction, gynecomastia, decreased libido.

General reactions : very frequently – edema; frequently – increased fatigue, asthenic syndrome, chest pain; infrequently – pain, general malaise, weakness, heavy head sensation, impaired glucose tolerance, pyrexia, peripheral edema, facial edema, weakness; frequency unknown – flu-like symptoms.

Laboratory data frequently – hyperkalemia, slight decrease in hematocrit and hemoglobin, increased blood glucose concentration, increased alkaline phosphatase activity; infrequently – slight increase in plasma urea and creatinine concentration, dose-dependent increase in creatine phosphokinase activity, increased plasma glycated hemoglobin concentration; very rarely – increased liver transaminase activity, increased plasma bilirubin concentration; frequency unknown – hyponatremia.

Contraindications

Hypersensitivity to any component of the fixed combination; severe arterial hypotension (systolic BP less than 90 mm Hg); shock (including cardiogenic); hemodynamically unstable heart failure after acute myocardial infarction; left ventricular outflow tract obstruction (e.g., severe aortic stenosis); renal impairment (creatinine clearance less than 30 ml/min) or patients on hemodialysis; moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment; myopathy; predisposition to myotoxic complications; primary hyperaldosteronism; concomitant use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or renal impairment (GFR less than 60 ml/min/1.73 m²); concomitant use with ACE inhibitors in patients with diabetic nephropathy; concomitant use with cyclosporine; children under 18 years of age; pregnancy, breastfeeding period, female patients of childbearing potential not using effective contraception methods.

With caution

Bilateral renal artery stenosis or stenosis of the artery to a single kidney; hyperkalemia, hyponatremia; status after kidney transplantation (no experience of use); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; severe heart failure (NYHA class III-IV); heart failure with life-threatening arrhythmias, with concomitant severe renal impairment; cerebrovascular diseases; history of angioedema, patients with hereditary angioedema or with a history of angioedema during treatment with ACE inhibitors or angiotensin II receptor blockers; arterial hypotension; concomitant use with inhibitors and inducers of the CYP3A4 isoenzyme, water-electrolyte balance disorders; mild to moderate renal impairment; coronary artery disease and/or clinically significant cerebral atherosclerosis (with excessive BP reduction there is a risk of increased ischemic disorders, up to the development of acute myocardial infarction and/or stroke); unstable angina or myocardial infarction; sick sinus syndrome (severe bradycardia, tachycardia); reduced blood volume (e.g., during treatment with high-dose diuretics, salt restriction, diarrhea, vomiting) – symptomatic arterial hypotension may occur; hepatic insufficiency (less than 7 points on the Child-Pugh scale); history of liver disease (patients with active liver disease, including persistently elevated serum liver transaminase levels or an increase in serum liver transaminase levels 3 times the upper limit of normal); sepsis; major surgical interventions; trauma;
Uncontrolled seizures; hypothyroidism; diabetes mellitus;
History of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; history of hereditary muscle diseases; age over 65 years;
Conditions associated with increased plasma concentration of rosuvastatin; use in patients of Mongoloid race; with concomitant use with fibrates;
With concomitant use with HIV protease inhibitors; with excessive alcohol consumption.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment.

With caution: hepatic insufficiency less than 7 points on the Child-Pugh scale; history of liver disease, patients with active liver disease, including persistently elevated serum liver transaminase levels or an increase in serum liver transaminase levels 3 times the upper limit of normal.

Use in Renal Impairment

Contraindication: renal impairment (creatinine clearance less than 30 ml/min) or patients on hemodialysis.

With caution: bilateral renal artery stenosis or stenosis of the artery to a single kidney; hyperkalemia, hyponatremia; status after kidney transplantation; mild to moderate renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Calcium channel blockers, including Amlodipine, should be used with caution in patients with chronic heart failure due to the possible risk of other cardiovascular complications and mortality.

Dosage adjustment of the drug in elderly patients is not required. Dose increase should be carried out with caution, as in elderly patients the T_1/2 of amlodipine may increase and clearance may decrease.

Maintenance of dental hygiene and observation by a dentist is necessary (to prevent soreness, bleeding and gingival hyperplasia).

Discontinuation of amlodipine treatment is desirable by gradually reducing the dose.

Patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue) should be under strict medical supervision.

Symptomatic arterial hypotension, especially after the first dose or after a dose increase, may occur in patients with hypovolemia and/or hyponatremia resulting from high-dose diuretic use, salt-restricted diet, diarrhea or vomiting. Either correction of these conditions should be carried out before prescribing the drug, or lower doses of the drug should be used or prescribed.

Regular monitoring of plasma potassium levels and creatinine clearance indicators is necessary. Patients with heart failure and creatinine clearance from 30 to 50 ml/min require particularly strict observation.

In patients with heart failure with or without renal impairment, as with the use of other drugs acting on the RAAS, there is a risk of developing severe arterial hypotension and acute renal failure.

In patients receiving angiotensin II antagonists, arterial hypotension may develop during general anesthesia and surgery as a result of RAAS blockade. Very rarely, cases of severe arterial hypotension requiring intravenous fluid administration and/or vasopressor drugs may occur.

Measurement of creatine phosphokinase activity should not be performed after intense physical exertion or in the presence of other possible causes of increased creatine phosphokinase activity, as this may lead to misinterpretation of the results obtained. If the baseline creatine phosphokinase activity is significantly elevated (5 times the upper limit of normal), a repeat measurement should be performed after 5-7 days. Therapy should not be initiated if the repeat test confirms the baseline creatine phosphokinase activity (more than 5 times the upper limit of normal).

When using rosuvastatin, as well as when using other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis.

The patient should be informed of the need to immediately report to the physician any cases of unexpected muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, creatine phosphokinase activity should be determined. Therapy should be discontinued if creatine phosphokinase activity is significantly elevated (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if creatine phosphokinase activity is increased less than 5 times the upper limit of normal). If symptoms disappear and creatine phosphokinase activity returns to normal, consideration should be given to re-prescribing the drug or other HMG-CoA reductase inhibitors at lower doses with careful patient monitoring. Routine monitoring of creatine phosphokinase activity in the absence of symptoms is not appropriate.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying diseases should be carried out before starting treatment with the drug.

In pharmacokinetic studies among Chinese and Japanese patients, an increase in the systemic concentration of rosuvastatin was noted compared with the indicators obtained among Caucasian patients.

Drugs of the statin class can cause an increase in blood glucose concentration. In some patients at high risk of developing diabetes mellitus, such changes may lead to its manifestation, which is an indication for the prescription of hypoglycemic therapy. However, the reduction in the risk of vascular diseases while taking statins outweighs the risk of developing diabetes mellitus, so this factor should not be a reason for discontinuing statin therapy. Patients at risk (fasting blood glucose 5.6-6.9 mmol/l, BMI > 30 kg/m², hypertriglyceridemia, history of arterial hypertension) should be placed under medical supervision and regular monitoring of biochemical parameters should be carried out.

Effect on ability to drive vehicles and mechanisms

Due to the possible pronounced decrease in BP and the development of dizziness, caution should be exercised when driving vehicles and engaging in other activities requiring concentration and speed of psychomotor reactions while taking this combination, especially at the beginning of treatment and when increasing the dosage. If the described adverse reactions occur, one should refrain from performing these activities.

Drug Interactions

No interactions between the two active substances included in this fixed-dose combination drug were identified in clinical studies.

Amlodipine

Concomitant use of amlodipine with potent or moderate inhibitors of the CYP3A4 isoenzyme (HIV protease inhibitors, antifungal drugs from the azole group, macrolides, for example, erythromycin or clarithromycin, as well as with verapamil or diltiazem) may be accompanied by a significant increase in systemic exposure indicators of amlodipine, resulting in an increased risk of a sharp decrease in BP. The clinical manifestations of these concomitant use options may be more pronounced in elderly patients; medical supervision is necessary for possible dose adjustment of the drugs.

When used concomitantly with inducers of the CYP3A4 isoenzyme, the concentration of amlodipine may vary. BP should be monitored; the possibility of adjusting the dose of amlodipine during and after concomitant administration should be considered, especially concomitantly with strong inducers of the CYP3A4 isoenzyme (e.g., rifampicin and preparations of St. John’s wort).

The use of amlodipine against the background of consumption of grapefruit or grapefruit juice is not recommended, as in some patients (with genetic polymorphism of the CYP3A4 isoenzyme) this may lead to an increase in the bioavailability of the drug and, accordingly, to an enhancement of the antihypertensive effect.

In animals receiving verapamil in combination with intravenous dantrolene, the development of lethal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia was observed. Due to the risk of hyperkalemia, it is recommended to avoid the use of calcium channel blockers, such as Amlodipine, concomitantly with dantrolene in patients prone to developing malignant hyperthermia, as well as for the treatment of this condition.

Interaction studies of cyclosporine and amlodipine have not been conducted either in healthy volunteers or in any other populations, except for patients who have undergone kidney transplantation. In these patients, an increase in residual plasma concentrations of cyclosporine (up to 40%) was detected. In patients receiving Amlodipine in combination with cyclosporine after kidney transplantation, it is recommended to monitor cyclosporine concentrations and, if necessary, reduce its dose.

Concomitant use of tacrolimus with amlodipine is characterized by a risk of increasing the plasma concentration of tacrolimus. Patients taking Amlodipine should have their plasma tacrolimus concentration monitored, as well as dose adjustment if necessary to avoid the toxic effects of tacrolimus.

When amlodipine and sildenafil were used concomitantly, it was shown that each of the drugs had an independent hypotensive effect.

Enhancement of the antianginal and hypotensive effects of calcium channel blockers is possible with concomitant use with thiazide and loop diuretics, ACE inhibitors, beta-blockers, nitrates, as well as enhancement of their hypotensive effect when interacting with alpha₁-blockers and antipsychotics.

Calcium preparations may reduce the effect of slow calcium channel blockers.

Losartan

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, syncope, hyperkalemia and renal impairment (including acute renal failure) compared with the use of a single drug affecting the RAAS.

Use of losartan concomitantly with aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m²) and is not recommended in other patients.

Use of losartan in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use of losartan with diuretics has an additive effect.

Concomitant use with other drugs that can cause arterial hypotension as an adverse reaction (e.g., tricyclic antidepressants, antipsychotic drugs, baclofen and amifostine) may increase the risk of developing arterial hypotension.

Losartan is predominantly metabolized with the participation of the CYP2C9 isoenzyme to form the active carboxylic acid metabolite. A clinical study showed that fluconazole (an inhibitor of the CYP2C9 isoenzyme) reduces the formation of the active metabolite by approximately 50%. Concomitant use of losartan with rifampicin (an inducer of metabolic enzymes) has been found to lead to a 40% decrease in the plasma concentration of the active metabolite. The clinical significance of this effect remains unclear. When the drug was used concomitantly with fluvastatin (a weak inhibitor of the CYP2C9 isoenzyme), no changes in the metabolite concentration were noted.

Experience with other drugs acting on the RAAS shows that concomitant therapy with potassium-sparing diuretics (spironolactone and its derivative eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, and other agents that can increase plasma potassium levels (e.g., heparin) may lead to the development of hyperkalemia.

The antihypertensive effect of the combination may be weakened when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

As with ACE inhibitors, concomitant administration of losartan and NSAIDs may lead to an increased risk of renal impairment, including possible acute renal failure and hyperkalemia, especially in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients receiving concomitant treatment with losartan and NSAIDs should receive adequate fluid intake and be under medical supervision with simultaneous monitoring of renal function parameters.

Reversible increases in plasma lithium concentration and its toxic effects have been reported during concomitant use of lithium preparations with ACE inhibitors. In very rare cases, similar reports have been registered with the concomitant use of lithium preparations with angiotensin II receptor antagonists. If the need for this combination is proven, then regular monitoring of plasma lithium levels is recommended for patients during treatment.

Rosuvastatin

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

Cyclosporine: when rosuvastatin and cyclosporine were used concomitantly, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers. It does not affect the plasma concentration of cyclosporine. Rosuvastatin is contraindicated in patients taking cyclosporine.

HIV protease inhibitors: although the precise mechanism of interaction is unknown, concomitant administration with HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure. A pharmacokinetic study of the simultaneous use of 20 mg rosuvastatin with a combination product containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in an approximately 2-fold and 5-fold increase in rosuvastatin AUC_0-24 and C_max, respectively. Therefore, the concomitant use of rosuvastatin and HIV protease inhibitors is not recommended.

Gemfibrozil and other lipid-lowering agents: concomitant administration of rosuvastatin and gemfibrozil results in a 2-fold increase in C_max and AUC of rosuvastatin. Based on specific interaction data, no pharmacokinetically significant interaction with fenofibrate is expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of nicotinic acid (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 as monotherapy. When the drug is used concomitantly with gemfibrozil, fibrates, or nicotinic acid in lipid-lowering doses, an initial rosuvastatin dose of 5 mg is recommended for patients; the use of a 40 mg dose is contraindicated when co-administered with fibrates.

Fusidic acid: specific studies on the drug interaction between fusidic acid and rosuvastatin have not been conducted. As with other statins, post-marketing reports of rhabdomyolysis have been received. Patients should be closely monitored. Temporary discontinuation of rosuvastatin may be considered if necessary.

Ezetimibe: concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe was associated with an increase in the AUC of rosuvastatin in patients with hypercholesterolemia. An increased risk of adverse effects due to the pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be ruled out.

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

Erythromycin: concomitant use of rosuvastatin and erythromycin leads to a 20% decrease in the AUC of rosuvastatin and a 30% decrease in the C_max of rosuvastatin. This interaction may occur as a result of increased intestinal motility caused by erythromycin intake.

The drug dose should be adjusted if concomitant use with drugs that increase rosuvastatin exposure is necessary. If an increase in exposure of 2-fold or more is expected, the initial dose of rosuvastatin should be 5 mg once daily. The maximum daily dose of the drug should also be adjusted so that the expected exposure to rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs interacting with rosuvastatin. For example, the maximum daily dose of rosuvastatin when used concomitantly with gemfibrozil is 20 mg (1.9-fold increase in exposure), and with ritonavir/atazanavir it is 10 mg (3.1-fold increase in exposure).

Vitamin K antagonists: initiation of therapy or an increase in the dose of rosuvastatin in patients receiving concomitant vitamin K antagonists (e.g., warfarin) may lead to an increase in INR. Discontinuation or reduction of the rosuvastatin dose may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives/Hormone replacement therapy: concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and the AUC of norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting the dose of oral contraceptives.

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

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.