INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIVERAM® 10 mg/5 mg/5 mg (TRIVERAM® 10 mg/5 mg/5 mg) TRIVERAM® 20 mg/5 mg/5 mg (TRIVERAM® 20 mg/5 mg/5 mg) TRIVERAM® 20 mg/10 mg/5 mg (TRIVERAM® 20 mg/10 mg/5 mg) TRIVERAM® 20 mg/10 mg/10 mg (TRIVERAM® 20 mg/10 mg/10 mg) TRIVERAM® 40 mg/10 mg/10 mg (TRIVERAM® 40 mg/10 mg/10 mg)

Composition:

Active substances: atorvastatin, perindopril, amlodipine;

TRIVERAM® 10 mg/5 mg/5 mg: 1 tablet contains: 10.82 mg of atorvastatin calcium trihydrate, equivalent to 10 mg of atorvastatin; 5 mg of perindopril arginine, equivalent to 3.40 mg of perindopril, and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine;

TRIVERAM® 20 mg/5 mg/5 mg: 1 tablet contains: 21.64 mg of atorvastatin calcium trihydrate, equivalent to 20 mg of atorvastatin; 5 mg of perindopril arginine, equivalent to 3.40 mg of perindopril, and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine;

TRIVERAM® 20 mg/10 mg/5 mg: 1 tablet contains: 21.64 mg of atorvastatin calcium trihydrate, equivalent to 20 mg of atorvastatin; 10 mg of perindopril arginine, equivalent to 6.79 mg of perindopril, and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine;

TRIVERAM® 20 mg/10 mg/10 mg: 1 tablet contains: 21.64 mg of atorvastatin calcium trihydrate, equivalent to 20 mg of atorvastatin; 10 mg of perindopril arginine, equivalent to 6.79 mg of perindopril, and 13.87 mg of amlodipine besylate, equivalent to 10 mg of amlodipine;

TRIVERAM® 40 mg/10 mg/10 mg: 1 tablet contains: 43.28 mg of atorvastatin calcium trihydrate, equivalent to 40 mg of atorvastatin; 10 mg of perindopril arginine, equivalent to 6.79 mg of perindopril, and 13.87 mg of amlodipine besylate, equivalent to 10 mg of amlodipine;

Excipients: calcium carbonate (E170); lactose monohydrate; microcrystalline cellulose; sodium starch glycolate; hydroxypropylcellulose; maltodextrin; magnesium stearate; film coating: glycerin; hypromellose; macrogol 6000; magnesium stearate; titanium dioxide (E171); iron oxide yellow (E172).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

TRIVERAM® 10 mg/5 mg/5 mg: yellow, round-shaped, film-coated tablets, with embossing «1» on one side and «» on the other.

TRIVERAM® 20 mg/5 mg/5 mg: yellow, round-shaped, film-coated tablets, with embossing «2» on one side and «» on the other.

TRIVERAM® 20 mg/10 mg/5 mg: yellow, square-shaped, film-coated tablets, with embossing «3» on one side and «» on the other.

TRIVERAM® 20 mg/10 mg/10 mg: yellow, elongated-shaped, film-coated tablets, with embossing «4» on one side and «» on the other.

TRIVERAM® 40 mg/10 mg/10 mg: yellow, elongated-shaped, film-coated tablets, with embossing «5» on one side and «» on the other.

Pharmacotherapeutic group. Lipid-regulating agents in combination with other substances; atorvastatin, amlodipine and perindopril. ATC code C10BX11.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase – the enzyme that limits the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into very low-density lipoproteins (VLDL) and released into blood plasma for transport to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and are primarily catabolized via interaction with receptors having high affinity for LDL (LDL receptors).

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme [ACE]) – an ACE inhibitor (iACE). The converting enzyme, or kinase, is an exopeptidase that converts angiotensin I into the vasoconstrictor angiotensin II, and also causes degradation of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to reduced angiotensin II concentration in blood, resulting in increased plasma renin activity (due to inhibition of negative feedback on renin release) and reduced aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also increases the activity of circulating and local kallikrein-kinin system (which in turn leads to activation of the prostaglandin system). This mechanism is believed to explain the antihypertensive effect of ACE inhibitors and partially accounts for some adverse effects of drugs in this class (e.g., dry cough).

Perindopril acts via its active metabolite, perindoprilat. Other metabolites do not demonstrate ACE inhibition activity in vitro.

Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker, or calcium ion antagonist) that blocks transmembrane calcium ion influx into smooth muscle cells of the myocardium and blood vessels.

Pharmacodynamic Effects

Atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and, consequently, cholesterol biosynthesis in the liver, and by increasing the number of LDL receptors on the surface of hepatic cells, thereby enhancing the uptake and catabolism of LDL.

Atorvastatin reduces the formation of LDL and the number of LDL particles, induces pronounced and sustained increase in LDL receptor activity, and causes favorable changes in the properties of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol levels in patients with homozygous familial hypercholesterolemia – a patient population that typically does not respond to lipid-lowering therapy.

Perindopril effectively reduces arterial blood pressure in mild, moderate, and severe arterial hypertension. Reduction in systolic and diastolic blood pressure is observed both in supine and standing positions.

Perindopril reduces peripheral vascular resistance, leading to decreased arterial blood pressure. Peripheral blood flow increases without affecting heart rate.

Renal blood flow generally increases, while glomerular filtration rate (GFR) remains unchanged.

Perindopril reduces cardiac workload by decreasing preload and afterload.

Amlodipine. The antihypertensive effect of amlodipine is due to direct vasodilatory action on vascular smooth muscle. Amlodipine reduces total ischemic load: it dilates peripheral arterioles, thereby decreasing total peripheral resistance (afterload); since heart rate remains unchanged, reduced cardiac load decreases myocardial energy consumption and oxygen demand; amlodipine dilates major coronary arteries and arterioles in both normal and ischemic areas. This increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal's angina, or variant angina).

Pharmacokinetics.

In a drug interaction study involving healthy volunteers, concomitant administration of atorvastatin 40 mg, amlodipine 10 mg, and perindopril arginine 10 mg resulted in a 23% increase in atorvastatin AUC, which is not clinically significant. A maximum concentration of perindopril increased by approximately 19%, but the pharmacokinetics of perindoprilat, the active metabolite, remained unchanged. No significant difference in the rate and extent of amlodipine absorption was observed when administered concomitantly with atorvastatin and perindopril compared to amlodipine monotherapy.

Atorvastatin

Absorption

Atorvastatin is rapidly absorbed after oral administration; peak plasma concentration (Cmax) is reached within 1–2 hours. The extent of absorption increases proportionally with dose. Absolute bioavailability is approximately 12%, and systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is ≥ 98%.

Biotransformation

Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and other products of β-oxidation. In addition to other metabolic pathways, these products undergo further glucuronidation. In vitro studies show that ortho- and parahydroxylated metabolites inhibit HMG-CoA reductase activity to an extent equivalent to that of atorvastatin. Active metabolites account for 70% of circulating HMG-CoA reductase inhibitory activity.

Elimination

Atorvastatin is primarily eliminated via bile after hepatic and/or extrahepatic metabolism. However, the drug is unlikely to undergo significant enterohepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours. The half-life of HMG-CoA reductase inhibitory activity is approximately 20–30 hours due to the presence of active metabolites.

Special Patient Populations

Elderly patients. Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly individuals than in younger patients, but lipid-lowering effects are fully comparable.

Gender. Plasma concentrations of atorvastatin and its active metabolites differ between women and men (Cmax is approximately 20% higher in women, while AUC is approximately 10% lower). This difference did not lead to clinically significant differences in lipid effects between women and men.

Renal impairment. Renal disease does not affect plasma concentrations or lipid effects of atorvastatin and its active metabolites.

Hepatic impairment. Plasma concentrations of atorvastatin and its active metabolites are significantly increased (Cmax nearly 16-fold higher, AUC 11-fold higher) in patients with chronic alcoholic liver disease (Child-Pugh class B).

Perindopril

Absorption. After administration, perindopril is rapidly absorbed; Cmax in blood is reached within 1 hour. Elimination half-life is 1 hour.

Biological transformation. Perindopril is a prodrug. 27% of the administered dose reaches systemic circulation as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five other inactive metabolites. Cmax of perindoprilat in blood is reached within 3–4 hours. Food intake reduces the conversion of perindopril to perindoprilat and decreases its bioavailability. Perindopril arginine is recommended to be taken before meals.

Linearity. A linear relationship exists between perindopril dose and its plasma concentration.

Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, mainly to angiotensin-converting enzyme, and is dose-dependent.

Elimination. Perindoprilat is excreted in urine; the terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of treatment initiation.

Special Patient Populations

Elderly patients. Elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal impairment.

Patients with renal impairment. Dose adjustment is required depending on the degree of renal impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min.

Patients with liver cirrhosis. Hepatic clearance is reduced by half, but the amount of formed perindoprilat does not decrease; therefore, dose adjustment is not required.

Amlodipine

Absorption. After administration, amlodipine is well absorbed and reaches Cmax in blood within 6–12 hours. Absolute bioavailability is 64–80%. Food intake does not affect amlodipine bioavailability.

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine in blood is protein-bound.

Biological transformation and elimination. The terminal elimination half-life of amlodipine from blood is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is primarily metabolized in the liver to inactive metabolites; 10% is excreted unchanged, and 60% of metabolites are excreted in urine.

Special Patient Populations

Patients with hepatic impairment. Clinical data are limited. In patients with hepatic impairment, amlodipine clearance is reduced, prolonging elimination half-life and increasing AUC by approximately 40–60%.

Elderly patients. Time to reach Cmax of amlodipine in plasma is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. Increased AUC and elimination half-life in patients with congestive heart failure corresponded to the age characteristics of the studied patients.

Clinical characteristics.

Indications.

Treatment of essential arterial hypertension and/or ischemic heart disease with primary hypercholesterolemia or mixed hyperlipidemia in adult patients who require treatment with atorvastatin, perindopril, and amlodipine in doses available in fixed combination.

Contraindications.

• Hypersensitivity to the active substances or to any other angiotensin-converting enzyme (ACE) inhibitors, dihydropyridine derivatives, statins, or to any of the excipients of the medicinal product.
• Active liver disease or persistent elevation (more than three times the upper limit of normal) of serum transaminases of unknown origin.
• Pregnancy, breastfeeding. Contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.
• Concomitant use with antiviral agents for the treatment of hepatitis C, glecaprevir/pibrentasvir.
• Severe arterial hypotension.
• Shock (including cardiogenic shock).
• Left ventricular outflow tract obstruction (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
• Heart failure with unstable hemodynamics following acute myocardial infarction.
• Angioedema (Quincke's edema) associated with previous therapy with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Concomitant use of aliskiren-containing products in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²).
• Concomitant use with sacubitril/valsartan. TRIVERAM® must not be administered earlier than 36 hours after the last dose of sacubitril/valsartan.
• Extracorporeal treatments leading to blood contact with negatively charged surfaces.
• Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Interaction with other medicinal products and other types of interactions.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased frequency of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent. Therefore, dual RAAS blockade by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Drug interaction studies between TRIVERAM® and other drugs have not been conducted; however, individual studies have been performed with atorvastatin, amlodipine, and perindopril. The results of these studies are presented below.

Drugs that increase the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.

Concomitant use of ACE inhibitors with racemadol, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema.

Drugs causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with TRIVERAM®. Certain drugs or therapeutic classes of drugs may cause hyperkalemia, including aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these drugs increases the risk of hyperkalemia; therefore, their concomitant use is not recommended. If concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels is required.

Concomitant use is contraindicated

Perindopril

Aliskiren. Concomitant use with TRIVERAM® is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²). Increased risk of hyperkalemia, worsening renal function, cardiovascular disease, and death.

Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions. If necessary, consider using a different type of dialysis membrane or another class of antihypertensive agents.

Atorvastatin

Glecaprevir/pibrentasvir. Concomitant use with TRIVERAM® is contraindicated due to increased risk of myopathy.

Concomitant use is not recommended

Atorvastatin

Strong CYP3A4 inhibitors. Atorvastatin is metabolized by the cytochrome P450 3A4 (CYP3A4) system and is a substrate for hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Concomitant use with CYP3A4 inhibitors or transporter protein inhibitors may increase atorvastatin plasma concentrations and lead to myopathy. This risk may be increased when atorvastatin is used concomitantly with other drugs capable of causing myopathy (fibrates and ezetimibe).

Strong CYP3A4 inhibitors significantly increase atorvastatin concentrations. Concomitant use of TRIVERAM® with strong CYP3A4 inhibitors (such as cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for hepatitis C treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided. If concomitant use cannot be avoided, TRIVERAM® should be used with a lower atorvastatin dose and clinical monitoring of the patient is recommended.

Perindopril

Aliskiren. Concomitant use with TRIVERAM® is not recommended in other patients (excluding patients with diabetes or impaired renal function, for whom concomitant use is contraindicated).

Concomitant therapy with ACE inhibitors and angiotensin receptor blockers. Not recommended. Dual blockade (i.e., combination of ACE inhibitors with angiotensin II receptor antagonists) may be used only in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine. Increased risk of angioedema.

Lithium. Concomitant use with ACE inhibitors may lead to reversible increases in serum lithium concentration and lithium toxicity. Concomitant use of TRIVERAM® with lithium is not recommended. If such combination is justified, regular monitoring of serum lithium levels is necessary.

Potassium-sparing diuretics (e.g., triamterene or amiloride, eplerenone, spironolactone), potassium salts. Hyperkalemia (potentially fatal) may occur, especially in patients with renal impairment (additive hyperkalemic effect). These drugs are not recommended for concomitant use with TRIVERAM®. If concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium and creatinine levels is required.

Amlodipine

Dantrolene (infusion). Due to the risk of hyperkalemia, concomitant use of calcium channel antagonists, including TRIVERAM®, is recommended to be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Atorvastatin/Amlodipine

Grapefruit or grapefruit juice. Concomitant use of TRIVERAM®, containing amlodipine and atorvastatin, with grapefruit or grapefruit juice is not recommended. Increased bioavailability of amlodipine and, consequently, enhanced hypotensive effect may occur. Increased atorvastatin concentration.

Concomitant use requiring special attention

Atorvastatin

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin concentrations. Increased risk of myopathy has been observed with concomitant use of erythromycin and statins. Studies on the effect of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil inhibit the activity of cytochrome CYP3A4 enzymes. Concomitant use with atorvastatin may lead to increased atorvastatin concentrations. When atorvastatin is used concomitantly with moderate CYP3A4 inhibitors, TRIVERAM® should be prescribed with a lower maximum atorvastatin dose. Clinical monitoring is recommended after initiation of treatment and after dose adjustment of the inhibitor.

Cytochrome P450 3A4 inducers. Concomitant use of atorvastatin with inducers of the cytochrome P450 3A system (efavirenz, rifampicin, St. John's wort) may lead to decreased plasma concentration of atorvastatin.

Digoxin. Repeated administration of digoxin in combination with 10 mg atorvastatin was associated with a slight increase in steady-state digoxin blood concentration. Patients taking digoxin should be under appropriate monitoring.

Ezetimibe. Use of ezetimibe as monotherapy has been associated with adverse effects on the muscular system, including rhabdomyolysis. The risk of these effects increases when ezetimibe is used concomitantly with atorvastatin in TRIVERAM®. Clinical monitoring is recommended.

Fusidic acid. Systemic concomitant use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis (including fatal cases) have been reported with the use of these drug combinations.

If systemic use of fusidic acid is necessary, TRIVERAM® should be discontinued.

Gemfibrozil/fibric acid derivatives. Use of fibrates as monotherapy may be associated with adverse effects on the muscular system, including rhabdomyolysis. The risk of these effects increases when fibric acid derivatives are used concomitantly with atorvastatin. If concomitant use cannot be avoided, TRIVERAM® should be prescribed with the lowest possible atorvastatin dose.

Inhibitors of transport proteins. Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase atorvastatin concentrations. If concomitant use cannot be avoided, dose reduction and clinical monitoring are recommended. TRIVERAM® is not recommended for concomitant use with letermovir and cyclosporine.

Warfarin. Monitoring of prothrombin time is required before initiation of TRIVERAM® treatment in patients taking coumarin anticoagulants, and monitoring should continue at the beginning of treatment and when adjusting the atorvastatin dose in TRIVERAM® to detect any disturbances. After confirming stability of prothrombin time, monitoring can be performed according to standard recommended intervals for coumarin anticoagulants. Atorvastatin treatment has not been associated with bleeding episodes or changes in prothrombin time in patients not taking anticoagulants.

Perindopril

Antidiabetic agents (insulin, oral antidiabetic agents). Concomitant use with ACE inhibitors may enhance the hypoglycemic effect with risk of hypoglycemia. This most commonly occurs during the first weeks of treatment and in patients with renal impairment. Blood glucose monitoring is required during the first month of treatment.

Baclofen. Enhances the antihypertensive effect. Blood pressure should be monitored, and dose adjustment may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid ≥ 3 g/day). Concomitant use of ACE inhibitors with NSAIDs (such as acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may lead to reduced antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including acute renal failure, and increased serum potassium levels, especially in patients with established renal impairment. Combination of TRIVERAM® and NSAIDs should be prescribed with caution, particularly in elderly patients. Fluid balance should be restored and renal function monitored after initiation of combination therapy and during treatment.

Amlodipine

CYP3A4 inhibitors. Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, imidazole and triazole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may cause significant increases in amlodipine concentrations. Clinical manifestations may be more pronounced in elderly patients. Clinical monitoring and dose adjustment are required. Increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close observation is recommended.

CYP3A4 inducers. Blood concentrations of amlodipine may vary when used concomitantly with known CYP3A4 inducers. Blood pressure should be monitored and dose adjustment performed during and after concomitant use with CYP3A4 inducers (particularly strong CYP3A4 inducers such as rifampicin, St. John's wort (Hypericum perforatum)).

Concomitant use requiring attention

Atorvastatin

Colchicine. Cases of myopathy have been reported with concomitant use of atorvastatin and colchicine. Use with caution.

Cholestyramine. Blood concentrations of atorvastatin and its active metabolites were lower (approximately 25%) when atorvastatin was used concomitantly with cholestyramine. The lipid-lowering effect of this combination exceeded the effect of each drug used separately.

Daptomycin. Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions").

Oral contraceptives. Concomitant use of atorvastatin and oral contraceptives increases blood concentrations of norethindrone and ethinylestradiol.

Perindopril

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Tricyclic antidepressants/antipsychotics/anesthetics. Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further reduction in blood pressure.

Gold. Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may cause reactions similar to those seen with nitrates (symptoms: facial flushing (hot flushes), nausea, vomiting, and hypotension).

Amlodipine

Digoxin, atorvastatin, and warfarin. Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, and warfarin.

Tacrolimus. Risk of increased blood levels of tacrolimus with concomitant use of amlodipine. Blood levels of tacrolimus should be monitored and dose adjusted if necessary when used concomitantly with amlodipine.

Inhibitors of mechanistic target of rapamycin (mTOR). mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use with mTOR inhibitors may increase mTOR inhibitor concentrations.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted. In kidney transplant patients, cyclosporine concentrations have fluctuated with average increases of 0%–40%. In kidney transplant patients taking amlodipine, cyclosporine blood levels should be monitored and dose reduced if necessary.

Amlodipine/perindopril

Antihypertensive agents and vasodilators. Concomitant use of these agents may enhance the hypotensive effect of TRIVERAM®. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may lead to additional reduction in blood pressure.

Effect of other medicinal products on atorvastatin pharmacokinetics when used concomitantly.

• Tipranavir 500 mg BID/ritonavir 200 mg BID, 8 days (from day 14 to day 21) with atorvastatin 40 mg on day 1, 10 mg on day 20 – AUC&9.4. Telaprevir 750 mg every 8 hours, 10 days with atorvastatin 20 mg, QD, for 8 days – AUC&7.9. Cyclosporine 5.2 mg/kg/day, steady dose with atorvastatin 10 mg, QD, for 28 days – AUC&8.7. If concomitant use with atorvastatin is necessary, do not exceed 10 mg atorvastatin per day. Clinical monitoring is recommended#.

• Lopinavir 400 mg BID/ritonavir 100 mg BID, 14 days with atorvastatin 20 mg, QD, for 4 days – AUC&5.9. Clarithromycin 500 mg BID, 9 days with atorvastatin 80 mg, QD, for 8 days – AUC&4.5. If concomitant use with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. Clinical monitoring is recommended# when atorvastatin dose exceeds 20 mg.

• Saquinavir 400 mg BID/ritonavir (300 mg BID from days 5–7, increased to 400 mg BID on day 8), days 4–18, 30 minutes after atorvastatin 40 mg, QD, for 4 days – AUC&3.9. Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days with atorvastatin 10 mg, QD, for 4 days – AUC&3.4. Itraconazole 200 mg QD, 4 days with atorvastatin 40 mg, QD – AUC&3.3. Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days with atorvastatin 10 mg, QD, for 4 days – AUC&2.5. Fosamprenavir 1400 mg BID, 14 days with atorvastatin 10 mg, QD, for 4 days – AUC&2.3. If concomitant use with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. Clinical monitoring is recommended# when atorvastatin dose exceeds 40 mg.

• Letermovir 480 mg QD, 10 days with atorvastatin 20 mg, QD – AUC&3.29. Atorvastatin dose should not exceed 20 mg per day during concomitant use with letermovir-containing products.

• Nelfinavir 1250 mg BID, 14 days with atorvastatin 10 mg, QD, for 28 days – AUC&1.74. No special recommendations required.

• Grapefruit juice 240 mL QD* with atorvastatin 40 mg, QD – AUC&1.37. Concomitant consumption of large amounts of grapefruit juice and atorvastatin is not recommended#.

• Diltiazem 240 mg QD, 28 days with atorvastatin 40 mg, QD – AUC&1.51. Appropriate clinical monitoring is recommended after initiation or dose adjustment of diltiazem#.

• Erythromycin 500 mg QID, 7 days with atorvastatin 10 mg, QD – AUC&1.33. Lower maximum doses and clinical monitoring are recommended#.

• Amlodipine 10 mg, QD with atorvastatin 80 mg, QD – AUC&1.18. Cimetidine 300 mg QID, 2 weeks with atorvastatin 10 mg, QD, for 2 weeks – AUC&1. Colestyramine 10 g, BID, 24 weeks with atorvastatin 40 mg, QD, for 8 weeks – AUC&0.74**. Antacid suspension of magnesium and aluminum oxide, 30 mL QID, 17 days with atorvastatin 10 mg, QD, for 15 days – AUC&0.66. Efavirenz 600 mg QD, 14 days with atorvastatin 10 mg for 3 days – AUC&0.59. No special recommendations required.

• Rifampicin 600 mg QD, 7 days, simultaneous administration with atorvastatin 40 mg QD – AUC&1.12. Rifampicin 600 mg QD, 5 days (delayed administration) with atorvastatin 40 mg QD – AUC&0.20. If concomitant use cannot be avoided, simultaneous administration of these drugs is recommended with clinical monitoring.

• Gemfibrozil 600 mg BID, 7 days with atorvastatin 40 mg QD – AUC&1.35. Fenofibrate 160 mg QD, 7 days with atorvastatin 40 mg QD – AUC&1.03. Lower initial doses and clinical monitoring are recommended.

• Boceprevir 800 mg TID, 7 days with atorvastatin 40 mg QD – AUC&2.3. Lower initial doses and clinical monitoring are recommended. Atorvastatin dose should not exceed 20 mg per day during concomitant use with boceprevir.

• Glecaprevir 400 mg QD/pibrentasvir 120 mg QD, 7 days with atorvastatin 10 mg QD for 7 days – AUC&8.3. Concomitant use with medicinal products containing glecaprevir or pibrentasvir is contraindicated.

• Elbasvir 50 mg QD/grazoprevir 200 mg QD, 13 days with atorvastatin 10 mg QD – AUC&1.95. Atorvastatin dose should not exceed 20 mg per day during concomitant use with elbasvir- or grazoprevir-containing products.

QD – once daily, SD – single dose, BID – twice daily, QID – four times daily, TID – three times daily.

& Area under the curve (AUC) ratio.

See sections "Special precautions" and "Interaction with other medicinal products and other types of interactions."

* Contains one or more components that inhibit CYP3A4 and may increase plasma concentration of drugs metabolized by CYP3A4. Consumption of 240 mL grapefruit juice also results in a 20.4% reduction in AUC for the active ortho-hydroxymetabolite. Large amounts of grapefruit juice (more than 1.2 L per day for 5 days) increased atorvastatin AUC by 2.5-fold and AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) by 1.3-fold.

** Ratio based on a single sample taken 8–16 hours after drug administration.

Effect of atorvastatin on pharmacokinetics of medicinal products when used concomitantly.

• Atorvastatin 80 mg, QD, for 10 days with digoxin 0.25 mg, QD, for 20 days – AUC&1.15. Patients taking digoxin should be under appropriate monitoring.
• Atorvastatin 40 mg, QD, for 22 days with oral contraceptives QD, for 2 months (norethindrone 1 mg and ethinylestradiol 35 mcg) – AUC&1.28 and 1.19. Atorvastatin 80 mg, QD, for 15 days with phenazone*, 600 mg, SD – AUC&1.03. Atorvastatin 10 mg, SD with tipranavir 500 mg, BID/ritonavir 200 mg BID, 7 days – AUC&1.08. Atorvastatin 10 mg, QD, for 4 days with fosamprenavir 1400 mg, BID, 14 days – AUC&0.73. Atorvastatin 10 mg, QD, for 4 days with fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days – AUC&0.99. No special recommendations required.

& Area under the curve (AUC) ratio.

* Repeated concomitant use of atorvastatin and phenazone had no effect or only a negligible effect on phenazone clearance.

Special precautions for use.

Hepatic impairment. Since atorvastatin is a component of the medicinal product, liver function tests should be periodically monitored. If symptoms of hepatic dysfunction occur, liver function tests should be performed. Clinical monitoring is required until liver enzyme levels return to normal in case of elevated transaminase activity. If transaminase levels exceed three times the upper limit of normal (ULN), clinical monitoring is required until normalization of parameters. If transaminase levels exceed three times the ULN, dose reduction of atorvastatin using single-component agents or discontinuation of therapy is recommended. TRIVERAM® should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

In case of development of jaundice or elevated liver enzymes, TRIVERAM® should be discontinued and appropriate medical assistance sought.

In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are increased; dosage recommendations have not been established. Patients with severe hepatic impairment receiving TRIVERAM® should be under close surveillance.

Due to the effects of atorvastatin, perindopril, and amlodipine, the use of TRIVERAM® is contraindicated in active liver disease or in persistent elevations of serum transaminases of unknown etiology exceeding three times the ULN. TRIVERAM® should be used with caution in patients with hepatic dysfunction and in those who abuse alcohol and/or have a history of hepatic dysfunction. If dose adjustment is required, the doses of each component should be individually titrated.

Skeletal muscle effects. Atorvastatin, like other HMG-CoA reductase inhibitors, may affect skeletal muscles and cause muscle pain, myositis, and myopathy, which may progress to rhabdomyolysis—a potentially life-threatening condition characterized by marked elevation of creatine kinase (CK) (>10 times ULN), myoglobinemia, and myoglobinuria, which may lead to renal failure.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with certain statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy, positive testing for antibodies to HMG-CoA reductase, and improvement with immunosuppressive therapy.

Measurement of creatine kinase (CK) levels. If CK levels are markedly elevated at the start of treatment (>5 times ULN), these values should be rechecked after 5–7 days to confirm results.

Before treatment: atorvastatin should be prescribed with caution to patients with risk factors for rhabdomyolysis. Before initiating statin therapy, CK levels should be determined in the following cases: renal impairment, hypothyroidism, personal or family history of muscle disorders, previous history of statin or fibrate myotoxicity, previous history of liver disease and/or alcohol abuse, elderly age (>70 years; CK measurement should be considered if other risk factors for rhabdomyolysis are present); conditions that may lead to increased plasma levels, such as drug interactions and special populations, including genetic subpopulations. The risk of treatment should be evaluated relative to potential benefit, and clinical monitoring is recommended.

If CK levels are markedly elevated (>5 times ULN), treatment should not be initiated.

During treatment: patients should be advised to promptly consult a physician if symptoms such as muscle pain, cramps, or weakness occur—especially if accompanied by malaise or fever. If such symptoms occur during treatment with TRIVERAM®, CK levels should be checked. If CK levels are significantly elevated (>5 times ULN), treatment should be discontinued. If muscle symptoms are severe or cause daily discomfort, even if CK elevation is ≤5 × ULN, discontinuation of treatment should be considered. If symptoms resolve and CK levels normalize, reinitiation of atorvastatin or another statin at the lowest dose should be considered, with careful monitoring of the patient. Treatment with TRIVERAM® should be immediately discontinued in case of clinically significant elevation of CK levels (>10 × ULN) or diagnosed or suspected rhabdomyolysis.

Concomitant therapy with other medicinal products. Due to the presence of atorvastatin in the formulation, the risk of rhabdomyolysis increases when TRIVERAM® is used concomitantly with medicinal products that may increase plasma concentrations of atorvastatin, e.g., strong CYP3A4 inhibitors or transporter proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir). The risk of myopathy increases with concomitant use of gemfibrozil and other fibrinic acid derivatives, antiviral agents for hepatitis C (boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. If possible, alternative (non-interacting) therapy should be used.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily discontinuing TRIVERAM® in patients receiving daptomycin unless the benefit of concomitant use outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be under close surveillance for any signs or symptoms suggestive of myopathy.

If concomitant use of TRIVERAM® with the above-mentioned medicinal products is necessary, the benefit and risk of concomitant therapy should be carefully weighed. When using medicinal products that increase atorvastatin plasma concentrations, a lower dose of atorvastatin is recommended, and use of single-component agents may be appropriate. When using strong CYP3A4 inhibitors, consideration should be given to using a lower initial dose of atorvastatin and close monitoring of patients.

Due to the presence of atorvastatin in the formulation, concomitant use with systemic fusidic acid and during the 7 days following discontinuation of fusidic acid treatment is contraindicated. If systemic fusidic acid is required, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported with concomitant use of these substances. Immediate medical attention should be sought if symptoms of muscle weakness, pain, or tenderness occur. Statin therapy may be resumed 7 days after discontinuation of fusidic acid treatment. Exceptionally, in cases requiring long-term systemic fusidic acid treatment (e.g., severe infections), the need for concomitant use of TRIVERAM® and fusidic acid should be individually assessed under close medical supervision.

Myasthenia gravis, ocular myasthenia: isolated cases have been reported where statins induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, TRIVERAM® should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Interstitial lung disease (ILD). Rare cases of ILD have been reported during therapy with certain statins (particularly during long-term treatment). Signs of this condition may include dyspnea, non-productive cough, and worsening general health (fatigue, weight loss, and fever). If ILD is suspected, treatment with TRIVERAM® should be discontinued.

Diabetes mellitus. Statins may increase blood glucose levels, which in patients at high risk of developing diabetes mellitus in the future may lead to hyperglycemia. Standard recommendations for managing patients with diabetes mellitus should be followed. This risk is less significant compared to the benefit of treatment (i.e., reduction in vascular disease risk) and therefore should not be a reason for discontinuing TRIVERAM® therapy. During treatment with TRIVERAM®, clinical and biochemical parameters in at-risk patients (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored according to current guidelines. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, glycemia should be closely monitored during the first month of treatment with ACE inhibitors, including TRIVERAM®.

Heart failure. TRIVERAM® should be prescribed with caution in patients with heart failure. Medicinal products containing calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Hypotension. ACE inhibitors, including perindopril, may cause a rapid decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and more likely in patients with hypovolemia, those taking diuretics, those on a low-salt diet, patients on dialysis, patients with diarrhea or vomiting, and patients with severe renin-dependent hypertension. Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. Symptomatic arterial hypotension is most likely in patients with severe heart failure who are taking high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of symptomatic arterial hypotension at the beginning of therapy and during dose titration should be under medical supervision. These precautions also apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, given intravenous isotonic sodium chloride solution 9 mg/mL (0.9%). Transient hypotension is not a contraindication for further use of the medicinal product after restoration of blood volume and increase in arterial pressure. In patients with congestive heart failure and normal or low blood pressure, perindopril may cause additional blood pressure reduction. This effect is expected and usually does not require discontinuation of treatment. If arterial hypotension becomes symptomatic, dose reduction or discontinuation of the medicinal product may be considered.

Aortic or mitral valve stenosis. Like other medicinal products containing ACE inhibitors, including perindopril, TRIVERAM® should be used with caution in patients with mitral valve stenosis or significant low-grade aortic stenosis. The use of the medicinal product is contraindicated in patients with severe left ventricular outflow tract obstruction.

Kidney transplantation. There is no experience with the use of perindopril arginine in patients who have recently undergone kidney transplantation.

Rénovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure. The use of diuretics may be a contributing factor. Renal function deterioration may be accompanied by only minor changes in blood creatinine levels, even in patients with unilateral renal artery stenosis.

Renal impairment. TRIVERAM® may be prescribed to patients with creatinine clearance ≥60 mL/min, but this medicinal product is not suitable for patients with creatinine clearance <60 mL/min (moderate or severe renal impairment). For such patients, dose titration using single-component agents is recommended. Patients with renal impairment should undergo monitoring of blood potassium and creatinine concentrations.

In patients with symptomatic heart failure, arterial hypotension at the beginning of ACE inhibitor therapy may lead to further deterioration of renal function, in some cases resulting in acute renal failure, which is usually reversible. In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, increased blood urea and creatinine concentrations have been observed during ACE inhibitor therapy, which usually returned to normal after discontinuation of treatment. This is most likely in patients with renal impairment. In the presence of concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure is increased. In some patients with arterial hypertension, in whom no renovascular disease was detected before treatment initiation, slight transient increases in blood urea and creatinine levels developed, especially when perindopril was used concomitantly with diuretics. This is more likely in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of diuretics and/or TRIVERAM® may be necessary. Amlodipine may be used in patients with renal impairment at usual doses. Changes in amlodipine blood concentrations do not correlate with the degree of renal function impairment. Amlodipine is not removed during dialysis. The effect of using the combination medicinal product TRIVERAM® in patients with renal impairment has not been established. TRIVERAM® doses should correspond to the doses of individual single-component agents.

Patients on hemodialysis. In patients undergoing dialysis with high-flux polyacrylonitrile membranes and concurrently taking ACE inhibitors, anaphylactoid reactions have been observed. Other types of dialysis membranes or another class of antihypertensive agents should be used.

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, mucous membranes, tongue, vocal cords, and/or larynx has been observed in isolated cases during treatment with ACE inhibitors, including perindopril. This may occur at any time during treatment. TRIVERAM® should be immediately discontinued and appropriate monitoring maintained until complete resolution of symptoms. In cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Antihistamine agents may be prescribed to alleviate symptoms. Angioedema associated with laryngeal edema may be fatal. In cases where swelling involves the tongue, vocal cords, or larynx, potentially causing airway obstruction, emergency treatment is required. The patient should remain under medical supervision until complete and sustained resolution of symptoms. Patients with a history of angioedema unrelated to ACE inhibitor therapy have an increased risk of developing angioedema when taking TRIVERAM®. Rare cases of intestinal angioedema have been reported in patients during ACE inhibitor therapy. In such patients, abdominal pain (with or without nausea and vomiting) was observed. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory dysfunction). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. In patients taking ACE inhibitors, potentially life-threatening anaphylactic reactions may occur during LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization therapy. Anaphylactic reactions may occur in patients receiving medicinal products containing ACE inhibitors, including TRIVERAM®, during desensitization therapy (e.g., hymenoptera venom). These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur if provocation tests are carelessly repeated.

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Cases of neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported with the use of ACE inhibitors. In patients with normal renal function and no other risk factors, neutropenia is rare. TRIVERAM® should be used with extreme caution in patients with collagenoses, during immunosuppressive therapy, with allopurinol or procainamide, and in patients with a combination of these risk factors, especially if renal impairment is present. In some of these patients, development of severe infectious diseases has been observed, in several cases resistant to intensive antibiotic therapy. If such patients are taking TRIVERAM®, periodic monitoring of white blood cell count is necessary, and patients should be instructed to report any signs of infection (e.g., sore throat, fever).

Racial factor. ACE inhibitors more frequently cause angioedema in black patients than in patients of other races. TRIVERAM®, which contains the ACE inhibitor perindopril, is less effective in lowering blood pressure in black patients compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Cough. Cough has been reported during ACE inhibitor therapy. The cough is non-productive, persistent, and resolves after discontinuation of the medicinal product. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough in patients taking TRIVERAM®.

Surgery/anesthesia. If a patient is scheduled for surgery or anesthesia with agents causing arterial hypotension, TRIVERAM® may block the formation of angiotensin II following compensatory renin release. Treatment with the medicinal product should be discontinued one day before surgery. If hypotension has already occurred and is due to the above, correction may be achieved by increasing circulating blood volume.

Hyperkalemia. Increased potassium concentration in blood may occur during treatment with ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. In patients with normal renal function, this effect is usually insignificant. Risk factors for hyperkalemia include: renal impairment or reduced renal function, age >70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements or potassium-containing salt substitutes, or other medicinal products affecting increased blood potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements and salt substitutes, potassium-sparing diuretics may lead to significant increase in blood potassium levels, especially in patients with renal impairment. Hyperkalemia may lead to serious, sometimes fatal arrhythmias. Patients taking ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and undergo careful monitoring of blood potassium levels and renal function. If concomitant use of these agents with TRIVERAM® is indicated, they should be used with caution and blood potassium levels should be frequently monitored.

Combinations with lithium. Concomitant use of lithium and medicinal products containing perindopril, including TRIVERAM®, is not recommended.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive therapy acting via inhibition of the renin-angiotensin system. Use of this medicinal product is not recommended in such patients.

Excipients. Due to the presence of lactose monohydrate in the formulation, TRIVERAM® should not be used in patients with rare hereditary galactose intolerance, glucose-galactose malabsorption, or total lactase deficiency.

Sodium content. One tablet of TRIVERAM® contains less than 1 mmol sodium (23 mg), i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

TRIVERAM® is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential. Women of childbearing potential should use appropriate contraceptive methods during treatment with TRIVERAM®.

Ability to affect reaction speed when driving vehicles or operating machinery

TRIVERAM® may cause dizziness, headache, fatigue, or nausea; therefore, the ability to drive vehicles or operate machinery may be impaired in patients taking the medicinal product. Caution is recommended, especially at the beginning of treatment.

Method of administration and dosage

For oral use. The medication should be taken once daily, one tablet in the morning before food.

This fixed-dose combination is not intended for initial therapy.

If dose adjustment is required, the doses of each component should be individually selected.

Concomitant use with other medications

For patients receiving antiviral agents for hepatitis C treatment (elbasvir/grazoprevir) or letermovir for cytomegalovirus infection prophylaxis concomitantly with TRIVIRAM®, the atorvastatin dose in TRIVIRAM® must not exceed 20 mg/day. The use of TRIVIRAM® is not recommended in patients taking letermovir together with cyclosporine.

Patients with renal impairment

TRIVIRAM® can be prescribed to patients with creatinine clearance ≥ 60 mL/min, but it is not suitable for patients with creatinine clearance < 60 mL/min. In such patients, individual dose titration of each component is recommended.

Elderly patients

Elderly patients should be prescribed TRIVIRAM® according to their renal function status.

Patients with hepatic impairment

TRIVIRAM® should be used with caution in patients with impaired liver function. TRIVIRAM® is contraindicated in patients with active liver disease.

Children

The safety and efficacy of TRIVIRAM® in children and adolescents have not been established. There are no data available. Therefore, the use of this medication in children and adolescents (under 18 years of age) is not recommended.

Overdose

There is no available data on overdose with TRIVIRAM®.

Atorvastatin

Symptoms and treatment. There is no specific antidote for atorvastatin overdose. In case of overdose, symptomatic treatment and appropriate supportive measures are recommended. Liver function tests should be performed and serum CK levels monitored. Due to the extensive plasma protein binding of atorvastatin, hemodialysis is not expected to significantly enhance its clearance.

Perindopril

Symptoms. Symptoms of overdose with any ACE inhibitor include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment. Intravenous administration of 9 mg/mL (0.9%) sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with elevated legs. If possible, infuse angiotensin II and/or intravenous catecholamines. Perindopril can be removed from the body by hemodialysis. In cases of refractory bradycardia, artificial cardiac pacing is indicated. Vital signs, serum electrolytes, and creatinine levels should be closely monitored.

Amlodipine

Data on amlodipine overdose are limited.

Symptoms. Significant overdose may cause excessive peripheral vasodilation and reflex tachycardia. Cases of severe, prolonged systemic hypotension and shock with fatal outcome have been reported.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment. Clinically significant hypotension requires active cardiovascular support, monitoring of cardiac and respiratory function, placement of the patient in a supine position with elevated legs, and monitoring of circulating blood volume and urine output. Administration of vasopressors may be beneficial in restoring vascular tone and normalizing blood pressure (in the absence of contraindications). Intravenous calcium gluconate may help reverse the effects of calcium channel blockade. Gastric lavage and activated charcoal may be considered. Amlodipine is highly protein-bound, and hemodialysis is considered ineffective.

Adverse reactions

The most commonly reported adverse reactions with atorvastatin, perindopril, and amlodipine when used individually are: nasopharyngitis, hypersensitivity, hyperglycaemia, headache, pharyngolaryngeal pain, epistaxis, constipation, flatulence, dyspepsia, nausea, diarrhoea, change in defecation rhythm, muscle pain, joint pain, limb pain, muscle spasms, joint swelling, ankle swelling, back pain, liver function test abnormalities, increased blood creatine kinase levels, somnolence, dizziness, palpitations, hot flushes, abdominal pain, oedema, fatigue, paraesthesia, visual disturbances, diplopia, tinnitus, vertigo, hypotension, cough, dyspnoea, vomiting, taste disturbances (dysgeusia), rash, pruritus, asthenia.

During treatment with atorvastatin, perindopril, or amlodipine, the following adverse reactions have been observed, classified by MedDRA organ system classes and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations: common – nasopharyngitis; uncommon – rhinitis.

Blood and lymphatic system disorders: uncommon* – eosinophilia; rare – thrombocytopenia; very rare – leukopenia/neutropenia, agranulocytosis or pancytopenia, haemolytic anaemia in patients with congenital G-6PDH deficiency.

Immune system disorders: common – hypersensitivity; very rare – anaphylaxis.

Metabolism and nutrition disorders: common – hyperglycaemia; uncommon – hypoglycaemia, anorexia; uncommon* – hyponatraemia, hyperkalaemia, which resolves after discontinuation of therapy.

Endocrine disorders: rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders: uncommon – insomnia, mood changes (including anxiety), sleep disorders, depression, nightmares; rare – confusion.

Nervous system disorders: common – somnolence, dizziness, headache, dysgeusia (taste disturbance), paraesthesia; uncommon – tremor, hypoesthesia, amnesia, loss of consciousness (syncope); rare – peripheral neuropathy; very rare – hypertension; excessive arterial hypotension in high-risk patients may lead to stroke; frequency not known – extrapyramidal disorders, myasthenia gravis.

Eye disorders: common – visual disturbances, diplopia; uncommon – blurred vision; frequency not known – ocular myasthenia.

Ear and labyrinth disorders: common – tinnitus, vertigo; very rare – hearing loss.

Cardiac disorders: common – palpitations; uncommon – arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation); uncommon* – tachycardia; very rare – myocardial infarction due to excessive hypotension in high-risk patients, angina.

Vascular disorders: common – hypotension (and hypotension-related effects), hot flushes; vasculitis (rare – atorvastatin, uncommon* – perindopril, very rare – amlodipine); frequency not known – Raynaud’s phenomenon.

Respiratory, thoracic and mediastinal disorders: common – pharyngolaryngeal pain, epistaxis, cough, dyspnoea; uncommon – bronchospasm; very rare – eosinophilic pneumonia.

Gastrointestinal disorders: common – nausea, vomiting, upper and lower abdominal pain, dyspepsia, diarrhoea, constipation, change in defecation rhythm, flatulence; uncommon – dry mouth, pancreatitis, belching; very rare – gastritis, gingival hyperplasia.

Hepatobiliary disorders: uncommon – cytolytic or cholestatic hepatitis; rare – cholestasis; very rare – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – urticaria, purpura, skin discoloration, hyperhidrosis, exanthema, alopecia, angioedema; uncommon* – pemphigoid; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug-induced lichenoid reaction; rare* – worsening of psoriasis symptoms; very rare – exfoliative dermatitis; photosensitivity reactions (uncommon* – perindopril, very rare – amlodipine).

Musculoskeletal and connective tissue disorders: common – joint swelling, ankle swelling, limb pain, arthralgia, muscle spasms, myalgia, back pain; uncommon – neck pain, muscle fatigue; rare – myopathy, myositis, rhabdomyolysis, muscle rupture, tendinopathy sometimes complicated by rupture; very rare – lupus-like syndrome; frequency not known – immune-mediated necrotizing myopathy.

Renal and urinary disorders: uncommon – micturition disorder, nocturia, pollakiuria, renal failure; rare – anuria/oliguria*, acute renal failure.

Reproductive system and breast disorders: uncommon – erectile dysfunction, gynaecomastia.

General disorders and administration site conditions: very common – oedema; common – asthenia, fatigue; uncommon – chest pain, pain, malaise, peripheral oedema, pyrexia.

Investigations: common – abnormal liver function biochemical parameters, increased blood creatine kinase levels; uncommon* – increased blood urea levels, increased blood creatinine levels; uncommon – weight gain, presence of leucocytes in urine, weight loss; rare – elevated liver enzymes, increased blood bilirubin levels; very rare – decreased haemoglobin and haematocrit levels.

Injury, poisoning and procedural complications: uncommon* – falls.

*Frequency determined from clinical trial data on adverse events identified from spontaneous reports.

As with other HMG-CoA reductase inhibitors, increased transaminase activity in blood has been reported in patients taking atorvastatin. These abnormalities are usually mild, reversible, and do not require discontinuation of treatment. Clinically significant increases (more than 3 times the ULN) in blood transaminase activity occurred in 0.8% of patients receiving atorvastatin. In all patients, such increases were dose-dependent and reversible.

Clinical trial data show that, as with other HMG-CoA reductase inhibitors, elevated creatine kinase (CK) levels more than 3 times the ULN were observed in 2.5% of patients treated with atorvastatin. CK levels more than 10 times the ULN were observed in 0.4% of patients receiving atorvastatin.

With the use of some statins, the following adverse events have been reported: sexual dysfunction, depression, rare cases of interstitial lung disease, particularly with long-term use, and diabetes mellitus (frequency depended on the presence or absence of risk factors: fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of hypertension).

Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

No special temperature storage conditions required. Keep container tightly closed to protect from moisture. Store out of reach of children.

Packaging.

30 tablets per tablet container; 1 or 3 tablet containers per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Les Laboratoires Servier Industrie, France.

Manufacturer’s location and address of manufacturing site.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd, Ireland.

Manufacturer’s location and address of manufacturing site.

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier, France.

Address of Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France.