Trinomia®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRINOMIA® (TRINOMIA®)

Composition:

Active substances:

1 capsule contains 100 mg acetylsalicylic acid, 20 mg atorvastatin (as atorvastatin calcium trihydrate), and 2.5 mg ramipril;

1 capsule contains 100 mg acetylsalicylic acid, 20 mg atorvastatin (as atorvastatin calcium trihydrate), and 5 mg ramipril;

1 capsule contains 100 mg acetylsalicylic acid, 20 mg atorvastatin (as atorvastatin calcium trihydrate), and 10 mg ramipril;

Excipients:

for capsules 100 mg/20 mg/2.5 mg:

for acetylsalicylic acid tablets: microcrystalline cellulose; sodium starch glycolate (type A); talc; Opadry AMB white OY-B-28920;

for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silicon dioxide; magnesium stearate; Opadry green 06O21881;

for ramipril tablets: hypromellose 2910; microcrystalline cellulose; pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMB yellow 80W32039;

hard capsule: gelatin; titanium dioxide (E 171); iron oxide, black (E 172); black ink;

for capsules 100 mg/20 mg/5 mg:

for acetylsalicylic acid tablets: microcrystalline cellulose; sodium starch glycolate (type A); talc; Opadry AMB white OY-B-28920;

for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silicon dioxide; magnesium stearate; Opadry green 06O21881;

for ramipril tablets: hypromellose 2910; microcrystalline cellulose; pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMB yellow 80W32656;

hard capsule: gelatin; titanium dioxide (E 171); iron oxide, black (E 172); iron oxide, red (E 172); black ink;

for capsules 100 mg/20 mg/10 mg:

for acetylsalicylic acid tablets: microcrystalline cellulose; sodium starch glycolate (type A); talc; Opadry AMB white OY-B-28920;

for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silicon dioxide; magnesium stearate; Opadry green 06O21881;

for ramipril tablets: hypromellose 2910; microcrystalline cellulose; pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMB yellow 80W32880;

hard capsule: gelatin; titanium dioxide (E 171); iron oxide, red (E 172); black ink.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

for capsules 100 mg/20 mg/2.5 mg:

opaque, hard gelatin capsules size 0, with light grey body and cap, marked “AAR 100/20/2.5”, containing two film-coated acetylsalicylic acid tablets, white or almost white, engraved “AS”, two film-coated atorvastatin tablets, greenish-brown, engraved “AT”, and one film-coated ramipril tablet, pale yellow, engraved “R2”;

for capsules 100 mg/20 mg/5 mg:

opaque, hard gelatin capsules size 0, with pale pink cap and light grey body, marked “AAR 100/20/5”, containing two film-coated acetylsalicylic acid tablets, white or almost white, engraved “AS”, two film-coated atorvastatin tablets, greenish-brown, engraved “AT”, and one film-coated ramipril tablet, pale yellow, engraved “R5”;

for capsules 100 mg/20 mg/10 mg:

opaque, hard gelatin capsules size 0, with pale pink body and cap, marked “AAR 100/20/10”, containing two film-coated acetylsalicylic acid tablets, white or almost white, engraved “AS”, two film-coated atorvastatin tablets, greenish-brown, engraved “AT”, and one film-coated ramipril tablet, pale yellow, engraved “R1”.

Pharmacotherapeutic group.

Agents acting on the cardiovascular system. Lipid-modifying agents, combinations. Atorvastatin, acetylsalicylic acid and ramipril. ATC code C10BX06.

Pharmacological Properties.

Pharmacodynamics.

Acetylsalicylic acid. Acetylsalicylic acid irreversibly inhibits platelet aggregation. This effect on platelets is due to acetylation of cyclooxygenase, which irreversibly inhibits the synthesis of thromboxane A2 (a substance that promotes platelet aggregation and causes vasoconstriction) in platelets. This effect is permanent and typically lasts throughout the 8-day lifespan of platelets. Acetylsalicylic acid also suppresses the synthesis of prostacyclin (a prostaglandin that inhibits platelet aggregation but causes vasodilation) in vascular endothelial cells. This effect is transient. After acetylsalicylic acid is eliminated from the blood, nucleated endothelial cells resume prostacyclin synthesis. As a result, a single low daily dose of acetylsalicylic acid (< 100 mg/day) inhibits thromboxane A2 synthesis in platelets without significantly affecting prostacyclin synthesis. Acetylsalicylic acid belongs to the group of acid-forming nonsteroidal anti-inflammatory drugs with analgesic, antipyretic, and anti-inflammatory properties. Their mechanism of action involves irreversible inhibition of cyclooxygenase enzymes involved in prostaglandin synthesis. Higher doses of acetylsalicylic acid are used to treat mild to moderate pain, elevated body temperature, and acute and chronic inflammatory conditions such as rheumatoid arthritis. Experimental data have shown that when administered concomitantly with low doses of acetylsalicylic acid, ibuprofen may interfere with platelet aggregation. In a study comparing the effect of a single 400 mg dose of ibuprofen taken 8 hours or 30 minutes before 81 mg of acetylsalicylic acid (as an immediate-release tablet), a reduction in the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation was observed. However, these data are limited, as there is uncertainty regarding extrapolation of these findings to clinical practice. Therefore, no definitive conclusion can be drawn regarding regular use of ibuprofen, and data on potential clinical effects related to occasional ibuprofen use are lacking.

Atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the 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 lipoprotein (VLDL) particles, which enter plasma and are transported to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is primarily catabolized via interaction with high-affinity LDL receptors (LDL receptors). Atorvastatin reduces plasma cholesterol levels and serum lipoprotein concentrations by inhibiting HMG-CoA reductase, thereby suppressing hepatic cholesterol biosynthesis, and by increasing the number of hepatic LDL receptors on the cell surface, which enhances the uptake and catabolism of LDL. Atorvastatin reduces LDL formation and the number of LDL particles. It induces a pronounced and sustained increase in LDL receptor activity, along with a favorable change in the quality of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol levels in patients with homozygous familial hypercholesterolemia (a group that has not always responded to lipid-lowering therapy). Atorvastatin has demonstrated the ability to reduce total cholesterol (30–46%), LDL cholesterol (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), while variably increasing HDL cholesterol and apolipoprotein A1 concentrations in dose-response studies. These results are consistent in patients with heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed hyperlipidemia, including patients with insulin-independent diabetes mellitus. Reductions in total cholesterol, LDL cholesterol, and apolipoprotein B levels have been proven to reduce the risk of cardiovascular disease and mortality from these conditions.

Ramipril. Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidyl-carboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the vasoconstrictive substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin degradation lead to vasodilation. Since angiotensin II also stimulates aldosterone release, ramiprilat causes decreased aldosterone secretion. In patients of non-Caucasian race (Afro-Caribbean origin) with arterial hypertension (typically patients with low-renin hypertension), the average response to monotherapy with an angiotensin-converting enzyme (ACE) inhibitor has been lower than in patients of other racial backgrounds.

Antihypertensive properties. Administration of ramipril results in a marked reduction in peripheral arterial resistance. Renal plasma flow and glomerular filtration rate usually remain unchanged. In patients with arterial hypertension, ramipril reduces blood pressure in both supine and standing positions without compensatory increases in heart rate. In most patients, after oral administration of a single dose, antihypertensive effects appear within 1–2 hours, peak effects occur within 3–6 hours, and the effect typically lasts for 24 hours. With continued ramipril therapy, the maximum antihypertensive effect is usually achieved within 3–4 weeks. Long-term therapy has been shown to maintain the antihypertensive effect for up to 2 years. Abrupt discontinuation of ramipril does not cause rapid or excessive rebound increase in blood pressure.

Heart failure. As an adjunct to diuretic and cardiac glycoside therapy, ramipril has demonstrated efficacy in patients with heart failure classified as functional classes II–IV according to the New York Heart Association classification. The drug exerts beneficial effects on cardiac hemodynamics (reduction in filling pressures of the left and right ventricles, reduction in total peripheral vascular resistance, increased cardiac output, and improved cardiac index). It also reduces neuroendocrine activation.

Pharmacokinetics.

Acetylsalicylic acid. Acetylsalicylic acid is metabolized to its primary active metabolite, salicylic acid, before, during, and after absorption. Metabolites are primarily excreted by the kidneys. In addition to salicylic acid, the main metabolites of acetylsalicylic acid are salicyluric acid (the glycine conjugate of salicylic acid), glucuronide esters and complex esters of salicylic acid (salicyl phenol glucuronide and salicyl acyl glucuronide), and gentisic acid formed by oxidation of salicylic acid and its glycine conjugate. Absorption of acetylsalicylic acid after oral administration is rapid, complete, and formulation-dependent. Hydrolysis of the acetyl group of acetylsalicylic acid occurs partially during passage through the gastrointestinal mucosa. Peak plasma concentrations are reached within 10–20 minutes (for acetylsalicylic acid) or 0.3–2 hours (for total salicylate).

The elimination kinetics of salicylic acid are highly dose-dependent, as the capacity to metabolize salicylic acid is limited (elimination half-life ranges from 2 to 30 hours).

The elimination half-life of acetylsalicylic acid is only a few minutes; the half-life of salicylic acid is 2 hours after a 0.5 g dose of acetylsalicylic acid, 4 hours after a 1 g dose, and increases to 20 hours after a single 5 g dose.

Plasma protein binding in humans is concentration-dependent; values reported range from 49% to over 70% (for acetylsalicylic acid) and from 66% to 98% (for salicylic acid). Salicylic acid is detectable in cerebrospinal fluid and synovial fluid after administration of acetylsalicylic acid. Salicylic acid crosses the placenta and enters breast milk.

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 atorvastatin dose. After oral administration, the bioavailability of atorvastatin in film-coated tablets and oral solution is 95% and 99%, respectively.

Absolute bioavailability of atorvastatin is approximately 12%, and systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is due to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver.

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 para-hydroxylated derivatives and other beta-oxidation products. In addition to other metabolic pathways, these products undergo further glucuronidation. In vitro, ortho- and para-hydroxylated metabolites inhibit HMG-CoA reductase to an extent equivalent to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is due to circulating metabolites by nearly 70%.

Elimination. Atorvastatin is primarily eliminated via bile after hepatic and/or extrahepatic metabolism. However, atorvastatin does not undergo significant hepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours. The half-life of inhibitory activity against HMG-CoA reductase is approximately 20–30 hours due to the presence of active metabolites.

Atorvastatin is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Elderly patients. Time to peak concentration of atorvastatin and its active metabolites in plasma is longer in healthy elderly volunteers compared to healthy younger adult volunteers.

Sex. Plasma concentrations of atorvastatin in women differ from those in men (Cmax is approximately 20% higher and AUC is 10% lower). These differences are not clinically significant and do not lead to meaningful clinical differences in lipid effects between men and women.

Renal impairment. Renal impairment does not have a significant effect on plasma concentrations of atorvastatin or its lipid effects and active metabolites.

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

SLCO1B1 polymorphism. Hepatic uptake of HMG-CoA reductase inhibitors, including atorvastatin, is mediated by the OATP1B1 transporter. Patients with SLCO1B1 polymorphism are at risk of increased atorvastatin exposure, which may increase the risk of rhabdomyolysis (see section "Special precautions"). The presence of the SLCO1B1 c.521CC genotype is associated with a 2.4-fold increase in atorvastatin exposure (AUC) compared to patients without this genotype (c.521TT). These patients may also have genetically impaired hepatic uptake of atorvastatin. The potential impact on efficacy is unknown.

Ramipril.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract; maximum plasma concentrations of ramipril are reached within 1 hour. Based on urinary excretion, the extent of absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45%.

Food reduces the mean AUC by 26%, delays the time to maximum concentration (Tmax) of ramipril by 1.2 hours, and reduces Cmax by approximately 69% after a single dose. The effect of food on AUC and Cmax of ramipril is not considered clinically significant. Maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. After repeated daily dosing of ramipril, steady-state plasma concentrations of ramiprilat are achieved after approximately 4 days of treatment.

Distribution. Plasma protein binding of ramipril is approximately 73%, and that of ramiprilat is about 56%.

Metabolism. Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolites are primarily excreted via renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, ramiprilat exhibits a prolonged terminal elimination phase even at very low plasma concentrations.

The effective elimination half-life of ramiprilat after repeated doses of 5–10 mg ramipril once daily is 13–17 hours and is longer with lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat.

After a single oral dose, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

Renal impairment (see section "Dosage and administration"). Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportionally dependent on creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Hepatic impairment (see section "Dosage and administration"). In patients with impaired liver function, the metabolism of ramipril to ramiprilat is delayed due to reduced activity of hepatic esterases, resulting in increased plasma levels of ramipril. However, peak concentrations of ramiprilat in these patients do not differ from those observed in individuals with normal liver function.

Clinical characteristics.

Indications.

Secondary prevention of cardiovascular complications in adult patients as replacement therapy when adequate control is achieved with monotherapy using equivalent therapeutic doses.

Contraindications.

• Hypersensitivity to the active substances or any of the excipients of the medicinal product, to other salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), other angiotensin-converting enzyme (ACE) inhibitors, or tartrazine.
• Hypersensitivity to soy or peanuts.
• History of asthma or other allergic reactions induced by acetylsalicylic acid or other nonsteroidal analgesics/anti-inflammatory agents.
• Acute or recurrent gastric ulcer and/or gastrointestinal bleeding in medical history, or other types of bleeding, such as cerebrovascular hemorrhage (see section "Special precautions for use").
• Hemophilia and other coagulation disorders (thrombocytopenia, hemorrhagic diathesis).
• Severe renal or hepatic impairment (see section "Dosage and administration").
• Contraindicated in patients undergoing hemodialysis (see section "Dosage and administration").
• Severe heart failure, arterial hypotension, hemodynamically unstable conditions.
• Concomitant use with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of the medicinal product with drugs containing aliskiren in patients with diabetes mellitus or renal function impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Nasal polyps associated with asthma that is caused or exacerbated by acetylsalicylic acid.
• Liver disease or persistent unexplained elevation of serum transaminases more than 3 times the upper limit of normal (see section "Special precautions for use").
• Pregnancy and breastfeeding. Contraindicated in women of childbearing potential who are not using effective contraception (see section "Use during pregnancy or breastfeeding").
• Concomitant use with tipranavir or ritonavir, or cyclosporine (due to risk of rhabdomyolysis) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• History of angioedema (hereditary, idiopathic, or induced by ACE inhibitors or angiotensin II receptor antagonists).
• Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
• Severe bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney.
• Ramipril should not be used in patients with hypotensive or hemodynamically unstable conditions.
• Pediatric population (under 18 years of age). In children under 16 years of age with fever, influenza, or varicella, there is a risk of Reye's syndrome.
• Contraindicated in patients who have received hepatitis C antiviral agents glecaprevir/pibrentasvir.
• Concomitant use with sacubitril/valsartan. Initiation of Trinomia**®** therapy should not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Acetylsalicylic acid: pharmacodynamic and pharmacokinetic interactions.

Effect of concomitantly administered medicinal products on acetylsalicylic acid.

Other platelet aggregation inhibitors. Platelet aggregation inhibitors such as ticlopidine and clopidogrel may prolong bleeding time.

Other nonsteroidal analgesics/anti-inflammatory and antirheumatic agents. These agents increase the risk of gastrointestinal bleeding and ulcers.

Systemic glucocorticoids (except hydrocortisone used as replacement therapy in Addison’s disease). Systemic glucocorticoids increase the risk of gastrointestinal ulcers and bleeding.

Diuretics. NSAIDs may cause acute renal failure, especially in dehydrated patients. When Trinomia**®** is used concomitantly with diuretics, adequate hydration of patients should be monitored.

Alcohol. Alcohol increases the risk of gastrointestinal ulcers and bleeding.

Selective serotonin reuptake inhibitors (SSRIs). SSRIs increase the risk of bleeding, particularly gastrointestinal bleeding, due to synergistic effects.

Uricosuric agents. Concomitant use of Trinomia**®** with uricosuric agents reduces their uric acid-lowering effect and increases plasma levels of acetylsalicylic acid due to decreased elimination.

Metamizole. When taken concomitantly, metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, this combination should be used with caution in patients receiving low-dose aspirin.

Effect of acetylsalicylic acid on concomitantly administered medicinal products.

Anticoagulant and thrombolytic therapy. Acetylsalicylic acid increases the risk of bleeding when used before or during anticoagulant and thrombolytic therapy. Therefore, patients requiring anticoagulant or thrombolytic treatment should be monitored for signs of external or internal bleeding.

Digoxin. NSAIDs increase digoxin plasma concentrations. Monitoring of plasma digoxin levels is recommended when Trinomia**®** is used concomitantly or discontinued.

Antidiabetic agents, including insulin. Concomitant use of Trinomia**®** with antidiabetic agents, including insulin, enhances their hypoglycemic effect. Blood glucose monitoring is recommended (see subsection below "Ramipril: pharmacodynamic and pharmacokinetic interactions. Precautions for use").

Methotrexate. Salicylates may displace methotrexate from plasma protein binding sites and reduce its renal clearance, leading to toxic methotrexate plasma concentrations. Concomitant use with methotrexate at doses of 15 mg or higher per week is contraindicated (see section "Contraindications"). When methotrexate doses below 15 mg per week are used, monitoring of renal function and complete blood count is recommended, especially at the beginning of treatment.

Valproic acid. Salicylates may displace valproic acid from plasma protein binding sites and reduce its metabolism, thereby increasing its plasma concentrations.

• Ibuprofen.* Data on potential interactions when acetylsalicylic acid and ibuprofen are used concomitantly over long periods are limited, although some studies have shown reduced antiplatelet effects.

Antacids. Antacids may increase renal excretion of salicylates by alkalinizing urine.

ACE inhibitors. Although there have been reports that acetylsalicylic acid may reduce the beneficial effects of ACE inhibitors by decreasing vasodilatory prostaglandin synthesis, some studies have shown that negative interactions with ACE inhibitors occur with high-dose (i.e., ≥ 325 mg), but not low-dose (i.e., ≤ 100 mg), acetylsalicylic acid.

Cyclosporine. NSAIDs may increase cyclosporine nephrotoxicity via effects mediated by renal prostaglandins. Careful monitoring of renal function is recommended, especially in elderly patients.

Vancomycin. Acetylsalicylic acid increases the risk of vancomycin ototoxicity.

Interferon α. Acetylsalicylic acid reduces the activity of interferon α.

Lithium. NSAIDs reduce lithium excretion, increasing its plasma levels to potentially toxic concentrations. Concomitant use of lithium and NSAIDs is not recommended. If such combination therapy is necessary, plasma lithium concentrations should be closely monitored at initiation, during dose adjustments, and upon discontinuation.

Barbiturates. Acetylsalicylic acid increases plasma levels of barbiturates.

Zidovudine. Acetylsalicylic acid may increase zidovudine plasma levels by competitively inhibiting its glucuronidation or directly inhibiting zidovudine metabolism by hepatic microsomal enzymes.

Phenytoin. Acetylsalicylic acid may increase phenytoin plasma levels.

Laboratory tests. Acetylsalicylic acid may affect the results of the following laboratory tests:

• Blood: increased levels (biological) of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), alkaline phosphatase, ammonia, bilirubin, cholesterol, creatine kinase, digoxin, free thyroxine, lactate dehydrogenase (LDH), thyroxine-binding globulin, triglycerides, uric acid, and valproic acid; increased levels (analytical interference) of glucose, paracetamol, and total protein; decreased levels (biological) of free thyroxine, glucose, phenytoin, thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), thyroxine, triglycerides, triiodothyronine, uric acid, and creatinine clearance; decreased levels (analytical interference) of transaminases (ALT), albumin, alkaline phosphatase, cholesterol, creatine kinase, lactate dehydrogenase (LDH), and total protein.

• Urine: decreased levels (biological) of estriol; decreased levels (analytical interference) of 5-hydroxyindoleacetic acid, 4-hydroxy-3-methoxymandelic acid, total estrogens, and glucose.

Atorvastatin: pharmacodynamic and pharmacokinetic interactions.

Effect of concomitantly administered medicinal products on atorvastatin.

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are also substrates of OATP1B1. Atorvastatin is also identified as a substrate of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacokinetics"). Concomitant use of medicinal products that are inhibitors of CYP3A4 or transporter proteins may lead to increased plasma concentrations of atorvastatin and increased risk of myopathy.

The risk is also increased when atorvastatin is used concomitantly with other medicinal products that may cause myopathy, such as fibric acid derivatives and ezetimibe (see sections "Contraindications" and "Special precautions for use").

Inhibitors of CYP3A4. As noted, potent inhibitors of CYP3A4 cause significant increases in atorvastatin concentrations (see Table 1 and related information below). Whenever possible, concomitant use of strong CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for HIV treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided. If concomitant use cannot be avoided, consideration should be given to reducing the initial and maximum dose of atorvastatin; appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate inhibitors of CYP3A4 (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations (see Table 1). An increased risk of myopathy has been observed when erythromycin is used concomitantly with statins. Interaction studies evaluating the effect of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity, and their concomitant use with atorvastatin may lead to increased atorvastatin exposure. Therefore, appropriate clinical monitoring is recommended when used concomitantly with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended upon initiation or dose adjustment of the inhibitor.

Inducers of CYP3A4. Concomitant use of atorvastatin with inducers of cytochrome P450 3A (e.g., efavirenz, rifampicin, St. John’s wort) may cause variable decreases in atorvastatin plasma concentrations. Due to the dual effect of rifampicin (induction of cytochrome P450 3A and inhibition of hepatic uptake transporter OATP1B1), simultaneous initiation of atorvastatin and rifampicin is recommended, as delayed administration of atorvastatin after rifampicin is associated with a significant reduction in atorvastatin plasma concentrations. However, the effect of rifampicin on atorvastatin concentrations in hepatocytes is unknown; therefore, if concomitant use cannot be avoided, careful clinical monitoring of efficacy is recommended in patients.

Inhibitors of transporter proteins. Inhibitors of transporter proteins (e.g., cyclosporine) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentration in hepatocytes is unknown. If concomitant use cannot be avoided, clinical monitoring of efficacy is recommended (see Table 1).

Gemfibrozil/fibric acid derivatives. Use of fibrates as monotherapy has occasionally been associated with muscle-related adverse reactions, including rhabdomyolysis. The risk of such events increases when fibric acid derivatives are used concomitantly with atorvastatin. If concomitant use cannot be avoided, clinical monitoring of the patient is recommended (see section "Special precautions for use").

Ezetimibe.

Use of ezetimibe as monotherapy has been associated with muscle-related adverse reactions, including rhabdomyolysis. The risk of such events increases when ezetimibe is used concomitantly with atorvastatin. Appropriate clinical monitoring of such patients is recommended.

Colestipol. When colestipol and atorvastatin are used concomitantly, plasma concentrations of atorvastatin and its active metabolites are reduced (by approximately 25%). However, lipid effects are greater when atorvastatin and colestipol are used together than when either agent is used as monotherapy.

Fusidic acid. Systemic use of fusidic acid concomitantly with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic fusidic acid is required, atorvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions for use").

Colchicine. Although interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with concomitant use of atorvastatin and colchicine; therefore, these agents should be co-prescribed with caution.

Effect of atorvastatin on concomitantly administered medicinal products.

Digoxin. A slight increase in steady-state digoxin concentrations has been observed when multiple doses of digoxin and 10 mg atorvastatin are used concomitantly. Close monitoring of patients taking digoxin is recommended.

Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases plasma concentrations of norethisterone and ethinylestradiol.

Warfarin. In a clinical study of patients receiving long-term warfarin therapy, concomitant use of atorvastatin 80 mg daily and warfarin caused a slight reduction in prothrombin time of nearly 1.7 seconds during the first 4 days of treatment, which returned to normal within 15 days. Although rare reports of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin therapy in patients receiving coumarin anticoagulants, and frequently monitored at the beginning of treatment to confirm absence of significant changes. After stable prothrombin time is established, monitoring can be performed at intervals typically recommended for patients receiving coumarin anticoagulants. The same procedure should be repeated when discontinuing Trinomia**®**. Atorvastatin therapy has not been associated with bleeding or changes in prothrombin time in patients not taking anticoagulants.

Table 1. Effect of concomitant use of medicinal products on the pharmacokinetics of atorvastatin

Concomitant drug therapy and dosing regimen	Atorvastatin
	Dose (mg)	Changes in AUC&	Clinical recommendations#
Tipranavir 500 mg twice daily / ritonavir 200 mg twice daily for 8 days (from day 14 to day 21)	40 mg on day 1, 10 mg on day 20	↑ 9.4-fold	Co-administration of Trinomia® is contraindicated in these cases.
Telaprevir 750 mg every 8 hours for 10 days	20 mg single dose	↑ 7.9-fold
Cyclosporine 5.2 mg/kg/day, stable dose	10 mg once daily for 28 days	↑ 8.7-fold
Lopinavir 400 mg twice daily / ritonavir 100 mg twice daily for 14 days	20 mg once daily for 4 days	↑ 5.9-fold	When concomitant use with atorvastatin is necessary, reduction of atorvastatin maintenance doses is recommended. Clinical monitoring of patients is recommended if atorvastatin dose exceeds 20 mg.
Clarithromycin 500 mg twice daily for 9 days	80 mg once daily for 8 days	↑ 4.4-fold
Saquinavir 400 mg twice daily / ritonavir (300 mg twice daily from day 5 to day 7, increased to 400 mg twice daily on day 8) for 5–18 days, administered 30 minutes after atorvastatin	40 mg once daily for 4 days	↑ 3.9-fold	When concomitant use with atorvastatin is necessary, reduction of atorvastatin maintenance doses is recommended. Clinical monitoring of patients is recommended if atorvastatin dose exceeds 40 mg.
Darunavir 300 mg twice daily / ritonavir 100 mg twice daily for 9 days	10 mg once daily for 4 days	↑ 3.3-fold
Itraconazole 200 mg once daily for 4 days	40 mg, single dose	↑ 3.3-fold
Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily for 14 days	10 mg once daily for 14 days	↑ 2.5-fold
Fosamprenavir 1400 mg twice daily for 14 days	10 mg once daily for 4 days	↑ 2.3-fold
Nelfinavir 1250 mg twice daily for 14 days	10 mg once daily for 28 days	↑ 1.7-fold^	No specific recommendations.
Grapefruit juice 240 mL once daily*	40 mg, single dose	↑ 37%	Consumption of large quantities of grapefruit juice together with atorvastatin is not recommended.
Diltiazem 240 mg once daily for 28 days	40 mg, single dose	↑ 51%	Clinical monitoring of patients is recommended after initiation or dose adjustment of diltiazem.
Erythromycin 500 mg four times daily for 7 days	10 mg, single dose	↑ 33%^	A lower maximum dose and appropriate clinical monitoring of patients are recommended.
Amlodipine 10 mg, single dose	80 mg, single dose	↑ 18%	No specific recommendations.
Cimetidine 300 mg four times daily for 2 weeks	10 mg once daily for 4 weeks	↓ less than 1%	No specific recommendations.
Antacid suspension of magnesium and aluminum hydroxide 30 mL four times daily for 2 weeks	10 mg once daily for 4 weeks	↓ 35%^	No specific recommendations.
Efavirenz 600 mg once daily for 14 days	10 mg for 3 days	↓ 41%	No specific recommendations.
Rifampicin 600 mg once daily for 7 days (concomitant administration)	40 mg, single dose	↑ 30%	When concomitant use of atorvastatin with rifampicin cannot be avoided, clinical monitoring of patients is recommended.
Rifampicin 600 mg once daily for 5 days (separate doses)	40 mg, single dose	↓ 80%
Gemfibrozil 600 mg twice daily for 7 days	40 mg, single dose	↑ 35%	A lower initial dose and appropriate clinical monitoring of patients are recommended.
Fenofibrate 160 mg once daily for 7 days	40 mg, single dose	↑ 3%	Clinical monitoring of patients is recommended.
Boceprevir 800 mg three times daily for 7 days	40 mg, single dose	↑ 2.3-fold	Lower initial doses are recommended and clinical monitoring of patients is required. During concomitant use with boceprevir, the atorvastatin dose should not exceed 20 mg daily.
Glecaprevir 400 mg once daily / pibrentasvir 120 mg once daily for 7 days	10 mg once daily for 7 days	↑ 8.3-fold	Concomitant use with products containing glecaprevir or pibrentasvir is contraindicated (see section "Contraindications").
Elbasvir 50 mg once daily / grazoprevir 200 mg once daily for 13 days	10 mg, single dose	↑ 1.95-fold	When used concomitantly with products containing elbasvir or grazoprevir, the atorvastatin dose should not exceed 20 mg per day.

&Data presented in terms of fold changes represent a simple ratio between coadministration and atorvastatin monotherapy (i.e., 1-fold = no change). Data presented as percentages represent differences relative to atorvastatin monotherapy (i.e., 0% = no change).

#See sections «Contraindications», «Special warnings and precautions for use», and «Interaction with other medicinal products and other forms of interaction» to determine clinical significance.

*Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of medicinal products metabolized by CYP3A4. Consumption of 1 glass (240 mL) of grapefruit juice also results in a 20.4% reduction in the area under the concentration-time curve of the active ortho-hydroxymetabolite.

Large quantities of grapefruit juice (more than 1.2 L per day for 5 days) increased the area under the concentration-time curve of atorvastatin by 2.5-fold and that of its active metabolite.

^Full equivalent activity of atorvastatin.

Increases are indicated as «↑», decreases as «↓».

Table 2. Effect of atorvastatin on the pharmacokinetics of coadministered medicinal products

Atorvastatin Dose and Dosing Regimen	Concomitantly Administered Medicinal Products
	Medicinal Product/Dose (mg)	Changes in AUC&	Clinical Recommendations
80 mg once daily for 10 days	Digoxin 0.25 mg once daily for 20 days	↑ 15%	Appropriate monitoring is recommended for patients taking digoxin.
40 mg once daily for 22 days	Oral contraceptive once daily for 2 months: norethisterone 1 mg; ethinylestradiol 35 mcg;	↑ 28% ↑ 19%	No special recommendations.
80 mg once daily for 15 days	*Phenazone, 600 mg, single dose	↑ 3.0%	No special recommendations.
10 mg single dose	Tipranavir 500 mg twice daily, ritonavir 200 mg twice daily for 7 days	No change	No special recommendations.
10 mg once daily for 4 days	Fosamprenavir 1400 mg twice daily for 14 days	↓ 27%	No special recommendations.
10 mg once daily for 4 days	Fosamprenavir 700 mg twice daily, ritonavir 100 mg twice daily for 14 days	No change	No special recommendations.

&Data presented as percentages represent differences compared to atorvastatin monotherapy (i.e., 0% = no change).

*Concomitant administration of multiple doses of atorvastatin and phenazone showed minimal or no effect on phenazone clearance.

Increase is indicated as "↑", decrease as "↓".

Ramipril: pharmacodynamic and pharmacokinetic interactions.

Combinations contraindicated.

• Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain highly permeable membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using an alternative type of dialysis membrane or another class of antihypertensive agents.
• Medicinal products that increase the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions").

Precautions during use.

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes.

Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), dietary supplements containing potassium, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when using these products concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride.

Therefore, combination of Trinomia**®** with the above-mentioned medicinal products is not recommended.

If concomitant use of these agents is indicated, treatment should be administered with caution and serum potassium levels should be monitored frequently.

Heparin. Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Antihypertensive agents (e.g., diuretics) and other substances that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, high-dose alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of hypotension should be anticipated.

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, adrenaline) that may reduce the antihypertensive effect of ramipril. Blood pressure monitoring is recommended.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions").

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril. Careful monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that may alter blood cell counts. Increased risk of hematological reactions (see section "Special precautions").

Lithium salts. Lithium excretion may be reduced when ACE inhibitors are administered, potentially leading to increased lithium toxicity. Monitoring of lithium levels is recommended.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Monitoring of blood glucose levels is recommended.

Medicinal products that increase the risk of angioedema. Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions").

Cyclosporine. Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Special precautions for use.

Trinomia® should only be used as replacement therapy in patients whose condition is adequately controlled with individual components administered simultaneously in equivalent therapeutic doses.

Precautions for special patient groups.

Particular medical supervision is recommended in the following cases:

• Hypersensitivity to other analgesics/anti-inflammatory/antipyretic/antirheumatic agents or other allergens (see section "Contraindications");
• Allergic reactions (e.g., skin reactions, pruritus, urticaria), bronchial asthma, hay fever, mucosal nasal swelling (adenoid vegetations), or other chronic respiratory diseases (see section "Contraindications");
• History of peptic ulcers or gastrointestinal bleeding (see section "Contraindications");
• Impaired liver and/or kidney function (see section "Dosage and administration");
• Risk of developing arterial hypotension: in patients with increased activity of the renin-angiotensin-aldosterone system, transient or persistent heart failure after myocardial infarction, in patients at risk of cardiac or cerebral ischemia; in cases of acute arterial hypotension, blood pressure should be monitored to reduce the risk of severe hypotension and worsening renal function associated with ACE inhibitors (see section "Contraindications");
• Circulatory disorders (vasorenal hypertension, congestive heart failure, dehydration, major surgery, sepsis, or severe hemorrhagic complications);
• Glucose-6-phosphate dehydrogenase deficiency;
• Risk of increased uric acid levels;
• High-dose alcohol consumption and/or history of liver disease;
• Pregnancy: treatment with Trinomia® should be discontinued immediately, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use in pregnancy or lactation").

ACE inhibitors more frequently cause angioedema in patients of non-Caucasian race compared to patients of other races.

Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in patients of non-Caucasian race due to the high prevalence of arterial hypertension with low renin levels in this population.

Patient monitoring during treatment is required in the following cases:

• Concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, selective serotonin reuptake inhibitors, antiplatelet agents, anticoagulants;
• Concomitant use with ibuprofen;
• Development of signs or symptoms of liver impairment.

Surgery. Treatment with Trinomia® should be temporarily discontinued several days before major surgery or in the event of a serious medical or surgical condition. In minor procedures, such as tooth extraction, the drug may prolong bleeding time.

Particular monitoring is required in patients with renal impairment (see section "Dosage and administration"). There is a risk of worsening renal function, especially in patients with congestive heart failure or after kidney transplantation.

ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. This effect is usually mild in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, other drugs that increase serum potassium levels (e.g., trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor antagonists. Caution is advised when using potassium-sparing diuretics and angiotensin receptor antagonists in patients taking ACE inhibitors. Serum potassium levels and renal function should be monitored in such patients (see section "Interaction with other medicinal products and other forms of interaction"). Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients with hypoaldosteronism, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis.

Warnings regarding specific adverse effects

Liver-related effects.

Liver function tests should be performed before initiating atorvastatin therapy and periodically thereafter. Liver function tests should also be performed in patients who develop any signs or symptoms suggestive of liver injury. Transaminase elevations should be monitored until they resolve. If transaminase levels remain elevated more than three times the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, dose reduction or discontinuation of treatment is recommended. Trinomia® should be used with caution in patients who consume large amounts of alcohol, or in patients with impaired liver function and/or history of liver disease.

Stroke prevention through aggressive cholesterol reduction (SPARCL).

In a post-hoc analysis of stroke subtypes in patients without coronary heart disease who recently experienced stroke or transient ischemic attack, the incidence of hemorrhagic stroke was higher in patients initially receiving 80 mg atorvastatin compared to those receiving placebo. The increased risk was particularly noted in patients with a history of hemorrhagic stroke or lacunar infarction at study entry. The risk-benefit balance of 80 mg atorvastatin therapy in patients with prior hemorrhagic stroke or lacunar infarction is not clearly established; therefore, the potential risk of hemorrhagic stroke should be carefully evaluated before initiating treatment.

Skeletal muscle-related effects.

Atorvastatin, like other HMG-CoA reductase inhibitors, rarely affects skeletal muscles and may cause myalgia, myositis, and myopathy, which may progress to rhabdomyolysis—a potentially life-threatening condition characterized by markedly elevated creatine kinase (CK) levels (>10 times ULN), myoglobinemia, and myoglobinuria, which may lead to renal failure.

Nervous system and visual organ-related effects.

There have been isolated reports that statins may induce de novo myasthenia gravis or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). Treatment with Trinomia® should be discontinued if symptoms worsen. Recurrences have been reported upon re-administration of the same or another statin.

Before treatment.

Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Creatine kinase levels should be measured before initiating statin therapy in the following situations:

• Impaired renal function;
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• History of muscle toxicity with statins or fibrates;
• History of liver disease and/or significant alcohol consumption;
• In elderly patients (>70 years), measurement should be considered based on the presence of risk factors for rhabdomyolysis;
• When increased plasma concentration of the drug is possible, e.g., due to interaction with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction") and in certain populations, including genetically susceptible subpopulations (see section "Pharmacokinetics").

In such cases, the risks associated with treatment should be weighed against the expected benefits, and clinical monitoring is recommended. If baseline creatine kinase levels are markedly elevated (>5 times ULN), treatment should not be initiated.

Measurement of creatine kinase.

Creatine kinase (CK) should not be measured after physical exertion or in the presence of any other likely alternative cause of CK elevation, as this complicates interpretation of results. If CK levels are markedly elevated at the start of treatment (>5 times ULN), repeat measurement should be performed within 5–7 days to confirm the results.

During treatment.

• Patients should be informed of the need to promptly report muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.
• If such symptoms occur during atorvastatin therapy, CK levels should be measured. If levels are markedly elevated (>5 times ULN), treatment should be discontinued.
• If muscle-related symptoms are severe and cause daily discomfort, discontinuation of treatment should be considered, even if CK levels do not exceed 5 times ULN.
• If symptoms resolve and CK levels return to normal, reinitiation of atorvastatin or an alternative statin with close monitoring should be considered.
• Treatment with Trinomia® should be discontinued in the event of clinically significant CK elevation (>10 times ULN) or diagnosis or suspicion of rhabdomyolysis.

There have been very rare reports of immune-mediated necrotizing myopathy (IMNM) occurring during or after statin therapy, including atorvastatin. Clinically, IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy.

Concomitant use with other medicinal products.

As with other statins, the risk of rhabdomyolysis increases when atorvastatin is used concomitantly with certain medicinal products that may increase atorvastatin plasma concentrations (e.g., potent CYP3A4 inhibitors or transporter proteins such as cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc.).

The risk of myopathy may also increase with concomitant use of gemfibrozil and other fibric acid derivatives, antiviral agents for hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, ezetimibe. Alternative (non-interacting) treatment regimens should be considered if possible. If these medicinal products must be used concomitantly with atorvastatin, the benefit-risk balance of combination therapy should be carefully evaluated. When patients receive medicinal products that increase atorvastatin plasma concentration, a lower maximum atorvastatin dose is recommended. Additionally, when using potent CYP3A4 inhibitors, a lower initial atorvastatin dose should be considered, and appropriate clinical monitoring is advised (see section "Interaction with other medicinal products and other forms of interaction").

Trinomia® must not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid. Statin therapy should be suspended for the entire duration of systemic fusidic acid treatment in patients for whom fusidic acid is considered necessary. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional circumstances, when long-term systemic fusidic acid treatment is required (e.g., for severe infections), the need for concomitant use of Trinomia® and fusidic acid should be considered on an individual basis and under strict medical supervision.

Interstitial lung diseases.

In rare cases, interstitial lung diseases have been reported with statin use, particularly during long-term therapy (see section "Adverse reactions"). Clinical manifestations may include dyspnea, dry cough, and worsening general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus.

Some data suggest that statins as a class may increase blood glucose levels and may induce hyperglycemia requiring treatment as diabetes in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in cardiovascular risk associated with statin use and therefore should not be a reason to discontinue statin therapy.

Clinical and biochemical monitoring of patients at risk of developing diabetes (fasting glucose 5.6–6.9 mmol/L, body mass index >30 kg/m², elevated triglycerides, arterial hypertension) should be performed according to recommendations.

Angioedema.

Angioedema has been reported in patients taking ACE inhibitors, including ramipril (see section "Adverse reactions"). If angioedema occurs, Trinomia® should be discontinued immediately.

Emergency treatment should be initiated immediately. The patient should be monitored for at least 12–24 hours or until complete resolution of symptoms.

Intestinal angioedema has been reported in patients taking ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients experienced abdominal pain (with or without nausea and vomiting).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Trinomia® should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway swelling or speech impairment with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is advised when using racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already taking ACE inhibitors.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been associated with increased risk of arterial hypotension, hyperkalemia, and worsening renal function (including acute kidney injury). Therefore, dual RAAS blockade by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction"). If such dual blockade therapy is considered absolutely necessary, it should be used only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Anaphylactic reactions during desensitization.

The likelihood and severity of anaphylactic and anaphylactoid reactions caused by insect venom and other allergens are increased with ACE inhibition. Temporary discontinuation of Trinomia® therapy should be considered before desensitization.

Neutropenia/agranulocytosis.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been rarely observed. Bone marrow suppression has been reported. Leukocyte count monitoring is recommended. More frequent monitoring is advised at the beginning of treatment in patients with impaired liver function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those taking other medicinal products that may affect hematological status (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Cough.

Cough has been reported with ACE inhibitor use. It is usually non-productive and persistent and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Trinomia® contains lactose. Therefore, it should not be prescribed to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free."

Use in pregnancy or lactation.

Women of childbearing potential.

Women of childbearing potential should use appropriate contraceptive measures during treatment (see section "Contraindications").

Pregnancy.

Trinomia® is contraindicated in pregnant women.

ACE inhibitors are not recommended during the first trimester of pregnancy (see section "Special precautions for use"). ACE inhibitors are contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester are inconclusive; therefore, a small increased risk cannot be excluded.

If continued ACE inhibitor therapy is not considered necessary, women planning pregnancy should switch to an alternative antihypertensive therapy with an established safety profile during pregnancy. When pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if necessary.

It is known that exposure to ACE inhibitors or angiotensin II receptor antagonists (AIIRAs) during the second and third trimesters of pregnancy causes fetotoxicity and neonatal toxicity.

If a woman took an ACE inhibitor during the second trimester of pregnancy, ultrasound evaluation of fetal kidney function and skull bone development is recommended.

Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for possible arterial hypotension, oliguria, and hyperkalemia. Acetylsalicylic acid should be used during the first and second trimesters of pregnancy only if strictly necessary. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors early in pregnancy. The risk increases with higher doses and longer duration of therapy.

Prior experience with daily doses of 50–150 mg acetylsalicylic acid in pregnant women during the second and third trimesters has not shown inhibition of labor, increased bleeding tendency, or premature closure of the arterial duct.

Available epidemiological data on miscarriage are inconsistent, but an increased risk of gastroschisis cannot be excluded with acetylsalicylic acid use.

Animal studies have shown reproductive toxicity of acetylsalicylic acid, atorvastatin, and ramipril.

For women planning pregnancy or pregnant in the first or second trimester, the dose of acetylsalicylic acid-containing preparations should be as low as possible, and treatment duration should be as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• Cardio-pulmonary toxicity (premature closure of the arterial duct and pulmonary hypertension);
• Impaired renal function with possible progression to renal failure and oligohydramnios.

At the end of pregnancy, prostaglandin synthesis inhibitors may affect the mother and fetus as follows:

• Prolonged bleeding time, antiplatelet effect, which may occur even after very low doses;
• Inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Controlled clinical trials of atorvastatin use in pregnant women have not been conducted. Isolated reports of congenital anomalies after in utero exposure to HMG-CoA reductase inhibitors have been received. Animal studies have demonstrated reproductive toxicity.

Use of atorvastatin in pregnancy may reduce fetal mevalonate levels, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering agents during pregnancy usually has minimal impact on long-term risk associated with primary hypercholesterolemia.

For these reasons, Trinomia® should not be used in pregnant women or in women attempting to become pregnant or who suspect pregnancy. The drug should be discontinued for the duration of pregnancy or until pregnancy is ruled out (see sections "Contraindications" and "Special precautions for use").

Lactation.

A small amount of acetylsalicylic acid and its metabolites passes into human breast milk.

It is unknown whether atorvastatin or its metabolites pass into human breast milk. Additionally, there is insufficient information on the use of ramipril during lactation.

Due to the fact that many medicinal products pass into human breast milk and serious adverse reactions may occur, women taking Trinomia® should not breastfeed (see section "Contraindications").

Fertility.

Animal studies showed that atorvastatin did not affect fertility in males or females.

Ability to influence reaction speed when driving or operating machinery.

Acetylsalicylic acid and atorvastatin have no or negligible effects on reaction speed when driving or operating machinery.

Due to the presence of ramipril, some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate and react quickly, which may be hazardous in situations where these abilities are critical (e.g., driving or operating machinery). This risk may be particularly relevant when switching from other treatments or increasing the dose. Therefore, driving or operating machinery is not recommended within several hours after taking Trinomia®.

Method of Administration and Dosage

Trinomia**®**, hard capsules, is intended for oral administration. The medication should be taken once daily, preferably after a meal. The capsule should be swallowed whole with an adequate amount of water. The capsule must not be chewed, crushed, or opened. The capsule's sealing system ensures preservation of the pharmacological properties of the active ingredients.

During treatment with Trinomia**®**, consumption of grapefruit juice is not recommended.

Adults

Patients who are adequately controlled on therapy with acetylsalicylic acid, atorvastatin, and ramipril at equivalent therapeutic doses may switch to treatment with Trinomia**®** hard capsules.

Treatment should be initiated under medical supervision (see section "Special Warnings and Precautions for Use").

To prevent cardiovascular complications, the maintenance dose of ramipril should be 10 mg once daily.

Special Patient Groups

Patients with Renal Impairment
The creatinine clearance value should be considered when determining the daily dose of the drug in patients with renal impairment:

• If creatinine clearance is ≥ 60 mL/min, the maximum daily dose of ramipril should be 10 mg;
• If creatinine clearance is 30–60 mL/min, the maximum daily dose of ramipril should be 5 mg.

Trinomia**®** is contraindicated in patients undergoing hemodialysis and/or with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

Patients with Hepatic Impairment
Trinomia**®** should be used with caution in patients with hepatic impairment. Liver function tests should be performed before initiating treatment and periodically during therapy. Patients who develop symptoms or signs of liver injury should undergo liver function testing. Patients with elevated transaminase levels should be monitored until abnormalities resolve. If transaminase levels exceed the upper limit of normal by three times or more, Trinomia**®** should be discontinued (see section "Adverse Reactions").

Additionally, the maximum daily dose of ramipril in this patient group should be 2.5 mg, and treatment should only be initiated under close medical supervision.

Trinomia**®** is contraindicated in patients with severe or acute hepatic impairment (see section "Contraindications").

Elderly Patients
Due to the high risk of adverse reactions, treatment should be initiated with caution in elderly and very frail patients.

Concomitant Use with Other Medicinal Products

For patients receiving antiviral agents for hepatitis C treatment (e.g., elbasvir/grazoprevir) concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children
Trinomia**®** is contraindicated in children (under 18 years of age) (see section "Contraindications").

Overdose

Acetylsalicylic Acid

In chronic overdose of acetylsalicylic acid, the most characteristic central nervous system (CNS) disturbances include drowsiness, dizziness, confusion, or nausea (salicylism). Acute intoxication with acetylsalicylic acid is indicated by a pronounced disturbance in acid-base balance. Even within therapeutic doses, increased respiratory rate may lead to respiratory alkalosis, which is compensated by increased renal excretion of bicarbonate to maintain normal blood pH. With toxic doses, compensation is insufficient, resulting in decreased blood pH and bicarbonate concentration. Plasma carbon dioxide partial pressure (pCO₂) may occasionally remain within normal limits. This condition—metabolic acidosis—is actually a combination of respiratory and metabolic acidosis caused by respiratory center depression due to toxic doses, accumulation of acids (particularly due to reduced renal excretion of sulfuric, phosphoric, salicylic, lactic, and acetoacetic acids), and severe carbohydrate metabolism disturbances. Additionally, electrolyte imbalance and significant potassium loss occur.

Symptoms of Acute Intoxication

In addition to acid-base and electrolyte imbalances (e.g., potassium loss), hypoglycemia, skin rash, and gastrointestinal bleeding, other symptoms may include hyperventilation, tinnitus, nausea, vomiting, visual and auditory disturbances, headache, dizziness, and disorientation. In severe overdose (over 400 µg/mL), delirium, tremor, respiratory distress syndrome, sweating, dehydration, hyperthermia, and coma may develop. In fatal intoxication, death is usually due to respiratory center failure.

Treatment of Intoxication

Management of acute intoxication due to acetylsalicylic acid overdose depends on the severity and clinical symptoms. Standard measures should be taken to reduce absorption of the active substance, restore fluid and electrolyte balance, and normalize body temperature and respiration. Measures should also aim to enhance elimination of the active substance and normalize acid-base and electrolyte balance. Diuretics are administered along with sodium bicarbonate and potassium chloride solutions. Urine pH should be maintained within normal range to increase ionization of salicylic acid, thereby reducing tubular reabsorption. Blood parameters (pH, pCO₂, bicarbonate, potassium) should be monitored. In severe cases, hemodialysis should be performed.

In suspected overdose, the patient should be observed for 24 hours, as symptoms and salicylate plasma levels may take several hours to appear.

Atorvastatin

There is no specific antidote for atorvastatin overdose. In case of overdose, symptomatic and supportive treatment should be administered as needed. Liver function tests and monitoring of serum creatine kinase levels are required. Due to the high degree of atorvastatin plasma protein binding, significant enhancement of atorvastatin clearance by hemodialysis is not expected.

Ramipril

Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked arterial hypotension or shock), bradycardia, electrolyte imbalance, and renal failure. Close monitoring of the patient is required. Treatment should be symptomatic and supportive. Supportive measures include initial decontamination (gastric lavage, administration of adsorbents) and interventions to restore hemodynamic stability, including use of α₁-adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is only minimally removed from the systemic circulation by hemodialysis.

Adverse reactions.

Trinomia® should only be used as a replacement therapy in patients who have achieved adequate control with the individual components administered at equivalent therapeutic doses.

Adverse effects are classified by frequency of occurrence into the following categories: 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); not known (frequency cannot be estimated from the available data).

Below are the adverse effects that may occur during monotherapy with one of the active substances.

Acetylsalicylic acid.

The most commonly reported adverse effects associated with aspirin therapy are gastrointestinal disturbances. Ulcers and gastrointestinal bleeding are rare. Gastrointestinal perforation occurs very rarely.

Immediate medical advice must be sought if vomiting of blood or black stools occur (signs of severe gastrointestinal bleeding).

Blood and lymphatic system disorders.

Rare: severe bleeding has been reported, which in some cases may be life-threatening, e.g., intracranial hemorrhage, particularly in patients with uncontrolled hypertension and/or concomitant anticoagulant therapy.

Bleeding events with possible prolongation of bleeding time have been observed, including epistaxis, skin hemorrhages, gingival bleeding, and genitourinary tract bleeding (see section "Special warnings and precautions for use"). This effect may last from 4 to 8 days after administration.

Gastrointestinal disorders.

Very common: gastrointestinal disturbances such as heartburn, nausea, vomiting, stomach pain, and diarrhea. Minor gastrointestinal blood loss (microbleeding).

Uncommon: peptic ulcers, gastrointestinal bleeding, iron-deficiency anemia due to occult gastrointestinal bleeding after long-term use, gastrointestinal inflammatory disorders.

Very rare: peptic ulcer perforation. Immediate medical advice should be sought in case of melena or vomiting blood (signs of severe gastrointestinal bleeding).

Respiratory system disorders.

Common: paroxysmal bronchospasm, severe dyspnea, rhinitis, nasal congestion.

Nervous system disorders. Headache, dizziness, hearing disturbances, or tinnitus and confusion may be symptoms of overdose (see section "Overdose").

Skin and subcutaneous tissue disorders.

Uncommon: skin reactions.

Very rare: erythema multiforme.

Immune system disorders.

Rare: hypersensitivity reactions affecting the skin, respiratory tract, gastrointestinal tract, and cardiovascular system, particularly in patients with asthma (possible symptoms include: hypotension, dyspnea, rhinitis, nasal congestion, anaphylactic shock, Quincke's edema).

Hepatobiliary disorders.

Very rare: increased liver function test parameters.

Renal and urinary system disorders.

Very rare: renal failure.

Metabolism and nutrition disorders.

Very rare: hypoglycemia. Acetylsalicylic acid at low doses reduces uric acid excretion. In susceptible individuals, this may trigger gout attacks.

Atorvastatin.

Myalgia (muscle pain, muscle cramps, joint swelling) is a common adverse effect during statin therapy. Myopathy and rhabdomyolysis are rare (less than 1 case per 1000). Monitoring of CK levels should be considered as part of the evaluation of patients with markedly elevated baseline CK levels (> 5 times the upper limit of normal). In placebo-controlled clinical trials involving 16,066 patients (8,755 receiving atorvastatin, 7,311 receiving placebo) treated for a mean duration of 53 weeks, 5.2% of patients receiving atorvastatin discontinued treatment due to adverse reactions compared to 4% in the placebo group. As with other HMG-CoA reductase inhibitors, increased serum transaminase levels have been reported in patients taking atorvastatin. These changes were mostly mild, transient, and did not require discontinuation of treatment. Clinically significant increases in serum transaminases (> 3 times the upper limit of normal) occurred in 0.8% of patients taking atorvastatin. These increases were dose-dependent and reversible in all patients. CK elevations greater than 3 times the upper limit of normal were generally observed in 2.5% of patients receiving atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Elevations exceeding 10 times the upper limit of normal were observed in 0.4% of patients taking atorvastatin (see section "Special warnings and precautions for use").

The following adverse reactions have been reported with the use of some statins:

• Sexual dysfunction;
• Depression;
• Rare cases of interstitial lung disease, particularly with long-term treatment (see section "Special warnings and precautions for use");
• Diabetes mellitus: frequency of this adverse reaction depends on the presence or absence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of hypertension).

Infections and parasitic disorders.

Common: nasopharyngitis.

Blood and lymphatic system disorders.

Rare: thrombocytopenia.

Immune system disorders.

Common: allergic reactions.

Very rare: anaphylaxis.

Metabolism and nutrition disorders.

Common: hyperglycemia.

Uncommon: hypoglycemia, weight gain, anorexia.

Psychiatric disorders.

Uncommon: nightmares, insomnia.

Nervous system disorders.

Common: headache.

Uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia.

Rare: peripheral neuropathy.

Not known: myasthenia.

Eye disorders.

Uncommon: blurred vision.

Rare: visual disturbances.

Not known: ocular myasthenia.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Very rare: hearing loss.

Respiratory system disorders.

Common: pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders.

Common: constipation, flatulence, dyspepsia, nausea, diarrhea.

Uncommon: vomiting, upper and lower abdominal pain, belching, pancreatitis.

Hepatobiliary disorders.

Uncommon: hepatitis.

Rare: cholestasis.

Very rare: hepatic failure.

Skin and subcutaneous tissue disorders.

Uncommon: urticaria, rash, pruritus, alopecia.

Rare: angioedema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders.

Common: myalgia, arthralgia, limb pain, muscle spasms, joint swelling, back pain.

Uncommon: neck pain, muscle fatigue.

Rare: myopathy, myositis, rhabdomyolysis, tendinopathy (sometimes complicated by tendon rupture).

Very rare: lupus-like syndrome.

Not known: immune-mediated necrotizing myopathy (see section "Special warnings and precautions for use").

Reproductive system and breast disorders.

Very rare: gynecomastia.

General disorders.

Uncommon: malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia.

Investigations.

Common: abnormal liver function tests, increased creatine kinase levels in blood.

Uncommon: presence of leukocytes in urine.

Ramipril.

During ramipril therapy, a persistent dry cough and adverse reactions related to arterial hypotension may occur. Serious adverse reactions include angioedema, hyperkalemia, renal or hepatic failure, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

Cardiac disorders.

Uncommon: myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema.

Blood and lymphatic system disorders.

Uncommon: eosinophilia.

Rare: decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, hemoglobin, platelets (thrombocytopenia).

Not known: bone marrow disorders, pancytopenia, hemolytic anemia.

Nervous system disorders.

Common: headache, dizziness.

Uncommon: vertigo, paresthesia, ageusia, dysgeusia.

Rare: tremor, loss of balance.

Not known: cerebral ischemia, including ischemic stroke and transient ischemic attacks, worsening of psychomotor skills, burning sensation, parosmia.

Eye disorders.

Uncommon: visual disturbances, including blurred vision.

Rare: conjunctivitis.

Ear and labyrinth disorders.

Rare: hearing impairment, tinnitus.

Respiratory system disorders.

Common: non-productive irritating cough, bronchitis, sinusitis, dyspnea.

Uncommon: bronchospasm, including asthma exacerbation, nasal congestion.

Gastrointestinal disorders.

Common: gastrointestinal inflammation, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting.

Uncommon: pancreatitis (in rare cases, fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth. Rare: glossitis.

Not known: aphthous stomatitis.

Renal and urinary system disorders.

Uncommon: renal disorders, including acute renal failure, increased urine production, worsening of existing proteinuria, increased blood urea, increased blood creatinine.

Skin and subcutaneous tissue disorders.

Common: skin eruptions, including maculopapular rash.

Uncommon: angioedema; in rare cases, fatal outcomes due to airway obstruction; pruritus, hyperhidrosis.

Rare: exfoliative dermatitis, urticaria, onycholysis.

Very rare: photosensitivity reactions.

Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis with complications, psoriasiform dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders.

Common: muscle cramps, myalgia.

Uncommon: arthralgia.

Metabolism and nutrition disorders.

Common: increased blood potassium levels.

Uncommon: anorexia, decreased appetite.

Not known: decreased blood sodium levels.

Vascular disorders.

Common: arterial hypotension, orthostatic hypotension, syncope. Uncommon: flushing.

Rare: vascular stenosis, hypoperfusion, vasculitis.

Not known: Raynaud's syndrome.

General disorders.

Common: chest pain, fatigue.

Uncommon: pyrexia.

Rare: asthenia.

Immune system disorders.

Not known: anaphylactic or anaphylactoid reactions, increased antinuclear antibody levels.

Hepatobiliary disorders.

Uncommon: increased liver enzymes and/or conjugated bilirubin.

Rare: cholestatic jaundice, hepatocellular disorders.

Not known: acute hepatic failure, cholestatic or cytolytic hepatitis (in rare cases, fatal outcomes have been reported).

Reproductive system and breast disorders.

Uncommon: temporary erectile dysfunction, decreased libido.

Not known: gynecomastia.

Psychiatric disorders.

Uncommon: depressive mood, anxiety, nervousness, restlessness, sleep disturbances, including insomnia.

Rare: confusion.

Not known: attention disturbances.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of the reach of children!

Packaging. 7 capsules in a blister; 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Ferrer Internacional, S.A., Spain.

Manufacturer's address.

Joan Buscalla, 1-9, SANT CUGAT DEL VALLES, 08173 Barcelona, Spain.