Instructions Trinomia hard capsules blister 100 mg + 20 mg + 2.5 mg No. 28
Composition
active ingredients:
1 capsule contains 100 mg of acetylsalicylic acid, 20 mg of atorvastatin (as atorvastatin calcium trihydrate) and 2.5 mg of ramipril;
1 capsule contains 100 mg of acetylsalicylic acid, 20 mg of atorvastatin (as atorvastatin calcium trihydrate) and 5 mg of ramipril;
1 capsule contains 100 mg of acetylsalicylic acid, 20 mg of atorvastatin (as atorvastatin calcium trihydrate) and 10 mg of ramipril;
excipients:
for capsules 100 mg/20 mg/2.5 mg:
for acetylsalicylic acid tablets: microcrystalline cellulose; sodium starch glycolate (type A); talc; Opadry AMV white OY-B-28920;
for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silica; magnesium stearate; Opadry green 06O21881;
for ramipril tablets: hypromellose 2910; microcrystalline cellulose, pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMV 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 AMV white OY-B-28920;
for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silica; magnesium stearate; Opadry green 06O21881;
for ramipril tablets: hypromellose 2910; microcrystalline cellulose, pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMV 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 AMV white OY-B-28920;
for atorvastatin tablets: lactose monohydrate; pregelatinized starch 1500; calcium carbonate; hydroxypropylcellulose; polysorbate 80; crospovidone type A; colloidal anhydrous silica; magnesium stearate; Opadry green 06O21881;
for ramipril tablets: hypromellose 2910; microcrystalline cellulose, pregelatinized starch 1500; sodium stearyl fumarate; Opadry AMV yellow 80W32880;
hard capsule: gelatin; titanium dioxide (E 171); iron oxide, red (E 172); black ink.
Dosage form
The capsules are hard.
Main physicochemical properties:
for capsules 100 mg/20 mg/2.5 mg:
opaque, hard gelatin capsules, size 0, with a light gray body and cap, marked "AAR 100/20/2.5", containing two white or almost white film-coated acetylsalicylic acid tablets with engraving "AS", two greenish-brown film-coated atorvastatin tablets with engraving "AT" and one pale yellow film-coated ramipril tablet with engraving "R2";
for capsules 100 mg/20 mg/5 mg:
opaque, hard gelatin capsules, size 0, with a pale pink cap and a light gray body, marked "AAR 100/20/5", containing two white or almost white film-coated acetylsalicylic acid tablets with engraving "AS", two greenish-brown film-coated atorvastatin tablets with engraving "AT" and one pale yellow film-coated ramipril tablet with engraving "R5".
for capsules 100 mg/20 mg/10 mg:
opaque, hard gelatin capsules, size 0, with a pale pink body and cap, marked "AAR 100/20/10", containing two white or almost white film-coated acetylsalicylic acid tablets with engraving "AS", two greenish-brown film-coated atorvastatin tablets with engraving "AT" and one pale yellow film-coated ramipril tablet with engraving "R1".
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Lipid-modifying drugs, combinations. Atorvastatin, acetylsalicylic acid and ramipril. ATC code C10B X06.
Pharmacological properties
Acetylsalicylic acid. Acetylsalicylic acid irreversibly inhibits platelet aggregation. This effect on platelets is due to the acetylation of cyclooxygenase. This irreversibly inhibits the synthesis of thromboxane A2 (which stimulates platelet aggregation and has a vasoconstrictor effect) in platelets. This effect is permanent and usually lasts throughout the 8-day life span of platelets. Acetylsalicylic acid also inhibits the synthesis of prostacyclin (a prostaglandin that inhibits platelet aggregation but has a vasodilator effect) in endothelial cells of blood vessels. This effect is temporary. After acetylsalicylic acid is eliminated from the blood, nucleated endothelial cells begin to synthesize prostacyclin again. As a result, a single low daily dose of acetylsalicylic acid (< 100 mg/day) causes inhibition of thromboxane A2 in platelets without a significant effect on prostacyclin synthesis. Acetylsalicylic acid belongs to the group of acid-forming non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory properties. Their mechanism of action is the irreversible inhibition of cyclooxygenase enzymes, which are involved in the synthesis of prostaglandins. Higher doses of acetylsalicylic acid are used to treat mild to moderate pain, fever, and acute and chronic inflammatory diseases such as rheumatoid arthritis. Experimental data have shown that ibuprofen can inhibit platelet aggregation when used simultaneously with low doses of acetylsalicylic acid. In a study comparing the effect of a single dose of ibuprofen 400 mg taken 8 hours or 30 minutes before taking 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 about the extrapolation of these data to clinical practice. Therefore, no relevant conclusion can be drawn regarding the regular use of ibuprofen, and there is no data regarding the relevant clinical effect that could be attributed to the occasional use of ibuprofen.
Atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoprotein (VLDL) molecules, enter the blood plasma, and are transported to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily by interaction with high-affinity LDL receptors (LDL receptors). Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver, and by increasing the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL. Atorvastatin reduces LDL formation and LDL particle size. Atorvastatin causes a marked and sustained increase in LDL receptor activity combined with a favorable change in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol (LDL) in patients with homozygous familial hypercholesterolemia (a group that has not always responded to therapy with lipid-lowering drugs). Atorvastatin has been shown to reduce total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), while causing variable increases in HDL-C and apolipoprotein A1 in a dose-dependent study. These results are consistent with data in patients with heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus. Reductions in total cholesterol, LDL-C, and apolipoprotein B have been shown to reduce the risk of cardiovascular disease and mortality.
Hypotensive properties. The use of ramipril causes a marked decrease in peripheral arterial resistance. Usually renal plasma flow and glomerular filtration rate do not change. The use of ramipril in patients with arterial hypertension causes a decrease in blood pressure in the standing and supine positions without a compensatory increase in heart rate. In most patients, after oral administration of a single dose, the antihypertensive effect is manifested after 1-2 hours, and the maximum effect is after 3-6 hours and usually lasts for 24 hours. With continued use of ramipril, the maximum antihypertensive effect is usually achieved after 3-4 weeks. It has been established that with long-term therapy, the antihypertensive effect is maintained for 2 years. Abrupt cessation of treatment with ramipril does not cause a rapid and excessive rebound increase in blood pressure.
Heart failure. As an adjunct to diuretic and cardiac glycoside therapy, ramipril has been shown to be effective in patients with heart failure functional classes II–IV according to the New York Heart Association classification. The drug has a beneficial effect on cardiac hemodynamics (reduction of left and right ventricular filling pressures, reduction of total peripheral vascular resistance, increase in cardiac output, and improvement of cardiac index). It also reduced neuroendocrine activation.
Pharmacokinetics.
Acetylsalicylic acid. Acetylsalicylic acid is metabolized to its main active metabolite salicylic acid before, during and after absorption. The metabolites are excreted mainly by the kidneys. In addition to salicylic acid, the main metabolites of acetylsalicylic acid are the glycine conjugate of salicylic acid (salicylicuric acid), the glucuronide ester and ester of salicylic acid (salicylicphenol glucuronide and salicylacyl glucuronide), as well as gentisic acid, which is formed by the oxidation of salicylic acid and its glycine conjugate. The absorption of acetylsalicylic acid after oral administration is rapid, complete and dependent on the galenic preparations. Hydrolysis of the acetyl residue of acetylsalicylic acid occurs to some extent during passage through the mucous membrane of the gastrointestinal tract. Maximum plasma concentrations are reached 10–20 minutes after administration (acetylsalicylic acid) or 0.3–2 hours (total salicylate).
The elimination kinetics of salicylic acid are largely dose-dependent, as the ability to metabolize salicylic acid is limited (the half-life ranges from 2 to 30 hours).
The half-life of acetylsalicylic acid is only a few minutes; the half-life of salicylic acid is 2 hours after a dose of 0.5 g of acetylsalicylic acid, 4 hours after 1 g, and increases to 20 hours after a single dose of 5 g.
Binding to plasma proteins in humans is concentration-dependent; values ranging from 49% to more than 70% (acetylsalicylic acid) and from 66% to 98% (salicylic acid) have been reported. Salicylic acid is found in cerebrospinal fluid and synovial fluid after administration of acetylsalicylic acid. Salicylic acid crosses the placenta and is excreted in breast milk.
Atorvastatin.
Absorption: Atorvastatin is rapidly absorbed after oral administration; peak plasma concentrations (Cmax) are reached within 1–2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. After oral administration, the bioavailability of atorvastatin in the form of film-coated tablets and oral solution is 95% and 99%, respectively.
The absolute bioavailability of atorvastatin is approximately 12%, and the 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 through 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 parahydroxylated derivatives and other beta-oxidation products. In addition to other metabolic pathways, these products are further glucuronidated. In vitro, ortho- and parahydroxylated metabolites cause inhibition of HMG-CoA reductase equivalent to its inhibition by atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is almost 70% determined by the activity of circulating metabolites.
Elimination: Atorvastatin is eliminated primarily in the bile following hepatic and/or extrahepatic metabolism. However, atorvastatin does not undergo significant hepatic recirculation. The mean elimination half-life of atorvastatin from 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.
Elderly patients: The time to peak plasma concentrations of atorvastatin and its active metabolites is longer in healthy elderly volunteers than in healthy younger adult volunteers.
Gender: Plasma concentrations of atorvastatin differed in women compared to men (approximately 20% higher Cmax and 10% lower AUC). These differences were not clinically significant and did not result in clinically relevant differences in lipid effects between men and women.
Renal impairment: Renal impairment has no significant effect on the plasma concentrations of atorvastatin or its lipid effects and its active metabolites.
Hepatic impairment: Concentrations of atorvastatin and its active metabolites are increased (Cmax approximately 16-fold and AUC approximately 11-fold) in patients with chronic alcoholic liver disease (Child-Pugh class B).
SLCO1B1 polymorphism. The uptake of HMG-CoA reductase inhibitors, including atorvastatin, into liver cells is mediated by the transport protein OATP1B1. Patients with the SLCO1B1 polymorphism are at risk of increased exposure to atorvastatin, which in turn may lead to an increased risk of rhabdomyolysis (see section 4.4). The presence of a polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) in a patient is associated with a 2.4-fold increase in atorvastatin exposure (AUC) compared with patients without this genotype variant (c.521TT). These patients may also have a genetic defect in the uptake of atorvastatin into liver cells. 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. Taking into account 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%.
After a single dose, food reduces the mean AUC by 26% and delays the time to maximum concentration (Tmax) of ramipril by 1.2 hours and reduces Cmax by approximately 69%. The effect of food on the AUC and Cmax of ramipril is not considered clinically significant. Maximum plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached 2-4 hours after administration of ramipril. After administration of usual doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are reached after approximately 4 days of treatment.
Distribution: Plasma protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.
Metabolism: Ramipril is almost completely metabolized to ramiprilat and diketopiperazine ester, diketopiperazine acid, as well as the glucuronides of ramipril and ramiprilat.
Elimination. Elimination of metabolites occurs mainly by renal excretion. The decline in plasma concentrations of ramiprilat is multiphasic. Due to the strong saturable binding to ACE and the slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase even at very low plasma concentrations.
The effective half-life of ramiprilat after repeated doses of 5–10 mg ramipril once daily is 13–17 hours and is longer at lower doses (1.25–2.5 mg). The difference is due to the saturable capacity of the enzyme to bind ramiprilat.
After a single oral dose, neither ramipril nor its metabolite were detected in breast milk. However, the effect of repeated doses is unknown.
Renal impairment (see section 4.2). Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportional to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.
Hepatic impairment (see section 4.2). In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat was delayed due to a decrease in hepatic esterase activity and an increase in plasma ramipril levels in these patients. However, peak ramiprilat concentrations in these patients did not differ from those observed in subjects with normal hepatic function.
Indication
Secondary prevention of cardiovascular complications in adult patients as replacement therapy when adequate control is provided during therapy with monocomponent agents in equivalent therapeutic doses.
Contraindication
Hypersensitivity to the active substances or other components of the drug, other salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), other angiotensin-converting enzyme (ACE) inhibitors or tartrazine.
Hypersensitivity to soy or peanuts.
History of asthma or other allergic reactions caused by the use of acetylsalicylic acid or other non-steroidal analgesics/anti-inflammatory drugs.
Hemophilia and other blood clotting disorders (thrombocytopenia, hemorrhagic diathesis).
Severe renal and hepatic insufficiency (see section "Method of administration and dosage").
Contraindicated in patients undergoing hemodialysis (see section "Method of administration and dosage").
Severe heart failure, hypotension, hemodynamically unstable conditions.
Concomitant use with methotrexate at a dose of 15 mg/week or more (see section "Interaction with other medicinal products and other types of interactions").
Concomitant use of the drug with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”).
Nasal polyps associated with asthma caused or exacerbated by the use of acetylsalicylic acid.
Liver disease or persistent unexplained elevation of serum transaminases greater than 3 times the upper limit of normal (see section 4.4).
Pregnancy and lactation. Contraindicated in women of reproductive age who are not using effective contraception (see section "Use during pregnancy or lactation").
Concomitant use with tipranavir or ritonavir, or cyclosporine (due to the risk of rhabdomyolysis) (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
History of angioedema (hereditary, idiopathic or associated with ACE inhibitors or angiotensin II receptor antagonists).
Extracorporeal treatments that result in blood coming into contact with negatively charged surfaces (see section “Interaction with other medicinal products and other types of interactions”).
Severe bilateral renal artery stenosis or renal artery stenosis in one functioning kidney.
Ramipril should not be used in patients with hypotensive or hemodynamically unstable conditions.
Children (under 18 years of age). Children under 16 years of age with fever, flu, or chickenpox are at risk of developing Reye's syndrome.
Contraindicated in patients receiving the hepatitis C antiviral drugs glecaprevir/pibrentasvir.
Concomitant use with sacubitril/valsartan: Trinomia® should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).
Interaction with other medicinal products and other types of interactions
Acetylsalicylic acid: pharmacodynamic and pharmacokinetic interactions.
Effect of concomitantly used drugs on acetylsalicylic acid.
Other platelet aggregation inhibitors: Platelet aggregation inhibitors, such as ticlopidine and clopidogrel, may prolong blood clotting time.
Other nonsteroidal analgesics/anti-inflammatory and antirheumatic drugs. These drugs increase the risk of gastrointestinal bleeding and ulcers.
Systemic glucocorticoids (except hydrocortisone as replacement therapy for Addison's disease). Systemic glucocorticoids increase the risk of gastrointestinal ulcers and bleeding.
Diuretics: NSAIDs may cause acute renal failure, especially in patients with dehydration. In the case of concomitant use of Trinomia® and diuretics, it is recommended to monitor adequate hydration of patients.
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 a synergistic effect.
Uricosuric agents. Concomitant use with Trinomia® reduces the effect of agents that promote the excretion of uric acid and increases plasma levels of acetylsalicylic acid due to reduced excretion.
Metamizole: When taken simultaneously, metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, this combination should be used with caution in patients taking low-dose aspirin.
The effect of acetylsalicylic acid on concomitantly used drugs.
Anticoagulant and thrombolytic therapy: Acetylsalicylic acid increases the risk of bleeding when used before or during anticoagulant and thrombolytic therapy. Therefore, patients requiring anticoagulant and thrombolytic treatment should be monitored for signs of external or internal bleeding.
Digoxin. NSAIDs increase the concentration of digoxin in the blood plasma. When used simultaneously with the drug Trinomia® or when it is discontinued, it is recommended to monitor the level of digoxin in the blood plasma.
Methotrexate. Salicylates may displace methotrexate from plasma protein binding and reduce its renal clearance, leading to toxic plasma concentrations of methotrexate. Concomitant use with methotrexate at doses of 15 mg or more per week is contraindicated (see section 4.3). Renal function and blood counts should be monitored when methotrexate is administered at doses below 15 mg per week, especially at the beginning of treatment.
Valproic acid: Salicylates may displace valproic acid from plasma protein binding and reduce its metabolism resulting in increased plasma concentrations.
Ibuprofen. There is no data on the possible interaction of acetylsalicylic acid and ibuprofen taken together for a long time, although some studies have shown a reduced effect on platelet aggregation.
Antacids: Antacids may increase the renal excretion of salicylates due to alkalinization of the urine.
ACE inhibitors: Although there have been reports that acetylsalicylic acid may reduce the beneficial effects of ACE inhibitors due to decreased synthesis of vasodilator prostaglandins, some studies have shown that the negative interaction with ACE inhibitors occurs with high (i.e. ≥ 325 mg) rather than low (i.e. ≤ 100 mg) doses of acetylsalicylic acid.
Cyclosporine: NSAIDs may increase the nephrotoxicity of cyclosporine through effects mediated by renal prostaglandins. Close 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 the excretion of lithium, increasing its plasma levels, which may reach toxic values. The combined use of lithium and NSAIDs is not recommended. If the use of such a combination is necessary, careful monitoring of plasma lithium concentrations should be carried out at the beginning, during dose adjustment and when treatment is discontinued.
Barbiturates: Acetylsalicylic acid increases plasma levels of barbiturates.
Zidovudine: Acetylsalicylic acid may increase plasma levels of zidovudine by competitively inhibiting the formation of its glucuronide or by directly inhibiting the metabolism of zidovudine by liver microsomal enzymes.
Phenytoin: Acetylsalicylic acid may increase plasma levels of phenytoin.
Laboratory tests: Acetylsalicylic acid may affect the results of the following 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 (TSH-RG), 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 concomitant medications on atorvastatin.
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate for the hepatic transporters organic anion-transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin has also been identified as a substrate for multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section 5.2). Concomitant use of medicinal products that are inhibitors of CYP3A4 or transport proteins may result in increased plasma concentrations of atorvastatin and an increased risk of myopathy.
CYP3A4 inhibitors: As mentioned, potent CYP3A4 inhibitors cause significant increases in atorvastatin concentrations (see Table 1 and related information below). Co-administration of potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for the treatment of HIV (e.g., elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. If co-administration of these medicinal products with atorvastatin cannot be avoided, a reduction in the initial and maximum dose of atorvastatin should be considered; appropriate clinical monitoring of the patient is also recommended (see Table 1).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). An increased risk of myopathy has been observed when erythromycin is co-administered with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity, and their co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, appropriate clinical monitoring of the patient is recommended when co-administered with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation of treatment or after dose adjustment of the inhibitor.
CYP3A4 inducers. Concomitant use of atorvastatin with cytochrome P450 3A inducers (such as efavirenz, rifampicin, St. John's wort) may result in variable decreases in plasma concentrations of atorvastatin. Due to the dual interaction of rifampicin (induction of cytochrome P450 3A and inhibition of the hepatic uptake transporter OATP1B1), simultaneous initiation of atorvastatin and rifampicin is recommended, as delayed administration of atorvastatin after rifampicin is associated with a significant decrease in plasma concentrations of atorvastatin. However, the effect of rifampicin on atorvastatin concentrations in hepatocytes is unknown, therefore, if concomitant use cannot be avoided, careful clinical monitoring of their efficacy in patients is recommended.
Transporter protein inhibitors. Transporter protein inhibitors (e.g., cyclosporine) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant use cannot be avoided, clinical monitoring of efficacy is recommended (see Table 1).
Gemfibrozil/fibric acid derivatives. The use of fibrates as monotherapy is sometimes associated with the occurrence of reactions from the muscular system, including rhabdomyolysis. The risk of such events is increased with the simultaneous use of fibric acid derivatives and atorvastatin. If concomitant use cannot be avoided, clinical monitoring of the patient is recommended (see section "Special instructions").
Ezetimibe.
The use of ezetimibe as monotherapy is associated with the occurrence of muscular reactions, including rhabdomyolysis. The risk of such events is increased when ezetimibe and atorvastatin are used concomitantly. Appropriate clinical monitoring of these patients is recommended.
Colestipol: Plasma concentrations of atorvastatin and its active metabolites were decreased (approximately 25%) when colestipol was coadministered with atorvastatin. However, the lipid effects were greater with the coadministration of atorvastatin and colestipol than with either drug administered alone.
Fusidic acid. Concomitant systemic use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the duration of fusidic acid administration (see section 4.4).
Colchicine: Although no interaction studies have been conducted between atorvastatin and colchicine, cases of myopathy have been reported when atorvastatin was used with colchicine, and caution should be exercised when these drugs are co-administered.
Effect of atorvastatin on concomitant medications.
Digoxin: Concomitant administration of multiple doses of digoxin and 10 mg atorvastatin resulted in a small increase in steady-state digoxin concentrations. Patients taking digoxin should be closely monitored.
Oral contraceptives: Concomitant use of atorvastatin with oral contraceptives results in increased plasma concentrations of norethisterone and ethinyl estradiol.
Warfar
