Atocord^® A (Capsules) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

C10BX08 (Atorvastatin and Acetylsalicylic acid)

Active Substances

Acetylsalicylic acid (Ph.Eur.)

Atorvastatin (Rec.INN)

Dosage Form

Atocord®A

Capsules 10 mg + 75 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 0e1, white, with black company marking ” on the capsule cap; the capsule contents are a capsule-shaped biconvex film-coated tablet, white or almost white, with a smooth surface on both sides; a round biconvex film-coated tablet, white or almost white, with a smooth surface on both sides.

* In the composition of the film-coated tablet 154.5 mg.
Excipients: calcium carbonate, lactose monohydrate, croscarmellose sodium, polysorbate 80, hydroxypropylcellulose, microcrystalline cellulose, magnesium stearate.
Film coating composition: Opadry OY-58900 white (hypromellose, titanium dioxide (E171), macrogol 400).

** In the composition of the enteric-coated tablet 114.725 mg.
Excipients: lactose monohydrate, pregelatinized starch, colloidal anhydrous silicon dioxide, stearic acid, hypromellose, triethyl citrate.
Enteric coating composition methacrylic acid copolymer dispersion (Eudragit L30 D-55), triethyl citrate, talc.
Film coating composition Opadry AMB clear (OY-B-29000) (polyvinyl alcohol, talc, soy lecithin, xanthan gum).

Composition of hard gelatin capsule size 0e1 titanium dioxide (E171), purified water, gelatin.
Composition of black ink for capsule imprinting shellac (E904), dehydrated alcohol (E1510), 2-propanol, butyl alcohol, propylene glycol, concentrated ammonia solution, black iron oxide dye (E172), potassium hydroxide, purified water.

30 pcs. – high-density polyethylene jars (1) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic combination drug (HMG-CoA reductase inhibitor + antiplatelet agent)

Pharmacotherapeutic Group

Combined hypolipidemic agent (HMG-CoA reductase inhibitor + antiplatelet agent)

Pharmacological Action

Combined medicinal product.

Atorvastatin

Hypolipidemic agent, a selective competitive inhibitor of HMG-CoA reductase, the key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor of steroids, including cholesterol.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia, Atorvastatin reduces the plasma levels of total cholesterol (TC), LDL-C and apolipoprotein B (apo-B), as well as VLDL-C and TG, and causes an unstable increase in HDL-C levels.

It reduces the concentration of cholesterol and lipoproteins in plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to enhanced uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles, causes a pronounced and sustained increase in LDL receptor activity combined with favorable qualitative changes in LDL particles, and also reduces LDL-C levels in patients with homozygous hereditary familial hypercholesterolemia resistant to therapy with other hypolipidemic agents.

In patients with isolated hypertriglyceridemia, Atorvastatin reduces the content of total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases HDL-C levels.

In patients with dysbetalipoproteinemia, Atorvastatin reduces the content of intermediate-density lipoprotein cholesterol. It reduces the concentration of total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50% and TG by 14-33%; causes an increase in the concentration of HDL cholesterol and apolipoprotein A.

In patients with hyperlipoproteinemia type IIa and IIb according to Fredrickson, the mean increase in HDL-C levels during treatment with atorvastatin (10-80 mg), compared to baseline, is 5.1%-8.7% and is dose-independent.

Acetylsalicylic acid

The mechanism of the antiplatelet action of acetylsalicylic acid (ASA) is based on the irreversible inhibition of COX-1, resulting in the blockade of thromboxane A2 synthesis and suppression of platelet aggregation.

The antiplatelet effect is most pronounced in platelets, as they are unable to resynthesize COX.

ASA is believed to have other mechanisms of platelet aggregation suppression, which expands its scope of application in various vascular diseases.

ASA also has anti-inflammatory, analgesic and antipyretic effects.

Pharmacokinetics

Atorvastatin is rapidly absorbed after oral administration; the time to reach C_max in plasma is 1-2 hours. In women, C_max is 20% higher and AUC is 10% lower than in men. The degree of absorption and plasma concentration increase proportionally to the dose. Absolute bioavailability is about 14%, and systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and/or during the “first pass” through the liver.

Food slightly reduces the rate and extent of absorption of atorvastatin (by 25% and 9%, respectively, as evidenced by C_max and AUC determinations), but the reduction in LDL-C is similar to that when atorvastatin is taken on an empty stomach.

Although plasma concentrations of atorvastatin after evening dosing are lower (C_max and AUC approximately 30%) than after morning dosing, the reduction in LDL-C concentration does not depend on the time of day Atorvastatin is taken.

The mean V_d of atorvastatin is about 381 L. Plasma protein binding is not less than 98%. The erythrocyte/plasma concentration ratio is about 0.25, i.e., Atorvastatin poorly penetrates into erythrocytes.

Atorvastatin is extensively metabolized to form ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro, the ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin.

Approximately 70% of the reduction in HMG-CoA reductase activity is due to the action of active circulating metabolites. The hepatic CYP3A4 isoenzyme is believed to play an important role in the metabolism of atorvastatin.

This is supported by an increase in plasma drug concentrations with concurrent administration of erythromycin, which is an inhibitor of this isoenzyme. It has also been shown that Atorvastatin is a weak inhibitor of the CYP3A4 isoenzyme.

Atorvastatin and its metabolites are excreted mainly in the bile after hepatic and/or extrahepatic metabolism (Atorvastatin does not undergo significant enterohepatic recirculation). T_1/2 is about 14 hours, and the inhibitory effect on HMG-CoA reductase is about 70% determined by the activity of circulating metabolites and persists for about 20-30 hours due to their presence.

Less than 2% of the administered dose is found in the urine after oral administration.

Acetylsalicylic acid after oral administration is rapidly and completely absorbed from the gastrointestinal tract. It is partially metabolized during absorption. During and after absorption, ASA is converted to the main metabolite, salicylic acid. The time to reach C_max of acetylsalicylic acid in plasma depends on the dosage form used. Food slows down the absorption of ASA without affecting the extent of absorption. ASA and salicylic acid are largely bound to plasma proteins and are rapidly distributed in the body. Salicylic acid crosses the placental barrier and is excreted in breast milk. The main metabolite of ASA is salicylic acid. Its metabolism occurs in the liver with the formation of salicyluric acid, phenolic glucuronide of salicylic acid, salicyl glucuronide and gentisic acid. The elimination of salicylic acid is dose-dependent, as its metabolism is limited by the capacity of the body’s enzymatic systems. T_1/2 ranges from 2-3 hours when using ASA in low doses to 15 hours when using the drug in high doses (usual doses of acetylsalicylic acid as an analgesic). Salicylic acid and its metabolites are excreted by the kidneys.

Indications

Prevention of cardiovascular complications to reduce mortality, myocardial infarctions, strokes, repeated hospitalizations for angina and the need for revascularization in adult patients with coronary artery disease without lipid metabolism disorders or with such lipid metabolism disorders as primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (type IIa according to the Fredrickson classification), or combined (mixed) hyperlipidemia (type IIb according to the Fredrickson classification), as an adjunct to diet, when the response to diet and other non-drug treatments is insufficient.

Prevention of thromboembolic complications after surgeries and invasive vascular interventions (e.g., coronary artery bypass grafting, carotid endarterectomy, coronary angioplasty and stenting) and reduction of elevated total cholesterol, LDL-C, apo-B and triglycerides in adult patients with such lipid metabolism disorders as primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (type IIa according to the Fredrickson classification), or combined (mixed) hyperlipidemia (type IIb according to the Fredrickson classification), as an adjunct to diet, when the response to diet and other non-drug treatments is insufficient.

ICD codes

Dosage Regimen

Take orally, once daily at any time of day, with or without food.

Swallow the capsule whole with a glass of water; do not crush or chew.

Initiate therapy at the 10 mg/75 mg strength. The dosage is fixed; do not adjust the individual component doses separately.

Adhere to a standard hypocholesterolemic diet throughout the entire treatment period.

Regularly monitor liver function tests before treatment, at 6 and 12 weeks after initiation, and periodically thereafter.

Immediately report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Discontinue use several days before planned surgical procedures to reduce the risk of bleeding, if possible.

Do not use in patients with active liver disease or unexplained persistent elevations in serum transaminases.

Avoid concurrent use with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors) or fusidic acid due to increased risk of myopathy.

This combination is contraindicated during pregnancy and lactation.

Adverse Reactions

From the hematopoietic system uncommon – hemorrhagic syndrome (nosebleeds, gum bleeding, hemorrhagic rash); these effects persist for 4-8 days from the moment of discontinuation of the drug – this should be taken into account when planning subsequent surgeries for patients; rare – anemia, increased blood clotting time, thrombocytopenia, granulocytosis.

From the immune system common – allergic reactions, anaphylactic reactions, including anaphylactic shock; very rare – bronchospasm, angioedema; formation based on the hapten mechanism of the “aspirin” triad (a combination of bronchial asthma, recurrent nasal and sinus polyposis and intolerance to acetylsalicylic acid and pyrazolone drugs).

From the metabolism common – hyperglycemia, hypoglycemia; uncommon – anorexia, weight gain.

From the nervous system common – headache; uncommon – dizziness, amnesia, paresthesia, hypesthesia, dysgeusia (taste disturbance); rare – peripheral neuropathy.

Mental disorders uncommon – insomnia, nightmares; frequency unknown – depression.

From the organ of vision uncommon – blurred vision; rare – visual perception disorder.

From the hearing organ and labyrinthine disorders: uncommon – tinnitus; very rare – hearing loss; frequency unknown – hearing loss, ringing in the ears.

From the respiratory system common – nosebleeds, sore throat; uncommon – rhinitis, shortness of breath; very rare – asthma attacks; frequency unknown – interstitial lung diseases (especially during long-term therapy).

From the digestive system common – nausea, heartburn, vomiting, epigastric pain; uncommon – constipation or diarrhea, flatulence, belching, abdominal pain, dysphagia, pancreatitis; rare – ulcer of the gastric and duodenal mucosa; very rare – perforated ulcers of the gastric and duodenal mucosa, diarrhea.

From the liver and biliary tract uncommon – hepatitis; rare – cholestasis; very rare – transient liver function disorders with increased activity of liver transaminases, liver failure.

From the skin and subcutaneous tissues common – skin rash; uncommon – skin itching, alopecia; rare – bullous dermatitis, erythema multiforme, erythema nodosum, purpura, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome); very rare – angioneurotic edema.

From the musculoskeletal system common – myalgia, arthralgia, limb pain, muscle spasm, back pain, joint swelling; uncommon – neck pain, muscle weakness; rare – myositis, myopathy, rhabdomyolysis, tendinopathy, sometimes complicated by tendon rupture; frequency unknown – immune-mediated necrotizing myopathy.

From the reproductive system and mammary gland common – menorrhagia; rare – gynecomastia; frequency unknown – sexual dysfunction.

General reactions common – nasopharyngitis; uncommon – peripheral edema, chest pain, asthenia, increased body temperature, increased fatigue; frequency unknown – diabetes mellitus, there are reports of cases of renal function impairment and acute renal failure.

From laboratory parameters common – increased serum creatine phosphokinase (CPK) activity; uncommon – leukocyturia; frequency unknown (for statins in general) – increased concentration of glycosylated hemoglobin.

Contraindications

Hypersensitivity to acetylsalicylic acid, atorvastatin, as well as to NSAIDs; active liver disease, severe liver failure (class B and C according to the Child-Pugh classification) or unexplained elevation of plasma liver transaminases more than 3 times the upper limit of normal; cirrhosis of the liver of any etiology; skeletal muscle diseases; bronchial asthma induced by salicylates and other NSAIDs: complete or incomplete combination of bronchial asthma, recurrent nasal and sinus polyposis, and intolerance to ASA and other NSAIDs;
Erosive and ulcerative lesions of the gastrointestinal tract (in the acute phase), including exacerbations of inflammatory bowel diseases (ulcerative colitis, Crohn’s disease); gastrointestinal bleeding, cerebrovascular bleeding or other forms of bleeding; hemorrhagic diatheses (hemophilia, von Willebrand disease, telangiectasia, hypoprothrombinemia, thrombocytopenia, thrombocytopenic purpura); vitamin K deficiency; severe renal failure (creatinine clearance less than 30 ml/min); chronic heart failure class III-IV according to the NYHA classification; simultaneous use with methotrexate at a dose of 15 mg/week and more; simultaneous use with fusidic acid; children and adolescents under 18 years of age.

With caution

In gout, hyperuricemia, history of ulcerative lesions of the gastrointestinal tract or gastrointestinal bleeding; in mild liver dysfunction (class A according to the Child-Pugh classification) and in patients with a history of liver disease; in the presence of risk factors for the development of rhabdomyolysis. simultaneous use with drugs that increase the risk of myopathy and rhabdomyolysis; in renal impairment (creatinine clearance more than 30 ml/min), as well as in circulatory disorders due to atherosclerosis of the renal arteries, congestive heart failure class I-II according to the NYHA classification, hypovolemia, major surgery, sepsis, cases of massive bleeding, since in all these cases ASA may increase the risk of acute renal failure and renal impairment; in bronchial asthma (not associated with NSAID use), chronic respiratory diseases, hay fever, nasal polyposis, drug allergy, including to NSAIDs (analgesics, anti-inflammatory, antirheumatic drugs) as separate diseases in the patient; in planned surgery (including minor, e.g., tooth extraction); in combined use with the following drugs: with methotrexate at a dose of less than 15 mg/week, NSAIDs and salicylic acid derivatives in high doses, including with ibuprofen, with digoxin, with oral hypoglycemic agents (sulfonylurea derivatives) and insulin, with valproic acid, with selective serotonin reuptake inhibitors, with anticoagulants, thrombolytic and antiplatelet drugs, with uricosuric drugs, with ACE inhibitors and diuretics, with corticosteroids, as well as with alcohol and in alcohol abuse.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Special Precautions

Atorvastatin

The use of HMG-CoA reductase inhibitors to reduce blood lipid concentrations may lead to changes in biochemical parameters reflecting the functional state of the liver. Liver function should be monitored before starting therapy, 6 and 12 weeks after starting the combination of atorvastatin with ASA, when increasing the drug dose, and periodically, for example, every 6 months.

Patients who show signs or symptoms of impaired liver function should undergo additional liver function testing. Patients with elevated activity of “liver” transaminases should be under medical supervision until their activity decreases. In case of a persistent increase in the activity of liver transaminases – ALT or AST more than 3 times the upper limit of normal, it is recommended to consider the possibility of discontinuing treatment.

Atorvastatin, like other HMG-CoA reductase inhibitors, can cause muscle pain, myositis, and myopathy, which in rare cases can progress to the development of rhabdomyolysis – a potentially life-threatening condition characterized by a significant increase in CPK activity – more than 10 times the upper limit of normal, myoglobinemia, and myoglobinuria, which can lead to renal failure. The diagnosis of “myopathy” should be considered in all patients undergoing statin treatment and presenting with such unexplained muscle symptoms as pain or tenderness, muscle weakness, or muscle cramps. In such cases, CPK activity should be determined.

If symptoms of possible myopathy occur or if there is a risk factor for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, major surgery, trauma, metabolic, endocrine, and water-electrolyte imbalances, and uncontrolled seizures), therapy with drugs containing Atorvastatin should be temporarily discontinued or completely withdrawn. CPK activity should not be determined after intense physical exertion. If CPK activity is significantly elevated at baseline, measurements should be repeated within 5-7 days.

Patients should be warned that they should immediately consult a doctor if unexplained pain or muscle weakness appears, especially if accompanied by malaise or fever.

Like other statins, Atorvastatin should be prescribed with caution to patients predisposed to rhabdomyolysis. CPK activity must be measured before starting treatment in the following situations: renal failure, hypothyroidism, individual or hereditary congenital muscle disorders, history of muscle intoxication with statins or fibrates, history of liver disease and/or consumption of significant amounts of alcohol, old age (>70 years); the decision on the need for these measurements should be made in accordance with the presence of other predispositions to rhabdomyolysis.

In such cases, the risk-benefit ratio of the treatment should be considered, and clinical monitoring is recommended. If CPK activity is significantly elevated at baseline (more than 5 times the upper limit of normal), treatment should not be started.

During therapy, if muscle pain, weakness, or cramps occur while the patient is undergoing statin treatment, their CPK activity should be determined. If this level is significantly elevated (more than 5 times the upper limit of normal), treatment must be discontinued. If muscle symptoms become severe and cause daily discomfort, even if CPK activity does not exceed a 5-fold increase relative to the upper limit of normal, treatment should be suspended.

If symptoms resolve and CPK activity returns to normal, a repeated administration of the drug containing Atorvastatin at the minimum dosage and under close supervision can be prescribed. An increase in CPK activity should be taken into account when assessing the possibility of myocardial infarction in the differential diagnosis of chest pain.

Isolated cases of the development of interstitial lung disease have been reported, especially during long-term therapy. The disease is characterized by shortness of breath, non-productive cough, and deterioration in general condition (increased fatigue, weight loss, and fever). If the development of interstitial lung disease is suspected, treatment with the drug containing Atorvastatin should be discontinued.

Acetylsalicylic acid

The inhibitory effect of ASA on platelet aggregation persists for several days after administration. If absolute exclusion of bleeding is necessary during planned surgery, it is necessary to completely discontinue the use of ASA in the preoperative period, if possible.

The use of ASA is associated with the risk of gastrointestinal bleeding. Patients should be informed about the symptoms of gastrointestinal bleeding and the need to consult a doctor. If ulcerative lesions of the gastrointestinal tract and gastrointestinal bleeding develop, treatment with ASA is stopped. Overdose is especially dangerous in elderly patients.

In severe forms of glucose-6-phosphate dehydrogenase deficiency, ASA can cause hemolysis and hemolytic anemia. Factors that may increase the risk of hemolysis include fever, acute infections, and high doses of the drug containing ASA.

In case of skin reactions and/or reactions of the mucous membranes, it is necessary to discontinue the use of this combination.

ASA reduces the excretion of uric acid from the body, which can cause an acute attack of gout in predisposed patients.

When taken simultaneously with diuretics, due to the risk of renal failure, it is necessary to hydrate patients and monitor renal function, especially at the beginning of treatment.

During simultaneous treatment with methotrexate, it is recommended to monitor the peripheral blood picture.

Effect on ability to drive vehicles and operate machinery

Given the possibility of dizziness, caution should be exercised during activities requiring increased concentration and high speed of psychomotor reactions.

Drug Interactions

Atorvastatin

In vitro studies have shown that the metabolism of atorvastatin, like other HMG-CoA reductase inhibitors, occurs with the participation of the CYP3A4 isoenzyme, which indicates the possibility of interaction with other drugs that are substrates of this isoenzyme (immunomodulators, many antiarrhythmic drugs, some slow calcium channel blockers, and some benzodiazepine derivatives). When atorvastatin is used concomitantly with these drugs, the possibility of changes in the plasma level of any of the drugs should be considered.

Caution is required when using atorvastatin concomitantly with inhibitors of the cytochrome P450 CYP3A4 isoenzyme (including macrolides and azole derivatives). Study results have been presented confirming both an increase and a decrease in plasma phenytoin levels, but the nature of the interaction with atorvastatin is unknown.

Strong inhibitors of the CYP3A4 isoenzyme – cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors (including ritonavir, lopinavir, atazanavir, indinavir, darunavir) significantly increase the concentration of atorvastatin, so their concomitant use with atorvastatin should be avoided, or the specified agents should be used at lower starting and maintenance doses in combination with regular patient monitoring.

Moderate inhibitors of the CYP3A4 isoenzyme (erythromycin, diltiazem, verapamil, and fluconazole) may increase the plasma concentration of atorvastatin. An increased risk of myopathy was observed with the use of erythromycin in combination with statins. It is known that amiodarone and verapamil inhibit the CYP3A4 isoenzyme, so their combination with atorvastatin may lead to an increase in the concentration of atorvastatin. The use of lower maintenance doses of the specified agents in combination with regular patient monitoring should also be considered.

The combination of tipranavir/ritonavir 1000 mg/400 mg per day leads to a 9.4-fold increase in the plasma concentration of atorvastatin; the combination of atorvastatin 20 mg/day and telaprevir 2250 mg/day leads to a 7.9-fold increase in the plasma concentration of atorvastatin. If concomitant use with cyclosporine is necessary, the dose of atorvastatin should also not exceed 10 mg/day.

Ingestion of more than 1.2 liters/day of grapefruit juice for 5 days led to a 2.5-fold increase in the AUC of atorvastatin and a 1.3-fold increase in the AUC of active HMG-CoA reductase inhibitors. Therefore, simultaneous intake of large quantities of grapefruit juice and atorvastatin is not recommended.

Concomitant use of atorvastatin with inducers of the CYP3A4 isoenzyme (such as efavirenz, rifampicin, or preparations of St. John’s wort) may lead to a decrease in the plasma concentration of atorvastatin.

Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), simultaneous administration of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after rifampicin intake leads to a significant decrease in the plasma concentration of atorvastatin. If concomitant administration cannot be avoided, the effectiveness of such a combination should be carefully monitored.

Cyclosporine is also an inhibitor of the hepatocyte transport protein OATP1B1 and can increase the bioavailability of atorvastatin. If concomitant use cannot be avoided, the effectiveness of such a combination should be carefully monitored. As already noted, when used concomitantly with cyclosporine (5.2 mg/kg/day), the dose of atorvastatin should not exceed 10 mg/day.

During therapy with fibrates (such as gemfibrozil/fibric acid derivatives), adverse events from the musculoskeletal system, including rhabdomyolysis, sometimes occur. The risk of developing these events may increase with the concomitant use of fibrates and atorvastatin (possibly due to inhibition of the glucuronidation process of atorvastatin). If combination therapy is necessary (especially with gemfibrozil), the use of lower initial and maintenance doses of the above agents in combination with regular patient monitoring should be considered.

During therapy with ezetimibe, adverse events from the musculoskeletal system, including rhabdomyolysis, are also possible. Regular patient monitoring is recommended when combining ezetimibe with atorvastatin therapy.

Concomitant use of atorvastatin and colestipol lowers the plasma concentration of atorvastatin; however, the hypolipidemic effect of this combination of drugs is greater than their effect separately.

When atorvastatin is used concomitantly with fusidic acid, the risk of developing myopathy, including rhabdomyolysis, increases. Temporary discontinuation of atorvastatin is necessary. Statin therapy can be resumed 7 days after the last dose of fusidic acid.

Concomitant oral administration of an antacid suspension (magnesium hydroxide and aluminum hydroxide) reduced the plasma concentration of atorvastatin by approximately 35%; however, the degree of reduction in LDL-C content did not change.

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the plasma concentration of digoxin increases.

The use of atorvastatin with an oral contraceptive containing norethisterone and ethinyl estradiol leads to an increase in the concentration of norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively. This should be taken into account when choosing an oral contraceptive for a woman taking Atorvastatin.

When warfarin is taken concomitantly with atorvastatin in the first days of therapy, a decrease in prothrombin time is possible; this effect disappears by the 15th day of therapy. Patients taking warfarin should be closely monitored (control of blood coagulation parameters) when atorvastatin is added to the course of treatment.

Caution should be exercised when using atorvastatin concomitantly with colchicine, as cases of myopathy development have been described.

Acetylsalicylic acid

When acetylsalicylic acid is used concomitantly with methotrexate (at a dose of more than 15 mg/week) – a decrease in the renal clearance of methotrexate and an increase in hematotoxicity.

Concomitant use with uricosuric drugs, including probenecid, is not recommended.

When acetylsalicylic acid is used concomitantly with anticoagulants such as coumarin, heparin, warfarin, and phenindione, antiplatelet drugs (clopidogrel, dipyridamole) and selective serotonin reuptake inhibitors (sertraline or paroxetine), thrombolytics – an increased risk of bleeding.

With hypoglycemic drugs (sulfonylurea derivatives) – an increase in the hypoglycemic properties of sulfonylurea derivatives.

With digoxin and lithium preparations – an increase in their plasma concentration, dose adjustment is required if necessary.

With diuretic and antihypertensive drugs – a decrease in the hypotensive effect. During simultaneous treatment with ASA and ACE inhibitors, the risk of acute renal failure increases.

With carbonic anhydrase inhibitors (acetazolamide) – may lead to severe acidosis and increased toxic effects on the central nervous system.

With systemic corticosteroids – an increased risk of ulcerative gastrointestinal lesions and gastrointestinal bleeding.

With methotrexate (at a dose of less than 15 mg/week) – a decrease in the renal clearance of methotrexate and an increase in hematotoxicity.

With other NSAIDs – an increased risk of ulcerative gastrointestinal lesions and gastrointestinal bleeding due to the synergy of effects.

With ibuprofen – a possible decrease in the antiplatelet properties of ASA.

With cyclosporine, tacrolimus – a possible increase in their nephrotoxicity, monitoring of renal function is necessary.

With valproic acid and its salts – ASA reduces the binding of valproate to serum albumin and thus increases the free plasma concentration of valproate.

With phenytoin – ASA reduces the binding of phenytoin to serum albumin and thus increases the free plasma concentration of phenytoin; however, this has no clinical significance.

With ethanol – an increased risk of gastrointestinal bleeding.

With antacids – a decrease in the antiplatelet properties of ASA.

ASA is incompatible with iron salts, carbonates, and alkaline hydroxides.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.