Cardiomagnyl (Tablets) Instructions for Use

Marketing Authorization Holder

Nizhpharm JSC (Russia)

Manufactured By

Takeda Pharmaceuticals, LLC (Russia)

Or

Takeda GmbH (Germany)

Packaging and Quality Control Release

TAKEDA PHARMACEUTICALS, LLC (Russia)

Or

TAKEDA GmbH (Germany)

Contact Information

NIZHPHARM group of companies (Russia)

ATC Code

B01AC30 (Platelet aggregation inhibitors in combination)

Active Substances

Magnesium hydroxide (Ph.Eur. European Pharmacopoeia)

Acetylsalicylic acid (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Cardiomagnyl	Film-coated tablets, 75 mg+15.2 mg: 30 or 100 pcs.
		Film-coated tablets, 150 mg+30.39 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, in the shape of a stylized “heart”.

Excipients: corn starch, microcrystalline cellulose, magnesium stearate, potato starch.

Shell composition: hypromellose (methylhydroxypropylcellulose 15), propylene glycol, talc.

30 pcs. – glass bottles^× (1) – cardboard packs.
100 pcs. – glass bottles^× (1) – cardboard packs.

Film-coated tablets white, oval in shape with a score on one side.

Excipients: corn starch, microcrystalline cellulose, magnesium stearate, potato starch.

Shell composition: hypromellose (methylhydroxypropylcellulose 15), propylene glycol, talc.

30 pcs. – glass bottles^× (1) – cardboard packs.
100 pcs. – glass bottles^× (1) – cardboard packs.

^× brown glass bottles, sealed with a white screw cap (made of polyethylene), with a built-in removable silica gel capsule and a ring providing first-opening control.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

The mechanism of action of acetylsalicylic acid (ASA) is based on the irreversible inhibition of the enzyme COX-1, resulting in the blockade of thromboxane A₂ synthesis and suppression of platelet aggregation. It is believed that ASA has other mechanisms for suppressing platelet aggregation, which expands its scope of application in various vascular diseases. ASA also has anti-inflammatory, analgesic, and antipyretic effects.

Magnesium hydroxide, which is part of the Cardiomagnyl preparation, may help protect the gastric mucosa from the effects of acetylsalicylic acid.

Pharmacokinetics

Acetylsalicylic acid

Absorption

After oral administration, ASA is rapidly and completely absorbed from the gastrointestinal tract. During and after absorption, ASA is converted into its main metabolite – salicylic acid (SA). C_max of ASA in blood plasma is reached within 20 minutes after oral administration, and of SA – within 1-2 hours. When taken simultaneously with food, a slowdown in ASA absorption is noted without affecting the extent of absorption. The bioavailability of ASA is about 70%, but this value fluctuates significantly since ASA undergoes presystemic hydrolysis (gastrointestinal mucosa, liver) into SA under the action of enzymes. The bioavailability of SA is 80-100%.

Distribution

ASA and SA are largely bound to plasma proteins and are rapidly distributed throughout the body. The degree of binding of SA to plasma proteins depends on the concentration. SA crosses the placental barrier and is excreted in breast milk.

Metabolism

The main metabolite of ASA is SA. The metabolism of SA occurs in the liver with the formation of salicyluric acid, phenolic glucuronide of salicylic acid, salicyl glucuronide, and gentisic acid.

Excretion

T_1/2 of ASA is about 15 minutes, because with the participation of enzymes, ASA is rapidly hydrolyzed to SA in the intestine, liver, and blood plasma. T_1/2 of SA is about 3 hours, but it can increase significantly with the simultaneous administration of large doses of ASA (more than 3.0 g) due to saturation of enzyme systems. SA and its metabolites are excreted mainly by the kidneys.

Magnesium hydroxide

Absorption

Magnesium hydroxide has low absorption and does not have a systemic effect.

Distribution and metabolism

Magnesium hydroxide is not metabolized.

Excretion

Magnesium hydroxide is excreted through the intestines.

The used doses of magnesium hydroxide do not affect the bioavailability of ASA.

Indications

The drug Cardiomagnyl is used for the treatment of adult patients.

• Unstable angina and stable angina;
• Prevention of recurrent myocardial infarction;
• Prevention of recurrent transient ischemic attack (TIA) and recurrent ischemic stroke in patients who have previously suffered from cerebrovascular accident;
• Prevention of thrombotic complications after surgeries and invasive interventions on blood vessels (such as coronary artery bypass grafting, carotid endarterectomy, arteriovenous bypass, coronary angioplasty and stenting, carotid angioplasty).

ICD codes

Dosage Regimen

Take orally. The tablets should be swallowed whole with water. If desired, the tablet can be broken in half, chewed, or pre-crushed.

Unstable and stable angina

1 tablet of Cardiomagnyl containing ASA at a dose of 75-150 mg, once a day.

Prevention of recurrent myocardial infarction

1 tablet of Cardiomagnyl containing ASA at a dose of 75-150 mg, once a day.

Prevention of recurrent transient ischemic attack (TIA) and recurrent ischemic stroke in patients who have previously suffered from cerebrovascular accident

1 tablet of Cardiomagnyl containing ASA at a dose of 75-150 mg, once a day.

Prevention of thrombotic complications after surgeries and invasive interventions on blood vessels (such as coronary artery bypass grafting, carotid endarterectomy, arteriovenous bypass, coronary angioplasty and stenting, carotid angioplasty)

1 tablet of Cardiomagnyl containing ASA at a dose of 75-150 mg, once a day.

Patients with impaired renal function

The drug Cardiomagnyl is contraindicated in patients with severe renal impairment. Cardiomagnyl should be used with caution in patients with impaired renal function, as ASA may increase the risk of renal failure and acute renal failure (see section “Special Precautions”).

Patients with impaired hepatic function

The drug Cardiomagnyl is contraindicated in patients with severe hepatic impairment. Cardiomagnyl should be used with caution in patients with impaired hepatic function.

Children

The safety and efficacy of ASA + magnesium hydroxide preparations in children under 18 years of age have not been established. Data are not available. The use of Cardiomagnyl in patients under 18 years of age is contraindicated.

The drug should be taken only according to the indications, method of administration, and doses specified in the instructions.

Adverse Reactions

Criteria for assessing the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown – cannot be estimated from the available data.

Blood and lymphatic system disorders uncommon – iron deficiency anemia (associated with bleeding); rare – hemorrhagic anemia; frequency unknown – hemolysis, hemolytic anemia (associated with severe forms of glucose-6-phosphate dehydrogenase deficiency).

Immune system disorders uncommon – hypersensitivity, drug intolerance, allergic edema and angioedema (Quincke’s edema); rare – anaphylactic reactions; frequency unknown – anaphylactic shock.

Nervous system disorders common – dizziness; uncommon – hemorrhagic stroke or intracranial bleeding (fatal cases occurred with the same frequency <0.1% in patients receiving ASA therapy and patients receiving placebo).

Ear and labyrinth disorders common – tinnitus.

Cardiac disorders frequency unknown – cardiorespiratory distress syndrome (associated with severe allergic reactions).

Vascular disorders uncommon – hematomas; rare – hemorrhage, muscle hemorrhages; frequency unknown – bleeding during medical procedures.

Respiratory, thoracic and mediastinal disorders common – epistaxis, rhinitis; uncommon – nasal congestion; frequency unknown – aspirin-induced bronchial asthma.

Gastrointestinal disorders common – dyspepsia, gastrointestinal and abdominal pain, gastrointestinal inflammation, gastrointestinal bleeding; uncommon – gingival bleeding, ulcers and erosions of the gastric and duodenal mucosa; rare – perforated ulcers of the gastric and duodenal mucosa.

Hepatobiliary disorders uncommon – impaired liver function; rare – increased activity of liver transaminases.

Skin and subcutaneous tissue disorders common – skin rash, skin itching; uncommon – urticaria.

Renal and urinary disorders common – genitourinary tract bleeding; rare – impaired renal function, acute renal failure (in patients with impaired renal function or cardiovascular disorders existing before starting treatment with drugs containing ASA).

If the patient experiences side effects listed in the instructions, or if they worsen, or if any other side effects not listed in the instructions occur, it is necessary to inform the doctor.

Contraindications

• Hypersensitivity to ASA, excipients of the drug and other NSAIDs;
• Cerebral hemorrhage;
• Bleeding tendency (vitamin K deficiency, thrombocytopenia, hemorrhagic diathesis);
• Bronchial asthma induced by the intake of salicylates and NSAIDs;
• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to ASA or other NSAIDs, including COX-2 inhibitors (including in history);
• Erosive and ulcerative lesions of the gastrointestinal tract (in the acute phase);
• Gastrointestinal bleeding;
• Severe hepatic impairment;
• Severe renal failure (CrCl <30 ml/min);
• Chronic heart failure of functional class III-IV according to the NYHA classification;
• Pregnancy (first trimester, second trimester after 20 weeks and third trimester of pregnancy);
• Breastfeeding period;
• Glucose-6-phosphate dehydrogenase deficiency;
• Concomitant use with methotrexate (more than 15 mg per week);
• Children under 18 years of age.

With caution in gout, hyperuricemia, history of ulcerative lesions of the gastrointestinal tract or gastrointestinal bleeding, impaired liver function, impaired renal function, bronchial asthma, hay fever, nasal polyposis, hypersensitivity to analgesics, anti-inflammatory drugs, antirheumatic drugs, as well as allergic reactions to other substances, during planned surgical intervention (including minor ones, e.g., tooth extraction); in the second trimester of pregnancy up to 20 weeks.

Caution should be exercised during concomitant therapy with the following drugs: methotrexate at a dose of less than 15 mg per week; anticoagulant, thrombolytic or other antiplatelet agents; metamizole and NSAIDs (including ibuprofen, naproxen), digoxin, oral hypoglycemic agents (sulfonylurea derivatives) and insulin, valproic acid, ethanol, selective serotonin reuptake inhibitors).

If any of the above diseases are present, it is necessary to consult a doctor before using the drug.

Use in Pregnancy and Lactation

Pregnancy

Animal studies have demonstrated the reproductive toxicity of ASA. The use of large doses of salicylates in the first 3 months of pregnancy is associated with an increased frequency of fetal developmental defects. In the first trimester of pregnancy, the use of drugs containing ASA is contraindicated. In the second trimester of pregnancy up to 20 weeks, salicylates can be prescribed only after a strict assessment of risk and benefit. The use of NSAIDs is contraindicated in women from the 20th week of pregnancy due to the possible development of oligohydramnios and/or kidney pathology in newborns (neonatal renal dysfunction).

In the last trimester of pregnancy, salicylates in high doses (more than 300 mg/day) cause inhibition of labor, premature closure of the fetal arterial duct, increased bleeding in the mother and fetus, and administration immediately before childbirth can cause intracranial hemorrhage, especially in premature infants.

Breastfeeding period

Salicylates and their metabolites penetrate into breast milk in small amounts. Available clinical data are insufficient to establish the possibility or impossibility of using the drug during breastfeeding. Before prescribing ASA during breastfeeding, the potential benefit of therapy with the drug should be assessed relative to the potential risk for infants.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment; should be used with caution in impaired hepatic function.

Use in Renal Impairment

The drug is contraindicated in severe renal failure (CrCl less than 30 ml/min); should be used with caution in impaired renal function.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

When taking low doses of ASA long-term as antiplatelet therapy, caution is necessary in elderly patients due to the risk of gastrointestinal bleeding.

Special Precautions

The drug should be used after a doctor’s prescription.

ASA can provoke bronchospasm, as well as cause attacks of bronchial asthma and other hypersensitivity reactions. Risk factors are a history of bronchial asthma, hay fever, nasal polyposis, chronic respiratory diseases, as well as allergic reactions to other drugs (e.g., skin reactions, itching, urticaria).

ASA can cause bleeding of varying severity during and after surgical interventions. Several days before a planned surgical intervention, the risk of bleeding should be assessed against the risk of ischemic complications in patients taking low doses of ASA. If the risk of bleeding is significant, ASA intake should be temporarily discontinued.

The combination of ASA with anticoagulants, thrombolytics, and antiplatelet drugs is accompanied by an increased risk of bleeding.

ASA in low doses can provoke the development of gout in predisposed patients (with reduced uric acid excretion).

The combination of ASA with methotrexate is accompanied by an increased frequency of side effects from the hematopoietic organs.

High doses of ASA have a hypoglycemic effect, which should be kept in mind when prescribing it to patients with diabetes mellitus receiving oral hypoglycemic agents and insulin.

When using systemic corticosteroids and salicylates concomitantly, it should be remembered that during treatment the concentration of salicylates in the blood is reduced, and after discontinuation of systemic corticosteroids, an overdose of salicylates is possible.

Metamizole and some NSAIDs (including ibuprofen, naproxen) may weaken the inhibitory effect of ASA on platelet aggregation. Patients taking ASA and planning to take metamizole or NSAIDs should discuss this with their doctor (see section “Drug Interactions”).

Exceeding the dose of ASA above the recommended therapeutic doses is associated with the risk of gastrointestinal bleeding.

When taking low doses of ASA long-term as antiplatelet therapy, caution is necessary in elderly patients due to the risk of gastrointestinal bleeding.

When taking ASA concomitantly with alcohol, the risk of damage to the gastrointestinal mucosa and prolongation of bleeding time is increased.

In patients with impaired renal function or in patients with circulatory disorders arising from renal artery disease, chronic heart failure, hypovolemia, extensive surgery, sepsis, or cases of massive bleeding, Cardiomagnyl should be used with caution, as ASA may increase the risk of acute renal failure and impaired renal function.

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

Drugs containing ASA should not be used in children and adolescents for the treatment of viral infections with or without fever without consulting a doctor. In certain viral diseases, in particular, influenza A, influenza B, and chickenpox, there is a risk of developing Reye’s syndrome – a very rare but life-threatening disease requiring immediate medical intervention. The risk may increase if ASA is used as concomitant therapy, but a causal relationship has not been confirmed. Persistent vomiting in these diseases may be a symptom of Reye’s syndrome.

When using the drug independently, one should not exceed the maximum duration and recommended doses. If the symptoms of the disease do not decrease or worsen, it is recommended to consult a doctor.

Effect on the ability to drive vehicles and mechanisms

During treatment with ASA preparations, caution must be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Moderate overdose symptoms: nausea, vomiting, tinnitus, hearing impairment, dizziness, confusion.

Treatment: gastric lavage should be performed, activated charcoal administered, and symptomatic therapy carried out.

Severe overdose symptoms: fever, hyperventilation, ketoacidosis, respiratory alkalosis, coma, cardiovascular and respiratory failure, severe hypoglycemia.

Treatment: immediate hospitalization in specialized departments for emergency therapy – gastric lavage, determination of acid-base balance, alkaline and forced alkaline diuresis, hemodialysis, administration of solutions, activated charcoal, symptomatic therapy. During alkaline diuresis, pH values between 7.5 and 8 must be achieved. Forced alkaline diuresis should be performed when the plasma salicylate concentration is greater than 500 mg/l (3.6 mmol/l) in adults and 300 mg/l (2.2 mmol/l) in children.

Drug Interactions

Concomitant use of the drug Cardiomagnyl with methotrexate may lead to increased hematological toxicity of methotrexate due to reduced renal clearance and displacement from plasma protein binding. Use with methotrexate at a dose of more than 15 mg per week is contraindicated. Use with methotrexate at a dose of less than 15 mg per week is possible with special caution if the benefit to the patient outweighs the risk.

When the drug is used concomitantly with other NSAIDs containing salicylates in large doses, an increased risk of ulcerogenic action and gastrointestinal bleeding is noted.

When used concomitantly, ASA enhances the effect of the following drugs

• Methotrexate (due to reduced renal clearance and displacement from protein binding);
• Heparin and indirect anticoagulants (due to impaired platelet function and displacement of indirect anticoagulants from protein binding);
• Thrombolytic, antiplatelet, and anticoagulant drugs;
• Digoxin (due to reduced renal excretion);
• Oral hypoglycemic agents (sulfonylurea derivatives) and insulin (due to the hypoglycemic properties of ASA itself in high doses and displacement of sulfonylurea derivatives from plasma protein binding);
• Valproic acid due to displacement from protein binding.

When used concomitantly (within 1 day) with metamizole and some NSAIDs (including ibuprofen and naproxen), antagonism regarding the irreversible inhibition of platelet function caused by ASA is noted. The clinical significance of this effect is unknown. The combination of ASA with metamizole or NSAIDs (including ibuprofen or naproxen) is not recommended in patients with a high risk of cardiovascular diseases due to a possible reduction in the cardioprotective effects of ASA.

When taking ASA in combination with ethanol (alcohol), there is an increased risk of damage to the gastrointestinal mucosa and prolongation of bleeding time as a result of mutual enhancement of the effects of ASA and ethanol.

ASA weakens the effect of uricosuric agents (benzbromarone) due to competitive tubular elimination of uric acid.

By enhancing the elimination of salicylates, systemic corticosteroids weaken their effect.

Antacids and cholestyramine reduce the absorption of the drug.

Concomitant use of ASA with selective serotonin reuptake inhibitors may lead to an increased risk of upper gastrointestinal bleeding due to a possible synergistic effect.

When diuretics are used concomitantly with ASA in high doses, a decrease in the glomerular filtration rate is noted due to reduced synthesis of prostaglandins in the kidneys.

When ACE inhibitors are combined with high doses of ASA, a decrease in the glomerular filtration rate is noted due to inhibition of vasodilatory prostaglandins. Furthermore, a weakening of the antihypertensive effect of ACE inhibitors is noted.

To prevent the risk of any adverse reactions, the patient should inform the attending physician about any medications being taken, including over-the-counter ones.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is available without a prescription.

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.