Cardiomagnil forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDIO MAGNIL FORTE (CARDIOMAGNYL® FORTE)

Composition:

Active substance:
acetylsalicylic acid;

One tablet contains 150 mg of acetylsalicylic acid;

Excipients:
corn starch, magnesium hydroxide, microcrystalline cellulose, magnesium stearate, potato starch, hypromellose, propylene glycol, talc.

Pharmaceutical form.
Film-coated tablets.

Main physicochemical properties:
white, oval-shaped film-coated tablets with a score line on one side.

Pharmacotherapeutic group.
Antithrombotic agents. Antiplatelet agents, excluding heparin.

ATC code B01AC06.

Pharmacological properties.

Acetylsalicylic acid is an analgesic, anti-inflammatory, antipyretic, and antiplatelet agent. Its antiplatelet properties increase bleeding time.

The main pharmacological effect is inhibition of prostaglandin and thromboxane production. The analgesic effect is an additional effect caused by inhibition of the enzyme cyclooxygenase. The anti-inflammatory effect is associated with reduced blood flow due to inhibition of PGE2 synthesis.

Acetylsalicylic acid irreversibly inhibits the synthesis of prostaglandins G/H. Its effect on platelets lasts longer than the presence of acetylsalicylic acid in the body. The effect of acetylsalicylic acid on thromboxane biosynthesis in platelets and on bleeding time persists for a prolonged period after discontinuation of treatment. The effect ceases only after new platelets appear in blood plasma.

Salicylic acid (the active metabolite of acetylsalicylic acid) exerts anti-inflammatory effects and also affects respiratory processes, acid-base balance, and gastric mucosa. Salicylates stimulate respiration, primarily through a direct action on the medulla oblongata. Salicylates indirectly affect gastric mucosa by inhibiting its vasodilatory and cytoprotective prostaglandins, thereby increasing the risk of ulcer development.

Pharmacokinetics.

Absorption.
After oral administration, acetylsalicylic acid is rapidly absorbed from the gastrointestinal tract. Absorption of the non-ionized form of acetylsalicylic acid occurs in the stomach and intestine. The rate of absorption is reduced by food intake and in patients experiencing migraine attacks, and increased in patients with achlorhydria or in those taking polysorbates or antacids. Maximum plasma concentration is achieved within 1–2 hours.

Distribution.
Protein binding of acetylsalicylic acid to plasma proteins is 80–90%. The volume of distribution in adults is 170 ml/kg body weight. At higher plasma concentrations, saturation of protein binding sites occurs, leading to an increased volume of distribution. Salicylates are extensively bound to plasma proteins and rapidly distributed throughout the body. Salicylates penetrate into breast milk and can cross the placental barrier.

Metabolism.
Acetylsalicylic acid is hydrolyzed to its active metabolite—salicylic acid—in the gastric wall. After absorption, acetylsalicylic acid is rapidly converted into salicylic acid, although it remains the predominant form in plasma during the first 20 minutes after oral administration.

Excretion.
Salicylic acid is metabolized primarily in the liver. Thus, the steady-state concentration of salicylic acid in plasma increases disproportionately to the orally administered dose. After a 325 mg dose of acetylsalicylic acid, elimination follows first-order kinetics. The elimination half-life is 2–3 hours. At high doses of acetylsalicylic acid, the elimination half-life increases to 15–30 hours. Salicylic acid is also excreted unchanged in urine. The amount of salicylic acid excreted depends on the dose and urinary pH. Approximately 30% of the dose of salicylic acid is excreted in urine when urine is alkaline, compared to only 2% when urine is acidic. Renal excretion occurs via glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Clinical characteristics.

Indications.

Acute and chronic ischemic heart disease.

Contraindications.

Cardiomagnil Forte is contraindicated in the following conditions/diseases:

• Known or suspected hypersensitivity to acetylsalicylic acid, other salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or to any component of the drug.
• Predisposition to bleeding (vitamin K deficiency, thrombocytopenia, hemophilia).
• Acute peptic ulcers.
• Severe renal impairment (glomerular filtration rate < 0.2 mL/s (10 mL/min)).
• Severe hepatic impairment.
• Severe heart failure.
• Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Contraindications for concomitant use.

Metotrexate.
The use of acetylsalicylic acid together with methotrexate at doses of 15 mg/week or higher increases the hematological toxicity of methotrexate (due to reduced renal clearance of methotrexate caused by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

ACE inhibitors.
ACE inhibitors in combination with high doses of acetylsalicylic acid lead to reduced glomerular filtration due to inhibition of the vasodilatory effect of prostaglandins and reduced antihypertensive effect.

Acetazolamide.
Increased acetazolamide concentration may occur, potentially leading to tissue penetration of salicylates from blood plasma and resulting in acetazolamide toxicity (fatigue, lethargy, drowsiness, confusion, hyperchloremic metabolic acidosis) and salicylate toxicity (vomiting, tachycardia, hyperpnea, confusion).

Probenecid, sulfinpyrazone.
When probenecid is used with high doses of salicylates (> 500 mg), metabolism of both drugs may be inhibited and excretion of uric acid may be reduced.

Combinations requiring caution.

Clopidogrel, ticlopidine.
Combined use of clopidogrel and acetylsalicylic acid has a synergistic effect. Such combined use should be performed with caution, as it increases the risk of bleeding.

Anticoagulants (warfarin, phenprocoumon).
Possible reduction in thrombin production, resulting in indirect inhibition of platelet activity (vitamin K antagonist), thereby increasing the risk of bleeding.

Abciximab, tirofiban, eptifibatide.
Possible inhibition of glycoprotein IIb/IIIa receptors on platelets, leading to increased risk of bleeding.

Heparin.
Possible reduction in thrombin production, resulting in indirect inhibition of platelet activity, thereby increasing the risk of bleeding.

If two or more of the above-mentioned substances are used concomitantly with acetylsalicylic acid, this may lead to a synergistic effect enhancing platelet inhibition and, as a result, increased hemorrhagic diathesis.

NSAIDs and COX-2 inhibitors (celecoxib).
Concomitant use increases the risk of gastrointestinal disorders, which may lead to gastrointestinal bleeding.

ibuprofen.
Concomitant use of ibuprofen inhibits the irreversible platelet aggregation induced by acetylsalicylic acid. Treatment with ibuprofen in patients with increased cardiovascular risk may reduce the cardioprotective effect of acetylsalicylic acid.

Patients taking acetylsalicylic acid once daily for prevention of cardiovascular diseases and occasionally taking ibuprofen should take acetylsalicylic acid at least 2 hours before ibuprofen.

Furosemide.
Possible inhibition of proximal tubular elimination of furosemide, leading to reduced diuretic effect.

Quinidine.
Possible additive effect on platelets, leading to prolonged bleeding time.

Spironolactone.
Possible altered renin effect, leading to reduced efficacy of spironolactone.

Selective serotonin reuptake inhibitors (SSRIs).
Concomitant use increases the risk of gastrointestinal disorders, which may lead to gastrointestinal bleeding.

Valproate.
When used concomitantly with valproate, acetylsalicylic acid displaces it from plasma protein binding, increasing its toxicity (central nervous system depression, gastrointestinal disturbances).

Systemic glucocorticosteroids
(except hydrocortisone used for replacement therapy in Addison's disease) reduce salicylate levels in blood and increase the risk of salicylate overdose after discontinuation of glucocorticosteroid therapy.

Antidiabetic agents.
Concomitant use of acetylsalicylic acid and antidiabetic agents increases the risk of hypoglycemia.

Antacids.
Possible increase in renal clearance and reduced renal absorption (due to increased urine pH), leading to reduced effect of acetylsalicylic acid.

Varicella vaccine.
Concomitant use increases the risk of Reye's syndrome.

Ginkgo biloba.
Concomitant use with Ginkgo biloba inhibits platelet aggregation, increasing the risk of bleeding.

Digoxin.
When used concomitantly with digoxin, plasma concentration of the latter increases due to reduced renal excretion.

Alcohol
promotes gastrointestinal mucosal damage and prolongs bleeding time due to synergism between acetylsalicylic acid and alcohol.

Metamizole.

Concomitant use of acetylsalicylic acid and metamizole may reduce clinically significant platelet aggregation. Therefore, combination of drugs containing acetylsalicylic acid and metamizole should be used with caution in patients taking low-dose aspirin for cardioprotection.

Special precautions for use.

To prevent the risk of adverse reactions, prolonged use of Cardiomagnil Forte in combination with other NSAIDs is not recommended.

Prolonged use of the drug in elderly patients for the treatment of pain, inflammation, fever, or rheumatic diseases is not recommended due to the risk of gastrointestinal bleeding. Because of the risk of gastrointestinal bleeding in elderly patients, low-dose acetylsalicylic acid should be used with caution for the treatment of acute or chronic ischemic heart disease, stroke, stroke prevention, or ischemic heart disease prevention.

Cardiomagnil Forte should be used with caution in the following situations:

• gastrointestinal mucosal disorders;
• predisposition to dyspepsia;
• concomitant treatment with anticoagulants (vitamin K antagonists and heparin) (see section "Interaction with other medicinal products and other types of interactions");
  • hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances;
  • gastrointestinal ulcers, including chronic and recurrent ulcer diseases or gastrointestinal bleeding in medical history;
  • concomitant use of anticoagulants;
  • impaired kidney function or cardiovascular circulation (e.g., renal vascular pathology, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), since acetylsalicylic acid may also increase the risk of kidney dysfunction and acute renal failure;
  • severe glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia;
  • especially in the presence of factors that may increase the risk of hemolysis (high drug doses, fever, or acute infectious processes);
  • impaired liver function.

Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Cardiomagnil Forte is used before starting ibuprofen as an analgesic, the patient should consult a physician.

Acetylsalicylic acid may cause bronchospasm or asthma attacks, or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory disease, and allergic reactions (e.g., skin reactions, pruritus, urticaria) to other substances in medical history.

Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of acetylsalicylic acid-containing drugs may increase the risk of bleeding during surgical procedures (including minor surgeries, such as tooth extraction).

When using low doses of acetylsalicylic acid, excretion of uric acid may be reduced. This may trigger gout attacks in predisposed patients.

Acetylsalicylic acid-containing drugs should not be used in children and adolescents with acute viral respiratory infections (ARVI), with or without fever, without consulting a physician. In certain viral diseases, particularly influenza A, influenza B, and varicella, there is a risk of Reye's syndrome, a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if acetylsalicylic acid is used as a concomitant medication, although a causal relationship has not been established. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

If the risk of increased bleeding outweighs the risk of ischemia, temporary discontinuation of low-dose Cardiomagnil Forte treatment should be considered several days before a scheduled surgery.

Fertility.

Acetylsalicylic acid may reduce fertility; therefore, its use is not recommended in women wishing to become pregnant. Discontinuation of acetylsalicylic acid should be considered in women who are unable to conceive or undergoing infertility evaluation (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate a risk of miscarriage and fetal malformations following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of therapy. According to available data, a link between acetylsalicylic acid use and an increased risk of miscarriage has not been confirmed.

Epidemiological data on the occurrence of birth defects are inconsistent; however, an increased risk of gastroschisis cannot be excluded with acetylsalicylic acid use. Results from a prospective study on early pregnancy exposure (1st–4th months) involving approximately 14,800 mother-child pairs did not indicate any association with an increased risk of malformations.

Animal studies indicate reproductive toxicity.

During the first and second trimesters of pregnancy, acetylsalicylic acid-containing drugs should not be prescribed without clear clinical necessity. For women who may be pregnant or are in the first or second trimester, the dose of acetylsalicylic acid-containing drugs should be as low as possible and the duration of treatment as short as possible.

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

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired kidney function, potentially leading to renal failure with oligohydramnios.

In women and newborns near the end of pregnancy, prostaglandin synthesis inhibitors may have the following effects:

• possible prolongation of bleeding time, anti-aggregatory effect, which may occur even after very low doses;
• inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Because of these risks, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Salicylates and their metabolites pass into breast milk in small amounts.

Since no harmful effects on the infant have been observed after the drug was taken by a woman during lactation, breastfeeding interruption is generally not required. However, with regular use or high-dose administration, breastfeeding should be discontinued at an early stage.

Fertility.

Acetylsalicylic acid should not be used in women wishing to become pregnant, as prostaglandin synthesis inhibitors reduce fertility.

If acetylsalicylic acid use is necessary, treatment duration should be as short as possible and the dose as low as possible. The effect on fertility is reversible.

Ability to affect reaction speed when driving or operating machinery. Cardiomagnil Forte does not affect or has a negligible effect on reaction speed when driving or operating machinery.

Dosage and Administration.

The medication is intended for oral use.

The recommended dose for adults is 150 mg (1 tablet) per day.

Tablets should be swallowed whole, with water if necessary. To ensure rapid absorption, the tablet may be chewed or dissolved in water.

Hepatic impairment.
The medication is contraindicated in patients with severe hepatic impairment. Dose adjustment may be required in patients with hepatic dysfunction.

Renal impairment.
The medication is contraindicated for treatment of patients with severe renal impairment (glomerular filtration rate < 0.2 mL/s [10 mL/min]). Dose adjustment may be required in patients with renal dysfunction.

Children.
For the specified indications (see section «Dosage and Administration»), Cardiomagnil Forte is not recommended for use in children.

Administration of acetylsalicylic acid to children under 15 years of age may cause serious adverse effects (including Reye's syndrome, one of the signs of which is persistent vomiting).

For detailed information, see section «Special precautions».

Overdose.

Toxicity. Toxic dose . Adults: 300 mg/kg body weight. Children: single dose of 150 mg/kg or more than 100 mg/kg per day for over 2 days.

Chronic salicylate poisoning may have an insidious onset, as its signs and symptoms are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism, typically occurs only after repeated administration of high doses.

Symptoms of moderate chronic poisoning (resulting from prolonged use of high doses): dizziness, vertigo, deafness, excessive sweating, fever, tachypnea, tinnitus, respiratory alkalosis, metabolic acidosis, lethargy, moderate dehydration, headache, confusion, nausea, and vomiting.

Acute intoxication is characterized by significant disturbances in acid-base balance, which may vary depending on age and severity of intoxication. The most common manifestation in children is metabolic acidosis. The severity of condition cannot be assessed solely based on plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of gastric concretions, or administration of enteric-coated tablets.

Symptoms of severe and acute poisoning (due to overdose): hypoglycemia (predominantly in children), encephalopathy, coma, hypotension, pulmonary edema, seizures, coagulopathy, cerebral edema, and cardiac arrhythmias.

Acute salicylate poisoning (> 300 mg/kg) often leads to acute renal failure, and a dose of 500 mg/kg may be fatal.

More pronounced toxic effects are observed in patients with chronic overdose or drug abuse, as well as in elderly patients or children.

Treatment. In case of acute overdose, gastric lavage and administration of activated charcoal are required. If ingestion of a dose exceeding 120 mg/kg body weight is suspected, repeated doses of activated charcoal should be administered.

Serum salicylate levels should be measured at least every 2 hours after ingestion until salicylate levels are consistently decreasing and acid-base balance is restored.

Prothrombin time and/or INR (International Normalized Ratio) should be checked, especially if bleeding is suspected.

Fluid and electrolyte balance must be restored. Effective methods for removing salicylates from plasma include alkaline diuresis and hemodialysis. Hemodialysis should be used in cases of severe intoxication, as this method significantly accelerates salicylate elimination and restores acid-base and fluid-electrolyte balance.

Due to the complex pathophysiological effects of salicylate poisoning, clinical manifestations and symptoms/laboratory findings may include:

Adverse Reactions

The most commonly reported adverse events are gastrointestinal disorders.

Adverse events are usually dose- and duration-dependent.

The information provided on adverse reactions is based on spontaneous post-marketing reports of adverse reactions during the use of all dosage forms and doses of acetylsalicylic acid (including short- and long-term oral treatment).

Adverse events are classified by frequency of occurrence into the following categories: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (< 1/10,000).

Investigations

Very common: prolonged bleeding time.

Rare: increased levels of transaminases and alkaline phosphatase.

Blood and lymphatic system disorders

Very common: inhibition of platelet aggregation.

Common: prolonged bleeding time.

Uncommon: occult bleeding.

Rare: anaemia with prolonged treatment, haemolysis in patients with congenital glucose-6-phosphate dehydrogenase deficiency.

Very rare: hypoprothrombinemia (with high doses), thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, aplastic anaemia.

Nervous system disorders

Common: headache.

Uncommon: dizziness, somnolence.

Rare: intracranial haemorrhage.

Ear and labyrinth disorders

Uncommon: tinnitus.

Rare: dose-related reversible hearing loss and deafness (occurring at lower plasma salicylate concentrations).

Respiratory system disorders

Common: bronchospasm in patients with asthma (see section "Special precautions for use").

Uncommon: dyspnoea, allergic reactions (rhinitis, nasal congestion).

Gastrointestinal disorders

Very common: heartburn, acid reflux, epigastric pain, abdominal pain.

Common: erosive-inflammatory lesions of the upper gastrointestinal tract, nausea, dyspepsia, vomiting, diarrhoea.

Uncommon: peptic ulcer, upper gastrointestinal bleeding, haematemesis, melena.

Due to its antiplatelet effect, acetylsalicylic acid may be associated with an increased risk of bleeding and prolonged bleeding time. Such bleeding events include perioperative haemorrhage, haematoma, genitourinary bleeding, epistaxis, and gingival bleeding.

Rare: severe upper gastrointestinal bleeding such as gastrointestinal haemorrhage, cerebral haemorrhage (particularly in patients with uncontrolled hypertension and/or concomitant use of antihemostatic agents), which in isolated cases could potentially be life-threatening, perforation.

Very rare: stomatitis, oesophagitis, toxic lesions of the lower gastrointestinal tract with ulceration, strictures, colitis, or exacerbation of inflammatory bowel disease.

Renal and urinary system disorders

Rare: impaired renal function, development of acute renal failure.

Skin and subcutaneous tissue disorders

Uncommon: allergic reactions (urticaria, swelling, pruritus, angioneurotic oedema^2).

Very rare: haemorrhagic rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Endocrine disorders

Rare: hypoglycaemia.

Vascular disorders

Rare: haemorrhagic vasculitis.

Immune system disorders

Uncommon: anaphylactic reactions.

Hepatobiliary disorders

Very rare: dose-related mild reversible toxic hepatitis in certain viral infections (influenza A, B, and varicella). Salicylates may be a contributing factor in the development of Reye's syndrome in children (see section "Special precautions for use"). Transient hepatic dysfunction with elevated serum transaminases and alkaline phosphatase has been reported.

Psychiatric disorders

Common: insomnia.

1 Haemorrhage may lead to acute and chronic post-haemorrhagic anaemia/iron-deficiency anaemia (due to so-called occult microbleeding) with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, hypoperfusion.

2 Angioneurotic oedema occurs more frequently in patients predisposed to allergies.

Shelf life.
3 years.

Storage conditions.
Store at temperatures not exceeding 25 °C. Keep out of the reach and sight of children!

Packaging.
30 or 100 tablets in a bottle; 1 bottle in a cardboard box.

Prescription status.
Over-the-counter – 30 tablets. Prescription only – 100 tablets.

Manufacturer.
Takeda GmbH, manufacturing site Oranienburg, Germany / Takeda GmbH Betriebsstätte Oranienburg, Germany.

Manufacturer's address.
Lehnitzstrasse 70-98, 16515 Oranienburg, Germany.