Magnicor

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MАGNICOR (MAGNICOR)

Composition:

Active substance: 1 tablet contains acetylsalicylic acid 75 mg;

Excipients: magnesium hydroxide; maize starch; microcrystalline cellulose; potato starch; magnesium stearate;

Coating: Opadry II White film-coating mixture ((hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; polyethylene glycol (macrogol); titanium dioxide (E 171); triacetin)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex tablets with a film coating.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. ATC code B01AC06.

Pharmacological Properties

Pharmacodynamics

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

The main pharmacological effect is inhibition of prostaglandin and thromboxane formation. The analgesic effect is a secondary 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) has anti-inflammatory activity 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 the 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, but is increased in patients with achlorhydria or in those taking polysorbates or antacids. Maximum plasma concentration is reached within 1–2 hours.

Distribution. Plasma protein binding of acetylsalicylic acid is 80–90%. The volume of distribution in adults is 170 mL/kg body weight. As plasma concentration increases, saturation of protein binding sites occurs, leading to an increase in the 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 compound in plasma during the first 20 minutes following oral administration.

Elimination. Salicylic acid undergoes metabolism primarily in the liver. Thus, the steady-state concentration of salicylic acid in plasma increases disproportionately to the orally administered dose. At a dose of 325 mg, acetylsalicylic acid is eliminated via first-order reaction 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 urine pH. Approximately 30% of the dose of salicylic acid is excreted in urine when urine pH 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.
• For prevention of recurrent thrombosis.
• For primary prevention of thrombotic events and cardiovascular diseases, such as acute coronary syndrome, in patients aged 50 years and older who have risk factors for cardiovascular disease: arterial hypertension, hypercholesterolemia, diabetes mellitus, obesity (body mass index > 30), family history (myocardial infarction in at least one parent, brother or sister before the age of 55). The use of low-dose aspirin for these indications should be considered only in the absence of clear contraindications. The decision on primary prevention should be made individually, taking into account both the risk of ischemia and the risk of bleeding.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or to any component of the medicinal product.
• Asthma induced by salicylates or substances with similar action, especially nonsteroidal anti-inflammatory drugs (NSAIDs), in medical history.
• Active peptic ulcers.
• Hemorrhagic diathesis.
• Severe renal failure.
• Severe hepatic failure.
• Severe heart failure.
• Combination with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindications for concomitant use.

Methotrexate. Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg/week or higher increases 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 decreased glomerular filtration due to inhibition of the vasodilatory effect of prostaglandins and reduced antihypertensive effect.

Acetazolamide. Possible increase in acetazolamide concentration may lead to tissue penetration of salicylates from plasma and cause acetazolamide toxicity (fatigue, lethargy, somnolence, confusion, hyperchloremic metabolic acidosis) and salicylate toxicity (vomiting, tachycardia, hyperpnea, confusion).

Not recommended combinations for concomitant use.

Uricosuric agents (probenecid, sulfinpyrazone). When probenecid and high doses of salicylates (> 500 mg) are used, metabolism of both drugs may be inhibited and excretion of uric acid may be reduced. Therefore, combination of these drugs should be avoided.

Combinations requiring caution.

Methotrexate. When acetylsalicylic acid is used concomitantly with methotrexate at doses less than 15 mg/week, hematological toxicity of methotrexate may increase (due to reduced renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

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

Anticoagulants (warfarin, phenprocoumon). Possible reduction in thrombin production, resulting in indirect effect on decreased 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 effect on decreased platelet activity, thereby increasing the risk of bleeding.

If two or more of the above substances are used concomitantly with acetylsalicylic acid, this may lead to a synergistic effect enhancing inhibition of platelet activity 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. Concurrent 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 who take acetylsalicylic acid once daily for cardiovascular disease prevention and occasionally use ibuprofen should take acetylsalicylic acid at least 2 hours before ibuprofen.

Metamizole. When used concomitantly with acetylsalicylic acid, metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, caution is recommended when using acetylsalicylic acid (as a cardioprotector) and metamizole concomitantly.

Cyclosporine, tacrolimus. Concomitant use of NSAIDs with cyclosporine or tacrolimus may increase nephrotoxicity of cyclosporine and tacrolimus. Renal function should be monitored when these drugs are used concomitantly with acetylsalicylic acid.

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.

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

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

Antidiabetic medicinal products. Concomitant use of acetylsalicylic acid and antidiabetic drugs 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, leading to increased risk of bleeding.

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

Barbiturates. Serum concentration of barbiturates may increase when used concomitantly with acetylsalicylic acid.

Penicillin. Prolongs penicillin half-life in plasma.

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

Special precautions for use.

The medicinal product Magnicor should be used with caution in the following cases:

• hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances;
• gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding in medical history;
• presence of symptoms of chronic gastric or duodenal dyspepsia or their recurrence;
• concomitant use of anticoagulants;
• arterial hypertension;
• renal function impairment or cardiovascular circulatory disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding) – since acetylsalicylic acid may also increase the risk of renal function impairment and acute renal failure;
• hepatic function impairment;
• severe glucose-6-phosphate dehydrogenase deficiency – acetylsalicylic acid may cause hemolysis or hemolytic anemia, especially in the presence of risk factors for hemolysis (e.g., high drug doses, fever, or acute infectious conditions).

Acetylsalicylic acid is not recommended for women with menorrhagia (during menstruation), as it may exacerbate menstrual bleeding.

Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Magnicor is used, patients should consult a physician before taking ibuprofen as an analgesic.

Acetylsalicylic acid may cause bronchospasm or an attack of bronchial asthma, 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 the past.

There have been reports of rare cases of serious skin adverse reactions, including Stevens-Johnson syndrome, associated with the use of acetylsalicylic acid (see section "Adverse reactions"). The drug should be discontinued if any clinical signs of hypersensitivity reactions occur, including skin or mucosal rashes.

Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of medicinal products containing acetylsalicylic acid increases the likelihood of occurrence or worsening of bleeding during surgical procedures (including minor surgical interventions, such as tooth extraction).

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

Medicinal products containing acetylsalicylic acid should not be used in children and adolescents with acute respiratory viral infections (ARVI), with or without fever, without prior consultation with 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 urgent medical intervention. The risk may be increased if acetylsalicylic acid is used concomitantly, although a causal relationship has not been established. Persistent vomiting in these conditions may be a manifestation of Reye's syndrome.

The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate a risk of miscarriage and fetal malformations (cardiac defects and gastroschisis) 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 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 ruled out with acetylsalicylic acid use. Available data on its effects during early pregnancy (1st–4th month) do not indicate any association with an increased risk of malformations.

Animal studies have shown reproductive toxicity.

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

Animal studies have shown that prostaglandin inhibitors lead to increased pre- and post-implantation losses and embryo/fetal death. In addition, a higher incidence of severe malformations, including cardiovascular defects, has been observed in animals treated with prostaglandin inhibitors during organogenesis.

According to previous experience, the risk is low when the drug is used at therapeutic doses.

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);

• renal function impairment, potentially leading to renal failure with oligohydramnios;

• affect the mother and child at the end of pregnancy as follows: *

• prolonged bleeding time, anti-aggregatory effect, which may occur even after very low doses;

• inhibition of uterine contractions, which may lead to delayed or prolonged labor.

Therefore, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Breastfeeding. Salicylates and their metabolites pass into breast milk in small amounts. Concentrations in breast milk are equivalent to or even higher than those in maternal plasma.

Since no harmful effects of the medicinal product on the infant have been observed after administration to lactating women, breastfeeding interruption is generally not required. However, in cases of regular use or high-dose administration (> 300 mg/day), breastfeeding should be discontinued in the early stages.

Fertility. There is some evidence that drugs which inhibit prostaglandin synthesis may impair female reproductive function by affecting ovulation. This effect is reversible and resolves upon discontinuation of treatment.

Ability to affect reaction speed when driving or operating machinery. No effect.

Method of Administration and Dosage

Acute and chronic ischemic heart disease.

Recommended initial dose – 2 tablets (150 mg) daily. Maintenance dose – 1 tablet (75 mg) daily.

Acute myocardial infarction. Unstable angina.

Recommended dose is 2–6 tablets (150 mg – 450 mg), administered as soon as possible after symptom onset.

Prevention of recurrent thrombosis.

Recommended initial dose – 2 tablets (150 mg) daily. Maintenance dose – 1 tablet (75 mg) daily.

Primary prevention in patients with diabetes who have high or very high risk of cardiovascular diseases.

Recommended preventive dose – 1 tablet (75 mg) daily.

Tablets should be swallowed whole, with water if necessary. For faster absorption, the tablet may be chewed or dissolved in water.

Hepatic impairment. The medicinal product must not be used in patients with severe hepatic dysfunction. Dose adjustment may be required in patients with impaired liver function.

Renal impairment. The medicinal product must not be used for treatment of patients with severe renal insufficiency (glomerular filtration rate < 0.2 mL/s (10 mL/min)). Dose adjustment may be required in patients with impaired renal function.

Children.

According to indications (see section "Method of Administration and Dosage"), the medicinal product Magnicor must not be used 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).

Overdose.

Toxicity.

Dangerous dose. Adults: 300 mg/kg body weight.

Chronic salicylate poisoning may be insidious in nature, as its signs and symptoms are nonspecific. Moderate chronic intoxication, or salicylism, caused by salicylates, usually occurs only after repeated administration of high doses.

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

Acute intoxication is characterized by pronounced disturbance of acid-base balance, which may vary depending on age and severity of intoxication. The most common manifestation in children is metabolic acidosis. 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 when administered in enteric-coated tablet form.

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

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 a dose exceeding 120 mg/kg body weight is suspected, repeated administration of activated charcoal is necessary.

Serum salicylate levels should be measured at least every 2 hours after dosing until the salicylate level is 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 salicylate 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 electrolyte balance.

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

Side effects.

Gastrointestinal system: frequent dyspeptic symptoms, nausea, vomiting, epigastric pain, and abdominal pain; in individual cases – gastrointestinal tract inflammation, erosive-ulcerative lesions of the gastrointestinal tract, which in rare instances may lead to gastrointestinal hemorrhages and perforations, with corresponding laboratory findings and clinical manifestations.

Blood and lymphatic system: due to the antiplatelet effect of acetylsalicylic acid, bleeding and prolonged bleeding time may occur. Such bleeding events as perioperative hemorrhages, hematomas, bleeding from the genitourinary organs, epistaxis, and gingival bleeding have been observed; rarely or very rarely – serious hemorrhages such as gastrointestinal hemorrhages and cerebral hemorrhages (especially in patients with uncontrolled hypertension and/or concomitant use of antihemostatic agents), which in isolated cases may be life-threatening.

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

In patients with severe forms of glucose-6-phosphate dehydrogenase deficiency, hemolysis and hemolytic anemia have been observed.

Thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia.

Renal and urinary system: renal function disorders and development of acute renal failure have been reported.

Hepatobiliary system: very rarely, transient liver dysfunction with increased serum transaminase and alkaline phosphatase levels has been reported.

Immune system: asthma; hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioneurotic edema, and hypotension progressing to shock; severe skin reactions including exudative multiform erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Nervous system: headache, dizziness; confusion and tinnitus may indicate overdose.

Metabolism and nutrition: hypoglycemia, acid-base imbalance.

Reproductive system: menorrhagia.

Hypersensitivity reactions with corresponding laboratory and clinical manifestations, including asthmatic episodes, mild to moderate skin reactions, and reactions involving the respiratory, gastrointestinal, and cardiovascular systems, including symptoms such as rash, urticaria, swelling, pruritus, rhinitis, nasal congestion, cardiorespiratory failure, and very rarely – severe reactions including anaphylactic shock.

Other: Reye's syndrome (see section "Special precautions").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a carton.

10 tablets in a blister; 10 blisters in a carton.

Supply category. Over-the-counter.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua