Magnicor forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MАGNICOR FORTE (MAGNICORFORTE)

Composition:

Active substance: 1 tablet contains acetylsalicylic acid 150 mg;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets with a score line, film-coated, white or almost white in colour.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. ATC code B01A C06.

Pharmacological Properties

Pharmacodynamics

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 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 when 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 by 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, 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, protein binding sites become saturated, 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 compound in plasma during the first 20 minutes after oral administration.

Elimination. Salicylic acid is primarily metabolized in the liver. Thus, plasma salicylic acid concentration increases disproportionately to the orally administered dose. At a dose of 325 mg 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 salicylic acid dose 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.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or to any component of the medicinal product.
• Asthma induced by salicylates or substances with similar action, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), in medical history.
• Acute 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 reduced glomerular filtration due to inhibition of the vasodilatory effect of prostaglandins and reduced antihypertensive effect.

Acetazolamide. Increased acetazolamide concentration may lead to penetration of salicylates from blood plasma into tissues and cause acetazolamide toxicity (fatigue, lethargy, drowsiness, 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 medicinal products is inhibited and excretion of uric acid may be reduced. Therefore, this combination should be avoided.

Combinations requiring caution.

Methotrexate. When acetylsalicylic acid and methotrexate at doses less than 15 mg/week are used, hematological toxicity of methotrexate increases (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 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 effect on reduced 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 reduced platelet activity, leading to increased risk of bleeding.

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

NSAIDs and COX-2 inhibitors (celecoxib). Concurrent 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 using 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 of furosemide.

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

Spironolactone. Possible modified effect on renin, leading to reduced effectiveness of spironolactone.

Selective serotonin reuptake inhibitors (SSRIs). Concurrent 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 glucocorticosteroids (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 medicinal products increases the risk of hypoglycemia.

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

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

Ginkgo biloba. Concurrent 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. Prolonged plasma half-life of penicillin.

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 should be used with caution in the following cases:

• hypersensitivity to analgesic, anti-inflammatory, or antirheumatic agents, as well as in the presence of allergy to other substances;
• gastrointestinal ulcers, including chronic and 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;
• impaired kidney function or cardiovascular circulation (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 dysfunction and acute kidney failure;
• impaired liver function;
• severe glucose-6-phosphate dehydrogenase deficiency – acetylsalicylic acid may cause hemolysis or hemolytic anemia, especially in the presence of risk factors for hemolysis, such as high drug doses, fever, or acute infectious conditions.

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

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

Acetylsalicylic acid may cause bronchospasm or an asthma attack, 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 medicinal product should be discontinued immediately upon the appearance of any clinical symptoms of hypersensitivity reactions, including skin rash and mucosal lesions.

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 risk of occurrence or worsening of bleeding during surgical procedures (including minor surgeries, such as tooth extraction).

When low doses of acetylsalicylic acid are used, excretion of uric acid may be reduced. This may trigger an attack of gout 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 developing Reye's syndrome, a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if acetylsalicylic acid is used concomitantly; however, a causal relationship has not been established. If these conditions are accompanied by persistent vomiting, this 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 negatively affect pregnancy and/or embryonic/fetal development. Available epidemiological data suggest an increased risk of miscarriage and congenital malformations (heart defects and gastroschisis) following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of treatment. According to available data, a link between the use of acetylsalicylic acid and an increased risk of miscarriage has not been confirmed. Epidemiological data on congenital malformations are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with the use of acetylsalicylic acid. 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 indicated reproductive toxicity.

During the first and second trimesters of pregnancy, medicinal products containing acetylsalicylic acid should not be prescribed unless clinically necessary. For women who may be pregnant, or during the first and second trimesters of pregnancy, the dose of medicinal products containing acetylsalicylic acid should be as low as possible and the duration of treatment as short as possible.

Animal studies have shown that the use of prostaglandin inhibitors leads to increased pre- and post-implantation loss and embryo/fetal death. In addition, a higher incidence of severe congenital 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 medicinal product 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);

• impaired kidney function, potentially leading to renal failure with oligohydramnios;

• affect the mother and child towards 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.

In view of the above, 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 women during lactation, breastfeeding generally does not need to be interrupted. However, in cases of regular use or administration of high doses (> 300 mg/day), breastfeeding should be discontinued at an early stage.

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 after discontinuation of treatment.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of Administration and Dosage

The recommended dose for adults is 1 tablet (150 mg) 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 medicinal product must not be used in patients with severe hepatic impairment. Dose adjustment may be necessary in patients with impaired liver function.

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

Children.

According to indications (see section "Method of Administration and Dosage"), the medicinal product 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.

Potentially toxic dose. Adults: 300 mg/kg body weight.

Chronic salicylate poisoning may have an insidious presentation, as its signs and symptoms are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism, 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, tachypnea, tinnitus, respiratory alkalosis, metabolic acidosis, lethargy, moderate dehydration, headache, confusion, nausea, and vomiting.

Acute intoxication is characterized by marked disturbances in acid-base balance, which may vary depending on age and severity of intoxication. Metabolic acidosis is the most common manifestation in children. Severity of condition cannot be assessed solely based on plasma salicylate concentrations. 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 should be considered.

Serum salicylate levels should be measured at least every 2 hours after ingestion 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 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 water-electrolyte balance.

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

Adverse Reactions

Gastrointestinal system: Common symptoms of dyspepsia, 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. Observed hemorrhages include perioperative bleeding, hematomas, bleeding from the genitourinary organs, epistaxis, and gingival bleeding; rarely or very rarely – severe bleeding such as gastrointestinal hemorrhage, cerebral hemorrhage (especially in patients with uncontrolled hypertension and/or concomitant use of antihemostatic agents), which in isolated cases could potentially 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 glucose-6-phosphate dehydrogenase deficiency, hemolysis and hemolytic anemia have been observed.

Thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia.

Renal and urinary system: Impaired kidney function and development of acute renal failure.

Hepatobiliary system: Very rarely reported transient liver dysfunction with elevated serum transaminase and alkaline phosphatase levels.

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 Warnings and Precautions for Use").

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per carton.

10 tablets per blister; 10 blisters per carton.

Prescription status.

Over-the-counter – 30 tablets.

By prescription – 100 tablets.

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