Aspenorm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASPENORM (ASPENORM)

Composition:

Active substance: acetylsalicylic acid;

1 tablet contains acetylsalicylic acid (calculated as 100% dry substance) 100 mg or 300 mg;

Excipients: microcrystalline cellulose, corn starch, crospovidone;

Coating: Kollicoat MAE, propylene glycol, titanium dioxide (E 171), talc.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical characteristics: round, biconvex, coated tablets of white or almost white color.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01AC06.

Pharmacological Properties

Pharmacodynamics

Acetylsalicylic acid (ASA) inhibits platelet aggregation by blocking the synthesis of thromboxane A2. Its mechanism of action involves irreversible inactivation of the enzyme cyclooxygenase (COX-1). This inhibitory effect is particularly pronounced in platelets, as they are unable to resynthesize this enzyme. It has also been noted that acetylsalicylic acid exerts other inhibitory effects on platelets. Due to these effects, it is used in the management of various vascular disorders.

Acetylsalicylic acid belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs) and has analgesic, antipyretic, and anti-inflammatory properties. When administered orally in higher doses, acetylsalicylic acid is used to relieve pain and mild febrile conditions such as colds and influenza, to reduce fever, and to alleviate joint and muscle pain. It is also used in acute and chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

Pharmacokinetics

After oral administration, acetylsalicylic acid is rapidly and completely absorbed from the gastrointestinal tract. During and after absorption, it is converted into its main active metabolite—salicylic acid. Maximum plasma concentration of acetylsalicylic acid is reached within 10–20 minutes, and that of salicylic acid within 20–120 minutes. Due to the enteric coating of Aspénorm 100 mg and 300 mg tablets, the release of the active substance occurs not in the stomach, but in the alkaline environment of the intestine. Therefore, absorption of acetylsalicylic acid is delayed to 3–6 hours after administration of the enteric-coated tablet, compared to a conventional acetylsalicylic acid tablet.

Acetylsalicylic acid and salicylic acid are completely bound to plasma proteins and rapidly distributed throughout the body. Salicylic acid crosses the placenta and is also excreted into breast milk.

Salicylic acid is metabolized primarily in the liver. Metabolites of salicylic acid include salicyluric acid, salicyl phenol glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid.

The elimination kinetics of salicylic acid are dose-dependent, as metabolism is limited by the activity of liver enzymes. The elimination half-life varies depending on the dose, increasing from 2–3 hours with low doses to 15 hours with high doses. Salicylic acid and its metabolites are primarily excreted from the body via the kidneys.

Preclinical Data

The preclinical safety profile of acetylsalicylic acid is well documented.

It is known that in animal studies, salicylates at high doses caused kidney damage without any other organic lesions.

Acetylsalicylic acid has been extensively studied for mutagenicity, but no evidence of mutagenic potential has been found. The same applies to carcinogenicity studies. It is also known that salicylates have teratogenic effects.

Impairments in implantation, embryotoxic and fetotoxic effects, as well as learning disabilities in offspring, have been reported following drug administration during the prenatal period.

Clinical characteristics.

Indications.

Prevention of thrombosis (prevention of reocclusion) after aortocoronary bypass grafting, percutaneous transluminal catheter angioplasty, and after arteriovenous shunting in patients undergoing dialysis.

Prevention of cerebrovascular stroke following transient ischemic attack (TIA).

Reduction of the risk of coronary thrombosis after myocardial infarction (prevention of recurrent infarction).

Prevention of myocardial infarction in combination with other therapeutic measures in patients at very high risk of cardiovascular events (based on benefit-risk assessment by the treating physician).

Unstable angina.

Prevention of arterial thrombosis following vascular surgery.

As part of standard therapy for acute myocardial infarction.

Prevention of vascular occlusion in arterial occlusive disease.

Contraindications.

Hypersensitivity to acetylsalicylic acid, other salicylates, or other anti-inflammatory agents, or to any component of the drug.

Asthma induced by salicylates or substances with similar action, especially NSAIDs, in medical history.

Acute peptic ulcers.

Hemorrhagic diathesis.

Severe renal failure.

Severe hepatic failure.

Severe congestive 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").

Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated.

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 by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates) (see section "Contraindications").

Combinations requiring caution.

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

Antidiabetic agents (e.g., insulin, sulfonylureas): possible reduction in blood glucose levels.

Potentiation of the effects of anticoagulants/thrombolytic agents, barbiturates, lithium, sulfonamides, and triiodothyronine.

Pharmacodynamic interactions may occur between selective serotonin reuptake inhibitors (SSRIs) and acetylsalicylic acid: increased risk of bleeding due to synergistic effects.

Increased plasma concentration of digoxin due to reduced renal excretion.

Elevated plasma levels of phenytoin and valproate. When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, reducing its metabolism. As a result, plasma valproate levels increase, leading to a higher incidence of adverse reactions related to intoxication symptoms such as tremor, nystagmus, ataxia, and personality changes.

Enhanced action and side effects of all non-steroidal anti-rheumatic agents.

Concomitant use with NSAIDs such as ibuprofen or naproxen may attenuate the irreversible inhibition of platelets by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with NSAIDs such as ibuprofen or naproxen in patients at risk of cardiovascular disease may reduce the cardioprotective effect of acetylsalicylic acid (see section "Special precautions").

Antihypertensive agents (ACE inhibitors and β-blockers): patients receiving Aspernorm and these medicinal products concomitantly should have their blood pressure carefully monitored and dosage adjusted if necessary.

Diuretics in combination with high doses of acetylsalicylic acid: reduced diuretic efficacy.

Reduced efficacy of uricosuric agents (e.g., probenecid, sulfinpyrazone).

Systemic glucocorticosteroids: increased risk of gastrointestinal ulcers and bleeding. Decreased blood levels of salicylates during corticosteroid therapy, risk of salicylate overdose after discontinuation of glucocorticoid treatment.

Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.

Prolonged plasma half-life of penicillin.

Concomitant use of metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, this combination should be used with caution in patients taking acetylsalicylic acid at low cardioprotective doses.

Special precautions for use.

Aspenorm should be used with caution in the following situations:

• Impaired renal function or cardiovascular disorders (e.g. renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), since acetylsalicylic acid may increase the risk of renal impairment and acute renal failure;
• Impaired liver function;
• Concomitant use of NSAIDs such as ibuprofen or naproxen, as NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Aspenorm is used, patients should consult their physician before starting NSAIDs for pain relief (see section "Interaction with other medicinal products and other forms of interaction");
• Presence of symptoms of chronic gastric or duodenal dyspepsia or its recurrence;
• Presence of bronchial asthma or general tendency to hypersensitivity, since acetylsalicylic acid may induce bronchospasm or an asthma attack, as well as other hypersensitivity reactions. Risk factors include history of asthma, hay fever, nasal polyps, chronic respiratory diseases, or allergic reactions (such as rash, itching, or urticaria) to other agents;
• Nasal polyps;
• Severe glucose-6-phosphate dehydrogenase deficiency, since acetylsalicylic acid may cause hemolysis or hemolytic anemia. Factors that may increase the risk of hemolysis include high drug doses, fever, or acute infectious illness;
• Concomitant use of anticoagulants;
• Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of products containing acetylsalicylic acid may increase the risk or severity of bleeding during surgical procedures (including minor surgeries such as tooth extraction);
• Use of acetylsalicylic acid in children and adolescents with fever and/or viral infections should only be done under medical supervision as second-line therapy (due to the risk of Reye's syndrome, a life-threatening encephalopathy characterized by severe vomiting, loss of consciousness, and hepatic dysfunction).

When used in low doses, ASA reduces uric acid excretion. In patients who normally have reduced uric acid excretion, this may lead to the development of gout.

Certain viral infections, particularly influenza A, influenza B, and varicella, are associated with 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 concomitantly, although a causal relationship has not been established. Persistent vomiting during these conditions may be a manifestation of Reye's syndrome;

• Gastrointestinal ulcers, including history of chronic or recurrent peptic ulcer disease or gastrointestinal bleeding;
• Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological studies suggest an increased risk of miscarriage and congenital heart defects and gastroschisis following the use of prostaglandin synthesis inhibitors during early pregnancy. The risk increases with higher doses and longer duration of treatment.

Epidemiological data do not confirm a link between the use of acetylsalicylic acid and an increased risk of miscarriage. Available data on miscarriage are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with acetylsalicylic acid use. Results from prospective studies on drug exposure during early pregnancy (months 1–4) in mother-child pairs do not indicate any association with an increased risk of malformations.

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

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

Based on previous experience, the risk is considered low when the drug is used at therapeutic doses.

All prostaglandin synthesis inhibitors may affect:

• the fetus:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • impaired renal function, potentially leading to renal failure with oligohydramnios;
• the mother and the fetus:
  • prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
  • inhibition of uterine contractions, bleeding in the pregnant woman, and prolonged duration of labor.

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

Breastfeeding. Salicylates pass into breast milk. Concentrations in breast milk are equivalent to or even higher than plasma concentrations in the mother.

If use is required during lactation, breastfeeding should be discontinued if high doses (> 300 mg/day) are used regularly.

Ability to affect reaction speed when driving or operating machinery.

There is no information available regarding the effect of the drug on the ability to drive or operate machinery.

Method of Administration and Dosage

Unless otherwise prescribed by a physician, the following dosage is recommended.

Cardiovascular indications without aortocoronary bypass surgery or percutaneous transluminal coronary angioplasty: 1 × 100 mg/day.

Prophylaxis of thrombosis after aortocoronary bypass surgery or percutaneous transluminal coronary angioplasty: 100–300 mg/day.

Prophylaxis of cerebrovascular stroke after transient ischemic attacks (TIA): 3 × 100 mg/day or 1 × 300 mg/day.

It is recommended to take the tablet with a small amount of liquid at least 30 minutes before food intake. Drink ½–1 glass of water. To prevent premature release of the active ingredient before reaching the alkaline environment of the intestine, the tablets must not be crushed, split, or chewed.

Acute myocardial infarction: In case of acute myocardial infarction, administer 200–300 mg of acetylsalicylic acid either intravenously or orally in a rapidly dissolving form (not enteric-coated). Enteric-coated acetylsalicylic acid tablets should be crushed or chewed before administration to achieve faster absorption. Thereafter, 100 mg of Aspenorm should be administered daily.

Children.

Aspenorm is not used in children and adolescents (under 18 years of age) due to lack of data on efficacy and safety in this patient group.

Administration of acetylsalicylic acid to children under 16 years of age may cause serious adverse effects (including Reye's syndrome, one of the signs of which is persistent vomiting). Please refer to the information provided in the section "Special precautions for use."

Overdose.

Severe intoxication may be life-threatening. Newborns are more sensitive than adults. Symptoms of severe poisoning may develop acutely or gradually, for example, within 12–24 hours after administration. After oral administration of a dose of ASA up to 150 mg/kg body weight, moderate intoxication may occur; with doses > 300 mg/kg body weight, severe intoxication may occur.

Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of concretions in the stomach, or when the drug is taken in the form of enteric-coated tablets.

The severity of the condition cannot be assessed solely based on plasma salicylate concentration. Arterial blood gas analysis (ABGA) must be carefully monitored, as therapy is based not on blood salicylate levels, but on clinical symptoms and ABGA.

Warning.

Local signs of irritation, which are typically predominant in ASA overdose, such as nausea, vomiting, and stomach pain, may be absent because this pharmaceutical form of ASA has an enteric coating and absorption occurs only in the small intestine.

Symptoms.

Headache, nausea, hypoglycemia or hyperglycemia, skin rash, dizziness, tinnitus, visual and hearing disturbances, tremor, confusion, hyperthermia, increased sweating, hyperventilation, respiratory alkalosis with metabolic compensation leading to metabolic acidosis, electrolyte imbalance, dehydration, seizures, coma, respiratory distress syndrome, cardiac arrhythmia.

Symptoms of chronic salicylate poisoning are nonspecific (e.g., tinnitus, headache, irritability, increased sweating, hyperventilation) and may therefore remain unnoticed.

Therapy.

Due to life-threatening conditions caused by severe intoxication, all necessary preventive measures should be taken immediately: immediate hospitalization, prevention or reduction of resorption by administering appropriate doses of activated charcoal within the first 4 hours (activated charcoal in a 10-fold amount relative to the mass of ASA); in cases of severe intoxication—gastric lavage or endoscopic removal of tablets.

Appropriate monitoring and correction of electrolytes. Administration of glucose and sodium bicarbonate in the early stages to correct acidosis and enhance elimination (urine pH > 8), improvement of diuresis, cooling in case of hyperthermia, benzodiazepines for seizures.

Hemodialysis may be considered in cases of severe intoxication.

Cases of decompensation leading to fatal outcomes after intubation have been reported. Therefore, if possible, intubation should be performed after initiation of alkalization, apnea time should be minimized, and support of hyperventilation should be maintained.

Detailed information can be obtained from a toxicology center.

Side effects

Within each group, adverse reactions are listed in decreasing order of severity: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000.

Spontaneous reports of other adverse reactions have been received for all dosage forms of acetylsalicylic acid, including oral short-term and long-term therapy; therefore, classification by frequency categories is not possible.

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

Due to the antiplatelet effect, the use of acetylsalicylic acid (ASA) may increase the risk of bleeding. Bleeding events such as perioperative bleeding, hematoma, epistaxis, urogenital bleeding, and gingival bleeding have been observed.

Serious bleeding events, such as gastrointestinal bleeding and hemorrhagic stroke, have been observed rarely or very rarely, especially in patients with uncontrolled arterial hypertension and/or concomitant use of anticoagulants, which in some cases may potentially be life-threatening.

Blood and lymphatic system disorders:

Prolongation of bleeding time;

Rare: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia.

Immune system disorders:

Uncommon: asthma;

Rare: hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioneurotic edema, hypotension progressing to shock;

Very rare: severe skin reactions including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Metabolism and nutrition disorders:

Very rare: hypoglycemia, acid-base imbalance.

Nervous system disorders:

Rare: headache, dizziness, tinnitus, visual disturbances, hearing disturbances, confusion.

Gastrointestinal disorders:

Very common: microbleeding (70%);

Common: gastric symptoms;

Uncommon: dyspepsia, nausea, vomiting, diarrhea;

Rare: gastrointestinal bleeding, gastrointestinal ulcers, which in very rare cases may lead to perforation.

Hepatobiliary disorders:

Rare: hepatic dysfunction;

Very rare: increased transaminase levels.

Renal and urinary disorders:

Rare: impaired renal function;

Cases of acute renal failure have been reported.

Other:

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

Bleeding 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, hypoperfusion.

Gastrointestinal disorders such as general symptoms and signs of dyspepsia, epigastric and abdominal pain; in individual cases, inflammation of the gastrointestinal tract, erosive-ulcerative lesions of the gastrointestinal tract, which may potentially in rare instances lead to gastrointestinal hemorrhage and perforation, with corresponding laboratory and clinical manifestations.

Hypersensitivity reactions with corresponding laboratory and clinical manifestations include asthmatic state, mild to moderate skin reactions, and reactions affecting the respiratory, gastrointestinal, and cardiovascular systems, including symptoms such as rash, swelling, pruritus, cardiorespiratory failure, and very rarely, severe reactions including anaphylactic shock.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

Tablets 100 mg: 10 tablets in a blister, 2 or 10 blisters in a cardboard pack.

Tablets 300 mg: 10 tablets in a blister, 2 blisters in a cardboard pack.

Prescription status. Over-the-counter.

Manufacturer.

LLC "FARMEX GROUP".

Manufacturer's address and location of business activity.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.