Acelyzin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACELISIN (ACELYSIN)

Composition:

Active substance: sterile acelisine;

1 vial contains sterile acelisine – 1 g;

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline white odourless powder or with a faint specific odour.

Pharmacotherapeutic group. Other analgesics and antipyretics. Salicylic acid and its derivatives. ATC code N02B A01.

Pharmacological Properties.

Pharmacodynamics.

Acelysin is an injectable form of acetylsalicylic acid possessing its characteristic properties, as well as enhancing its bioavailability and analgesic effect. It has analgesic, anti-inflammatory, antipyretic, and antiplatelet (antithrombotic) actions.

The drug inhibits cyclooxygenase, thereby suppressing the synthesis of prostaglandins and the formation of thromboxane A2 in platelets. The ability of platelets and erythrocytes to aggregate and adhere (adhesion) to the vascular endothelium is reduced. By decreasing the surface tension of erythrocyte membranes, the drug facilitates their deformation during passage through capillaries and improves blood flow.

Pharmacokinetics.

The drug is 80–90% bound to plasma proteins. It penetrates into most tissues of the body, including synovial, cerebrospinal, and peritoneal fluids. In the blood, it undergoes hydrolysis, forming acetylsalicylic acid and lysine. In the liver, acetylsalicylic acid is converted into salicylic acid. The half-life of acetylsalicylic acid is 15–20 minutes; that of salicylic acid and its active metabolites ranges from 3–6 hours (low doses) to 15–30 hours (high doses). The drug is excreted primarily by the kidneys, mainly in unchanged form (60%) and as metabolites.

Clinical characteristics.

Indications.

• Pain of various origins (headache, earache, toothache, postoperative pain, as well as myalgia, arthralgia, neuralgia, neuritis, colic-like pain, and pain associated with rheumatic diseases);
• Fever;
• Superficial venous thrombophlebitis;
• Prevention and treatment of postoperative thrombosis and embolism.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the drug.
• Bronchial asthma or angioneurotic edema induced by salicylates or substances with similar action, particularly NSAIDs, in medical history.
• Active peptic ulcers or recurrent peptic ulcers, including in medical history, and/or gastrointestinal/colonic bleeding or other types of hemorrhage, such as cerebrovascular.
• Hemorrhagic diathesis, coagulation disorders such as hemophilia and thrombocytopenia.
• Severe renal impairment (glomerular filtration rate <30 mL/h).
• Severe hepatic impairment, liver cirrhosis.
• Severe heart failure.
• Combination with methotrexate at doses of 15 mg/week or higher.
• Combination of acetylsalicylic acid in anti-inflammatory/antipyretic/analgesic doses with oral anticoagulants in patients with a history of gastroduodenal ulcer.
• Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

• 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 by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).
• Concomitant use of acetylsalicylic acid in anti-inflammatory/antipyretic/analgesic doses with oral anticoagulants in patients with a history of gastroduodenal ulcers: increased risk of bleeding.

Not recommended combinations.

• Concomitant use of acetylsalicylic acid in anti-inflammatory/antipyretic/analgesic doses with oral anticoagulants in patients without a history of gastroduodenal ulcers: increased risk of bleeding.
• Concomitant use of acetylsalicylic acid in antiplatelet doses with oral anticoagulants in patients with a history of gastroduodenal ulcers: increased risk of bleeding.
• Concomitant use with low-molecular-weight heparin or unfractionated heparin in elderly patients (over 65 years of age), regardless of heparin dose and anti-inflammatory/antipyretic/analgesic doses of acetylsalicylic acid.
• Concomitant use with clopidogrel (unless the combination is specifically indicated in patients with acute coronary syndrome).
• Concomitant use with ticlopidine, uricosuric agents.
• Concomitant use with glucocorticoids (except for replacement therapy) at anti-inflammatory doses of acetylsalicylic acid.
• Concomitant use with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance between 45 mL/min and 80 mL/min): increased risk of pemetrexed toxicity.
• Uricosuric agents (such as probenecid, sulfinpyrazone): concomitant use of salicylates with probenecid reduces uric acid excretion (due to competition for renal tubular excretion of uric acid). Acetylsalicylic acid reduces uric acid excretion even at low doses. This may provoke gout development in patients with impaired uric acid excretion. Therefore, such combination should be avoided.

Combinations requiring caution.

• Concomitant use of acetylsalicylic acid and methotrexate at doses less than 15 mg/week increases 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).
• Concomitant use of acetylsalicylic acid and ibuprofen interferes with irreversible platelet inhibition by acetylsalicylic acid. Treatment with ibuprofen in patients at risk of cardiovascular disease may reduce the cardioprotective effect of acetylsalicylic acid.
• Concomitant use of acetylsalicylic acid with anticoagulants, thrombolytics/other platelet aggregation inhibitors/hemostatic agents increases the risk of bleeding.
• Concomitant use of high-dose salicylates with NSAIDs (due to additive effects) increases the risk of gastrointestinal tract ulcers and gastrointestinal bleeding.
• Concomitant use with selective serotonin reuptake inhibitors (including citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) increases the risk of gastrointestinal bleeding due to possible synergistic effects.
• Digoxin and lithium: concomitant use with acetylsalicylic acid increases their plasma concentrations due to reduced renal excretion. Monitoring of plasma concentrations of digoxin and lithium is recommended at the beginning and throughout the treatment period with acetylsalicylic acid. Dose adjustment may be necessary.
• 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 cardioprotective agent) concomitantly with metamizole.
• Concomitant use of high-dose acetylsalicylic acid and sulfonylurea antidiabetic agents enhances the hypoglycemic effect of the latter due to displacement of sulfonylurea from plasma protein binding by acetylsalicylic acid.
• Diuretics combined with high-dose acetylsalicylic acid reduce glomerular filtration due to decreased renal prostaglandin synthesis.
• Systemic glucocorticosteroids (except hydrocortisone used for replacement therapy in Addison's disease) reduce blood salicylate levels. Concomitant use with corticosteroids increases the risk of gastrointestinal bleeding.
• ACE inhibitors combined with high-dose acetylsalicylic acid lead to reduced glomerular filtration due to inhibition of vasodilatory prostaglandin effects and also reduce antihypertensive efficacy.
• Concomitant use with valproic acid: acetylsalicylic acid displaces valproic acid from plasma protein binding, increasing its toxicity.
• Alcohol promotes gastrointestinal mucosal damage and prolongs bleeding time due to synergistic action with acetylsalicylic acid.
• Concomitant use of diuretics, ACE inhibitors, angiotensin II receptor antagonists with anti-inflammatory/antipyretic/analgesic doses of acetylsalicylic acid: risk of acute renal failure. At the beginning of treatment, ensure the patient is not dehydrated and monitor renal function regularly.
• Concomitant use with clopidogrel (according to approved indications for this combination in patients with acute coronary syndrome). Clinical monitoring is required if simultaneous use is necessary.
• Concomitant use with pemetrexed in patients with normal renal function.
• Concomitant use with low-molecular-weight heparin or unfractionated heparin in patients under 65 years of age.
• Concomitant use with thrombolytics.
• Concomitant use with oral anticoagulants in antiplatelet doses.
• Concomitant use with other nonsteroidal anti-inflammatory drugs in antiplatelet doses.
• Concomitant use with glucocorticosteroids (except for replacement therapy) at analgesic/antipyretic doses.
• Carbonic anhydrase inhibitors (acetazolamide): may cause severe cases of acidosis and increased neurotoxicity.
• Cyclosporine, tacrolimus: concomitant use of NSAIDs with cyclosporine or tacrolimus may increase the nephrotoxic effects of the latter. Renal function should be monitored when using this combination.
• Sulfonamides and triiodothyronine: enhanced effects of sulfonamides and triiodothyronine.
• Penicillin: prolonged plasma half-life of penicillin.
• Phenytoin: salicylates reduce phenytoin binding to plasma albumin. This may lead to decreased total phenytoin levels in plasma and increased fraction of free phenytoin. However, the concentration of unbound phenytoin and thus the therapeutic effect remain essentially unchanged.

Special precautions for use.

Acetylsalicylic acid should be used with caution in the following situations:

• Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as in the presence of allergy to other substances;
• Gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding in medical history;
• Concomitant use of anticoagulants;
• Impaired kidney function or cardiovascular circulation 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 dysfunction and development of acute kidney injury;
• Severe glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia, particularly in the presence of risk factors such as high drug doses, fever, or acute infection;
• Impaired liver function.

The medicinal product should be used with caution in patients with moderate hepatic insufficiency (severe degree is contraindicated) and in patients with liver disease. Patients with mild or moderate hepatic insufficiency should undergo regular liver function tests.

Regular use of acetylsalicylic acid may worsen the prognosis in patients with intracerebral hemorrhage. Therefore, patients at increased risk of intracerebral hemorrhage, such as those with high arterial blood pressure, should be closely monitored during acetylsalicylic acid therapy. An increased risk of intracerebral hemorrhage has also been observed in patients with a tendency to nosebleeds during acetylsalicylic acid use.

If prolonged vomiting, loss of consciousness, or abnormal behavior occurs during treatment with acetylsalicylic acid, administration should be discontinued.

Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation.

If Acelysin is used, patients should consult their physician before starting ibuprofen as an analgesic.

Acetylsalicylic acid may cause bronchospasm, asthma attacks, or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory diseases, and allergic reactions (e.g., skin reactions, pruritus, urticaria) to other substances. Rarely, serious skin reactions including Stevens-Johnson syndrome have been reported with acetylsalicylic acid use (see section "Adverse reactions"). Treatment with acetylsalicylic acid should be discontinued at the first signs of skin rash, mucosal lesions, or other symptoms of hypersensitivity.

The medicinal product should be used with caution in patients with hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as in patients with allergy to other substances.

Acetylsalicylic acid may cause Reye's syndrome in some children. Reye's syndrome may occur when acetylsalicylic acid-containing products are used in children with acute viral respiratory infection (AVRI), with or without fever, without prior medical consultation. Certain viral diseases, 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 indicate Reye's syndrome. The medicinal product is not recommended for use in children.

Due to acetylsalicylic acid’s ability to inhibit platelet aggregation, which persists for several days after administration, the use of acetylsalicylic acid-containing products may increase the risk or severity of bleeding during surgical procedures (including minor surgeries such as tooth extraction). Therefore, caution is required before any surgical intervention, including dental procedures. Temporary discontinuation of therapy may be necessary.

Acetylsalicylic acid is not recommended in cases of menorrhagia, as it may exacerbate menstrual bleeding.

Use with caution in patients with a history of gastritis, metrorrhagia, and/or menorrhagia.

When low doses of acetylsalicylic acid are used, urinary excretion of uric acid may be reduced. This may trigger gout attacks in predisposed patients.
Regular use of analgesics may lead to persistent kidney damage (with risk of kidney failure).

Gastrointestinal bleeding, ulcers, or perforations may occur at any time during treatment with the drug, even in the absence of prior history. The relative risk is increased in elderly patients, patients with low body weight, and those receiving anticoagulants or platelet aggregation inhibitors. If gastrointestinal bleeding occurs, treatment must be discontinued immediately.

When high anti-inflammatory doses are used in rheumatology, possible signs of overdose should be monitored. If hearing disturbances, tinnitus, or dizziness occur, treatment should be reassessed.

Acetylsalicylic acid may impair fertility in women and is not recommended for women planning pregnancy. For women experiencing difficulty conceiving or undergoing fertility evaluation, discontinuation of acetylsalicylic acid therapy should be considered.

Use during pregnancy or breastfeeding.

Salicylates should be used with caution during the first and second trimesters of pregnancy. Use of salicylates is contraindicated during the third trimester of pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Data suggest a possible risk of miscarriage and fetal malformations (cardiac defects and gastroschisis) following use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of therapy.

Data on developmental abnormalities are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with acetylsalicylic acid use. Results from prospective studies on exposure during early pregnancy (1st–4th months) do not indicate any association with increased risk of malformations.

During the first and second trimesters of pregnancy, acetylsalicylic acid-containing products 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 products should be as low as possible and the duration of treatment as short as possible.

Cases of implantation disorders, embryotoxic and fetotoxic effects, and effects on the child's learning ability have been reported following prenatal use of salicylates.

Animal studies indicate that salicylate use may cause adverse effects in the fetus (e.g., increased mortality, growth disturbances, salicylate intoxication); however, no controlled studies in pregnant women have been conducted.

Based on prior experience, the risk is considered 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:

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

Towards the end of pregnancy, all prostaglandin synthesis inhibitors may affect the mother and fetus as follows:

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

Due to the above, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Breastfeeding

Salicylates are excreted into breast milk. Concentrations in breast milk are equivalent to or even higher than those in maternal plasma.

In cases of medically required use 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.

No effects on the ability to drive a vehicle or operate machinery have been reported.

Administration and Dosage

Administer as prescribed and under medical supervision.

Acelizin is administered intramuscularly (deeply) and intravenously. For intramuscular administration, the contents of the vial should be dissolved immediately before use: 1 g (1 vial) in 5 mL of water for injections, shaking until the powder is completely dissolved.

For thrombosis prophylaxis, administer Acelizin intramuscularly (deeply) at a dose of 0.5–3 mL of solution once daily or every other day. The treatment course consists of up to 5 injections. Thereafter, if necessary, transition to oral forms of acetylsalicylic acid may be considered.

The single dose and frequency of repeated injections should be determined based on the dynamics of laboratory coagulation parameters following the first administration of Acelizin.

For intravenous administration of Acelizin in thrombosis prophylaxis, slow infusion is preferred. Before use, dissolve 1 g (1 vial) in 5 mL of water for injections, shaking until the powder is completely dissolved. Then dilute the prepared solution in 150–200 mL of 5% glucose solution or 0.9% sodium chloride solution and administer at a rate of 1 mL/minute.

For patients with moderate pain, fever, rheumatic disorders, or neuritis, a single dose of 1 g of Acelizin is recommended. In cases of severe pain or colicky pain, the single dose may be increased to 2 g. When Acelizin is administered repeatedly, the daily dose should not exceed 10 g.

The treatment course lasts 3–10 days.

Children. Injectable forms of acetylsalicylic acid are not indicated for use in children. Administration of acetylsalicylic acid to children may cause severe adverse effects (see section "Special Instructions").

Overdose.

Salicylate overdose may occur due to chronic intoxication resulting from prolonged therapy (administration exceeding 100 mg/kg/day for more than 2 days may cause toxic effects), or due to acute, life-threatening intoxication (overdose), which may result, for example, from accidental ingestion by children or unintentional overdose.

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

Symptoms. Disturbances in equilibrium, dizziness, tinnitus, hearing loss, excessive sweating, nausea and vomiting, headache, confusion. These symptoms are dose-dependent. Tinnitus may occur at plasma salicylate concentrations exceeding 150–300 mcg/mL. Serious adverse reactions occur at plasma salicylate concentrations exceeding 300 mcg/mL. In severe poisoning: hyperthermia, ketosis, respiratory alkalosis, metabolic acidosis, coma, cardiovascular collapse, respiratory failure, severe hypoglycemia, and severe hypokalemia.

Acute intoxication is characterized by marked disturbances in acid-base balance, which may vary depending on age and severity of intoxication. The severity of the condition cannot be determined solely based on plasma salicylate concentration.

Treatment. Management of intoxication caused by acetylsalicylic acid overdose depends on the severity and clinical symptoms and follows standard procedures used in poisoning cases. All measures should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Activated charcoal and forced alkaline diuresis are employed. Depending on the acid-base and electrolyte status, intravenous electrolyte solutions are administered. Hemodialysis is indicated in severe cases of intoxication.

Adverse Reactions

Adverse reactions are listed by system organ classes and frequency (very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). The following adverse reactions may occur during treatment with Acelysin:

Gastrointestinal disorders:

• Common: microbleeding (70%), gastric symptoms, abdominal pain, heartburn, esophagitis;
• Uncommon: dyspepsia, nausea, vomiting, diarrhea;
• Rare: erosive and ulcerative lesions of the gastrointestinal tract, which may lead to bleeding; gastrointestinal ulcers, which in very rare cases may result in perforation, with corresponding clinical symptoms and laboratory abnormalities.

Hepatobiliary disorders:

• Rare: hepatic dysfunction (e.g., elevated transaminase levels);
• Frequency not known: hepatic failure.

Blood and lymphatic system disorders:

• Rare: thrombocytopenia, post-hemorrhagic iron-deficiency anemia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, prolonged bleeding time.

Vascular disorders:

• Hemorrhagic vasculitis.

Immune system disorders:

• Uncommon: asthma;
• Rare: hypersensitivity reactions such as erythematous/eczematous skin reactions, pruritus, urticaria, bronchospasm, angioneurotic edema, allergic edema, anaphylactic reactions, hypotension progressing to shock.

Metabolism and nutrition disorders:

• Rare: hypoglycemia, acid-base imbalance;
• Frequency not known: hyperuricemia.

Respiratory system disorders:

• Frequency not known: nasal congestion, rhinitis, pulmonary edema, dyspnea.

Ear and labyrinth disorders:

• Frequency not known: reversible disturbances – tinnitus, hearing loss.

Nervous system disorders:

• Frequency not known: headache, dizziness, vertigo, tinnitus, visual disturbances, confusion.

Reproductive system and breast disorders:

• Rare: menorrhagia.

Skin and subcutaneous tissue disorders:

• Rare: purpura, nodular erythema.

Renal and urinary disorders:

• Frequency not known: impaired renal function and development of acute renal failure.

Other:

• Rare: acute renal failure, reversible impairment of renal and hepatic function, possible development of hepatotoxicity, Reye's syndrome, injection site reactions including pain.

Additional adverse reactions have been reported in spontaneous reports with all dosage forms of acetylsalicylic acid; however, the frequency of these reactions cannot be determined from the available data.

Due to the antiplatelet effect of acetylsalicylic acid, there is an associated risk of bleeding and prolonged bleeding time. Bleeding events observed include perioperative hemorrhage, hematoma, genitourinary tract bleeding, epistaxis, gingival bleeding, and purpura. Symptoms may persist for 4–8 days after discontinuation of acetylsalicylic acid. Serious bleeding events, such as cerebral hemorrhage (particularly in patients with uncontrolled hypertension and/or concomitant use of anticoagulants), have been reported and may, in rare cases, be potentially life-threatening.

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, and hypoperfusion.

Hemolysis or hemolytic anemia has been observed in patients with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature of 2 °C to 8 °C. Keep out of reach of children.

Packaging. 1 g in vials, 10 vials per carton; 1 g in vials.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's name and address of the place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.