INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LОSPİRIN® (LOWSPIRIN®)

Composition:

Active substance: acetylsalicylic acid;

One tablet contains 75 mg of acetylsalicylic acid;

Excipients: microcrystalline cellulose, pregelatinized starch, colloidal anhydrous silicon dioxide, stearic acid, Opadry Y-1-7000 white, Acryl-Eze 93O18359 white.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: white, round, biconvex, coated tablets.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01AC06.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid 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 the enzyme.

Acetylsalicylic acid exerts other inhibitory effects on platelets as well. Due to these effects, it can be used in the management of various vascular disorders.

Acetylsalicylic acid belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic, and anti-inflammatory properties.

Orally administered in higher doses, acetylsalicylic acid can be used to relieve pain and mild febrile conditions such as cold and flu, to reduce fever, and to alleviate joint and muscle pain, as well as in acute and chronic inflammatory disorders 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 of salicylic acid within 20–120 minutes, respectively. Due to the enteric coating of Lospinin® tablets, the active substance is released 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 predominantly in the liver. Metabolites of salicylic acid include salicyluric acid, phenolic and acyl glucuronides, 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 depends 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 by the kidneys.

Clinical characteristics.

Indications.

To reduce the risk of:

fatal outcomes in patients with suspected acute myocardial infarction;
morbidity and mortality in patients who have experienced myocardial infarction;
transient ischemic attacks (TIA) and stroke in patients with TIA;
morbidity and mortality in stable and unstable angina;
myocardial infarction in patients at high risk of cardiovascular complications (diabetes mellitus, controlled arterial hypertension) and individuals with multifactorial risk of cardiovascular diseases (hyperlipidemia, obesity, smoking, advanced age).

For prophylaxis of:

thrombosis and embolism following vascular surgery (percutaneous transluminal angioplasty, carotid endarterectomy, aortocoronary bypass, arteriovenous shunting);
deep vein thrombosis and pulmonary artery embolism following prolonged immobilization (after surgical procedures).

For secondary prevention of strokes.

Contraindications.

Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the drug.
History of asthma induced by salicylates or substances with similar action, especially NSAIDs.
Hemorrhagic diathesis.
Acute peptic ulcers.
Severe renal failure.
Severe hepatic failure.
Severe heart failure.
Gout.
Combination with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other types of interactions").
Age under 18 years. Acetylsalicylic acid may cause Reye's syndrome.
Third trimester of pregnancy.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations for concomitant use.

Methotrexate (at doses of 15 mg/week and higher):

Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg/week and higher increases hematological toxicity of methotrexate (due to decreased renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

Not recommended combinations for concomitant use.

Uricosuric agents (benzbromarone, probenecid)

Salicylates reduce the therapeutic efficacy of uricosuric agents in uric acid excretion. This may provoke gout development in patients with reduced uric acid excretion. Concomitant use of acetylsalicylic acid and uricosuric agents should be avoided.

Combinations requiring caution during use.

Anticoagulants, thrombolytics/other platelet aggregation inhibitors/hemostatic agents.

Concomitant use of acetylsalicylic acid with anticoagulants, thrombolytics/other platelet aggregation inhibitors/hemostatic agents enhances their effects and increases the risk of bleeding.

Selective serotonin reuptake inhibitors (SSRIs).

When used with selective serotonin reuptake inhibitors, the risk of gastrointestinal bleeding increases due to possible synergistic effects.

Oral antidiabetic agents.

Salicylates may enhance the hypoglycemic effect of oral antidiabetic agents, including sulfonylurea derivatives.

Barbiturates, sulfonamides, triiodothyronine.

Acetylsalicylic acid may potentiate their effects.

Digoxin/lithium.

Concomitant use of acetylsalicylic acid with digoxin/lithium increases their plasma concentrations due to reduced renal excretion. Monitoring of plasma concentrations of digoxin/lithium is recommended at the beginning and upon discontinuation of acetylsalicylic acid treatment, as dose adjustment may be necessary.

Diuretics and antihypertensive agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, may reduce the antihypertensive effect of diuretics and other antihypertensive agents. Concomitant use of NSAIDs with angiotensin-converting enzyme (ACE) inhibitors increases the risk of acute renal failure. Patients receiving acetylsalicylic acid together with these medicinal products should have their blood pressure carefully monitored and dose adjustments made if necessary.

Diuretic agents.

Concomitant use of acetylsalicylic acid with diuretics may lead to acute renal failure due to reduced glomerular filtration caused by decreased prostaglandin synthesis. Patient hydration and monitoring of kidney function at the start of therapy are recommended.

Carbonic anhydrase inhibitors (acetazolamide).

Concomitant use of carbonic anhydrase inhibitors with acetylsalicylic acid may result in severe acidosis and increased central nervous system toxicity.

Systemic corticosteroids.

Concomitant use of acetylsalicylic acid and systemic corticosteroids may increase the risk of gastrointestinal ulceration and bleeding.

Methotrexate at doses less than 15 mg/week.

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). Weekly blood count monitoring is required during the first weeks of treatment. Close monitoring is recommended for patients with impaired renal function, even if mild, and for elderly patients.

Other NSAIDs.

Concomitant use of acetylsalicylic acid and other NSAIDs may enhance their effects and adverse reactions. The risk of gastrointestinal ulceration and bleeding increases.

Ibuprofen.

Concomitant use with ibuprofen interferes with irreversible platelet inhibition by acetylsalicylic acid. Treatment with ibuprofen in patients at risk of cardiovascular diseases may reduce the cardioprotective effect of acetylsalicylic acid (see section "Special precautions for use").

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.

Antacids.

Concomitant use of acetylsalicylic acid with antacids may enhance its excretion (due to increased urine pH).

Antiepileptic agents (phenytoin, valproate).

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

Penicillin.

Prolongation of penicillin plasma half-life.

Alcohol.

Concomitant use of acetylsalicylic acid with alcohol may increase the risk of gastrointestinal ulceration and bleeding.

Special precautions for use.

Acetylsalicylic acid at a dose of 75 mg is not intended for use as an anti-inflammatory/analgesic/antipyretic agent.

Recommended for use in adults. The drug is contraindicated in patients under 18 years of age due to the risk of Reye's syndrome (see sections "Contraindications" and "Children").

Reye's syndrome

Reye's syndrome may occur when acetylsalicylic acid-containing drugs are administered to children with acute viral respiratory infections (AVRI), with or without fever, without prior medical consultation. Certain viral diseases, particularly influenza A, influenza B, and varicella, are associated with an increased 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 accompanying these conditions may be indicative of Reye's syndrome.

The drug should be used with caution in the following situations:

Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, or presence of allergy to other substances;
Nasal polyps;
Presence of symptoms of chronic gastric or duodenal dyspepsia or its recurrence;
Gastrointestinal ulcers, including history of chronic or recurrent peptic ulcer disease or gastrointestinal bleeding;
Arterial hypertension;
Concomitant use of anticoagulants;
In patients with impaired renal function or cardiovascular disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of renal dysfunction and acute renal failure;
In patients with severe glucose-6-phosphate dehydrogenase deficiency, 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.

ibuprofen

Ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). If ibuprofen is to be used as an analgesic after starting treatment with Lospyrin, patients should consult their physician.

Hypersensitivity

Acetylsalicylic acid may cause hypersensitivity reactions, including bronchospasm/asthma attack or other reactions. Risk factors for hypersensitivity reactions to acetylsalicylic acid include a history of asthma, hay fever, nasal polyps, chronic respiratory disease, or allergic reactions (e.g., skin reactions, pruritus, urticaria) to other substances. The drug should be used with caution in patients with hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, or in those with allergies to other substances.

The drug should be discontinued at the first signs of hypersensitivity reactions (e.g., skin rash, mucosal lesions).

Serious skin adverse reactions

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

Risk of occurrence or exacerbation of bleeding during surgical procedures

The antiplatelet effect of acetylsalicylic acid persists for several days after administration, potentially increasing the risk of bleeding or worsening hemorrhage during surgical procedures (including minor procedures such as tooth extraction). Temporary discontinuation of the drug may be necessary.

Gastrointestinal bleeding/ulcers

Patients should inform their physician of any unusual bleeding symptoms. If gastrointestinal bleeding or ulceration occurs, treatment should be discontinued.

Menorrhagia

Acetylsalicylic acid is not recommended for women with menorrhagia (during menstruation), as it may increase menstrual blood loss.

Impaired renal or hepatic function

Acetylsalicylic acid should be used with caution in patients with moderate impairment of renal or hepatic function (contraindicated in severe cases) or in patients showing signs of dehydration, as NSAID use may worsen renal function. In patients with mild to moderate hepatic insufficiency, liver function tests should be monitored.

Elderly patients

Elderly patients are particularly susceptible to adverse effects of NSAIDs, including acetylsalicylic acid, especially gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration"). Patients undergoing long-term acetylsalicylic acid therapy should be regularly monitored.

Gout

Small doses of acetylsalicylic acid may reduce uric acid excretion, potentially triggering gout attacks in predisposed patients. Acetylsalicylic acid is contraindicated in patients with gout (see section "Contraindications").

Medicinal products affecting hemostasis

Due to increased bleeding risk, concomitant use of acetylsalicylic acid with other agents affecting hemostasis (e.g., anticoagulants such as warfarin, thrombolytics, antiplatelet agents, anti-inflammatory drugs, selective serotonin reuptake inhibitors) is not recommended, except when such combination is absolutely necessary (see section "Interaction with other medicinal products and other forms of interaction"). Close monitoring for signs of bleeding is advised if such combination is used.

Ulcerogenic effect

Caution is advised when acetylsalicylic acid is used concomitantly with oral corticosteroids, selective serotonin reuptake inhibitors, or deferasirox due to increased risk of ulcerogenic effects (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia

Acetylsalicylic acid, when used in high doses, may potentiate the hypoglycemic effect of sulfonylureas and insulin, increasing the risk of hypoglycemia (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy

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. Epidemiological data indicate an increased risk of miscarriage and congenital malformations (cardiac defects and gastroschisis) following use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of treatment. However, current data do not confirm a causal link between acetylsalicylic acid use and increased risk of miscarriage.

Available epidemiological data on congenital malformations are inconsistent, but an increased risk of gastroschisis cannot be ruled out with acetylsalicylic acid use. Results from a prospective study on early pregnancy exposure (1st–4th month) involving approximately 14,800 mother-child pairs did not indicate any association with increased risk of malformations.

Animal studies have shown reproductive toxicity.

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

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

Animal studies indicate adverse fetal effects (e.g., increased mortality, growth disturbances, salicylate intoxication) with salicylate use, although controlled studies in pregnant women have not been conducted.

Based on prior experience, the risk is considered 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:

Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
Renal dysfunction, potentially leading to renal failure with oligohydramnios;

the mother and neonate at the end of pregnancy as follows:

Prolonged bleeding time, antiplatelet effect, which may occur even after very low doses;
Inhibition of uterine contractions, potentially leading 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. Concentrations in breast milk are equivalent to or even higher than those in maternal plasma. In cases of unavoidable use during lactation, breastfeeding should be discontinued if high doses (> 300 mg/day) are used regularly.

Ability to influence reaction speed when driving or operating machinery

No studies have been conducted.

Dosage and Administration.

Take the medication orally, 30–60 minutes before meals, without chewing, with sufficient amount of liquid.

Indications	Daily dose	Number of doses per day	Dosing frequency
Reduction of mortality risk in patients with suspected acute myocardial infarction*	75 – 300 mg	1 time	daily
Reduction of morbidity and mortality risk in patients who have had myocardial infarction	75 – 300 mg	1 time	daily
Secondary prevention of stroke	75 – 300 mg	1 time	daily
Reduction of risk of transient ischemic attacks (TIA) and stroke in patients with TIA	75 – 300 mg	1 time	daily
Reduction of risk of disease and mortality in patients with stable and unstable angina pectoris	75 – 300 mg	1 time	daily
Prophylaxis of deep vein thrombosis and pulmonary embolism after prolonged immobilization (post-surgical) – 100–200 mg daily or 300 mg every other day.	75 – 150 mg	1 time	daily
	300 mg	1 time	every other day
Prophylaxis of thromboembolic events following vascular procedures (percutaneous transluminal angioplasty, carotid endarterectomy, aortocoronary bypass, arteriovenous shunting)**	75 – 150 mg	1 time	daily
	300 mg	1 time	every other day
Prevention of myocardial infarction in patients at high risk of cardiovascular complications (diabetes mellitus, controlled arterial hypertension) and individuals with multifactorial cardiovascular risk (hyperlipidemia, obesity, smoking, advanced age)**	75 – 150 mg	1 time	daily
	300 mg	1 time	every other day

* - For 30 days after myocardial infarction, continue taking the maintenance dose of 75–300 mg per day. After 30 days, consider further prevention of myocardial infarction recurrence. The initial dose should be chewed to achieve rapid absorption.

** - use one of the treatment regimens.

Geriatric patients

In general, acetylsalicylic acid should be used with caution in elderly patients, who are more prone to adverse reactions (see section "Special instructions"). In the absence of severe renal or hepatic impairment, the usual adult dose is recommended. Treatment should be reviewed at regular intervals.

Children.

According to indications (see section "Indications"), the drug Lospirin® should not be administered to children.

Administration of acetylsalicylic acid to children under 18 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 instructions".

Overdose.

Symptoms of severe poisoning may develop slowly, 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 is possible, and when a dose > 300 mg/kg body weight is administered, severe intoxication may occur.

Chronic salicylate poisoning may have a concealed course, since its symptoms are nonspecific. Moderate chronic intoxication usually occurs only after repeated intake of large doses.

Acute intoxication is indicated by a pronounced disturbance of acid-base balance, which may vary depending on the patient's age and severity of intoxication. The most common manifestation in children is metabolic acidosis. The severity of the 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 if the drug is taken in enteric-coated tablet form.

Warning.

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

Symptoms.

Headache, nausea, hypocalcemia or hypoglycemia, skin rash, dizziness, gastrointestinal bleeding, inhibition of thrombogenesis up to coagulopathy, cardiovascular disorders (from arrhythmia and arterial hypotension to cardiac arrest), tinnitus, visual and hearing disturbances, tremor, confusion, hyperthermia, increased sweating, hyperventilation, disturbances of acid-base balance and electrolyte imbalance, dehydration, coma, and respiratory failure.

Tinnitus may occur at plasma salicylate concentrations above 150–300 mcg/mL. More serious adverse reactions occur at plasma salicylate concentrations above 300 mcg/mL.

Treatment.

Due to life-threatening conditions caused by severe intoxication, all necessary preventive measures should be taken immediately: prevention or reduction of absorption, gastric lavage in the early stages (within one hour after ingestion), activated charcoal, monitoring and appropriate correction of electrolytes. Administration of glucose. Sodium bicarbonate for correction of acidosis and for acceleration of excretion (urine pH > 8). Glycine: initial dose – 8 g orally, then 4 g every 2 hours for 16 hours. Hemoperfusion or hemodialysis may be possible (the need for application can be determined at a toxicology center).

Side effects.

Blood and lymphatic system disorders: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, anemia (post-hemorrhagic/iron-deficiency, aplastic) with corresponding laboratory findings and clinical manifestations; hemolysis and hemolytic anemia (in patients with severe glucose-6-phosphate dehydrogenase deficiency), prolonged bleeding time.

Immune system disorders: hypersensitivity reactions including asthmatic attacks, skin reactions, respiratory, gastrointestinal and cardiovascular disturbances, rash, swelling, itching, cardiorespiratory failure, anaphylactic shock; erythematous/eczematous skin reactions, severe skin reactions including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis; angioneurotic edema, allergic edema, rhinitis, nasal congestion, hypotension progressing to shock.

Metabolic disorders: hyperuricemia with corresponding laboratory findings and clinical manifestations (gout attacks), hypoglycemia, acid-base imbalance.

Nervous system disorders: headache, dizziness, disorientation, confusion.

Eye disorders: visual disturbances.

Ear disorders: hearing disturbances, tinnitus.

Gastrointestinal disorders: microbleeding (70%), dyspepsia, nausea, vomiting, diarrhea; epigastric pain, abdominal pain, heartburn, anorexia, gastrointestinal inflammation, gastrointestinal hemorrhage, gastrointestinal ulcers, which very rarely may lead to hemorrhage and perforation, with corresponding clinical symptoms and laboratory parameter changes.

Vascular system disorders: hemorrhagic vasculitis, bleeding (intraoperative hemorrhages, hematomas, genitourinary tract bleeding, epistaxis, gingival bleeding, gastrointestinal hemorrhages, hematemesis, melena, occult gastrointestinal bleeding, intracranial hemorrhage (especially in patients with uncontrolled hypertension and/or concomitant use of anticoagulants), with corresponding clinical symptoms including asthenia, pallor, hypoperfusion.

Hepatobiliary disorders: hepatic dysfunction, transient liver failure, increased liver transaminase levels.

Renal and urinary disorders: renal function impairment, acute renal failure.

Respiratory system disorders: rhinitis, dyspnea, bronchospasm, asthma attacks.

Reproductive system disorders: menorrhagia.

Skin and subcutaneous tissue disorders: purpura, nodular erythema, multiform erythema.

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

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per strip; 3, 8 or 10 strips per cardboard box.

30 tablets per strip; 1, 2, 3 or 4 strips per cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of business activity.

40020, Ukraine, Sumy region, city of Sumy, Skryabina Street, 54.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business activity.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and location of business activity.

40020, Ukraine, Sumy region, city of Sumy, Davydovskoho Hryhoriya Street, 54.