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

Composition:

Active substances: clopidogrel, acetylsalicylic acid;

1 capsule contains: granules of clopidogrel bisulfate equivalent to clopidogrel 75 mg;

sustained-release coated tablet of acetylsalicylic acid 75 mg;

Excipients for granules: betacyclodextrin, talc, silicon dioxide colloidal anhydrous; corn starch, microcrystalline cellulose;

Excipients for sustained-release acetylsalicylic acid tablet: starch, microcrystalline cellulose, purified talc, citric acid, stearic acid, silicon dioxide colloidal anhydrous;

Coating of acetylsalicylic acid tablet: cellulose acetophthalate, dibutyl phthalate, tartrazine (E 102).

Pharmaceutical form. Capsules.

Main physicochemical properties: blue capsule of size "0", containing granular powder from white to almost white and a yellow enteric-coated tablet of acetylsalicylic acid.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. ATC code B01AC30.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Aspigrél is a combination drug, the action of which is determined by the pharmacological properties of clopidogrel and acetylsalicylic acid (ASA) contained in its composition.

Clopidogrel belongs to prodrugs; one of its metabolites is an inhibitor of platelet aggregation. The metabolism of clopidogrel by enzymes of the cytochrome CYP450 system is required for the formation of the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor on the platelet surface and subsequent activation of the glycoprotein IIb/IIIa complex by ADP, thereby suppressing platelet aggregation. Due to the irreversible nature of binding, platelets that have interacted with clopidogrel remain under its effect throughout their lifespan (approximately 7–10 days); normal platelet function recovers at a rate corresponding to the rate of platelet renewal. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation via released ADP.

Since the active metabolite is formed via enzymes of the cytochrome CYP450 system, and some of these enzymes are polymorphic or inhibited by other medicinal products, adequate platelet inhibition does not occur in all patients.

Pharmacodynamic effects. Repeated administration of clopidogrel at a dose of 75 mg daily significantly inhibited ADP-induced platelet aggregation from the first day of treatment; this effect gradually increased and reached a steady state by day 3–7. At steady state, the mean level of platelet inhibition observed with the 75 mg daily dose ranged from 40% to 60%. Platelet aggregation and bleeding time gradually returned to baseline levels within approximately 5 days.

ASA inhibits platelet aggregation by irreversibly inhibiting cyclooxygenase prostaglandins, thereby suppressing the formation of thromboxane A2, which induces platelet aggregation and vasoconstriction. This effect persists throughout the platelet's lifespan.

Pharmacokinetics.

Clopidogrel. After oral administration of 75 mg daily, clopidogrel is rapidly absorbed, but plasma concentrations of the parent compound are low and fall below the limit of quantification (0.00025 mg/L) within 2 hours after dosing. Based on the measurement of urinary excretion of clopidogrel metabolites, its absorption is estimated to be approximately 50%.

Clopidogrel is metabolized in the liver. Its major metabolite (carboxylic acid derivative) is inactive and accounts for 85% of the circulating parent compound in plasma. Maximum plasma concentration of this metabolite (approximately 3 mg/L after repeated oral doses of 75 mg) is reached about 1 hour after administration. Clopidogrel is a prodrug of the active substance. Its active metabolite (thiol derivative) is formed via oxidation to 2-oxo-clopidogrel followed by hydrolysis. The oxidative step is primarily regulated by cytochrome P450 isoenzymes 2B6 and 3A4, and to a lesser extent by 1A1, 1A2, and 1C19. The active thiol metabolite, isolated in vitro, rapidly and irreversibly binds to platelet receptors, inhibiting platelet aggregation. This metabolite is not detectable in plasma. The kinetics of the major metabolite are linear (plasma concentration increases proportionally with dose) within the dose range of 50 to 150 mg of clopidogrel. Clopidogrel and the main circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). The elimination half-life of the main circulating metabolite is 8 hours after both single and repeated administration; 50% is excreted via the kidneys and 46% via the intestine.

Acetylsalicylic acid. After oral administration, ASA is converted into its main active metabolite – salicylic acid. Absorption of acetylsalicylic and salicylic acids from the gastrointestinal tract is rapid and complete. Maximum plasma concentration is achieved within 10–20 minutes (acetylsalicylic acid) or 45–120 minutes (total salicylates). The extent of protein binding depends on concentration and ranges from 49% to 70% for acetylsalicylic acid and from 66% to 98% for salicylic acid. ASA undergoes 50% metabolism during first-pass through the liver. Metabolites of acetylsalicylic acid, along with salicylic acid, include salicyluric acid (glycine conjugate of salicylic acid), gentisic acid, and its glycine conjugate. ASA is excreted primarily in the form of metabolites via the kidneys. The elimination half-life of acetylsalicylic acid is approximately 20 minutes. The elimination half-life of salicylic acid increases proportionally with the administered dose and is approximately 2, 4, and 20 hours. Acetylsalicylic acid penetrates into breast milk, cerebrospinal fluid, synovial fluid, and crosses the blood-brain barrier.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic complications in adults who are already taking clopidogrel and acetylsalicylic acid (ASA). For continuation of therapy in cases of:

Acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without pathological Q wave on ECG), including patients who have undergone stenting during percutaneous coronary intervention;
Acute ST-segment elevation myocardial infarction in patients receiving medical therapy, and when thrombolysis is feasible.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.
Severe hepatic impairment.
Acute pathological bleeding, such as peptic ulcer bleeding or intracranial hemorrhage.
Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), bronchial asthma, rhinitis, nasal polyps. Patients with existing mastocytosis in whom administration of acetylsalicylic acid may cause severe hypersensitivity reactions (including circulatory shock with flushing, arterial hypotension, tachycardia, and vomiting).
Severe renal impairment (creatinine clearance < 30 mL/min).
Acute peptic ulcers.
Hemorrhagic diathesis.
Severe heart failure.
Concomitant use of acetylsalicylic acid and methotrexate at doses of 15 mg/week or higher (due to increased hematological toxicity of methotrexate – salicylates reduce renal clearance of methotrexate and displace methotrexate from plasma protein binding).
Third trimester of pregnancy (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with bleeding risk.

There is an increased risk of bleeding due to potential additive synergy. Concomitant use of medicinal products associated with bleeding risk should be administered with caution (see section "Special precautions for use").

Other antiplatelet agents.

Concomitant use of antithrombotic medicinal products increases the risk of bleeding due to additive effects. Immediately assess any signs or symptoms of bleeding in patients treated concomitantly with other antiplatelet agents (see section "Special precautions for use").

Oral anticoagulants.

Combination use of Aspigrrel with oral anticoagulants is not recommended, as it may enhance bleeding intensity (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 75 mg/day in patients receiving long-term warfarin therapy did not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR), concomitant use of clopidogrel and warfarin increases the risk of bleeding due to independent effects of these agents on hemostasis.

Glycoprotein IIb/IIIa inhibitors.

Aspigrrel should be used with caution in patients who are concomitantly receiving glycop游戏副本

Special precautions for use.

Bleeding and hematological disorders.

Due to the risk of bleeding and hematological adverse reactions, if clinical symptoms associated with bleeding occur during treatment, urgent blood testing and/or monitoring of other appropriate parameters should be performed (see section "Adverse reactions"). Since Aspigrrel is an antiplatelet agent containing two active substances, it should be used with caution in patients who have an increased risk of bleeding related to trauma, surgical procedures, or other pathological conditions, as well as when used concomitantly with medicinal products that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and NSAIDs used on a regular basis), including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), potent CYP2C19 inducers, thrombolytics, or other medicinal products increasing the risk of bleeding such as pentoxifylline (see section "Interaction with other medicinal products and other forms of interaction"). Close monitoring of patients for any signs of bleeding, including occult bleeding, is required, especially during the first weeks of treatment and/or after invasive cardiological procedures or surgery. Concomitant use of Aspigrrel with oral anticoagulants is not recommended, as this may increase the severity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Before any planned surgery, and before starting any new medicinal product, patients should inform their physicians, including dentists, about taking Aspigrrel. When elective surgery is anticipated, the necessity of dual antiplatelet therapy should be reassessed in favor of using a single antiplatelet agent. If antiplatelet therapy with Aspigrrel needs to be temporarily discontinued, it should be stopped 7 days prior to surgery.

Aspigrrel prolongs bleeding time; it should be used with caution in patients with lesions predisposing to bleeding (e.g., gastrointestinal or intraocular).

Patients should also be warned about the possible prolonged time required to stop bleeding while taking Aspigrrel, and the need to inform their physician about any unusual bleeding (in terms of location or duration).

Thrombotic thrombocytopenic purpura (TTP).

Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported during clopidogrel treatment, sometimes even after short-term use. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurological symptoms, renal dysfunction, or fever. TTP may be life-threatening and requires immediate therapeutic measures, including plasmapheresis.

Acquired hemophilia.

Cases of acquired hemophilia have been reported after clopidogrel use. In case of confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be under medical supervision and receive appropriate treatment; clopidogrel use should be discontinued.

Recent transient ischemic attack or stroke.

It has been demonstrated that the use of clopidogrel in combination with ASA in patients who recently experienced a transient ischemic attack or stroke and are at high risk of recurrent ischemic events increases the risk of major bleeding. Therefore, caution should be exercised when using this combination, except in cases where a favorable effect has been proven.

Cytochrome P450 2C19 (CYP2C19).

Pharmacogenetics. In patients with poor CYP2C19 metabolism, administration of clopidogrel at recommended doses results in lower levels of the active metabolite and reduced effect on platelet function. Tests are available to determine the patient's CYP2C19 genotype.

Since clopidogrel is partially metabolized to its active metabolite via CYP2C19, concomitant use of medicinal products that inhibit this enzyme's activity is likely to reduce the levels of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Concomitant use of medicinal products that inhibit CYP2C19 activity should be avoided (list of CYP2C19 inhibitors, see section "Interaction with other medicinal products and other forms of interaction"; also see section "Pharmacokinetics").

It is likely that using medicinal products that induce CYP2C19 activity will increase the level of clopidogrel's active metabolite and may increase the risk of bleeding. As a precaution, concomitant use of potent CYP2C19 inducers should be avoided (see section "Adverse reactions").

Substrates of CYP2C8.

Clopidogrel should be prescribed with caution when used concomitantly with medicinal products that are substrates of CYP2C8 (see section "Interaction with other medicinal products and other forms of interaction").

Cross-reactivity among thienopyridines.

Patients should be screened for history of hypersensitivity to other thienopyridines (e.g., ticlopidine, prasugrel), as cross-reactivity among thienopyridines has been reported (see section "Adverse reactions"). Use of thienopyridines may lead to mild to severe allergic reactions such as rash, Quincke's edema, or hematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is recommended.

Renal impairment.

The combination of clopidogrel with ASA should not be used in patients with severe renal impairment (see section "Contraindications"). Experience with use in patients with moderate renal impairment is limited. Therefore, the combination of clopidogrel and ASA should be used with caution in this population.

Hepatic impairment.

The combination of clopidogrel with ASA should not be used in patients with severe hepatic impairment (see section "Contraindications"). Experience with use in patients with moderate hepatic disease, in whom hemorrhagic diathesis may occur, is limited. Therefore, the combination of clopidogrel and ASA should be used with caution in this population.

ASA should be used with caution:

in patients with a history of bronchial asthma or allergic reactions, as they may increase the risk of hypersensitivity reactions;
in patients with gout, as ASA even at low doses may increase uric acid concentration;
in children (under 18 years of age), due to possible association between ASA use and Reye’s syndrome. Reye’s syndrome is a very rare condition that may be life-threatening.

Alcohol

Alcohol promotes gastrointestinal mucosal damage and prolongs bleeding time due to the synergistic effect of ASA and alcohol. Patients should be informed about the risk of gastrointestinal mucosal damage and bleeding when taking the medicine concomitantly with alcohol, especially if alcohol consumption is chronic or substantial (see section "Interaction with other medicinal products and other forms of interaction").

Glucose-6-phosphate dehydrogenase deficiency

This medicinal product should be used under strict medical supervision in patients with glucose-6-phosphate dehydrogenase deficiency due to the risk of hemolysis (see section "Adverse reactions").

Gastrointestinal tract (GIT) disorders.

Aspigrrel should be used with caution in patients with a history of peptic ulcer, gastroduodenal bleeding, or other symptoms of upper gastrointestinal disorders, as these may be consequences of gastric ulceration, which could lead to gastric bleeding. Adverse effects related to the GIT, including stomach pain, heartburn, nausea, vomiting, and gastrointestinal bleeding, may occur. Although other upper GIT symptoms such as dyspepsia are common and may occur at any time during treatment, physicians should remain vigilant for signs of ulceration and bleeding, even in the absence of prior GIT symptoms. Patients should be informed about symptoms of GIT adverse effects and measures to be taken if they occur.

Patients who are concurrently taking nicorandil and nonsteroidal anti-inflammatory drugs (NSAIDs), including ASA and corticosteroids, have an increased risk of severe complications such as peptic ulcer, perforation, and gastrointestinal bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions for disposal of unused medicine and waste. Any unused medicine or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data on the use of Aspigrrel during pregnancy. Aspigrrel should not be used during the first and second trimesters of pregnancy, except when the woman's clinical condition requires treatment with clopidogrel/ASA.

Due to the presence of ASA in Aspigrrel, its use during the third trimester of pregnancy is contraindicated.

Clopidogrel.

As clinical data on the use of clopidogrel during pregnancy are currently lacking, as a precautionary measure, clopidogrel should preferably not be used during this period.

Animal studies have not shown any direct or indirect harmful effects of the drug on pregnancy, embryonic/fetal development, delivery, or postnatal development.

ASA.

Low doses (up to 100 mg/day). Clinical data confirm that doses up to 100 mg/day for limited use in obstetrics, requiring specialized monitoring, are safe.

Doses 100–500 mg/day. Clinical experience with doses exceeding 100 mg/day up to 500 mg/day is insufficient. Therefore, recommendations for doses equal to or exceeding 500 mg/day also apply to this dose range.

Doses equal to or exceeding 500 mg/day. Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage, congenital heart defects, and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of congenital heart defects increases from less than 1% to approximately 1.5%. The risk is considered to increase with dose and duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors resulted in reproductive toxicity. In the absence of an urgent need, acetylsalicylic acid should not be prescribed until week 24 of amenorrhea (5th month of pregnancy). If acetylsalicylic acid is used by a woman attempting to become pregnant or before week 24 of amenorrhea (5th month of pregnancy), the lowest possible dose for the shortest possible duration should be prescribed.

From the sixth month of pregnancy, all prostaglandin synthesis inhibitors may cause in the fetus:

pulmonary and cardiac toxicity (with premature closure of arterial ducts and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with oligohydramnios;

in the woman and the fetus at the end of pregnancy:

possible prolongation of bleeding time, antiaggregatory effect, which may occur even at very low doses;
inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding.

It is unknown whether clopidogrel is excreted in breast milk. It has been established that ASA is excreted in breast milk in limited amounts. Breastfeeding should be discontinued during treatment with Aspigrrel.

Fertility.

There are no data on the effect of Aspigrrel on fertility. Animal studies have shown that clopidogrel does not alter fertility. It is unknown whether ASA affects fertility.

Ability to affect reaction speed when driving or operating machinery.

Clopidogrel has no effect or a negligible effect on the ability to drive or operate machinery.

If dizziness occurs, patients should refrain from driving or operating machinery.

Dosage and Administration

For oral use. The medication can be taken independently of food intake.

Adults and elderly patients

Take Aspigrrel once daily. Aspigrrel should be used after treatment with clopidogrel and acetylsalicylic acid (ASA) as separate agents has been initiated.

Acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without pathological Q wave on ECG)

The optimal duration of treatment has not been officially established. Clinical trial data support use for up to 12 months, with the maximum beneficial effect observed by the end of the third month (see section "Pharmacological Properties"). If Aspigrrel is discontinued, continuing treatment with a single antithrombotic agent may also provide a beneficial effect in patients.

Acute myocardial infarction with ST-segment elevation

Treatment should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The beneficial effect of clopidogrel and ASA combination therapy beyond 4 weeks in this condition has not been studied (see section "Pharmacological Properties"). If Aspigrrel is discontinued, patients may continue treatment with a single antiplatelet agent.

Missed dose:

If less than 12 hours have passed since the scheduled dose time: patients should take the missed dose immediately and then take the next dose at the regular time;
If more than 12 hours have passed: patients should take the next dose at the regular time without doubling the dose.

Pharmacogenetics

Reduced CYP2C19-mediated metabolism leads to diminished clopidogrel effect. The optimal dosing regimen for patients with reduced metabolism has not been established (see sections "Pharmacological Properties" and "Pharmacokinetics").

Renal impairment

Aspigrrel must not be used in patients with severe renal impairment (see section "Contraindications"). Experience with use in patients with mild or moderate renal impairment is limited (see section "Special Warnings and Precautions for Use"). Therefore, Aspigrrel should be prescribed with caution in such patients.

Hepatic impairment

Aspigrrel must not be used in patients with severe hepatic impairment (see section "Contraindications"). Experience with use in patients with mild or moderate hepatic impairment is limited (see section "Special Warnings and Precautions for Use"). Therefore, Aspigrrel should be prescribed with caution in such patients.

Children

Safety and efficacy of Aspigrrel in children under 18 years of age have not been established. Aspigrrel is contraindicated in this patient group.

Overdose

There is no information available regarding overdose with Aspigrrel.

Clopidogrel

Overdose with clopidogrel may lead to prolonged bleeding time and bleeding complications. In case of bleeding, appropriate therapy should be administered.

No antidote for the pharmacological activity of clopidogrel has been identified. If rapid correction of prolonged bleeding time is required, platelet transfusion may be effective.

ASA (Acetylsalicylic acid)

Symptoms of moderate intoxication include: dizziness, headache, tinnitus, confusion, and gastrointestinal symptoms (nausea, vomiting, and epigastric pain).

In severe intoxication, serious acid-base imbalance occurs. Initial hyperventilation leads to respiratory alkalosis. Over time, due to respiratory center depression, respiratory acidosis develops. Additionally, the presence of salicylates causes metabolic acidosis. Since infants and young children often present to physicians at the late stage of intoxication, they usually already present with acidosis.

Other possible symptoms include: hyperthermia and sweating leading to dehydration, restlessness, seizures, hallucinations, and hypoglycemia. Central nervous system depression may progress to coma, cardiovascular collapse, and respiratory arrest. The lethal dose of acetylsalicylic acid is 25–30 g. A plasma salicylate concentration exceeding 300 mg/L (1.67 mmol/L) indicates intoxication.

Overdose with a fixed-dose combination medication containing ASA and clopidogrel may result in enhanced bleeding and subsequent hemorrhagic complications due to the pharmacological activity of both clopidogrel and ASA.

Acute and chronic ASA overdose may lead to non-cardiogenic pulmonary edema (see section "Adverse Reactions").

In case of ingestion of a toxic dose, hospitalization is required. In moderate intoxication, vomiting should be induced; if unsuccessful, gastric lavage is indicated. Subsequently, activated charcoal (adsorbent) and sodium sulfate (laxative) should be administered. Urine alkalization is recommended (250 mmol sodium bicarbonate over 3 hours) with monitoring of urine pH. In severe intoxication, hemodialysis should be performed. Other symptoms of intoxication should be treated symptomatically.

Side effects

The most commonly reported adverse reaction both during clinical studies and in the post-marketing period was bleeding. Reports were mainly received during the first month of treatment.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, eosinophilia, neutropenia, including severe neutropenia, thrombotic thrombocytopenic purpura (TTP) (see section "Special precautions"), bone marrow suppression, aplastic anemia, pancytopenia, bicytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (see section "Special precautions").

Immune system disorders: hypersensitivity reactions, including anaphylactoid/anaphylactic reactions, anaphylactic shock, angioedema, asthmatic state; serum sickness, exacerbation of allergic symptoms of food allergy, cross-hypersensitivity among thienopyridines (such as ticlopidine, prasugrel 5) (see section "Special precautions"), worsening of food allergy symptoms, insulin autoimmune syndrome which may lead to severe hypoglycemia, particularly in patients with human leukocyte antigen subtype DRA*04 (more common in Japanese). Possible hypersensitivity reactions involving the respiratory tract, gastrointestinal tract, and cardiovascular system, including rhinitis, nasal congestion, cardiopulmonary failure.

Metabolism and nutrition disorders: hypoglycemia, gout (see section "Special precautions").

Psychiatric disorders: hallucinations, confusion.

Nervous system disorders: intracranial hemorrhage (some fatal cases reported), headache, paresthesia, dizziness, taste disturbances, ageusia.

Eye disorders: ocular hemorrhage (conjunctival, ocular, retinal).

Ear and labyrinth disorders: vertigo, hearing loss or tinnitus.

Cardiac disorders: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction caused by mediators of allergy) in the context of hypersensitivity reaction to ASA or clopidogrel.

Vascular disorders: hematomas, serious hemorrhages, bleeding from surgical wounds, vasculitis (including Henoch-Schönlein purpura), arterial hypotension.

Respiratory, thoracic and mediastinal disorders: epistaxis, respiratory tract hemorrhages (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, non-cardiogenic pulmonary edema with prolonged use of the drug and as part of hypersensitivity reaction to acetylsalicylic acid, eosinophilic pneumonia, asthma, rhinitis, nasal congestion.

Gastrointestinal disorders: gastrointestinal hemorrhages, bleeding from gums, retroperitoneal hemorrhages, gastrointestinal and retroperitoneal hemorrhages with fatal outcome; diarrhea, abdominal pain, dyspepsia, vomiting, nausea, constipation, abdominal distension (flatulence); gastric and duodenal ulcers, perforation of gastric and duodenal ulcers; stomatitis; pancreatitis, acute pancreatitis as part of hypersensitivity to ASA; colitis (including ulcerative or lymphocytic colitis), disorders of upper gastrointestinal tract (esophagitis, esophageal ulcer, perforation, erosive gastritis, erosive duodenitis; gastroduodenal ulcer/perforation); disorders of lower gastrointestinal tract (ulcers of small intestine [jejunum and ileum] and large intestine [colon and rectum], colitis and intestinal perforation); symptoms of upper gastrointestinal tract such as stomach pain (see section "Special precautions"); gastrointestinal reactions associated with ASA use may occur with or without bleeding/hemorrhage and may develop during treatment with any dose of ASA, both in patients with or without prior warning symptoms or serious gastrointestinal events in history.

Hepatobiliary disorders: liver function abnormalities, acute liver failure, liver injury predominantly hepatocellular, hepatitis, increased levels of liver enzymes, deviations from normal liver function tests, chronic hepatitis.

Skin and subcutaneous tissue disorders: bruising; rash, pruritus, skin hemorrhages (purpura); bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), acute generalized exanthematous pustulosis, angioedema, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, lichen planus, fixed erythema.

Musculoskeletal and connective tissue disorders: hemorrhages into musculoskeletal system (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: renal function impairment, bleeding from genitourinary organs, hematuria, renal failure, acute renal failure (particularly in patients with renal impairment, heart failure decompensation, nephrotic syndrome or concomitant use of diuretics), glomerulonephritis, elevated blood creatinine levels.

General disorders and administration site conditions: bleeding at injection site, fever, edema.

Investigations: prolonged bleeding time, decreased neutrophil count, decreased platelet count.

Reproductive system disorders: gynecomastia.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio of this medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via national reporting systems.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging and in a place inaccessible to children.

Packaging. 10 capsules per blister, 3 blisters or 10 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Mepro Pharmaceuticals Private Limited.

Manufacturer's address and location of operations.

Unit II, Q-Road, Phase IV, GIDC, Vadodhan, Surendranagar, Gujarat, 363 035, India.

Marketing authorization holder. Mili Healthcare Limited.

Address of the marketing authorization holder.

Fairfax House 15, Falwood Place, London, WC1V 6AY, United Kingdom.

Aspigrel