INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GОDASAL® (GODASAL®)

Composition:

Active substance: acetylsalicylic acid;

1 tablet contains 100 mg of acetylsalicylic acid;

Excipients: glycine, corn starch, powdered cellulose, powdered lemon flavor, sodium saccharin.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white, or yellowish-white tablets with a lemon odor or lemon with a slight odor of acetic acid, round, biconvex, with a score line on one side.

Pharmacotherapeutic group. Antithrombotic agents. Antiaggregants.

ATC code B01AC06.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. The antithrombotic effect of acetylsalicylic acid (ASA) is due to inhibition of thromboxane A2 synthesis in platelets. Even small doses of ASA are absorbed, leading to irreversible inhibition of all circulating platelets in the prehepatic mesenteric blood vessels as they pass from the gastrointestinal tract to the liver. Meanwhile, the concentration of ASA during posthepatic circulation only slightly inhibits endothelial cyclooxygenase (responsible for prostacyclin synthesis), as it recovers more rapidly. Platelet function related to hemostasis remains largely unchanged.

Clinical efficacy

Primary prevention. In a meta-analysis by the U.S. Preventive Services Task Force (Ann Intern Med 2002;136:161–172), based on five prospective clinical trials, it was demonstrated that the risk of myocardial infarction (relative risk 0.72 [95% confidence interval: 0.60–0.87]) is reduced with prophylactic ASA treatment at doses of 75–125 mg over 5–7 years in patients without prior cardiovascular events but with various risk factors (age > 50 years, arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia, family history). This benefit was observed only for non-fatal cardiovascular events; no advantages were seen regarding stroke incidence or overall mortality. The risk of severe gastrointestinal bleeding compared to control was 0.8% vs. 0.48%, and the risk of intracranial hemorrhage was 0.22% vs. 0.17%. The risk of bleeding was higher in patients aged 70 years and older.

Prevention should only be initiated after adequate control of blood pressure has been established and in combination with other therapeutic measures (diet, management of diabetes, lipid-lowering therapy, smoking cessation). Risk can be assessed using scales from the European Society of Cardiology (European Heart Journal, 1998, 19:1434–1503).

Secondary prevention. In a meta-analysis conducted by the Antithrombotic Trialists' Collaboration (BMJ 2002; 324: 71–85), the effects of ASA versus placebo were compared in 287 studies involving 135,000 high-risk patients. Additional comparisons among different platelet aggregation inhibitors were performed in 77,000 patients. High-risk patients were defined as those with acute cardiovascular events or a history of cardiovascular events (myocardial infarction, transient ischemic attack [TIA], unstable angina, arterial occlusive disease, post-surgical procedures such as aortocoronary bypass grafting, percutaneous transluminal coronary angioplasty, peripheral angioplasty, and patients with arteriovenous shunts on dialysis).

A reduction in the risk of serious cardiovascular events (relative reduction by 25%; p < 0.0001) and cardiovascular mortality was observed. The absolute benefit outweighed the risk of extracranial bleeding across all high-risk patient categories.

Pharmacokinetics

Absorption. After oral administration, ASA is rapidly and completely absorbed from the gastrointestinal tract. During and after absorption, it is converted into its main active metabolite, salicylic acid. Due to the enteric coating of the tablets, the release of the active substance occurs not in the stomach but in the alkaline environment of the intestine, which in turn results in delayed absorption of ASA. Because of the protective effect on the gastric mucosa, this dosage form is superior to conventional ASA formulations, especially during long-term therapy. Compared to uncoated ASA, peak plasma concentrations of salicylates are reached 2–7 hours later.

Distribution. Salicylic acid is 60–90% bound to plasma proteins.

The bioavailability of salicylates ranges from 80 to 100%.

Metabolism. The half-life of systemically available ASA is approximately 15 minutes. Salicylic acid, formed via hydrolysis, has a half-life of about 2–3 hours, which significantly increases after administration of high doses (> 3 g) due to saturation of the conjugating enzyme system.

Biotransformation of salicylic acid occurs primarily in the liver. Salicylate metabolites are formed mainly by conjugation of salicylic acid with glycine and further conjugation with glucuronic acid or sulfuric acid. A small portion is oxidized to gentisic acid and converted into gentisuric acid.

Elimination. Elimination occurs almost entirely via the kidneys, primarily as salicyluric acid (approximately 75%), salicylic acid (approximately 10%), and conjugates of salicyluric acid (approximately 10%). The elimination half-life ranges from 2–3 hours after low-dose administration to 12 hours after analgesic doses.

Pharmacokinetics in special patient populations

Elimination in patients with hepatic impairment. Since ASA metabolism occurs primarily in the liver, a slower conversion of ASA to salicylic acid (with potential accumulation) is expected.

Elimination in patients with renal impairment. Renal impairment does not affect the rate of salicylic acid breakdown; however, it increases the concentration of inactive metabolites of salicylic acid, primarily conjugated salicyluric acid.

Salicylates cross the placenta, but are excreted into breast milk only in small amounts.

Preclinical data

The preclinical safety profile of ASA is well documented. In animal studies, salicylates caused kidney damage without other organ toxicity. ASA has been extensively studied for mutagenicity and carcinogenicity, and no relevant evidence of mutagenic or carcinogenic properties has been found. Salicylates showed embryotoxic and teratogenic effects in animal studies across various species (e.g., cardiac and skeletal malformations, gastroschisis).

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

Clinical Characteristics

Indications

Prevention of thrombosis (prevention of reocclusions) after aortocoronary bypass grafting, percutaneous transluminal catheter angioplasty, and after arteriovenous shunting in patients undergoing dialysis.
Prevention of cerebrovascular stroke following transient ischemic attacks (warning signs).
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 after vascular surgery.
As part of standard therapy for acute myocardial infarction.
Prevention of vascular occlusion in arterial occlusive disease.

Contraindications

Hypersensitivity to salicylates and/or other anti-inflammatory agents, or to any component of the drug.
History of bronchospasm, urticaria, or allergic symptoms after intake of acetylsalicylic acid (ASA) or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Hemorrhagic diathesis.
Active gastric and/or duodenal ulcer or gastrointestinal bleeding. Inflammatory gastrointestinal diseases (such as Crohn’s disease, ulcerative colitis).
Severe hepatic insufficiency (liver cirrhosis and ascites).
Severe renal insufficiency (creatinine clearance < 30 mL/min).
Severe heart failure (NYHA functional class III–IV).
Combination with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other forms of interactions").
Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").
Treatment of postoperative pain following coronary artery bypass grafting (using cardiopulmonary bypass).

Interaction with other medicinal products and other forms of interactions

Contraindicated combinations

When used concomitantly with methotrexate at doses of 15 mg/week or higher, hematological toxicity of methotrexate increases (due to decreased renal clearance of methotrexate caused 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 toxicity of methotrexate (due to decreased renal clearance of methotrexate caused 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 ASA: increased risk of bleeding due to synergistic effects.
Increased plasma concentration of digoxin due to reduced renal excretion.
Increased plasma levels of phenytoin and valproate. When used concomitantly with valproic acid, ASA displaces it from plasma protein binding and reduces its metabolism. As a result, plasma levels of valproate increase, leading to a higher incidence of adverse reactions such as tremor, nystagmus, ataxia, and personality changes.
Potentiation of the effects and adverse reactions of all NSAIDs.
Concomitant use with NSAIDs such as ibuprofen or naproxen on the same day may attenuate the irreversible platelet inhibition 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 ASA (see section "Special precautions for use").
Metamizole may reduce the effect of ASA on platelet aggregation when administered concomitantly. Therefore, metamizole should be used with caution in patients receiving low-dose ASA for cardioprotection.
Antihypertensive agents (ACE inhibitors and β-blockers): patients receiving this drug concomitantly with these agents should have their blood pressure carefully monitored and dosage adjusted if necessary.
Diuretics in combination with high doses of ASA: reduced diuretic efficacy.
Reduced effect of uricosuric agents (e.g., probenecid, sulfinpyrazone).
Systemic glucocorticoids: increased risk of gastrointestinal ulcers and bleeding. Decreased salicylate blood levels during corticosteroid therapy and risk of salicylate overdose after discontinuation of glucocorticoid therapy.
Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.
Prolongation of the plasma half-life of penicillin.

Special precautions for use

The medicinal product Godasal® should be used with caution in the following situations:

Impaired renal function or disturbances of cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis or severe bleeding), since acetylsalicylic acid may also increase the risk of impaired renal function and acute renal failure;
Impaired liver function;
Concomitant use of NSAIDs such as ibuprofen and naproxen, since NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Godasal® is used before starting NSAIDs as an analgesic, the patient should consult a physician (see section "Interaction with other medicinal products and other forms of interaction");
Symptoms of chronic gastric or duodenal dyspepsia or their recurrence;
Bronchial asthma or general tendency to hypersensitivity, since acetylsalicylic acid may cause bronchospasm, an asthma attack, or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory disease: allergic reactions (e.g. rash, itching, or urticaria) to other substances in the past;
Nasal polyps;
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 infection;
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 of bleeding or exacerbate existing bleeding during surgical procedures (including minor surgical interventions, such as tooth extraction);
Gastrointestinal ulcers, including chronic and recurrent ulcer diseases or gastrointestinal bleeding in medical history;
Hypersensitivity to analgesics, anti-inflammatory or antirheumatic agents, as well as allergy to other substances.

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

The use of ASA in children with fever and/or viral infections is possible only on a physician's prescription as second-line therapy (due to the risk of Reye's syndrome, a life-threatening encephalopathy whose main symptoms are severe vomiting, loss of consciousness, and hepatic dysfunction).

With certain viral infections, particularly influenza A, influenza B, and varicella, there is a risk of developing Reye's syndrome, a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if ASA is used as a concomitant medication, although a causal relationship has not been established. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

Gastrointestinal ulcers, bleeding, or perforation may occur at any time, including without warning symptoms or signs in medical history, during treatment with COX-2-selective or non-selective NSAIDs. To reduce this risk, the lowest effective dose should be used for the shortest possible duration of therapy.

Placebo-controlled studies of certain selective COX-2 inhibitors have revealed an increased risk of thrombotic cardiovascular and cerebrovascular complications. It is currently unknown whether this risk is directly correlated with the COX-1/COX-2 selectivity of the respective NSAID. Since comparable clinical trial data for ASA used at maximum doses and as long-term therapy are currently lacking, such an increased risk cannot be excluded. Until appropriate data are available, acetylsalicylic acid should be used only after careful assessment of benefit/risk in patients with clinically confirmed ischemic heart disease, cerebrovascular disease, occlusive peripheral arterial disease, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). In such cases, the lowest effective dose should also be used for the shortest possible duration of therapy.

The effect of NSAIDs on the kidneys is manifested, in particular, by fluid retention with edema and/or arterial hypertension. ASA should be used with caution in patients with cardiac dysfunction and other conditions causing fluid retention.

Caution is also required in patients who are simultaneously receiving diuretics or angiotensin-converting enzyme (ACE) inhibitors, and in those with an increased risk of hypovolemia.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Available epidemiological data suggest a risk of miscarriage and congenital heart defects and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy.

Available epidemiological data do not confirm an association between ASA use and an increased risk of miscarriage. Epidemiological data on miscarriage are inconsistent; however, an increased risk of gastroschisis cannot be excluded with ASA use. Results from a prospective study on drug exposure in early pregnancy (1st–4th months) involving approximately 14,800 mother-child pairs did not indicate any association with an increased risk of malformations.

During the first and second trimesters of pregnancy

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

Animal studies have shown that the use of prostaglandin inhibitors leads to increased pre- and post-implantation losses and embryo/fetal death. In addition, a higher frequency of severe developmental abnormalities, including cardiovascular malformations, has been observed in animals treated with prostaglandin inhibitors during organogenesis.

According to previous experience, the risk is low when the medicinal product is used at therapeutic doses. Prenatal monitoring to detect constriction of the ductus arteriosus after acetylsalicylic acid intake should be considered starting from the 20th week of pregnancy. If constriction of the ductus arteriosus occurs, acetylsalicylic acid therapy should be discontinued.

During the third trimester of pregnancy

All prostaglandin synthesis inhibitors may:

Affect the fetus in the following ways:
- Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
- Impaired renal function with possible subsequent development of renal failure with oligohydramnios;
Affect the mother and fetus in the following ways:
- Prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
- Inhibition of uterine contractions and bleeding in the pregnant woman, and prolonged duration of labor.

Therefore, ASA is contraindicated during the third trimester of pregnancy.

Fertility. The use of ASA may impair female fertility; therefore, its use is not recommended in women wishing to become pregnant. For women attempting to conceive or undergoing infertility investigations, discontinuation of ASA should be considered.

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

In cases of unavoidable use during lactation, breastfeeding should be discontinued if high doses (> 300 mg/day) are used regularly.

Ability to affect reaction speed when driving vehicles or operating machinery

The medicinal product does not affect the reaction speed when driving vehicles or operating machinery.

Method of Administration and Dosage

Method of Administration

Tablets may be taken without chewing, preferably after food intake, with a large amount of water (ideally a glass of water), or they may be sucked or chewed. If necessary, the tablet can be taken with a liquid. Do not take on an empty stomach.

For the treatment of acute myocardial infarction, the first tablet should be bitten or chewed. The medicinal product Godasal® is intended for long-term use. The duration of treatment is determined by a physician.

If the physician has not prescribed otherwise, the following dosages are recommended:

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

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

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

Acute myocardial infarction: in case of acute myocardial infarction, administer 200–300 mg of ASA either intravenously or orally in a rapidly releasing form of acetylsalicylic acid (not enteric-coated formulation). Afterwards, 100 mg of Godasal® should be administered daily.

Children

Godasal® should not be used in children (under 18 years of age) due to lack of data on efficacy and safety in this patient population.

Administration of acetylsalicylic acid to children under 16 years of age may cause severe adverse reactions (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

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 ASA doses up to 150 mg/kg body weight, moderate intoxication may occur; with doses > 300 mg/kg body weight, severe intoxication may develop.

Absorption of ASA may be delayed due to delayed gastric emptying, formation of concretions in the stomach, or if the drug is taken in enteric-coated tablet form.

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 usually predominate 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 absorption 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 gastroscopic removal of tablets.

Appropriate monitoring and correction of electrolytes. Administration of glucose and sodium bicarbonate in 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, side effects are listed in order of decreasing severity: 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 the available data).

Information on other side effects has been reported in spontaneous reports for all dosage forms of acetylsalicylic acid (ASA), including oral short-term and long-term therapy; therefore, classification by frequency category is not possible.

Blood and lymphatic system disorders:

Prolonged bleeding time;

Rare: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron deficiency anemia;

Frequency not known: hemolysis and hemolytic anemia have been observed in patients with severe forms of glucose-6-phosphate dehydrogenase deficiency.

Due to its antiplatelet effect, ASA use may increase the risk of bleeding. Bleeding events such as perioperative bleeding, hematomas, epistaxis, urogenital bleeding, and bleeding from gums 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.

Immune system disorders:

Uncommon: asthma;

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

Very rare: severe skin reactions including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

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.

Formation of intestinal diaphragm-like structures, particularly with prolonged use.

Hepatobiliary disorders:

Rare: hepatic dysfunction;

Very rare: increased transaminase levels.

Renal and urinary disorders:

Rare: impaired kidney function;

Frequency not known: acute renal failure.

Other:

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Keep out of reach of children.

Packaging. 10 tablets per blister. 2, 5, or 10 blisters per cardboard box.

Dispensing category. Over-the-counter – tablets No. 20.

By prescription only – tablets No. 50, No. 100.

Manufacturer

Dr. Pfleger Arzneimittel GmbH, Germany.

Manufacturer's address and location of operations

Dr.-Robert-Pfleger-Str. 12, 96052, Bamberg, Germany.