Asasantine (Dipyridamole – ASA)

ASASANTINE®

Boehringer Ingelheim

Dipyridamole – ASA

Inhibitor of Platelet Adhesion and Aggregation

Action And Clinical Pharmacology: The combined use of dipyridamole and ASA causes a significant reduction in the incidence of new fatal and nonfatal coronary events in patients with a previously documented myocardial infarction.

In a randomized, double blind study, the effects of combined dipyridamole and ASA treatment were compared to ASA alone and to placebo in 2 026 patients who had suffered a myocardial infarction 8 weeks to 5 years previously.

Combined treatment with dipyridamole 75 mg and ASA 325 mg 3 times daily reduced the life-table rates for coronary incidence over a range of 37.0 to 66.7% when compared to placebo in the 4- to 24-month period after starting treatment. Similarly, for ASA alone, these reductions ranged from 29.1 to 52.4% over the same period. The differences between combined treatment and placebo were statistically significant at each 4-month evaluation. Differences between ASA alone and placebo were statistically significant only at 8 and 24 months. At the end of the follow-up, 41 months later, essentially no differences were found between ASA and dipyridamole-ASA treatments, but both drug treated groups showed 21 to 25% lower coronary mortality and coronary incidence compared to placebo. This was no longer statistically significant.

Hospitalization longer than 2 weeks for recurrent myocardial infarction was significantly reduced in both drug treatment groups compared to the placebo group.

The patient sub-group (447 or about 20% of the total sample) entering the trial within 6 months after their last myocardial infarction showed the largest reduction in total and coronary mortality. However, the only statistically significant finding was a 63.6% reduction in life-table rates for coronary death in the dipyridamole/ASA group compared to placebo after 36 months of treatment.

A randomized, double blind trial comparing dipyridamole (begun 2 days before operation) plus ASA (begun 7 hours after operation) against placebo, in 407 patients undergoing coronary bypass, showed a statistically significant reduction in the rate of graft occlusion in patients receiving dipyridamole and ASA. Long-term follow-up (median 12 months) showed that treatment with dipyridamole and ASA continued to be effective in preventing late development of vein-graft occlusion after operation, and such treatment should be continued for at least 1 year.

Dipyridamole: When given to man, dipyridamole normalizes increased platelet adhesiveness and tendency to aggregate (Hellem’s method). Dose-related increases in platelet survival time in patients with prosthetic heart valves have been observed: 400 mg/day, or 100 mg/day plus 1 g ASA, normalizes pathologically-shortened platelet survival. In combination with anticoagulants, 400 mg/day of dipyridamole causes a significant reduction in the postoperative incidence of thromboembolic phenomena associated with prosthetic heart valves (mitral and/or aortic valve replacement) without increasing hemorrhagic complications. Use of dipyridamole preoperatively in the prevention of bypass vein grafts has not been associated with an increase of chest tube blood loss or transfusion requirements following coronary bypass surgery.

In vitro, dipyridamole potentiates the aggregation-inhibiting effects of adenosine and prostaglandin E1, inhibits platelet uptake of adenosine, serotonin and glucose and increases platelet cyclic AMP levels. At higher concentrations dipyridamole inhibits platelet aggregation induced by ADP or collagen.

Myocardial blood flow increases in a dose-dependent fashion after i.v. or oral dipyridamole, with flows 170% or more above normal. Maximal increases are achieved at about 2.0 µg/mL with 0.8 µg/mL being the threshold serum level. Single oral doses of 150 mg dipyridamole produce the maximal response. At normal therapeutic doses, no significant alterations of peripheral blood flow, systemic blood pressure or heart rate have been observed.

Dipyridamole is readily absorbed from the gastrointestinal tract, reaching peak plasma levels in man 1 to 3 hours following oral administration. Peak plasma levels are dose-dependent and range from about 0.5 µg/mL after a 25 mg dose to 1.6 µg/mL after a 75 mg dose. Blood levels are quite variable depending on food intake and gastrointestinal peristalsis. Ingestion on an empty stomach may result in higher blood levels.

Following i.v. administration, the half-life in man is about 25 minutes and after oral administration about 3 hours. When plasma levels of drug are followed for up to 60 hours after i.v. administration of 20 mg, 3 exponential components of the decline in plasma levels are detectable with half-lives of 5 minutes, 53 minutes and 11.3 hours. The volume of distribution is about 140 litres with about 92 to 99% binding to plasma proteins, primarily a1-acid glycoprotein.

ASA: ASA interferes with the production of prostaglandins in various organs and tissues through the acetylation of the enzyme cyclo-oxygenase. Prostaglandins are powerful irritants and sensitize pain receptors to histamine and bradykinin. Thus, ASA acts as an analgesic and anti-inflammatory agent by reducing tissue levels of prostaglandins. Its antipyretic activity is due to inhibition of prostaglandin E1 in the brain.

In vitro, ASA inhibits platelet aggregation induced by ADP, collagen and adrenaline. The release of ADP by platelets which leads to the second wave of aggregation is suppressed by ASA. The number of platelet aggregates in the myocardial microcirculation found distal to an electrically induced coronary thrombus is significantly reduced by ASA. It can normalize the increased tendency to platelet aggregation in some patients as determined by in vitro platelet function tests. Bleeding time is prolonged by ASA but platelet survival or half-life is not influenced. ASA combined with dipyridamole, however, was restricted to post-operative drug administration in the prevention of bypass graft occlusion because of the heightened risk of perioperative bleeding in humans.

Orally ingested ASA is absorbed partly from the stomach but primarily from the upper small intestine, with peak serum concentration of salicylate reached at about 2 hours. The drug is distributed throughout most body tissues and transcellular fluids by pH-dependent passive processes. It has been detected in synovial, spinal and peritoneal fluid and in saliva and milk. It crosses the blood-brain barrier relatively slowly because the largest fraction of drug is in the ionized form. Salicylate readily crosses the placental barrier.

Following absorption ASA is rapidly hydrolyzed to salicylate by esterases in the gastrointestinal mucosa, liver, plasma and erythrocytes. By 30 minutes after dosing, only 27% of total plasma salicylate is in the acetylated form. The plasma half-life of ASA is approximately 30 minutes. Due to the rapid hydrolysis of ASA, plasma concentrations of salicylate rarely exceed 20 µg/mL at therapeutic doses. Eighty to 90% of plasma salicylate is protein-bound, primarily to albumin.

Biotransformation takes place primarily in the liver where the salicylate is conjugated with glycine to form salicyluric acid, or with glucuronic acid by an ether (phenolic) or ester (acyl) bond.

A small fraction is oxidized to gentisic acid. Salicylates are excreted mainly by the kidney. In man, the urine contains free salicyclic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (1%). The excretion of free salicylate can be increased to 85% of the ingested drug by alkalinization of urine or decreased to 5% in acidic urine.

The plasma half-life of salicylate is 2 to 3 hours in low doses and 15 to 30 hours in high doses due to saturated metabolic processes in the liver.

Indications And Clinical Uses: Combined therapy with dipyridamole and ASA is indicated in patients who are recovering from a myocardial infarction. The rate of re-infarction is significantly reduced by such therapy.

Combined treatment with dipyridamole and ASA is indicated for the prevention of occlusion of saphenous vein coronary artery bypass grafts.

Contra-Indications: Known sensitivity to salicylates or to other nonsteroidal anti-inflammatory agents, hypersensitivity to dipyridamole, diagnosed ulcers of the gastrointestinal tract, pathological risk of increased bleeding.

Pregnancy: The use of ASA containing products is contraindicated during the last trimester of pregnancy. Salicylates interfere with maternal and infant blood clotting and lengthen the duration of pregnancy and parturition time (see Precautions).

Lactation: The use of ASA containing products is contraindicated during lactation (see Precautions).

Manufacturers’ Warnings In Clinical States: Patients should be cautioned about the possibility of additive toxic effects of ASA if they are taking over-the-counter ASA containing remedies, including cough and cold medications.

Since excessive doses of dipyridamole can produce peripheral vasodilation, dipyridamole should be used with caution in patients with hypotension, rapidly worsening angina, subvalvular aortic stenosis, or hemodynamic instability. In rare cases, such patients may be at risk for developing myocardial ischemia and infarction.

Precautions: ASA should be administered cautiously to patients with asthma and other allergic conditions, a history of gastrointestinal ulcerations, significant anemia or hypoprothrombinemia.

Products containing salicylates should be used cautiously in patients with impaired renal function since salicylate and its metabolites are excreted almost exclusively in the urine. Hematocrit and renal function should be monitored periodically in patients receiving prolonged salicylate therapy or high salicylate doses since iron deficiency or adverse renal effects may occur. Because of increased risk of hepatotoxicity, hepatic function should also be monitored in patients with juvenile arthritis, active systemic lupus erythematosus, rheumatic fever or pre-existing hepatic impairment.

Since salicylates may cause or aggravate hemolysis in patients with pyruvate kinase deficiency or with rare variants of glucose-6-phosphate dehydrogenase, Asasantine should be used cautiously in such patients.

The use of ASA containing products should be avoided in teenagers and young adults with varicella or influenza-like illnesses as the use of salicylates in such conditions has been associated with an increased risk of developing Reye’s syndrome.

Salicylates can produce changes in thyroid function tests.

Children: Not recommended for use in children.

Pregnancy: Reproductive studies have been performed in mice, rats, and rabbits at doses of up to 125 mg/kg and have not revealed evidence of impaired embryonic development attributable to dipyridamole. However, there have not been adequate, well-controlled studies in pregnant women and the drug should be used during pregnancy only if the expected benefits outweigh the potential risks.

Lactation: Dipyridamole is excreted in human milk. Caution should therefore be used when this drug is administered to nursing mothers.

Drug Interactions: Patients taking 2 to 3 g of ASA daily are at an increased risk of developing severe gastrointestinal bleeding following the ingestion of alcohol.

Caution is necessary when salicylates and dipyridamole are used concurrently with anticoagulants or thrombolytics as the combined use of such agents may result in an increased risk of hemorrhage.

ASA induced hypoprothrombinemia, gastrointestinal ulceration, or hemorrhage may be potentiated by the following medications; some cephalosporins (e.g., cefamandole, cefoperazone, moxalactam), some penicillins (e.g., carbenicillin, piperacillin, ticarcillin), dextran, divalproex and valproic acid.

Patients receiving concurrent salicylates and hypoglycemic therapy should be monitored closely, since reduction of the hypoglycemic drug dosage may be necessary.

Although salicylates in large doses are uricosuric agents, smaller amounts may depress uric acid clearance and thus decrease the uricosuric effects of probenecid, sulfinpyrazone, oxyphenbutazone and phenylbutazone.

Caution should be exercised when corticosteroids and salicylates are used concurrently.

Salicylate ingestion should be restricted in patients receiving indomethacin (and perhaps other NSAIDs) for conditions such as rheumatoid arthritis.

Sodium excretion produced by spironolactone may be decreased by salicylate administration.

Concomitant ingestion of salicylates and aminosalicylic acid (PAS) or aminobenzoic acid (PABA) in normal doses may lead to increased toxicity and salicylism.

Salicylates reportedly displace sulfonylureas, penicillins and methotrexate from their binding sites on plasma proteins. Salicylates also retard the renal elimination of methotrexate.

The use of oral maintenance xanthines (e.g., theophylline, aminophylline) or xanthine derivatives (e.g., found in coffee, tea) may weaken the effect of Asasantine.

Adverse Reactions: In a recurrent myocardial infarction trial of 2 026 patients, the most common patient complaints, except for headaches, were those associated with ASA administration. In order of frequency of occurrence, these were stomach pain, headaches, heartburn, dizziness, constipation, hematemesis, bloody stools and/or black, tarry stools, nausea and vomiting. An increased frequency of elevations of serum urea nitrogen, uric acid and creatinine were noted in the active treatment groups but increases for individual patients were small and not associated with clinical problems. There was also a slightly greater frequency of elevated systolic blood pressure readings in the active treatment groups.

When dipyridamole has been used alone, headache, dizziness, nausea, flushing, syncope or weakness and skin rash have occurred during initiation of therapy. In most cases, these tend to be minimal and transient. Gastric irritation, emesis and abdominal cramping may occur at high dosage levels. Rare cases of what appears to be an aggravation of angina pectoris have been reported, usually at the initiation of therapy. On those uncommon occasions when adverse reactions have been persistent or intolerable to the patient, withdrawal of medication has been followed promptly by cessation of the undesirable symptoms.

For ASA alone the following side effects have been reported:

Gastrointestinal: nausea, vomiting, diarrhea, gastrointestinal bleeding and/or ulceration.

Ear: tinnitus, vertigo, hearing loss.

Hematologic: leukopenia, thrombocytopenia, purpura.

Dermatologic and Hypersensitivity: urticaria, angioedema, pruritus, skin eruptions, asthma, anaphylaxis.

Miscellaneous: acute, reversible hepatotoxicity, mental confusion, drowsiness, sweating, thirst.

Symptoms And Treatment Of Overdose: Symptoms: Hypotension, as a result of high serum levels of dipyridamole, is likely to be of short duration if it occurs but vasopressor substances may be used if necessary.

Salicylate overdosage symptoms may include rapid and deep breathing, nausea, vomiting, vertigo, tinnitus, flushing, sweating, thirst and tachycardia. In more severe cases, acid-base disturbances including respiratory alkalosis and metabolic acidosis can occur. Severe cases may show fever, hemorrhage, excitement, confusion, convulsions or coma and respiratory failure.

Treatment: Treatment of salicylate overdosage consists of prevention and management of acid-base and fluid and electrolyte disturbances. Renal clearance is increased by increasing urine flow and by alkaline diuresis but care must be taken in this approach to not further aggravate metabolic acidosis and hypokalemia. Acidemia should be prevented by administration of adequate sodium containing fluids and sodium bicarbonate.

Hypoglycemia is an occasional accompaniment of salicylate overdosage and can be managed by glucose solutions. If a hemorrhagic diathesis is evident, give Vitamin K. Hemodialysis may be useful in complex acid base disturbances particularly in the presence of abnormal renal function.

Dosage And Administration: Prevention of recurrent myocardial infarction: The recommended oral dose is 1 capsule, containing dipyridamole 75 mg and ASA 330 mg, 3 times a day, in patients who have suffered a previous myocardial infarction.

For prevention of occlusion of saphenous vein coronary artery bypass grafts:

For 2 days preoperatively: Persantine 100 mg (oral) q.i.d.

Day of surgery: morning of operation: Persantine 100 mg (oral); 1 hour postop: Persantine 100 mg (via nasogastric tube); 7 hours postop: Asasantine (Persantine/ASA) 1 capsule.

Daily maintenance dosage: (for the next 12 months): Asasantine (Persantine/ASA) 1 capsule t.i.d.

Availability And Storage: Each opaque orange and yellow hard gelatin capsule contains: dipyridamole 75 mg and ASA 330 mg. Nonmedicinal ingredients: acacia, aluminum stearate, gelatin, lactose, magnesium stearate, maize starch, polyvinylpyrrolidone, sodium starch glycollate, sucrose and talc. Energy: 1.39 kJ (0.33 kcal). Packages of 100 and bottles of 500. Store at room temperature (15 to 30°C).

ASASANTINE® Boehringer Ingelheim Dipyridamole – ASA Inhibitor of Platelet Adhesion and Aggregation

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