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| Medication |
Strength |
Quantity |
| Aggrenox (dipyridamole + ASA) |
200mg/25mg |
60 |
Aggrenox
Dipyridamole--ASA
Aggrenox - Aggrenox Side Effects - Aggrenox Information
Pharmacology: Blood platelets participate actively in the pathogenesis of atherosclerotic lesions and thrombosis which is the principle cause of most strokes and transient ischemic attacks (TIAs). Platelets are believed to adhere to denuded, dysfunctional endothelium and to release mitogenic substances, such as platelet-derived growth factor (PDGF), that foster the lesion's progression to rupture and thrombosis. The antithrombotic action of Aggrenox is the result of the additive antiplatelet effects of dipyridamole and ASA.
Dipyridamole: Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in a dose dependent manner at therapeutic plasma concentrations (0.5 to 1.9 µg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A 2-receptor, thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3', 5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Reduced platelet aggregation reduces platelet consumption towards normal levels.
Dipyridamole also inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3', 5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).
ASA: ASA inhibits platelet aggregation by irreversible inhibition of platelet cyclo-oxygenase and thus inhibits the generation of thromboxane A 2, a powerful inducer of platelet aggregation and vasoconstriction. In studies of platelet activity inhibition, 25 mg ASA was administered b.i.d. to 5 subjects for 2.5 days. Complete inhibition of collagen-induced aggregation was achieved by the 5 th dose of ASA, and maximal effect persisted up to 2 to 3 days following stoppage of drug.
Pharmacokinetics: There are no significant interactions between ASA and dipyridamole. The kinetics of the components are unchanged by their coadministration as Aggrenox. Aggrenox is not interchangeable with the individual components of ASA and dipyridamole.
Dipyridamole: Absorption: The dissolution and absorption of dipyridamole from Aggrenox is independent of the pH of the gastrointestinal tract. Peak plasma levels are achieved in 1.5 to 2 h after administration. The absolute bioavailability of dipyridamole from Aggrenox is about 70%. With a daily maintenance dose of 400 mg of the extended release formulation, peak plasma levels at steady state are between 1.5 to 3 µg/mL and trough levels are between 0.4 to 0.8 µg/mL.
Pharmacokinetic studies to determine the effect of food have not been conducted with Aggrenox.
Distribution: Due to its high lipophilicity, dipyridamole distributes to many organs; however it has been shown that the drug does not cross the blood brain barrier to any significant extent.
Metabolism and Elimination: Dipyridamole is metabolized in the liver. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). The dominant half-life for elimination after oral or i.v. administration is about 40 minutes.
Pharmacokinetics of Dipyridamole in Special Populations: Geriatrics: Plasma concentrations (determined as area under the curve, AUC) of dipyridamole in healthy elderly subjects (>65 years) are about 30 to 50% higher than in subjects younger than 55 years, on treatment with Aggrenox. The difference is caused mainly by reduced clearance.
Hepatic Dysfunction: Patients with mild to severe hepatic insufficiency show no change in plasma concentrations of dipyridamole compared to healthy volunteers, but show an increase in the pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be dosed without restriction as long as there is no evidence of liver failure.
Renal Dysfunction: Renal excretion of dipyridamole is very low (about 5%). In patients with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite.
ASA: Absorption: The rate of absorption of ASA from the gastrointestinal tract is dependent on the dosage form, the presence or absence of food, gastric pH, and other physiologic factors. Since ASA produces its pharmacodynamic effect via the irreversible acetylating of platelets, the time course of its pharmacodynamic activity is not dependent on the pharmacokinetics of ASA but rather on the lifespan of the platelets (approximately 8 to 10 days). Therefore, small differences in the pharmacokinetics of ASA, such as variations in its absorption rate or in elimination, are largely irrelevant to its pharmacologic activity with chronic administration. ASA undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50 to 75% of an administered dose reaching the systemic circulation as intact ASA. Peak plasma levels of ASA are achieved 0.5 to 1 hour after administration of a 50 mg ASA daily dose from Aggrenox (given as 25 mg b.i.d.). Peak mean plasma concentration at steady state is 319 ng/mL (175 to 463 ng/mL).
Distribution: ASA is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). At low plasma concentrations (<100 µg/mL), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body including the CNS, breast milk, and fetal tissues. Early signs of salicylate overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approximating 200 µg/mL (see Adverse Effects and Overdose: Symptoms and Treatment).
Metabolism: ASA is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 15 to 30 minutes. Plasma levels of ASA are essentially undetectable 1 to 2 hours after dosing and peak salicylic acid concentrations occur within 1 to 2 hours of administration of ASA. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to over 20 hours.
Elimination: The elimination of salicylic acid follows first order kinetics at lower doses, with a resultant half-life of approximately 2 to 3 hours. Renal excretion of unchanged drug depends upon urinary pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalinization of the urine is a key concept in the management of salicylate overdose (see Overdose: Symptoms and Treatment). Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, in urine.
Pharmacokinetics of ASA in Special Populations: Hepatic Dysfunction: Due to the ASA component, Aggrenox is to be avoided in patients with severe hepatic insufficiency.
Renal Dysfunction: Due to the ASA component, Aggrenox is to be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/min).
Indications: Prevention of stroke in patients who have had a previous stroke or a transient ischemic attack (TIA).
Contraindications: In patients with hypersensitivity to dipyridamole, ASA or any of the other product components.
Due to the ASA component, Aggrenox is also contraindicated in patients with known allergy to NSAID products and in patients with the syndrome of asthma, rhinitis, and nasal polyps.
Warnings: Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking Aggrenox, due to the ASA component.
Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using Aggrenox, which can cause gastric mucosal irritation, and bleeding, due to the ASA component.
Children: Safety and effectiveness of Aggrenox in pediatric patients has not been studied. Therefore, Aggrenox should not be used in pediatric patients.
Pregnancy: There are no adequate and well-controlled studies of Aggrenox in pregnant women. Because animal reproduction studies are not always predictive of human response, Aggrenox should be given during the first two trimesters of pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Due to the ASA component, Aggrenox should not be prescribed during the third trimester of pregnancy.
Precautions: General: Aggrenox should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction), due to the vasodilatory effect of the dipyridamole component. Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole.
For stroke or TIA patients for whom ASA is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the dose of ASA in Aggrenox has not been proven to provide adequate treatment for these cardiac indications.
ASA should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of ASA in certain viral illnesses.
Due to the ASA component, Aggrenox should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/min) and in patients with severe hepatic insufficiency.
Aggrenox should be used with caution in patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders, due to the fact that even low doses of ASA can inhibit platelet function leading to an increase in bleeding time.
Gastrointestinal side effects include stomach pain, heartburn, nausea, vomiting, diarrhea, and gross gastrointestinal bleeding. Although minor upper gastrointestinal symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous gastrointestinal symptoms. Physicians should inform patients about the signs and symptoms of gastrointestinal side effects and what steps to take if they occur.
Carcinogenesis and Impairment of Fertility: Carcinogenesis: In carcinogenicity studies in rats and mice with the combination of dipyridamole and ASA at the ratio of 1:6 over a period of 125 and 105 weeks respectively, no significant tumorigenic effect was observed at maximum doses of 450 mg/kg (corresponding to a share of 75 mg/kg of dipyridamole, 9 times the maximum recommended daily human dose for a 50 kg person on a mg/kg basis [or 1.5 to 2.1 times on a mg/m 2 basis]), and 375 mg/kg ASA, 375 times the maximum recommended daily human dose for a 50 kg person on a mg/kg basis (or 58 to 83 times on a mg/m 2 basis).
Fertility: Fertility studies with dipyridamole revealed no evidence of impaired fertility in rats at oral dosages of up to 1250 mg/kg, 156 times the maximum recommended human dose on a mg/kg basis for a 50 kg person (or 35 times on a mg/m 2 basis). ASA inhibits ovulation in rats.
Lactation: Dipyridamole and ASA are excreted in human breast milk in low concentrations. Therefore, caution should be exercised when Aggrenox is administered to a nursing woman.
Laboratory Tests: ASA has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time. Over the course of the 24-month study (ESPS2), patients treated with Aggrenox showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x10 6/mm 3.
Drug Interactions : Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.
Cholinesterase Inhibitors: The dipyridamole component of Aggrenox may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.
The following drug interactions are associated with the ASA component of Aggrenox:
Angiotensin Converting Enzyme (ACE) Inhibitors: Due to the indirect effect of the ASA component on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of Aggrenox.
Acetazolamide: Due to the ASA component, concurrent use of Aggrenox and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.
Anticoagulant Therapy (heparin and warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and effects on platelets. ASA can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. The ASA component of Aggrenox can increase the anticoagulant activity of heparin, increasing bleeding risk.
Anticonvulsants: The ASA component of Aggrenox can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.
Beta-blockers: The hypotensive effects of beta-blockers may be diminished by the concomitant administration of Aggrenox due to inhibition of renal prostaglandins by ASA, leading to decreased renal blood flow and salt and fluid retention.
Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of Aggrenox due to inhibition of renal prostaglandins by ASA, leading to decreased renal blood flow and salt and fluid retention.
Methotrexate: The ASA component of Aggrenox can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renally impaired.
NSAIDs: Due to the ASA component, the concurrent use of Aggrenox with other NSAIDs may increase bleeding or lead to decreased renal function.
Oral Hypoglycemics: Aggrenox may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and sulfinpyrazone): The ASA component of Aggrenox antagonizes the uricosuric action of uricosuric agents.
Adverse Effects: A 24-month, multicentre, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of Aggrenox with placebo, extended release dipyridamole alone and ASA alone. The study was conducted in a total of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within 3 months prior to randomization.
Discontinuation due to adverse events in ESPS2 was 27.8% for Aggrenox, 28.2% for extended release dipyridamole, 23.2% for ASA, and 23.7% for placebo.
Rare Adverse Reactions: Adverse reactions that occurred in less than 1% of patients treated with Aggrenox in the ESPS2 study and that were medically judged to be possibly related to either dipyridamole or ASA are listed below.
Body as a Whole: allergic reaction, fever.
Cardiovascular: hypotension, flushing.
CNS: coma, dizziness, paresthesia.
Gastrointestinal: gastritis, ulceration, perforation.
Hearing and Vestibular Disorders: tinnitus and deafness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.
Heart Rate and Rhythm: tachycardia, palpitation, arrhythmia, supraventricular tachycardia.
Liver and Biliary Systems: cholelithiasis, jaundice, abnormal hepatic function.
Metabolic and Nutritional: hyperglycemia, thirst.
Platelet, Bleeding and Clotting Disorders: hematoma, gingival bleeding, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage.
Note: There was 1 case of pancytopenia recorded in a patient within the Aggrenox treatment group, from which the patient recovered without discontinuation of Aggrenox.
Psychiatric: agitation.
Reproductive: uterine hemorrhage.
Respiratory: hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema.
Special Senses: taste loss.
Skin and Appendages: pruritus, urticaria.
Urogenital: renal insufficiency and failure, hematuria.
Postmarketing Experience: The following is a list of additional adverse reactions that have been reported either in the literature or are from postmarketing spontaneous reports for either dipyridamole or ASA.
Body as a Whole: hypothermia.
Cardiovascular: angina pectoris.
CNS: cerebral edema.
Fluid and Electrolyte: hyperkalemia, metabolic acidosis, respiratory alkalosis.
Gastrointestinal: pancreatitis, Reye's syndrome.
Hearing and Vestibular: hearing loss.
Hypersensitivity: acute anaphylaxis, laryngeal edema.
Liver and Biliary: hepatitis.
Musculoskeletal: rhabdomyolysis.
Metabolic and Nutritional: hypoglycemia, dehydration.
Platelet, Bleeding and Clotting Disorders: prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia.
Reproductive: prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding.
Respiratory: tachypnea.
Skin and Appendages: rash, alopecia, angioedema.
Urogenital: interstitial nephritis, papillary necrosis, proteinuria.
Laboratory Changes: Over the course of the 24-month study (ESPS2), patients treated with Aggrenox showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13´10 6/mm 3.
Overdose: Because of the dose ratio of dipyridamole to ASA, overdosage of Aggrenox is likely to be dominated by signs and symptoms of dipyridamole overdose. For real or suspected overdose, a Poison Control Centre should be contacted immediately. Careful medical management is essential.
Symptoms:
Dipyridamole: Based upon the known hemodynamic effects of dipyridamole, symptoms such as feeling warm, flushes, sweating, restlessness, feeling of weakness and dizziness may occur. A drop in blood pressure and tachycardia might also be observed.
ASA: In mild overdosage these 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, convulsion or coma and respiratory failure.
Treatment: Dipyridamole: Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.
ASA: Treatment 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 not to aggravate further the metabolic acidosis that develops and the 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 administration of 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: For oral administration. The recommended dose is 1 capsule twice daily, 1 in the morning and 1 in the evening, with or without food. The capsules should be swallowed whole without chewing.
Information for the Patient: See Blue Section--Information for the Patient Aggrenox.
Supplied: Each hard gelatin capsule, with a red cap and an ivory-colored body, imprinted in red with the Boehringer Ingelheim logo and with 01A, contains: dipyridamole 200 mg as extended-release pellets (a mixture of 2 release rate pellets) and ASA 25 mg as an immediate-release sugar-coated tablet. Nonmedicinal ingredients: acacia, aluminum stearate, colloidal silicon dioxide, cornstarch, dimethicone, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide and triacetin; capsule shell: gelatin, red iron oxide, titanium dioxide, water and yellow iron oxide. Polypropylene tubes of 60. Store at 15 to 30°C. Protect from excessive moisture.
IMPORTANT NOTE: THE FOLLOWING INFORMATION IS INTENDED TO SUPPLEMENT, NOT SUBSTITUTE FOR, THE EXPERTISE AND JUDGMENT OF YOUR PHYSICIAN, PHARMACIST OR OTHER HEALTHCARE PROFESSIONAL. IT SHOULD NOT BE CONSTRUED TO INDICATE THAT USE OF THE DRUG IS SAFE, APPROPRIATE, OR EFFECTIVE FOR YOU. CONSULT YOUR HEALTHCARE PROFESSIONAL BEFORE USING THIS DRUG.
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