英文药名：AGGRENOX(aspirin/extended-release dipyridamole Capsules)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Aggrenox Capsules safely and effectively. See full prescribing information for Aggrenox Capsules.
AGGRENOX® (aspirin/extended-release dipyridamole) Capsules
Initial U.S. Approval: 1999
RECENT MAJOR CHANGES
Warnings and Precautions
Risk of Bleeding (5.1) 9/2012
INDICATIONS AND USAGE
AGGRENOX is a combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1)
DOSAGE AND ADMINISTRATION
One capsule twice daily (morning and evening) with or without food (2)
In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2)
Do not chew capsule (2)
Not interchangeable with the individual components of aspirin and dipyridamole tablets (2)
Dispense in this unit-of-use container (16)
DOSAGE FORMS AND STRENGTHS
Capsule: 25 mg aspirin/200 mg extended-release dipyridamole (3)
Hypersensitivity to any product ingredients (4.1)
Patients with known allergy to NSAIDs (4.2)
Patients with the syndrome of asthma, rhinitis, and nasal polyps (4.2)
WARNINGS AND PRECAUTIONS
AGGRENOX increases the risk of bleeding (5.1)
Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3)
Can cause fetal harm when administered to a pregnant woman, especially in the third trimester (5.4)
The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea, and diarrhea (6)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Co-administration with anticoagulants, antiplatelets, or NSAIDS can increase risk of bleeding (7.1)
Decreased renal function can occur with co-administration with NSAIDS (7.1)
USE IN SPECIFIC POPULATIONS
Pregnancy Category D (8.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
AGGRENOX is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.
2 DOSAGE AND ADMINISTRATION
AGGRENOX is not interchangeable with the individual components of aspirin and dipyridamole tablets.
The recommended dose of AGGRENOX is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. AGGRENOX can be administered with or without food.
2.1 Alternative Regimen in Case of Intolerable Headaches
In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.
3 DOSAGE FORMS AND STRENGTHS
25 mg/200 mg capsules with a red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and a round white tablet incorporating immediate-release aspirin. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with "01A".
AGGRENOX is contraindicated in patients with known hypersensitivity to any of the product components.
Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm.
4.3 Reye Syndrome
Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome.
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Bleeding
AGGRENOX increases the risk of bleeding. Risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1)].
In ESPS2 the incidence of intracranial hemorrhage was 0.6% in the AGGRENOX group, 0.5% in the extended-release dipyridamole (ER-DP) group, 0.4% in the aspirin (ASA) group and 0.4% in the placebo groups.
Gastrointestinal (GI) Side Effects
GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI 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 GI symptoms. Inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.
In ESPS2 the incidence of gastrointestinal bleeding was 4.1% in the AGGRENOX group, 2.2% in the extended-release dipyridamole group, 3.2% in the aspirin group, and 2.1% in the placebo groups.
Peptic Ulcer Disease
Avoid using aspirin in patients with a history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding.
Because AGGRENOX contains aspirin, counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.
5.2 Renal Failure
Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
5.3 Hepatic Insufficiency
Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Because AGGRENOX contains aspirin, AGGRENOX can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death. Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), avoid AGGRENOX in the third trimester of pregnancy [see Use in Specific Populations (8.1)].
Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. These doses, which also resulted in a high resorption rate in rats (63% of implantations versus 5% in controls), are, on a mg/m2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of AGGRENOX. Reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There are no adequate and well-controlled studies of the use of AGGRENOX in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while taking AGGRENOX, inform the patient of the potential hazard to the fetus.
5.5 Coronary Artery Disease
Dipyridamole has a vasodilatory effect. Chest pain may be precipitated or aggravated in patients with underlying coronary artery disease who are receiving dipyridamole.
For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications.
Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.
AGGRENOX capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
Hypersensitivity [see Contraindications (4.1)].
Allergy [see Contraindications (4.2)].
Risk of Bleeding [see Warnings and Precautions (5.1)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The efficacy and safety of AGGRENOX was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo controlled study that evaluated 6602 patients over the age of 18 years who had a previous ischemic stroke or transient ischemic attack within ninety days prior to entry. Patients were randomized to either AGGRENOX, aspirin, ER-DP, or placebo [see Clinical Studies (14)]; primary endpoints included stroke (fatal or nonfatal) and death from all causes.
This 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX with placebo, extended-release dipyridamole alone and aspirin 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 three months prior to randomization
Table 1 presents the incidence of adverse events that occurred in 1% or more of patients treated with AGGRENOX where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.
Table 1 Incidence of Adverse Events in ESPS2*
* Reported by ≥1% of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.
Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID
NOS = not otherwise specified.
Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to Table 2)
Table 2 Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the AGGRENOX Group
Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID
Headache was most notable in the first month of treatment.
Other Adverse Events
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 aspirin are listed below.
Body as a Whole: Allergic reaction, fever
Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage
Gastrointestinal: Gastritis, ulceration and 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 Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia
Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal
Metabolic and Nutritional Disorders: Hyperglycemia, thirst
Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding
Psychiatric Disorders: Agitation
Reproductive: Uterine hemorrhage
Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema
Special Senses Other Disorders: Taste loss
Skin and Appendages Disorders: Pruritus, urticaria
Urogenital: Renal insufficiency and failure, hematuria
Vascular (Extracardiac) Disorders: Flushing
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 0.13x106/mm3.
6.2 Post-Marketing Experience
The following is a list of additional adverse reactions that have been reported either in the literature or are from post-marketing spontaneous reports for either dipyridamole or aspirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AGGRENOX.
Body as a Whole: Hypothermia, chest pain
Cardiovascular: Angina pectoris
Central Nervous System: Cerebral edema
Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia
Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis
Hearing and Vestibular Disorders: Hearing loss
Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema
Liver and Biliary System Disorders: Hepatitis, hepatic failure
Metabolic and Nutritional Disorders: 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, dyspnea
Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria
Vascular (Extracardiac Disorders): Allergic vasculitis
Other Adverse Events: anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.
7 DRUG INTERACTIONS
7.1Drug Interaction Study Information Obtained From Literature
Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.
Angiotensin Converting Enzyme (ACE) Inhibitors
Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.
Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.
Anticoagulants and Antiplatelets
Patients taking AGGRENOX in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.
Salicylic acid 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.
The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.
The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.
Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and sulfinpyrazone)
Salicylates antagonize the uricosuric action of uricosuric agents.
8 USE IN SPECIFIC POPULATIONS
Teratogenic Effects, Pregnancy Category D. [see Warnings and Precautions (5.4)].
8.2 Labor and Delivery
Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy [see Warnings and Precautions (5.4)], avoid AGGRENOX in the third trimester of pregnancy and during labor and delivery.
8.3 Nursing Mothers
Both dipyridamole and aspirin are excreted in human milk. Exercise caution when AGGRENOX capsules are administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended [see Contraindications (4.3)].
8.5 Geriatric Use
Of the total number of subjects in ESPS2, 61 percent were 65 and over, while 27 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
8.6 Patients with Severe Hepatic or Severe Renal Dysfunction
AGGRENOX has not been studied in patients with hepatic or renal impairment. Avoid using aspirin containing products, such as AGGRENOX in patients with severe hepatic or severe renal (glomerular filtration rate < 10 mL/min) dysfunction [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].
Because of the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOX is likely to be dominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential.
Based upon the known hemodynamic effects of dipyridamole, symptoms such as warm feeling, flushes, sweating, restlessness, feeling of weakness and dizziness may occur. A drop in blood pressure and tachycardia might also be observed.
Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. Severity of aspirin intoxication is determined by measuring the blood salicylate level. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 µg/mL. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Plasma concentrations of aspirin above 300 µg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 µg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g.
Treatment of overdose consists primarily of supporting vital functions, increasing drug elimination, and correcting acid-base disturbances. Consider gastric emptying and/or lavage as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal as a slurry may be beneficial if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. Follow acid-base status closely with serial blood gas and serum pH measurements. Maintain fluid and electrolyte balance. Administer replacement fluid intravenously and augment with correction of acidosis. Treatment may require the use of a vasopressor. Infusion of glucose may be required to control hypoglycemia.
Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Plasma electrolytes and pH should be monitored serially to promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required to treat salicylic overdose, however since dipyridamole is highly protein bound, dialysis is not likely to remove dipyridamole. Exchange transfusion may be indicated in infants and young children.
AGGRENOX is a combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: acacia, aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide and triacetin.
Each capsule shell contains gelatin, red iron oxide and yellow iron oxide, titanium dioxide and water.
Dipyridamole is an antiplatelet agent chemically described as 2,2',2'',2'''-[(4,8-Dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula:
Dipyridamole is an odorless yellow crystalline substance, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and is practically insoluble in water.
The antiplatelet agent aspirin (acetylsalicylic acid) is chemically known as benzoic acid, 2- (acetyloxy)-, and has the following structural formula:
Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The antithrombotic action of AGGRENOX is the result of the additive antiplatelet effects of dipyridamole and aspirin.
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 concentrations (0.5–1.9 µg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-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).
Dipyridamole 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).
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.
The effect of either agent on the other's inhibition of platelet reactivity has not been evaluated.
There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their co-administration as AGGRENOX.
Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg AGGRENOX (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 µg/mL (1.01–3.99 µg/mL) and the steady-state trough concentration is 0.53 µg/mL (0.18–1.01 µg/mL).
Effect of Food
When AGGRENOX capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 20-30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant.
Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin.
Metabolism and Elimination
Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. 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%). With intravenous (i.v.) treatment of dipyridamole, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a half-life of about 39 minutes, (which, together with the alpha phase accounts for about 70% of the total area under the curve, AUC) and a prolonged elimination phase λz with a half-life of about 15.5 hours. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with AGGRENOX which, in Trial 9.123 was 13.6 hours.
Geriatric Patients: In ESPS2 [see Clinical Studies (14)], plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with AGGRENOX.
Hepatic Dysfunction: No study has been conducted with AGGRENOX in patients with hepatic dysfunction.
In a study conducted with an intravenous formulation of dipyridamole, patients with mild to severe hepatic insufficiency showed no change in plasma concentrations of dipyridamole but showed an increase in the pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be dosed without restriction as long as there is no evidence of hepatic failure.
Renal Dysfunction: No study has been conducted with AGGRENOX in patients with renal dysfunction.
In ESPS2 patients [see Clinical Studies (14)], 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 if data were corrected for differences in age.
Peak plasma levels of aspirin are achieved 0.63 hours (0.5–1 hour) after administration of a 50 mg aspirin daily dose from AGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175–463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%–75% of an administered dose reaching the systemic circulation as intact aspirin.
Effect of Food
When AGGRENOX capsules were taken with a high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in Cmax was not considered clinically relevant based on a similar degree of cyclooxygenase inhibition comparing the fed and fasted state.
Aspirin is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration-dependent (nonlinear). At low 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 central nervous system, 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 Reactions (6) and Overdosage (10)].
Metabolism and Elimination
Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2–2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5–2 hours) after administration of aspirin. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. 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 (10–20 g), the plasma half-life may be increased to over 20 hours.
The elimination of acetylsalicylic acid follows first-order kinetics with AGGRENOX and has a half-life of 0.33 hours. The half-life of salicylic acid is 1.71 hours. Both values correspond well with data from the literature at lower doses which state a resultant half-life of approximately 2–3 hours. At higher doses, the elimination of salicylic acid follows zero-order kinetics (i.e., the rate of elimination is constant in relation to plasma concentration), with an apparent half-life of 6 hours or higher. 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 Overdosage (10)]. Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, as the phenolic and acyl glucuronides, in urine.
Hepatic Dysfunction: Avoid aspirin in patients with severe hepatic insufficiency.
Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min).
A dedicated drug interaction study was conducted in 60 healthy volunteers to evaluate the effects of omeprazole 80 mg administered once daily on the pharmacokinetics (PK) of dipyridamole and the pharmacodynamics (PD) of acetylsalicylic acid when co-administered with AGGRENOX twice daily. Dipyridamole exposure (Cmax and AUC) at steady-state were similar with or without omeprazole co-administration. The pharmacokinetics of acetylsalicylic acid was not characterized. However, the antiplatelet activity as measured by arachidonic acid induced platelet aggregation was similar between the treatment arms at steady-state.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats.
Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.
Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.
14 CLINICAL STUDIES
ESPS2 (European Stroke Prevention Study 2) was a double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: AGGRENOX (aspirin/extended-release dipyridamole) 25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by a blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had a trend towards more events.
AGGRENOX reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (Table 3). AGGRENOX reduced the risk of stroke by 36.8% compared to placebo (p <0.001).
Table 3 Summary of First Stroke (Fatal or Nonfatal): ESPS2: Intent-to-Treat Population
*0.010 < p-value ≤0.050; **p-value ≤0.010.
Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID
ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal)
Over 24 months of Follow-UP
Combined Stroke or Death Endpoint
In ESPS2, AGGRENOX reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. AGGRENOX reduced the risk of stroke or death by 24.2% compared to placebo.
The incidence rate of all cause mortality was 11.3% for AGGRENOX, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the AGGRENOX, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for AGGRENOX and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
AGGRENOX capsules are available as a hard gelatin capsule, with a red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and a round white tablet incorporating immediate-release aspirin. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with "01A".
AGGRENOX capsules are supplied in unit-of-use bottles of 60 capsules (NDC 0597-0001-60).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from excessive moisture.
脑康平Aggrenox(aspirin 25mg+dipyridamole 200mg)-预防二度中风新药
Aggrenox(内含25mg aspirin及200mg dipyridamole)胶囊为最近上市用于预防二度暂时性脑血管缺血或缺血性脑中风药物。美国药物食品管理局于1999年11月22日核准Aggrenox胶囊在美国上市，核准剂量为每天两次，每次一颗胶囊。 Aggrenox内含两种不同机转的抗凝血药物;低剂量aspirin能选择性抑制cox脢在血小板的作用，增加PGI2浓度，提高抗凝血效果，而dipyridamole主要作用机转于细胞内,借抑制phosphodiesterase活性，增加cAMP细胞内的浓度，启动一连串抗凝血机转。两者相辅相乘，提高预防二度中风的效果。
根据大型ESPS-2(1)(2)针对预防二度中风的大型临床试验发现，6602位在试验前三个月内发生中风或TIA的受试者，在两年的follow-up期间发现，四组(1)aspirin 25mg bid: 1649 pts. (2)dipyridamole 200mg bid: 1654 pts.(3)aspirin 25mg+ dipyridamole 200mg bid: 1650 pts. (4)placebo bid: 1649 pts,每天两次服用指定药物的结果，Aspirin组及dipyridamole组达到降低二度中风统计上的意义，分别降低16%及18%机率，而aspirin+dipyridamole组和placebo相比，降低37%中风机率(p<0.001)。和aspirin组相比，降低23%机率(p=0.006)，其ARR(absolute risk reduction)两年为3%，也就是每年约1.5%。
Aggrenox是目前唯一合并aspirin及dipyridamole的药物，目前并无试验比较其与clopidogrel或ticlopidine预防二度中风的效果差异。但根据ESPS-2, TASS, CAPRIE三个分别针对Aggrenox, ticlopidine, clopidogrel的大型临床试验发现，Aggrenox似乎比另外两者在预防二度中风有较好的效果。
AGGRENOX 25mg/200mg/capsule 60capsules/box 12 HR
脑康平 25毫克/200毫克/胶囊 60胶囊/瓶 12小时复方缓释胶囊
AGGRENOX 25mg/200mg/capsule Extended Release 50capsules/box
脑康平缓释胶囊 25毫克/200毫克/胶囊 50胶囊/瓶
Boehringer Ingelheim pharma Gmb H&CO.KG
AGGRENOX 25mg/200mg/capsule Extended Release100capsules/box
脑康平 25毫克/200毫克/胶囊 100胶囊/瓶
Boehringer Ingelheim pharma Gmb H&CO.KG