Components:
Treatment option:
Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 15.03.2022
Attention! Information on this page is intended only for medical professionals! Information is collected in open sources and may contain significant errors! Be careful and double-check all the information on this page!
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”.
Storage And Handling
%medicine_name% 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”.
%medicine_name% 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). Protect from excessive moisture.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Revised: November 2015
%medicine_name% 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.
%medicine_name% is not interchangeable with the individual components of aspirin and dipyridamole tablets.
The recommended dose of %medicine_name% is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. %medicine_name% can be administered with or without food.
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.
Hypersensitivity
%medicine_name% is contraindicated in patients with known hypersensitivity to any of the product components.
Allergy
Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug (NSAID) products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm.
Reye Syndrome
Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Risk Of Bleeding
%medicine_name% 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, anagrelide, fibrinolytic therapy, and chronic use of NSAIDs).
Intracranial Hemorrhage
In European Stroke Prevention Study-2 (ESPS2), the incidence of intracranial hemorrhage was 0.6% in the %medicine_name% 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 %medicine_name% 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.
Alcohol Warning
Because %medicine_name% 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.
Renal Failure
Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).
Hepatic Insufficiency
Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration.
Pregnancy
Because %medicine_name% contains aspirin, %medicine_name% 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 %medicine_name% in the third trimester of pregnancy.
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 %medicine_name%. 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 %medicine_name% in pregnant women. If %medicine_name% is used during pregnancy, or if the patient becomes pregnant while taking %medicine_name%, inform the patient of the potential hazard to the fetus.
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.
Hypotension
Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.
General
%medicine_name% capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
- Risk of Bleeding
Inform patients that as with other antiplatelet agents, there is a general risk of bleeding including intracranial and gastrointestinal bleeding. Inform patients about the signs and symptoms of bleeding, including occult bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding.
Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. - Pregnancy
Inform patients that aspirin is known to be harmful to fetuses and ask the patient to notify them if they are or become pregnant. - Headaches
Some patients may experience headaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact their physician. - Dosage and Administration
Tell patients that %medicine_name% capsules should be swallowed whole, and not chewed or crushed. If you miss a dose, continue with your next dose on your regular schedule. Do not take a double dose. - Storage
Inform patients to protect %medicine_name% from moisture.
Nonclinical Toxicology
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.
Use In Specific Populations
Pregnancy
Teratogenic Effects, Pregnancy Category D..
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 , avoid %medicine_name% in the third trimester of pregnancy and during labor and delivery.
Nursing Mothers
Both dipyridamole and aspirin are excreted in human milk. Exercise caution when %medicine_name% capsules are administered to a nursing woman.
Pediatric Use
Safety and effectiveness of %medicine_name% in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended.
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.
Patients With Severe Hepatic Or Severe Renal Dysfunction
%medicine_name% has not been studied in patients with hepatic or renal impairment. Avoid using aspirin containing products, such as %medicine_name% in patients with severe hepatic or severe renal (glomerular filtration rate < 10 mL/min) dysfunction.
SIDE EFFECTS
The following adverse reactions are discussed elsewhere in the labeling:
- Hypersensitivity
- Allergy
- Risk of Bleeding
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 %medicine_name% 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 %medicine_name%, aspirin, ER-DP, or placebo ; 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 %medicine_name% 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 %medicine_name% 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 ESPS2a
Individual Treatment Group | ||||||||
Body System/Preferred Term | %medicine_name% | ER-DP Alone | ASA Alone | Placebo | ||||
Total Number of Patients | 1650 | 1654 | 1649 | 1649 | ||||
Total Number (%) of Patients With at Least One On-Treatment Adverse Event | 1319 (80%) | 1305 (79%) | 1323 (80%) | 1304 (79%) | ||||
Central and Peripheral Nervous System Disorders | ||||||||
Headache | 647 (39%) | 634 (38%) | 558 (34%) | 543 (33%) | ||||
Convulsions | 28 (2%) | 15 (1%) | 28 (2%) | 26 (2%) | ||||
Gastrointestinal System Disorders | ||||||||
Dyspepsia | 303 (18%) | 288 (17%) | 299 (18%) | 275 (17%) | ||||
Abdominal Pain | 289 (18%) | 255 (15%) | 262 (16%) | 239 (14%) | ||||
Nausea | 264 (16%) | 254 (15%) | 210 (13%) | 232 (14%) | ||||
Diarrhea | 210 (13%) | 257 (16%) | 112 (7%) | 161 (10%) | ||||
Vomiting | 138 (8%) | 129 (8%) | 101 (6%) | 118 (7%) | ||||
Hemorrhage Rectum | 26 (2%) | 22 (1%) | 16 (1%) | 13 (1%) | ||||
Melena | 31 (2%) | 10 (1%) | 20 (1%) | 13 (1%) | ||||
Hemorrhoids | 16 (1%) | 13 (1%) | 10 (1%) | 10 (1%) | ||||
GI Hemorrhage | 20 (1%) | 5 (0%) | 15 (1%) | 7 (0%) | ||||
Body as a Whole - General Disorders | ||||||||
Pain | 105 (6%) | 88 (5%) | 103 (6%) | 99 (6%) | ||||
Fatigue | 95 (6%) | 93 (6%) | 97 (6%) | 90 (5%) | ||||
Back Pain | 76 (5%) | 77 (5%) | 74 (4%) | 65 (4%) | ||||
Accidental Injury | 42 (3%) | 24 (1%) | 51 (3%) | 37 (2%) | ||||
Malaise | 27 (2%) | 23 (1%) | 26 (2%) | 22 (1%) | ||||
Asthenia | 29 (2%) | 19 (1%) | 17 (1%) | 18 (1%) | ||||
Syncope | 17 (1%) | 13 (1%) | 16 (1%) | 8 (0%) | ||||
Psychiatric Disorders | ||||||||
Amnesia | 39 (2%) | 40 (2%) | 57 (3%) | 34 (2%) | ||||
Confusion | 18 (1%) | 9 (1%) | 22 (1%) | 15 (1%) | ||||
Anorexia | 19 (1%) | 17 (1%) | 10 (1%) | 15 (1%) | ||||
Somnolence | 20 (1%) | 13 (1%) | 18 (1%) | 9 (1%) | ||||
Musculoskeletal System Disorders | ||||||||
Arthralgia | 91 (6%) | 75 (5%) | 91 (6%) | 76 (5%) | ||||
Arthritis | 34 (2%) | 25 (2%) | 17 (1%) | 19 (1%) | ||||
Arthrosis | 18 (1%) | 22 (1%) | 13 (1%) | 14 (1%) | ||||
Myalgia | 20 (1%) | 16 (1%) | 11 (1%) | 11 (1%) | ||||
Respiratory System Disorders | ||||||||
Coughing | 25 (2%) | 18 (1%) | 32 (2%) | 21 (1%) | ||||
Upper Respiratory Tract Infection | 16 (1%) | 9 (1%) | 16 (1%) | 14 (1%) | ||||
Cardiovascular Disorders, General | ||||||||
Cardiac Failure | 26 (2%) | 17 (1%) | 30 (2%) | 25 (2%) | ||||
Platelet, Bleeding and Clotting Disorders | ||||||||
Hemorrhage NOS | 52 (3%) | 24 (1%) | 46 (3%) | 24 (1%) | ||||
Epistaxis | 39 (2%) | 16 (1%) | 45 (3%) | 25 (2%) | ||||
Purpura | 23 (1%) | 8 (0%) | 9 (1%) | 7 (0%) | ||||
Neoplasm | ||||||||
Neoplasm NOS | 28 (2%) | 16 (1%) | 23 (1%) | 20 (1%) | ||||
Red Blood Cell Disorders | ||||||||
Anemia | 27 (2%) | 16 (1%) | 19 (1%) | 9 (1%) | ||||
aReported by ≥ 1% of patients during %medicine_name%
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 %medicine_name%, 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 %medicine_name% Group
Treatment Groups | ||||
%medicine_name% | ER-DP | ASA | Placebo | |
Total Number of Patients | 1650 | 1654 | 1649 | 1649 |
Patients with at least one Adverse Event that led to treatment discontinuation | 417 (25%) | 419 (25%) | 318 (19%) | 352 (21%) |
Headache | 165 (10%) | 166 (10%) | 57 (3%) | 69 (4%) |
Dizziness | 85 (5%) | 97 (6%) | 69 (4%) | 68 (4%) |
Nausea | 91 (6%) | 95 (6%) | 51 (3%) | 53 (3%) |
Abdominal Pain | 74 (4%) | 64 (4%) | 56 (3%) | 52 (3%) |
Dyspepsia | 59 (4%) | 61 (4%) | 49 (3%) | 46 (3%) |
Vomiting | 53 (3%) | 52 (3%) | 28 (2%) | 24 (1%) |
Diarrhea | 35 (2%) | 41 (2%) | 9 ( < 1%) | 16 ( < 1%) |
Stroke | 39 (2%) | 48 (3%) | 57 (3%) | 73 (4%) |
Transient Ischemic Attack | 35 (2%) | 40 (2%) | 26 (2%) | 48 (3%) |
Angina Pectoris | 23 (1%) | 20 (1%) | 16 ( < 1%) | 26 (2%) |
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 %medicine_name% 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
Cardiovascular: Hypotension
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
Laboratory Changes
Over the course of the 24-month study (ESPS2), patients treated with %medicine_name% 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.
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 %medicine_name%.
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
Musculoskeletal: Rhabdomyolysis
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.
DRUG INTERACTIONS
Drug Interaction Study Information Obtained From Literature
Adenosine
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.
Acetazolamide
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 %medicine_name% 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.
Anagrelide
Patients taking aspirin in combination with anagrelide are at an increased risk of bleeding.
Anticonvulsants
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.
Beta Blockers
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.
Cholinesterase Inhibitors
Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.
Diuretics
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.
Methotrexate
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.
Oral Hypoglycemics
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.
Because %medicine_name% contains aspirin, %medicine_name% 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 %medicine_name% in the third trimester of pregnancy.
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 %medicine_name%. 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 %medicine_name% in pregnant women. If %medicine_name% is used during pregnancy, or if the patient becomes pregnant while taking %medicine_name%, inform the patient of the potential hazard to the fetus.
The following adverse reactions are discussed elsewhere in the labeling:
- Hypersensitivity
- Allergy
- Risk of Bleeding
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 %medicine_name% 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 %medicine_name%, aspirin, ER-DP, or placebo ; 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 %medicine_name% 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 %medicine_name% 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 ESPS2a
Individual Treatment Group | ||||||||
Body System/Preferred Term | %medicine_name% | ER-DP Alone | ASA Alone | Placebo | ||||
Total Number of Patients | 1650 | 1654 | 1649 | 1649 | ||||
Total Number (%) of Patients With at Least One On-Treatment Adverse Event | 1319 (80%) | 1305 (79%) | 1323 (80%) | 1304 (79%) | ||||
Central and Peripheral Nervous System Disorders | ||||||||
Headache | 647 (39%) | 634 (38%) | 558 (34%) | 543 (33%) | ||||
Convulsions | 28 (2%) | 15 (1%) | 28 (2%) | 26 (2%) | ||||
Gastrointestinal System Disorders | ||||||||
Dyspepsia | 303 (18%) | 288 (17%) | 299 (18%) | 275 (17%) | ||||
Abdominal Pain | 289 (18%) | 255 (15%) | 262 (16%) | 239 (14%) | ||||
Nausea | 264 (16%) | 254 (15%) | 210 (13%) | 232 (14%) | ||||
Diarrhea | 210 (13%) | 257 (16%) | 112 (7%) | 161 (10%) | ||||
Vomiting | 138 (8%) | 129 (8%) | 101 (6%) | 118 (7%) | ||||
Hemorrhage Rectum | 26 (2%) | 22 (1%) | 16 (1%) | 13 (1%) | ||||
Melena | 31 (2%) | 10 (1%) | 20 (1%) | 13 (1%) | ||||
Hemorrhoids | 16 (1%) | 13 (1%) | 10 (1%) | 10 (1%) | ||||
GI Hemorrhage | 20 (1%) | 5 (0%) | 15 (1%) | 7 (0%) | ||||
Body as a Whole - General Disorders | ||||||||
Pain | 105 (6%) | 88 (5%) | 103 (6%) | 99 (6%) | ||||
Fatigue | 95 (6%) | 93 (6%) | 97 (6%) | 90 (5%) | ||||
Back Pain | 76 (5%) | 77 (5%) | 74 (4%) | 65 (4%) | ||||
Accidental Injury | 42 (3%) | 24 (1%) | 51 (3%) | 37 (2%) | ||||
Malaise | 27 (2%) | 23 (1%) | 26 (2%) | 22 (1%) | ||||
Asthenia | 29 (2%) | 19 (1%) | 17 (1%) | 18 (1%) | ||||
Syncope | 17 (1%) | 13 (1%) | 16 (1%) | 8 (0%) | ||||
Psychiatric Disorders | ||||||||
Amnesia | 39 (2%) | 40 (2%) | 57 (3%) | 34 (2%) | ||||
Confusion | 18 (1%) | 9 (1%) | 22 (1%) | 15 (1%) | ||||
Anorexia | 19 (1%) | 17 (1%) | 10 (1%) | 15 (1%) | ||||
Somnolence | 20 (1%) | 13 (1%) | 18 (1%) | 9 (1%) | ||||
Musculoskeletal System Disorders | ||||||||
Arthralgia | 91 (6%) | 75 (5%) | 91 (6%) | 76 (5%) | ||||
Arthritis | 34 (2%) | 25 (2%) | 17 (1%) | 19 (1%) | ||||
Arthrosis | 18 (1%) | 22 (1%) | 13 (1%) | 14 (1%) | ||||
Myalgia | 20 (1%) | 16 (1%) | 11 (1%) | 11 (1%) | ||||
Respiratory System Disorders | ||||||||
Coughing | 25 (2%) | 18 (1%) | 32 (2%) | 21 (1%) | ||||
Upper Respiratory Tract Infection | 16 (1%) | 9 (1%) | 16 (1%) | 14 (1%) | ||||
Cardiovascular Disorders, General | ||||||||
Cardiac Failure | 26 (2%) | 17 (1%) | 30 (2%) | 25 (2%) | ||||
Platelet, Bleeding and Clotting Disorders | ||||||||
Hemorrhage NOS | 52 (3%) | 24 (1%) | 46 (3%) | 24 (1%) | ||||
Epistaxis | 39 (2%) | 16 (1%) | 45 (3%) | 25 (2%) | ||||
Purpura | 23 (1%) | 8 (0%) | 9 (1%) | 7 (0%) | ||||
Neoplasm | ||||||||
Neoplasm NOS | 28 (2%) | 16 (1%) | 23 (1%) | 20 (1%) | ||||
Red Blood Cell Disorders | ||||||||
Anemia | 27 (2%) | 16 (1%) | 19 (1%) | 9 (1%) | ||||
aReported by ≥ 1% of patients during %medicine_name%
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 %medicine_name%, 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 %medicine_name% Group
Treatment Groups | ||||
%medicine_name% | ER-DP | ASA | Placebo | |
Total Number of Patients | 1650 | 1654 | 1649 | 1649 |
Patients with at least one Adverse Event that led to treatment discontinuation | 417 (25%) | 419 (25%) | 318 (19%) | 352 (21%) |
Headache | 165 (10%) | 166 (10%) | 57 (3%) | 69 (4%) |
Dizziness | 85 (5%) | 97 (6%) | 69 (4%) | 68 (4%) |
Nausea | 91 (6%) | 95 (6%) | 51 (3%) | 53 (3%) |
Abdominal Pain | 74 (4%) | 64 (4%) | 56 (3%) | 52 (3%) |
Dyspepsia | 59 (4%) | 61 (4%) | 49 (3%) | 46 (3%) |
Vomiting | 53 (3%) | 52 (3%) | 28 (2%) | 24 (1%) |
Diarrhea | 35 (2%) | 41 (2%) | 9 ( < 1%) | 16 ( < 1%) |
Stroke | 39 (2%) | 48 (3%) | 57 (3%) | 73 (4%) |
Transient Ischemic Attack | 35 (2%) | 40 (2%) | 26 (2%) | 48 (3%) |
Angina Pectoris | 23 (1%) | 20 (1%) | 16 ( < 1%) | 26 (2%) |
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 %medicine_name% 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
Cardiovascular: Hypotension
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
Laboratory Changes
Over the course of the 24-month study (ESPS2), patients treated with %medicine_name% 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.
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 %medicine_name%.
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
Musculoskeletal: Rhabdomyolysis
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.
Because of the dose ratio of dipyridamole to aspirin, overdosage of %medicine_name% 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.
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 %medicine_name%.
Dipyridamole
Absorption Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg %medicine_name% (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 %medicine_name% capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 2030% 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.
Distribution
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 %medicine_name% which, in Trial 9.123 was 13.6 hours.