Aspirin and Extended-Release Dipyridamole: Package Insert and Label Information

ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE- aspirin and dipyridamole capsule
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1 INDICATIONS AND USAGE

Aspirin and extended-release dipyridamole capsules are 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

Aspirin and extended-release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

The recommended dose of aspirin and extended-release dipyridamole capsules is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Aspirin and extended-release dipyridamole capsules 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 opaque cap and a yellow opaque body, filled with light yellow to yellow extended-release dipyridamole pellets and a white to off-white, round, film-coated, biconvex, unscored, plain aspirin tablet. The capsule is imprinted axially with “AN” in yellow ink on the cap and “596” in red ink on the body.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Aspirin and extended-release dipyridamole capsules are contraindicated in patients with known hypersensitivity to any of the product components.

4.2 Allergy

Aspirin, USP 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, USP may cause severe urticaria, angioedema or bronchospasm.

4.3 Reye Syndrome

Do not use aspirin, USP in children or teenagers with viral infections because of the risk of Reye syndrome.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Bleeding

Aspirin and extended-release dipyridamole 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) [see Drug Interactions (7.1)] .

Intracranial Hemorrhage

In European Stroke Prevention Study-2 (ESPS2), the incidence of intracranial hemorrhage was 0.6% in the aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole capsules contain 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)] .

5.4 Pregnancy

Because aspirin and extended-release dipyridamole capsules contain aspirin, aspirin and extended-release dipyridamole capsules 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 aspirin and extended-release dipyridamole 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/m 2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of aspirin and extended-release dipyridamole. 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 1,000 mg/kg, respectively (about 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m 2 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 aspirin and extended-release dipyridamole in pregnant women. If aspirin and extended-release dipyridamole is used during pregnancy, or if the patient becomes pregnant while taking aspirin and extended-release dipyridamole, 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.

5.6 Hypotension

Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.

5.7 General

Aspirin and extended-release dipyridamole 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:

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 aspirin and extended-release dipyridamole was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo-controlled study that evaluated 6,602 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 aspirin and extended-release dipyridamole, 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 aspirin and extended-release dipyridamole with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in a total of 6,602 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 aspirin and extended-release dipyridamole 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 a

Individual Treatment Group

Aspirin and Extended-release Dipyridamole

ER-DP Alone ASA Alone Placebo
Body System/Preferred Term
1,650 1,654 1,649 1,649
Total Number of Patients
Total Number (%) of Patients With at Least One On-Treatment Adverse Event
1,319 (80%) 1,305 (79%) 1,323 (80%) 1,304 (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%)

a Reported by ≥1% of patients during aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole, 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 Aspirin and Extended-release Dipyridamole Group

Treatment Groups

Aspirin and Extended-release Dipyridamole

ER-DP ASA Placebo
Total Number of Patients 1,650 1,654 1,649 1,649
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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole 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.

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