Prescription Drug Information: Aspirin and Extended-Release Dipyridamole

ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE- aspirin and dipyridamole capsule
ANI Pharmaceuticals, Inc.

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 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.

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

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 annualized event rate for intracranial hemorrhage was 0.39%/year in the aspirin and extended-release dipyridamole group, 0.26%/year in the extended-release dipyridamole (ER-DP) group, 0.24%/year in the aspirin (ASA) group, and 0.29%/year 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 annualized event rate for gastrointestinal bleeding was 2.97%/year in the aspirin and extended-release dipyridamole group, 1.58%/year in the extended-release dipyridamole group, 2.06%/year in the aspirin group, and 1.40%/year 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 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.

5.5 Hypotension

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

5.6 Stress Testing with Intravenous Dipyridamole and Other Adenosinergic Agents

Clinical experience suggests that patients being treated with aspirin and extended-release dipyridamole who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt aspirin and extended-release dipyridamole for 24 to 48 hours prior to stress testing [see Drug Interactions (7.1)].

Intake of aspirin and extended-release dipyridamole 24 to 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents may increase the risk for cardiovascular side effects of these agents and impair the sensitivity of the test.

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:

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 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 annualized event rate for adverse events that occurred in 1%/year or more of patients treated with aspirin and extended-release dipyridamole where the incidence was also at least 1%/year 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

Aspirin and Extended-release Dipyridamole

ER-DP Alone

ASA Alone

Placebo

n (%/year)b

n (%/year)b

n (%/year)b

n (%/year)b

Total Number of Patients

1,650

1,654

1,649

1,649

Central and Peripheral Nervous System Disorders

Headache

647

(28.25)

634

(27.91)

558

(22.10)

543

(22.29)

Gastrointestinal System Disorders

Dyspepsia

303

(13.23)

288

(12.68)

299

(11.84)

275

(11.29)

Abdominal Pain

289

(12.62)

255

(11.22)

262

(10.38)

239

(9.81)

Nausea

264

(11.53)

254

(11.18)

210

(8.32)

232

(9.53)

Diarrhea

210

(9.17)

257

(11.31)

112

(4.44)

161

(6.61)

Vomiting

138

(6.03)

129

(5.68)

101

(4.00)

118

(4.84)

Platelet, Bleeding and Clotting Disorders

Hemorrhage NOS

52

(2.27)

24

(1.06)

46

(1.82)

24

(0.99)

a Reported by ≥1%/year of patients during aspirin and extended-release dipyridamole treatment where the incidence was at least 1%/year greater than in those treated with placebo.

b Annual event rate per 100 pt-years = 100* number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25.

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 Treatmenta

Treatment Groups

Aspirin and Extended-release Dipyridamole

ER-DP

ASA

Placebo

n (%/year)b

n (%/year)b

n (%/year)b

n (%/year)b

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

(18.21)

419

(18.44)

318

(12.59)

352

(14.45)

Headache

165

(7.20)

166

(7.31)

57

(2.26)

69

(2.83)

Nausea

91

(3.97)

95

(4.18)

51

(2.02)

53

(2.18)

Abdominal Pain

74

(3.23)

64

(2.82)

56

(2.22)

52

(2.13)

Vomiting

53

(2.31)

52

(2.29)

28

(1.11)

24

(0.99)

a Reported by ≥1%/year of patients during aspirin and extended-release dipyridamole treatment where the incidence was at least 1%/year greater than in those treated with placebo.

b Annual event rate per 100 pt-years = 100* number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25.

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.

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