Aspirin and Dipyridamole

ASPIRIN AND DIPYRIDAMOLE- aspirin and dipyridamole capsule
Roxane Laboratories, 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 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 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”.

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 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 Capsules 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) ].

Intracranial Hemorrhage
In ESPS2 the incidence of intracranial hemorrhage was 0.6% in the Aspirin and Extended Release Dipyridamole Capsules 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 Capsules 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 WarningBecause Aspirin and Extended Release Dipyridamole Capsules 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)].

5.4  Pregnancy

Because Aspirin and Extended Release Dipyridamole Capsules contains 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 Capsules 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 Aspirin and Extended Release Dipyridamole Capsules. 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 Aspirin and Extended Release Dipyridamole Capsules in pregnant women. If Aspirin and Extended Release Dipyridamole Capsules is used during pregnancy, or if the patient becomes pregnant while taking Aspirin and Extended Release Dipyridamole Capsules, 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:

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 capsules 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 aspirin and extended release dipyridamole capsules, 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 capsules 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 aspirin and extended release dipyridamole capsules 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*
Individual Treatment Group
Body System/Preferred Term ASA/ER-DP ER-DP Alone ASA Alone Placebo
* Reported by ≥1% of patients during aspirin and extended release dipyridamole capsules treatment where the incidence was greater than in those treated with placebo.
Note:              ASA/ER-DP = aspirin 25 mg/extended release dipyridamole 200 mg; ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID                           NOS = not otherwise specified.

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 TractInfection

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%)

Discontinuation due to adverse events in ESPS2 was 25% for aspirin and extended release dipyridamole capsules, 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 Capsules Group
Treatment Groups
ASA/ER-DP ER-DP ASA Placebo
Note: ASA/ER-DP = aspirin 25 mg/extended release dipyridamole 200 mg; ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID

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%)

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 capsules 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 capsules showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13×106 /mm3.

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