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

ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE- aspirin and dipyridamole capsule, extended release
Lannett Company, 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

No. 00 capsule with Pink Opaque cap and Yellow Opaque body imprinted in black with “Lannett” and “330”, and filled with pellets and powder blend.

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 Capsules increase 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 Capsules 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 Capsules 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 Capsules who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt Aspirin and Extended-Release Dipyridamole Capsules for 24-48 hours prior to stress testing [see Drug Interactions (7.1)].

Intake of Aspirin and Extended-Release Dipyridamole Capsules 24-48 hours prior to stress testing with intravenous dipyridamole or other adrenosinergic 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 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 annualized event rate for adverse events that occurred in 1%/year or more of patients treated with Aspirin and Extended-Release Dipyridamole Capsules 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
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 Capsules 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.

Individual Treatment Group
Body System/Preferred Term

Aspirin and Extended-Release Dipyridamole Capsules

b

ER-DP Alone

n (%/year)b

ASA Alone

n (%/year)b

Placebo

b
Total Number of Patients 1650 1654 1649 1649
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)

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 Treatmenta
Treatment Groups

Aspirin and Extended-Release Dipyridamole Capsules

b

ER-DP

b

ASA

b

Placebo

b
Total Number of Patients 1650 1654 1649 1649
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 Capsules 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.

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 Aspirin and Extended-Release Dipyridamole Capsules.

Body as a Whole : Hypothermia, chest pain, allergic reaction, syncope

Cardiovascular : Angina pectoris, hypotension

Central Nervous System : Cerebral edema, dizziness, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage

Fluid and Electrolyte : Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia

Gastrointestinal : Pancreatitis, Reye syndrome, hematemesis, gastritis, ulceration and perforation, hemorrhage rectum, melena, GI hemorrhage

Hearing and Vestibular Disorders : Hearing loss

Heart Rate and Rhythm Disorders: Tachycardia, palpitation

Immune System Disorders : Hypersensitivity, acute anaphylaxis, laryngeal edema

Liver and Biliary System Disorders : Hepatitis, hepatic failure, cholelithiasis, jaundice, hepatic function abnormal

Musculoskeletal : Rhabdomyolysis, myalgia

Metabolic and Nutritional Disorders : Hypoglycemia, dehydration

Platelet, Bleeding and Clotting Disorders : Prolongation of the prothrombin time, disseminated intravascular coagulation,

coagulopathy, thrombocytopenia, hematoma, gingival bleeding, epistaxis, purpura

Psychiatric Disorders: Confusion, agitation

Respiratory : Tachypnea, dyspnea, hemoptysis

Skin and Appendages Disorders : Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising,

ecchymosis, and hematoma, pruritus, uticaria

Urogenital : Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria

Vascular (Extracardiac) Disorders : Allergic vasculitis, flushing

Other Adverse Events : Anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

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