AGGRENOX 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.

• AGGRENOX is a combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1)

AGGRENOX is not interchangeable with the individual components of aspirin and dipyridamole tablets.

The recommended dose of AGGRENOX is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. AGGRENOX can be administered with or without food.

• One capsule twice daily (morning and evening) with or without food (2)
• In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2)
• Do not chew capsule (2)
• Not interchangeable with the individual components of aspirin and dipyridamole tablets (2)
• Dispense in this unit-of-use container (16)

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 to any product ingredients (4.1)
• Patients with known allergy to NSAIDs (4.2)
• Patients with the syndrome of asthma, rhinitis, and nasal polyps (4.2)

AGGRENOX is contraindicated in patients with known hypersensitivity to any of the product components.

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.

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

• AGGRENOX increases the risk of bleeding (5.1)
• Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3)
• Can cause fetal harm when administered to a pregnant woman, especially in the third trimester (5.4)

AGGRENOX 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 AGGRENOX 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 AGGRENOX 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 AGGRENOX 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.

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) ].

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) ].

Because AGGRENOX contains aspirin, AGGRENOX 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 AGGRENOX 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 AGGRENOX. 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 AGGRENOX in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while taking AGGRENOX, inform the patient of the potential hazard to the fetus.

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.

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

AGGRENOX capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

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) ]

• The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea, and diarrhea (6)

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 AGGRENOX 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 AGGRENOX, 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 AGGRENOX 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 AGGRENOX 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
	AGGRENOX		ER-DP Alone		ASA Alone		Placebo
Body System/Preferred Term
aReported by ≥1% of patients during AGGRENOX 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.
	1650		1654		1649		1649
Total Number of Patients
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%)

Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 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 AGGRENOX Group

	Treatment Groups
	AGGRENOX		ER-DP		ASA		Placebo
Note:     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 AGGRENOX 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 AGGRENOX 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.

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 AGGRENOX.

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.