Aggrenox

Name: Aggrenox

Aggrenox Precautions

Serious side effects have been reported with Aggrenox, including the following:

  • Bleeding. Tell your health care provider right away if you have some or all of the following symptoms of bleeding:
    • Black or bloody stools
    • Vomiting blood or experiencing coffee ground-looking vomit
    • Bruising that does not go away
  • Worsening of liver disease in those with severe liver disease
  • Worsening of kidney disease in those with severe kidney disease
  • Harm to unborn children when used in pregnant women, especially in the third trimester
  • Heart disease, as this medication can cause/worsen chest pain
  • Low blood pressure, as this medication can lower blood pressure

Do not take Aggrenox if you:

  • are allergic to aspirin, dipyridamole, or to any of its ingredients
  • are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)
  • have asthma or nasal polyps
  • are younger than 18 years of age and have a viral infection

Aggrenox and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

Aggrenox has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from this medication, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered.

What is aspirin and dipyridamole?

Aspirin is in a group of drugs called salicylates (sa-LIS-il-ates). It works by reducing substances in the body that cause pain, fever, and inflammation.

Dipyridamole keeps platelets in your blood from sticking together to form clots.

Aspirin and dipyridamole is a combination medicine used to reduce the risk of stroke in people who have had blood clots or a "mini-stroke" (also called a transient ischemic attack or TIA).

Aspirin and dipyridamole may also be used for purposes not listed in this medication guide.

Before Using Aggrenox

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of aspirin and dipyridamole combination in the pediatric population. Because of aspirin's toxicity, use in children and teenagers is not recommended.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of aspirin and dipyridamole combination in the elderly.

Pregnancy

Pregnancy Category Explanation
All Trimesters D Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Defibrotide
  • Dichlorphenamide
  • Influenza Virus Vaccine, Live
  • Ketorolac
  • Riociguat

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Abciximab
  • Acarbose
  • Aceclofenac
  • Acemetacin
  • Alipogene Tiparvovec
  • Alteplase, Recombinant
  • Amiloride
  • Amineptine
  • Amitriptyline
  • Amitriptylinoxide
  • Amoxapine
  • Amtolmetin Guacil
  • Anagrelide
  • Anisindione
  • Apixaban
  • Ardeparin
  • Argatroban
  • Bemiparin
  • Bendroflumethiazide
  • Benzthiazide
  • Betrixaban
  • Bivalirudin
  • Bromfenac
  • Bufexamac
  • Bumetanide
  • Celecoxib
  • Certoparin
  • Chlorothiazide
  • Chlorpropamide
  • Chlorthalidone
  • Choline Salicylate
  • Cilostazol
  • Citalopram
  • Clomipramine
  • Clonixin
  • Clopamide
  • Clopidogrel
  • Cyclopenthiazide
  • Cyclosporine
  • Dabigatran Etexilate
  • Dalteparin
  • Danaparoid
  • Desipramine
  • Desirudin
  • Desmopressin
  • Desvenlafaxine
  • Dexibuprofen
  • Dexketoprofen
  • Diazoxide
  • Dibenzepin
  • Diclofenac
  • Dicumarol
  • Diflunisal
  • Digoxin
  • Dipyrone
  • Dothiepin
  • Doxepin
  • Droxicam
  • Duloxetine
  • Edoxaban
  • Enoxaparin
  • Eplerenone
  • Eptifibatide
  • Escitalopram
  • Ethacrynic Acid
  • Etodolac
  • Etofenamate
  • Etoricoxib
  • Felbinac
  • Fenoprofen
  • Fepradinol
  • Feprazone
  • Feverfew
  • Floctafenine
  • Flufenamic Acid
  • Fluoxetine
  • Flurbiprofen
  • Fluvoxamine
  • Fondaparinux
  • Furosemide
  • Ginkgo
  • Glimepiride
  • Glipizide
  • Glyburide
  • Gossypol
  • Heparin
  • Hydrochlorothiazide
  • Hydroflumethiazide
  • Ibuprofen
  • Imipramine
  • Indapamide
  • Indomethacin
  • Ketoprofen
  • Ketorolac
  • Lepirudin
  • Levomilnacipran
  • Lithium
  • Lofepramine
  • Lornoxicam
  • Loxoprofen
  • Lumiracoxib
  • Meclofenamate
  • Mefenamic Acid
  • Melitracen
  • Meloxicam
  • Metformin
  • Methotrexate
  • Methyclothiazide
  • Metolazone
  • Milnacipran
  • Morniflumate
  • Nabumetone
  • Nadroparin
  • Naproxen
  • Nateglinide
  • Nefazodone
  • Nepafenac
  • Nicorandil
  • Niflumic Acid
  • Nimesulide
  • Nimesulide Beta Cyclodextrin
  • Nortriptyline
  • Opipramol
  • Oxaprozin
  • Oxyphenbutazone
  • Parecoxib
  • Parnaparin
  • Paroxetine
  • Pemetrexed
  • Pentosan Polysulfate Sodium
  • Pentoxifylline
  • Phenindione
  • Phenprocoumon
  • Phenylbutazone
  • Piketoprofen
  • Piracetam
  • Piroxicam
  • Polythiazide
  • Pralatrexate
  • Pranoprofen
  • Prasugrel
  • Proglumetacin
  • Propyphenazone
  • Proquazone
  • Protein C
  • Protriptyline
  • Repaglinide
  • Reteplase, Recombinant
  • Reviparin
  • Rivaroxaban
  • Rofecoxib
  • Salicylic Acid
  • Salsalate
  • Sertraline
  • Sodium Salicylate
  • Spironolactone
  • Streptokinase
  • Sulfinpyrazone
  • Sulindac
  • Tacrolimus
  • Tenoxicam
  • Tianeptine
  • Tiaprofenic Acid
  • Ticagrelor
  • Ticlopidine
  • Tinzaparin
  • Tirofiban
  • Tolazamide
  • Tolbutamide
  • Tolfenamic Acid
  • Tolmetin
  • Torsemide
  • Treprostinil
  • Triamterene
  • Trichlormethiazide
  • Trimipramine
  • Valdecoxib
  • Varicella Virus Vaccine
  • Venlafaxine
  • Vilazodone
  • Vortioxetine
  • Warfarin
  • Xipamide

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Acebutolol
  • Adenosine
  • Atenolol
  • Betamethasone
  • Betaxolol
  • Bisoprolol
  • Captopril
  • Carteolol
  • Carvedilol
  • Celiprolol
  • Cortisone
  • Delapril
  • Dexamethasone
  • Enalaprilat
  • Enalapril Maleate
  • Esmolol
  • Imidapril
  • Labetalol
  • Levobunolol
  • Lisinopril
  • Methylprednisolone
  • Metipranolol
  • Metoprolol
  • Nadolol
  • Nebivolol
  • Nitroglycerin
  • Oxprenolol
  • Paramethasone
  • Penbutolol
  • Pindolol
  • Practolol
  • Prednisolone
  • Prednisone
  • Probenecid
  • Propranolol
  • Sotalol
  • Streptokinase
  • Tamarind
  • Temocapril
  • Tenecteplase
  • Timolol
  • Triamcinolone
  • Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Alcohol use (3 or more drinks per day) or
  • Bleeding problems or
  • Liver disease, severe or
  • Stomach ulcer, history of—May cause side effects to become worse.
  • Angina (severe chest pain), unstable or
  • Heart attack, recent or
  • Heart disease (e.g., coronary artery disease) or
  • Hypotension (low blood pressure) or
  • Kidney disease, severe or
  • Myasthenia gravis (severe muscle weakness)—Use with caution. May make these conditions worse.
  • Asthma with nasal polyps and rhinitis, history of or
  • Nonsteroidal antiinflammatory drug (NSAID) allergy (e.g., diclofenac, ibuprofen, naproxen, Advil®, Aleve®, Celebrex®, Voltaren®) or
  • Reye's syndrome (metabolic disorder)—Should not be used in patients with these conditions.

Contraindications

  Hypersensitivity

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

  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.

  Reye Syndrome

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

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)]

  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 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 ESPS2a
  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.

  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 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.

Description

Aggrenox is a combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: acacia, aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide and triacetin.

Each capsule shell contains gelatin, red iron oxide and yellow iron oxide, titanium dioxide and water.

Dipyridamole
Dipyridamole is an antiplatelet agent chemically described as 2,2',2'',2'''-[(4,8-Dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula:

Dipyridamole is an odorless yellow crystalline substance, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and is practically insoluble in water.

Aspirin
The antiplatelet agent aspirin (acetylsalicylic acid) is chemically known as benzoic acid, 2- (acetyloxy)-, and has the following structural formula:

Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water.

Clinical studies

ESPS2 (European Stroke Prevention Study-2) was a double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: Aggrenox (aspirin/extended-release dipyridamole) 25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by a blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had a trend towards more events.

Stroke Endpoint
Aggrenox reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (Table 3). Aggrenox reduced the risk of stroke by 36.8% compared to placebo (p <0.001).

Table 3  Summary of First Stroke (Fatal or Nonfatal): ESPS2: Intent-to-Treat Population
  Total
Number
of Patients
n
Number of Patients
With
Stroke Within 2 Years
n (%)
Kaplan-Meier Estimate
of Survival at 2 Years
(95% C.I.)
Gehan-Wilcoxon
Test
P-value
Risk Reduction
at 2 Years
Odds Ratio
(95% C.I.)
a0.010 <p‑value ≤0.050; bp‑value ≤0.010.
Note:   ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.
 
Individual Treatment
Group
        Aggrenox 1650 157 ( 9.5%) 89.9% (88.4%, 91.4%) - - -
        ER-DP 1654 211 (12.8%) 86.7% (85.0%, 88.4%) - - -
        ASA 1649 206 (12.5%) 87.1% (85.4%, 88.7%) - - -
        Placebo 1649 250 (15.2%) 84.1% (82.2%, 85.9%) - - -
 
Pairwise Treatment Group Comparisons
 
        Aggrenox        vs.
                ER-DP
- - - 0.002b 24.4% 0.72 (0.58, 0.90)
        Aggrenox        vs.
                ASA
- - - 0.008b 22.1% 0.74 (0.59, 0.92)
        Aggrenox        vs.
                Placebo
- - - <0.001b 36.8% 0.59 (0.48, 0.73)
        ER-DP vs. Placebo - - - 0.036a 16.5% 0.82 (0.67, 1.00)
        ASA vs. Placebo - - - 0.009b 18.9% 0.80 (0.66, 0.97)

ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal)
Over 24 months of Follow-UP

Combined Stroke or Death Endpoint
In ESPS2, Aggrenox reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. Aggrenox reduced the risk of stroke or death by 24.2% compared to placebo.

Death Endpoint
The incidence rate of all-cause mortality was 11.3% for Aggrenox, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the Aggrenox, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for Aggrenox and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling (Patient Information).


  • Risk of Bleeding
    Inform patients that as with other antiplatelet agents, there is a general risk of bleeding including intracranial and gastrointestinal bleeding. Inform patients about the signs and symptoms of bleeding, including occult bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding.

    Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.
  • Pregnancy
    Inform patients that aspirin is known to be harmful to fetuses and ask the patient to notify them if they are or become pregnant.
  • Headaches
    Some patients may experience headaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact their physician.
  • Dosage and Administration
    Tell patients that Aggrenox capsules should be swallowed whole, and not chewed or crushed. If you miss a dose, continue with your next dose on your regular schedule. Do not take a double dose.
  • Storage
    Inform patients to protect Aggrenox from moisture.

Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

Licensed from:
Boehringer Ingelheim International GmbH

Copyright © 2015 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED

OT1000MK132015
302420-02

Patient Information

Aggrenox® (AG-reh-nox)
(aspirin/extended-release dipyridamole)
Capsules

Read this Patient Information before you start taking Aggrenox and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is Aggrenox?

Aggrenox is a prescription medicine that contains aspirin and a medicine that is slowly released in your body, called dipyridamole. Aggrenox is used to lower the risk of stroke in people who have had a "mini-stroke" (transient ischemic attack or TIA) or stroke due to a blood clot.

It is not known if Aggrenox is safe and effective in children. See "Who should not take Aggrenox?"

Who should not take Aggrenox?

Do not take Aggrenox if you:

  • are allergic to any of the ingredients in Aggrenox. See the end of this leaflet for a list of ingredients in Aggrenox.
  • are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)
  • have asthma in combination with runny nose and nasal polyps

Do not give Aggrenox to a child or teenager with a viral illness. Reye syndrome, a life-threatening condition, can happen when aspirin (an ingredient in Aggrenox) is used in children and teenagers who have certain viral illnesses.

What should I tell my doctor before using Aggrenox?

Before taking Aggrenox, tell your healthcare provider if you:

  • have stomach ulcers
  • have a history of bleeding problems
  • have heart problems
  • have kidney or liver problems
  • have low blood pressure
  • have myasthenia gravis
  • have any other medical conditions
  • are pregnant or plan to become pregnant. Aggrenox can harm your unborn baby, especially if you take it in the last (third) trimester of pregnancy. You should not take Aggrenox during pregnancy without first talking to your healthcare provider. Tell your healthcare provider right away if you become pregnant while taking Aggrenox.
  • are breast-feeding or plan to breast-feed. Aggrenox can pass into your milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Aggrenox.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Aggrenox and other medicines may affect each other causing side effects. Aggrenox may affect the way other medicines work, and other medicines may affect how Aggrenox works.

Especially tell your healthcare provider if you take:

  • a medicine for high blood pressure, irregular heart beat, or heart failure
  • acetazolamide [Diamox®]
  • any blood thinner medicines
  • warfarin sodium [Coumadin®, Jantoven®]
  • a heparin medicine
  • anagrelide [Agrylin®]
  • a seizure medicine
  • a medicine for Alzheimer’s disease
  • a water pill
  • methotrexate sodium [Trexall®]
  • aspirin or a non-steroidal anti-inflammatory drug (NSAIDs). You should not take NSAIDs during treatment with Aggrenox. Using these medicines with Aggrenox can increase your risk of bleeding.
  • a medicine for diabetes
  • probenecid [Probalan®, Col-Probenecid®]

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of them and show your healthcare provider and pharmacist when you get a new medicine.

How should I take Aggrenox?

  • Take Aggrenox exactly as prescribed. Your healthcare provider will tell you how many Aggrenox to take and when to take them.
  • Headaches are not uncommon when you first start taking Aggrenox, but often lessen as treatment continues. Tell your healthcare provider if you have a severe headache. Your healthcare provider may change the instructions for taking Aggrenox.
  • Swallow Aggrenox whole. Do not crush or chew the capsules.
  • You can take Aggrenox with or without food.
  • If you miss a dose, take your next dose at the usual time. Do not take two doses at one time.
  • If you take more Aggrenox (overdose) than prescribed, call your healthcare provider or Poison Control Center, or get emergency help right away.

Symptoms of an overdose of Aggrenox include:

  • a warm feeling or flushing
  • sweating
  • restlessness
  • weakness or dizziness
  • a fast heart rate
  • ringing in the ears

What should I avoid while using Aggrenox?

  • heavy alcohol use. People who drink three or more alcoholic drinks every day have a higher risk of bleeding during treatment with Aggrenox, because it contains aspirin.

What are the possible side effects of Aggrenox?

Aggrenox may cause serious side effects, including:

  • increased risk of bleeding. You may bleed more easily during Aggrenox treatment, and it may take longer than usual for bleeding to stop. This can include:
    • bleeding into your brain (intracranial hemorrhage). This can be a medical emergency. Get medical help right away if you have any of these symptoms while taking Aggrenox:
      • severe headache with drowsiness
      • confusion or memory change
      • pass out (become unconscious)
    • bleeding in your stomach or intestine.
      • stomach pain
      • heartburn or nausea
      • vomiting blood or vomit looks like "coffee grounds"
      • red or bloody stools
      • black stools that look like tar
  • new or worsening chest pain in some people with heart disease. Tell your healthcare provider if you have new chest pain or have any change in your chest pain during treatment with Aggrenox.
  • liver problems, including increased liver function tests and liver failure. Tell your healthcare provider if you have any of these symptoms of a liver problem while taking Aggrenox:
    • loss of appetite
    • pale colored stool
    • stomach area (abdomen) pain
    • yellowing of your skin or whites of your eyes
    • dark urine
    • itching

Call your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of Aggrenox include:

  • headache
  • upset stomach
  • diarrhea

These are not all the possible side effects of Aggrenox. Tell your healthcare provider or pharmacist if you have any side effect that bothers you or that does not go away.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Aggrenox?

  • Store Aggrenox at 59°F to 86°F (15°C to 30°C).
  • Keep Aggrenox capsules dry.
  • Safely throw away medicine that is out of date or no longer needed.

Keep Aggrenox and all medicines out of the reach of children.

General information about Aggrenox

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use Aggrenox for a condition for which it was not prescribed. Do not give Aggrenox to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information summarizes the most important information about Aggrenox. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Aggrenox that is written for health professionals.

For more information, go to www.Aggrenox.com, scan the code below or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.

What are the ingredients in Aggrenox?

Active Ingredients: dipyridamole in an extended-release form and aspirin
Inactive Ingredients: acacia, aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide and triacetin. Each capsule shell contains gelatin, red iron oxide and yellow iron oxide, titanium dioxide, and water.

Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

Licensed from:
Boehringer Ingelheim International GmbH

Copyright © 2015 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED

Revised: November 2015

OT1000MK132015
302420-02

Aggrenox
(60) 25 mg/200 mg Capsules
NDC: 0597-0001-60

Aggrenox 
aspirin and dipyridamole capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0597-0001
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
aspirin (aspirin) aspirin 25 mg
dipyridamole (dipyridamole) dipyridamole 200 mg
Product Characteristics
Color RED (red) , WHITE (ivory) Score no score
Shape CAPSULE (capsule) Size 24mm
Flavor Imprint Code 01A;
Contains     
Packaging
# Item Code Package Description
1 NDC:0597-0001-60 1 BOTTLE in 1 CARTON
1 60 CAPSULE, EXTENDED RELEASE in 1 BOTTLE
2 NDC:0597-0001-11 1 BOTTLE in 1 CARTON
2 10 CAPSULE, EXTENDED RELEASE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020884 12/19/1999
Labeler - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944)
Registrant - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944)
Establishment
Name Address ID/FEI Operations
Polpharma S.A. 422195139 API MANUFACTURE(0597-0001)
Establishment
Name Address ID/FEI Operations
Boehringer Ingelheim Espana, SA 460940841 API MANUFACTURE(0597-0001)
Establishment
Name Address ID/FEI Operations
Boehringer Ingelheim Pharma GmbH and Co. KG 340700520 MANUFACTURE(0597-0001), ANALYSIS(0597-0001)
Establishment
Name Address ID/FEI Operations
Novacyl 383661402 API MANUFACTURE(0597-0001)
Revised: 03/2017   Boehringer Ingelheim Pharmaceuticals, Inc.

Dosing & Uses

Dosage Forms & Strengths

aspirin/dipyridamole

capsule, extended release

  • 25mg/200mg

Stroke

Secondary prophylaxis of transient ischemic attack (TIA) or cerebrovascular accident (CVA)

1 capsule PO q12hr

Dosing considerations

  • Not interchangeable with individual components of aspirin/dipyridamole
  • Intolerable headaches during initial treatment: Switch to 1 capsule PO at bedtime; patient should return to normal regimen when possible (usually 1 week)

Dosing Modifications

GFR <10 mL/min: Use not recommended

Administration

Swallow capsules whole, without chewing

Safety and efficacy not established

Patient Handout

Print without Office InfoPrint with Office Info

What is aspirin and dipyridamole (aggrenox)?

Aspirin is in a group of drugs called salicylates (sa-LIS-il-ates). It works by reducing substances in the body that cause pain, fever, and inflammation.

Dipyridamole keeps platelets in your blood from sticking together to form clots.

The combination of aspirin and dipyridamole is used to reduce the risk of stroke in people who have had blood clots or a "mini-stroke" (also called a transient ischemic attack or TIA).

Aspirin and dipyridamole may also be used for other purposes not listed in this medication guide.

What happens if i miss a dose (aggrenox)?

Take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and wait until your next regularly scheduled dose. Do not use extra medicine to make up the missed dose.

What is Aggrenox?

Aggrenox contains a combination of aspirin and dipyridamole. Aspirin belongs to a group of drugs called salicylates (sa-LIS-il-ates). It works by reducing substances in the body that cause pain, fever, and inflammation.

Dipyridamole keeps platelets in your blood from sticking together to form clots.

Aggrenox is used to reduce the risk of stroke in people who have had blood clots or a "mini-stroke" (also called a transient ischemic attack or TIA).

Aggrenox is supplied as a capsule containing 200mg dipyridamole in extended-release pellets and a round white tablet incorporating immediate-release aspirin 25mg.

Aspirin / dipyridamole Breastfeeding Warnings

US: Use should be avoided. UK: Benefit should outweigh risk. AU: Caution is recommended. Excreted into human milk: Yes (aspirin, dipyridamole) Comments: According to some experts, low-dose aspirin (75 to 162 mg daily) may be considered for antiplatelet therapy in breastfeeding women. Avoiding breastfeeding for 1 to 2 hours following a low dose of aspirin may minimize the risk of antiplatelet effects in the infant.

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