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Aggrenox

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Aggrenox

Aggrenox

SIDE EFFECTS

The following adverse reactions are discussed elsewhere in the labeling:

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]; 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, extendedrelease 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*

Body System/Preferred Term Individual Treatment Group
AGGRENOX ER-DP Alone ASA Alone Placebo
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 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%)
* Reported 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.

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
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%)
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.

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.

Read the Aggrenox (aspirin, extended-release dipyridamole capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No pharmacokinetic drug-drug interaction studies were conducted with AGGRENOX capsules. The following information was obtained from the literature.

Adenosine

Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.

Angiotensin Converting Enzyme (ACE) Inhibitors

Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.

Acetazolamide

Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.

Anticoagulant Therapy (heparin and warfarin)

Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and effects on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.

Anticonvulsants

Salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Beta Blockers

The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Cholinesterase Inhibitors

Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.

Diuretics

The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Methotrexate

Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.

Oral Hypoglycemics

Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.

Uricosuric Agents (probenecid and sulfinpyrazone)

Salicylates antagonize the uricosuric action of uricosuric agents.

Read the Aggrenox Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/14/2012
This monograph has been modified to include the generic and brand name in many instances.

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