AGGRENOX is indicated for:

• the prevention of stroke in patients who have had a previous stroke or a transient ischemic attack (TIA).

Safety and effectiveness of AGGRENOX in pediatric patients has not been studied. Therefore, AGGRENOX should not be used in pediatric patients.

ASA should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of ASA in certain viral illnesses.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• Due to the ASA component, AGGRENOX is also contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis and nasal polyps.

  
  

• Patients with rare hereditary problems of fructose intolerance and/or galactose intolerance (e.g. galactosaemia) should not take this medicine. AGGRENOX contains approximately 23 mg sucrose and 106 mg of lactose per maximum recommended daily dose.

  
  

Patients who consume three or more alcoholic drinks every day should be counselled about the bleeding risks involved with chronic, heavy alcohol use while taking AGGRENOX, due to the ASA component.

If a patient is to undergo elective surgery, consideration should be given to discontinue AGGRENOX 10 days prior to surgery to allow for the reversal of the effect.

As any antiplatelet agents, which cause bleeding, the use of AGGRENOX may increase the risk of bleeding such as skin haemorrhage, gastrointestinal bleeding and intracerebral haemorrhage. The addition of other antiplatelet agents (e.g. Clopidogrel, Ticlopidine) to AGGRENOX may further increase the risk of serious bleeding. Even though no study has been conducted, such combination is not recommended.

Due to the ASA component, the concomitant use of AGGRENOX with either selective serotonin reuptake inhibitors (SSRIs) or corticosteroids can increase the gastrointestinal bleeding.

This product contains 106 mg of lactose and 22.5 mg sucrose per maximum recommended daily dose. Patients with rare hereditary problems of fructose intolerance and/or galactose intolerance e.g. galactosaemia should not take this medicine.

In carcinogenicity studies in rats and mice with the combination of dipyridamole and ASA at the ratio of 1:6 over a period of 125 and 105 weeks respectively, no significant tumorigenic effect was observed at maximum doses of 450 mg/kg (corresponding to a share of 75 mg/kg of dipyridamole, 9 times the maximum recommended daily human dose for a 50 kg person on a mg/kg basis [or 1.5-2.1 times on a mg/m² basis]), and 375 mg/kg ASA, 375 times the maximum recommended daily human dose for a 50 kg person on a mg/kg basis (or 58-83 times on a mg/m² basis).

AGGRENOX should be used with caution in patients with severe coronary artery disease (e.g. unstable angina or recently sustained myocardial infarction), due to the vasodilatory effect of the dipyridamole component. Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole. Patients being treated with AGGRENOX should not receive additional intravenous dipyridamole. If pharmacological stress testing with intravenous dipyridamole for coronary artery disease is considered necessary, then AGGRENOX should be discontinued twenty-four hours prior to testing, otherwise the sensitivity of the intravenous stress test could be limited.

For stroke or TIA patients for whom ASA is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the dose of ASA in AGGRENOX has not been proven to provide adequate treatment for these cardiac indications.

Patients with a history of active peptic ulcer disease should avoid using AGGRENOX, which can cause gastric mucosal irritation, and bleeding, due to the ASA component.

GI side effects include stomach pain, heartburn, nausea, vomiting, diarrhoea, 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. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.

AGGRENOX should be used with caution in patients with inherited (haemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders, due to the fact that even low doses of ASA can inhibit platelet function leading to an increase in bleeding time.

Due to the ASA component, AGGRENOX should be avoided in patients with severe hepatic insufficiency.

Due to the ASA component, AGGRENOX should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/min).

Fertility studies with dipyridamole revealed no evidence of impaired fertility in rats at oral dosages of up to 1250 mg/kg, 156 times the maximum recommended human dose on a mg/kg basis for a 50 kg person (or 35 times on a mg/m2 basis). ASA inhibits ovulation in rats.

There are no adequate and well-controlled studies of AGGRENOX in pregnant women. Because animal reproduction studies are not always predictive of human response, AGGRENOX should be given during the first two trimesters of pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Due to the ASA component, AGGRENOX should not be prescribed during the third trimester of pregnancy.

Dipyridamole and ASA are excreted in human breast milk in low concentrations. Therefore, caution should be exercised when AGGRENOX is administered to a nursing woman.

Safety and effectiveness of AGGRENOX in pediatric patients has not been studied. Therefore, AGGRENOX should not be used in pediatric patients. ASA should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of ASA in certain viral illnesses.

ASA has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time. 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 0.13×106/mm³.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

A 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 ASA 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. Discontinuation due to adverse events in ESPS2 was 27.8% for AGGRENOX, 28.2% for extended release dipyridamole, 23.2% for ASA, and 23.7% for placebo.

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 those patients treated with placebo.

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 ASA are listed below.

allergic reaction, fever.

hypotension, flushing.

coma, dizziness, paraesthesia.

gastritis, ulceration and perforation.

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.

tachycardia, palpitation, arrhythmia, supraventricular tachycardia.

cholelithiasis, jaundice, abnormal hepatic function.

hyperglycemia, thirst.

haematoma, gingival bleeding, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage.

Note: There was one case of pancytopenia recorded in a patient within the AGGRENOX treatment group, from which the patient recovered without discontinuation of AGGRENOX.

agitation.

uterine hemorrhage.

hypernea, asthma, bronchospasm, haemoptysis, pulmonary edema.

taste loss.

pruritus, urticaria.

renal insufficiency and failure, hematuria.

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 0.13×106/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 ASA.

hypothermia, migraine-like headache (especially at the beginning of treatment).

angina pectoris, worsening of symptoms of coronary heart disease.

cerebral edema.

hyperkalemia, metabolic acidosis, respiratory alkalosis.

pancreatitis, Reyes Syndrome.

hearing loss.

acute anaphylaxis, laryngeal edema.

hepatitis, incorporated into gallstones.

rhabdomyolysis.

hypoglycemia, dehydration.

prolongation of the prothrombin time, prolongation of bleeding time, increased bleeding during and after surgery, disseminated intravascular coagulation, coagulopathy, thrombocytopenia.

prolonged pregnancy and labour, stillbirths, lower birth weight infants, antepartum and postpartum bleeding.

tachypnea.

rash, alopecia, angioedema, skin haemorrhages such as contusion, ecchymosis and haematoma.

interstitial nephritis, papillary necrosis, proteinuria.

When AGGRENOX is used in combination with acetylsalicylic acid or with warfarin the statements regarding precautions, warnings and tolerance for these preparations must be observed. Because of the increased risk of bleeding, the concomitant administration of heparin, or warfarin with AGGRENOX should be undertaken with caution.

The drugs listed in Table 2 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).