Aggrenox 200mg/25mg

Pharmacokinetic studies to determine the effect of herb or food have not been conducted with AGGRENOX.

Pharmacokinetic studies to determine the effect of lifestyle have not been conducted with AGGRENOX.

Pharmacokinetic studies to determine the effect of laboratory interactions have not been conducted with AGGRENOX.

For oral administration.

The recommended dose of AGGRENOX is one capsule twice daily, one in the morning and one in the evening, with or without food.

In the event of intolerable headaches during treatment initiation, a regimen of one capsule of AGGRENOX at bedtime, along with low-dose (not 500-1000 mg) acetylsalicylic acid (ASA) alone in the morning may be used.

Since it is expected that headaches related to the vasodilatory properties of dipyridamole will subside over time, the standard twice-daily regimen of AGGRENOX may generally be resumed within a week or so.

The capsules should be swallowed whole without chewing.

eye haemorrhage.

prolongation of the prothrombin time, prolongation of bleeding time, operative haemorrhage (increased bleeding during surgery), post-procedural haemorrhage (increased bleeding after surgery), disseminated intravascular coagulation, coagulopathy, thrombocytopenia (reduction of platelet count), anaemia, iron deficiency anaemia due to occult gastrointestinal bleeding.

pancreatitis, vomiting, nausea, diarrhoea, dyspepsia, gastric ulcer, duodenal ulcer, gastritis erosive, gastrointestinal haemorrhage, abdominal pain, gastric ulcer perforation, duodenal ulcer perforation, melaena, haematemesis.

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.

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.

hyperkalemia, metabolic acidosis, respiratory alkalosis.

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.

taste loss.

hypoglycaemia (children), dehydration, hyperglycaemia, thirst, hyperkaleamia, metabolic acidosis, respiratory alkalosis.

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

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

tachypnea, epistaxis, dyspnoea, gingival bleeding, laryngeal oedema, hyperventilation, pulmonary oedema, tachypnoea.

tachycardia, palpitation, arrhythmia, supraventricular tachycardia.

prolonged pregnancy and labour, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, small for dates baby.

acute anaphylaxis, laryngeal edema, hypersensitivity reactions including rash, urticaria, severe bronchospasm and angio-oedema, anaphylactic reactions (especially in patients with asthma).

rhabdomyolysis, myalgia.

Incidence of Adverse Events in ESPS2 Reported by >1% of Patients During AGGRENOX Treatment Where the Incidence was Greater Than Those Treated with Placebo

interstitial nephritis, renal failure, renal papillary necrosis, proteinuria.

Two large scale trials (ESPS-2, PRoFESS) enrolling a total of 26 934 patients, thereof 11 831 patients treated with AGGRENOX (ESPS2: 1650, PRoFESS: 10, 055), were used to define the side effects profile of AGGRENOX. The duration of the trials was 24-months and 2.5 years for ESPS-2 and PRoFESS respectively. In addition, from spontaneous reporting also those events where facts and evidence qualified these as side effects have been included.

Serious adverse events from controlled clinical trials were bleeding disorders, clotting disorders, gastrointestinal disorders, syncope, headache, and hypotension. Bleeding events (major bleeding, hemorrhage intracranial and gastrointestinal hemorrhage) were reported in patients treated with AGGRENOX in both of these trials. In the PRoFESS trial, major hemorrhagic events were reported in 4.1% and 3.6% of patients in the AGGRENOX treatment group and the clopidogrel treatment group respectively. Any intracranial hemorrhage was reported in 1.4% (AGGRENOX) and 1.0% (clopidogrel) of patients (see Warnings and Precautions).

The most common adverse reactions were dizziness, dyspepsia, abdominal pain, anaemia, hypersensitivity, worsening of symptoms of CAD, epistaxis, gastrointestinal hemorrhage, headache, myalgia, vomiting, and nausea. Events that most commonly lead to discontinuation of AGGRENOX were headache, vomiting and nausea.

cerebral edema, dizziness, headache, also migraine-like headache (especially at the beginning of treatment), agitation, brain oedema, lethargy, convulsion.

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.

hepatitis, incorporated into gallstones, Reye’s Syndrome.

liver function test abnormal, blood uric acid increased (may lead to gout attacks), prothrombin time prolonged.

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.

confusional state.

hearing loss, tinnitus, deafness.

angina pectoris, worsening of symptoms of coronary heart disease, tachycardia, syncope, hypotension, hot flush, arrhythmia.

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.

In mild overdosage these may include rapid and deep breathing, nausea, vomiting, vertigo, tinnitus, flushing, sweating, thirst and tachycardia. In more severe cases acid base disturbances including respiratory alkalosis and metabolic acidosis can occur. Severe cases may show fever, hemorrhage, excitement, confusion, convulsion or coma, and respiratory failure.

It consists of prevention and management of acid-base and fluid and electrolyte disturbances. Renal clearance is increased by increasing urine flow and by alkaline diuresis but care must be taken in this approach not to aggravate further the metabolic acidosis that develops and the hypokalemia. Acidemia should be prevented by administration of adequate sodium containing fluids and sodium bicarbonate. Hypoglycemia is an occasional accompaniment of salicylate overdosage and can be managed by administration of glucose solutions. If a hemorrhagic diathesis is evident, give vitamin K. Haemodialysis may be useful in complex acid base disturbances particularly in the presence of abnormal renal function.

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

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.

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

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 risk of bleeding, as with other antiplatelet agents, AGGRENOX should be used with caution in patients at increased bleeding risk and patients should be followed carefully for any signs of bleeding, including occult bleeding. In patients with recent transient ischaemic attack (TIA) or strokes who are at high risk of recurrent ischemic events, AGGRENOX has been shown to increase major hemorrhagic events and hemorrhagic strokes (see Adverse Reactions).

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

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.

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.

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.

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.

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).

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.

Headache or migraine-like headache which may occur especially at the beginning of AGGRENOX therapy should not be treated with analgesic doses of acetylsalicylic acid (see Dosage and Administration,Alternative Regimen in Case of Intolerable Headaches).

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.

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.

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.

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.

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

Plasma concentrations (determined as area under the curve, AUC) of dipyridamole in healthy elderly subjects (>65 years) are about 30-50% higher than in subjects younger than 55 years, on treatment with AGGRENOX. The difference is caused mainly by reduced clearance.

ASA is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). At low plasma concentrations (<100 µg/mL), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system, breast milk, and fetal tissues. Early signs of salicylate overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approximating 200 µg/mL. (See Adverse Reactions and Overdosage.)

There are no significant interactions between ASA and dipyridamole. The kinetics of the components are unchanged by their co-administration as AGGRENOX. AGGRENOX is not interchangeable with the individual components of ASA and dipyridamole.

The rate of absorption of ASA from the gastrointestinal tract is dependent on the dosage form, the presence or absence of food, gastric pH, and other physiologic factors. Since ASA produces its pharmacodynamic effect via the irreversible acetylating of platelets, the time course of its pharmacodynamic activity is not dependent on the pharmacokinetics of ASA but rather on the lifespan of the platelets (approximately 8-10 days). Therefore, small differences in the pharmacokinetics of ASA, such as variations in its absorption rate or in elimination, are largely irrelevant to its pharmacologic activity with chronic administration. ASA undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%-75% of an administered dose reaching the systemic circulation as intact ASA. Peak plasma levels of ASA are achieved 0.5-1 hour after administration of a 50 mg ASA daily dose from AGGRENOX (given as 25 mg b.i.d.). Peak mean plasma concentration at steady state is 319 ng/mL (175-463 ng/mL).

Blood platelets participate actively in the pathogenesis of atherosclerotic lesions and thrombosis which is the principle cause of most strokes and transient ischemic attacks (TIAs). Platelets are believed to adhere to denuded, dysfunctional endothelium and to release mitogenic substances, such as platelet-derived growth factor (PDGF), that foster the lesion's progression to rupture and thrombosis. The antithrombotic action of AGGRENOX is the result of the additive antiplatelet effects of dipyridamole and acetylsalicylic acid (ASA).

The elimination of salicylic acid follows first order kinetics at lower doses, with a resultant half-life of approximately 2-3 hours, which may rise to 30 hours at higher doses because of nonlinearity in metabolism and plasma protein binding. Renal excretion of unchanged drug depends upon urinary pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalinization of the urine is a key concept in the management of salicylate overdose (see Overdosage). Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, in urine.

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

ASA is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 15-30 minutes. Plasma levels of ASA are essentially undetectable 1-2 hours after dosing and peak salicylic acid concentrations occur within 1-2 hours of administration of ASA. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10-20 g), the plasma half-life may be increased to over 20 hours.