^
Distributed by: BoehringerIngelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Licensed from: Boehringer IngelheimInternational GmbH
Copyright© 2015 Boehringer Ingelheim International GmbH ALL RIGHTSRESERVED
Revised: November 2015
OT1000MK132015302420-02
^ Pregnancy
Teratogenic Effects, Pregnancy Category D. [ see Warnings and Precautions (5.4) ].
^6 Adverse Reactions
The following adverse reactions are discussedelsewhere in the labeling:
^ Mechanism Of Action
The antithrombotic action of AGGRENOX is the result of the additive antiplatelet effects of dipyridamole and aspirin.
^ Hypersensitivity
AGGRENOX is contraindicated in patients with known hypersensitivity to any of the product components.
^ Post-marketing Experience
The following is a list of additional adversereactions that have been reported either in the literature or arefrom post-marketing spontaneous reports for either dipyridamole oraspirin. Because these reactions are reported voluntarily from a populationof uncertain size, it is not always possible to estimate reliablytheir frequency or establish a causal relationship to drug exposure.Decisions to include these reactions in labeling are typically basedon one or more of the following factors: (1) seriousness of the reaction,(2) frequency of reporting, or (3) strength of causal connection toAGGRENOX.
Bodyas 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 SystemDisorders: Hepatitis, hepatic failure
Musculoskeletal: Rhabdomyolysis
Metabolic and Nutritional Disorders: Hypoglycemia, dehydration
Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascularcoagulation, 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, skinhemorrhages such as bruising, ecchymosis, and hematoma
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria
Vascular (Extracardiac) Disorders: Allergic vasculitis
Other Adverse Events: anorexia, aplasticanemia, migraine, pancytopenia, thrombocytosis.
^ Labor And Delivery
Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy [ see Warnings and Precautions (5.4) ], avoid AGGRENOX in the third trimester of pregnancy and during labor and delivery.
^ Renal Failure
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) ].
^ Drug Interactionstudy Information Obtained From Literature
Adenosine Dipyridamole hasbeen reported to increase the plasma levels and cardiovascular effectsof adenosine. Adjustment of adenosine dosage may be necessary.
Angiotensin Converting Enzyme(ACE) Inhibitors Due to the indirect effect ofaspirin on the renin-angiotensin conversion pathway, the hyponatremicand hypotensive effects of ACE inhibitors may be diminished by concomitantadministration of aspirin.
Acetazolamide Concurrent use of aspirin and acetazolamidecan lead to high serum concentrations of acetazolamide (and toxicity)due to competition at the renal tubule for secretion.
Anticoagulants and Antiplatelets Patients taking AGGRENOX in combination with anticoagulants, antiplatelets,or any substance impacting coagulation are at increased risk for bleeding. Aspirin can displace warfarin from protein binding sites, leadingto prolongation of both the prothrombin time and the bleeding time.Aspirin can increase the anticoagulant activity of heparin, increasingbleeding risk.
Anagrelide Patients taking aspirin in combinationwith anagrelide are at an increased risk of bleeding.
Anticonvulsants Salicylicacid can displace protein-bound phenytoin and valproic acid, leadingto a decrease in the total concentration of phenytoin and an increasein serum valproic acid levels.
Beta Blockers The hypotensive effectsof beta blockers may be diminished by the concomitant administrationof aspirin due to inhibition of renal prostaglandins, leading to decreasedrenal blood flow and salt and fluid retention.
Cholinesterase Inhibitors Dipyridamole may counteract the anticholinesterase effect of cholinesteraseinhibitors, thereby potentially aggravating myasthenia gravis.
Diuretics Theeffectiveness of diuretics in patients with underlying renal or cardiovasculardisease may be diminished by the concomitant administration of aspirindue to inhibition of renal prostaglandins, leading to decreased renalblood flow and salt and fluid retention.
Methotrexate Salicylatecan inhibit renal clearance of methotrexate, leading to bone marrowtoxicity, especially in the elderly or renal impaired.
Nonsteroidal Anti-InflammatoryDrugs (NSAIDs) The concurrent use of aspirin withother NSAIDs may increase bleeding or lead to decreased renal function.
Oral Hypoglycemics Moderate doses of aspirin may increase the effectiveness of oralhypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and sulfinpyrazone) Salicylates antagonize the uricosuric action of uricosuricagents.
^1 Indications And Usage
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.
^ Hepatic Insufficiency
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) ].
^ Patients With Severehepatic Or Severe Renal Dysfunction
AGGRENOX has not been studied in patients with hepaticor renal impairment. Avoid using aspirin containing products, suchas AGGRENOX in patients with severe hepatic or severe renal (glomerularfiltration rate <10 mL/min) dysfunction [ seeWarnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3) ].
^ Patient Counseling Information
Advise the patient to read the FDA-approved patientlabeling (Patient Information).
^ Allergy
Aspirin is contraindicated in patients withknown allergy to nonsteroidal anti-inflammatory drug (NSAID) productsand in patients with the syndrome of asthma, rhinitis, and nasal polyps.Aspirin may cause severe urticaria, angioedema or bronchospasm.
^ Pregnancy
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.
^2 Dosage And Administration
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.
^ Nursing Mothers
Both dipyridamole and aspirin are excreted in human milk. Exercise caution when AGGRENOX capsules are administered to a nursing woman.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats.
Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.
Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.
^ Pharmacodynamics
The effect of either agent on the other's inhibition of platelet reactivity has not been evaluated.
^ Pediatric Use
Safety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended [ see Contraindications (4.3) ].
^ Hypotension
Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.
^Aspirin/er Dipyridamole
^ General
AGGRENOX capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.
^ Clinical Trialsexperience
Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.
The efficacy and safety of AGGRENOX was establishedin the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind,placebo-controlled study that evaluated 6602 patients over the ageof 18 years who had a previous ischemic stroke or transient ischemicattack within ninety days prior to entry. Patients were randomizedto either AGGRENOX, aspirin, ER-DP, or placebo [ see Clinical Studies (14) ]; primary endpoints included stroke (fatal or nonfatal)and death from all causes.
This24-month, multicenter, double-blind, randomized study (ESPS2) wasconducted to compare the efficacy and safety of AGGRENOX with placebo,extended-release dipyridamole alone and aspirin alone. The study wasconducted in a total of 6602 male and female patients who had experienceda previous ischemic stroke or transient ischemia of the brain withinthree months prior to randomization.
Table 1 presents the incidence of adverse events that occurred in1% or more of patients treated with AGGRENOX where the incidence wasalso greater than in those patients treated with placebo. There isno clear benefit of the dipyridamole/aspirin combination over aspirinwith respect to safety.
Discontinuationdue to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-releasedipyridamole, 19% for aspirin, and 21% for placebo (refer to Table2)
Headache was most notable in thefirst month of treatment.
Other Adverse Events Adversereactions that occurred in less than 1% of patients treated with AGGRENOXin the ESPS2 study and that were medically judged to be possibly relatedto either dipyridamole or aspirin are listed below.
Body as a Whole: Allergic reaction, fever
Cardiovascular: Hypotension
Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranialhemorrhage, subarachnoid hemorrhage
Gastrointestinal: Gastritis,ulceration and perforation
Hearing and Vestibular Disorders: Tinnitus,and deafness. Patients with high frequency hearing loss may have difficultyperceiving tinnitus. In these patients, tinnitus cannot be used asa clinical indicator of salicylism
Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia
Liver and Biliary SystemDisorders: Cholelithiasis, jaundice, hepatic functionabnormal
Metabolicand Nutritional Disorders: Hyperglycemia, thirst
Platelet, Bleeding andClotting 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 courseof the 24-month study (ESPS2), patients treated with AGGRENOX showeda decline (mean change from baseline) in hemoglobin of 0.25 g/dL,hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.
^ 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.
^ 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 hadan ischemic stroke (76%) or transient ischemic attack (TIA, 24%) withinthree months prior to entry. Patients were enrolled in 13 Europeancountries between February 1989 and May 1995 and were randomized toone 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 populationwas 66.7 years with 58% of them being males. Patients received onecapsule twice daily (morning and evening). Efficacy assessments includedanalyses 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 orgender; patients who were older had a trend towards more events.
^ Coronary Artery Disease
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.
^3 Dosage Forms And Strengths
25 mg/200 mg capsules with a red cap andan ivory-colored body, containing yellow extended-release pelletsincorporating dipyridamole and a round white tablet incorporatingimmediate-release aspirin. The capsule body is imprinted in red withthe Boehringer Ingelheim logo and with "01A".
^ Reye Syndrome
Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome.
^ Alternative Regimen In Case Of Intolerable Headaches
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.
^ Geriatric Use
Of the total number of subjects in ESPS2, 61 percent were 65 and over, while 27 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [ see Clinical Pharmacology (12.3) ].
^ Risk Of Bleeding
AGGRENOX increases the risk of bleeding.Risk factors for bleeding include the use of other drugs that increasethe risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin,anagrelide, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1) ].
IntracranialHemorrhage In European Stroke PreventionStudy-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 includestomach pain, heartburn, nausea, vomiting, and gross GI bleeding.Although minor upper GI symptoms, such as dyspepsia, are common andcan occur anytime during therapy, physicians should remain alert forsigns of ulceration and bleeding, even in the absence of previousGI symptoms. Inform patients about the signs and symptoms of GI sideeffects and what steps to take if they occur.
In ESPS2, the incidence of gastrointestinal bleedingwas 4.1% in the AGGRENOX group, 2.2% in the extended-release dipyridamolegroup, 3.2% in the aspirin group, and 2.1% in the placebo groups.
Peptic Ulcer Disease Avoid using aspirin in patients with a historyof active peptic ulcer disease, which can cause gastric mucosal irritationand bleeding.
Alcohol Warning Because AGGRENOX containsaspirin, counsel patients who consume three or more alcoholic drinksevery day about the bleeding risks involved with chronic, heavy alcoholuse while taking aspirin.
^ How Supplied/storage And Handling
AGGRENOX capsules are available as a hard gelatin capsule, with a red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and a round white tablet incorporating immediate-release aspirin. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with "01A".
AGGRENOX capsules are supplied in unit-of-use bottles of 60 capsules (NDC 0597-0001-60).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from excessive moisture.
^ Pharmacokinetics
There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their co-administration as AGGRENOX.
^ Overdosage
Becauseof the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOXis likely to be dominated by signs and symptoms of dipyridamole overdose.In case of real or suspected overdose, seek medical attention or contacta Poison Control Center immediately. Careful medical management isessential.
Based upon the knownhemodynamic effects of dipyridamole, symptoms such as warm feeling,flushes, sweating, restlessness, feeling of weakness and dizzinessmay occur. A drop in blood pressure and tachycardia might also beobserved.
Salicylate toxicitymay result from acute ingestion (overdose) or chronic intoxication.Severity of aspirin intoxication is determined by measuring the bloodsalicylate level. The early signs of salicylic overdose (salicylism),including tinnitus (ringing in the ears), occur at plasma concentrationsapproaching 200 µg/mL. In severe cases, hyperthermia and hypovolemiaare the major immediate threats to life. Plasma concentrations ofaspirin above 300 µg/mL are clearly toxic. Severe toxic effects areassociated with levels above 400 µg/mL. A single lethal dose of aspirinin adults is not known with certainty but death may be expected at30 g.
Treatment of overdose consistsprimarily of supporting vital functions, increasing drug elimination,and correcting acid-base disturbances. Consider gastric emptying and/orlavage as soon as possible after ingestion, even if the patient hasvomited spontaneously. After lavage and/or emesis, administrationof activated charcoal as a slurry may be beneficial if less than 3hours have passed since ingestion. Charcoal absorption should notbe employed prior to emesis and lavage. Follow acid-base status closelywith serial blood gas and serum pH measurements. Maintain fluid andelectrolyte balance. Administer replacement fluid intravenously andaugment with correction of acidosis. Treatment may require the useof a vasopressor. Infusion of glucose may be required to control hypoglycemia.
Administration of xanthine derivatives(e.g., aminophylline) may reverse the hemodynamic effects of dipyridamoleoverdose. Plasma electrolytes and pH should be monitored seriallyto promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threateningintoxication, dialysis is usually required to treat salicylic overdose;however, since dipyridamole is highly protein bound, dialysis is notlikely to remove dipyridamole. Exchange transfusion may be indicatedin infants and young children.