aspirin 25 MG / dipyridamole 200 MG 12HR Extended Release Oral Capsule

Details

DRUG INTERACTIONS

7 •Co-administration with anticoagulants, antiplatelets, or NSAIDS can increase risk of bleeding (7.1) •Decreased renal function can occur with co-administration with NSAIDS (7.1) 7.1 Drug Interaction Study Information Obtained From 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.

Anticoagulants and Antiplatelets Patients taking aspirin and extended release dipyridamole capsules in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding.

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.

OVERDOSAGE

10 Because of the dose ratio of dipyridamole to aspirin, overdosage of aspirin and extended release dipyridamole capsules is likely to be dominated by signs and symptoms of dipyridamole overdose.

In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately.

Careful medical management is essential.

Based upon the known hemodynamic effects of dipyridamole, symptoms such as warm feeling, flushes, sweating, restlessness, feeling of weakness and dizziness may occur.

A drop in blood pressure and tachycardia might also be observed.

Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication.

Severity of aspirin intoxication is determined by measuring the blood salicylate level.

The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 µg/mL.

In severe cases, hyperthermia and hypovolemia are the major immediate threats to life.

Plasma concentrations of aspirin above 300 µg/mL are clearly toxic.

Severe toxic effects are associated with levels above 400 µg/mL.

A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g.

Treatment of overdose consists primarily of supporting vital functions, increasing drug elimination, and correcting acid-base disturbances.

Consider gastric emptying and/or lavage as soon as possible after ingestion, even if the patient has vomited spontaneously.

After lavage and/or emesis, administration of activated charcoal as a slurry may be beneficial if less than 3 hours have passed since ingestion.

Charcoal absorption should not be employed prior to emesis and lavage.

Follow acid-base status closely with serial blood gas and serum pH measurements.

Maintain fluid and electrolyte balance.

Administer replacement fluid intravenously and augment with correction of acidosis.

Treatment may require the use of a vasopressor.

Infusion of glucose may be required to control hypoglycemia.

Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose.

Plasma electrolytes and pH should be monitored serially to promote alkaline diuresis of salicylate if renal function is normal.

In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required to treat salicylic overdose, however since dipyridamole is highly protein bound, dialysis is not likely to remove dipyridamole.

Exchange transfusion may be indicated in infants and young children.

DESCRIPTION

11 Aspirin and extended release dipyridamole capsules are 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.

dipyridamole 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.

acetylsalicylic-acid

CLINICAL STUDIES

14 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: aspirin and extended release dipyridamole (ASA/ER-DP) 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 Aspirin and extended release dipyridamole capsules 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).

Aspirin and extended release dipyridamole capsules 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.) *0.010 < p-value ≤0.050; **p-value ≤0.010.

Note: ASA/ER-DP = aspirin 25 mg/extended release dipyridamole 200 mg; ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg.

The dosage regimen for all treatment groups is BID Individual Treatment Group ASA/ER-DP 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 ASA/ER-DP vs.

ER-DP – – – 0.002** 24.4% 0.72 (0.58, 0.90) ASA/ER-DP vs.

ASA – – – 0.008** 22.1% 0.74 (0.59, 0.92) ASA/ER-DP vs.

Placebo – – – <0.001** 36.8% 0.59 (0.48, 0.73) ER-DP vs.

Placebo – – – 0.036* 16.5% 0.82 (0.67, 1.00) ASA vs.

Placebo – – – 0.009** 18.9% 0.80 (0.66, 0.97) Combined Stroke or Death Endpoint In ESPS2, aspirin and extended release dipyridamole capsules 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.

Aspirin and extended release dipyridamole capsules 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 aspirin and extended release dipyridamole capsules, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone.

The differences between the aspirin and extended release dipyridamole capsules, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant.

These incidence rates for aspirin and extended release dipyridamole capsules and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.

Figure 1

RECENT MAJOR CHANGES

Warnings and Precautions Risk of Bleeding (5.1) 9/2012

DOSAGE FORMS AND STRENGTHS

3 25 mg/200 mg capsules 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”.

•Capsule: 25 mg aspirin/200 mg extended-release dipyridamole (3)

INDICATIONS AND USAGE

1 Aspirin and Extended Release Dipyridamole Capsules are indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

•Aspirin and Extended Release Dipyridamole Capsules are a combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1)

PREGNANCY

5.4 Pregnancy Because Aspirin and Extended Release Dipyridamole Capsules contains aspirin, Aspirin and Extended Release Dipyridamole Capsules 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 Aspirin and Extended Release Dipyridamole Capsules 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 Aspirin and Extended Release Dipyridamole Capsules.

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 Aspirin and Extended Release Dipyridamole Capsules in pregnant women.

If Aspirin and Extended Release Dipyridamole Capsules is used during pregnancy, or if the patient becomes pregnant while taking Aspirin and Extended Release Dipyridamole Capsules, inform the patient of the potential hazard to the fetus.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Aspirin and Extended Release Dipyridamole Capsules increases the risk of bleeding (5.1) •Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3) •Can cause fetal harm when administered to a pregnant woman, especially in the third trimester (5.4) 5.1 Risk of Bleeding Aspirin and Extended Release Dipyridamole Capsules increases the risk of bleeding.

Risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1) ].

Intracranial Hemorrhage In ESPS2 the incidence of intracranial hemorrhage was 0.6% in the Aspirin and Extended Release Dipyridamole Capsules 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 include stomach pain, heartburn, nausea, vomiting, 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.

Inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.

In ESPS2 the incidence of gastrointestinal bleeding was 4.1% in the Aspirin and Extended Release Dipyridamole Capsules group, 2.2% in the extended-release dipyridamole group, 3.2% in the aspirin group, and 2.1% in the placebo groups.

Peptic Ulcer Disease Avoid using aspirin in patients with a history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding.

Alcohol Warning Because Aspirin and Extended Release Dipyridamole Capsules contains aspirin, counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.

5.2 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) ].

5.3 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) ].

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.

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 Aspirin and Extended Release Dipyridamole Capsules in pregnant women.

5.5 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.

5.6 Hypotension Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.

5.7 General Aspirin and Extended Release Dipyridamole Capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling 17.1 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.

17.2 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.

17.3 Headaches Some patients may experience headaches upon treatment initiation; these are usually transient.

In case of intolerable headaches, tell the patient to contact their physician.

17.4 Dosage and Administration Tell patients that aspirin and extended release dipyridamole 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.

17.5 Storage Inform patients to protect aspirin and extended release dipyridamole capsules from moisture.

DOSAGE AND ADMINISTRATION

2 Aspirin and extended release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

The recommended dose of aspirin and extended release dipyridamole is one capsule given orally twice daily, one in the morning and one in the evening.

Swallow capsules whole without chewing.

Aspirin and extended release dipyridamole capsules can be administered with or without food.

•One capsule twice daily (morning and evening) with or without food (2) •In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2) •Do not chew capsule (2) • Not interchangeable with the individual components of aspirin and dipyridamole tablets (2) •Dispense in this unit-of-use container (16) 2.1 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.