Duplinal

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Duplinal uses


1  INDICATIONS AND USAGE

Duplinal 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.

2  DOSAGE AND ADMINISTRATION

Duplinal is not interchangeable with the individual components of Duplinal and dipyridamole tablets.

The recommended dose of Duplinal is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Duplinal can be administered with or without food.

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 Duplinal 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.

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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 Duplinal. The capsule body is imprinted in red withthe Boehringer Ingelheim logo and with "01A".

4  CONTRAINDICATIONS


4.1  Hypersensitivity

Duplinal is contraindicated in patients with known hypersensitivity to any of the product components.

4.2  Allergy

Duplinal is contraindicated in patients withknown allergy to nonsteroidal anti-inflammatory drug productsand in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm.

4.3  Reye Syndrome

Do not use Duplinal in children or teenagers with viral infections because of the risk of Reye syndrome.

5  WARNINGS AND PRECAUTIONS

5.1  Risk of Bleeding

Duplinal 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 Duplinal group, 0.5% in the extended-release dipyridamole (ER-DP)group, 0.4% in the Duplinal (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 Duplinal group, 2.2% in the extended-release dipyridamolegroup, 3.2% in the Duplinal group, and 2.1% in the placebo groups.

Peptic Ulcer Disease

Avoid using Duplinal in patients with a historyof active peptic ulcer disease, which can cause gastric mucosal irritationand bleeding.

Alcohol Warning

Because Duplinal containsaspirin, counsel patients who consume three or more alcoholic drinksevery day about the bleeding risks involved with chronic, heavy alcoholuse while taking Duplinal.

5.2  Renal Failure

Avoid Duplinal in patients with severe renal failure [ 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) ].

5.4  Pregnancy

Because Duplinal contains Duplinal, Duplinal can cause fetal harm when administered to a pregnant woman. Maternal Duplinal 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 on the fetal cardiovascular system (closure of the ductus arteriosus), avoid Duplinal in the third trimester of pregnancy [ see Use in Specific Populations (8.1) ].

Duplinal 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 Duplinal contained in the maximum recommended daily human dose of Duplinal. 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 Duplinal in pregnant women. If Duplinal is used during pregnancy, or if the patient becomes pregnant while taking Duplinal, inform the patient of the potential hazard to the fetus.

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 Duplinal is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the Duplinal 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

Duplinal capsules are not interchangeable with the individual components of Duplinal and dipyridamole tablets.

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6  ADVERSE REACTIONS

The following adverse reactions are discussedelsewhere in the labeling:

To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1  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 Duplinal 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 Duplinal, Duplinal, 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 Duplinal with placebo,extended-release dipyridamole alone and Duplinal 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 Duplinal 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.

Individual Treatment Group
Duplinal ER-DP Alone ASA Alone Placebo
Body System/Preferred Term
aReportedby ≥1% of patients during Duplinal treatment where the incidence wasgreater than in those treated with placebo.
Note:              ER-DP = extended-releasedipyridamole 200 mg; ASA = Duplinal 25 mg. The dosage regimen for alltreatment groups is BID.

                           NOS= not otherwise specified.

1650 1654 1649 1649
Total Number ofPatients
Total Number (%) of Patients Withat

Least One On-Treatment Adverse

Event


1319


(80%)


1305


(79%)


1323


(80%)


1304


(79%)

Central and Peripheral Nervous SystemDisorders

        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%)

Discontinuationdue to adverse events in ESPS2 was 25% for Duplinal, 25% for extended-releasedipyridamole, 19% for Duplinal, and 21% for placebo (refer to Table2)

Treatment Groups
Duplinal ER-DP ASA Placebo
Note:     ER-DP = extended-release dipyridamole200 mg; ASA = Duplinal 25 mg. The dosage regimen for all treatmentgroups is BID.
Total Number of Patients 1650 1654 1649 1649
Patients with at least one AdverseEvent

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%)
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 Duplinal 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 Duplinal showeda decline (mean change from baseline) in hemoglobin of 0.25 g/dL,hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.

6.2  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.

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7  DRUG INTERACTIONS

7.1  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 Duplinal.

Acetazolamide

Concurrent use of Duplinal 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 Duplinal in combination with anticoagulants, antiplatelets,or any substance impacting coagulation are at increased risk for bleeding. Duplinal 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 Duplinal 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 Duplinal 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 Duplinal withother NSAIDs may increase bleeding or lead to decreased renal function.

Oral Hypoglycemics

Moderate doses of Duplinal may increase the effectiveness of oralhypoglycemic drugs, leading to hypoglycemia.

Uricosuric Agents (probenecid and sulfinpyrazone)

Salicylates antagonize the uricosuric action of uricosuricagents.

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8  USE IN SPECIFIC POPULATIONS


8.1  Pregnancy

Teratogenic Effects, Pregnancy Category D. [ see Warnings and Precautions (5.4) ].

8.2  Labor and Delivery

Duplinal 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 Duplinal during the later stages of pregnancy [ see Warnings and Precautions ], avoid Duplinal in the third trimester of pregnancy and during labor and delivery.

8.3  Nursing Mothers

Both dipyridamole and Duplinal are excreted in human milk. Exercise caution when Duplinal capsules are administered to a nursing woman.

8.4  Pediatric Use

Safety and effectiveness of Duplinal in pediatric patients have not been studied. Due to the Duplinal component, use of this product in the pediatric population is not recommended [ see Contraindications ].

8.5  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) ].

8.6  Patients with SevereHepatic or Severe Renal Dysfunction

Duplinal has not been studied in patients with hepaticor renal impairment. Avoid using Duplinal containing products, suchas Duplinal 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) ].

10  OVERDOSAGE

Becauseof the dose ratio of dipyridamole to Duplinal, 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 Duplinal 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.

11  DESCRIPTION

Duplinal 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 Duplinal, 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 chemicallydescribed 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 yellowcrystalline substance, having a bitter taste. It is soluble in diluteacids, methanol and chloroform, and is practically insoluble in water.

aggrenox-structure-1 Duplinal

The antiplatelet agent Duplinal (acetylsalicylic acid)is chemically known as benzoic acid, 2- (acetyloxy)-, and has thefollowing structural formula:

Duplinal is an odorless white needle-likecrystalline or powdery substance. When exposed to moisture, aspirinhydrolyzes into salicylic and acetic acids, and gives off a vinegaryodor. It is highly lipid soluble and slightly soluble in water.

aggrenox-structure-2

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

The antithrombotic action of Duplinal is the result of the additive antiplatelet effects of dipyridamole and Duplinal.

Dipyridamole

Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo ; the inhibition occurs in a dose-dependent manner at therapeutic concentrations. This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP).

Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).

Duplinal

Duplinal inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.

12.2  Pharmacodynamics

The effect of either agent on the other's inhibition of platelet reactivity has not been evaluated.

12.3  Pharmacokinetics

There are no significant interactions between Duplinal and dipyridamole. The kinetics of the components are unchanged by their co-administration as Duplinal.

Dipyridamole

Absorption

Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg Duplinal (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 µg/mL (1.01–3.99 µg/mL) and the steady-state trough concentration is 0.53 µg/mL (0.18–1.01 µg/mL).

Effect of Food

When Duplinal capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 20-30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant.

Distribution

Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin.

Metabolism and Elimination

Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a half-life of about 39 minutes, (which, together with the alpha phase accounts for about 70% of the total area under the curve, AUC) and a prolonged elimination phase λz with a half-life of about 15.5 hours. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with Duplinal which, in Trial 9.123 was 13.6 hours.

Special Populations

Geriatric Patients : In ESPS2 [ see Clinical Studies (14) ], plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with Duplinal.

Hepatic Dysfunction : No study has been conducted with Duplinal in patients with hepatic dysfunction.

In a study conducted with an intravenous formulation of dipyridamole, patients with mild to severe hepatic insufficiency showed no change in plasma concentrations of dipyridamole but showed an increase in the pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be dosed without restriction as long as there is no evidence of hepatic failure.

Renal Dysfunction : No study has been conducted with Duplinal in patients with renal dysfunction.

In ESPS2 patients [ see Clinical Studies (14) ], with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age.

Duplinal

Absorption

Peak plasma levels of Duplinal are achieved 0.63 hours(0.5–1 hour) after administration of a 50 mg Duplinal daily dose fromAGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-stateis 319 ng/mL (175–463 ng/mL). Duplinal undergoes moderate hydrolysisto salicylic acid in the liver and the gastrointestinal wall, with50%–75% of an administered dose reaching the systemic circulationas intact Duplinal.

Effect of Food

When AGGRENOXcapsules were taken with a high fat meal, there was no differencefor Duplinal in AUC at steady-state, and the approximately 50% decreasein Cmax was not considered clinically relevantbased on a similar degree of cyclooxygenase inhibition comparing thefed and fasted state.

Distribution

Aspirinis poorly bound to plasma proteins and its apparent volume of distributionis low (10 L). Its metabolite, salicylic acid, is highly bound toplasma proteins, but its binding is concentration-dependent (nonlinear).At low concentrations (<100 µg/mL), approximately 90% of salicylicacid is bound to albumin. Salicylic acid is widely distributed toall tissues and fluids in the body, including the central nervoussystem, breast milk, and fetal tissues. Early signs of salicylateoverdose (salicylism), including tinnitus (ringing in the ears), occurat plasma concentrations approximating 200 µg/mL [ see Adverse Reactions (6) and Overdosage (10) ].

Metabolism and Elimination

Duplinal is rapidly hydrolyzed in plasma tosalicylic acid, with a half-life of 20 minutes. Plasma levels of aspirinare essentially undetectable 2–2.5 hours after dosing and peak salicylicacid concentrations occur 1 hour (range: 0.5–2 hours) after administrationof Duplinal. Salicylic acid is primarily conjugated in the liver toform salicyluric acid, a phenolic glucuronide, an acyl glucuronide,and a number of minor metabolites. Salicylate metabolism is saturableand total body clearance decreases at higher serum concentrationsdue to the limited ability of the liver to form both salicyluric acidand phenolic glucuronide. Following toxic doses (10–20 g), the plasmahalf-life may be increased to over 20 hours.

The elimination of acetylsalicylic acid follows first-orderkinetics with Duplinal and has a half-life of 0.33 hours. The half-lifeof salicylic acid is 1.71 hours. Both values correspond well withdata from the literature at lower doses which state a resultant half-lifeof approximately 2–3 hours. At higher doses, the elimination of salicylicacid follows zero-order kinetics (i.e., the rate of elimination isconstant in relation to plasma concentration), with an apparent half-lifeof 6 hours or higher. Renal excretion of unchanged drug depends uponurinary pH. As urinary pH rises above 6.5, the renal clearance offree salicylate increases from <5% to >80%. Alkalinization of theurine is a key concept in the management of salicylate overdose [ see Overdosage (10) ]. Following therapeutic doses, about 10% is excreted assalicylic acid and 75% as salicyluric acid, as the phenolic and acylglucuronides, in urine.

Special Populations

Hepatic Dysfunction : Avoid aspirinin patients with severe hepatic insufficiency.

Renal Dysfunction : Avoid Duplinal in patients with severe renal failure (glomerularfiltration rate less than 10 mL/min).

Duplinal

DrugInteraction

A dedicated drug interaction studywas conducted in 60 healthy volunteers to evaluate the effects ofomeprazole 80 mg administered once daily on the pharmacokinetics (PK)of dipyridamole and the pharmacodynamics (PD) of acetylsalicylic acidwhen co-administered with Duplinal twice daily. Dipyridamole exposure(Cmax and AUC) at steady-state were similar with or without omeprazoleco-administration. The pharmacokinetics of acetylsalicylic acid wasnot characterized. However, the antiplatelet activity as measuredby arachidonic acid induced platelet aggregation was similar betweenthe treatment arms at steady-state.

13  NONCLINICAL TOXICOLOGY

13.1  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 Duplinal (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). Duplinal, 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 Duplinal 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). Duplinal inhibits ovulation in rats.

14  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: Duplinal (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.

Stroke Endpoint

Duplinal reduced the risk of stroke by 22.1%compared to Duplinal 50 mg/day alone (p = 0.008) and reduced the riskof stroke by 24.4% compared to extended-release dipyridamole 400 mg/dayalone (p = 0.002) (Table 3). Duplinal reduced the risk of stroke by36.8% compared to placebo (p <0.001).

Total

Number

of Patients

n

Number of Patients

With

StrokeWithin 2 Years

n (%)

Kaplan-Meier Estimate

of Survival at 2Years

(95% C.I.)

Gehan-Wilcoxon

Test

P-value

Risk Reduction

at 2 Years

Odds Ratio

(95% C.I.)

a0.010 <p‑value≤0.050; bp‑value ≤0.010.
Note: ER-DP = extended-release dipyridamole200 mg; ASA = Duplinal 25 mg. The dosage regimen for all treatmentgroups is BID.
Individual Treatment

Group

        AGGRENOX 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
        AGGRENOX        vs.

                ER-DP

- - - 0.002b 24.4% 0.72 (0.58, 0.90)
        AGGRENOX        vs.

                ASA

- - - 0.008b 22.1% 0.74 (0.59, 0.92)
        AGGRENOX        vs.

                Placebo

- - - <0.001b 36.8% 0.59 (0.48, 0.73)
        ER-DP vs. Placebo - - - 0.036a 16.5% 0.82 (0.67, 1.00)
        ASA vs. Placebo - - - 0.009b 18.9% 0.80 (0.66, 0.97)
ESPS2: CumulativeStroke Rate (Fatal or Nonfatal)

Over24 months of Follow-UP

Combined Stroke or Death Endpoint

In ESPS2, Duplinal reduced the risk of stroke or death by 12.1% compared to Duplinal alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. Duplinal reduced the risk of stroke or death by 24.2% compared to placebo.

Death Endpoint

The incidence rate of all-cause mortality was11.3% for Duplinal, 11.0% for Duplinal alone, 11.4% for extended-releasedipyridamole alone and 12.3% for placebo alone. The differences betweenthe Duplinal, Duplinal alone and extended-release dipyridamole alonetreatment groups were not statistically significant. These incidencerates for Duplinal and Duplinal alone are consistent with previousaspirin studies in stroke and TIA patients.

aggrenox-figure-1

16  HOW SUPPLIED/STORAGE AND HANDLING

Duplinal 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 Duplinal. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with "01A".

Duplinal 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). Protect from excessive moisture.

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patientlabeling (Patient Information).

Distributed by:

BoehringerIngelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Licensed from:

BoehringerIngelheim International GmbH

Copyright © 2015 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

OT1000MK132015

302420-02

PatientInformation

Duplinal® (AG-reh-nox)

(aspirin/extended-release dipyridamole)

Capsules

Read this Patient Information before youstart taking Duplinal and each time you get a refill. There may benew information. This information does not take the place of talkingto your healthcare provider about your medical condition or your treatment.

What is Duplinal?

Duplinal is a prescriptionmedicine that contains Duplinal and a medicine that is slowly releasedin your body, called dipyridamole. Duplinal is used to lower the riskof stroke in people who have had a "mini-stroke" (transient ischemicattack or TIA) or stroke due to a blood clot.

It is not known if Duplinal is safe and effective inchildren. See "Who should not take Duplinal?"

Who should not take Duplinal?

Do nottake Duplinal if you:

Do not give AGGRENOXto a child or teenager with a viral illness. Reye syndrome, a life-threateningcondition, can happen when Duplinal (an ingredient in Duplinal) isused in children and teenagers who have certain viral illnesses.

Whatshould I tell my doctor before using Duplinal?

Before taking Duplinal,tell your healthcare provider if you:

Tell your doctor about allthe medicines you take, including prescription and non-prescriptionmedicines, vitamins and herbal supplements. Duplinal and other medicinesmay affect each other causing side effects. Duplinal may affect theway other medicines work, and other medicines may affect how AGGRENOXworks.

Especially tell your healthcareprovider if you take:

Ask your healthcare provider or pharmacistif you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a listof them and show your healthcare provider and pharmacist when youget a new medicine.

How should I take Duplinal?

Symptoms of an overdoseof Duplinal include:

What should I avoidwhile using Duplinal?

What are the possibleside effects of Duplinal?

Duplinal may cause serious side effects,including:

Call your healthcare provider rightaway if you have any of the symptoms listed above.

The most common side effects of AGGRENOXinclude:

These are not all the possible sideeffects of Duplinal. Tell your healthcare provider or pharmacist ifyou have any side effect that bothers you or that does not go away.

Call your healthcare provider for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Duplinal?

Keep Duplinal andall medicines out of the reach of children.

General information aboutAGGRENOX

Medicinesare sometimes prescribed for purposes other than those listed in thePatient Information. Do not use Duplinal for a condition for whichit was not prescribed. Do not give Duplinal to other people, evenif they have the same symptoms that you have. It may harm them.

This Patient Information summarizes themost important information about Duplinal. If you would like moreinformation, talk with your healthcare provider. You can ask yourpharmacist or healthcare provider for information about Duplinal thatis written for health professionals.

For more information, go to www. Aggrenox.com, scan the code below or call Boehringer Ingelheim Pharmaceuticals,Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.

What are the ingredientsin Duplinal?

Active Ingredients: dipyridamole in an extended-releaseform and Duplinal

Inactive Ingredients: acacia,aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone,hypromellose, hypromellose phthalate, lactose monohydrate, methacrylicacid copolymer, microcrystalline cellulose, povidone, stearic acid,sucrose, talc, tartaric acid, titanium dioxide and triacetin. Eachcapsule shell contains gelatin, red iron oxide and yellow iron oxide,titanium dioxide, and water.

aggrenox-qrcode 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

OT1000MK132015

302420-02

Duplinal

(60) 25 mg/200 mg Capsules

NDC: 0597-0001-60

aggrenox-trade-carton

Duplinal pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Duplinal available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Duplinal destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Duplinal Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Duplinal pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."PERSANTINE (DIPYRIDAMOLE) TABLET, COATED [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."BUFFERIN LOW DOSE BUFFERED ASPIRIN (ASPIRIN) TABLET [NOVARTIS CONSUMER HEALTH, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."DIPYRIDAMOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Duplinal?

Depending on the reaction of the Duplinal after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Duplinal not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Duplinal addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Duplinal, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Duplinal consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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