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DRUGS & SUPPLEMENTS
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Arreno
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Arreno uses
- indications and usage
- dosage and administration
- dosage forms and strengths
- contraindications
- warnings and precautions
- adverse reactions
- drug interactions
- use in specific populations
- overdosage
- description
- clinical pharmacology
- nonclinical toxicology
- clinical studies
- how supplied/storage and handling
- patient counseling information
1 INDICATIONS AND USAGE
Arreno 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.- Arreno is 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)
2 DOSAGE AND ADMINISTRATION
Arreno is not interchangeable with the individual components of Arreno and dipyridamole tablets.The recommended dose of Arreno is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Arreno can be administered with or without food.
- One capsule twice daily with or without food (2)
- In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose Arreno in the morning; resume BID dosing within one week (2)
- Do not chew capsule (2)
- Not interchangeable with the individual components of Arreno 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 Arreno 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.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 Arreno. The capsule body is imprinted in red withthe Boehringer Ingelheim logo and with "01A".- Capsule: 25 mg aspirin/200 mg extended-release dipyridamole (3)
4 CONTRAINDICATIONS
- Hypersensitivity to any product ingredients
- Patients with known allergy to NSAIDs (4.2)
- Patients with the syndrome of asthma, rhinitis, and nasalpolyps (4.2)
4.1 Hypersensitivity
Arreno is contraindicated in patients with known hypersensitivity to any of the product components.4.2 Allergy
Arreno 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 Arreno in children or teenagers with viral infections because of the risk of Reye syndrome.5 WARNINGS AND PRECAUTIONS
- Arreno increases the risk of bleeding
- 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
Arreno 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 Arreno group, 0.5% in the extended-release dipyridamole (ER-DP)group, 0.4% in the Arreno (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 Arreno group, 2.2% in the extended-release dipyridamolegroup, 3.2% in the Arreno group, and 2.1% in the placebo groups.
Peptic Ulcer Disease
Avoid using Arreno in patients with a historyof active peptic ulcer disease, which can cause gastric mucosal irritationand bleeding.
Alcohol Warning
Because Arreno containsaspirin, counsel patients who consume three or more alcoholic drinksevery day about the bleeding risks involved with chronic, heavy alcoholuse while taking Arreno.
5.2 Renal Failure
Avoid Arreno 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 Arreno contains Arreno, Arreno can cause fetal harm when administered to a pregnant woman. Maternal Arreno 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 Arreno in the third trimester of pregnancy [ see Use in Specific Populations (8.1) ].Arreno 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 Arreno contained in the maximum recommended daily human dose of Arreno. 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 Arreno in pregnant women. If Arreno is used during pregnancy, or if the patient becomes pregnant while taking Arreno, 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 Arreno is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the Arreno 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
Arreno capsules are not interchangeable with the individual components of Arreno and dipyridamole tablets.6 ADVERSE REACTIONS
The following adverse reactions are discussedelsewhere in the labeling:- Hypersensitivity [ see Contraindications ]
- Allergy [ see Contraindications (4.2) ]
- Risk of Bleeding [ see Warnings and Precautions (5.1) ]
- The most frequently reported adverse reactions (>10% andgreater than placebo) were headache, dyspepsia, abdominal pain, nausea,and diarrhea (6)
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 Arreno 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 Arreno, Arreno, 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 Arreno with placebo,extended-release dipyridamole alone and Arreno 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 Arreno 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 | ||||||||
|---|---|---|---|---|---|---|---|---|
| Arreno | ER-DP Alone | ASA Alone | Placebo | |||||
| Body System/Preferred Term | ||||||||
| aReportedby ≥1% of patients during Arreno treatment where the incidence wasgreater than in those treated with placebo. | ||||||||
| Note: ER-DP = extended-releasedipyridamole 200 mg; ASA = Arreno 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 Arreno, 25% for extended-releasedipyridamole, 19% for Arreno, and 21% for placebo (refer to Table2)
| Treatment Groups | ||||||||
|---|---|---|---|---|---|---|---|---|
| Arreno | ER-DP | ASA | Placebo | |||||
| Note: ER-DP = extended-release dipyridamole200 mg; ASA = Arreno 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%) |
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 Arreno 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 Arreno 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.
7 DRUG INTERACTIONS
- Co-administration with anticoagulants, antiplatelets, orNSAIDs can increase risk of bleeding
- Decreased renal function can occur with co-administrationwith NSAIDs (7.1)
7.1 Drug InteractionStudy Information Obtained From Literature
AdenosineDipyridamole 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 Arreno.
Acetazolamide
Concurrent use of Arreno 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 Arreno in combination with anticoagulants, antiplatelets,or any substance impacting coagulation are at increased risk for bleeding. Arreno 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 Arreno 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 Arreno 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 Arreno withother NSAIDs may increase bleeding or lead to decreased renal function.
Oral Hypoglycemics
Moderate doses of Arreno may increase the effectiveness of oralhypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and sulfinpyrazone)
Salicylates antagonize the uricosuric action of uricosuricagents.
8 USE IN SPECIFIC POPULATIONS
- Pregnancy Category D
8.1 Pregnancy
Teratogenic Effects, Pregnancy Category D. [ see Warnings and Precautions (5.4) ].8.2 Labor and Delivery
Arreno 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 Arreno during the later stages of pregnancy [ see Warnings and Precautions ], avoid Arreno in the third trimester of pregnancy and during labor and delivery.8.3 Nursing Mothers
Both dipyridamole and Arreno are excreted in human milk. Exercise caution when Arreno capsules are administered to a nursing woman.8.4 Pediatric Use
Safety and effectiveness of Arreno in pediatric patients have not been studied. Due to the Arreno 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
Arreno has not been studied in patients with hepaticor renal impairment. Avoid using Arreno containing products, suchas Arreno 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 Arreno, 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 Arreno 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
Arreno 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 Arreno, 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 Arreno
The antiplatelet agent Arreno (acetylsalicylic acid)is chemically known as benzoic acid, 2- (acetyloxy)-, and has thefollowing structural formula:
Arreno 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The antithrombotic action of Arreno is the result of the additive antiplatelet effects of dipyridamole and Arreno. 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).
Arreno
Arreno 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 Arreno and dipyridamole. The kinetics of the components are unchanged by their co-administration as Arreno. Dipyridamole
Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg Arreno (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).
When Arreno 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.
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.
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 Arreno which, in Trial 9.123 was 13.6 hours.
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 Arreno.
Hepatic Dysfunction : No study has been conducted with Arreno 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 Arreno 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.
Arreno
Peak plasma levels of Arreno are achieved 0.63 hours(0.5–1 hour) after administration of a 50 mg Arreno daily dose fromAGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-stateis 319 ng/mL (175–463 ng/mL). Arreno undergoes moderate hydrolysisto salicylic acid in the liver and the gastrointestinal wall, with50%–75% of an administered dose reaching the systemic circulationas intact Arreno.
When AGGRENOXcapsules were taken with a high fat meal, there was no differencefor Arreno 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.
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) ].
Arreno 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 Arreno. 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 Arreno 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.
Hepatic Dysfunction : Avoid aspirinin patients with severe hepatic insufficiency.
Renal Dysfunction : Avoid Arreno in patients with severe renal failure (glomerularfiltration rate less than 10 mL/min).
Arreno
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 Arreno 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 Arreno (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). Arreno, 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 Arreno 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). Arreno 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: Arreno (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
Arreno reduced the risk of stroke by 22.1%compared to Arreno 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). Arreno 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 = Arreno 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) |
Over24 months of Follow-UP
Combined Stroke or Death Endpoint
In ESPS2, Arreno reduced the risk of stroke or death by 12.1% compared to Arreno alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. Arreno 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 Arreno, 11.0% for Arreno alone, 11.4% for extended-releasedipyridamole alone and 12.3% for placebo alone. The differences betweenthe Arreno, Arreno alone and extended-release dipyridamole alonetreatment groups were not statistically significant. These incidencerates for Arreno and Arreno alone are consistent with previousaspirin studies in stroke and TIA patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
Arreno 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 Arreno. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with "01A".Arreno 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).- Risk of Bleeding
Inform patientsthat as with other antiplatelet agents, there is a general risk ofbleeding including intracranial and gastrointestinal bleeding. Informpatients about the signs and symptoms of bleeding, including occultbleeding. Tell patients to notify their physician if they are prescribedany drug which may increase risk of bleeding.
Counsel patients who consume three or more alcoholic drinks dailyabout the bleeding risks involved with chronic, heavy alcohol usewhile taking Arreno.
- Pregnancy
Inform patients that aspirinis known to be harmful to fetuses and ask the patient to notify themif they are or become pregnant.
- Headaches
Some patients may experienceheadaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact theirphysician.
- Dosage and Administration
Tell patientsthat Arreno capsules should be swallowed whole, and not chewed orcrushed. If you miss a dose, continue with your next dose on yourregular schedule. Do not take a double dose.
- Storage
Inform patients to protectAGGRENOX from moisture.
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
Arreno® (AG-reh-nox)
(aspirin/extended-release dipyridamole)
Capsules
Read this Patient Information before youstart taking Arreno 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 Arreno?
Arreno is a prescriptionmedicine that contains Arreno and a medicine that is slowly releasedin your body, called dipyridamole. Arreno 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 Arreno is safe and effective inchildren. See "Who should not take Arreno?"
Who should not take Arreno?
Do nottake Arreno if you:
- are allergic to any of the ingredients in Arreno. Seethe end of this leaflet for a list of ingredients in Arreno.
- are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)
- have asthma in combination with runny nose and nasal polyps
Whatshould I tell my doctor before using Arreno?
Before taking Arreno,tell your healthcare provider if you:
- have stomach ulcers
- have a history of bleeding problems
- have heart problems
- have kidney or liver problems
- have low blood pressure
- have myasthenia gravis
- have any other medical conditions
- are pregnant or plan to become pregnant. Arreno can harmyour unborn baby, especially if you take it in the last (third) trimesterof pregnancy. You should not take Arreno during pregnancy withoutfirst talking to your healthcare provider. Tell your healthcare providerright away if you become pregnant while taking Arreno.
- are breast-feeding or plan to breast-feed. Arreno canpass into your milk and may harm your baby. Talk to your healthcareprovider about the best way to feed your baby if you take Arreno.
Especially tell your healthcareprovider if you take:
- a medicine for high blood pressure, irregularheart beat, or heart failure
- acetazolamide [Diamox®]
- any blood thinner medicines
- warfarin sodium [Coumadin®, Jantoven®]
- a heparin medicine
- anagrelide [Agrylin®]
- a seizure medicine
- a medicine for Alzheimer’s disease
- a water pill
- methotrexate sodium [Trexall®]
- Arreno or a non-steroidal anti-inflammatorydrug (NSAIDs). You should not take NSAIDs during treatment with Arreno. Using these medicines with Arreno can increase your riskof bleeding.
- a medicine for diabetes
- probenecid [Probalan®, Col-Probenecid®]
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 Arreno?
- Take Arreno exactly as prescribed. Your healthcare providerwill tell you how many Arreno to take and when to take them.
- Headaches are not uncommon when you first start taking Arreno,but often lessen as treatment continues. Tell your healthcare providerif you have a severe headache. Your healthcare provider may changethe instructions for taking Arreno.
- Swallow Arreno whole. Do not crush or chew the capsules.
- You can take Arreno with or without food.
-
If you miss a dose, takeyour next dose at the usual time. Do not take two doses at one time. - If you take more Arreno (overdose) than prescribed, callyour healthcare provider or Poison Control Center, or get emergencyhelp right away.
- a warm feeling or flushing
- sweating
- restlessness
- weakness or dizziness
- a fast heart rate
- ringing in the ears
- heavy alcohol use. Peoplewho drink three or more alcoholic drinks every day have a higher riskof bleeding during treatment with Arreno, because it contains Arreno.
Arreno may cause serious side effects,including:
- increased risk of bleeding. You may bleed more easily during Arreno treatment, and it maytake longer than usual for bleeding to stop. This can include:
- bleeding into your brain (intracranial hemorrhage). This can be a medical emergency. Get medical help right awayif you have any of these symptoms while taking Arreno:
- severe headache with drowsiness
- confusion or memory change
- pass out (become unconscious)
- bleeding in your stomach or intestine.
- stomach pain
- heartburn or nausea
- vomiting blood or vomit looks like "coffee grounds"
- red or bloody stools
- black stools that look like tar
- bleeding into your brain (intracranial hemorrhage). This can be a medical emergency. Get medical help right awayif you have any of these symptoms while taking Arreno:
- new or worsening chest pain in some peoplewith heart disease. Tell your healthcare providerif you have new chest pain or have any change in your chest pain duringtreatment with Arreno.
- liver problems, includingincreased liver function tests and liver failure. Tell your healthcareprovider if you have any of these symptoms of a liver problem whiletaking Arreno:
- loss of appetite
- pale colored stool
- stomach area (abdomen) pain
- yellowing of your skin or whites of your eyes
- dark urine
- itching
The most common side effects of AGGRENOXinclude:
- headache
- upset stomach
- diarrhea
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 Arreno?
- Store Arreno at 59°F to 86°F (15°C to 30°C).
- Keep Arreno capsules dry.
- Safely throw away medicine that is out of date or no longerneeded.
General information aboutAGGRENOX
Medicinesare sometimes prescribed for purposes other than those listed in thePatient Information. Do not use Arreno for a condition for whichit was not prescribed. Do not give Arreno to other people, evenif they have the same symptoms that you have. It may harm them.
This Patient Information summarizes themost important information about Arreno. If you would like moreinformation, talk with your healthcare provider. You can ask yourpharmacist or healthcare provider for information about Arreno 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 Arreno?
Active Ingredients: dipyridamole in an extended-releaseform and Arreno
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.
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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
Arreno
(60) 25 mg/200 mg Capsules
NDC: 0597-0001-60
aggrenox-trade-carton
Arreno pharmaceutical active ingredients containing related brand and generic drugs:
Arreno available forms, composition, doses:
Arreno destination | category:
Arreno Anatomical Therapeutic Chemical codes:
Arreno pharmaceutical companies:
References
- Dailymed."PERSANTINE (DIPYRIDAMOLE) TABLET, COATED [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."BUFFERIN LOW DOSE BUFFERED ASPIRIN (ASPIRIN) TABLET [NOVARTIS CONSUMER HEALTH, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- 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 Arreno?Depending on the reaction of the Arreno after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Arreno 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 Arreno 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.
Review
sdrugs.com conducted a study on Arreno, 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 Arreno 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.Visitor reports
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The information was verified by Dr. Rachana Salvi, MD Pharmacology