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DRUGS & SUPPLEMENTS
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When are you taking this medicine? |
The recommended dose of Licuamon is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Licuamon can be administered with or without food.
IntracranialHemorrhage
In European Stroke PreventionStudy-2 (ESPS2), the incidence of intracranial hemorrhage was 0.6%in the Licuamon group, 0.5% in the extended-release dipyridamole (ER-DP)group, 0.4% in the Licuamon (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 Licuamon group, 2.2% in the extended-release dipyridamolegroup, 3.2% in the Licuamon group, and 2.1% in the placebo groups.
Peptic Ulcer Disease
Avoid using Licuamon in patients with a historyof active peptic ulcer disease, which can cause gastric mucosal irritationand bleeding.
Alcohol Warning
Because Licuamon containsaspirin, counsel patients who consume three or more alcoholic drinksevery day about the bleeding risks involved with chronic, heavy alcoholuse while taking Licuamon.
Licuamon 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 Licuamon contained in the maximum recommended daily human dose of Licuamon. 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 Licuamon in pregnant women. If Licuamon is used during pregnancy, or if the patient becomes pregnant while taking Licuamon, inform the patient of the potential hazard to the fetus.
For stroke or TIA patients for whom Licuamon is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the Licuamon in this product may not provide adequate treatment for the cardiac indications.
The efficacy and safety of Licuamon 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 Licuamon, Licuamon, 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 Licuamon with placebo,extended-release dipyridamole alone and Licuamon 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 Licuamon 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 | ||||||||
---|---|---|---|---|---|---|---|---|
Licuamon | ER-DP Alone | ASA Alone | Placebo | |||||
Body System/Preferred Term | ||||||||
aReportedby ≥1% of patients during Licuamon treatment where the incidence wasgreater than in those treated with placebo. | ||||||||
Note: ER-DP = extended-releasedipyridamole 200 mg; ASA = Licuamon 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 Licuamon, 25% for extended-releasedipyridamole, 19% for Licuamon, and 21% for placebo (refer to Table2)
Treatment Groups | ||||||||
---|---|---|---|---|---|---|---|---|
Licuamon | ER-DP | ASA | Placebo | |||||
Note: ER-DP = extended-release dipyridamole200 mg; ASA = Licuamon 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 Licuamon 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 Licuamon showeda decline (mean change from baseline) in hemoglobin of 0.25 g/dL,hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.
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.
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 Licuamon.
Acetazolamide
Concurrent use of Licuamon 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 Licuamon in combination with anticoagulants, antiplatelets,or any substance impacting coagulation are at increased risk for bleeding. Licuamon 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 Licuamon 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 Licuamon 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 Licuamon withother NSAIDs may increase bleeding or lead to decreased renal function.
Oral Hypoglycemics
Moderate doses of Licuamon may increase the effectiveness of oralhypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and sulfinpyrazone)
Salicylates antagonize the uricosuric action of uricosuricagents.
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 Licuamon 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.
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 Licuamon
The antiplatelet agent Licuamon (acetylsalicylic acid)is chemically known as benzoic acid, 2- (acetyloxy)-, and has thefollowing structural formula:
Licuamon 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.
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).
Licuamon
Licuamon 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.
Dipyridamole
Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg Licuamon (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 Licuamon 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 Licuamon 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 Licuamon.
Hepatic Dysfunction : No study has been conducted with Licuamon 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 Licuamon 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.
Licuamon
Peak plasma levels of Licuamon are achieved 0.63 hours(0.5–1 hour) after administration of a 50 mg Licuamon daily dose fromAGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-stateis 319 ng/mL (175–463 ng/mL). Licuamon undergoes moderate hydrolysisto salicylic acid in the liver and the gastrointestinal wall, with50%–75% of an administered dose reaching the systemic circulationas intact Licuamon.
When AGGRENOXcapsules were taken with a high fat meal, there was no differencefor Licuamon 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) ].
Licuamon 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 Licuamon. 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 Licuamon 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 Licuamon in patients with severe renal failure (glomerularfiltration rate less than 10 mL/min).
Licuamon
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 Licuamon 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.
Combinations of dipyridamole and Licuamon (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). Licuamon, 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 Licuamon 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). Licuamon inhibits ovulation in rats.
Stroke Endpoint
Licuamon reduced the risk of stroke by 22.1%compared to Licuamon 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). Licuamon 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 = Licuamon 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, Licuamon reduced the risk of stroke or death by 12.1% compared to Licuamon alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. Licuamon 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 Licuamon, 11.0% for Licuamon alone, 11.4% for extended-releasedipyridamole alone and 12.3% for placebo alone. The differences betweenthe Licuamon, Licuamon alone and extended-release dipyridamole alonetreatment groups were not statistically significant. These incidencerates for Licuamon and Licuamon alone are consistent with previousaspirin studies in stroke and TIA patients.
Licuamon 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.
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 Licuamon.
Inform patients that aspirinis known to be harmful to fetuses and ask the patient to notify themif they are or become pregnant.
Some patients may experienceheadaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact theirphysician.
Tell patientsthat Licuamon 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.
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
Licuamon® (AG-reh-nox)
(aspirin/extended-release dipyridamole)
Capsules
Read this Patient Information before youstart taking Licuamon 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 Licuamon?
Licuamon is a prescriptionmedicine that contains Licuamon and a medicine that is slowly releasedin your body, called dipyridamole. Licuamon 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 Licuamon is safe and effective inchildren. See "Who should not take Licuamon?"
Who should not take Licuamon?
Do nottake Licuamon if you:
Whatshould I tell my doctor before using Licuamon?
Before taking Licuamon,tell your healthcare provider if you:
Especially tell your healthcareprovider if you take:
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 Licuamon?
Licuamon may cause serious side effects,including:
The most common side effects of AGGRENOXinclude:
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 Licuamon?
General information aboutAGGRENOX
Medicinesare sometimes prescribed for purposes other than those listed in thePatient Information. Do not use Licuamon for a condition for whichit was not prescribed. Do not give Licuamon to other people, evenif they have the same symptoms that you have. It may harm them.
This Patient Information summarizes themost important information about Licuamon. If you would like moreinformation, talk with your healthcare provider. You can ask yourpharmacist or healthcare provider for information about Licuamon 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 Licuamon?
Active Ingredients: dipyridamole in an extended-releaseform and Licuamon
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
Licuamon
(60) 25 mg/200 mg Capsules
NDC: 0597-0001-60
aggrenox-trade-carton
Depending on the reaction of the Licuamon after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Licuamon 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 Licuamon 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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The information was verified by Dr. Rachana Salvi, MD Pharmacology