Reference ID: 3815987

DURLAZA can cause gastric mucosal irritation and bleeding. Patientswith a history of active peptic ulcer disease are at particular risk. (5.2) DURLAZA can cause fetal harm when administered to a pregnantwoman. (5.3, 8.1)HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useDURLAZA safely and effectively. See full prescribing information forDURLAZA.DURLAZA (aspirin) Extended Release Capsules, for oral useInitial U.S. Approval: INDICATIONS AND USAGEDURLAZA is a nonsteroidal anti-inflammatory drug indicated to reduce therisk of death and myocardial infarction (MI) in patients with chronic coronaryartery disease, such as patients with a history of MI or unstable anginapectoris or with chronic stable angina and to reduce the risk of death andrecurrent stroke in patients who have had an ischemic stroke or transientischemic attack (1)Limitation of Use: Use immediate-release aspirin, not DURLAZA insituations where a rapid onset of action is required (such as acute treatment ofmyocardial infarction or before percutaneous coronary intervention). (1, 4)ADVERSE REACTIONS Most common adverse reactions are Gastrointestinal (6).To report SUSPECTED ADVERSE REACTIONS, contact New HavenPharmaceuticals. DOSAGE AND ADMINISTRATIONThe recommended dose is 162.5 mg per day with a full glass of water at thesame time each day (2)DOSAGE FORMS AND STRENGTHS Capsules, 162.5 mg (3) USE IN SPECIFIC POPULATIONS Pregnancy: Avoid use during the third trimester (8.1) Hepatic Impairment: Avoid use in patients with severe impairment (8.6) Renal Impairment: Avoid use in patients with GFR less than 10 mL/min(8.7)CONTRAINDICATIONS Hypersensitivity to nonsteroidal anti-inflammatory drug products (4) Asthma, rhinitis, and nasal polyps (4)WARNINGS AND PRECAUTIONS Increased risk of bleeding. (5.1)FULL PRESCRIBING INFORMATION: CONTENTS*123456789INDICATIONS AND USAGEDOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHSCONTRAINDICATIONSWARNINGS AND PRECAUTIONSADVERSE REACTIONSDRUG INTERACTIONSUSE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric UseDRUG ABUSE AND DEPENDENCEReference ID: 3815987DRUG INTERACTIONSAlcohol: do not take DURLAZA 2 hours before or 1 hour afterconsuming alchohol (7)Dual inhibition of the renin-angiotensin system: Increased risk of renalimpairment, hypotension and hyperkalemia (7)Anticoagulant and antiplatelets: increased risk of bleeding (7)Anticonvulsants: decreased phenytoin concentration and increasedserum valproic acid levels (7)Methotrexate: increased risk of bone marrow toxicity (7)NSAIDs: Increased risk of bleeding. Nonselective NSAIDs mayinterfere with DURLAZAs antiplatelet effect (7)See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.Revised: AL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 PharmacokineticsNONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or PharmacologyCLINICAL STUDIESREFERENCESHOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing informationare not listed.

FULL PRESCRIBING INFORMATION1INDICATIONS AND USAGEDURLAZA is indicated to:1. Reduce the risk of death and myocardial infarction (MI) in patients with chroniccoronary artery disease, such as patients with a history of MI or unstable anginapectoris or with chronic stable angina2. Reduce the risk of death and recurrent stroke in patients who have had an ischemicstroke or transient ischemic attackLimitation of Use: Use immediate-release aspirin, not DURLAZA in situations where a rapidonset of action is required (such as acute treatment of myocardial infarction or beforepercutaneous coronary intervention).2DOSAGE AND ADMINISTRATIONThe recommended dose of DURLAZA is one capsule (162.5 mg) once daily. Take the capsuleswith a full glass of water at the same time each day.Swallow DURLAZA capsules whole. Do not cut, crush or chew capsules.Do not take DURLAZA 2 hours before or 1 hour after consuming alcohol [see Warnings andPrecautions (5)].3DOSAGE FORMS AND STRENGTHSDURLAZA (aspirin) Extended Release Capsules are supplied as white to off-white opaquecapsules each containing 162.5 mg of aspirin.4CONTRAINDICATIONSDURLAZA is contraindicated: In patients with a hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with the syndrome of asthma, rhinitis, and nasal polyps. DURLAZA maycause severe urticaria, angioedema, or bronchospasm.55.1WARNINGS AND PRECAUTIONSRisk of BleedingDURLAZA increases the risk of bleeding. Risk factors for bleeding include the use of otherdrugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic useof NSAIDs) [see Drug Interactions (7)].5.2Peptic Ulcer DiseaseReference ID: 3815987

DURLAZA may cause gastric ulceration and bleeding. Avoid DURLAZA in patients with activepeptic ulcer disease.5.3Fetal ToxicityDURLAZA can cause fetal harm when administered to a pregnant woman. Maternal aspirin useduring later stages of pregnancy may cause low birth weight, increased incidence for intracranialhemorrhage in premature infants, stillbirths and neonatal death. Because NSAIDs may causepremature closure of the fetal ductus arteriosus, avoid DURLAZA in the third trimester ofpregnancy [see Use in Specific Populations (8.1)].66.1ADVERSE REACTIONSClinical Trials ExperienceThe following is a list of adverse reactions that have been reported in the literature for productscontaining low dose aspirin [see Warnings and Precautions (5)].Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache,lethargy, seizures.Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis.Gastrointestinal: Dyspepsia, hepatic enzyme elevation, hepatitis, Reye's SyndromeRenal: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure.7DRUG INTERACTIONSAlcohol: Do not take DURLAZA 2 hours before or 1 hour after consuming alcohol. Alcohol caninterfere with the controlled release properties of DURLAZA.Renin-angiotensin system (RAS) inhibitors: In patients who are elderly, volume-depleted(including those on diuretic therapy), or who have compromised renal function,coadministration of NSAIDs, including DURLAZA, with RAS inhibitors may result indeterioration of renal function, including possible acute renal failure. These effects areusually reversible. Monitor renal function periodically in patients receiving RAS inhibitorsand DURLAZA.NSAIDs, including DURLAZA may attenuate the antihypertensive effects of RAS inhibitors.Anticoagulant and antiplatelets: Increased risk of bleedingAnticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to adecrease in the total concentration of phenytoin and an increase in serum valproic acid levels.Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrowtoxicity, especially in the elderly or renal impaired.Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concurrent use of DURLAZA with otherNSAIDs increases the risk of bleeding and may result in renal impairment.Ibuprofen can interfere with the anti-platelet effect of low dose aspirin. Patients who useDURLAZA and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 2-4Reference ID: 3815987

hours or longer after ingestion of DURLAZA. Wait 8 hours after ibuprofen dosing, before givingaspirin, to avoid significant interference.Nonselective NSAIDs may interfere with the antiplatelet effect of low-dose aspirin.8USE IN SPECIFIC POPULATIONS8.1PregnancyAvoid use during the third trimester of pregnancy because NSAIDs such as DURLAZA maycause premature closure of the fetal ductus arteriosus. Salicylate products have also beenassociated with alterations in maternal and neonatal hemostasis mechanisms, decreased birthweight, and with perinatal mortality.8.2Labor and DeliveryAvoid DURLAZA 1 week prior to and during labor and delivery because it can result inexcessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandininhibition have been reported.8.3Nursing MothersBecause of the potential for serious adverse reactions in nursing infants from DURLAZA,choose either to discontinue DURLAZA or discontinue nursing.8.4Pediatric UseSafety and effectiveness in pediatric patients have not been established.8.5Geriatric UseIn a large collaborative overview of aspirin for vascular event prevention, including over 14000patients over 65 years of age, no overall differences in safety or effectiveness were observedbetween these subjects and younger subjects, and other reported clinical experience has notidentified differences in responses between the elderly and younger patients.8.6Hepatic ImpairmentAvoid DURLAZA in patients with severe hepatic insufficiency.8.7Renal ImpairmentAvoid DURLAZA in patients with severe renal failure (glomerular filtration rate less than10 mL/minute).10OVERDOSAGESalicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The earlysigns of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasmaReference ID: 3815987

concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mLare clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL [see ClinicalPharmacology (12.3)]. A single lethal dose of aspirin in adults is not known with certainty butdeath may be expected at 30 g. For real or suspected overdose, contact a Poison Control Centerimmediately.Signs and Symptoms: In acute overdose, severe acid-base and electrolyte disturbances mayoccur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs earlywhile hyperventilation is present, but is quickly followed by metabolic acidosis.Treatment: Treatment consists primarily of supporting vital functions, increasing salicylateelimination, and correcting the acid-base disturbance. Gastric emptying or lavage isrecommended as soon as possible after ingestion, even if the patient has vomited spontaneously.After lavage or emesis, administer activated charcoal, as a slurry, if less than 3 hours have passedsince ingestion.Severity of aspirin intoxication is determined by measuring the blood salicylate level. Monitoracid-base status with serial blood gas and serum pH measurements. Maintain fluid andelectrolyte balance.In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Replacefluid intravenously and correct acidosis. Monitor plasma electrolytes and pH to promote alkalinediuresis of salicylate if renal function is normal. Glucose may be required to controlhypoglycemia.Hemodialysis and peritoneal dialysis can reduce the body aspirin content. In patients with renalinsufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchangetransfusion may be indicated in infants and young children.11DESCRIPTIONDURLAZA Capsules contain aspirin, which is a platelet aggregation inhibitor, for oraladministration. Chemically, aspirin is acetylsalicylic acid. It has the following structural formula:Aspirin is white or almost white crystalline powder or colorless crystals consisting of cubical andsquared crystals. It is slightly soluble in water, and soluble in ethanol. When exposed tomoisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It has amolecular weight of 180.16 g/mole and a molecular formula C9H8O4.Durlaza capsules also include the following inactive ingredients: ethylcellulose, povidone, castoroil, tartaric acid, magnesium stearate, colloidal anhydrous silica, and talc.The capsule shell contains gelatin and titanium dioxide.Reference ID: 3815987

12CLINICAL PHARMACOLOGY12.1Mechanism of ActionAspirin [acetylsalicylic acid (ASA)] inhibits prostaglandin synthesis resulting in inhibition ofplatelet aggregation for their lifespan of about 7-10 days. The acetyl group of aspirin binds witha serine residue of cyclooxygenase-1 (COX-1), resulting in irreversible inactivation of theenzyme. Inhibition of COX-1 prevents conversion of arachidonic acid to thromboxane A2(TXA2), which is a potent agonist of platelet aggregation.12.2PharmacodynamicsThe dose-response relationship for DURLAZA and immediate release (IR) aspirin towardsCOX-1 inhibition was characterized by examining the inhibition of serum TXB2 and urine 11 dehydro-TXB2 at 24 h following a single dose. Doses over the range of 20 mg to 325 mg forDURLAZA and 5 mg to 81 mg for IR aspirin respectively were studied. Half-maximalinhibition of serum TXB2 and urine 11-dehydro-TXB2 occurred with doses of DURLAZA (ID50)about 2-fold the dose of immediate release (IR) aspirin. Based on this relationship, thepharmacodynamic effect of DURLAZA 162.5 mg is similar to that attained with IR aspirin 81mg. The mean inhibition of serum TXB2 following DURLAZA (82%) is lower when comparedto IR aspirin 81 mg (93%) following the first dose. However, upon repeat administration, nearmaximal inhibition of serum TXB2 is achieved, similar to what is achieved following repeateddaily doses of IR aspirin.12.3PharmacokineticsFollowing oral administration, DURLAZA exhibits extended release of aspirin from theencapsulated microparticles, thereby prolonging the absorption of aspirin across the GI tractcompared to IR aspirin (Figure 1). Once absorbed, aspirin is metabolized, distributed, andexcreted in a manner similar to that of aspirin absorbed from IR dosage forms.Reference ID: 3815987

Figure 1:Mean acetylsalicylic acid concentration-time profile following single doseadministration of 162.5 mg DURLAZA or 81 mg immediate release ASAAbsorption: