DURLAZA (Page 2 of 3)

11 DESCRIPTION

DURLAZA Capsules contain aspirin, which is a platelet aggregation inhibitor, for oral administration. Chemically, aspirin is acetylsalicylic acid. It has the following structural formula:

Structural Formula

Aspirin is white or almost white crystalline powder or colorless crystals consisting of cubical and squared crystals. It is slightly soluble in water, and soluble in ethanol. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It has a molecular weight of 180.16 g/mole and a molecular formula C9 H8 O4 .

Durlaza capsules also include the following inactive ingredients: ethylcellulose, povidone, castor oil, tartaric acid, magnesium stearate, colloidal anhydrous silica, and talc.

The capsule shell contains gelatin and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Aspirin [acetylsalicylic acid (ASA)] inhibits prostaglandin synthesis resulting in inhibition of platelet aggregation for their lifespan of about 7-10 days. The acetyl group of aspirin binds with a serine residue of cyclooxygenase-1 (COX-1), resulting in irreversible inactivation of the enzyme. Inhibition of COX-1 prevents conversion of arachidonic acid to thromboxane A2 (TXA2 ), which is a potent agonist of platelet aggregation.

12.2 Pharmacodynamics

The dose-response relationship for DURLAZA and immediate release (IR) aspirin towards COX-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 for DURLAZA and 5 mg to 81 mg for IR aspirin respectively were studied. Half-maximal inhibition 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, the pharmacodynamic effect of DURLAZA 162.5 mg is similar to that attained with IR aspirin 81 mg. The mean inhibition of serum TXB2 following DURLAZA (82%) is lower when compared to IR aspirin 81 mg (93%) following the first dose. However, upon repeat administration, near maximal inhibition of serum TXB2 is achieved, similar to what is achieved following repeated daily doses of IR aspirin.

12.3 Pharmacokinetics

Following oral administration, DURLAZA exhibits extended release of aspirin from the encapsulated microparticles, thereby prolonging the absorption of aspirin across the GI tract compared to IR aspirin (Figure 1). Once absorbed, aspirin is metabolized, distributed, and excreted in a manner similar to that of aspirin absorbed from IR dosage forms.

Figure 1
(click image for full-size original)

Absorption: Following administration of DURLAZA, the time to reach peak plasma concentration of aspirin is slightly longer compared to following IR aspirin dosage form. Median Tmax for DURLAZA is about 2 h when compared to 1 h following IR aspirin (see Figure 1). The mean Cmax for DURLAZA is approximately 35% of that following IR aspirin 81 mg. The area under the plasma concentration-time curve for aspirin following administration of DURLAZA is approximately 70% of that following IR aspirin. The rate of DURLAZA absorption is dependent on food, alcohol, and gastric pH.

Distribution: The volume of distribution of usual doses of aspirin in normal subjects averages approximately 170 mL/kg of body weight.

Metabolism: Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin following DURLAZA administration are essentially undetectable 4-8 hours after dosing. In contrast to immediate release aspirin, measurable levels of salicylic acid at 24 hours following a single dose of DURLAZA were observed. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites.

Elimination: The mean plasma half-life of aspirin may range from 20 to 60 min. Following therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as salicylic acid, and 10% phenolic and 5% acyl glucuronides of salicylic acid.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenesis, mutagenesis or impairment of fertility studies were conducted with DURLAZA. Aspirin is not considered to be genotoxic or carcinogenic. Studies with oral aspirin in pregnant rats demonstrated the occurrence of fetal malformations at oral doses at or above 250 mg/kg [Human equivalent dose (HED) 40 mg/kg].

13.2 Animal Toxicology and/or Pharmacology

A single oral dose of 2500 mg/kg (HED 405 mg/kg) DURLAZA was well-tolerated in the gastrointestinal tract of the rat whereas a single oral dose of IR aspirin ≥740 mg/kg (HED 120 mg/kg) caused lethality and gastric mucosal damage.

14 CLINICAL STUDIES

14.1 Chronic Coronary Artery Disease

This indication is supported by the results of six large, randomized, multi-center, placebo controlled trials of predominantly male post-MI subjects and one randomized placebo-controlled study of men with unstable angina pectoris. Aspirin therapy in MI subjects gave about 20% reduction in the relative risk of the combined endpoint of death or nonfatal reinfarction. In the study of male unstable angina patients, aspirin reduced the event rate from 10% in the placebo patients to 5% in the patients treated with aspirin.

It is also supported by a randomized, multi-center, double-blind trial designed to assess the effect of aspirin in reducing the risk of MI in patients with chronic stable angina pectoris. Aspirin reduced the relative risk of the primary combined endpoint of nonfatal MI, fatal MI, and sudden death by 34%. The secondary endpoint for vascular events (the first occurrence of MI, stroke, or vascular death) was also significantly reduced.

14.2 Ischemic Stroke and Transient Ischemic Attack (TIA)

In clinical trials of subjects with ischemic stroke or TIAs, aspirin has been shown to reduce the relative risk of the combined endpoint of stroke or death and the combined endpoint of TIA, stroke, or death by about 13 — 18%.

16 HOW SUPPLIED/STORAGE AND HANDLING

DURLAZA Capsules, 162.5 mg, are supplied as follows:

Size 2 white to off-white opaque capsules imprinted with the name Durlaza

Bottles of 30 capsules NDC 58487-001-01

Bottles of 90 capsules NDC 58487-001-02

Special Precautions for Storage: Store at 25 °C (77 °F); excursions permitted to 15 — 30°C (59 -86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Discuss the following with patients prior to initiating treatment with DURLAZA and periodically during the course of ongoing treatment:

Bleeding

  • Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their physician any prolonged, unusual or excessive bleeding. Inform patients to notify their physician about blood in their stool or urine and the signs and symptoms of occult bleeding [see Warnings and Precautions (5)].
  • Inform patients about the signs and symptoms of GI side effects and seek medical advice when experiencing any of these signs and symptoms [see Warnings and Precautions (5)].

Hypersensitivity

  • Advise the patient to discontinue DURLAZA and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur [see Contraindications (4)].

Alcohol Consumption

  • Inform patients they should not take DURLAZA 2 hours before or 1 hour after consuming alcohol. Counsel patients who drink three or more alcoholic drinks every day about the risk of bleeding involved in chronic, heavy alcohol use while taking DURLAZA [see Warnings and Precautions (5)].

Administration Instructions

  • Advise patients to swallow DURLAZA capsules whole and not to chew or crush them.
  • Remind patients not to discontinue DURLAZA without first notifying and discussing with their physician. Advise patients not to use extra medicine to make up a missed dose.
  • Advise patients not to take ibuprofen around the same time as DURLAZA [see Drug Interactions (7)].

Pregnancy and Lactation

  • Advise patients that ASA containing products such as DURLAZA cause harm to fetuses especially during the third trimester of pregnancy. Inform patients to notify their physician if they are pregnant, plan to become pregnant, breastfeed or are considering breastfeeding prior or during receiving treatment with DURLAZA [See Use in Special Populations (8.2, 8.3)].

Manufactured for New Haven Pharmaceuticals, Inc.
North Haven, CT 06473
DURLAZA Capsules manufactured in USA
Distributed by Cardinal Health 105, Inc.

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