(Acetylsalicylic acid chewable tablets, USP) 81 mg
(Acetylsalicylic acid delayed-release tablets, USP) 81 mg Platelet aggregation inhibitor Pendopharm, Division of Pharmascience, Inc Date of Revision: 8580 Esplanade Avenue June 3, 2008 Montreal, Quebec H4P 2T4
(Acetylsalicylic acid chewable tablets, USP) 81 mg
(Acetylsalicylic acid delayed release tablets, USP) 81 mg
Platelet aggregation inhibitor.
ACTION AND CLINICAL PHARMACOLOGY
ASA interferes with the production of prostaglandins in various organs and tissues through acetylation of the enzyme cyclo-oxygenase. Prostaglandins are themselves powerful irritants and produce headaches and pain on injection in man. Prostaglandins also appear to sensitize pain receptors to other noxious substances such as histamine and bradykinin. By preventing the synthesis and release of prostaglandins in inflammation, ASA may avert the sensitization of pain receptors. The antipyretic activity of ASA is due to its ability to interfere with the production of prostaglandin E 1 in the brain. Prostaglandin E 1 is one of the most powerful pyretic agents known. The inhibition of platelet aggregation by ASA is due to its ability to interfere with the production of thromboxane A 2 within the platelet. Thromboxane A 2 is largely responsible for the aggregating properties of platelets.
INDICATIONS AND CLINICAL USE
ENTROPHEN 81 mg and ENTROPHEN CHEWABLE 81 mg are indicated for the following uses, based on its platelet aggregation inhibitory properties:
-For reducing the risk of morbidity and death in patients with unstable angina and in those with previous myocardial infarction.
-For reducing the risk of transient ischemic attacks (TIA) and for secondary prevention of atherothrombotic cerebral infarction;
In addition, ENTROPHEN 81 mg is also indicated for the following uses, based on its platelet aggregation inhibitory properties:
-For reducing the risk of vascular mortality in patients with a suspected acute myocardial infarction.
-For reducing the risk of a first non-fatal myocardial infarction in individuals deemed to be at sufficient risk of such an event by their physician. There is no evidence for a reduction in the risk of first fatal myocardial infarction. ASA does not reduce the risk of either cardiovascular mortality or first strokes, fatal or non- fatal. The decrease in the risk of first non-fatal myocardial infarction must be assessed against a much smaller but significant increase in the risk of haemorrhagic stroke as well as gastrointestinal bleeding.
Use of Entrophen Chewable 81 mg or Entrophen 81 mg is contraindicated in patients: who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see COMPOSITION and AVAILABILITY OF DOSAGE FORMS sections of the product monograph. with a history of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory drugs also taking methotrexate at doses of 15 mg/week or more during their last trimester of pregnancy with any Hemorrhagic diathesis with an Active peptic ulcer.
General
ASA is one of the most frequent causes of accidental poisonings in toddlers and infants. Tablets should be kept well out of the reach of children. Salicylates should be administered cautiously to patients with: Hypersensitivity to anti-inflammatory or antirheumatic drugs or other allergens impaired renal function or hepatic function a history of chronic or recurrent gastrointestinal ulcerations and bleeds a history of bleeding tendencies, significant anemia and/or hypothrombinemia
Hypersensitivity
ENTROPHEN may precipitate bronchospasm and induce asthma attacks or other hypersensitivity reactions. Risk factors are present bronchial asthma, hay fever, nasal polyps, or chronic respiratory disease. This applies also for patients showing allergic reactions (e.g. cutaneous reactions, itching, urticaria) to other substances.
Hematologic
Due to effect on platelet aggregation, ENTROPHEN may be associated with an increased risk of bleeding. Caution is necessary when salicylates and anticoagulants are prescribed concurrently, as salicylates can depress the concentration of prothrombin in the plasma.
Peri-Operative Considerations
Due to its inhibitory effect on platelet aggregation ENTROPHEN may lead to an increased bleeding tendency during and after surgical operations (including minor surgeries, e.g. dental extractions).
Special Populations
Pregnant Women:
Use of salicylates in the first 3 months of pregnancy has been associated in several epidemiological studies with an elevated risk of malformations (cleft palate, heart malformations). After normal therapeutic doses this risk seems to be low: a prospective study with exposure of about 32,000 mother-child pairs has not yielded any association with the risk of malformations. Salicylates should be taken during pregnancy only after strict risk benefit evaluation.
In the last 3 months of pregnancy, administration of salicylates in high doses (>300mg/day) can lead to prolongation of the gestation period, premature closure of the arterial duct and inhibition of uterine contractions. An increased hemorrhagic tendency has been observed in both mother and child.
Administration of ENTROPHEN in high doses (> 300 mg/d) shortly before birth, can lead to intracranial hemorrhages, particularly in premature babies.
ENTROPHEN and its metabolites pass into breast milk in small quantities. Since no adverse effects on the infant have been observed after occasional use, interruption of breast-feeding is usually unnecessary. However, on regular use or on intake of high doses, breast feeding should be discontinued early.
A possible association between Reye's syndrome and the use of salicylates has been suggested but not established. Reye's syndrome has also occurred in many patients not exposed to salicylates. ENTROPHEN should not be used in children and teenagers for viral infections with or without fever without consulting a physician. In certain viral illnesses, especially influenza A, influenza B and varicella, there is a risk of Reye's syndrome, a very rare but possibly life- threatening illness requiring immediate medical action. The risk may be increased when ENTROPHEN is given concomitantly; however, no causal relationship has been proven. Should persistent vomiting occur with such diseases; this may be a sign of Reye's syndrome.
At low doses, ENTROPHEN reduces excretion of uric acid. This can trigger gout in patients who already tend to have low uric acid excretion.
Salicylates can produce changes in thyroid function tests. Isolated cases of liver function disturbances (transaminases increase) have been
described.
Many adverse reactions due to ENTROPHEN ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature and from both clinical and post- marketing experience.
Gastrointestinal:
(the frequency and severity of these adverse effects are dose-related): nausea, vomiting, diarrhea, gastrointestinal bleeding and/or ulceration, dyspepsia, heartburn, hematemesis and melena.
Ear: tinnitus, vertigo, hearing loss. Hematologic: leukopenia, thrombocytopenia, purpura, anemia.
Dermatologic and hypersensitivity:
urticaria, angioedema, pruritus, skin eruptions, asthma, anaphylaxis.
Miscellaneous:
mental confusion, drowsiness, sweating, thirst.
Overview
ENTROPHEN should be used with caution with other products that have anticoagulation or antiplatelet effects, as these effects may be potentiated. Drugs that bind to protein binding sites should also be used cautiously since ENTROPHEN may displace drugs from their protein, binding site.
Salicylates may retard the elimination of methotrexate by decreasing renal clearance of methotrexate, displacing methotrexate from protein binding sites, and thereby increasing its hematological toxicity.
e.g. warfarin, heparin: Caution is necessary when salicylates and anticoagulants are prescribed concurrently, as salicylates can depress the concentration of prothrombin in the plasma.
, e.g. insulin, sulfonylureas: Large doses of salicylates have a hypoglycemic action and may enhance the effect of oral hypoglycemic agents. Diabetics receiving concurrent salicylate and hypoglycemic therapy should be monitored closely; reduction of the sulfonylurea
hypoglycemic drug dosage may be necessary.
: Sodium excretion produced by spironolactone may be decreased by salicylate administration.
Salicylates in large doses are uricosuric agents; smaller amounts may depress uric acid clearance and thus decrease the uricosuric effects of other drugs.
Salicylates may alter valproic acid (VPA) metabolism and may displace VPA from protein binding sites, possibly intensifying the effects of VPA. Caution is recommended when VPA is administered concomitantly with salicylates.
Decreased blood salicylate levels during corticosteroid treatment and risk of salicylate overdose after this treatment is stopped via increased elimination of salicylates by corticosteroids.
The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of ENTROPHEN due to its indirect effect on the rennin-angiotensin conversion pathway. The potential interaction may be related to the dose of ENTROPHEN (3g/day or more).
Plasma concentrations of digoxin are increased due to a decrease in renal excretion.
The use of other non-steroidal anti-inflammatory drugs with salicylates at high doses ($3g/day) may increase the risk of ulcers and gastrointestinal bleeding due to a synergistic effect. Ibuprofen: Ibuprofen may interfere with the cardioprotective effects and platelet aggregation inhibitory properties of ENTROPHEN. Patients should talk to their doctor if they are on an ENTROPHEN regimen and take ibuprofen for pain. Studies have shown that single doses and multiple doses of ibuprofen may interfere with the anti-platelet effects of low dose ENTROPHEN.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herb have not been established.
Drug-Laboratory Interactions
Salicylates can produce changes in thyroid function tests.
Drug-Lifestvle Interactions
Patients taking ENTROPHEN daily are at an increased risk of developing gastrointestinal bleeding following the ingestion of alcohol.
Platelet aggregation inhibitor:
For suspected acute myocardial infarction: An initial dose of at least 160 -162.5 mg chewed or crushed to ensure rapid absorption as soon as a myocardial infarction is suspected. The same dose should be given as maintenance over the next 30 days. After 30 days, consider further therapy based on dosage and administration for prevention of recurrent MI (see Prior Myocardial Infarction). For the prevention of a first non-fatal myocardial infarction: 80 - 325 mg daily according to the individual needs of the patient, as determined by the physician. For reducing the risk of morbidity and death in patients with unstable angina and in those with previous myocardial infarction: 80 - 325 mg daily according to the individual needs of the patient, as determined by the physician. For reducing the risk of transient ischemic attacks (TIA) and for secondary prevention of atherothrombotic cerebral infarction: 80 - 325 mg daily according to the individual needs of the patient, as determined by the physician.
Drug Substance
Proper Name
: Acetylsalicylic acid
Chemical Names
: 2-(Acetyloxy) benzoic acid;
Salicylic acid acetate. Structure:
O
OH
O O
CH 3 Molecular Formula: C9H8O4
Molecular Weight
: 180.16
Description
: White granules, commonly tabular or needle-like, or white crystalline powder. Odorless or having a faint odor.
Solubility
: Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and ether; sparingly soluble in absolute ether.
pK value (25degC)
: 3.49
Melting Point
: 135degC (rapid heating)
Entrophen chewable:
Each chewable tablet contains 81 mg acetylsalicylic acid as active
ingredient. Non-medicinal ingredients: DC Yellow #10, FDC Red #40, mannitol, orange flavor, pregelatinized starch, sodium saccharin, stearic acid. Entrophen: Each enteric-coated tablet contains 81 mg acetylsalicylic acid as active ingredient. Non-medicinal ingredients: Pregalatinized starch, lactose anhydrous, stearic acid, acryl-eze white, antifoam, purified water.
Entrophen chewable:
Each chewable, salmon coloured, round, biconvex tablet,
embossed "81" contains 81 mg acetylsalicylic acid. In packages of 30 and 120 tablets and in blister packs of 7 tablets.
Entrophen:
Each round, white enteric-coated tablet contains 81 mg acetylsalicylic acid. In packages of 30,120, 150, 180, 225 and 255 tablets and in blister packs of 7 tablets.
Store at room temperature (15deg-30degC).