PRODUCT MONOGRAPH

CHEWABLE DAILY LOW DOSE ASA

(Acetylsalicylic acid chewable tablets, USP)
81 mg

Analgesic, anti-inflammatory, antipyretic and

platelet aggregation inhibitor

PHARMASCIENCE INC. Date of Preparation:

6111 Royalmount Ave, Suite # 100 April 5, 2012
Montreal, Quebec
H4P2T4

Submission Control No: 154310

 PRODUCT MONOGRAPH

CHEWABLE DAILY LOW DOSE ASA

(Acetylsalicylic acid chewable tablets, USP)
81 mg

THERAPEUTIC OR PHARMACOLOGICAL CLASSIFICATION

Analgesic, anti-inflammatory, anti-pyretic and 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

Acetylsalicylic acid (ASA) is indicated for the relief of pain, fever and inflammation of a variety
of conditions such as influenza, common cold, low back and neck pain, dysmenorrhea, headache,
toothache, sprains and strains, fractures, myositis, neuralgia, synovitis, arthritis, bursitis, burns,
injuries, following surgical and dental procedures.

CHEWABLE DAILY LOW DOSE ASA 81 mg are also 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;

-For prophylaxis of venous thromboembolism after total hip replacement;

-For reduction of adhesive properties of platelets in patients following carotid

endarterectomy to prevent recurrence of TIA and in hemodialysis patients with a silicone
rubber arteriovenous cannula.

In addition, CHEWABLE DAILY LOW DOSE ASA 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

3
 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 not
insignificant increase in the risk of haemorrhagic stroke as well as gastrointestinal
bleeding.

CONTRAINDICATIONS

Salicylate sensitivity, active peptic ulcer.

WARNINGS

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.

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. However, caution is advised when prescribing salicylate-containing medications for
children and teenagers with influenza or chickenpox.

PRECAUTIONS

Salicylates should be administered cautiously to patients with asthma and other allergic
conditions, a history of gastrointestinal ulcerations; bleeding tendencies; significant anemia or
hypoprothrombinemia.

Patients taking ASA daily are at an increased risk of developing gastrointestinal bleeding
following the ingestion of alcohol.

Caution is necessary when salicylates and anticoagulants are prescribed concurrently, as

salicylates can depress the concentration of prothrombin in the plasma.

4
Diabetics receiving concurrent salicylate and hypoglycemic therapy should be monitored closely;
reduction of the sulfonylurea hypoglycemic drug dosage may be necessary; insulin requirements
may change.

High doses (3g daily) of ASA during pregnancy may lengthen the gestation and parturition time.

Salicylates can produce changes in thyroid function tests.

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 retard the renal elimination of methotrexate.

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.

The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the
concomitant administration of ASA due to its indirect effect on the renin-angiotensin conversion
pathway. The potential interaction may be related to the dose of ASA.

ADVERSE REACTIONS

Gastrointestinal: (the frequency and severity of these adverse effects are dose-related): nausea,
vomiting, diarrhea, gastrointestinal bleeding and/or ulceration, dyspepsia, heartburn.
Ear: tinnitus, vertigo, hearing loss.

Hematologic: leukopenia, thrombocytopenia, purpura, anemia.

5
Dermatologic and hypersensitivity: urticaria, angioedema, pruritus, skin eruptions, asthma,
anaphylaxis.

Miscellaneous: mental confusion, drowsiness, sweating, thirst.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms: in mild overdosage these may include rapid and deep breathing, nausea, vomiting,
vertigo, tinnitus, flushing, sweating, thirst, arid tachycardia. In more severe cases, acid-base
disturbances including respiratory alkalosis and metabolic acidosis can occur. Severe cases may
show fever, hemorrhage, excitement, confusion, convulsions or coma and respiratory failure.

Treatment consists of prevention and management of acid-base and fluid and electrolyte
disturbances. Renal clearance is increased by increasing urine flow and by alkaline diuresis but
care must be taken in this approach to not aggravate further the metabolic acidosis that develops
and the hypokalemia. Acidemia should be prevented by administration of adequate sodium
containing fluids and sodium bicarbonate. Hypoglycemia is an occasional accompaniment of
salicylate overdosage and can be managed by glucose solutions. If a hemorrhagic diathesis is
evident, give vitamin K. Hemodialysis may be useful in complex acid base disturbances
particularly in the presence of abnormal renal function.

6
 DOSAGE AND ADMINISTRATION

Analgesic and antipyretic:

Adults: 1-2 tablets (325 mg to 650 mg) orally every 4 hours.
Children under 12: 10 to 15 mg/kg every 6 hours, not to exceed a total daily dose of 2.4 g.

Anti-inflammatory:
Adults: 3 tablets (975 mg) 4 to 6 times a day, up to 30 tablets daily, may be required for optimal
anti-inflammatory effect. A blood level between 15 and 30 mg per 100 mL is in the desirable
therapeutic range.
Children: 60 to 125 mg/kg daily in 4 to 6 divided doses.

Platelet aggregation inhibitor:

- 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. CHEWABLE DAILY LOW DOSE
ASA 81 mg (Acetylsalicylic acid chewable tablets) is specifically indicated for these
uses.

- 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. CHEWABLE DAILY LOW DOSE
ASA 81 mg (Acetylsalicylic acid chewable tablets) is specifically indicated for these
uses.

- For prophylaxis of venous thromboembolism after total hip replacement: 650 mg twice a
day (1,300 mg daily), started 1 day before surgery and continued for 14 days.
CHEWABLE DAILY LOW DOSE ASA 81 mg (Acetylsalicylic acid chewable
tablets) is specifically indicated for these uses.

7
 PHARMACEUTICAL INFORMATION

Drug Substance
Proper Name: Acetylsalicylic acid

Chemical Names: 2-(Acetyloxy) benzoic acid;

Salicylic acid acetate.

Structure:
O

OH
O
O
CH3

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 (25°C): 3.49

Melting Point: 135°C (rapid heating)

8
 COMPOSITION

CHEWABLE DAILY LOW DOSE ASA:

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.

AVAILABILITY OF DOSAGE FORM

CHEWABLE DAILY LOW DOSE ASA:

Each chewable, salmon coloured, round, biconvex tablet,
embossed A81@ contains 81 mg acetylsalicylic acid. In packages of
30,120, 150 and 180 tablets.

STABILITY AND STORAGE RECOMMENDATIONS

Store at room temperature (15°-30°C).

PATIENT INFORMATION TO BE DISTRIBUTED ONLY BY

PHYSICIANS/PHARMACISTS

CHEWABLE DAILY LOW DOSE ASA 81 mg

This section provides you with information about CHEWABLE DAILY LOW DOSE ASA 81
mg acetylsalicylic acid (chewable) tablets and how to take this medication. Please read carefully
before you take this medication.

9
Your physician has recommended CHEWABLE DAILY LOW DOSE ASA 81 mg for
supervised adult long-term preventative therapy.

Follow your physician's instructions concerning the use of CHEWABLE DAILY LOW DOSE
ASA 81 mg as well as any lifestyle changes, e.g. diet and/or exercise that he/she may have
recommended. Always contact your physician if you experience any difficulties while taking
this product.

CHEWABLE DAILY LOW DOSE ASA 81 mg contains acetylsalicylic acid, commonly

referred to as ASA, as its active ingredient. Plain (uncoated) ASA, particularly when taken
regularly, may cause stomach upset in some people. The special enteric coating of
CHEWABLE DAILY LOW DOSE ASA 81 mg tablets allows them to pass intact through the
stomach and on into the intestine before they dissolve which may reduce the risk of stomach
upset.

Your physician has specifically recommended CHEWABLE DAILY LOW DOSE ASA 81 mg
because it contains a special, low-dose, enteric-coated, formulation of ASA. Other medications
such as acetaminophen or ibuprofen that are meant to relieve pain do not have the same
preventative action as CHEWABLE DAILY LOW DOSE ASA 81 mg which has been
specifically formulated for your condition.

DIRECTIONS FOR USE

It is very important that you take this medication as directed by your physician. If you have not
seen a physician, do not take this medication until you have done so.

Dosage:
1 to 4 tablets daily of CHEWABLE DAILY LOW DOSE ASA 81 mg depending on your
doctor's instructions. Your doctor may tell you to take or with other medications. He/she may
also advise you to make certain lifestyle changes, (e.g. diet, exercise, smoking cessation), to
safeguard your health. You should take this medication at the same time every day to help you
to remember to take it. For maximum effectiveness, it is very important to take CHEWABLE

10
DAILY LOW DOSE ASA 81 mg every day, as directed by your physician. Do not take more
tablets than your physician recommends.

CHEWABLE DAILY LOW DOSE ASA 81 mg (Acetylsalicylic Acid Chewable) Tablets are
chewable and therefore must be chewed well and swallowed.

11
 ANSWERS TO COMMONLY ASKED QUESTIONS

WHY WAS CHEWABLE DAILY LOW DOSE ASA 81 mg RECOMMENDED BY MY

DOCTOR?
FOR PREVENTION OF A SECOND HEART ATTACK OR STROKE (DAILY
THERAPY)
It can be used to prevent a second stroke or heart attack. If you have experienced either a stroke
or a heart attack you may be at risk for a second one. There are certain risk factors that can place
you at an increased risk:
-Overweight -Stress
-Smoking -High blood cholesterol
-Inactive (sedentary) lifestyle -High blood pressure

These can be discussed with your physician in order to complement the effectiveness of
CHEWABLE DAILY LOW DOSE ASA 81 mg.

Your doctor may recommend changes in diet, exercise and lifestyle for your benefit in avoiding a
second heart attack or stroke.
If you experience any difficulties with your treatment always discuss with your doctor or
pharmacist.

USE DURING A HEART ATTACK

If you think you are having a heart attack, you should immediately chew 2 CHEWABLE
DAILY LOW DOSE ASA 81 mg tablets and call an ambulance. It is important to chew or
crush the product, to ensure this medicine quickly works. Then get to a hospital immediately for
medical attention. Taking CHEWABLE DAILY LOW DOSE ASA 81 mg at the first signs
and symptoms can reduce your risk of dying from the heart attack.

The signs and symptoms of a heart attack include:

12
 1. uncomfortable pressure, fullness, squeezing or pain in the center of the chest that lasts
more than a few minutes, or goes away quickly and comes back,
2. pain that spreads to the shoulders, neck or arms,
3. chest discomfort with lightheadedness, fainting, sweating, nausea or shortness of breath.
At the hospital, the doctor will then recommend appropriate therapy

WHAT IF I FORGET TO TAKE MY MEDICATION?

If you forget to take your medication at the usual time, take it when you remember. Do not take
extra medication to compensate for a missed dosage unless instructed by your physician.

WILL I EXPERIENCE ANY SIDE EFFECTS WITH THIS MEDICINE?

Like any medication, ASA may occasionally produce unwanted side effects. You should call
your physician if you experience any of the following: nausea, vomiting, bleeding or stomach
irritation, dizziness, weakness, fainting spells, any loss of hearing, including ringing or buzzing
in the ears or pain; skin rashes, hives or itching and breathing difficulties. Regular use of alcohol
while on ASA daily therapy may increase your risk of developing gastrointestinal bleeding.

13
WHAT ELSE SHOULD I KNOW BEFORE TAKING THIS MEDICINE?

Your doctor will ask you many questions about your health, lifestyle, and medications before
recommending CHEWABLE DAILY LOW DOSE ASA 81 mg.
This is why it is very important that you tell your doctor all such information. If you have
forgotten to tell your doctor about any of the following, call your doctor or pharmacist before
you take this medicine.
- Allergy to salicylates - Are pregnant or breast-feeding
- Asthma - Will be having surgery in five to seven days
- Stomach problems - Are taking other medications containing salicylates or
acetaminophen
- Peptic ulcer -Are taking anti-inflammatory drugs, anticonvulsants, anti-
diabetics or gout medication
- Severe liver disease -Are taking or planning to take this medication while consuming
alcohol
- Severe anemia - History of blood clotting defects or receiving blood thinners

CAUTION

This product is not recommended for children or teenagers. This package contains enough
drug to seriously harm a child. Keep out of children's reach. Do not administer to children and
teenagers for chicken pox or flu symptoms before a doctor is consulted. Reye's Syndrome,
which can occur in children or teenagers, is a rare but serious illness reported to be associated
with ASA.

It is especially important not to use this medication during the last 3 months of pregnancy unless
specifically directed to do so by your physician because it may cause problems in the unborn
child or complications during delivery.

Call your doctor before taking this drug when nursing.

14
In case of accidental overdose call a doctor or hospital immediately, even if there are no
symptoms.

Product Monograph is available to health professionals upon request.

For further information or questions about this product, contact Pharmascience Inc., Montreal,
Canada at their Medical Information Hotline between 8:30am and 4:30pm, Eastern Standard
Time, Monday to Friday. Call toll-free at 1-888-550-6060.

15
 PHARMACOLOGY
Absorption, distribution, metabolism and excretion:
When ASA is taken orally, it is rapidly absorbed from the stomach and proximal small intestine.
The gastric mucosa is permeable to the non-ionized form of acetylsalicylic acid, which passes
through the stomach wall by a passive diffusion process.

Optimum absorption of salicylate in the human stomach occurs in the pH range of 2.15 to 4.10.
Absorption in the small intestine occurs at a significantly faster rate than in the stomach. After
an oral dose of 0.65 g ASA, the plasma acetylsalicylate concentration in man usually reaches a
level between 0.6 and 1.0 mg% in 20 minutes after ingestion and drops to 0.2 mg% within an
hour. Within the same period of time, half or more of the ingested dose is hydrolyzed to salicylic
acid by esterases in the gastrointestinal mucosa and the liver, the total plasma salicylate
concentration reaching a peak between one or two hours after ingestion, averaging between 3
and 7 mg%. Many factors influence the speed of absorption of ASA in a particular individual at
a given time; tablet disintegration, solubility, particle size, gastric emptying time, psychological
state, physical condition, nature and quantity of gastric contents, etc., all affect absorption.

Distribution of salicylate throughout most body fluids and tissues proceeds at a rapid rate after
absorption. Aside from the plasma itself, fluids which have been found to contain substantial
amounts of salicylate after oral ingestion include spinal, peritoneal and synovial fluids, saliva
and milk. Tissues containing high concentrations of the drug are the kidney, liver, heart and
lungs. Concentrations in the brain are usually low, and are minimal in feces, bile and sweat.

The drug readily crosses the placental barrier. At clinical concentrations, from 50% to 90% of
the salicylate is bound to plasma proteins especially albumin, while acetylsalicylic acid itself is
bound to only a very limited extent. However, ASA has the capacity of acetylating various
proteins, hormones, DNA, platelets and hemoglobin, which at least partly explains its
wide-ranging pharmacological actions.

16
The liver appears to be the principal site for salicylate metabolism, although other tissues may
also be involved. The three chief metabolic products of ASA or salicylic acid are salicyluric
acid, the ether or phenolic glucuronide and the ester or acyl glucuronide. A small fraction is also
converted to gentisic acid and other hydroxybenzoic acids. The half-life of ASA in the
circulation is from 13 to 19 minutes so that the blood level drops quickly after absorption is
complete. However, the half-life of the salicylate ranges between 3.5 and 4.5 hours, which
means that 50% of the ingested dose leaves the circulation within that time.

Excretion of salicylates occurs principally via the kidney, through a combination of glomerular
filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, as well as
phenolic and acyl glucuronides. Salicylate can be detected in the urine shortly after its ingestion
but the full dose requires up to 48 hours for complete elimination. The rate of excretion of free
salicylate is extremely variable, reported recovery rates in human urine ranging from 10% to
85%, depending largely on urinary pH. In general, it can be stated that acid urine facilitates
reabsorption of salicylate by renal tubules, while alkaline urine promotes excretion of the drug.

Analgesia:
The analgesic effect of ASA has been recognized and utilized clinically for more than half a
century. The degree of analgesia attained with ASA is moderate but it has proved highly suitable
in the management of pathological pain of mild to moderate severity. As regards site of action,
both peripheral and CNS factors appear to contribute significantly to the pain relief afforded by
ASA. As for mechanism of action, the accumulated evidence of recent years indicates that ASA
acts by interfering with the synthesis and release of prostaglandins, thereby averting the
sensitization of pain receptors to mechanical stimulation or to other mediators.

Antipyresis:
Interference with the synthesis and release of prostaglandins is also involved in ASA=s
antipyretic activity. ASA effects a significant reduction in elevated body temperature, but has
little effect on normal body temperature. This latter is maintained by a delicate balance between
heat production and heat loss, with the hypothalamus regulating the set point at which body
temperature is maintained. Fever is induced by synthesis and release of prostaglandins in this

17
temperature-regulating area and ASA acts by interfering with this process. Heat production is not
inhibited but dissipation of heat is augmented by increased peripheral blood flow and by
sweating.

Anti-inflammatory effect:
Components of the anti-inflammatory action of the salicylates are increased capillary resistance,
thus reducing capillary leakage in response to local toxins, interference with the production of
tissue-destructive lysosomal enzymes and inhibition of the synthesis of prostaglandin E
compounds which have been shown to be potent mediators of the inflammatory process. Besides
interfering with the synthesis of prostaglandins ASA also acts by interfering with lymphocyte
activation and lymphokine production. Lymphokines are produced by activated thymus
lymphocytes, which are abundant in the inflammatory tissues of patients suffering from
rheumatoid arthritis. They cause increased vascular permeability and white blood cell
chemotaxis, activate macrophages and stimulate lymphocyte DNA synthesis. They also induce
release of tissue-destructive lysosomal enzymes as well as prostaglandins. The prostaglandins
themselves, beside causing many manifestations of inflammation also act as a potent negative
feedback mechanism by inhibiting lymphokine production. An indepth review of the effects of
ASA on the lymphocyte-macrophage axis in inflammation has recently been published.

Effects on platelets: relation to hemostasis and thrombosis.

Platelets play an important role in normal hemostasis and clinical pathologic and experimental
evidence indicates that their aggregation may play an equally important role in the evolution of a
variety of disease states including cerebrovascular disease, ischemic heart disease and
myocardial infarction. CHEWABLE DAILY LOW DOSE ASA 81mg inhibits platelet
aggregation by irreversibly acetylating platelet cyclo-oxygenase, thereby blocking the production
of prostaglandin endoperoxides PGG2 and PGH2 which are precursors of the major platelet-
aggregating material, thromboxane A2, which is also a powerful vasoconstrictor. However,
CHEWABLE DAILY LOW DOSE ASA 81mg does not prevent the adherence of platelets to
damaged vessel walls or the release of granule contents from these adherent platelets. As the
anuclear platelets are unable to synthesize new enzyme molecules to replace those that have been

18
inactivated, inhibition of platelet aggregation by CHEWABLE DAILY LOW DOSE ASA 81mg
thus persist for the life of the platelets.
Daily administration of 20 to 40 mg of ASA to healthy volunteers reduced platelet thromboxane
production but inhibited platelet aggregation only partially. When administered to patients
recovering from myocardial infarction, 50 mg ASA daily had the same effects on thromboxane
production, platelet aggregation and bleeding times as 324 mg daily. Other studies show that
ASA doses of 40 to 325 mg daily suppressed thromboxane production by at least 80 %, but 80
mg ASA daily was the lowest dose required for maximum cumulative thrombocyte function
inhibition. The protective effect of ASA against experimentally induced thrombosis or
atherosclerosis has been demonstrated in several animal models.

Besides inhibiting the biosynthesis of thromboxane A2 by platelets, ASA also interferes with the
production of prostacyclin (PGI2) by vascular endothelial cells, the above-mentioned
prostaglandin endoperoxides being common precursors of both thromboxane A2 and
prostacyclin. This latter compound is one of the most powerfully acting platelet deaggregators
and vasodilators and thus it would appear that the interference with the hemostatic processes by
ASA depends on the thromboxane-prostacyclin balance. In fact, it has been suggested that under
some conditions, high doses of ASA may be thrombogenic. However, in contrast to platelets,
the vascular endothelial cells are able to regenerate cyclo-oxygenase in a relatively short time
and therefore therapeutic doses of ASA are likely to produce a lesser inhibition of the vascular
prostacyclin system than of the platelet thromboxane-forming mechanism. In fact, there is no
clinical evidence to indicate that high doses of ASA would result in an increased risk of
thromboembolism. Indeed, quite the contrary was observed and , in a controlled study,
paradoxical shortening of the bleeding time was not observed at a daily ASA dose 3.6 g. Lower
dosages of ASA make selective blocking of the TxA2-synthesis without a simultaneous blocking
of PGI2-production possible.

The use of ASA in patients with a suspected acute myocardial infarction was investigated in a
large multicenter trial involving over 17,000 patients. Treatment with ASA resulted in a 23%
reduction in the risk of vascular mortality versus placebo at 5 weeks. This use translates to a
reduction of 24 deaths and 14 non-vascular events per 1000 patients treated.

19
The effect of time to therapy revealed that patients treated with ASA Aearly@ (0 to 4 hours) versus
Alate@ (5 to 24 hours) after symptom onset experienced reductions in the odds of vascular death
of 25% versus 21%, versus placebo at 5 weeks. >Early= treatment with ASA resulted in the
saving of 4 additional lives per 1000 patients versus >late= treatment.

Long term follow-up (up to 10 years) of patients in this study established that the early survival
advantage to ASA persisted long term, and that this prolonged benefit was additive to that of
fibrinolytic therapy.

The use of ASA for secondary prevention of thrombotic events is supported by a comprehensive
overview of a number of clinical trials involving patients who already had some type of vascular
disease (myocardial infarction, unstable angina, stroke or transient cerebral ischemia). Overall,
these studies point to a 26-28% reduction of the combined endpoints of MI, stroke, or vascular
deaths by treatment with ASA alone at doses of 75 to 325 mg daily. Studies which directly
compared low doses with higher doses (30-1200 mg/day), indicated that the incidence of
gastrointestinal adverse effects were significantly less common with the lower doses.

Recent discussions have focused on the efficacy of ASA for the primary prevention of
myocardial infarction and stroke. Two large scale randomized trials, aimed at evaluating
prophylactic use of ASA, were conducted among apparently healthy male physicians (22,000 in
the United States and 5,000 in the United Kingdom respectively and their results have been
published. In the summary overview of the combined results presented by the principal
investigators, the authors state that:

A.....Taken together, these two primary-prevention studies demonstrate a significant (P<0.0001)

reduction in nonfatal myocardial infarction of about one third.@

On the other hand, the same two studies have not indicated any reduction in overall vascular
mortality and also suggested a slight increase in the risk of non-fatal disabling stroke. Current
controversy exists about the applicability of these findings, obtained in a selected population, to

20
the general public. As well, the optimum dosage regimen still remains an open question in this
regard. Thus, the use of ASA for primary prevention should remain, in the words of the
principal investigators:

AA matter of judgment in which the physician considers the cardiovascular risk profile of the
patient and balances the known hazards of aspirin...against the clearly established reduction in
the incidence of a first myocardial infarction.@

TOXICOLOGY

The clinical and pathological signs of poisoning from toxic and lethal oral doses of ASA have
been extensively described for man, much less extensively for other species.

The acute toxicity of ASA in animals has been studied and reviewed in detail by Boyd. The signs
of poisoning in rats from doses in the lethal range are due to varying degrees of gastroenteritis,
hepatitis, nephritis, pulmonary edema, encephalopathy, shock and minor toxic effects on other
organs and tissues. Death is due to convulsions or cardiovascular shock. The major difference
between species appears to be the ability to vomit toxic doses seen in man, cats and dogs, but not
in mice, rats and rabbits. Otherwise, the pathological reaction to toxic doses of ASA is similar in
all species in which such studies have been reported. The acute oral LD50 values have been
reported as being over 1.0 g/kg in man, cat and dog, 0.92 g/kg in female and 1.48 g/kg in male
albino rats, 1.19 g/kg in guinea pig, 1.1 g/kg in mouse and 1.8 g/kg in rabbit.

Chronic toxicity studies were reported in mice and rats. When ASA was administered at 2 to 20
times the maximum tolerated clinical dose to mice for up to one year, a dose-related deleterious
effect was observed on mean survival time, number of young born and number of young raised
to wearing age, no evidence of carcinogenic effect was found.

The chronic oral LD50 in male albino rats has been reported as 0.24g/kg/day when given for 100
days. At these daily doses ASA produced no anorexia and no loss of body weight. It did produce
polydipsia, aciduria, diuresis, drowsiness, hyperreflexia, piloeraction, rapid and deep respiration,

21
tachycardia, and during the second month, soft stools, epistaxis, sialorrhea, dacryorrhea and
death in hypothermic coma. Autopsy disclosed the presence of a hypertrophied stomach, renal
congestion, mild hepatitis and pneumonitis. While teratogenic effects were noted in animals at
near lethal doses, there is no evidence to indicate that ASA is teratogenic in man.

22
 BIBLIOGRAPHY

1. Abbott F, Kassam J, Orr J, and K. Farrell, The effects of aspirin on valproic acid
metabolism. Clin. Pharmacol. Ther. 1986;40:94-100.

2. Altman R, Boullon F, Rouvier J, Raca R, de la Fuente, Favaloro R. Aspirin and

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Thorac Cardiovasc Surg 1976; 72: 127_9.

3. Amrein PC, Ellman L, Harris WH. ASPIRIN prolongation of bleeding time and
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5b Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of

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therapy. Br Med J 1994; 308: 158-68.

5c Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of

antiplatelet therapy - III: Reduction in venous thrombosis and pulmonary embolism by
antiplatelet prophylaxis among surgical and medical patients. Br Med J 1994; 308: 235-
46.

6. Aspirin Myocardial Infarction Study Research Group. A randomized controlled trial of

aspirin in persons recovered from myocardial infarction. JAMA 1980; 243: 661_9.

7. Aspirin Myocardial Infarction Study Research Group: The aspirin myocardial infarction
study: final results. Circulation 1980; 62 (Suppl V): V79_V84.

8. Bailey JM. Prostacyclins, thromboxane and cardiovascular disease. Tr Biochem Sci

1979; 4: 68_71.

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