NAME OF DRUG

ASPIRIN *

(acetylsalicylic acid tablets, USP)

ACTIONS

Acetylsalicylic acid (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, ASPIRIN * may avert the sensitization of pain receptors. The antipyretic activity of ASA is due to its ability to interfere with the production of prostaglandin E1 in the brain. Prostaglandin E1 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 A2 within the platelet. Thromboxane A2 is, largely, responsible for the aggregating properties of platelets.

CONTRAINDICATIONS

• Hypersensitivity to acetylsalicylic acid, to other salicylates, or to any other components of the product; 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, 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. 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 (3 g 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 (3g/day or more).

PHARMACOLOGY

Absorption, distribution, metabolism and excretion:

When ASPIRIN * 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 ASPIRIN *, 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. The liver appears to be the principal site for salicylate metabolism, although other tissues may also be involved. The three chief metabolic products of ASPIRIN * 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 ASPIRIN * 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

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 analgetic effect of ASPIRIN * has been recognized and utilized clinically for more than half a century. The degree of analgesia attained with ASPIRIN * 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 ASPIRIN *. As for mechanism of action, the accumulated evidence of recent years indicates that ASPIRIN * acts by interfering with the synthesis and release of prostaglandins, thereby averting the sensitization of pain receptors to mechanical stimulation or to other mediators.

Migraine:

Migraines are reoccurring headaches that last 4-72 hours and are characterized by lateralized throbbing, moderate to severe pain intensity and at least one other of the following symptoms: nausea, photophobia, phonophobia. Routine physical activity aggravates the symptoms. Some individuals also experience neurological aura such as blurring of vision before the pain and associated symptoms occur. Evidence suggests that there are at least three mechanisms involved in the pathophysiology of migraines: extracranial arterial vasodilatation, extracranial neurogenic inflammation and decrease inhibition of central pain transmission. It has been shown that the degree of inflammatory activity is proportional to the intensity of the pain felt and as the blood pulses, the characteristic throbbing emerges. An estimated two million Canadians have been diagnosed with migraines but many migraineurs never receive a clinical diagnosis; therefore, the actual numbers of Canadians who suffer from migraines could be over 3 million. Over 70% of migraine suffers are women and the majority are aged between 20 and 50 years. This prevalence is based in part due to hormonal fluctuations that women experience related to menstruation, oral contraceptive use, pregnancy, menopause and hormone replacement therapy. The use of a single dose of ASPIRIN * (2 x 500mg tablets) in patients with a migraine attack was investigated in two placebo-controlled clinical studies conducted by Bayer. Treatment with ASPIRIN * resulted in a statistically significant relief of migraine pain and in the associated symptoms of photophobia and phonophobia that continued throughout the 6 hour post-dose observation. The results also showed a significant improvement in overall quality of life for migraine sufferers but there was no difference between ASPIRIN * and placebo groups in headache recurrence.

Antipyresis:

Interference with the synthesis and release of prostaglandins is also involved in the antipyretic activity of ASPIRIN *. ASPIRIN * 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 temperature-regulating area and ASPIRIN * 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 ASPIRIN * 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 ASPIRIN * 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. ASPIRIN * 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, ASPIRIN * 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 inactivated, inhibition of platelet aggregation by ASPIRIN * thus persists 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 ASPIRIN * against experimentally induced thrombosis or atherosclerosis has been demonstrated in several animal models. Besides inhibiting the biosynthesis of thromboxane A2 by platelets, ASPIRIN * 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 ASPIRIN * depends on the thromboxane-prostacyclin balance. In fact, it has been suggested that under some conditions, high doses of ASPIRIN * 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 ASPIRIN * 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 ASPIRIN * 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 of 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 ASPIRIN * in patients with a suspected acute myocardial infarction was investigated in a large multi-centre trial involving over 17,000 patients. Treatment with ASPIRIN * 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. The effect of time to therapy revealed that patients treated with ASPIRIN * "early" (0 to 4 hours) versus "late" (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 ASPIRIN * 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 ASPIRIN * persisted long term, and that this prolonged benefit was additive to that of fibrinolytic therapy. The use of ASPIRIN * 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.

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 weaning age. No evidence of carcinogenic effect was found.

The chronic oral LD50 in male albino rats has been reported as 0.24 g/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, piloerection, rapid and deep respiration, 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. *Registered Trademark of Bayer AG

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