Jusprin 81 is 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.

-   Acetylsalicylic acid does not reduce the risk of either cardiovascular mortality or Aspirin 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.

§ 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.

Jusprin 81 should preferably be taken after meals, with plenty of liquid.

Dosing Considerations

Please see below for specific dosing instructions for each indication.

Recommended Dose and Dosage Adjustment

Platelet aggregation inhibitor:

Suspected Acute Myocardial Infarction: An initial dose of at least 162 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).

Prevention of a first non-fatal myocardial infarction: 81 - 325 mg once daily, according to the individual needs of the patient, as determined by the physician.

Prior Myocardial Infarction or Unstable Angina Pectoris: 81 - 325 mg daily according to the individual needs of the patient, as determined by the physician.

Transient Ischemic Attack and Secondary Prevention of Atherothrombotic Cerebral

Infarction: 81 - 325 mg daily according to the individual needs of the patient, as determined by the physician.

Prophylaxis of Venous Thromboembolism after total hip replacement: 162 - 325mg (of aspirin) daily according to the individual needs of the patient, as determined by the physician.

General                  

Aspirin 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.

acetylsalicylic acid should be administered cautiously to patients with:

-   uncontrolled hypertension

-   impaired hepatic, renal function or cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, volume depletion, major surgery, sepsis or major haemorrhagic events)

-   a history of bleeding tendencies, significant anemia and/or hypothrombinemia

-   concomitant treatment with anticoagulants (see section “4.5”)

-   concomitant treatment with NSAIDs, such as ibuprofen and naproxen in patients on an acetylsalicylic acid regimen (see section “4.5”)

Hypersensitivity

Acetylsalicylic acid 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, acetylsalicylic acid 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 which persists for several days after administration, acetylsalicylic acid may lead to an increased bleeding tendency during and after surgical operations (including minor surgeries, e.g. dental extractions).

Special Populations

Women attempting to conceive:

During the first and second trimester of pregnancy, acetylsalicylic acid containing drugs should not be given unless clearly necessary. If acetylsalicylic acid containing drugs are used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low as possible and duration of treatment as short as possible.

Pregnant Women:

Acetylsalicylic acid inhibits prostaglandin synthesis. Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of malformations after the use of a prostaglandin synthesis inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy. Available data do not support any association between intake of acetylsalicylic acid and an increased risk for miscarriage. For acetylsalicylic acid the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in early pregnancy (1^st-4^th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

§ cardiopulmonary toxicity (with premature closure of the ductus ateriosus and pulmonary hypertension);

§ renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

Use of any prostaglandin synthesis inhibitors at the end of pregnancy may expose the mother and the child to:

§ possible prolongation of bleeding time, an anti-aggregating effect which may occur even after very low doses

§ inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, acetylsalicylic acid is contraindicated in the third trimester of pregnancy.

Nursing Women:

Acetylsalicylic acid 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 breastfeeding is usually unnecessary. However, on regular use or on intake of high doses, breast feeding should be discontinued early.

Pediatrics

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. Acetylsalicylic acid 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 acetylsalicylic acid 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.

Low Uric Acid Excretion:

At low doses, acetylsalicylic acid reduces excretion of uric acid. This can trigger gout in patients who already tend to have low uric acid excretion.

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency:

In patient suffering from glucose-6-phosphate dehydrogenase (G6PD) deficiency, acetylsalicylic acid may induce hemolysis or haemolytic anemia. Factors that may increase the risk of haemolysis are high dosage, fever, or acute infections.

Elderly

In general, acetylsalicylic acid should be used with caution in elderly patients (≥ 60 years of age), as these patients may be more susceptible to adverse reactions.

Monitoring and Laboratory Tests

Salicylates can produce changes in thyroid function tests.

Isolated cases of liver function disturbances (transaminases increase) have been described.

Overview

Acetylsalicylic acid 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 acetylsalicylic acid may displace drugs from their protein binding site.

Contraindicated Interactions

Methotrexate, used at doses of 15 mg/week or more: Increased hematological toxicity of methotrexate (due to decreased renal clearance of methotrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding by salicylates). See section“4.3”.

Drug-Drug Interactions

Methotrexate, used at 15 mg/week or less: 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.

Anti-coagulants, thrombolytics / other inhibitors of platelet aggregation / hemostasis, e.g. warfarin, heparin: Caution is necessary when salicylates and anticoagulants, thrombolytics / other inhibitors of platelet aggregation / hemostasis prescribed concurrently, as salicylates can depress the concentration of prothrombin in the plasma, leading to an increased risk of bleeding.

Oral hypoglycemics, 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.

Diuretics: Diuretics in combination with acetylsalicylic acid at higher doses leads to decreased glomerular filtration via decreased prostaglandin synthesis. As a result, sodium excretion may be decreased by salicylate administration.

Uricosuric Agents: Salicylates in large doses are uricosuric agents; smaller amounts may depress uric acid clearance and thus decrease the uricosuric effects of other drugs.

Valproic Acid: 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.

Glucocorticoids (systemic), except hydrocortisone used as replacement therapy in

Addison’s disease: Decreased blood salicylate levels during corticosteroid treatment and risk of salicylate overdose after this treatment is stopped via increased elimination of salicylates by corticosteroids.

Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of acetylsalicylic acid due to its indirect effect on the renin-angiotensin conversion pathway (i.e. inhibition of vasodilatory prostaglandins leading to decreased glomerular filtration). The potential interaction may be related to the dose of acetylsalicylic acid (3g/day or more).

Selective Serotonin Re-uptake Inhibitors (SSRIs): Increased risk of upper gastrointestinal bleeding due to possibly synergistic effect.

Digoxin: Plasma concentrations of digoxin are increased due to a decrease in renal excretion.

NSAIDS:

Acetylsalicylic acid and other NSAIDs: The use of other NSAIDs with salicylates at high doses (≥ 3g/day) may increase the risk of ulcers and gastrointestinal bleeding due to a synergistic effect.

Ibuprofen: Ibuprofen can interfere with the anti-platelet effect of low dose acetylsalicylic acid (81-325 mg per day). Long-term daily use of ibuprofen may render acetylsalicylic acid less effective when used for cardioprotection and stroke prevention. To minimize this interaction, regular users of ibuprofen and of low-dose, immediate-release acetylsalicylic acid should take the ibuprofen at least one hour after and 11 hours before the daily acetylsalicylic acid dose. The use of delayed-release (e.g. enteric-coated) acetylsalicylic acid is not recommended when using ibuprofen regularly.

Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of ibuprofen and acetylsalicylic acid.

Naproxen: Naproxen may attenuate the irreversible platelet inhibition induced by acetylsalicylic acid. Clinical pharmacodynamic data suggest that concurrent (same day) naproxen sodium usage for more than one day consecutively inhibits the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping naproxen sodium therapy. The clinical relevance of this interaction is not known. Treatment with naproxen, in patients with increased cardiovascular risk may limit the cardiovascular protection of acetylsalicylic acid (see section“4.4”).

Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of NSAIDs (i.e. ibuprofen or naproxen) and acetylsalicylic acid.

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-Lifestyle Interactions

Alcohol: Increased damage to gastrointestinal mucosa and prolonged bleeding time due to additive effects of acetylsalicylic acid and alcohol. Patients having 3 or more alcoholic drinks per day should consult their physician before use.

Women attempting to conceive:

During the first and second trimester of pregnancy, acetylsalicylic acid containing drugs should not be given unless clearly necessary. If acetylsalicylic acid containing drugs are used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low as possible and duration of treatment as short as possible.

Pregnant Women:

Acetylsalicylic acid inhibits prostaglandin synthesis. Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of malformations after the use of a prostaglandin synthesis inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy. Available data do not support any association between intake of acetylsalicylic acid and an increased risk for miscarriage. For acetylsalicylic acid the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in early pregnancy (1st-4th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

§ cardiopulmonary toxicity (with premature closure of the ductus ateriosus and pulmonary hypertension);

§ renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

Use of any prostaglandin synthesis inhibitors at the end of pregnancy may expose the mother and the child to:

§ possible prolongation of bleeding time, an anti-aggregating effect which may occur even after very low doses

§ inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, acetylsalicylic acid is contraindicated in the third trimester of pregnancy.

Nursing Women:

Acetylsalicylic acid 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 breastfeeding is usually unnecessary. However, on regular use or on intake of high doses, breast feeding should be discontinued early.

Not stated.

Many adverse reactions due to acetylsalicylic acid 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, melena, abdominal pain, and rarely gastrointestinal inflammation.

Bleeding: Due to platelet inhibition, bleedings e.g. perioperative haemorrhage, hematomas, epistaxis, urogenital bleedings, and gingival bleedings may occur.

Serious bleedings, such as gastrointestinal tract hemorrhages, and cerebral hemorrhages are rare.

Isolated cases of potentially life threatening bleedings have been reported, especially in patients with uncontrolled hypertension and/or concomitant antihemostatic agents.

Ear: dizziness, tinnitus, vertigo, hearing loss. Dizziness and tinnitus have been reported, which may be indicative of an overdose.

Hematologic: leukopenia, thrombocytopenia, purpura, anemia. Anemia with respective laboratory and clinical signs and symptoms, such as asthenia, pallor, and hypoperfusion is generally caused by bleeding (e.g. occult microbleeding, acute or chronic bleeding). Hemolysis and hemolytic anemia in patients with severe forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency has been reported.

Dermatologic and hypersensitivity: urticaria, pruritus, skin eruptions, asthma, anaphylaxis, edema, nasal congestion and rhinitus. Severe allergic reactions, including anaphylactic shock are very rarely reported.

Miscellaneous: mental confusion, drowsiness, sweating, thirst. Transient hepatic impairment with increase in liver transaminases has very rarely been reported. Renal impairment and acute renal failure have been reported.

To report any side effect(s):

·   Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

- SFDA Call Centre: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

·   Other GCC States:

- Please contact the relevant competent authority.

Mild Overdose or Early Poisoning - burning in the mouth, lethargy, nausea, vomiting, tinnitus, sweating, thirst, tachycardia or dizziness.

Moderate Overdose - all of the symptoms from mild overdose plus tachypnea, hyperpyrexia, sweating, dehydration, loss of coordination, restlessness, mental confusion.

Severe Overdose - all of the symptoms from moderate overdose plus hypotension, hallucinations, stupor, hypoglycemia, convulsions, cerebral edema, oliguria, renal failure, cardiovascular failure, coma, hemorrhage, metabolic acidosis, respiratory alkalosis and/or failure.

Emergency Management:

1.    Immediate transfer to hospital and maintain cardiovascular and respiratory support.

2.    Gastric lavage, administration of activated charcoal,

3.    Check of acid-base balance and correct if necessary.

4.    Alkaline diuresis so as to obtain urine pH between 7.5 and 8 should be considered when plasma salicylate concentration is greater than 500 mg/L (3.6 mmol/L) in adults or 300mg/L (2.2 mmol/L) in children

5.    Hemodialysis should be considered in severe poisoning 800mg/L (5.8 mmol/L) in adults and 700mg/L (5.0 mmol/L) in children, as renal elimination of salicylates may be slow due to the presence of acidic urine and renal failure. Hemodialysis should also be considered if the patient is experiencing severe systemic metabolic acidosis (arterial pH < 7.2), acute renal failure, pulmonary edema or CNS symptoms such as: drowsiness, agitation, coma or convulsions.

6.    Fluid losses should be replaced with hypotonic solution (e.g. half saline) and supplemented with glucose 50 to 100 g/L.

7.    Symptomatic treatment.

Fatal Dose: varies from 10 to 30g of acetylsalicylic acid. However, (in one case) 130 g of acetylsalicylic acid was ingested without fatal outcome.

Acetylsalicylic acid 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, acetylsalicylic acid may avert the sensitization of pain receptors.

The antipyretic activity of acetylsalicylic acid 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 acetylsalicylic acid 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.

In vitro studies have shown that acetylsalicylic acid enhances the activity of the Nitric oxide (NO)-cGMP system and heme oxygenase-1 (HO-1) by acting on endothelial NO synthase site.

Absorption:

When acetylsalicylic acid 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 acetylsalicylic acid, 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 acetylsalicylic acid 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:                                                                                   

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, acetylsalicylic acid has the capacity of acetylating various proteins, hormones, DNA, platelets and hemoglobin, which at least partly explains its wide-ranging pharmacological actions.

Metabolism:

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

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.

With the administration of 325 mg, elimination of acetylsalicylic acid is linear following a first order kinetics. At high concentrations, elimination half-life increases.

Special Populations and Conditions:

Absorption and clearance of salicylates are not affected by gender or age.

Not Stated.          

For Seal Coating:

For Enteric Coated:     

  ** Qty. of Microcrystalline cellulose (Avicel 112) compensated based on potency calculation of Aspirin 3020 (Crystalline).

     # 40% extra quantity of Opadry Clear 03K19229 calculated for process loss.

   ## 40% extra quantity of Acryl Eze 93A18597 White calculated for process loss.

    $$ 40% extra quantity of Triethyl Citrate calculated for process loss.

      $ 40% extra quantity of Simethicone Antifoam M-30 calculated for process loss.QTY. based on 30% dispersion.

Not Applicable

Store below 30ºC, in a dry place

After Opening: Use within 30 days.

§ 30’s tablets packed in 40 CC HDPE bottle with silica gel canister, cotton and closed with CRC cap with induction sealing along with a leaflet.

§ 90’s tablets packed in 40 CC HDPE bottle with silica gel canister, cotton and closed with CRC cap with induction sealing along with a leaflet.

No special instructions needed.