- Secondary prevention of myocardial infarction.

 - Prevention of cardiovascular morbidity in patients suffering from stable angina pectoris.

 - History of unstable angina pectoris, except during the acute phase.

 - Prevention of graft occlusion after Coronary Artery Bypass Grafting (CABG).

- Coronary angioplasty, except during the acute phase.

- Secondary prevention of transient ischemic attacks (TIA) and ischemic cerebrovascular accidents (CVA), provided intracerebralhemorrhages have been ruled out.

Aspicot is not recommended in emergency situations. It is restricted to secondary prevention with chronic treatment.

Adults

For the management of cardiovascular or cerebrovascular disease:

The advice of a doctor should be sought before commencing therapy for the first time. The usual dosage, for long term use, is 100-200 mg once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 300 mg a day may be used on the advice of a doctor.

Elderly

In general, acetylsalicylic acid should be used with caution in elderly patients who are more prone to adverse events. The usual adult dose is recommended in the absence of severe renal or hepatic insufficiency. Treatment should be reviewed at regular intervals.

Pediatric population

Acetylsalicylic acid should not be administered to children and adolescents younger than 16 years, except on medical advice where the benefit outweighs the risk (see section 4.4).

Method of administration

For oral use.

The tablets should be swallowed whole with sufficient fluid (1/2 glass of water). Due to the gastro resistant coating the tablets should not be crushed, broken or chewed because coating prevents irritant effects on the gut.

- Known intolerance to acetylsalicylic acidor other non-steroidal anti-inflammatory drugs (NSAIDs) orany of the other ingredients of this medicine (listed in section 6.1). - Acetylsalicylic acid is contraindicated in patients with active peptic ulceration or a history of peptic ulceration and those with hemophilia or other clotting disorders or gout. - Known hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to acetylsalicylic acid or non-steroidal anti-inflammatory drugs. - Acetylsalicylic acid should not be taken concurrently with anti-coagulants.

Before commencing long term acetylsalicylic acid therapy for the management of cardiovascular or cerebrovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.

Acetylsalicylic acid may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g. with skin reactions, itching or urticaria).

Use with caution in cases of impaired renal or hepatic function. There is an increased risk of hemorrhage particularly during or after operative procedures (even in cases of minor procedures, e.g. tooth extraction). Use with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary. Do not exceed the stated dose.

Aspicot is not indicated in children and young people less than 16 years of age. There is a risk of Reye's syndrome when children take acetylsalicylic acid.

Contraindicated combinations

Methotrexate (used at doses >15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, enhance hematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15 mg/week) with acetylsalicylic acidis contraindicated.

Not recommended combinations

Uricosuric agents, e.g. probenecid Salicylates reverse the effect of probenecid. The combination should be avoided.

Combinations requiring precautions for use or to be taken into account

Anticoagulants e.g. coumarin, heparin, warfarin

Increased risk of bleeding due to inhibited thrombocyte function, injury of the duodenal mucosa and displacement of oral anticoagulants from their plasma protein binding sites. The bleeding time should be monitored.

Anti-platelet agents (e.gclopidogrel and dipyridamole) and selective serotonin reuptake inhibitors (SSRIs; such as sertraline or paroxetine)

Increased risk of gastrointestinal bleeding.

Antidiabetics, e.g. sulphonylureas

 Salicylates may increase the hypoglycemic effect of sulphonylureas.

Digoxin and lithium

Acetylsalicylic acid impairs the renal excretion of digoxin and lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin and lithium is recommended when initiating and terminating treatment with acetylsalicylic acid. Dose adjustment may be necessary.

Diuretics and antihypertensives

NSAIDs may decrease the antihypertensive effects of diuretics and other antihypertensive agents. As for other NSAIDs concomitant administration with ACE-inhibitors increases the risk of acute renal insufficiency.

Diuretics: Risk of acute renal failure due to the decreased glomerual filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended.

Carbonic anhydrase inhibitors (acetazolamide)

May result in severe acidosis and increased central nervous system toxicity.

Systemic corticosteroids

The risk of gastrointestinal ulceration and bleeding may be increased when acetylsalicylic acid and corticosteroids are co-administered.

Methotrexate (used at doses <15 mg/week):

 The combined drugs, methotrexate and acetylsalicylic acid, may increase hematological toxicity of methotrexate due to decreased renal clearance of methotrexate by acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring should take place in the presence of even mildly impaired renal function, as well, as in elderly.

Other NSAIDs

 Increased risk of ulcerations and gastrointestinal bleeding due to synergistic effects.

Ibuprofen

Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Ciclosporin, tacrolimus

Concomitant use of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin and tacrolimus. The renal function should be monitored in case of concomitant use of these agents and acetylsalicylic acid.

Valproate

 Acetylsalicylic acid has been reported to decrease the binding of valproate to serum albumin, thereby increasing its free plasma concentrations at steady state.

Phenytoin

 Salicylate diminishes the binding of phenytoin to plasma albumin. This may lead to decreased total phenytoin levels in plasma, but increased free phenytoin fraction. The unbound concentration, and thereby the therapeutic effect, does not appear to be significantly altered.

Iron salts, alkalis and antacids:

 Acetylsalicylic acid is pharmaceutically incompatible with iron salts and alkalis. Antacids will reduce the effect of acetylsalicylic acid.

Alcohol

Concomitant administration of alcohol and acetylsalicylic acid increases the risk of gastrointestinal bleeding.

 

Pregnancy

Pregnancy Category C:

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Pregnancy Category D in third trimester:

 There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Acetylsalicylic acid is best avoided in late pregnancy and during breast-feeding as it may prolong labour and cause bleeding in the neonate.

High doses of acetylsalicylic acid may result in closure of fetal ductusarteriosusin utero and possibly persistent pulmonary hypertension in the new born.

 Kernicterus may be a consequence of jaundice in neonates.

Acetylsalicylic acid should be avoided during lactation, as there is a risk of Reye's syndrome.

Regular use of high doses could impair platelet function and produce hypothrombinemia in the infant if neonatal vitamin K stores are low.

No studies on the effects on the ability to drive and use machines have been performed with acetylsalicylic acid.

Based on the pharmacodynamic properties and the side effects of acetylsalicylic acid, no influence on the reactivity and the ability to drive or use machines is expected.

 

Side effects are grouped on the basis of System Organ Class. Within each system organ class the frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)

To report any side effect(s):

 

• Saudi Arabia:

- The National Pharmacovigilance and Drug Safety Centre (NPC)

 o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

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

o Website: www.sfda.gov.sa/npc

 

Although considerable inter-individual variations are involved, it can be considered that the toxic dose is about 200 mg/kg in adults and 100 mg/kg in children. The lethal dose of acetylsalicylic acid is 25-30 grams. Plasma salicylate concentrations above 300 mg/l indicate intoxication. Plasma concentrations above 500 mg/l in adults and 300 mg/l in children generally cause severe toxicity.

Overdose may be harmful for elderly patients and particularly for small children (therapeutic overdose or frequent accidental intoxications may be fatal).

Symptoms of moderate intoxications

Tinnitus, hearing disorders, headache, vertigo, confusion and gastrointestinal symptoms (nausea, vomiting and abdominal pain).

Symptoms of severe intoxications

Symptoms are related to severe disruption of the acid-base balance. In the first instance hyperventilation occurs, which results in respiratory alkalosis. Respiratory acidosis ensues due to suppression of the respiratory centre. In addition, metabolic acidosis occurs as a result of the presence of salicylate. Since younger children are often not seen until they have reached a late stage of intoxication, they are usually in the stage of acidosis.

Furthermore, the following symptoms may occur: hyperthermia and perspiration, resulting in dehydration: feelings of restlessness, convulsions, hallucinations and hypoglycemia. Depression of the nervous system may lead to coma, cardiovascular collapse or respiratory arrest.

Treatment of overdose

If a toxic dose has been ingested, hospital admission is required. In the event of moderate intoxication, inducing the patient to vomit should be attempted.

If this fails, gastric lavage may be attempted during the first hour after ingestion of a substantial amount of the medicine. Afterwards, administer activated carbon (adsorbent) and sodium sulphate (laxative).

Activated charcoal may be given as a single dose (50 g for an adult, 1 g/kg body weight for a child up to 12 years).

 Alkalization of the urine (250 mmol NaHCO3, for three hours) whilst checking urine pH levels may be considered.

In the event of severe intoxication, hemodialysis is to be preferred.

Other symptoms are to be treated symptomatically.

Pharmacotherapeutic group: Antithrombotic agents: platelet aggregation inhibitors excl. heparin, ATC code: B01AC06.

Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which plays a role in the complications of the atheromatosic lesions.

Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesize new cyclooxygenase, which had been acetylated by acetylsalicylic acid.

The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%.

Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7-10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption.

Acetylsalicylic acid extends bleeding time on average by approximately 50 to 100%, but individual variations can be observed.

Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly.

In one study, when a single dose of ibuprofen 400 mg was taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Absorption

After oral administration, acetylsalicylic acid is rapidly and completely absorbed from the gastrointestinal tract. The principal site of absorption is the proximal small intestine. However, a significant portion of the dosage is already hydrolyzed to salicylic acid in the intestinal wall during the absorption process. The degree of hydrolysis is dependent on the rate of absorption.

After intake of acetylsalicylic acid the maximum plasma levels of acetylsalicylic acid and salicylic acid are reached after about 5 hours and 6 hours, respectively, following administration in the fasted state. If the tablets are taken with food, maximum plasma levels are reached approximately 3 hours later than in the fasted state.

Distribution

Acetylsalicylic acid as well as the main metabolite salicylic acid, are extensively bound to plasma proteins, primarily albumin, and distributed rapidly into all parts of the body. The degree of protein binding of salicylic acid is strongly dependant of both the salicylic acid and albumin concentration. The volume of distribution of acetylsalicylic acid is ca. 0.16 l/kg of body weight. Salicylic acid slowly diffuses into the synovial fluid, crosses the placental barrier and passes into breast milk.

Biotransformation

 

Acetylsalicylic acid is rapidly metabolized to salicylic acid, with a half-life of 15-30 minutes. Salicylic acid is subsequently predominantly converted into glycine and glucuronic acid conjugates, and traces of gentisic acid.

Elimination kinetics of salicylic acid is dose-dependent, because the metabolism is limited by liver enzyme capacity. Thus, elimination half-time varies and is 2-3 hours after low doses, 12 hours after usual analgetic doses and 15-30 hours after high therapeutic doses or intoxication.

 

Excretion

Salicylic acid and its metabolites are predominantly excreted via the kidneys.

The preclinical safety profile of acetylsalicylic acid is well documented.

 In experimental animal studies, salicylates have shown no other organ injury than renal damage. In rat studies, fetotoxicity and teratogenic effects were observed with acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in non-clinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications.

Acetylsalicylic acid was extensively investigated with regard to mutagenic and carcinogenic effects. The results as a whole show no relevant signs for any mutagenic or carcinogenic effects in mice and rat studies.

Tablet core:

Colloidal anhydrous silica

Maize starch

Microcrystalline cellulose

Stearic acid

 

Film-coating:

Methacrylic acid-ethyl acrylate copolymer

Triethyl citrate

Simethicone emulsion

Talc

Not applicable.

3 years.

Store below 30ºC.

Do not refrigerate. Keep away from light and humidity.

30 enteric coated tablets filled in 3 Aluminum lid stock & opaque PVC/PE/PVdCblisters and packed in carton box with leaflet inside.

No special requirements