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Asagrel

Zolon Healthcare Limited
37 Osolo way, Isolo, Lagos, Nigeria

Brand Name

Asagrel

Manufacturer

BHARAT PARENTERALS LTD. Vill. Haripura, Ta. Savli, Dist. Vadodara - 391 520 (Gujarat). India.

Therapeutic Class

Antiplatelet drugs

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Tablets(NRN: A4-6557): Each film coated tablet contains: Clopidogrel Bisulfate USP eq. to Clopidogrel 75 mg, Aspirin BP (as enteric coated granules) 75 mg, Excipients q.s. Colour: Sunset Yellow FCF & Titanium Dioxide

Pack Size: Box of 3 X 10 Tablets 

Pharmacology

Pharmacodynamics: 

Clopidogrel:

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-medicated activation of the glycoprotein GPllb/llla complex, thereby inhibiting platelet aggregation Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated.

Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP.

Clopidogrel does not inhibit phosphodiesterase activity. 

Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their life span.
Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day and inhibition reaches steady state between day 3 and day 7.

At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. 

Aspirin:

Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibit the generation thromboxane A, a powerful inducer of platelet aggregation and vasoconstriction. 

PHARMACOKINETICS: 

Clopidogrel: After repeated 75 mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing. 

ABSORPION AND DISTRIBUTION:

Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel, with peak plasma levels (approx. 3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing.

The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg clopidogrel. Absorption is at least 50 based on urinary excretion of clopidogrel-related metabolites. 

Clopidogrel and the main Circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 µg/mL. 

METABOLISM AND ELIMINATION:

Clopidogrel is extensively metabolised by the liver and the main metabolite, which is inactive, is the carboxylic acid derivative, which represents about 85% of the circulating compound in plasma. Peak plasma levels of this metabolite (approx. 3mg/L after repeated 75 mg oral doses) occurred approximately 1 hour after dosing.

Following an oral dose of 14 C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration.

Aspirin: 

ABSORPTION AND DISTRIBUTION: Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%- 75% of an administered dose reaching the systemic circulation as intact aspirin. 

Aspirin is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration-dependent (nonlinear).

At low concentrations 

METABOLISM AND ELIMINATION:

Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2-2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5-2 hours) after administration of aspirin. Salicylic acid is primarily conjugated in the liver to form salicylic acid, a phenolic glucuronide, an acyl glucuronide and a number of minor metabolites.

Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10-20 g), the plasma half-life may be increased to over 20 hours 

The elimination half-life of acetylsalicylic acid is 0.33 hours. The half-life of salicylic acid is 1.71 hours. At higher doses, the elimination of salicylic acid follows zero-order kinetics (i.e., the rate of elimination is constant in relation to plasma concentration), with an apparent half-life of 6 hours or higher.

Renal excretion of unchanged drug depends upon urinary pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, as the phenolic and acyl glucuronides in urine.

Indications

ASAGREL is indicated for the prevention of ischemic events, myocardial infarction, stroke and cardiovascular death in patients with acute coronary syndrome. 

Contra-indications

 Hypersensitivity to clopidogrel 

 Hypersensitivity to aspirin and/or non-steroidal anti-inflammatory agents 

 Recent history of gastrointestinal bleeding

 Active pathological bleeding such as peptic ulcer or intracranial haemorrhage, or bleeding disorders like haemophilia

Precautions/Warnings

Interactions

Oral anticoagulants: ASAGREL should be used with caution when anticoagulants are prescribed concurrently, since both aspirin and clopidogrel may depress the concentration of prothrombin in plasma and therapy increase bleeding time.

Hypoglycemic agents: Large doses of salicylate have hypoglycemic action and may enhance the effect of the oral hypoglycemics. Consequently, they should not be given concomitantly; if however this is necessary, the dosage of the hypoglycemic agent must be reduced while the salicylate is given.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). In healthy volunteers receiving naproxen, concomitant administration of clopidogrel was associated with increased occult gastrointestinal blood loss. NSAIDs and clopidogrel should be coadministered with caution. ASAGREL is contraindicated in patients who are hypersensitive to NSAIDs 

Uricosuric agents: Although salicylate at larger doses are uricosuric agents, smaller amounts may decrease the uricosuric effects of probenecid, sulfinpyrazone and phenylbutazone. Aspirin may decrease the effects of probenecid, sulfinpyrazone and phenylbutazone. 

Spironolactone: Sodium excretion produced by spironolactone may be decreased in the presence of salicylates. Salicylates can produce changes in thyroid function tests. Salicylates should be used with caution in patients with severe hepatic damage, pre-existing hypoprothrombinemia or

Vitamin K deficiency and in those undergoing surgery. 

Alcohol: Has a synergistic effect with aspirin in causing gastrointestinal bleeding. 

Corticosteroids: Concomitant administration of aspirin"" with- corticosteroids may increase the risk of gastrointestinal ulceration and may reduce serum salicylate levels 

Pyrazolone derivatives (phenylbutazone, oxyphenbutal.one and possibly dipyrone): Concomitant administration may increase the risk of gastrointestinal ulceration. 

Urinary alkalinizes: Decrease aspirin effectiveness by increasing the risk of salicylate renal excretion.

Phenobarbital: Decreases aspirin effectiveness by enzyme induction. 

Phenytoin, tamoxifen, tolbutamide, torsemide, fluvastatin: At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, torsemide and fluvastatin, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with clopidogrel. Aspirin may also increase serum levels of phenytoin. 

Propranolol: May decrease aspirin's anti-inflammatory action by competing for the same receptors. 
Thrombotic thrombocytopenic purpura (TIP): TIP has been reported rarely following use of clopidogrel, sometimes after a short exposure (<2weeks).

TTP is a serious condition requiring prompt treatment. It is characterized by thrombocytopenia, microangiopathic haemolytic anemia, neurological findings, renal dysfunction and fever. TTP has been reported at a rate of about four cases per million patients exposed or about 11 cases per million patient-years. 

GI Bleeding: ASAGREL prolongs the bleeding time. ASAGREL should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesion (such as aspirin and other (NSAlDs]) should be used with caution in patients taking clopidogrel. 

Reye's syndrome: Reye's syndrome may develop in individuals who have chicken pox, influenza or flu symptoms. ASAGREL is not recommended for use in patients with chicken pox, influenza or flu symptoms 

Nasal polyps or nasal allergies: ASAGREL should be administered with caution to patients with nasal polyps or nasal allergies. In patients receiving large doses of aspirin and/or prolonged therapy, mild salicylate intoxication (salicylism) may develop that may be reversed by reduction in dosage. 

General: As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery. 

Hepatic Impairment: ASAGREL should be avoided with impaired hepatic function. 

Renal Impairment: ASAGREL should be avoided in patients with impaired renal function. Aspirin caused sodium and water retention in patients with renal impairment and increases the, risk of gastrointestinal bleeding 

Pregnancy: Adverse effects are increased in the mother and the foetus following chronic ingestion of aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal blood loss, ASAGREL should be avoided during the last three months of pregnancy. 

Lactation: ASAGREL should be avoided in nursing mothers because of the possible risk of developing Reye's syndrome. Regular use of high doses of aspirin could impair platelet function and produce hypoprothrombinemia in infants if neonatal vitamin K levels are low.

Pediatric Use: Safety and effectiveness of ASAGREL in the pediatric population have not been established.

Adverse Effects

The drug is generally well tolerated. Side effects that have been reported include abdominal pain, dyspepsia, gastritis, diarrhoea, nausea, vomiting, constipation, gastrointestinal haemorrhage, ulceration, neutropenia, rash, palpitation, syncope, drowsiness, asthenia, neuralgia, paresthesia and vertigo.

Dosage & Administration

Prevention of ischaemic events: The recommended dose is one tablet once daily. 

Acute coronary syndrome: 

Loading Dose: Four tablets. 

Maintenance: One tablet daily.

OVERDOSAGE, 
Clopidogrel: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 mg/kg or 2000 mg/kg was lethal to mice and rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing and gastrointestinal haemorrhage in all species. 

Recommendations about Specific treatment Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of clopidogrel if quick reversal is required. 

Aspirin: Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 µg/mL. Plasma concentrations of aspirin above 300 µg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 µg/mL.

A single lethal dose of aspirin in adults is not known with certainity but death may be expected at 30 g. Treatment consist primarily of supporting vital functions, increasing salicylate elimination and correcting the acid-base disturbance. Gastric emptying and for lavage are recommended as soon as possible after ingestion even if the patient bas vomited charcoal, as a slurry, is beneficial, if less than 3 hours passed since ingestion.

Charcoal absorption should not be employed prior to emesis and ravage. 
Severity (If aspirin intoxication is determined by measuring the blood salicylate level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and-electrolyte balance should also be maintained. 

In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes end pH should be monitored to promote alkaline diuresis of salicylate 'if renal function is normal.

Infusion of glucose may be required to control hypoglycemia. 
Haemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children.

Storage/Handling Recommendations

Protect from moisture. Store at a temperature not exceeding 30°C. 

KEEP OUT OF REACH OF CHILDREN. 

Review Date

2016-04-04 01:11:37