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Placta

13:48
PLACTA
Clopidogrel

Composition
Placta 75 mg Film Coated Tablet: Each film-coated tablet contains Clopidogrel bisulfate 97.87 mg (equivalent to 75.0 mg Clopidogrel base)

PHARMACOLOGYCAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutical group: platelet aggregation inhibitors excl. Heparin, ATC Code: B01AC/04.
Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover.
Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.

Pharmacokinetic properties
After repeated doses of 75 mg per day, clopidogrel is rapidly absorbed. However, plasma concentrations of the parent compound are very low and below the quantification limit (0.00025 mg/1) beyond 2 hours. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Clopidogrel is extensively metabolized 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. 3 mg/1 after repeated 75 mg oral doses) occurred approximately 1 hour after dosing.
Clopidogrel is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. The oxidative step is regulated primarily by Cytochrome P450 isoenzymes 2B6 and 3A4 and to a lesser extent by 1 A1,1 A2 and 2C19. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. This metabolite has not been detected in plasma. The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150mgofclopidogrel.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range.
Following an oral dose of 14C-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.
After repeated doses of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite were lower in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min) compared to subjects with moderate renal disease (creatinine clearance from 30 to 60 ml/min) and to levels observed in other studies with healthy subjects.
Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, the prolongation of bleeding was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

Indications
Clopidogrel is indicated for the reduction of atherothrombotic events in:
  • Patients who suffering from myocardial infarction (from a few days until less than 35 days), ischemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
  • Patients who suffering from non-ST segment elevation acute coronary syndrome (unstable angina or non Q-wave myocardial infarction) in combination with ASA.

Posology
Adults and elderly:
Clopidogrel should be given as a single daily dose of 75 mg with or without food.
In patients with non-ST segment elevation acute coronary syndrome (unstable angina or non Q-wave myocardial infarction), Clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued at 75 mg once a day (with ASA 75 - 325 mg daily). Since higher doses of ASA were associated with higher bleeding risk, it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established.
Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months.

Children:
This product is not recommended for children and adolescents. Safety and efficacy in those below the age of 18 is not proven.
For oral administration.

Overdose
Overdose in treatment with clopidogrel may provoke prolongation of bleeding time, which may lead to hemorrhagic complications. With regards to mechanism of its action, it may be expected positive effect at infusion of thrombocytic mass.
There is no specific antidote.

Contraindications
Allergy to the active substance or any of the other ingredients;
Active pathological bleeding (like in peptic ulcer or intracranial hemorrhage);
Severe hepatic failure;
Pregnancy and breast-feeding;
Children.

DRUG INTERACTION
Warfarin: co-application of clopidogrel with warfarin is not recommended due to increased bleeding risk.
Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with great caution to patients with increased bleeding risk due to trauma, surgical manipulations or other pathological states and co-treated with glycoprotein IIb/IIIa inhibitors.
Acetylsalicylic acid (ASA): ASA does not change clopidogrel-mediated inhibition of thrombocyte aggregation (adhesion of thrombocytes), but clopidogrel potentates the effect of ASA on thrombocyte aggregation. It is possible this interaction between clopidogrel and ASA to lead to increased bleeding risk. Therefore their co-application should be done with caution, although there is accumulated experience in such application within one year.

Heparin: clopidogrel does not change either the general necessity of heparin or heparin action on blood clotting. Co-application with heparin has no effect on inhibition of thrombocyte aggregation induced by clopidogrel.
Thrombolytics (medicinal products destroying formation of thrombi): safety from co-application of clopidogrel, thrombolytic - recombinant plasminogen activator (rt-PA) and heparin is studied in clinical tests on patients with fresh myocardial infarction. The frequency of clinically significant bleedings is analogical to that, observed at application of rt-PA and heparin, co-administered with ASA. Safety at co-application of clopidogrel with other thrombolytics is not studied sufficiently due to which it should be carried out with caution.
Non-steroidal anti-inflammatory drugs (NSAIDs): in healthy volunteers, receiving naproxen, co-application of clopidogrel is associated with increasing the frequency of occult bleeding from gastrointestinal tract. NSAIDs and clopidogrel should be used jointly with caution.
Other concomitant therapy: no clinically significant interactions are observed when clopidogrel is co-administered with atenolol, nifedipine or simultaneously atenolol and nifedipine. Clopidogrel effect is affected insignificantly from the application of phenobarbital, cimetidine or estrogen.

WARNINGS AND PRECAUTIONS
Due to risk of bleeding and undesirable hematological effects, it is necessary to control blood cells count and/or to carry out other suitable tests when there are suspected clinical symptoms during the therapeutic course. The patients should be monitored accurately for symptoms of bleeding, incl. occult (imperceptible with bare eye) bleeding, especially in the first weeks of therapy and/or after instrumental cardiac procedures or operations. Co-application of clopidogrel with warfarin is not recommended because It may increase bleeding frequency.
Clopidogrel prolongs bleeding time and therefore it should be used with great caution in patients with high risk of intense bleeding in traumas, operations or other pathological states (especially gastrointestinal and intraocular) and in such who receive treatment with acetylsalicylic acid, non-steroidal anti-inflammatory drugs, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. If the patients shall be subjected to surgical manipulation and antiaggregant effect is not desirable, the treatment with Clopidogrel Actavis should be discontinued 7 days prior to operation.
The patients should be informed that the time for discontinuance of bleeding may be prolonged more than the usual one, when they administer clopidogrel (alone or in combination with acetylsalicylic acid) and that they should report to their doctor about any unusual bleeding (site and duration).The patients should inform the doctors and dentists about the fact that they administer clopidogrel prior to each surgical manipulation and before starting the treatment with new medicinal product.
Thrombotic thrombocytopenic purpura (TTP) (lesion with symptoms of bleeding, due to reduced count of thrombocytes in blood) is reported very rare after application of clopidogrel, sometimes even after short application.
It is outlined by low thrombocyte count and anemia, due to accumulation of miniature thrombi in the smallest vessels of muscles and organs, leading to neurological changes, renal dysfunction or fever. TTP is a potential lifethreatening status, necessitating instant treatment, including plasmapheresis (purification of plasma by special device).
Clopidogrel Actavis should be prescribed with caution to patients with severely damaged hepatic function, in whom bleeding may arise, due to the limited experience with its application in such patients.
The experience with application of clopidogrel in patients with gravely damaged renal function is limited too, due to which it should be applied with caution to such patients.

Pregnancy and lactation
Pregnancy: There are no adequate and well controlled clinical studies for safety in administration of clopidogrel during pregnancy. Therefore Clopidogrel Actavis should not be applied during pregnancy except in absolute necessity.
Lactation: There are no data for excretion of clopidogrel in the human breast milk.
Due to potential risk for the suckling, Clopidogrel Actavis is not applied in the breastfeeding period. If its application is imperative, breast-feeding should be discontinued.

Undesirable effects
Hemorrhagic symptoms (bleeding): gastrointestinal bleeding (2.0%), hemorrhagic insult (0.4%), purpura (subcutaneous bleedings), epistaxis (nose bleeding), hematuria (blood in urine) and eye hemorrhage (mainly conjunctival).
Hematological disorders: neutropenia (reduced count of neutrophils type of white blood cells executing protection functions), thrombocytopenia (reduced count of thrombocytes).
Central and peripheral nervous system:
- headache, dizziness, paresthesia
- vertigo
Gastrointestinal system:
- heartburn, warmth, abdominal pains, diarrhea
- nausea, gastritis, flatulence, constipation, vomiting, stomach and duodenal ulcer
Disorders in thrombocytes, processes of bleeding and clotting:
- prolonged bleeding time, reduced thrombocytes count
Skin and appendices:
- rash, itching
Changes in white blood count:
- changes in the count of some cellular lines (leucopenia, neutropenia, eosinophilia)

Post-registration and post-marketing monitoring: Most frequently reported are the bleeding symptoms, mainly in the first month of therapy.

Blood and lymph system:
- Thrombotic thrombocytopenic purpura (TTP) (1/200 000), changes in the count of cells of various blood lines (severe thrombocytopenia.granulocytopenia, agranulocytosis, anemia, aplastic anemia/pancitopenia)

Immune system:
- anaphylactoid reactions
Mental:
- confusion, hallucinations.
Nervous system:
- taste disorder
Vascular system:
- vasculitis (vascular inflammation), hypotension (low arterial pressure)
Gastrointestinal system:
- colitis (incl. ulcerous or lymphocyte colitis), pancreatitis, stomatitis.
Hepatic:
- hepatitis, acute hepatic failure.
Skin and hypoderma:
- angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome), erythematous rash, urticaria, eczema, lichen planus.
Musculoskeletal:
- arthritis, muscular and articular pains
Renal:
- glomerulonephritis
General:
- fever.
Laboratory changes:
- elevated values of the indices of hepatic function, elevated serum creatinine.

Storage
Store at cool temperature (15-25°C)

Presentation
Placta 75 mg Film coated tablet:
Available in boxes containing 3 blisters@ 10 film coated tablets
Reg. No: DKL0905514917A1

Manufactured by
Actavis Ltd., Malta
Imported and secondary pack by
PT Actavis Indonesia, Jakarta
Actavis Group, Iceland

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