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PLOGREL

Trade name: PLOGREL

 

International non-proprietary name: Clopidogrel

 

Chemical name: methyl ether (2S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c] pyridine-5-yl)-acetate acid sulfate (1:1).

 

Dosage form: film-coated tablets.

 

Composition

Each tablet contains:

Active substance: Clopidogrel hydrosulfate which is the equivalent of 75 mg of Clopidogrel base;

Excipients: Povidone K 30, sodium croscarmellose, lactose monohydrate, microcrystalline cellulose, hydrogenised castor oil;

Film coating: Insta Moistshild (hypromellose, diethylphthalate, ethylcellulose, talc, titanium dioxide, iron oxide red).

 

Description: pink colored round biconvex film-coated tablets, with the break line on one side, odorless or nearly odorless; in the cross section the nucleus of white or almost white color is evident.

Pharmacotherapeutic group: anti-aggregant agent.

 

ATC code: B01АC04.

Pharmacologic properties.

Pharmacodynamics.

Clopidogrel is an anti-aggregant agent. It selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex thereby inhibiting platelet aggregation.

It decreases platelet aggregation induced by agonists other than ADP, by preventing their activation by released ADP, and does not affect the activity of phosphodiesterase (PDE).

It is irreversibly bound to platelet ADP-receptors, which are non-sensitive to ADP stimulation during their lifespan (about 7 days).

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after initial single oral doses of 400 mg (40 % inhibition level). Peak inhibition effect (60 % platelet aggregation inhibition) reaches steady state between day 4 and day 7 of repeated doses administration of 50 – 100 mg of the drug per day. Anti-aggregation effect remains during the total platelet lifespan (for 7 – 10 days).

Pharmacokinetics.

Absorption is rapid after the single and after repeated administration with a dose of 75 mg Clopidogrel per day.

The rates of absorption and bioavailability are high. However, the plasma concentration of initial substance is low, and 2 hours after administration does not reach the level of determination (0,025 µg/l).

Is bound (98 % – 94 %) to plasma proteins. Is a prodrug.

Clopidogrel is extensively metabolized in the liver. The active metabolite is not detected in blood. The main detected metabolite is inactive carboxylic acid derivative, whose time of reaching peak concentration (TCmax) after repeated oral administration of 75 mg maintenance dose occurs approximately in an hour; the peak concentration (Cmax) is about 3 mg/l.

Following an oral dose of Clopidogrel in humans, approximately 50 % of total dosage is excreted in urine and approximately 46 % in feces over the 120 hours post-dosing. After single and repeated oral administrations of 75 mg daily dosage, the active metabolite has a half-life (T ½) of approximately 8 hours. Concentrations of metabolites to be renally excreted are 50 %.

Plasma concentration of the main active metabolite after 75 mg maintenance daily dose administration is lower in patients with severe chronic renal failure (creatinine clearance (CC) is 5 – 15 ml/min.), compared to those with moderate chronic renal failure (creatinine clearance (CC) is from 30 to 60 ml/min.), and to healthy people.

Indications.

Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial disease.

In combination with acetylsalicylic acid (ASA): for prevention of thrombotic complications in patients with acute coronary syndrome: with ST-segment elevation if thrombolytic therapy is permissible; in patients with non-ST-segment elevation (instable angina pectoris or myocardial infarction without Q-wave), including patients who are to be with coronary revascularization.

Contraindications:

Hypersensitivity to the active substance or to any drug’s excipient.

Intolerance to lactose, lactase deficiency and glucose-galactose malabsorption syndrome.

Age below 18 years (efficacy and safety of administration are not established).

Severe hepatic failure.

Acute hemorrhage (including peptic ulcer or intracranial hemorrhage).

Pregnancy and lactation period.

With caution:

Moderate hepatic failure, chronic hepatic failure (CHF), pathological conditions, which increase the risk of hemorrhage development (including, traumas, surgical interventions), predisposition to hemorrhages, simultaneous administration of ASA, warfarin, non-steroid anti-inflammatory drugs (NSAIDs) (including COG-2 inhibitors), heparin, glycoprotein IIb/IIIa inhibitors, hereditary decrease of CYP2C19 iso-enzyme function.

Administration in pregnancy and during lactation period.

Because there are no adequate data, the drug administration in pregnant women and nursing mothers  is contraindicated.

Posology and mode of administration.

Orally, regardless of meals.

For prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial disease – daily dose is 75 mg once daily.

In patients with myocardial infarction, the treatment may be started from first days to 35th day of myocardial infarction manifestations, and in patients with ischemic stroke, the treatment may be started from 7 days to 6 months after the ischemic stroke is diagnosed.

For prevention of thrombotic complications in patients with acute coronary syndrome with non-ST-segment elevation (instable angina pectoris or myocardial infarction without Q-wave), the treatment may be started from a single administration of a loading dosage of 300 mg daily, and proceeded with a maintenance dosage of 75 mg daily (in combination with ASA in the range of daily dosages from 75 to 325 mg, the recommended dosage is 100 mg daily). The maximal beneficial effect occurs in 3 months. The duration of administration is up to one year.

For prevention of thrombotic complications in patients with acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation), the treatment may be started from a single administration of a loading dosage of 75 mg daily in combination with ASA and thrombolytic agents (or without thrombolytic agents).

Combined therapy should be started as soon as possible after the symptoms occur, and it should be proceeded with for, at least, 4 weeks. Patients above 75 years old should be treated with Clopidogrel without administration of the loading dosage.

Patients with hereditary decrease of CYP2C19 iso-enzyme function may demonstrate the decrease of Clopidogrel’s therapeutic effect. Optimal dosage for such group of patients is not established.

Experience of the drug’s usage in patients with CHF or moderate hepatic failure is limited.

Side effects.

Hemorrhage is the most common reaction that occurs during the first month of the drug’s administration. Severe hemorrhages are detected in patients who administer Clopidogrel simultaneously with ASA, or Clopidogrel with ASA and heparin (see Section “Special precautions”).

The frequency of side effects is determined according to the following definitions: very common – more than 1/10, common – more than 1/100 and less than 1/10, uncommon – more than 1/1000 and less than 1/100, rarely – more than 1/10000 and less than 1/1000, very rarely – less than 1/10000, including spontaneous reports. Within each frequency class side effects are indicated in the descending order of severity.

Hematologic system: uncommon – thrombocytopenia, leukocytopenia, eosinophilia; rarely – neutropenia, including, to the marked degree; very rarely – thrombotic thrombocytopenic purpura, anemia, including aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia.

Central nervous system: uncommon – headache, dizziness, paresthesia, intracranial hemorrhages, including, with a lethal outcome; very rarely – disorientation, hallucinations, taste perversions.

Special senses: uncommon – hemorrhages in conjunctiva, eyes, retina; rarely – vertigo.

Cardiovascular system: common – hematomas, very rarely – severe hemorrhages, bleeding from surgical wounds, vasculitis, decrease in the blood pressure.

Respiratory system: very common – nasal hemorrhage, very rarely – bronchiospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.

Gastrointestinal system: common – diarrhea, epigastria pain, dyspepsia, gastrointestinal hemorrhage; uncommon – gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely – retroperitoneal hemorrhage; very rarely – pancreatitis, colitis, including ulcerative or lymphocytic colitis, stomatitis, acute hepatic failure, hepatitis, violation of functional hepatic indicators, hemorrhage of gastrointestinal tract with a lethal outcome.

Skin and soft tissues: very common – subcutaneous hemorrhages; uncommon – skin rash, itching, purpura; very rarely – angioneurotic edema, urticaria; erythema, including erythema multiforme and Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen ruber planus.

Locomotive system: very rarely – hemarthrosis, arthritis, arthralgia, myalgia.

Genitourinary system: uncommon – hematuria, very rarely – glomerulonephritis,  hypercreatinemia.

Allergic reactions: very rarely – anaphylactic reactions, serum sickness.

Laboratory tests: uncommon – elongation of bleeding time, violation of functional hepatic indicators, elevation of blood creatinine level.

Other: very rarely – body temperature elevation.

Overdosage.

Overdose following Clopidogrel administration may result in elongation of bleeding time and further hemorrhagic complications. When hemorrhage is observed, the appropriate treatment measures should be taken.

No antidotes of pharmaceutical activity of Clopidogrel are found.

If a rapid correction of elongated bleeding time is necessary, the platelet mass transfusion may be recommended.

Drug – drug interactions.

Simultaneous administration of Clopidogrel with warfarin may increase the risk of intense bleeding, thus, the coadministration of Clopidogrel with warfarin is not recommended.

Concomitant use of IIb/IIIa glycoprotein inhibitors, ASA, heparin with Clopidogrel may increase the risk of hemorrhages development.

Coadministration of Clopidogrel and NSAIDs increases the risk of bleedings.

Concomitant use of CYP2C19 isoenzyme inhibitors (for instance, omeprasol) should be avoided.

The active metabolite of Clopidogrel inhibits the CYP2C19 isoenzyme activity, which may result in the increase in plasma concentrations of phenytoin, tolbutamide and NSAIDs.

Special warnings.

Within the treatment course, such indicators of hemostasis system as activated partial thromboplastin time (APTT), platelet count, functional platelet activity tests should be under control; functional hepatic activity should be periodically examined.

Clopidogrel should be taken with caution in patients having the risk of the marked hemorrhage in traumas, surgical interventions, in patients with traumas, in patients to be susceptible to bleeding (especially, gastrointestinal and intraocular), and in patients who administer ASA, non-steroid anti-inflammatory drugs (NSAIDs) (including COG-2 inhibitors), heparin or glycoprotein IIb/IIIa inhibitors. Patients should be thoroughly monitored in order to detect any signs of bleeding, including concealed hemorrhage, especially, within first weeks of the drug’s administration and/or after cardiac invasive procedures or surgical interventions. Coadministration of Clopidogrel with warfarin is not recommended as far as the bleeding may be increased.

In case of surgical interventions, if the antiaggregant activity is undesirable, the treatment course should be terminated 7 days before the surgical intervention.

Patients should be informed that, because the arrest of bleeding while administration of Clopidogrel (in combination with ASA or without it) needs more time, they are to tell their doctors about every bleeding episode. Patients should also inform the doctor about the administration of the medicine if they are to subject to surgical interventions.

After administration of Clopidogrel, thrombotic thrombocytopenic purpura (TTP) was observed very rarely, sometimes, after a short-term administration. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia connected with neurologic symptoms, violation of renal function or fever.

TTP is potentially dangerous condition, which requires immediate treatment, including the usage of plasmapheresis.

Due to the lack of data, Clopidogrel cannot be recommended at acute (less than 7 days) ischemic strokes.

Experience of Clopidogrel administration in patients with renal failure is limited, thus, this group of patients should take Clopidogrel with caution.

In case of severe hepatic failure, the risk of development of hemorrhagic diathesis should be considered, the experience of Clopidogrel administration in patients with moderate hepatic failure is limited, thus, this group of patients should take Clopidogrel with caution.

Effects on ability to drive and operate machines.

Clopidogrel may cause such side effects from the nervous system as headache, dizziness, system vertigo, confusion, hallucinations, which may affect the ability to drive vehicles and performing other potentially dangerous activities, which require the increased concentration of attention and rapid psychomotor reactions.

Dosage form:

Film-coated tablets, 75 mg.

7, 10 or 14 tablets per a blister made of polyvinylchloride film and aluminum foil. 2, 4, 8 or 12 blisters (each containing 7 tablets) along with the instruction on medical use into a carton box. 3 or 9 blisters (each containing 10 tablets) along with the instruction on medical use into a carton box. 1 or 2 blisters (each containing 14 tablets) along with the instruction on medical use into a carton box.

 

Storage conditions.

Keep at temperature below 25 оС in a light-protected place. Keep the drug out of the reach of children

 

Shelf life.

3 years. Do not use after the expiration of the shelf life.

 

Terms of discharge.

According to doctor’s prescription.

 

Manufacturing company:

Oxford Laboratories Pvt., Ltd.

B 306, Crystal Plaza, New Link Road, Andheri (West), Mumbai, 400 053, India.

 

Address and phone number of authorized company (for raising customers’ claims):

Representative office of Oxford Laboratories Pvt., Ltd., India.

119571, Moscow, 26th Bakinskikh Komissarov Str., 9, office 117.

Phone / fax:     8-(495) 935-81-52.

Round seal is applied: “Oxford Laboratories Pvt., Ltd.”, Representative office, Moscow, Registration Chamber with the Ministry of Justice of the RF, No. 7489.

Stamp is applied: FGU, Rosdravnadzora, NCESMP, Expert report is valid for this version of the document. 0000000000.