2010/06/15

Plavix

Composition, structure and packing

Tablets, film-coated pink, round, slightly convex, engraved with "75" on one side and "1171" - on the other, the core tablets are white. 1 tab. clopidogrel hydrosulfate 97,875 mg, which is equivalent to the contents of clopidogrel 75 mg base .. Excipients: mannitol, macrogol 6000, microcrystalline cellulose (low water content, 90 microns), hydrogenated castor oil, gipromelloza nizkozameschennaya. The composition of the shell: Opadry 32K14834 (lactose, gipromelloza, triacetin, titanium dioxide, iron oxide red), carnauba wax.

Clinico-pharmacological group: antiagrigant.

Pharmacological action

Inhibition of platelet aggregation. Clopidogrel (or more precisely its active metabolite) irreversibly binds to the platelet ADP receptors (adenosine receptors) and selectively inhibits the binding of ADP to the ADP receptors of platelets and subsequent activation of the complex GPIIb / IIIa under the influence of ADP, thus inhibited ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists, due to the fact that blocks the activation of platelets freed as ADP. Clopidogrel irreversibly binds to ADP-receptor inhibitors.

Consequently, platelets, which came to him in the interaction, immune to the stimulation of ADP during the entire period of their lives, and normal platelet function is restored with the same speed as renovation of platelets. Clopidogrel is capable of preventing the development of atherothrombosis in all localizations of atherosclerosis, particularly in lesions of cerebral, coronary or peripheral arteries.

With daily administration of clopidogrel 75 mg on the first day of admission showed a significant inhibition of ADP-induced platelet aggregation, which is gradually increased for 3-7 days and then goes to a constant level (when reaching the equilibrium state). In equilibrium, platelet aggregation is suppressed on average by 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time returned to its original level within an average of 5 days.

Pharmacokinetics

The absorption and distribution

During the regular ingestion Plavix 75 mg / day clopidogrel quickly absorbiruetsya.Ishodya from data on the removal of clopidogrel metabolite in urine, the absorption of clopidogrel is at least 50%. However, its concentration in blood plasma is negligible, and 2 h after administration does not reach the measurement limit (0.25 mg / l). Clopidogrel and the main metabolite is reversibly bound to plasma proteins (98% and 94% respectively), this relationship is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is a prodrug and quickly biotransformiruetsya in the liver. Its active metabolite, thiol derivative, is formed by oxidation of clopidogrel in a 2-oxo-clopidogrel and subsequent hydrolysis. The oxidation process is governed primarily isoenzymes CYP2B6 and CYP3A4, and to a lesser extent - CYP1A1, 1A2, and 1S19.

Active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. This metabolite in plasma is not detected. The main metabolite of clopidogrel, (carboxyl derivative), is about 85% of circulating plasma metabolites of clopidogrel and has no pharmacological activity, but it is capable in vitro to inhibit the activity of 2C9 isoenzyme family of cytochrome P450. Cmax of the metabolite in blood plasma after repeated receptions Plavix 75 mg is about 3 mg / L and observed after approximately 1 h after administration.

The pharmacokinetics of the major metabolite is linear (plasma concentrations increase in proportion to dose) Clopidogrel in the dose range from 50 to 150 mg.

Withdrawal

Within 120 h after ingestion by man 14C-labeled clopidogrel about 50% of radiolabel excreted in the urine and approximately 46% - with the feces. T1 / 2 in the main circulating metabolite was 8 hours after single and repeated receptions.

Pharmacokinetics in special clinical situations

Concentrations of the main circulating metabolite in plasma with regular admission at a dose of 75 mg / day were lower in patients with renal failure severe (CC 5-15 ml / min) compared with patients with renal insufficiency moderately (CC 30-60 ml / min) and healthy volunteers. Although the inhibitory effect on ADP-induced platelet aggregation was reduced (25%) compared with the same effect in healthy volunteers, bleeding time was lengthened to the same extent as in healthy volunteers, PLAVIX 75 mg / day.

Clinical tolerability of clopidogrel in patients with renal failure did not differ from that in healthy individuals. In patients with liver cirrhosis (class A or B on the scale of Child-Pugh) daily for 10 days of receiving clopidogrel 75 mg / day was safe and well-tolerated, as well as in healthy individuals.

In patients with liver cirrhosis (class A or B on the scale of Child-Pugh) Cmax clopidogrel after the single dose and Cssmax clopidogrel after taking regular doses of the drug against the course of treatment were many times higher than in patients without cirrhosis. However, Cmax main circulating metabolite in the blood and the degree of suppression of clopidogrel ADP-induced aggregation of platelets, and bleeding time in patients with cirrhosis and without it were comparable.

Statement

Preventing atherothrombotic events in patients with myocardial infarction, ischemic insultomili diagnosed with occlusive disease of the peripheral arteries.

Preventing atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:
without ST segment elevation ST (unstable angina or myocardial infarction without teeth Q), including patients who underwent a stenting during percutaneous coronary intervention;
c-segment elevation ST (acute myocardial infarction) with medical treatment and the possibility of thrombolysis.

Dosage regimen

For the prevention of ischemic disorders in patients after myocardial infarction, ischemic stroke and diagnose peripheral arterial occlusive lesion adults (including elderly patients) designate 75 mg 1 time / day irrespective of food intake. Treatment should begin with the first days to 35 days after myocardial infarction and from 7 days to 6 months - after ischemic stroke.

In acute coronary syndrome without ST elevation ST (unstable angina or myocardial infarction without teeth Q) treatment should be started with the appointment of a single loading dose of 300 mg, and then continue to use the drug at a dose of 75 mg 1 time / day (with a simultaneous appointment of acetylsalicylic acid in a dose 75-325 mg / day). Since the use of acetylsalicylic acid in high doses is associated with greater risk of bleeding, the recommended dose should not exceed 100, the course of treatment - up to 1 year.

In acute myocardial infarction with ST-segment elevation medication prescribed at a dose of 75 mg of 1 times / day with initial loading dose in combination with acetylsalicylic acid in combination with or without thrombolytics. For patients aged over 75 years of clopidogrel treatment should be carried out without loading dose. Combination therapy begins as soon as possible after the onset of symptoms and continued for at least 4 weeks.

Side effect

Safety of clopidogrel has been studied in clinical trials of more than 42 000 patients, including over 9000 patients receiving the drug for a year or longer. Clinically important side effects observed in trials CAPRIE, CURE, CLARITY and COMMIT, are discussed below. Tolerability of clopidogrel in a dose of 75 mg / day in CAPRIE trial corresponded to the tolerance of acetylsalicylic acid in a dose of 325 mg / day. Overall tolerability was similar tolerability of acetylsalicylic acid, regardless of age, sex and race of patients. From the blood coagulation system: a test of CAPRIE - the overall frequency of bleeding in patients treated with clopidogrel or acetylsalicylic acid, was 9.3%, the frequency of severe cases in the application of clopidogrel was 1.4%, and the application of acetylsalicylic acid - 1.6%.

Patients who received clopidogrel, gastrointestinal bleeding occurred in 2.0% of cases, and in 0.7% of the cases required hospitalization.

In patients treated with acetylsalicylic acid, the corresponding rate was 2.7% and 1.1%. The frequency of other bleeding was higher in patients treated with clopidogrel, compared with acetylsalicylic acid (7.3 and 6.5% respectively). However, the frequency of severe cases was the same in both groups (0.6 and 0.4% respectively). The most frequently observed in both groups purpura / bruising / hematoma and epistaxis. Less frequent bruising, haematuria and eye bleeding (mainly conjunctival). The frequency of intracranial hemorrhage was 0.4% in patients treated with clopidogrel and 0.5% in patients treated with acetylsalicylic acid.

In a trial CURE - use a combination of clopidogrel + aspirin compared with placebo + combination of acetylsalicylic acid does not lead to a statistically significant increase in life-threatening bleeding (frequency of 2.2% compared to 1.8%) or fatal bleeding (frequency of 0.2% compared to 0.2% respectively), but the risk of large, small and other bleeding was significantly higher when using a combination of clopidogrel + aspirin: major bleeding, do not pose danger to life (1.6% - clopidogrel + aspirin, 1.0% - placebo + aspirin), primarily gastrointestinal bleeding and bleeding at the injection site, as well as small bleeding (5.1% - clopidogrel + aspirin, 2.4% - placebo + aspirin). The frequency of intracranial bleeding in both groups was 0.1%.

The frequency of major bleeding when using a combination of clopidogrel + aspirin depended on the dose of the latter (<100> 200 mg: 4.9%), as well as the application of a combination of aspirin with placebo (≤ 100 mg: 2.0%; 100-200 mg: 2.3%> 200 mg: 4.0%). During the test, the risk of bleeding (life-threatening, large, small, other) decreased: 0-1 months [clopidogrel: 599/6259 (9.6%), placebo: 413/6303 (6.6%)], 1-3 months [ clopidogrel: 276/6123 (4.5%), placebo: 144/6168 (2.3%)], 3-6 months [clopidogrel: 228/6037 (3.8%), placebo: 99/6048 (1.6%)], 6-9 months [clopidogrel: 162/5005 (3.2%), placebo: 74/4972 (1.5%)], 9-12 months [clopidogrel: 73/3841 (1.9%), placebo: 40/3844 (1.0%)].

In patients who have stopped taking the drug for more than 5 days before coronary artery bypass surgery, there was no increase in the frequency of major bleeding within 7 days after surgery for coronary bypass surgery (4.4% in the clopidogrel + aspirin and 5.3% for placebo + aspirin). In patients who continued taking the drug for five days prior to coronary bypass surgery, the frequency was 9.6% in the clopidogrel + aspirin and 6.3% - in the case of placebo + aspirin.

In the CLARITY trial observed a general increase in the frequency of bleeding in the group of clopidogrel + aspirin (17.4%) compared with placebo + aspirin (12.9%). The frequency of major bleeding were similar in both gpyppax (1.3% and 1.1% in gpyppax clopidogrel + aspirin and placebo + aspirin, respectively). This value was sustained in all subgroups of patients defined by the underlying characteristics and type of fibrinolytic and heparin therapy.

The frequency of fatal bleeding (0.8% and 0.6% in the clopidogrel + aspirin and placebo + aspirin, respectively) and intracranial hemorrhage (0.5% and 0.7% in the clopidogrel + aspirin and placebo + aspirin, respectively) was low and similar in both gpyppax. In the COMMIT trial the overall frequency of major bleeding netserebralnyh or cerebral bleeding was low and similar in both groups (0.6% and 0.5% in the clopidogrel + aspirin and placebo + aspirin, respectively). On the part of the hemopoietic system: a test CAPRIE - severe neutropenia (<0.45h109 / l) was observed in 4 patients (0.04%) treated with clopidogrel and 2 patients (0.02%) treated with acetylsalicylic acid.

In 2 patients from 9599 who received clopidogrel, the number of neutrophils was zero, and none of 9586, receiving acetylsalicylic acid, such values are not observed. In the course of clopidogrel treatment was observed one case of aplastic anemia.

Frequency of severe trombopitopenii (<80> 1 / 100, <1> 1 / 1000, <1> 1 / 10000, <1 / 1000). Within each group the frequency of side effects is presented in order of decreasing severity.
From the central nervous system and peripheral nervous system: sometimes - headache, dizziness, paresthesias, rare - vertigo.
On the part of the digestive system: often - dyspepsia, diarrhea, abdominal pain, sometimes - nausea, gastritis, flatulence, constipation, vomiting, stomach ulcer and duodenal ulcer.
From the blood coagulation system: sometimes - lengthening the time of bleeding.
On the part of the hemopoietic system: sometimes - leukopenia, reducing the number of neutrophils and eosinophils, reducing the number of platelets. Dermatological reactions: sometimes - a rash and itching.

Post marketing surveillance data
From the blood coagulation system: the most common - hemorrhage (in most cases - during the first month of treatment). There are several fatal cases (intracranial, gastrointestinal and retroperitoneal bleeding), there are reports of severe cases of skin bleeding (purpura), musculoskeletal bleeding (Hemarthrosis, hematoma), ocular hemorrhages (conjunctival, ocular, retinal), epistaxis , hemoptysis, pulmonary hemorrhage, hematuria, and bleeding from the wound, the patients taking clopidogrel simultaneously with acetylsalicylic acid or acetylsalicylic acid and heparin, have also been cases of severe bleeding.

In addition to these clinical trials were spontaneously declared the following side effects. In each class of bodies (classification MedDRA), they are showing the frequency. The term "very rare" corresponds to a frequency <1 / 10000. Within each group the frequency of side effects is presented in order of decreasing severity.
On the part of the hemopoietic system: very rarely - thrombocytopenic purpura trombogemoliticheskaya (1 in 200 000 patients), severe thrombocytopenia (platelet count ≤ 30 000/mkl), granulocytopenia, agranulocytosis, anemia, and aplastic anemia / pancytopenia.
From the side of the central nervous system: very rarely - confusion, hallucinations.
Since the cardiovascular system: a very rare - vasculitis, hypotension.
On the part of the respiratory system: very rarely - bronchospasm, interstitial pneumonitis.
On the part of the digestive system: very rarely - colitis (including ulcerative colitis or lymphocytic), pancreatitis, changes in taste, stomatitis, hepatitis, acute liver failure, increase in liver enzymes.
On the part of the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia.
From the urinary system: very rarely - glomerulonephritis, increased blood creatinine. Dermatological reactions: very rare - Bullous rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), erythematous rash (associated with clopidogrel or acetylsalicylic acid), eczema, shingles, flat. Allergic reactions: seldom - angioedema, urticaria, anaphylactoid reactions, serum sickness. Other: very rarely - fever.

Contraindications
severe hepatic insufficiency.
acute pathological bleeding such as bleeding ulcers izpepticheskoy vnutricherepnoekrovoizliyanie.
a rare hereditary galactose intolerance, lactase deficiency syndrome and glucose-galactose malabsorption.
Pregnancy
Lactation (breastfeeding).
Children age 18 years (safety and efficacy not established);
Hypersensitivity to the drug's components.

Be wary prescribers with moderate hepatic insufficiency, in which the possible predisposition to bleeding (limited clinical experience with) renal impairment (limited clinical experience using) for injuries, surgical procedures, the diseases for which there is a predisposition to the development of bleeding (especially gastrointestinal -intestinal or intraocular), while taking NSAIDs, including selective COX-2 inhibitor, while the appointment of warfarin, heparin, inhibitors of glycoprotein IIb / IIIa.

Precautions should be prescribed the drug for liver and kidney (including at moderate hepatic and / or renal insufficiency), trauma, preoperative states.

Pregnancy and lactation

Given the lack of data is not advisable to appoint Plavix during pregnancy and lactation (breastfeeding). In experimental studies did not establish any direct or indirect adverse effects on pregnancy, fetal development, childbirth and postnatal development. In studies on rats have shown that clopidogrel and / or its metabolites are excreted with breast milk.

It is not known whether clopidogrel is allocated with breast milk in humans.

Application for violations of liver function

Precautions should be prescribed the drug to treat liver diseases (including those with moderate hepatic insufficiency). Do not use this with hepatic failure and severe.

Application for violations of renal function

Precautions should be prescribed a drug for kidney (including renal failure of moderate degree).

Cautions

When using Plavix, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery, it is necessary to closely monitor patients for signs of bleeding exceptions, including hidden.

Because of the risk of bleeding and haematological side effects in case of a course of treatment of clinical symptoms suspicious for bleeding, should urgently make clinical blood test to determine APTT, platelet count, indicators of functional activity of platelets and conduct other necessary investigations.

Plavix, as well as other antiplatelet drugs should be used with caution in patients with increased risk of bleeding associated with trauma, surgery or other pathological conditions as well as combination therapy with acetylsalicylic acid, NSAIDs (including inhibitors COX-2), heparin or inhibitors of glycoprotein IIb / IIIa. Combined use of clopidogrel with warfarin may increase bleeding, so, except in rare clinical situations (such as the presence of floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the combined use of Plavix, and warfarin is not recommended.

With the planned surgical treatment Plavix should be discontinued 7 days before surgery. Clopidogrel should be used with caution in patients with the risk of bleeding (particularly gastrointestinal and intraocular).

Patients should be warned that while taking Plavix (alone or in combination with acetylsalicylic acid) to stop the bleeding may require more time, and that in case they have an unusual (for containment or duration) of bleeding, they should inform about your doctor. Before any of the forthcoming operation and before taking any new drug patients should inform the doctor (including dental) for the admission of clopidogrel. There were also cases of thrombotic thrombocytopenic purpura (TTP) after administration of clopidogrel. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with any neurological symptoms, impaired renal function or fever.

Development of TTP may be life-threatening and require urgent action, including plasmapheresis. Because of insufficient data clopidogrel should not be given in acute ischemic stroke (in the first 7 days). The drug should be prescribed with caution in patients with impaired renal function. In the period of treatment necessary to control the functional activity of the liver.

In severe liver disease should be aware of the risk of hemorrhagic diathesis. Patients with congenital intolerance galactose malabsorption syndrome, glucose-galaktazy and lactase deficiency should not be given Plavix.

Effects on ability to driving and management mechanisms

No signs of deterioration in the ability of driving a car or reduce mental performance after taking Plavix found.

Overdose

Symptoms: Extension of time of bleeding and subsequent complications in the form of bleeding. Treatment: If you experience bleeding should be carried out appropriate therapy. If you need quick correction lengthens bleeding time, platelet transfusion is recommended. No specific antidote.

Drug Interactions

Combined use of clopidogrel with warfarin is not recommended because this combination can increase the intensity of bleeding. Appointment of inhibitors of glycoprotein IIb / IIIa with Plavix requires caution. Acetylsalicylic acid does not alter the inhibitory effect of Plavix on ADP-induced platelet aggregation, but enhances the effect of Plavix aspirin on collagen-induced platelet aggregation. The combined use of these drugs requires caution. However, in acute coronary syndrome without ST segment elevation is recommended for a long joint use of Plavix and aspirin (up to 1 year). When applied simultaneously with heparin, according to a clinical trial conducted in healthy volunteers, Plavix did not alter either the overall need for heparin, or the effect of heparin on blood coagulation.

The simultaneous use of heparin did not alter the inhibitory effect of Plavix on platelet aggregation. However, the safety of such combinations has not yet been established, and the simultaneous use of these drugs requires caution.

Safety joint for clopidogrel, fibrin-specific and fibrin-nonspecific thrombolytic agents and heparin was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of joint use of thrombolytic drugs and heparin with acetylsalicylic acid. Appointment of NSAIDs (including COX-2 inhibitor), together with Plavix requires caution.

In a clinical study involving healthy volunteers, the combined use of clopidogrel and naproxen increased the hidden loss of blood through the digestive tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs is not currently known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. A number of clinical studies with clopidogrel and other drugs at the same time appointed to examine the possible pharmacodynamic and pharmacokinetic interactions, which showed the following.

Clopidogrel with atenolol, nifedipine, or both drugs simultaneously clinically significant pharmacodynamic interactions were observed (according to clinical studies to examine the possible pharmacodynamic and pharmacokinetic interactions). The simultaneous use of phenobarbital, cimetidine, and estrogen had no significant effect on the pharmacodynamics clopidogrel (based on clinical studies to examine the possible pharmacodynamic and pharmacokinetic interactions).

Pharmacokinetic parameters of digoxin and theophylline did not change at their joint application to clopidogrel (based on clinical studies to examine the possible pharmacodynamic and pharmacokinetic interactions). Antacid not reduce absorption clopidogrel (according to clinical studies to examine the possible pharmacodynamic and pharmacokinetic interactions).

Phenytoin and tolbutamide may be safety used in conjunction with clopidogrel (study CAPRIE), despite the fact that the data obtained in studies with human liver microsomes indicate that the carboxyl metabolite of clopidogrel could inhibit the activity of the 2C9 isoenzyme of cytochrome P450 family, which may lead to an increase of plasma concentrations of certain drugs (phenytoin, tolbutamide and certain NSAIDs), which are metabolized by 2C9 isoenzyme family of cytochrome P450.

In clinical studies found no clinically significant adverse interactions clopidogrel with ACE inhibitors, diuretics, β-blockers, calcium channel blockers, lipid-lowering drugs, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic drugs, hormone replacement therapy and antagonist GPIIb / IIIa.

Terms and Conditions of storage

List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 3 years.