Actions of Clopidogrel 1A Pharma 75 mg in details
Pharmacology: Clopidogrel 1A Pharma 75 mg is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atherosclerotic cardiovascular disease as evidenced by stroke or transient ischemic attacks, myocardial infarction or need for bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.
Pharmacodynamics: Clopidogrel 1A Pharma 75 mg is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of Clopidogrel 1A Pharma 75 mg to 2-oxo-Clopidogrel 1A Pharma 75 mg and subsequent hydrolysis. Clopidogrel 1A Pharma 75 mg selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of Clopidogrel 1A Pharma 75 mg is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel 1A Pharma 75 mg also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel 1A Pharma 75 mg does not inhibit phosphodiesterase activity. Clopidogrel 1A Pharma 75 mg acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to Clopidogrel 1A Pharma 75 mg are affected for the remainder of their lifespan.
Dose-dependent inhibition of platelet aggregation can be seen 2 hrs after single oral doses of Clopidogrel 1A Pharma 75 mg. Repeated doses of Clopidogrel 1A Pharma 75 mg 75 mg/day inhibit ADP-induced platelet aggregation on the 1st day and inhibition reaches steady-state between day 3 and day 7. At steady-state, the average inhibition level observed with a dose of Clopidogrel 1A Pharma 75 mg 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values after treatment is discontinued, generally in about 5 days.
Pharmacokinetics: Effect of Food: Administration of Clopidogrel 1A Pharma 75 mg with meals did not significantly modify the bioavailability of Clopidogrel 1A Pharma 75 mg as assessed by the pharmacokinetics of the main circulating metabolite.
Absorption and Distribution: Clopidogrel 1A Pharma 75 mg is rapidly absorbed after oral administration of repeated doses of Clopidogrel 1A Pharma 75 mg 75 mg (base), with peak plasma levels (≥3 mg/L) of the main circulating metabolite occurring approximately 1 hr after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of Clopidogrel 1A Pharma 75 mg 50-150 mg. Absorption is at least 50% based on urinary excretion of Clopidogrel 1A Pharma 75 mg-related metabolites.
Clopidogrel 1A Pharma 75 mg and the main circulating metabolite bind reversibly in vitro to human plasma protein (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.
Metabolism and Elimination: In vitro and in vivo, Clopidogrel 1A Pharma 75 mg undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.
How should I take Clopidogrel 1A Pharma 75 mg?
Take Clopidogrel 1A Pharma 75 mg exactly as directed by your doctor. Clopidogrel 1A Pharma 75 mg will not work properly if you take less of it than directed. Taking more Clopidogrel 1A Pharma 75 mg than directed may increase the chance of serious side effects without increasing the helpful effects.
Clopidogrel 1A Pharma 75 mg comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.
You may take Clopidogrel 1A Pharma 75 mg with or without food.
If you are also taking omeprazole (Prilosec®), do not use it at the same time that you take Clopidogrel 1A Pharma 75 mg. Talk with your doctor about using a different antacid.
If you are using Clopidogrel 1A Pharma 75 mg for a condition called acute coronary syndrome, your doctor may tell you to take aspirin while you are using Clopidogrel 1A Pharma 75 mg. In this case, do not change the dose or stop taking the aspirin without talking to your doctor first.
Dosing
The dose of Clopidogrel 1A Pharma 75 mg will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Clopidogrel 1A Pharma 75 mg. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- For prevention of blood clots:
- Adults—75 milligrams (mg) once a day. In some patients, a single dose of 300 mg is given first. Your doctor may also give you aspirin together with Clopidogrel 1A Pharma 75 mg.
- Children—Use and dose must be determined by your doctor.
- For prevention of blood clots:
Missed Dose
If you miss a dose of Clopidogrel 1A Pharma 75 mg, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Clopidogrel 1A Pharma 75 mg administration
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Take this medication with a full glass of water.
Clopidogrel 1A Pharma 75 mg can be taken with or without food.
Because Clopidogrel 1A Pharma 75 mg keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.
If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using Clopidogrel 1A Pharma 75 mg. You may need to stop using the medicine for at least 5 days before having surgery, to prevent excessive bleeding. Follow your doctor's instructions and start taking Clopidogrel 1A Pharma 75 mg again as soon as possible.
Do not stop using Clopidogrel 1A Pharma 75 mg without first talking to your doctor. Use Clopidogrel 1A Pharma 75 mg regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
While using Clopidogrel 1A Pharma 75 mg, you may need frequent blood tests at your doctor's office.
Store at room temperature away from moisture and heat.
Clopidogrel 1A Pharma 75 mg pharmacology
Mechanism Of Action
Clopidogrel 1A Pharma 75 mg is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
Pharmacodynamics
Clopidogrel 1A Pharma 75 mg must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of Clopidogrel 1A Pharma 75 mg 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. This action is irreversible. Consequently, platelets exposed to Clopidogrel 1A Pharma 75 mg's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Clopidogrel 1A Pharma 75 mg. Repeated doses of 75 mg Clopidogrel 1A Pharma 75 mg 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 1A Pharma 75 mg 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.
Geriatric Patients
Elderly ( ≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.
Renally-Impaired Patients
After repeated doses of 75 mg Clopidogrel 1A Pharma 75 mg per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.
Hepatically-Impaired Patients
After repeated doses of 75 mg Clopidogrel 1A Pharma 75 mg per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.
Gender
In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
Pharmacokinetics
Clopidogrel 1A Pharma 75 mg is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
Absorption
After single and repeated oral doses of 75 mg per day, Clopidogrel 1A Pharma 75 mg is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of Clopidogrel 1A Pharma 75 mg metabolites.
Effect of Food
Clopidogrel 1A Pharma 75 mg can be administered with or without food. In a study in healthy male subjects when Clopidogrel 1A Pharma 75 mg 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Clopidogrel 1A Pharma 75 mg 300 mg loading dose was administered with a high-fat breakfast.
Metabolism
Clopidogrel 1A Pharma 75 mg is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize Clopidogrel 1A Pharma 75 mg to a 2-oxo-Clopidogrel 1A Pharma 75 mg intermediate metabolite. Subsequent metabolism of the 2-oxo-Clopidogrel 1A Pharma 75 mg intermediate metabolite results in formation of the active metabolite, a thiol derivative of Clopidogrel 1A Pharma 75 mg. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg Clopidogrel 1A Pharma 75 mg loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.
Elimination
Following an oral dose of 14C-labeled Clopidogrel 1A Pharma 75 mg in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, Clopidogrel 1A Pharma 75 mg has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.
Drug Interactions
Clopidogrel 1A Pharma 75 mg is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of Clopidogrel 1A Pharma 75 mg and a reduction in platelet inhibition.14
Proton Pump Inhibitors (PPI)
The effect of proton pump inhibitors (PPI) on the systemic exposure to the Clopidogrel 1A Pharma 75 mg active metabolite following multiple doses of Clopidogrel 1A Pharma 75 mg 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
Figure 1: Exposure to Clopidogrel 1A Pharma 75 mg Active Metabolite Following Multiple Doses of Clopidogrel 1A Pharma 75 mg 75 mg Alone or with Proton Pump Inhibitors (PPIs)
Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.
Pharmacogenomics
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-Clopidogrel 1A Pharma 75 mg intermediate metabolite. Clopidogrel 1A Pharma 75 mg active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of Clopidogrel 1A Pharma 75 mg's active metabolite.
The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6, 15 *7, and *8. A patient with poor metabolizer status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status
In CURE, the use of Clopidogrel 1A Pharma 75 mg was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with Clopidogrel 1A Pharma 75 mg were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of Clopidogrel 1A Pharma 75 mg was observed independently of the dose of aspirin (75-325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.19
Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study
The use of Clopidogrel 1A Pharma 75 mg in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the Clopidogrel 1A Pharma 75 mg group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the Clopidogrel 1A Pharma 75 mg group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of Clopidogrel 1A Pharma 75 mg in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the Clopidogrel 1A Pharma 75 mg group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).
COMMIT
In patients with STEMI, the safety and efficacy of Clopidogrel 1A Pharma 75 mg were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). 20
Patients were randomized to receive Clopidogrel 1A Pharma 75 mg (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figure 4 and Figure 5 below, Clopidogrel 1A Pharma 75 mg significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002).
Table 5: Outcome Events in the COMMIT Analysis
* All treated patients received aspirin.22
Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study*
* All treated patients received aspirin.
The effect of Clopidogrel 1A Pharma 75 mg did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.
Figure 6: Effects of Adding Clopidogrel 1A Pharma 75 mg to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study
* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.
Figure 7: Effects of Adding Clopidogrel 1A Pharma 75 mg to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study
Recent Myocardial Infarction, Recent Stroke, Or Established Peripheral Arterial Disease
CAPRIE
The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing Clopidogrel 1A Pharma 75 mg (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.
Table 6: Outcome Events in the CAPRIE Primary Analysis
The statistical significance favoring Clopidogrel 1A Pharma 75 mg over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of Clopidogrel 1A Pharma 75 mg is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of Clopidogrel 1A Pharma 75 mg relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of Clopidogrel 1A Pharma 75 mg over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, Clopidogrel 1A Pharma 75 mg was not numerically superior to aspirin.26
Lack Of Established Benefit Of Clopidogrel 1A Pharma 75 mg Plus Aspirin In Patients With Multiple Risk Factors Or Established Vascular Disease
CHARISMA
The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing Clopidogrel 1A Pharma 75 mg (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75-162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the Clopidogrel 1A Pharma 75 mg group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to Clopidogrel 1A Pharma 75 mg.
References
- EPA DSStox. "Clopidogrel: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
