Ridlor

Ridlor

clopidogrel

Manufacturer:

Mega Lifesciences

Distributor:

Maxxcare
Full Prescribing Info
Contents
Clopidogrel bisulphate.
Description
Each tablet contains clopidogrel bisulphate equivalent to clopidogrel 75 mg. It also contains the following inactive ingredients: Microcrystalline cellulose (PH102), mannitol (DC-grade), L-hydroxypropyl cellulose (LH-21), crospovidone, polyethylene glycol 6000, L-hydroxypropyl cellulose (LH-11), hydrogenated castor oil, Opadry II pink IH, purified water. Colours: Titanium dioxide, red iron oxide.
Chemically it is methyl(+)-(S)-α-(2-chlorophenyl)-6, 7-dihydrothieno[3,2c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C16H16CINO2S·H2SO4 and its molecular weight is 419.9.
Clopidogrel bisulphate is a white to off-white crystalline powder.
Action
Pharmacology: Pharmacodynamics: Ridlor (clopidogrel bisulfate) is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
Mechanism of Action: Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel 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's active metabolite are affected for the remainder of their lifespan (about 7-10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Dose-dependent inhibition of platelet aggregation can be seen 2 hrs after single oral doses of clopidogrel. Repeated doses of clopidogrel 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 75 mg/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.
Pharmacokinetics: Absorption: After single and repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 min after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of Food: The effect of food on the bioavailability of the parent compound or active metabolite is currently not known.
Distribution: Clopidogrel and the main circulating inactive 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 mcg/mL.
Metabolism: Clopidogrel is extensively metabolized by the liver. In vitro and in vivo, clopidogrel is metabolized according to 2 main metabolic pathways: One mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination: Following an oral dose of 14C-labeled clopidogrel 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 has a t½ of approximately 6 hrs. The elimination half-life of the inactive acid metabolite was 8 hrs after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.
Pharmacogenetics: Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism.
The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population. Published frequencies for the common CYP2C19 phenotypes and genotypes are listed in the table as follows.

Click on icon to see table/diagram/image

Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel's active metabolite.
Special Populations: The pharmacokinetics of clopidogrel's active metabolite is not known in these special populations.
Geriatric Patients: In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Renally-Impaired Patients: After repeated doses of clopidogrel 75 mg/day in patients with severe renal impairment (creatinine clearance from 5-15 mL/min), inhibition of ADP-induced platelet aggregation was lower (<25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving clopidogrel 75 mg/day.
Hepatically-Impaired Patients: After repeated doses of clopidogrel 75 mg/day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the 2 groups.
Gender: The incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
Race: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity.
Indications/Uses
Reduction of atherothrombotic events as follows: Recent MI, Recent Stroke or Established Peripheral Arterial Disease: For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, it has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.
Dosage/Direction for Use
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: The recommended daily dose of Ridlor is 75 mg once daily.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), Ridlor should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Aspirin (75 mg-325 mg once daily) should be initiated and continued in combination with Ridlor. For patients with ST-segment elevation acute myocardial infarction, the recommended dose of Ridlor is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. Ridlor may be initiated with or without a loading dose.
CYP2C19 poor metabolizer status is associated with diminished response to clopidogrel. The optimal dose regimen for poor metabolizers has yet to be determined.
No dosage adjustment is necessary for elderly patients or patients with renal disease.
Overdosage
Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing and gastrointestinal hemorrhage in all species.
Recommendations about Specific Treatment: Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of Ridlor if quick reversal is required.
Contraindications
Hypersensitivity to the drug substance or any component of Ridlor.
Active pathological bleeding eg, peptic ulcer or intracranial hemorrhage.
Warnings
Reduced effectiveness due to impaired CYP2C19 function.
The inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. Clopidogrel is metabolized to this active metabolite in part by CYP2C19. This metabolism can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Avoid use of Ridlor in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity.
Genetic Variations: Patients with genetically reduced CYP2C19 function have diminished antiplatelet responses and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function.
Thrombotic Thrombocytopenic Purpura (TTP): TTP has been reported rarely following use of clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia [schistocytes (fragmented RBCs) seen on peripheral smear], neurological findings, renal dysfunction and fever.
Special Precautions
General: Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.
Due to the risk of bleeding and undesirable hematological effects, blood cell count determination and/or other appropriate testing should be promptly considered, whenever such suspected clinical symptoms arise during the course of treatment.
In patients with recent TIA or stroke who are at high risk of recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.
GI Bleeding: Clopidogrel should be used with caution in patients who have lesions with a propensity to bleed (eg, ulcers). Drugs that might induce such lesions should be used with caution in patients taking clopidogrel.
Use in Hepatically-Impaired Patients: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Clopidogrel should be used with caution in this population.
Use in Renally-Impaired Patients: Experience is limited in patients with severe renal impairment. Clopidogrel should be used with caution in this population.
Information for Patients: Patients should be told that while taking Ridlor or Ridlor combined with aspirin that: It may take them longer than usual to stop bleeding; they may bruise and/or bleed more easily; they should report any unusual bleeding to their physician; they should tell their physician about any other medications they are taking, including prescription or over-the-counter omeprazole; they should inform physicians and dentists that they are taking Ridlor and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.
Effects on the Ability to Drive or Operate Machinery: No impairment of driving or psychometric performance was observed following clopidogrel administration.
Carcinogenicity, Mutagenicity & Impairment of Fertility: There is no evidence of tumorigenicity. Clopidogrel is not genotoxic. Clopidogrel has found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day (52 times the recommended human dose on a mg/m2 basis).
Use in pregnancy: Pregnancy Category B.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Ridlor should be used during pregnancy only if clearly needed.
Use in lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
Use in children: Safety and effectiveness in the pediatric population have not been established.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category B.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Ridlor should be used during pregnancy only if clearly needed.
Use in lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
Adverse Reactions
Hemorrhagic: Gastrointestinal hemorrhage, major noncerebral and noncerebral bleeding have been reported in studies.
Common adverse reactions reported in clinical studies are: Body as a Whole: General Disorders: Chest pain, accidental/inflicted injury, influenza-like symptoms, pain, fatigue. Asthenia, fever, hernia.
Cardiovascular Disorders: Edema, hypertension, cardiac failure.
Central and Peripheral Nervous System Disorders: Headache, dizziness, leg cramps, hypoesthesia, neuralgia, paraesthesia, vertigo.
Gastrointestinal System Disorders: Abdominal pain, dyspepsia, diarrhea, nausea, constipation.
Metabolic and Nutritional Disorders: Hypercholesterolemia, gout, hyperuricemia, increased non-protein nitrogen.
Musculoskeletal System Disorders: Arthralgia, back pain, arthritis, arthrosis.
Platelet, Bleeding and Clotting Disorders: Purpura, epistaxis, GI hemorrhage, hematoma and decreased platelet.
Psychiatric Disorders: Depression, anxiety, insomnia.
Respiratory System Disorders: Upper respiratory tract infection, dyspnea, rhinitis, bronchitis, coughing, pneumonia, sinusitis.
Skin and Appendage Disorders: Rash, pruritis, eczema, skin ulceration.
Urinary System Disorders: Urinary tract infection.
Vision Disorders: Cataract, conjunctivitis.
Red Blood Cell Disorders: Anemia.
Drug Interactions
Co-administration of clopidogrel with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hrs apart. There is no evidence that other drugs that reduce stomach acid eg, most H2 blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids interfere with the antiplatelet activity of clopidogrel.
Aspirin: In clinical studies, aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of aspirin 500 mg twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel. Clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. Clopidogrel and aspirin have been administered together for up to 1 year.
Heparin: Co-administration of heparin had no effect on inhibition of platelet aggregation induced by clopidogrel.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs and clopidogrel should be co-administered with caution.
Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine or both atenolol and nifedipine. The pharmacodynamic activity of clopidogrel was also not significantly influenced by the co-administration of phenobarbital or estrogen.
The pharmacokinetics of digoxin or theophylline was not modified by the co-administration of clopidogrel bisulfate.
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine and ticlopidine.
Storage
Store below 25°C in a dry place. Protect from light and moisture.
Shelf-Life: 24 months.
ATC Classification
B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
FC tab (pink, round-shaped, biconvex) 75 mg x 3 x 10's.
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