SANOFI PLAVIX Clopidogrel Bisulfate Tablets For Arteriosclerosis 75mg*7

[Drug Name]
Generic Name: Clopidogrel Bisulfate Tablets
Trade Name: Plavix
Chinese Pinyin: LiusuanQinglvbigeleiPian

[Ingredients]
Chemical Name: Methyl ()-(S)-α-chlorophenyl-6,7-dichlorothiophene[3,2-C]piperidinyl-5(4H)-acetate bisulfate Chemical Structure: Molecular Formula: C₁₆H₁₆ClNO₂S·H₂SO₄ Molecular Weight: 419.9

[Appearance]
Plavix 75mg film-coated tablets are pink, round, biconvex, film-coated, and engraved with "75" on one side and "1171" on the other side.

[Indications]
Clopidogrel is indicated for the prevention of atherothrombotic events in the following patients: · Patients with a recent myocardial infarction (from a few days to less than 35 days), a recent ischemic stroke (from 7 days to less than 6 months), or patients with established peripheral arterial disease. Patients with Acute Coronary Syndrome: - Non-ST-segment Elevation Acute Coronary Syndrome (including unstable angina or non-Q-wave myocardial infarction), including patients undergoing percutaneous coronary intervention with stent implantation, in combination with aspirin. - For patients with ST-segment Elevation Acute Coronary Syndrome, in combination with aspirin, and may be used in conjunction with thrombolytic therapy. For more information, see [Clinical Trials].

[Dosage and Administration]
Adults and Elderly
The recommended dose of Plavix is ​​75 mg once daily.
For Patients with Acute Coronary Syndrome:
- Patients with Non-ST-segment Elevation Acute Coronary Syndrome (unstable angina or non-Q-wave myocardial infarction) should start with a single loading dose of clopidogrel 300 mg, followed by a continuous dose of 75 mg once daily (in combination with aspirin 75-325 mg/day). Due to the increased risk of bleeding with higher doses of aspirin, the recommended aspirin dose should not exceed 100 mg. The optimal duration of treatment has not yet been formally established. Clinical trial data support 12 months of treatment, with maximal efficacy observed after 3 months. (See [Clinical Trials])
-ST-segment elevation acute myocardial infarction: Start with a loading dose of clopidogrel, followed by 75 mg once daily, with aspirin, with or without a thrombolytic agent. Do not use a loading dose of clopidogrel in patients over 75 years of age. Combination therapy should be initiated as soon as possible after symptom onset and continued for at least 4 weeks. No studies have demonstrated the benefit of combined clopidogrel and aspirin treatment beyond 4 weeks (see [Clinical Trials]).
- The recommended dose is 75 mg daily for patients with a recent myocardial infarction (from a few days to less than 35 days), a recent ischemic stroke (from 7 days to less than 6 months), or established peripheral arterial disease. If a dose is missed:
- If a dose is missed within 12 hours of the usual dosing time: Patients should take a standard dose immediately and take the next dose at the usual time.
- If a dose is missed more than 12 hours after the usual dosing time: Patients should take the standard dose at the next usual dosing time without doubling the dose.
Children and Adolescents: Safety and efficacy in patients under 18 years of age have not been established.
Renal Impairment: There is limited experience in patients with renal impairment. (See [Precautions])
Hepatic Impairment: There is limited experience in patients with moderate hepatic impairment who have a bleeding tendency. (See [Precautions])
Dosage: Oral, with or without food.
Adverse Reactions: The safety of clopidogrel has been evaluated in over 42,000 patients, 9,000 of whom were treated for at least one year. Clinically relevant adverse reactions observed in CAPRIE, CURE, CLARITY, and COMMIT are discussed below. In the CAPRIE study, clopidogrel 75 mg/day was better tolerated than aspirin 325 mg/day. In this study, the overall tolerability of clopidogrel was similar to that of aspirin, regardless of age, gender, or race. In addition to clinical study experience, there are also spontaneous reports of adverse reactions. Bleeding was the most common adverse reaction in clinical studies and post-marketing reports, often reported within the first month of treatment. In the CAPRIE study, the overall incidence of bleeding events was 9.3% for patients receiving clopidogrel or aspirin. The incidence of serious events with clopidogrel was similar to that with aspirin. In the CURE study, patients who discontinued clopidogrel for more than 5 days before surgery experienced fewer major bleeding events within 7 days of coronary artery bypass grafting. Within 5 days of bypass grafting, patients who continued treatment had event rates of 9.6% with clopidogrel and 6.3% with placebo and aspirin, respectively. In the CLARITY study, clopidogrel plus aspirin was associated with an increase in overall bleeding compared with placebo plus aspirin. The incidence of major bleeding was similar between the two treatment groups. The results were consistent across subgroups divided by baseline characteristics, fibrinolytic type, or heparin treatment. In COMMIT, the overall rates of non-intracranial major hemorrhage and intracranial hemorrhage were low and similar in both groups. Clinical studies and spontaneous adverse reaction reports are shown in the table below. Adverse reaction incidence is defined as: common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000 to <1/1000); and very rare (<1/10,000). Within each organ group, adverse drug reactions are ranked in descending order of severity.

[Contraindications]
1. Hypersensitivity to the active substance or any component of this product. 2. Severe hepatic impairment. 3. Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage.

[Precautions]
Bleeding and Hematologic Abnormalities Due to the risk of bleeding and hematologic adverse reactions, blood counts and/or other appropriate tests should be immediately considered if clinical symptoms of bleeding occur during treatment. As with other antiplatelet drugs, clopidogrel should be used with caution in patients at increased risk of bleeding due to trauma, surgery, or other pathological conditions, as well as in patients receiving aspirin, nonsteroidal anti-inflammatory drugs, heparin, platelet glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, or thrombolytics. Patients should be closely followed for any signs of bleeding, including occult bleeding, particularly during the initial weeks of treatment and after cardiac intervention or surgery. The concomitant use of clopidogrel with warfarin is not recommended due to the potential for exacerbation of bleeding. In patients undergoing elective surgery, if antiplatelet therapy is not necessary, clopidogrel should be discontinued for at least 7 days prior to surgery. Clopidogrel prolongs bleeding time and should be used with caution in patients with bleeding disorders (particularly gastrointestinal and intraocular disorders). Patients should be informed that bleeding may take longer than usual to stop while taking clopidogrel (alone or with aspirin) and should report any unusual bleeding (location and duration) to their physician. Discontinuation of clopidogrel should be avoided. If discontinuation of clopidogrel is necessary, it should be resumed as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events. Thrombotic thrombocytopenic purpura (TTP) can rarely occur after clopidogrel administration, sometimes occurring shortly after initiation. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and associated neurological manifestations, renal impairment, or fever. TTP is a condition requiring urgent treatment, including plasma exchange. Due to a lack of data, clopidogrel is not recommended within 7 days of acute ischemic stroke. Pharmacogenetics of cytochrome P450 2C19 (CYP2C19): In patients with poor CYP2C19 metabolizers, the blood concentration of the active metabolite of clopidogrel at the recommended dose is reduced, resulting in a reduced antiplatelet effect. Methods are available for testing patients' CYP2C19 genotypes. Because clopidogrel is partially metabolized to its active metabolite by CYP2C19, the use of drugs that inhibit this enzyme may reduce the conversion of clopidogrel to its active metabolite. The clinical relevance of drug interactions is uncertain. Strong or moderate CYP2C19 inhibitors are not recommended. In patients with a recent transient ischemic event or ischemic stroke who are at increased risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone; however, it increases the risk of bleeding. Renal Impairment: Experience with clopidogrel in patients with renal impairment is limited; therefore, clopidogrel should be used with caution in these patients. Hepatic Impairment: Experience with clopidogrel in patients with moderate liver disease who may have a bleeding diathesis is limited; therefore, clopidogrel should be used with caution in these patients. The excipient Plavix contains lactose; patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not use this drug. Clopidogrel has not been shown to affect driving or operating machinery following administration. This medication contains hydrogenated castor oil, which may cause stomach upset and diarrhea.

[Special Use]
Precautions for Pediatric Use:
There is no experience with its use in children.

Precautions for Pregnancy and Lactation:
·During Pregnancy, because there are no clinical data available regarding its use during pregnancy, it is prudent to avoid its use in pregnant women. Animal studies have not shown direct or indirect evidence of adverse effects on pregnancy, embryonic/fetal development, delivery, or postnatal growth. (See [Pharmacology and Toxicology]) ·Studies in rats during lactation have shown that clopidogrel and/or its metabolites are excreted in breast milk, but it is unknown whether this drug is excreted in human breast milk. As a precaution, breastfeeding should be discontinued while taking Plavix. ·Fertility: Clopidogrel has not been shown to alter reproductive function in animal studies.

Precautions for Elderly People:
See [Dosage and Administration].

[Drug Interactions]
Oral Anticoagulants: Due to the potential for increased bleeding intensity, coadministration of Plavix with oral anticoagulants is not recommended (see Precautions). Although daily administration of 75 mg of clopidogrel does not alter the pharmacokinetics or international normalized ratio of S-warfarin in patients receiving long-term warfarin therapy, the combined use of warfarin and clopidogrel may increase the risk of bleeding due to their independent inhibition of hemostasis. Glycoprotein IIb/IIIa Antagonists: Caution should be exercised when clopidogrel and glycoprotein Ib/IIIa antagonists are coadministered. Acetylsalicylic acid (aspirin): Aspirin does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances aspirin's inhibitory effect on collagen-induced platelet aggregation. However, coadministration of 500 mg of aspirin twice daily for one day did not significantly increase the prolonged bleeding time associated with clopidogrel. Pharmacodynamic interactions between clopidogrel and aspirin may increase the risk of bleeding; therefore, caution should be exercised when these two drugs are coadministered (see Precautions). However, clopidogrel has been used in combination with aspirin for more than one year (see Pharmacological Properties). Heparin: Studies in healthy volunteers have shown that clopidogrel does not alter the coagulation effects of heparin, and no change in heparin dosage is necessary. Coadministration of heparin does not affect clopidogrel's inhibitory effect on platelet aggregation. Pharmacodynamic interactions between clopidogrel and heparin may increase the risk of bleeding, so careful observation should be exercised when the two drugs are used together (see Precautions). Thrombolytics: The safety of combined use of clopidogrel, rt-PA, and heparin has been evaluated in patients with recent myocardial infarction. The incidence of clinical bleeding was similar to that observed with combined use of rt-PA, heparin, and aspirin (see Adverse Reactions). Nonsteroidal anti-inflammatory drugs (NSAIDs): In clinical trials in healthy volunteers, the concomitant use of clopidogrel and naproxen increased occult gastrointestinal bleeding. Due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is unclear whether the concomitant use of clopidogrel with all NSAIDs increases the risk of gastrointestinal bleeding. Therefore, caution should be exercised when coadministering NSAIDs, including Cox-2 inhibitors, with clopidogrel (see Precautions). Other Concomitant Therapies: Because clopidogrel is partially metabolized to its active metabolite by CYP2C19, the use of drugs that inhibit this enzyme may result in decreased levels of the active metabolite and reduced clinical effectiveness. Coadministration with drugs that inhibit CYP2C19, such as omeprazole, is not recommended (see Precautions and Pharmacokinetics). Drugs that inhibit CYP2C19 include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, clopidogrel, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol. Proton pump inhibitors (PPIs): Omeprazole 80 mg once daily, taken with clopidogrel or 12 hours apart, decreased plasma concentrations of the active metabolite of clopidogrel by 45% (loading dose) and 40% (maintenance dose). These plasma concentrations result in a 39% reduction in platelet aggregation inhibition at the loading dose and 21% reduction at the maintenance dose, respectively. Esomeprazole and clopidogrel may experience similar interactions. Observational and clinical studies have shown inconsistent results regarding the impact of pharmacokinetic (PK)/pharmacodynamic (PD) interactions on clinical outcomes such as major cardiovascular events. Coadministration of clopidogrel with omeprazole or esomeprazole is not recommended (see [Precautions]). No significant decrease in the plasma concentrations of clopidogrel metabolites was observed following coadministration of pantoprazole and lansoprazole with clopidogrel. Coadministration of 80 mg of pantoprazole once daily decreased plasma concentrations of the active clopidogrel metabolite by 20% (loading dose) and 14% (maintenance dose), respectively, associated with a 15% and 11% decrease in mean platelet aggregation inhibition, respectively. These results suggest that coadministration of clopidogrel with pantoprazole is appropriate. There is no evidence that other drugs that inhibit gastric acid secretion, such as H2 blockers (excluding the CYP2C19 inhibitor cimetidine) or antacids, interfere with the antiplatelet activity of clopidogrel. Other Medications: The pharmacodynamic and pharmacokinetic interactions of clopidogrel with other concomitant medications have been investigated in numerous other clinical studies. No clinically significant pharmacodynamic interactions were observed when clopidogrel was used alone or concurrently with atenolol or nifedipine. Furthermore, coadministration of clopidogrel with phenobarbital, cimetidine, or estradiol had no significant effect on the pharmacodynamic activity of clopidogrel. Clopidogrel did not alter the pharmacokinetics of digoxin or theophylline. Antacids did not alter the absorption of clopidogrel. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely coadministered with clopidogrel. In addition to the aforementioned clear drug interaction information, interactions between clopidogrel and commonly used medications in patients with atherothrombotic disease have been investigated. However, in clinical trials, patients receiving clopidogrel concurrently received a variety of concomitant medications, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, lipid-lowering drugs, coronary vasodilators, antidiabetic drugs (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa receptor antagonists, with no clinically significant adverse interactions observed.

[Pharmacological Action]
Pharmacodynamic Properties: Therapeutic Classification: Platelet Aggregation Inhibitors, excluding Heparin, ATC Number: BO1AC-04. Clopidogrel is a prodrug, one of whose metabolites is a platelet aggregation inhibitor. Clopidogrel must be metabolized by the CPY450 enzyme to produce its active metabolite, which inhibits platelet aggregation. This active metabolite 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. Because binding is irreversible, the remaining lifespan of platelets exposed to clopidogrel (approximately 7-10 days) is affected, while the rate of recovery of normal platelet function is consistent with platelet turnover. Blocking the pathway that activates platelet aggregation induced by released ADP also inhibits platelet aggregation induced by agonists other than ADP. Because active metabolites are formed via CYP450 enzymes, some of which are polymorphic or inhibited by other drugs, not all patients will achieve adequate platelet inhibition. Repeated once-daily dosing of 75 mg of clopidogrel significantly inhibits ADP-induced platelet aggregation starting on day 1, with increasing inhibition reaching steady-state within 3-7 days. At steady-state, the mean inhibition level with daily 75 mg of clopidogrel ranges from 40% to 60%, and platelet aggregation and bleeding time generally return to baseline within 5 days after discontinuation of treatment. Toxicology studies: In preclinical studies in rats and baboons, the most common reaction was hepatic changes. These hepatic changes are due to the drug's effects on hepatic metabolizing enzymes at a dose 25 times the exposure achieved in humans with a 75 mg/day dose of clopidogrel. Clopidogrel has no effect on hepatic metabolizing enzymes at therapeutic doses in humans. Very high doses of clopidogrel have been shown to affect gastric tolerance (gastritis, gastric ulcers, and/or vomiting) in rats and baboons. No evidence of carcinogenicity has been found in mice and rats at doses up to 77 mg/kg daily for 78 weeks and in rats for 104 weeks. This dose produces plasma concentrations 25 times greater than the recommended human dose (75 mg/day). Clopidogrel has been shown to be non-genotoxic in a series of in vivo and in vitro studies. Clopidogrel had no effect on fertility in female and male rats and was non-teratogenic in rats and rabbits. Clopidogrel administration to lactating rats slightly delayed pup development. Pharmacokinetic studies have shown that clopidogrel and/or its metabolites are excreted in breast milk. Therefore, direct (mild toxicity) or indirect (unpleasant taste) effects of clopidogrel cannot be ruled out.

Storage: No special storage requirements.
Strength: 75mg
Packaging: 75mg x 7 tablets
Expiry Period: 36 months
Approval Number: National Medical Products Approval No. HJ20171237/National Medical Products Approval No. HJ20171238