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辛伐他汀片(舒降之) USPI

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辛伐他汀片(舒降之) USPI 9876253 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZOC...
辛伐他汀片(舒降之) USPI
9876253 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZOCOR safely and effectively. See full prescribing information for ZOCOR. ZOCOR (simvastatin) Tablets Initial U.S. Approval: 1991 ---------------------------RECENT MAJOR CHANGES --------------------------- Dosage and Administration Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products (2.5) 03/2010 Warnings and Precautions Myopathy/Rhabdomyolysis (5.1) 03/2010 ----------------------------INDICATIONS AND USAGE ---------------------------- ZOCOR® is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: • Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. (1.1) • Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (1.2) • Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta­ lipoproteinemia. (1.2) • Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. (1.2) • Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. (1.2, 1.3) Limitations of Use ZOCOR has not been studied in Fredrickson Types I and V dyslipidemias. (1.4) ----------------------- DOSAGE AND ADMINISTRATION------------------------ • Dose range is 5-80 mg/day. (2.1) • Recommended usual starting dose is 20-40 mg once a day in the evening. (2.1) • Recommended starting dose for patients at high risk of CHD is 40 mg/day. (2.1) • Adolescents (10-17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. (2.3) --------------------- DOSAGE FORMS AND STRENGTHS --------------------- Tablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg (3) -------------------------------CONTRAINDICATIONS ------------------------------- • Hypersensitivity to any component of this medication. (4, 6.2) • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. (4, 5.2) • Women who are pregnant or may become pregnant. (4, 8.1) • Nursing mothers. (4, 8.3) ------------------------WARNINGS AND PRECAUTIONS------------------------ • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain CYP3A4 inhibitors, gemfibrozil, cyclosporine, danazol, amiodarone, and verapamil. Predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. (5.1, 8.5, 8.6) • Patients should be advised to report promptly any symptoms of myopathy. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. (5.1) • Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. Patients titrated to the 80-mg dose should receive more frequent liver function tests than patients on lower doses. (5.2) ------------------------------ ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., Inc. at 1-877-888-4231 or FDA at 1-800-FDA- 1088 or www.fda.gov/medwatch -------------------------------DRUG INTERACTIONS ------------------------------- Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4) Interacting Agents Prescribing Recommendations Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily Amiodarone, verapamil Do not exceed 20 mg simvastatin daily Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily) • Coumarin anticoagulants: Concomitant use with ZOCOR prolongs INR. Achieve stable INR prior to starting ZOCOR. Monitor INR frequently until stable upon initiation or alteration of ZOCOR therapy. (7.7) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- • Severe renal impairment: patients should be started at 5 mg/day and be closely monitored. (2.4, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 03/2010 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 1.1 Reductions in Risk of CHD Mortality and Cardiovascular 2.1 Recommended Dosing Events 2.2 Patients with Homozygous Familial Hypercholesterolemia 1.2 Hyperlipidemia 2.3 Adolescents (10-17 years of age) with Heterozygous Familial 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia Hypercholesterolemia (HeFH) 2.4 Patients with Renal Impairment 1.4 Limitations of Use ZOCOR® (simvastatin) 9876253 2.5 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day 8.6 Renal Impairment Niacin) of Niacin-Containing Products 8.7 Hepatic Impairment 2.6 Coadministration with Other Drugs 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Myopathy/Rhabdomyolysis 12.2 Pharmacodynamics 5.2 Liver Dysfunction 12.3 Pharmacokinetics 6 ADVERSE REACTIONS 13 NONCLINICAL TOXICOLOGY 6.1 Clinical Trials Experience 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6.2 Post-Marketing Experience 13.2 Animal Toxicology and/or Pharmacology 7 DRUG INTERACTIONS 14 CLINICAL STUDIES 7.1 CYP3A4 Interactions 14.1 Clinical Studies in Adults 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When 14.2 Clinical Studies in Adolescents Given Alone 16 HOW SUPPLIED/STORAGE AND HANDLING 7.3 Cyclosporine or Danazol 17 PATIENT COUNSELING INFORMATION 7.4 Amiodarone or Verapamil 17.1 Muscle Pain 7.5 Niacin 17.2 Liver Enzymes 7.6 Digoxin 17.3 Pregnancy 7.7 Coumarin Anticoagulants 17.4 Breastfeeding 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy *Sections or subsections omitted from the full prescribing information 8.3 Nursing Mothers are not listed. 8.4 Pediatric Use 8.5 Geriatric Use FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, ZOCOR1 can be started simultaneously with diet. 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, ZOCOR is indicated to: • Reduce the risk of total mortality by reducing CHD deaths. • Reduce the risk of non-fatal myocardial infarction and stroke. • Reduce the need for coronary and non-coronary revascularization procedures. 1.2 Hyperlipidemia ZOCOR is indicated to: • Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb). • Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia). • Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia). • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) ZOCOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: 1. LDL cholesterol remains ≥190 mg/dL; or 2. LDL cholesterol remains ≥160 mg/dL and 1 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright © 1999-2008 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved 2 ZOCOR® (simvastatin) 9876253 • There is a positive family history of premature cardiovascular disease (CVD) or • Two or more other CVD risk factors are present in the adolescent patient. The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined. 1.4 Limitations of Use ZOCOR has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The dosage range is 5-80 mg/day. In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet. The recommended usual starting dose is 20 to 40 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. 2.2 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 2.3 Adolescents (10-17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines2 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more. 2.4 Patients with Renal Impairment Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when ZOCOR is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 2.5 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products Because of an increased risk for myopathy, caution should be used when treating Chinese patients with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1).] 2.6 Coadministration with Other Drugs Concomitant Lipid-Lowering Therapy • ZOCOR may be used concomitantly with bile acid sequestrants. • Combination therapy with gemfibrozil increases simvastatin exposure. Therefore, if ZOCOR is used in combination with gemfibrozil, the dose of ZOCOR should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. Patients taking Cyclosporine or Danazol • ZOCOR therapy should begin with 5 mg/day and should not exceed 10 mg/day [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. 2 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992. 3 ZOCOR® (simvastatin) 9876253 Patients taking Amiodarone or Verapamil • The dose of ZOCOR should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS • Tablets ZOCOR 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and ZOCOR 5 on the other. • Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other. • Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other. • Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other. • Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other. 4 CONTRAINDICATIONS ZOCOR is contraindicated in the following conditions: • Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)]. • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)]. • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with ZOCOR during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ZOCOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with ZOCOR should not breastfeed their infants [see Use in Specific Populations (8.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Myopathy/Rhabdomyolysis Simvastatin, like other statins, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), uncontrolled hypothyroidism, and renal impairment. As with other statins, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with ZOCOR with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 4 ZOCOR® (simvastatin) 9876253 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes. Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). The use of ZOCOR concomitantly with these CYP3A4 inhibitors should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with ZOCOR should be suspended during the course of treatment. [See Drug Interactions (7).] The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: gemfibrozil, other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), cyclosporine, danazol, amiodarone, or verapamil. Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone. Cases of myopathy/rhabdomyolysis have been observed with s
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