Cholesterol absorption inhibitor/HMG-CoA reductase inhibitor (statin)
Adjunct to diet to: Reduce elevated total cholesterol (total-C), LDL, apolipoprotein B, TGs, non-HDL, and to increase HDL in patients w/ primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia. Reduce elevated total-C and LDL in patients w/ homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.
Primary Hyperlipidemia/Mixed Hyperlipidemia
Primary (Heterozygous Familial and Nonfamilial) Hyperlipidemia/Mixed Hyperlipidemia:
Reduction of Elevated Total Cholesterol (Total-C), LDL, Apolipoprotein B, TGs, Non-HDL, and to Increase HDL:
Initial: 10mg/10mg or 10mg/20mg qpm
Usual: 10mg/10mg to 10mg/40mg qpm
Titrate: After initiation or titration, analyze lipid levels after ≥2 weeks and adjust dose, if needed
Patients Requiring Larger LDL Reduction (>55%):
Initial: 10mg/40mg qpm
Homozygous Familial Hypercholesterolemia
Adjunct to Other Lipid-Lowering Treatments (eg, LDL Apheresis) or if Such Treatments are Unavailable to Reduce Elevated Total-C and LDL:
Homozygous Familial Hypercholesterolemia:
Reduce dose by 50% if initiating lomitapide
Max: 10mg/20mg/day (or 10mg/40mg/day for patients who have previously taken simvastatin 80mg/day chronically [eg, for ≥12 months] w/o evidence of muscle toxicity)
Verapamil, Diltiazem, Dronedarone:
Max: 10mg/10mg qd
Amiodarone, Amlodipine, Ranolazine:
Max: 10mg/20mg qd
Bile Acid Sequestrants:
Take either ≥2 hrs before or ≥4 hrs after bile acid sequestrant
Chinese Patients Taking Lipid-Modifying Doses (≥1g/Day Niacin): Caution w/ doses >10mg/20mg/day; do not give 10mg/80mg dose
Chronic Kidney Disease (GFR <60mL/min/1.73m2):
Usual: 10mg/20mg qpm
Other Important Considerations
Use 10mg/80mg dose only in patients who have been taking 10mg/80mg dose chronically (eg, for ≥12 months) w/o evidence of muscle toxicity
If currently tolerating 10mg/80mg dose and needs to be initiated on drug that is contraindicated or is associated w/ a dose cap for simvastatin, switch to an alternative statin or statin-based regimen w/ less potential for drug-drug interaction
Do not titrate to 10mg/80mg, but place on alternative LDL lowering treatment that provides greater LDL lowering, if unable to achieve LDL goal w/ 10mg/40mg dose
Take qpm w/ or w/o food
Tab: (Ezetimibe/Simvastatin) 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mg
Concomitant administration of strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, or danazol. Active liver disease or unexplained persistent elevations in hepatic transaminases, women who are or may become pregnant, and nursing mothers.
Use doses >10mg/20mg w/ caution and close monitoring in patients w/ moderate to severe renal impairment. Myopathy (including immune-mediated necrotizing myopathy [IMNM]) and rhabdomyolysis reported; predisposing factors include advanced age (≥65 yrs of age), female gender, uncontrolled hypothyroidism, and renal impairment. Risk of myopathy, including rhabdomyolysis, is dose related and greater w/ simvastatin 80mg. D/C if markedly elevated CPK levels occur or myopathy is suspected/diagnosed, and temporarily withhold if experiencing an acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis. Increases in serum transaminases reported. Fatal and nonfatal hepatic failure (rare) reported; promptly interrupt therapy if serious liver injury w/ clinical symptoms and/or hyperbilirubinemia or jaundice occurs and do not restart if no alternate etiology found. Caution w/ history of liver disease, substantial alcohol consumption, and in elderly. Increases in HbA1c and FPG levels reported.
Headache, increased ALT, myalgia, URTI, diarrhea.
See Contraindications and Dose Modification. Due to the risk of myopathy/rhabdomyolysis, avoid grapefruit juice and caution w/ fenofibrates (eg, fenofibrate, fenofibric acid), lipid-modifying doses (≥1g/day) of niacin, colchicine, verapamil, diltiazem, dronedarone, lomitapide, amiodarone, amlodipine, and ranolazine. If coadministered w/ a fenofibrate, immediately d/c both agents if myopathy is suspected/diagnosed, and perform gallbladder studies/consider alternative lipid-lowering therapy if cholelithiasis is suspected. Simvastatin: May slightly elevate plasma digoxin concentrations; monitor patients taking digoxin when therapy is initiated. May potentiate effect of coumarin anticoagulants; determine PT before initiation and frequently during therapy. Ezetimibe: Reduced levels w/ cholestyramine; incremental LDL reduction may be reduced. Increased INR reported w/ warfarin.
PREGNANCY AND LACTATION
Category X, not for use in nursing.
MECHANISM OF ACTION
Ezetimibe: Cholesterol absorption inhibitor. Reduces blood cholesterol by inhibiting absorption of cholesterol by the small intestine. Targets the sterol transporter, Niemann-Pick C1-Like 1, which is involved in intestinal uptake of cholesterol and phytosterols. Simvastatin: HMG-CoA reductase inhibitor. Inhibits conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. Also reduces VLDL, TGs, and increases HDL.
Absorption: Simvastatin: Bioavailability (<5% as β-hydroxyacid). Distribution: Plasma protein binding: Ezetimibe: (>90%). Simvastatin: (95%). Metabolism: Ezetimibe: Small intestine, liver via glucuronide conjugation; ezetimibe-glucuronide (active metabolite). Simvastatin: Liver (extensive 1st pass), by hydrolysis via CYP3A4; β-hydroxyacid, 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene (major active metabolites). Elimination: Ezetimibe: Feces (78%, 69% ezetimibe), urine (11%, 9% ezetimibe-glucuronide); T1/2=22 hrs. Simvastatin: Feces (60%), urine (13%).
Assess for history of or active liver disease, unexplained persistent hepatic transaminase elevations, predisposing factors for myopathy, renal impairment, alcohol consumption, drug hypersensitivity, any other conditions where treatment is contraindicated or cautioned, pregnancy/nursing status, and possible drug interactions. Assess lipid profile and LFTs.
Monitor for signs/symptoms of myopathy (including IMNM), rhabdomyolysis, liver dysfunction, increases in HbA1c and FPG levels, and other adverse reactions. Monitor lipid profile, and LFTs. Check PT w/ coumarin anticoagulants.
Inform of benefits/risks of therapy. Advise to adhere to the National Cholesterol Education Program recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Inform about substances that should be avoided during therapy, and advise to discuss all medications, both Rx and OTC, w/ physician. Instruct to report promptly any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs/symptoms persist after discontinuation, or any symptoms that may indicate liver injury. Inform patients using the 10mg/80mg dose that the risk of myopathy, including rhabdomyolysis, is increased. Instruct women to use an effective method of birth control to prevent pregnancy while on therapy, to d/c therapy and call physician if pregnant, and not to breastfeed while on therapy.
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