Primary Hypercholesterolemia and Mixed Dyslipidemia
Use alone or in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia. Effects on cardiovascular morbidity and mortality not established.
Use in fixed combination with simvastatin (i.e., Vytorin®) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia.
Use in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia. Effects on cardiovascular morbidity and mortality not established. Use with a fibric acid derivative other than fenofibrate not studied and currently not recommended. (See Specific Drugs under Interactions.)
Produces negligible increases in HDL-cholesterol concentrations.
Drug therapy is not a substitute for but an adjunct to nondrug therapies and measures (e.g., dietary management, weight control, physical activity, management of potentially contributory disease), which should be continued when drug therapy is initiated.
Homozygous Familial Hypercholesterolemia
Use in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDLapheresis) or when such therapies are not available.
Effects in patients currently undergoing LDL apheresis compared with those in patients not undergoing the procedure not established. Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) not established.
Adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia.
Reductions in sitosterol and campesterol concentrations were consistent between patients receiving ezetimibe with or without bile acid sequestrants.
Effect of reducing plasma concentrations of sitosterol and campesterol on cardiovascular morbidity and mortality not established.
Dosage and Administration
General
Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug.
Monitoring during Antilipemic Therapy
Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.
Administration
Oral Administration
Administer orally without regard to meals.
Combination therapy with a statin or fenofibrate: May administer ezetimibe at same time as the statin or fenofibrate, in accordance with recommended dosing schedule for these drugs.
Combination therapy with a bile acid sequestrant: Administer ≥2 hours before or ≥4 hours after bile acid sequestrant.
Ezetimibe/simvastatin fixed-combination preparation: Administer orally in the evening without regard to meals.
Dosage
Pediatric Patients
Dyslipidemias
Primary Hypercholesterolemia and Mixed Dyslipidemia
Oral
Children ≥10 years of age: 10 mg once daily.
Homozygous Familial Hypercholesterolemia
Oral
Children ≥10 years of age: 10 mg once daily.
Homozygous Familial Sitosterolemia
Oral
Children ≥10 years of age: 10 mg once daily.
Adults
Dyslipidemias
Primary Hypercholesterolemia and Mixed Dyslipidemia
Oral
10 mg once daily.
Ezetimibe/simvastatin fixed combination (Vytorin®): Initially, ezetimibe 10 mg/simvastatin 20 mg once daily in the evening. In patients requiring less aggressive LDL-cholesterol lowering, consider dosage of ezetimibe 10 mg/simvastatin 10 mg once daily. In patients requiring LDL-cholesterol reductions ≥55%, may initiate therapy with ezetimibe 10 mg/simvastatin 40 mg once daily. Determine serum cholesterol concentrations ≥2 weeks after initiation of therapy and adjust dosage as needed. Usual maintenance dosage range is ezetimibe 10 mg and simvastatin 10–80 mg once daily.
Homozygous Familial Hypercholesterolemia
Oral
10 mg once daily.
Ezetimibe/simvastatin fixed combination (Vytorin®): Ezetimibe 10 mg/simvastatin 40 mg or ezetimibe 10 mg/simvastatin 80 mg once daily in the evening. Use as adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Homozygous Familial Sitosterolemia
Oral
10 mg once daily.
Special Populations
Hepatic Impairment
Ezetimibe
No dosage adjustment needed in patients with mild hepatic impairment. Do not use in patients with moderate or severe hepatic impairment.
Ezetimibe/Simvastatin Fixed Combination
No dosage adjustment needed in patients with mild hepatic impairment. Do not use in patients with moderate or severe hepatic impairment.
Renal Impairment
Ezetimibe
No dosage adjustment needed in patients with renal impairment.
Ezetimibe/Simvastatin Fixed Combination
No dosage adjustment needed in patients with mild to moderate renal impairment. Do not use in patients with severe renal impairment unless patient has already tolerated treatment with a simvastatin dosage ≥5 mg daily; in such patients, exercise caution and monitor closely.
Geriatric Patients
Ezetimibe
No dosage adjustment needed in geriatric patients (≥65 years of age).
Ezetimibe/Simvastatin Fixed Combination
No dosage adjustment needed in geriatric patients (≥65 years of age).
Cautions
Contraindications
Known hypersensitivity to ezetimibe or any ingredient in the formulation.
Transient elevations in serum aminotransferase (transaminase) concentrations (i.e., AST, ALT) >3 times the ULN reported. Elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy. Hepatitis reported during postmarketing surveillance; however, causal relationship not established.
When used with a statin, perform liver function tests at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin.
Musculoskeletal Effects
Marked (>10 times ULN) elevations of CK (CPK) reported. Elevations in CK concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.
Myalgia, myopathy (i.e., unexplained muscle pain, tenderness, or weakness and CK concentration >10 times ULN), and/or rhabdomyolysis reported during postmarketing experience. Most cases of rhabdomyolysis occurred in patients receiving statin therapy prior to initiating ezetimibe; however, rhabdomyolysis also reported very rarely following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).
Immediately discontinue ezetimibe and any concomitant statin or fibric acid derivative (e.g., gemfibrozil, fenofibrate) if myopathy is diagnosed or suspected.
General Precautions
Combination Therapy with Statins or Fenofibrate
When used in combination or fixed combination with a statin or fenofibrate, consult prescribing information of specific statin or fenofibrate for detailed information on usual cautions, precautions, and contraindications of these drugs.
Risk of Cancer
Fixed combination of ezetimibe and simvastatin (Vytorin®) reported in one trial (Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] study) to be possibly associated with an increased risk of cancer. Preliminary results of this study in approximately 1900 patients revealed a higher incidence of cancer and fatal cancer in patients receiving fixed-combination preparation (11.1 and 4.1%, respectively) compared with those receiving placebo (7.5 and 2.5%, respectively). However, interim data from 2 ongoing randomized trials evaluating >20,000 patients with chronic kidney disease or acute coronary syndrome showed no increased risk of cancer following use of fixed-combination preparation. FDA will review final study report of the SEAS trial to assess additional safety data and provide insight into the risk of cancer.
Specific Populations
Pregnancy
Category C.
Fixed combination of ezetimibe and simvastatin (Vytorin®): Category X (due to simvastatin component).
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Use in nursing women not recommended unless potential benefits justify possible risks to infant.
Pediatric Use
Safety and efficacy not established in children <10 years of age; use not recommended in these children.
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.
Hepatic Impairment
Safety of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently not known; use not recommended in such patients.
Ezetimibe in combination with a statin: Upper respiratory tract infection, headache, back pain, influenza, myalgia, abdominal pain, sinusitis, arthralgia, diarrhea, pharyngitis, pain in extremity, chest pain, dizziness.
Adverse effects associated with combination therapy generally similar to those reported with monotherapy. However, elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.
Interactions
Does not inhibit or induce CYP1A2, 2D6, 2C8, 2C9, or 3A4. Pharmacokinetic interactions with drugs metabolized by these isoenzymes (e.g., caffeine, dextromethorphan, tolbutamide, IV midazolam) unlikely.
No formal drug interaction studies performed with fixed-combination preparation. When using this preparation, consider the drug interactions associated with simvastatin.
Increased ezetimibe and cyclosporine concentrations; possible greater ezetimibe exposure in patients with severe renal impairment
Increased risk of myopathy/rhabdomyolysis when used concomitantly with fixed-combination preparation of ezetimibe and simvastatin (particularly at higher dosages)
Use concomitantly with caution; monitor cyclosporine concentrations with concomitant use
Do not administer fixed-combination preparation unless patient has already tolerated simvastatin dosage ≥5 mg daily. If used concomitantly, dosage of fixed-combination preparation should not exceed ezetimibe 10 mg/simvastatin 10 mg once daily
Ezetimibe associated with increased cholesterol excretion in gall bladder bile; fibric acid derivatives may increase cholesterol excretion in bile, leading to cholelithiasisCholecystectomy reported
Very rare postmarketing reports of myopathy/rhabdomyolysis with concomitant use
Concomitant use with a fibric acid derivative other than fenofibrate currently not recommended (see Musculoskeletal Effects under Cautions)
If concomitant use with gemfibrozil cannot be avoided, manufacturer states that dosage of fixed-combination preparation should not exceed ezetimibe 10 mg/simvastatin 10 mg once daily
If cholelithiasis is suspected during concomitant use with fenofibrate, perform gallbladder studies and consider alternative antilipemic therapy
Pharmacokinetic and pharmacologic interaction unlikely based on one study
Increased INR with combined ezetimibe-warfarin therapy reported during post-marketing experience; most patients also on other drugs
Monitor INR appropriately if ezetimibe is initiated in a patient receiving warfarin
Pharmacokinetics
Absorption
Bioavailability
Approximately 93% of dose is absorbed systemically following oral administration.
Bioavailability is variable. Absolute bioavailability cannot be determined because ezetimibe is virtually insoluble in aqueous media suitable for injection. Ezetimibe/simvastatin fixed-combination preparation is bioequivalent to corresponding dosages of the individual components.
Peak plasma concentrations attained within 4–12 hours following oral administration.
Onset
Maximal or near-maximal reductions in serum lipoprotein and apolipoprotein concentrations achieved within 2 weeks.
Duration
Reductions in serum lipoprotein and apolipoprotein concentrations maintained during continued therapy.
Food
Food (high-fat or nonfat meals) does not affect extent of absorption. High-fat meals associated with increased peak plasma concentrations.
Special Populations
Increased plasma concentrations in geriatric individuals (≥65 years of age), in patients with hepatic impairment, and in patients with severe renal impairment. (See Special Populations under Dosage and Administration.)
No differences in pharmacokinetic parameters between blacks and Caucasians. Studies in Asian individuals indicated similar pharmacokinetics as observed in Caucasian individuals.
Distribution
Plasma Protein Binding
>90%.
Elimination
Metabolism
Rapidly metabolized principally in small intestine and liver to ezetimibe glucuronide (active). Ezetimibe and ezetimibe glucuronide constitute approximately 10–20% and 80–90%, respectively, of total drug in plasma.
Possible enterohepatic recycling.
Elimination Route
Excreted in feces (78%) and urine (11%) within 10 days after dosing. Major component in feces is ezetimibe (69% of administered dose); major component in urine is ezetimibe glucuronide (9% of administered dose).
Half-life
Approximately 22 hours for both ezetimibe and ezetimibe glucuronide.
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C). Protect from moisture.
Ezetimibe/simvastatin fixed-combination preparation: Well-closed containers at 20–25°C. When subdividing contents of a large-quantity container, repackage into tightly closed, light-resistant containers; entire contents must be repackaged immediately upon opening.
Actions
Localizes at brush border of small intestine and inhibits absorption of cholesterol, resulting in decreased delivery of intestinal cholesterol to liver. Intestinal absorption of cholesterol reduced by approximately 54% in a limited number of patients with hypercholesterolemia.
Has been shown to reduce concentrations of noncholesterol sterols, including sitosterol and campesterol.
Does not appear to inhibit hepatic cholesterol synthesis or increase bile acid excretion. Does not appear to inhibit absorption of triglycerides, fatty acids, bile acids, progesterone, or ethyl estradiol. No clinically relevant effects on plasma concentrations of fat-soluble vitamins A, D, and E; does not appear to impair adrenocortical steroid production.
Cholesterol-lowering effects of ezetimibe and statins or of ezetimibe and fenofibrate are additive.
Advice to Patients
Importance of adherence to prescribed directions for use, particularly when used concomitantly with other antilipemic agents.
Importance of adherence to National Cholesterol Education Program (NCEP)’s dietary recommendations.
Risk of myopathy; importance of promptly informing clinicians of unexplained muscle pain, weakness, or tenderness.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 11/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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