Usual Adult Dose for Hyperlipidemia

Doses expressed as EZETIMIBE-SIMVASTATIN:
Initial dose: 10/10-mg or 10/20-mg orally once a day

• May initiate at 10/40-mg orally once a day if a larger reduction in LDL-C is needed (e.g., greater than 55%)

Maintenance dose: 10/10-mg to 10/40-mg orally once a day

RESTRICTED DOSING: The 10/80-mg dose should only be used in patients who have tolerated this drug for 12 months or more without evidence of muscle toxicity; patients unable to achieve LDL-C goal with the 10/40-mg dose should not be titrated to the 10/80-mg dose, but should be placed on alternative LDL-C lowering therapies

Comments:

• Patients should be placed on a standard cholesterol-lowering diet before initiating therapy and should continue this diet during treatment; doses should be individualized according to patients' goals and response.
• This drug is used to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.
• Due to increased risk of myopathy and rhabdomyolysis, use of the 10/80-mg dose is restricted as described above; patients tolerating the 10/80-mg dose who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction.

Use: For the treatment of primary hyperlipidemia as an adjunct to diet when response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate.

Usual Adult Dose for Homozygous Familial Hypercholesterolemia

Doses expressed as EZETIMIBE-SIMVASTATIN:
Maintenance dose: 10/40-mg orally once a day

RESTRICTED DOSING: The 10/80-mg dose should only be used in patients who have tolerated this drug for 12 months or more without evidence of muscle toxicity; patients unable to achieve LDL-C goal with the 10/40-mg dose should not be titrated to the 10/80-mg dose, but should be placed on alternative LDL-C lowering therapies

Comments:

• Due to increased risk of myopathy and rhabdomyolysis, use of the 10/80-mg dose is restricted as described above; patients tolerating the 10/80-mg dose who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction.

Use: As an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Usual Pediatric Dose for Hyperlipidemia

Doses expressed as EZETIMIBE-SIMVASTATIN:
10 years or older:
Initial dose: 10/10-mg or 10/20-mg orally once a day
Maintenance dose: 10/10-mg to 10/40-mg orally once a day

Comments:

• Patients should be placed on a standard cholesterol-lowering diet before initiating therapy and should continue this diet during treatment; doses should be individualized according to patients' goals and response.
• This drug is used to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.
• Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied

in patients younger than 10 years; additionally, this combination has not been studied in premenarchal girls.

Use: For the treatment of primary hyperlipidemia as an adjunct to diet when response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate.

Usual Pediatric Dose for Homozygous Familial Hypercholesterolemia

Doses expressed as EZETIMIBE-SIMVASTATIN:
10 years or older:
Maintenance dose: 10/40-mg orally once a day

Comments:

• Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in patients younger than 10 years; additionally, this combination has not been studied in premenarchal girls.

Use: As an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Renal Dose Adjustments

eGFR 60 mL/min/1.73 m2 or greater: No dosage adjustment recommended
eGFR less than 60 mL/min/1.73 m2: Maintenance dose: ezetimibe 10 mg-simvastatin 20 mg orally once a day in the evening; doses higher than this should be used with caution and close monitoring

Liver Dose Adjustments

Active liver disease or unexplained transaminase elevations: Contraindicated

• Substantial alcohol ingestion and/or past history of liver disease: Use with caution

Interrupt therapy if serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develop; investigate cause, if an alternative etiology is not found, do not restart

Dose Adjustments

Restricted Use of ezetimibe 10 mg-simvastatin 80 mg/day:

• Only for use in patients who have tolerated this dose chronically (e.g., for 12 months or more) without evidence of muscle toxicity
• If a patient on ezetimibe 10 mg-simvastatin 80 mg/day needs to initiate an interacting drug (one that will increase simvastatin concentrations); simvastatin should be switched to an alternative statin with less potential for drug-drug interaction.

Chinese Patients:

• Coadministration with lipid-modifying doses (1 g/day or greater) of niacin-containing products is not recommended due to increased incidence of myopathy

DRUG INTERACTIONS:

• Coadministration of Strong CYP450 3A4 Inhibitors: Contraindicated
• Coadministration of gemfibrozil, cyclosporine, or danazol: Contraindicated
• Coadministration with verapamil, diltiazem, or dronedarone: ezetimibe/simvastatin dose should not exceed 10/10-mg
• Coadministration with amiodarone, amlodipine, or ranolazine: ezetimibe/simvastatin dose should not exceed 10/20-mg
• Coadministration with lomitapide: For patients with homozygous familial hyperlipidemia, reduce simvastatin dose by 50%
• Coadministration with daptomycin: Temporarily suspend ezetimibe-simvastatin
• Avoid coadministration of grapefruit juice

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC):

• Normal Function SLCO1B1 Phenotype: Follow prescribed dosing guidelines and adjust doses based on disease-specific guidelines
• Intermediate and Low Function SLCO1B1 Phenotype: Initiate therapy with a lower dose or consider an alternative statin (e.g. pravastatin or rosuvastatin); consider routine CK monitoring

Precautions

CONTRAINDICATIONS:

• Hypersensitivity to active substances or any product excipient
• Pregnancy, or woman who may become pregnant
• Lactation
• Active liver disease or unexplained persistent elevations in serum transaminases
• Concomitant administration of strong CYP450 3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and cobicistat-containing products)
• Concomitant administration of gemfibrozil, cyclosporine, or danazol

Safety and effectiveness have not been established in pediatric patients less than 10 years of age.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally once a day in the evening
• Bile acid sequestrants should not be taken within 2 hours before or 4 hours after taking this drug

General:

• Therapy with lipid-altering agents should be one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
• No incremental benefit of this drug on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
• This drug has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

Monitor:

• Obtain liver function tests prior to initiating therapy and as clinically indicated
• Monitor lipid levels 2 weeks after initiation or titration
• Periodic creatine kinase determinations may be considered to monitor for myopathy, however, there is no assurance that such monitoring will prevent myopathy
• Patients with moderate to severe renal impairment should be closely monitored
• Chinese patients may be a higher risk of myopathy and should be closely monitored

Patient advice:

• Patients should be instructed to read the US FDA-approved patient labeling (Patient Information).
• Patients should be advised to adhere to a diet and exercise program.
• Patients should be instructed to discuss all medication use including herbal products and over the counter products with their healthcare professional; patients should be advised to avoid grapefruit juice during therapy.
• Patients should understand the risk of myopathy and should be instructed to report unexplained muscle pain promptly, especially if accompanied by malaise or fever.
• Patients should be instructed to report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
• Women of childbearing potential should be advised to use an effective method of birth control.