Ezetimibe and Simvastatin

EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin tablet
Actavis Pharma, Inc.

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.

1.1 Primary Hyperlipidemia

Ezetimibe and simvastatin tablets are indicated for the reduction of 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 non-familial) hyperlipidemia or mixed hyperlipidemia.

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

Ezetimibe and simvastatin tablets are indicated for the reduction of elevated 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 Limitations of Use

No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Ezetimibe and simvastatin tablets have not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The usual dosage range is 10 mg/10 mg/day to 10 mg/40 mg/day. The recommended usual starting dose is 10 mg/10 mg/day or 10 mg/20 mg/day. Ezetimibe and simvastatin should be taken as a single daily dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10 mg/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate less than 60 mL/min/1.73 m²). After initiation or titration of ezetimibe and simvastatin, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.

2.2 Restricted Dosing for 10 mg/ 80 mg

Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10 mg/80-mg dose of ezetimibe and simvastatin should be restricted to patients who have been taking ezetimibe and simvastatin 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].

Patients who are currently tolerating the 10 mg/80-mg dose of ezetimibe and simvastatin 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.

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80-mg dose of ezetimibe and simvastatin, patients unable to achieve their LDL-C goal utilizing the 10 mg/40-mg dose of ezetimibe and simvastatin should not be titrated to the 10 mg/80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

2.3 Coadministration with Other Drugs

Patients taking Verapamil, Diltiazem, or Dronedarone

• The dose of ezetimibe and simvastatin should not exceed 10 mg/10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Amiodarone, Amlodipine or Ranolazine

• The dose of ezetimibe and simvastatin should not exceed 10 mg/20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Bile Acid Sequestrants

• Dosing of ezetimibe and simvastatin should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.5)].

2.4 Patients with Homozygous Familial Hypercholesterolemia

The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe and simvastatin 10 mg/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10 mg/80 mg (2.2)]. Ezetimibe and simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ezetimibe and simvastatin tablets should be reduced by 50% if initiating lomitapide. Ezetimibe and simvastatin tablets dosage should not exceed 10 mg/20 mg/day (or 10 mg/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.

2.5 Patients with Renal Impairment/Chronic Kidney Disease

In patients with mild renal impairment (estimated GFR greater than or equal to 60 mL/min/1.73 m²), no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate less than 60 mL/min/1.73 m² , the dose of ezetimibe and simvastatin is 10 mg/20 mg/day in the evening. In such patients, higher doses should be used with caution and close monitoring [see Warnings and Precautions (5.1); Clinical Pharmacology (12.3)].

2.6 Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

• Ezetimibe and simvastatin tablets 10 mg/10 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 511 on one side and on opposite side.

• Ezetimibe and simvastatin tablets 10 mg/20 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 512 on one side and on opposite side.

• Ezetimibe and simvastatin tablets 10 mg/40 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 513 on one side and on opposite side.

• Ezetimibe and simvastatin tablets 10 mg/80 mg are light tan, slightly speckled, capsule shaped, unscored, biconvex tablets debossed with 515 on one side and on opposite side.