Recommended Dosing

The usual dosage range is 5 to 40 mg/day. FLOLIPID should be taken in the evening on an empty stomach [see Clinical Pharmacology (12.3)] . Shake bottle well for at least 20 seconds before using. In patients with CHD or at high risk of CHD, FLOLIPID can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day. 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. It is recommended to use FLOLIPID 40 mg/5 mL for dosages greater than or equal to 40 mg. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

Patients should be advised to measure FLOLIPID with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Restricted Dosing for 80 mg

Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of an 80-mg dose of FLOLIPID should be restricted to patients who have been taking FLOLIPID 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 an 80-mg dose of FLOLIPID 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 with less potential for the drug-drug interaction.

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

Coadministration with Other Drugs

Patients taking Verapamil, Diltiazem, or Donedarone

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

Patients with Homozygous Familial Hypercholesterolemia

The recommended dosage is 40 mg/day in the evening on an empty stomach [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. FLOLIPID 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 FLOLIPID should be reduced by 50% if initiating lomitapide. FLOLIPID dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken 80 mg/day of simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.

Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia

The recommended usual starting dose is 10 mg once a day in the evening on an empty stomach. The recommended dosing range is 10 to 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 Guidelines 1 and Clinical Studies (14.2)] . Adjustments should be made at intervals of 4 weeks or more.

1

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

Patients with Renal Impairment

Because simvastatin 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 FLOLIPID 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)].

Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products

Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses 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).]