Ezetimibe

EZETIMIBE- ezetimibe tablet
ScieGen Pharmaceuticals 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

​ Monotherapy

​ Ezetimibe, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and nonhigh-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.

​ Combination Therapy with HMG-CoA Reductase Inhibitors (Statins)

​ Ezetimibe, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia.

​ Combination Therapy with Fenofibrate

​ Ezetimibe, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.Ezetimibe, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

The combination of ezetimibe and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

1.3 Homozygous Sitosterolemia

Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

1.4 Limitations of Use

The effect of ezetimibe on cardiovascular morbidity and mortality has not been determined.

Ezetimibe has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

The recommended dose of ezetimibe is 10 mg once daily.

Ezetimibe can be administered with or without food.

2.2 Concomitant Lipid-Lowering Therapy

Ezetimibe tablets may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.

2.3 Co-Administration with Bile Acid Sequestrants

Dosing of ezetimibe should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)] .

2.4 Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4)] .

2.5 Patients with Renal Impairment

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

When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m 2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring [see Use in Specific Populations (8.6)] .

2.6 Geriatric Patients

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

3 DOSAGE FORMS AND STRENGTHS

10 mg tablets are white to off-white, capsule shaped tablets debossed with “SG” on one side and “379” on the other side.

4 CONTRAINDICATIONS

Ezetimibe is contraindicated in the following conditions:

• The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
• Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. [See Use in Specific Populations (8.1)].
• Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ezetimibe treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3)].
• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe [see Adverse Reactions (6.2)] .

5 WARNINGS AND PRECAUTIONS

5.1 Use with Statins or Fenofibrate

Concurrent administration of ezetimibe with a specific statin or fenofibrate should be in accordance with the product labeling for that medication.

5.2 Liver Enzymes

In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥ 3 x the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).

In controlled clinical combination studies of ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥ 3 X ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ezetimibe is co-administered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥ 3 x ULN persist, consider withdrawal of ezetimibe and/or the statin.

5.3 Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) > 10 x ULN was 0.2% for ezetimibe vs 0.1% for placebo, and 0.1% for ezetimibe co-administered with a statin vs 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (> 65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.

In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level > 10 x the ULN indicates myopathy.