Atorvastatin + Ezetimibe

Indications

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.

Primary Hyperlipidemia: This tablet is 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.

Homozygous Familial Hypercholesterolemia (HoFH): This tablet is 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.

Pharmacology

Atorvastatin: In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.

Ezetimibe
: Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins.

Dosage & Administration

The dosage range is 10/10 mg to 80/20 mg daily. The recommended starting dose is 10/10 mg or 20/10 mg daily. This can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 40/10 mg daily. After initiation and/or upon titration of this medicine, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.

Patients with Homozygous Familial Hypercholesterolemia: The dosage in patients with homozygous familial hypercholesterolemia is 40/10 mg or 80/10 mg daily. This should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Patients with Hepatic Impairment: This is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.

Patients with Renal Impairment: A history of renal impairment may be a risk factor for statin-associated myopathy. These patients need closer monitoring for skeletal muscle effects. In patients with renal impairment, no dosage adjustment is necessary.

Interaction

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole). The coadministration of this combination with cyclosporine should be avoided. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of this combination with gemfibrozil should be avoided. The risk of skeletal muscle effects may be enhanced when this combination is used in combination with niacin. Patients taking digoxin should be monitored appropriately. The increase in AUC values for norethindrone and ethinyl estradiol should be considered when selecting an oral contraceptive for a woman taking this combination. Caution should be exercised when prescribing this combination with colchicine. If this combination is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

Contraindications

Active liver disease or unexplained persistent elevations of hepatic transaminase levels. Hypersensitivity to any component of this preparation.

Side Effects

Common side effects are rhabdomyolysis, myopathy, liver enzyme abnormalities, myalgia, abdominal pain, increased hepatic enzymes.

Pregnancy & Lactation

Pregnancy Category X. This tablet is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk.

Precautions & Warnings

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing this combination with colchicine. This combination therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis.

Liver Enzymes: It is recommended that liver enzyme tests be obtained prior to initiating therapy with this combination and repeated as clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with this combination, promptly interrupt therapy. If an alternate etiology is not found, do not restart this combination. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of this combination.

Endocrine Function: Caution should be exercised if this combination is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in Special Populations

Pediatric Use: Safety and effectiveness have not been established in pediatric patients.

Geriatric Use: In geriatric patients, no dosage adjustment is necessary.

Overdose Effects

No specific treatment of overdosage can be recommended. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Therapeutic Class

Other lipid regulating drugs

Storage Conditions

Do not store above 30°C. Keep in a dry place. Protect from light and keep out of the reach of children.