Mechanism of Action:
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine.
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.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide.
Maximum plasma atorvastatin concentrations after oral administration occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. Atorvastatin is ≥98% bound to plasma proteins. Atorvastatin is likely to be secreted in human milk. Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism.
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.
Ezerva is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apo lipoprotein 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):
Ezerva 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.
Limitations of Use:
No incremental benefit of Ezerva on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. Ezerva has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
- Active liver disease or unexplained persistent elevations of hepatic transaminase levels.
- Hypersensitivity to any component of the product.
- Women who are pregnant or may become pregnant.
- Nursing mothers.
The most common adverse reactions that led to treatment discontinuation were: myalgia, abdominal pain, increased hepatic enzymes, increased ALT, increased AST, and musculoskeletal pain, dizziness, coughing, nausea, arthralgia, hyperkalemia, bronchitis, sinusitis, hot flushes, diarrhea, fatigue, influenza, nasopharyngitis, pain in extremity, urinary tract infection.
Warnings and Precautions:
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects .Myopathy should be considered in any patient with difuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly
unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing the drug. Therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with the drug and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, promptly interrupt therapy. If an alternate etiology is not found, do not restart the drug. It should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use.
Pregnancy: Pregnancy Category X
It 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.
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using the drug. Discuss future pregnancy plans with your patients, and discuss when to stop taking the drug if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking the drug and call their healthcare professional.
Women who are breast-feeding should be advised to not use the drug. Patients who have a lipid disorder and are breast-feeding should be advised to discuss the options with their healthcare professionals.
Safety and effectiveness have not been established in pediatric patients.
Since advanced age (≥65 years) is a predisposing factor for myopathy, it should be prescribed with caution in the elderly. In geriatric patients, no dosage adjustment is necessary.
It is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
A history of renal impairment may be a risk factor for statin-associated myopathy. These patients merit closer monitoring for skeletal muscle effects. In patients with renal impairment, no dosage adjustment is necessary.
Strong Inhibitors of Cytochrome P450 3A4:
Because it contains atorvastatin, the risk of myopathy during treatment is increased with concurrent administration of:
Clarithromycin: caution should be used when the dose exceeds 10/20 mg.
Combination of Protease Inhibitors: In patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose should not exceed 10/20 mg and should be used with. In patients taking the HIV protease inhibitor nelfnavir or the hepatitis C protease inhibitor boceprevir, the dose should not exceed 10/40 mg daily and close clinical monitoring is recommended.
Itraconazole: do not use dose that exceeds 10/20 mg.
Cyclosporine: The coadministration with cyclosporine should be avoided.
Grapefruit Juice: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis concomitant administration should be avoided.
Fenofibrates (e.g., Fenofibrate and Fenofibric Acid): Because it is known that the risk of myopathy during treatment is increased with concurrent administration it should be administered with caution when used concomitantly. Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasisis suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.
Niacin: The risk of skeletal muscle defects may be enhanced when used in combination with niacin; a reduction in the drug dosage should be considered in this setting.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking the drug.
Elbasvir and Grazoprevir: Concomitant administration may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin may be necessary. Therefore, the dose should not exceed 10/20 mg daily.
Rifampin Or Other Inducers Of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous coadministration is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing with colchicine.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.
Coumarin Anticoagulants: If it is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.
Dosage & Administration:
The dosage range is 10/10 mg/day to 10/80 mg/day. The recommended starting dose of is 10/10 mg/day or 10/20 mg/day. It 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 10/40 mg/day. After initiation and/or upon titration of the drug, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly. Patients should swallow tablets whole. Tablets should not be crushed, dissolved, or chewed.
Patients with Homozygous Familial Hypercholesterolemia:
The dosage of Ezerva in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day. Ezerva should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Coadministration with Other Drugs:
Bile Acid Sequestrants: Dosing of Ezerva should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
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.
Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.
Store at 20-25°C, excursions permitted to 15-30°C.
Ezerva 10/10: Boxes of 10 or 20 film coated tablets in blister (Alu-Alu).
Ezerva 10/20 & 10/40: Boxes of 30 or 90 film coated tablets in blister (Alu-Alu).