|
VYTORIN (ezetimibe and simvastatin) Tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VYTORIN safely and effectively. See full prescribing information for VYTORIN.
VYTORIN ® (ezetimibe and simvastatin) Tablets
Initial U.S. Approval: 2004
INDICATIONS AND USAGE
VYTORIN, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to:
-
reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1)
-
reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. (1.2)
Limitations of Use (1.3)
-
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
-
VYTORIN has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
DOSAGE AND ADMINISTRATION
-
Dose range is 10/10 mg/day to 10/40 mg/day. (2.1)
-
Recommended usual starting dose is 10/10 or 10/20 mg/day. (2.1)
-
Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10/80-mg dose of VYTORIN should be restricted to patients who have been taking VYTORIN 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. (2.2)
-
Patients who are currently tolerating the 10/80-mg dose of VYTORIN 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. (2.2)
-
Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80-mg dose of VYTORIN, patients unable to achieve their LDL-C goal utilizing the 10/40-mg dose of VYTORIN should not be titrated to the 10/80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. (2.2)
-
Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. (2.3, 7.5)
DOSAGE FORMS AND STRENGTHS
-
Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80 (3)
CONTRAINDICATIONS
-
Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1)
-
Concomitant administration of gemfibrozil, cyclosporine, or danazol. (4, 5.1)
-
Hypersensitivity to any component of this medication (4, 6.2)
-
Active liver disease or unexplained persistent elevations of hepatic transaminase levels (4, 5.2)
-
Women who are pregnant or may become pregnant (4, 8.1)
-
Nursing mothers (4, 8.3)
WARNINGS AND PRECAUTIONS
-
Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10/80-mg dose. (5.1)
-
Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. VYTORIN should be discontinued immediately if myopathy is diagnosed or suspected. (5.1)
-
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. (4, 5.1, 8.5, 8.6)
-
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.2)
ADVERSE REACTIONS
-
Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
|
Interacting Agents |
Prescribing Recommendations |
|
|
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
|
Verapamil, diltiazem, dronedarone |
Do not exceed 10/10 mg VYTORIN daily |
|
Amiodarone, amlodipine, ranolazine |
Do not exceed 10/20 mg VYTORIN daily |
|
Lomitapide |
For patients with HoFH, do not exceed 10/20 mg VYTORIN daily* |
|
Grapefruit juice |
Avoid grapefruit juice |
-
Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting VYTORIN. Monitor INR frequently until stable upon initiation or alteration of VYTORIN therapy. (7.8)
-
Cholestyramine: Combination decreases exposure of ezetimibe. (2.3, 7.5)
-
Other Lipid-lowering Medications: Use with fenofibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with VYTORIN. (5.1, 7.2, 7.4)
-
Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (7.2, 7.7, 12.3)
USE IN SPECIFIC POPULATIONS
-
Moderate to severe renal impairment: Doses exceeding 10/20 mg/day should be used with caution and close monitoring (2.5, 8.6).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 10/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
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
VYTORIN® 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.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)
VYTORIN 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.
1.3 Limitations of Use
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
VYTORIN has 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 10/10 mg/day to 10/40 mg/day. The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. VYTORIN 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 10/40 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 VYTORIN, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.
2.2 Restricted Dosing for 10/80 mg
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10/80-mg dose of VYTORIN should be restricted to patients who have been taking VYTORIN 10/80 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 10/80-mg dose of VYTORIN 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 10/80-mg dose of VYTORIN, patients unable to achieve their LDL-C goal utilizing the 10/40-mg dose of VYTORIN should not be titrated to the 10/80-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
Patients taking Amiodarone, Amlodipine or Ranolazine
Patients taking Bile Acid Sequestrants
-
Dosing of VYTORIN 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 VYTORIN 10/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)]. VYTORIN 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 VYTORIN should be reduced by 50% if initiating lomitapide. VYTORIN dosage should not exceed 10/20 mg/day (or 10/40 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 VYTORIN is 10/20 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)].
2.7 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 VYTORIN doses exceeding 10/20 mg/day coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 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).]
3 DOSAGE FORMS AND STRENGTHS
-
VYTORIN® 10/10, (ezetimibe 10 mg and simvastatin 10 mg tablets) are white to off-white capsule-shaped tablets with code "311" on one side.
-
VYTORIN® 10/20, (ezetimibe 10 mg and simvastatin 20 mg tablets) are white to off-white capsule-shaped tablets with code "312" on one side.
-
VYTORIN® 10/40, (ezetimibe 10 mg and simvastatin 40 mg tablets) are white to off-white capsule-shaped tablets with code "313" on one side.
-
VYTORIN® 10/80, (ezetimibe 10 mg and simvastatin 80 mg tablets) are white to off-white capsule-shaped tablets with code "315" on one side.
4 CONTRAINDICATIONS
VYTORIN is contraindicated in the following conditions:
-
Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions (5.1)].
-
Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)].
-
Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].
-
Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].
-
Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, VYTORIN may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of VYTORIN use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. VYTORIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, VYTORIN should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
-
Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require VYTORIN treatment should not breastfeed their infants [see Use in Specific Populations (8.3)].
5 WARNINGS AND PRECAUTIONS
5.1 Myopathy/Rhabdomyolysis
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 10/80-mg dose of VYTORIN should be used only in patients who have been taking VYTORIN 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)]. If, however, a patient who is currently tolerating the 10/80-mg dose of VYTORIN needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately [see Warnings and Precautions (5.2)].
In the Study of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) was 0.2% for VYTORIN and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for VYTORIN and 0.02% for placebo.
In postmarketing 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 fibric acid derivatives. VYTORIN and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with VYTORIN or whose dose of VYTORIN is being increased should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing VYTORIN. VYTORIN therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with VYTORIN or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking VYTORIN merit closer monitoring.
VYTORIN therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. VYTORIN therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, tel |
|
