Vytorin tablet

Recent major changes section

Dosage and Administration

Recommended Dosing ( 2.1) 01/2012

Restricted Dosing for 10/80 mg ( 2.2) 06/2011

Coadministration with Other Drugs ( 2.3) 10/2011

Patients with Homozygous Familial Hypercholesterolemia ( 2.4) 06/2011

Patients with Renal Impairment/Chronic Kidney Disease ( 2.6) 01/2012

Chinese Patients Taking Lipid-Modifying Doses (1g/day Niacin) of
Niacin-Containing Products ( 2.8) 06/2011

Contraindications ( 4) 02/2012

Warnings and Precautions

Myopathy/Rhabdomyolysis ( 5.1) 02/2012

Liver Enzymes ( 5.2) 01/2012

Endocrine Function ( 5.4) 10/2011

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.

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, ApoB, 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.

1.1 primary hyperlipidemia

VYTORIN ®is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), 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

  • Dose range is 10/10mg/day to 10/40mg/day. ( 2.1)
  • Recommended usual starting dose is 10/10 or 10/20mg/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 2hours before or 4hours after administration of a bile acid sequestrant. ( 2.3, 7.5)

2.1 recommended dosing

The usual dosage range is 10/10mg/day to 10/40mg/day. The recommended usual starting dose is 10/10 mg/day or 10/20mg/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 10/40mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m 2). 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 or Diltiazem

Patients taking Amiodarone, Amlodipine or Ranolazine

Patients taking Bile Acid Sequestrants

  • Dosing of VYTORIN should occur either 2 hours before or 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.

2.5 patients with hepatic impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.3)].

2.6 patients with renal impairment/chronic kidney disease

In patients with mild renal impairment (estimated GFR 60 mL/min/1.73 m 2), no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate <60 mL/min/1.73 m 2, 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 geriatric patients

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

2.8 chinese patients taking lipid-modifying doses (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 (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 (1g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80mg 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 10mg/simvastatin 10mg tablets) are white to off-white capsule-shaped tablets with code "311" on one side.
  • VYTORIN ®10/20, (ezetimibe 10mg/simvastatin 20mg tablets) are white to off-white capsule-shaped tablets with code "312" on one side.
  • VYTORIN ®10/40, (ezetimibe 10mg/simvastatin 40mg tablets) are white to off-white capsule-shaped tablets with code "313" on one side.
  • VYTORIN ®10/80, (ezetimibe 10mg/simvastatin 80mg tablets) are white to off-white capsule-shaped tablets with code "315" on one side.
  • Tablets (ezetimibemg/simvastatinmg): 10/10, 10/20, 10/40, 10/80 ( 3)

4 contraindications

VYTORIN is contraindicated in the following conditions:

  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) [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 breast-feed their infants [see Use in Specific Populations (8.3)].
  • 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)

5 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 symptoms of myopathy. 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. ( 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)
  • VYTORIN is not recommended in patients with moderate or severe hepatic impairment. ( 5.3, 12.3)

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 (65years), 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 4years, 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 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 very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates.

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. 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 simvastatin 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, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or large quantities of grapefruit juice (>1quart daily). Combination of these drugs with VYTORIN is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN must be suspended during the course of treatment. [See Contraindications (4)and Drug Interactions (7).] In vitrostudies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the VYTORIN dose may be needed to reduce the risk of myopathy/rhabdomyolysis if voriconazole must be used concomitantly with VYTORIN. [See Drug Interactions (7.1).]

The combined use of VYTORIN with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4)and Drug Interactions ( 7.1and 7.2)].

Caution should be used when prescribing other fibrates with VYTORIN, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered [see Drug Interactions ( 7.2, 7.7)].

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing VYTORIN with colchicine [see Drug Interactions (7.9)].

The benefits of the combined use of VYTORIN with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates or 1g/day of niacin), amiodarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3)and Table 6in Clinical Pharmacology (12.3)].

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (1g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40mg or ezetimibe/simvastatin 10/40mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with VYTORIN in doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80mg coadministered with lipid-modifying doses of niacin-containing products. It is 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 Drug Interactions (7.4)].

Prescribing recommendations for interacting agents are summarized in Table1 [see also Dosage and Administration (2.3), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations

Strong CYP3A4 Inhibitors, e.g.:
Itraconazole
Ketoconazole
Posaconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Gemfibrozil
Cyclosporine
Danazol

Contraindicated with VYTORIN
Verapamil
Diltiazem
Do not exceed 10/10mg VYTORIN daily
Amiodarone
Amlodipine
Ranolazine
Do not exceed 10/20mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1quart daily)

5.2 liver enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with VYTORIN 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

In 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 consecutive elevations of transaminases (>3 ULN) was 0.7% for VYTORIN and 0.6% for placebo.

It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with VYTORIN, promptly interrupt therapy. If an alternate etiology is not found do not restart VYTORIN. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].

VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.

5.3 hepatic impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, VYTORIN is not recommended in these patients. [See Clinical Pharmacology (12.3).]

5.4endocrine function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

6 adverse reactions

The following serious adverse reactions are discussed in greater detail in other sections of the label:

  • 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 MSP Distribution Services (C) LLC, a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 clinical trials experience

VYTORIN

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.


In the VYTORIN (ezetimibe/simvastatin) placebo-controlled clinical trials database of 1420patients (age range 20-83years, 52%women, 87%Caucasians, 3%Blacks, 5%Hispanics, 3%Asians) with a median treatment duration of 27weeks, 5%of patients on VYTORIN and 2.2% of patients on placebo discontinued due to adverse reactions.

The most common adverse reactions in the group treated with VYTORIN that led to treatment discontinuation and occurred at a rate greater than placebo were:

  • Increased ALT (0.9%)
  • Myalgia (0.6%)
  • Increased AST (0.4%)
  • Back pain (0.4%)

The most commonly reported adverse reactions (incidence 2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

VYTORIN has been evaluated for safety in more than 10,189patients in clinical trials.

Table2 summarizes the frequency of clinical adverse reactions reported in 2% of patients treated with VYTORIN (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.

Table 2: Clinical Adverse Reactions Occurring in 2% of Patients Treated with VYTORIN and at an Incidence Greater than Placebo, Regardless of Causality
Body System/Organ Class
Adverse Reaction
Placebo
(%)
n=371
Ezetimibe
10mg
(%)
n=302
Simvastatin
(%)
n=1234
VYTORIN id-75dbc8a3-1c92-41bd-8b74-20c971576a6b
(%)
n=1420
Body as a whole general disorders
Headache 5.4 6.0 5.9 5.8
Gastrointestinal system disorders
Diarrhea 2.2 5.0 3.7 2.8
Infections and infestations
Influenza 0.8 1.0 1.9 2.3
Upper respiratory tract infection 2.7 5.0 5.0 3.6
Musculoskeletal and connective tissue disorders
Myalgia 2.4 2.3 2.6 3.6
Pain in extremity 1.3 3.0 2.0 2.3

Study of Heart and Renal Protection

In SHARP ,9270 patients were allocated to VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to VYTORIN and placebo, respectively. Comparing those allocated to VYTORIN vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (>3 ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each study visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the VYTORIN and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to VYTORIN and placebo, respectively.

Ezetimibe

Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders:arthralgia; Infections and infestations:sinusitis; Body as a whole general disorders:fatigue.

Simvastatin

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.

Other adverse reactions reported with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Cardiac disorders:atrial fibrillation; Ear and labyrinth disorders:vertigo; Gastrointestinal disorders:abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders:eczema, rash; Endocrine disorders:diabetes mellitus; Infections and infestations:bronchitis, sinusitis, urinary tract infections; Body as a whole general disorders:asthenia, edema/swelling; Psychiatric disorders:insomnia.

Laboratory Tests

Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and -glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions (5.1)].

6.2 post-marketing experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in post-marketing experience for VYTORIN or ezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase.

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported.

In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

7 drug interactions

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole,
posaconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem Do not exceed 10/10mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1quart daily)
  • 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 other fibrate products 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).

7.1 strong cyp3a4 inhibitors, cyclosporine, or danazol

Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the simvastatin component of VYTORIN. Hence when VYTORIN is used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of VYTORIN. [See Warnings and Precautions (5.1)and Clinical Pharmacology (12.3).]Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)].If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN must be suspended during the course of treatment.

Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro(human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of VYTORIN be considered during concomitant use of voriconazole and VYTORIN to reduce the risk of myopathy, including rhabdomyolysis. [see Warnings and Precautions (5.1)].

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4) , Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)].

7.2 lipid-lowering drugs that can cause myopathy when given alone

Gemfibrozil: Contraindicated with VYTORIN [see Contraindications (4) and Warnings and Precautions (5.1)].

Other fibrates: Caution should be used when prescribing with VYTORIN [see Warnings and Precautions (5.1)].

7.3 amiodarone, ranolazine, or calcium channel blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or amlodipine [see Dosage and Administration (2.3)and Warnings and Precautions (5.1)and Table 6in Clinical Pharmacology (12.3)].

7.4 niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (1g/day niacin) of niacin-containing products. The benefits of the combined use of VYTORIN with niacin should be carefully weighed against the potential risks of myopathy/rhabdomyolysis. In particular, caution should be used when treating Chinese patients with VYTORIN doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. [See Warnings and Precautions (5.1).]

7.5 cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction.

7.6 digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when VYTORIN is initiated.

7.7 fibrates

The safety and effectiveness of VYTORIN administered with fibrates have not been established. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fibrates, VYTORIN should be administered with caution when used concomitantly with fibrates (other than gemfibrozil, which is contraindicated) [see Contraindications (4)and Warnings and Precautions (5.1)].

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Animal Toxicology and/or Pharmacology (13.2)].

7.8 coumarin anticoagulants

Simvastatin 20-40mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting VYTORIN and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Concomitant administration of ezetimibe (10mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications.

The effect of VYTORIN on the prothrombin time has not been studied.

7.9 colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing VYTORIN with colchicine.

8 use in specific populations

  • Moderate to severe renal impairment: Doses exceeding 10/20 mg/day should be used with caution and close monitoring ( 2.6, 8.6).

8.1 pregnancy

Pregnancy CategoryX.

[See Contraindications (4) .]

VYTORIN

VYTORIN is contraindicated in women who are or may become pregnant. 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. There are no adequate and well-controlled studies of VYTORIN use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because 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. If VYTORIN is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential, who require VYTORIN treatment for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of VYTORIN should be considered. If pregnancy occurs, VYTORIN should be immediately discontinued.

Ezetimibe

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000mg/kg/day (~10times the human exposure at 10mg daily based on AUC 0-24hrfor total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000mg/kg/day (150times the human exposure at 10mg daily based on AUC 0-24hrfor total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in coadministration therapy compared to monotherapy.

Simvastatin

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10mg/kg/day, respectively) that resulted in 3times the human exposure based on mg/m 2surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.

There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review of approximately 100prospectively followed pregnancies in women exposed to simvastatin or another structurally-related statin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

8.3 nursing mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4) ].

In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take VYTORIN [see Contraindications (4)].

8.4 pediatric use

The effects of ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142boys and 106postmenarchal girls, 10 to 17years of age (mean age 14.2years, 43%females, 82%Caucasians, 4%Asian, 2%Blacks, 13%multiracial) with HeFH were randomized to receive either ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225mg/dL (range: 161-351mg/dL) in the ezetimibe coadministered with simvastatin group compared to 219mg/dL (range: 149-336mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe and simvastatin (10mg, 20mg, or 40mg) or simvastatin monotherapy (10mg, 20mg, or 40mg) for 6weeks, coadministered ezetimibe and 40mg simvastatin or 40mg simvastatin monotherapy for the next 27weeks, and open-label coadministered ezetimibe and simvastatin (10mg, 20mg, or 40mg) for 20weeks thereafter.

The results of the study at Week6 are summarized in Table 3. Results at Week33 were consistent with those at Week6.

Table 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia
Total-C LDL-C Apo B Non-HDL-C TG HDL-C
Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1%
95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9, +4) (-3, +3)

From the start of the trial to the end of Week33, discontinuations due to an adverse reaction occurred in 7(6%)patients in the ezetimibe coadministered with simvastatin group and in 2(2%)patients in the simvastatin monotherapy group.

During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST 3 X ULN) occurred in four(3%)individuals in the ezetimibe coadministered with simvastatin group and in two(2%)individuals in the simvastatin monotherapy group. Elevations of CPK (10 X ULN) occurred in two (2%) individuals in the ezetimibe coadministered with simvastatin group and in zero individuals in the simvastatin monotherapy group.

In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

Coadministration of ezetimibe with simvastatin at doses greater than 40mg/day has not been studied in adolescents. Also, VYTORIN has not been studied in patients younger than 10years of age or in pre-menarchal girls.


Ezetimibe

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10years of age are not available.


Simvastatin

The pharmacokinetics of simvastatin has not been studied in the pediatric population.

8.5 geriatric use

Of the 10,189 patients who received VYTORIN in clinical studies, 3242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (65years) is a predisposing factor for myopathy, VYTORIN should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3).]

Because advanced age (65 years) is a predisposing factor for myopathy, including rhabdomyolysis, VYTORIN should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients 65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1)and Clinical Pharmacology (12.3).]

8.6 renal impairment

In the SHARP trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m 2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to VYTORIN 10/20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of VYTORIN exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment. [See Dosage and Administration (2.6), Adverse Reactions (6.1), and Clinical Studies (14.3).]

8.7 hepatic impairment

VYTORIN is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminases. VYTORIN is not recommended in patients with moderate to severe hepatic impairment. [See Contraindications (4) and Warnings and Precautions (5.2).]

10 overdosage

VYTORIN

No specific treatment of overdosage with VYTORIN can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.

Ezetimibe

In clinical studies, administration of ezetimibe, 50mg/day to 15healthy subjects for up to 14days, or 40mg/day to 18patients with primary hyperlipidemia for up to 56days, was generally well tolerated.

A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin

Significant lethality was observed in mice after a single oral dose of 9g/m 2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100g/m 2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6g. All patients recovered without sequelae.

The dialyzability of simvastatin and its metabolites in man is not known at present.

11 description

VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor.

The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C 24H 21F 2NO 3and its molecular weight is 409.4.

Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is:

image of ezetimibe structural formula

Simvastatin, an inactive lactone, is hydrolyzed to the corresponding -hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S-[1,3,7,8(2 S*,4 S*),-8a]]. The empirical formula of simvastatin is C 25H 38O 5and its molecular weight is 418.57.

Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is:

image of simvastatin structural formula

VYTORINis available for oral use as tablets containing 10mg of ezetimibe, and 10mg of simvastatin (VYTORIN10/10), 20mg of simvastatin (VYTORIN 10/20), 40mg of simvastatin (VYTORIN 10/40), or 80mg of simvastatin (VYTORIN 10/80). Each tablet contains the following inactive ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.

12 clinical pharmacology

12.1 mechanism of action

VYTORIN

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.


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 18hypercholesterolemic 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 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 [see Clinical Studies (14)].


Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active -hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C.

12.2 pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and ApoB, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

12.3 pharmacokinetics

The results of a bioequivalence study in healthy subjects demonstrated that the VYTORIN (ezetimibe/simvastatin) 10mg/10mg to 10mg/80mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe (ZETIA ®) and simvastatin (ZOCOR ®) as individual tablets.

Absorption

Ezetimibe

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).


Simvastatin

The availability of the -hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction.

Effect of Food on Oral Absorption

Ezetimibe

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The C maxvalue of ezetimibe was increased by 38% with consumption of high-fat meals.


Simvastatin

Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.

Distribution

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

Simvastatin

Both simvastatin and its -hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.

Metabolism and Excretion

Ezetimibe

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14C-ezetimibe (20mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

Simvastatin

Simvastatin is a lactone that is readily hydrolyzed invivoto the corresponding -hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the -hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the -hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4hours and declined rapidly to about 10% of peak by 12hours postdose.

Specific Populations

Geriatric Patients

Ezetimibe

In a multiple-dose study with ezetimibe given 10mg once daily for 10days, plasma concentrations for total ezetimibe were about 2-fold higher in older (65 years) healthy subjects compared to younger subjects.


Simvastatin

In a study including 16elderly patients between 70 and 78years of age who received simvastatin 40mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18patients between 18-30years of age.

Pediatric Patients:[See Pediatric Use (8.4).]

Gender

Ezetimibe

In a multiple-dose study with ezetimibe given 10mg once daily for 10days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.

Race

Ezetimibe

Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in Caucasian subjects.

Hepatic Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.

Renal Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl30mL/min/1.73m 2), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9).


Simvastatin

Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal impairment (as measured by creatinine clearance).

Drug Interactions [See also Drug Interactions (7).]

No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. No specific pharmacokinetic drug interaction studies with VYTORIN have been conducted other than the following study with NIASPAN (Niacin extended-release tablets).

Niacin:The effect of VYTORIN (10/20mg daily for 7days) on the pharmacokinetics of NIASPAN extended-release tablets (1000mg for 2days and 2000mg for 5days following a low-fat breakfast) was studied in healthy subjects. The mean C maxand AUC of niacin increased 9% and 22%, respectively. The mean C maxand AUC of nicotinuric acid increased 10% and 19%, respectively (N=13). In the same study, the effect of NIASPAN on the pharmacokinetics of VYTORIN was evaluated (N=15). While concomitant NIASPAN decreased the mean C maxof total ezetimibe (1%), and simvastatin (2%), it increased the mean C maxof simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%).

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (1g/day niacin) of niacin-containing products. [See Warnings and Precautions (5.1)and Drug Interactions (7.4).]

Cytochrome P450:Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. [See Warnings and Precautions (5.1); Drug Interactions (7.1).]


Ezetimibe

Table 4: Effect of Coadministered Drugs on Total Ezetimibe
Coadministered Drug and Dosing Regimen Total Ezetimibe
Change in AUC Change in C max
Cyclosporine-stable dose required (75-150mg BID) , 240% 290%
Fenofibrate, 200mg QD, 14days id-9d260128-46ae-4fb0-923e-2f550c68d3c2 48% 64%
Gemfibrozil, 600mg BID, 7days id-9d260128-46ae-4fb0-923e-2f550c68d3c2 64% 91%
Cholestyramine, 4g BID, 14days id-9d260128-46ae-4fb0-923e-2f550c68d3c2 55% 4%
Aluminum & magnesium hydroxide combination antacid, single dose 4% 30%
Cimetidine, 400mg BID, 7days 6% 22%
Glipizide, 10mg, single dose 4% 8%
Statins
Lovastatin 20mg QD, 7days 9% 3%
Pravastatin 20mg QD, 14days 7% 23%
Atorvastatin 10mg QD, 14days 2% 12%
Rosuvastatin 10mg QD, 14days 13% 18%
Fluvastatin 20mg QD, 14days 19% 7%
Table 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs
Coadministered Drug and its Dosage Regimen Ezetimibe Dosage Regimen

Change in AUC

of Coadministered Drug

Change in C max

of Coadministered Drug
Warfarin, 25mg single dose on Day7 10mg QD, 11days

2% (R-warfarin)

4% (S-warfarin)

3% (R-warfarin)

1% (S-warfarin)
Digoxin, 0.5mg single dose 10mg QD, 8days 2% 7%
Gemfibrozil, 600mg BID, 7days 10mg QD, 7days 1% 11%
Ethinyl estradiol & Levonorgestrel, QD, 21days 10mg QD, Days 8-14 of 21day oral contraceptive cycle

Ethinyl estradiol

0%

Levonorgestrel

0%

Ethinyl estradiol

9%

Levonorgestrel

5%
Glipizide, 10mg on Days1 and 9 10mg QD, Days2-9 3% 5%
Fenofibrate, 200mg QD, 14days id-c23d7959-ae1b-4879-b1c8-2792a1166b15 10mg QD, 14days 11% 7%
Cyclosporine, 100mg single dose Day7 id-c23d7959-ae1b-4879-b1c8-2792a1166b15 20mg QD, 8days 15% 10%
Statins
Lovastatin 20mg QD, 7days 10mg QD, 7days 19% 3%
Pravastatin 20mg QD, 14days 10mg QD, 14days 20% 24%
Atorvastatin 10mg QD, 14days 10mg QD, 14days 4% 7%
Rosuvastatin 10mg QD, 14days 10mg QD, 14days 19% 17%
Fluvastatin 20mg QD, 14days 10mg QD, 14days 39% 27%

Simvastatin

Table 6: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin

Geometric Mean Ratio

(Ratio with / without
coadministered drug)

No Effect=1.00
AUC C max
Contraindicated with VYTORIN [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin 200mg QD for 4days 80mg simvastatin acid
simvastatin
12
8.9
15
5.3
Nelfinavir id-54a86ac7-9c3e-4951-ab13-32846d04be4a 1250mg BID for 14days 20mg QD for 28days simvastatin acid id-7ca5b34d-dd33-4fe1-93bb-9e00f7add8d3
simvastatin

6

6.2
Itraconazole id-54a86ac7-9c3e-4951-ab13-32846d04be4a 200mg QD for 4days 80mg simvastatin acid id-7ca5b34d-dd33-4fe1-93bb-9e00f7add8d3
simvastatin

13.1

13.1
Posaconazole

100mg (oral suspension) QD for 13 days

200 mg (oral suspension) QD for 13 days

40 mg



40 mg

simvastatin acid id-7ca5b34d-dd33-4fe1-93bb-9e00f7add8d3
simvastatin


simvastatin acid id-7ca5b34d-dd33-4fe1-93bb-9e00f7add8d3

simvastatin

7.3
10.3


8.5
10.6

9.2
9.4


9.5
11.4

Gemfibrozil 600mg BID for 3days 40mg simvastatin acid id-7ca5b34d-dd33-4fe1-93bb-9e00f7add8d3
simvastatin

2.85

1.35

2.18

0.91
Avoid >1quart of grapefruit juice with VYTORIN [see Warnings and Precautions (5.1)]

Grapefruit Juice

(high dose)
200mL of double-strength TID 60mg single dose simvastatin acid
simvastatin
7
16

Grapefruit Juice id-d5a83f24-f9c8-4341-82f3-8b7c6c1a13e8

(low dose)
8oz (about 237mL) of single-strength 20mg single dose simvastatin acid
simvastatin
1.3
1.9
Avoid taking with >10/10 mg VYTORIN,based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]
Verapamil SR 240mg QD Days1-7 then 240mg BID on Days8-10 80mg on Day 10 simvastatin acid
simvastatin
2.3
2.5
2.4
2.1
Diltiazem 120 mg BID for 10 days 80mg on Day 10 simvastatin acid
simvastatin
2.69
3.10
2.69
2.88
Diltiazem 120 mg BID for 14 days 20mg on Day 14 simvastatin 4.6 3.6
Avoid taking with >10/20mg VYTORIN, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]
Amiodarone 400mg QD for 3 days 40mg on Day 3 simvastatin acid
simvastatin
1.75
1.76
1.72
1.79
Amlodipine 10mg QD for 10days 80mg on Day 10 simvastatin acid
simvastatin
1.58
1.77
1.56
1.47
Ranolazine SR 1000 mg BID for 7days 80mg on Day 1 and Days 6-9 simvastatin acid
simvastatin
2.26
1.86
2.28
1.75
No dosing adjustments required for the following:
Fenofibrate 160mg QD for 14days 80 mg QD on Days8-14 simvastatin acid
simvastatin
0.64
0.89
0.89
0.83
Propranolol 80mg single dose 80mg single dose total inhibitor

active inhibitor
0.79

0.79
from 33.6 to 21.1 ngeq/mL
from 7.0 to 4.7 ngeq/mL

13 nonclinical toxicology

13.1 carcinogenesis, mutagenesis, impairment of fertility

VYTORIN

No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity in vitroin a microbial mutagenicity (Ames) test with Salmonella typhimuriumand Escherichia coliwith or without metabolic activation. No evidence of clastogenicity was observed in vitroin a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivomouse micronucleus test.

Ezetimibe

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500mg/kg/day (males) and 500mg/kg/day (females) (~20 times the human exposure at 10mg daily based on AUC 0-24hrfor total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500mg/kg/day (>150 times the human exposure at 10mg daily based on AUC 0-24hrfor total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitroin a microbial mutagenicity (Ames) test with Salmonella typhimuriumand Escherichia coliwith or without metabolic activation. No evidence of clastogenicity was observed in vitroin a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivomouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000mg/kg/day in male or female rats (~7times the human exposure at 10mg daily based on AUC 0-24hrfor total ezetimibe).


Simvastatin

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8times higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1times higher than humans given 80mg simvastatin as measured by AUC).

In a two-year study in rats at 25mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11times higher levels of simvastatin than in humans given 80mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15times (males) and 22 and 25times (females) the mean human plasma drug exposure after an 80-mg daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitroalkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitrochromosome aberration study in CHO cells, or an in vivochromosomal aberration assay in mouse bone marrow.

There was decreased fertility in male rats treated with simvastatin for 34weeks at 25mg/kg body weight (4times the maximum human exposure level, based on AUC, in patients receiving 80mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180mg/kg/day (which produces exposure levels 22times higher than those in humans taking 80mg/day based on surface area, mg/m 2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10mg/kg/day (approximately 2times the human exposure, based on AUC, at 80mg/day). The clinical significance of these findings is unclear.

13.2 animal toxicology and/or pharmacology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14weeks at 180mg/kg/day, a dose that produced mean plasma drug levels about 12times higher than the mean plasma drug level in humans taking 80mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14weeks at 180mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with simvastatin at a dose of 360mg/kg/day, a dose that produced mean plasma drug levels that were about 14times higher than the mean plasma drug levels in humans taking 80mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100mg/kg/day (22 and 25times the human AUC at 80mg/day, respectively) and in dogs after three months at 90mg/kg/day (19times) and at two years at 50mg/kg/day (5times).


Ezetimibe

The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED 50value of 0.5g/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED 50values in dogs, rats, and mice were 7, 30, and 700g/kg/day, respectively. These results are consistent with ezetimibe being a potent cholesterol absorption inhibitor.

In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.

In 1-month studies in dogs given ezetimibe (0.03 to 300mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.

A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug-metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

14 clinical studies

14.1 primary hyperlipidemia

VYTORIN

VYTORIN reduces total-C, LDL-C, ApoB, TG, and non-HDL-C, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2weeks and maintained during chronic therapy.

VYTORIN is effective in men and women with hyperlipidemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of VYTORIN.

Five multicenter, double-blind studies conducted with either VYTORIN or coadministered ezetimibe and simvastatin equivalent to VYTORIN in patients with primary hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin.

In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528hyperlipidemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10mg), simvastatin (10mg, 20mg, 40mg, or 80mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).

When patients receiving VYTORIN were compared to those receiving all doses of simvastatin, VYTORIN significantly lowered total-C, LDL-C, ApoB, TG, and non-HDL-C. The effects of VYTORIN on HDL-C were similar to the effects seen with simvastatin. Further analysis showed VYTORIN significantly increased HDL-C compared with placebo. (See Table7.) The lipid response to VYTORIN was similar in patients with TG levels greater than or less than 200mg/dL.

Table 7: Response to VYTORIN in Patients with Primary Hyperlipidemia (Mean% Change from Untreated Baseline)
Treatment
(Daily Dose)
N Total-C LDL-C Apo B HDL-C TG id-270e50dc-12e3-420f-9804-cad3b239eba8 Non-HDL-C
Pooled data (All VYTORIN doses) 609 -38 -53 -42 +7 -24 -49
Pooled data (All simvastatin doses) id-11e062b7-e92c-4b42-8069-46f3b0070d7f 622 -28 -39 -32 +7 -21 -36
Ezetimibe 10 mg 149 -13 -19 -15 +5 -11 -18
Placebo 148 -1 -2 -2 -2
VYTORIN by dose
10/10 152 -31 -45 -35 +8 -23 -41
10/20 156 -36 -52 -41 +10 -24 -47
10/40 147 -39 -55 -44 +6 -23 -51
10/80 154 -43 -60 -49 +6 -31 -56
Simvastatin by dose
10 mg 158 -23 -33 -26 +5 -17 -30
20 mg 150 -24 -34 -28 +7 -18 -32
40 mg 156 -29 -41 -33 +8 -21 -38
80 mg 158 -35 -49 -39 +7 -27 -45

In a multicenter, double-blind, controlled, 23-week study, 710patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C 130mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10, 10/20, and 10/40) or simvastatin 20mg. Patients not reaching an LDL-C <100mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80mg.

At Week5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20mg (see Table 8).

Table 8: Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk Equivalents and an LDL-C 130mg/dL
Simvastatin
20mg
VYTORIN
10/10
VYTORIN
10/20
VYTORIN
10/40
N 253 251 109 97
Mean baseline
LDL-C
174 165 167 171
Percent change
LDL-C
-38 -47 -53 -59

In a multicenter, double-blind, 6-week study, 1902 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups: VYTORIN (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).

Across the dosage range, when patients receiving VYTORIN were compared to those receiving milligram-equivalent statin doses of atorvastatin, VYTORIN lowered total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10/40mg and 10/80mg VYTORIN doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of VYTORIN on TG were similar to the effects seen with atorvastatin. (See Table9.)

Table 9: Response to VYTORIN and Atorvastatin in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline)
Treatment
(Daily Dose)
N Total-C LDL-C id-36a13696-0706-4409-8936-cac29c9ab83d Apo B id-36a13696-0706-4409-8936-cac29c9ab83d HDL-C TG id-528065da-fced-45df-a251-c57357955b3e Non-HDL-C id-36a13696-0706-4409-8936-cac29c9ab83d
VYTORIN by dose
10/10 230 -34 -47 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -37 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d +8 -26 -43 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d
10/20 233 -37 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -51 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -40 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d +7 -25 -46 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d
10/40 236 -41 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -57 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -46 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d +9 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -27 -52 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d
10/80 224 -43 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -59 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -48 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d +8 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d -31 -54 id-5619abbb-7a1f-4ae4-bb9b-0168a31de89d
Atorvastatin by dose
10 mg 235 -27 -36 -31 +7 -21 -34
20 mg 230 -32 -44 -37 +5 -25 -41
40 mg 232 -36 -48 -40 +4 -24 -45
80 mg 230 -40 -53 -44 +1 -32 -50

In a multicenter, double-blind, 24-week, forced-titration study, 788patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) or atorvastatin 10mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80mg. At each pre-specified dose comparison, VYTORIN lowered LDL-C to a greater degree than atorvastatin (see Table10).

Table 10: Response to VYTORIN and Atorvastatin in Patients with Primary Hyperlipidemia (Mean% Change from Untreated Baseline)
Treatment N Total-C LDL-C Apo B HDL-C TG id-4a4b06c8-9a5f-4efe-af22-041961d4d452 Non-HDL-C
Week 6
Atorvastatin 10mg 262 -28 -37 -32 +5 -23 -35
VYTORIN10/10 263 -34 -46 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -38 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +8 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -26 -43 id-7457f6f1-83bd-4a24-ac8d-543afb80a645
VYTORIN 10/20 263 -36 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -50 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -41 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +10 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -25 -46 id-7457f6f1-83bd-4a24-ac8d-543afb80a645
Week 12
Atorvastatin 20mg 246 -33 -44 -38 +7 -28 -42
VYTORIN 10/20 250 -37 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -50 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -41 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +9 -28 -46 id-7457f6f1-83bd-4a24-ac8d-543afb80a645
VYTORIN 10/40 252 -39 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -54 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -45 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +12 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -31 -50 id-7457f6f1-83bd-4a24-ac8d-543afb80a645
Week 18
Atorvastatin 40mg 237 -37 -49 -42 +8 -31 -47
VYTORIN 10/40 482 -40 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -56 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -45 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +11 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -32 -52 id-7457f6f1-83bd-4a24-ac8d-543afb80a645
Week 24
Atorvastatin 80mg 228 -40 -53 -45 +6 -35 -50
VYTORIN 10/80 id-e1f5ac24-3c34-45d9-bc74-64812e458a5b 459 -43 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -59 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -49 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 +12 id-7457f6f1-83bd-4a24-ac8d-543afb80a645 -35 -55 id-7457f6f1-83bd-4a24-ac8d-543afb80a645

In a multicenter, double-blind, 6-week study, 2959 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: VYTORIN (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg).

The effects of VYTORIN and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table11.

Table 11: Response to VYTORIN and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean% Change from Untreated Baseline)
Treatment
(Daily Dose)
N Total-C LDL-C id-6344060d-c73d-4ca1-ae92-4a07c74a21b2 Apo B id-6344060d-c73d-4ca1-ae92-4a07c74a21b2 HDL-C TG id-b3ba260b-75ea-4d59-8124-7f8df04e100d Non-HDL-C id-6344060d-c73d-4ca1-ae92-4a07c74a21b2
VYTORIN by dose
10/20
476 -37 -52 id-d5445e01-b328-4255-9b03-c6f59589d14d -42 id-d5445e01-b328-4255-9b03-c6f59589d14d +7 -23 id-d5445e01-b328-4255-9b03-c6f59589d14d -47 id-d5445e01-b328-4255-9b03-c6f59589d14d
10/40 477 -39 -55 id-3ed3335c-34d1-451e-a7a5-79e1561a686a -44 id-3ed3335c-34d1-451e-a7a5-79e1561a686a +8 -27 -50 id-3ed3335c-34d1-451e-a7a5-79e1561a686a
10/80 474 -44 -61 id-5a0cf775-7343-4923-8d90-d35f695b7840 -50 id-5a0cf775-7343-4923-8d90-d35f695b7840 +8 -30 id-5a0cf775-7343-4923-8d90-d35f695b7840 -56 id-5a0cf775-7343-4923-8d90-d35f695b7840
Rosuvastatin by dose
10 mg
475 -32 -46 -37 +7 -20 -42
20 mg 478 -37 -52 -43 +8 -26 -48
40 mg 475 -41 -57 -47 +8 -28 -52

In a multicenter, double-blind, 24-week trial, 214patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3months and simvastatin 20mg for a minimum of 6weeks were randomized to receive either simvastatin 40mg or the coadministered active ingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were 89mg/dL and 7.1%, respectively.

VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40mg. The median percent changes from baseline for VYTORIN vs. simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; ApoB -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.


Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719patients with primary hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), ApoB (-14%), and TG(-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.


Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4,444 patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures.

No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

14.2 homozygous familial hypercholesterolemia (hofh)

A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40mg at baseline. Increasing the dose of simvastatin from 40 to 80mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40mg. Coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40mg. In those patients coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40mg was produced.

14.3 chronic kidney disease (ckd)

The Study of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo-controlled, double-blind trial that investigated the effect of VYTORIN on the time to a first major vascular event (MVE) among 9438 patients with moderate to severe chronic kidney disease (approximately one-third on dialysis at baseline) who did not have a history of myocardial infarction or coronary revascularization. An MVE was defined as nonfatal MI, cardiac death, stroke, or any revascularization procedure. Patients were allocated to treatment using a method that took into account the distribution of 8 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups.

For the first year, 9438 patients were allocated 4:4:1, to VYTORIN 10/20, placebo, or simvastatin 20 mg daily, respectively. The 1-year simvastatin arm enabled the comparison of VYTORIN to simvastatin with regard to safety and effect on lipid levels. At 1 year the simvastatin-only arm was re-allocated 1:1 to VYTORIN 10/20 or placebo. A total of 9270 patients were ever allocated to VYTORIN 10/20 (n=4650) or placebo (n=4620) during the trial. The median follow-up duration was 4.9 years. Patients had a mean age of 61 years; 63% were male, 72% were Caucasian, and 23% were diabetic; and, for those not on dialysis at baseline, the median serum creatinine was 2.5 mg/dL and the median estimated glomerular filtration rate (eGFR) was 25.6 mL/min/1.73 m 2, with 94% of patients having an eGFR < 45 mL/min/1.73m 2. Eligibility did not depend on lipid levels. Mean LDL-C at baseline was 108 mg/dL. At 1 year, the mean LDL-C was 26% lower in the simvastatin arm and 38% lower in the VYTORIN arm relative to placebo. At the midpoint of the study (2.5 years), the mean LDL-C was 32% lower for VYTORIN relative to placebo. Patients no longer taking study medication were included in all lipid measurements.

In the primary intent-to-treat analysis, 639 (15.2%) of 4193 patients initially allocated to VYTORIN and 749 (17.9%) of 4191 patients initially allocated to placebo experienced an MVE. This corresponded to a relative risk reduction of 16% (p=0.001) (see Figure 1). Similarly, 526 (11.3%) of 4650 patients ever allocated to VYTORIN and 619 (13.4%) of 4620 patients ever allocated to placebo experienced a major atherosclerotic event (MAE; a subset of the MVE composite that excluded non-coronary cardiac deaths and hemorrhagic stroke), corresponding to a relative risk reduction of 17% (p=0.002). The trial demonstrated that treatment with VYTORIN 10/20 mg versus placebo reduced the risk for MVE and MAE in this CKD population. The study design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect.

The treatment effect of VYTORIN on MVE was attenuated among patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3023 patients on dialysis at baseline, VYTORIN reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80-1.09) compared with 22% (RR 0.78: 95% CI 0.69-0.89) among 6247 patients not on dialysis at baseline (interaction P=0.08).

Figure 1: Effect of VYTORIN on the Primary Endpoint of Risk of Major Vascular Events
image of Figure 1

The individual components of MVE in all patients ever allocated to VYTORIN or placebo are presented in Table 12.

Table 12 Number of First Events for Each Component of the Major Vascular Event Composite Endpoint in SHARP
Outcome VYTORIN 10/20
(N=4650)
Placebo
(N=4620)
Risk Ratio
(95% CI)
P-value
Major Vascular Events 701 (15.1%) 814 (17.6%) 0.85 (0.77-0.94) 0.001
Nonfatal MI 134 (2.9%) 159 (3.4%) 0.84 (0.66-1.05) 0.12
Cardiac Death 253 (5.4%) 272 (5.9%) 0.93 (0.78-1.10) 0.38
Any Stroke 171 (3.7%) 210 (4.5%) 0.81 (0.66-0.99) 0.038
Non-hemorrhagic Stroke 131 (2.8%) 174 (3.8%) 0.75 (0.60-0.94) 0.011
Hemorrhagic Stroke 45 (1.0%) 37 (0.8%) 1.21 (0.78-1.86) 0.40
Any Revascularization 284 (6.1%) 352 (7.6%) 0.79 (0.68-0.93) 0.004

Among patients not on dialysis at baseline, VYTORIN did not reduce the risk of progressing to end-stage renal disease compared with placebo (RR 0.97: 95% CI 0.89-1.05).

16 how supplied/storage and handling

No. 3873 Tablets VYTORIN 10/10 are white to off-white capsule-shaped tablets with code "311" on one side.

They are supplied as follows:

Bottles of 30
NDC 54868-5250-0

No. 3874 Tablets VYTORIN 10/20 are white to off-white capsule-shaped tablets with code "312" on one side.

They are supplied as follows:

Bottles of 15
NDC 54868-5187-2
Bottles of 30
NDC 54868-5187-0

No. 3875 Tablets VYTORIN 10/40 are white to off-white capsule-shaped tablets with code "313" on one side.

They are supplied as follows:

Bottles of 30
NDC 54868-5189-0
Bottles of 90
NDC 54868-5189-1

No. 3876 Tablets VYTORIN 10/80 are white to off-white capsule-shaped tablets with code "315" on one side.

They are supplied as follows:

Bottles of 30
NDC 54868-5259-0
Bottles of 90
NDC 54868-5259-1

Storage

Store at 20-25C (68-77F). [See USP Controlled Room Temperature.] Keep container tightly closed.



17 patient counseling information

See FDA-Approved Patient Labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patients should be advised about substances they should not take concomitantly with VYTORIN [see Contraindications (4) and Warnings and Precautions (5.1) ].Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking VYTORIN.

17.1 muscle pain

All patients starting therapy with VYTORIN should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Patients using the 10/80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with the use of the 10/80-mg dose.The risk of myopathy, including rhabdomyolysis, occurring with use of VYTORIN is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.

17.2 liver enzymes

It is recommended that liver function tests be performed before the initiation of VYTORIN, and thereafter when clinically indicated. All patients treated with VYTORIN should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

17.3 pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using VYTORIN. Discuss future pregnancy plans with your patients, and discuss when to stop taking VYTORIN if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking VYTORIN and call their healthcare professional.

17.4 breast-feeding

Women who are breast-feeding should be advised to not use VYTORIN. Patients who have a lipid disorder and are breast-feeding should be advised to discuss the options with their healthcare professional.

Spl unclassified section

Manufactured for: MSP Distribution Services (C) LLC, a subsidiary of
MERCK & CO., INC.,Whitehouse Station, NJ 08889, USA

By:
MSD International GmbH (Singapore Branch)
Singapore 637766

Or

Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 Pavia, Italy

Or

Merck Sharp & Dohme Ltd.
Cramlington, Northumberland, UK NE23 3JU

Or

Jointly manufactured by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 Pavia, Italy
and
MSD International GmbH (Singapore Branch)
Singapore 637766

U.S. Patent Nos. 5,846,966 and RE42,461

Revised: 02/2012

9619523


Spl unclassified section

Distributed and Repackaged by:
Physicians Total Care, Inc.
Tulsa, Oklahoma 74146

Spl patient package insert section

VYTORIN ®(ezetimibe/simvastatin) Tablets
Patient Information about VYTORIN (VI-tor-in)

Generic name: ezetimibe/simvastatin tablets

Read this information carefully before you start taking VYTORIN ®. Review this information each time you refill your prescription for VYTORIN as there may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about VYTORIN, ask your doctor. Only your doctor can determine if VYTORIN is right for you.

What is VYTORIN?

VYTORIN contains two cholesterol-lowering medications, ezetimibe and simvastatin. VYTORIN is a prescription medicine used to lower levels of total cholesterol, LDL (bad) cholesterol, and fatty substances called triglycerides in the blood. In addition, VYTORIN raises levels of HDL (good) cholesterol. VYTORIN is for patients who cannot control their cholesterol levels by diet and exercise alone. You should stay on a cholesterol-lowering diet while taking this medicine.

VYTORIN works to reduce your cholesterol in two ways. It reduces the cholesterol absorbed in your digestive tract, as well as the cholesterol your body makes by itself. VYTORIN does not help you lose weight.

VYTORIN has not been shown to reduce heart attacks or strokes more than simvastatin alone.

The usual dose of VYTORIN is 10/10 mg to 10/40 mg 1 time each day.

VYTORIN 10/80 mg increases your chance of developing muscle damage. The 10/80 mg dose should only be used by people who:

  • have been taking VYTORIN 10/80 mg chronically (such as 12 months or more) without having muscle damage
  • do not need to take certain other medicines with VYTORIN that would increase your chance of getting muscle damage.

If you are unable to reach your LDL-cholesterol goal using VYTORIN 10/40 mg, your doctor should switch you to another cholesterol-lowering medicine.

For more information about cholesterol, see the section called "What should I know about high cholesterol?"

Who should not take VYTORIN?

Do not take VYTORIN if you take:

  • Certain anti-fungal medicines including:
    • itraconazole
    • ketoconazole
    • posaconazole
  • HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir)
  • Certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir)
  • Certain antibiotics, including:
    • erythromycin
    • clarithromycin
    • telithromycin
  • nefazodone
  • A fibric acid medicine for lowering cholesterol called gemfibrozil
  • cyclosporine
  • danazol

Ask your doctor if you are not sure if your medicine is listed above.

Also do not take VYTORIN:

  • If you are allergic to ezetimibe or simvastatin, the active ingredients in VYTORIN, or to the inactive ingredients. For a list of inactive ingredients, see the "Inactive ingredients" section at the end of this information sheet.

  • If you have active liver disease or repeated blood tests indicating possible liver problems.

  • If you are pregnant, or think you may be pregnant, or planning to become pregnant or breast-feeding.

  • If you are a woman of childbearing age, you should use an effective method of birth control to prevent pregnancy while using VYTORIN.

VYTORIN has not been studied in children under 10years of age.

What should I tell my doctor before and while taking VYTORIN?

Tell your doctor right away if you have unexplained muscle pain, tenderness, or weakness while you take VYTORIN. Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.

The risk of muscle breakdown is greater at higher doses of VYTORIN, particularly the 10/80 mg dose.

The risk of muscle breakdown is greater in people 65 years of age and older, females, and people with kidney or thyroid problems.

Taking VYTORIN with certain substances can increase the risk of muscle problems. It is especially important to tell your doctor if you take:

  • fibric acid derivatives (such as fenofibrate)
  • amiodarone (a drug used to treat an irregular heartbeat)
  • verapamil, diltiazem, amlodipine, or ranolazine (drugs used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions)
  • large quantities of grapefruit juice (more than 1 quart daily)
  • colchicine (a medicine used to treat gout)
  • voriconazole (an anti-fungal medicine)
  • large doses of niacin or nicotinic acid

Tell your doctor if you are taking niacin or a niacin-containing product, as this may increase your risk of muscle problems, especially if you are Chinese.

It is also important to tell your doctor if you are taking coumarin anticoagulants (drugs that prevent blood clots, such as warfarin).

Tell your doctor about all the medicines you take, including any prescription and nonprescription medicines, vitamins, and herbal supplements.

If you have more than 1 doctor, tell all of your doctors that you take VYTORIN. This is especially important when they prescribe a new medicine or increase the dose of your other medicines.

Tell your doctor about all your medical conditions including allergies.

Tell your doctor if you:

  • drink substantial quantities of alcohol or ever had liver problems. VYTORIN may not be right for you.

  • are pregnant or plan to become pregnant. Do not use VYTORIN if you are pregnant, trying to become pregnant or suspect that you are pregnant. If you become pregnant while taking VYTORIN, stop taking it and contact your doctor immediately.

  • are breast-feeding. Do not use VYTORIN if you are breast-feeding.

Tell other doctors prescribing a new medication that you are taking VYTORIN.

How should I take VYTORIN?


  • Take VYTORIN exactly as your doctor tells you to take it.

  • Take VYTORIN once a day, in the evening, with or without food.

  • If you miss a dose, do not take an extra dose. Just resume your usual schedule.

  • Continue to follow a cholesterol-lowering diet while taking VYTORIN. Ask your doctor if you need diet information.

  • Keep taking VYTORIN unless your doctor tells you to stop. If you stop taking VYTORIN, your cholesterol may rise again.

What should I do in case of an overdose?

Contact your doctor immediately.

What are the possible side effects of VYTORIN?

See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor should do blood tests to check your liver before you start taking VYTORIN and if you have any symptoms of liver problems while you take VYTORIN. Call your doctor right away if you have the following symptoms of liver problems:

  • feel tired or weak
  • loss of appetite
  • upper belly pain
  • dark urine
  • yellowing of your skin or the whites of your eyes

In clinical studies patients reported the following common side effects while taking VYTORIN: headache, muscle pain, and diarrhea (see What should I tell my doctor before and while taking VYTORIN?).

The following side effects have been reported in general use with VYTORIN or with ezetimibe or simvastatin tablets (tablets that contain the active ingredients of VYTORIN):

  • allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (which may require treatment right away), rash, hives; raised red rash, sometimes with target-shaped lesions; joint pain; muscle pain; alterations in some laboratory blood tests; liver problems (sometimes serious); inflammation of the pancreas; nausea; dizziness; tingling sensation; depression; gallstones; inflammation of the gallbladder; trouble sleeping; poor memory; memory loss; confusion; erectile dysfunction; breathing problems including persistent cough and/or shortness of breath or fever.

Tell your doctor if you are having these or any other medical problems while on VYTORIN. This is nota complete list of side effects. For a complete list, ask your doctor or pharmacist.

What should I know about high cholesterol?

Cholesterol is a type of fat found in your blood. Cholesterol comes from two sources. It is produced by your body and it comes from the food you eat. Your total cholesterol is made up of both LDL and HDL cholesterol.

LDL cholesterol is called "bad" cholesterol because it can build up in the wall of your arteries and form plaque. Over time, plaque build-up can cause a narrowing of the arteries. This narrowing can slow or block blood flow to your heart, brain, and other organs. High LDL cholesterol is a major cause of heart disease and one of the causes for stroke.

HDL cholesterol is called "good" cholesterol because it keeps the bad cholesterol from building up in the arteries.

Triglycerides also are fats found in your body.

General Information about VYTORIN

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use VYTORIN for a condition for which it was not prescribed. Do not give VYTORIN to other people, even if they have the same condition you have. It may harm them.

This summarizes the most important information about VYTORIN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about VYTORIN that is written for health professionals. For additional information, visit the following web site: vytorin.com.

Inactive ingredients:

Butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.

Spl unclassified section

Manufactured for: MSP Distribution Services (C) LLC, a subsidiary of
MERCK & CO., INC.,Whitehouse Station, NJ 08889, USA

This patient information has been approved by the U.S. Food and Drug Administration

Revised: 02/2012

9619523

Ingredients and appearance - Product information

Vytorin tablet- Ezetimibe and simvastatin

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5250
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Ezetimibe ( UNII: EOR26LQQ24)( Ezetimibe - UNII: EOR26LQQ24 ) 10 mgin 1
Simvastatin ( UNII: AGG2FN16EV)( Simvastatin - UNII: AGG2FN16EV ) 10 mgin 1

Inactive Ingredients

Ingredient Name Code
Butylated hydroxyanisole ( UNII: REK4960K2U)
Citric acid monohydrate ( UNII: 2968PHW8QP)
Croscarmellose sodium ( UNII: M28OL1HH48)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propyl gallate ( UNII: 8D4SNN7V92)
Cellulose, microcrystalline ( UNII: OP1R32D61U)

Product Characteristics

Color white (white to off-white) Size 8 mm
Shape OVAL (capsule-shaped) Score 1
Imprint Code 311

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA021687 USA

Vytorin tablet- Ezetimibe and simvastatin

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5187
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Ezetimibe ( UNII: EOR26LQQ24)( Ezetimibe - UNII: EOR26LQQ24 ) 10 mgin 1
Simvastatin ( UNII: AGG2FN16EV)( Simvastatin - UNII: AGG2FN16EV ) 20 mgin 1

Inactive Ingredients

Ingredient Name Code
Butylated hydroxyanisole ( UNII: REK4960K2U)
Citric acid monohydrate ( UNII: 2968PHW8QP)
Croscarmellose sodium ( UNII: M28OL1HH48)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propyl gallate ( UNII: 8D4SNN7V92)
Cellulose, microcrystalline ( UNII: OP1R32D61U)

Product Characteristics

Color white (white to off-white) Size 11 mm
Shape OVAL (capsule-shaped) Score 1
Imprint Code 312

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA021687 USA

Vytorin tablet- Ezetimibe and simvastatin

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5189
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Ezetimibe ( UNII: EOR26LQQ24)( Ezetimibe - UNII: EOR26LQQ24 ) 10 mgin 1
Simvastatin ( UNII: AGG2FN16EV)( Simvastatin - UNII: AGG2FN16EV ) 40 mgin 1

Inactive Ingredients

Ingredient Name Code
Butylated hydroxyanisole ( UNII: REK4960K2U)
Citric acid monohydrate ( UNII: 2968PHW8QP)
Croscarmellose sodium ( UNII: M28OL1HH48)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propyl gallate ( UNII: 8D4SNN7V92)
Cellulose, microcrystalline ( UNII: OP1R32D61U)

Product Characteristics

Color white (white to off-white) Size 14 mm
Shape OVAL (capsule-shaped) Score 1
Imprint Code 313

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA021687 USA

Vytorin tablet- Ezetimibe and simvastatin

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5259
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Ezetimibe ( UNII: EOR26LQQ24)( Ezetimibe - UNII: EOR26LQQ24 ) 10 mgin 1
Simvastatin ( UNII: AGG2FN16EV)( Simvastatin - UNII: AGG2FN16EV ) 80 mgin 1

Inactive Ingredients

Ingredient Name Code
Butylated hydroxyanisole ( UNII: REK4960K2U)
Citric acid monohydrate ( UNII: 2968PHW8QP)
Croscarmellose sodium ( UNII: M28OL1HH48)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propyl gallate ( UNII: 8D4SNN7V92)
Cellulose, microcrystalline ( UNII: OP1R32D61U)

Product Characteristics

Color white (white to off-white) Size 17 mm
Shape OVAL (capsule-shaped) Score 1
Imprint Code 315

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA021687 USA

Labeler - Physicians Total Care, Inc.( 194123980)

Establishment

Name ID/FEI Business Operations
Physicians Total Care, Inc. 194123980 relabel( 54868-5259, 54868-5189, 54868-5187, 54868-5250), repack( 54868-5259, 54868-5189, 54868-5187, 54868-5250)

Package label.principal display panel

PRINCIPAL DISPLAY PANEL - Bottle Label 10/10

VYTORIN ®10/10
(ezetimibe/simvastatin)

Each tablet contains 10 mg ezetimibe and
10 mg simvastatin.

Store at 20-25C (68-77F).
[See USP Controlled Room Temperature.]
Keep container tightly closed.

Rx only

USUAL ADULT DOSAGE:
See accompanying circular.

Package label.principal display panel

PRINCIPAL DISPLAY PANEL - Bottle Label 10/20

VYTORIN ®10/20
(ezetimibe/simvastatin)

Each tablet contains 10 mg ezetimibe and
20 mg simvastatin.

Store at 20-25C (68-77F).
[See USP Controlled Room Temperature.]
Keep container tightly closed.

Rx only

USUAL ADULT DOSAGE:
See accompanying circular.

Package label.principal display panel

PRINCIPAL DISPLAY PANEL - Bottle Label 10/40

VYTORIN ®10/40
(ezetimibe/simvastatin)

Each tablet contains 10 mg ezetimibe and
40 mg simvastatin.

Store at 20-25C (68-77F).
[See USP Controlled Room Temperature.]
Keep container tightly closed.

Rx only

USUAL ADULT DOSAGE:
See accompanying circular.

Package label.principal display panel

PRINCIPAL DISPLAY PANEL - Bottle Label 10/80

VYTORIN ®10/80
(ezetimibe/simvastatin)

Each tablet contains 10 mg ezetimibe and
80 mg simvastatin.

Store at 20-25C (68-77F).
[See USP Controlled Room Temperature.]
Keep container tightly closed.

Rx only

USUAL ADULT DOSAGE:
See accompanying circular.

All doses.
See 7. Drug Interactions
See 7. Drug Interactions
Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
Simvastatin acid refers to the -hydroxyacid of simvastatin.
The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
For triglycerides, median % change from baseline
VYTORIN doses pooled (10/10-10/80) significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin and significantly increased HDL-C compared to placebo.
For triglycerides, median % change from baseline
VYTORIN doses pooled (10/10-10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10-80).
p<0.05 for difference with atorvastatin at equal mg doses of the simvastatin component
For triglycerides, median % change from baseline
p0.05 for difference with atorvastatin in the specified week
Data pooled for common doses of VYTORIN at Weeks 18 and 24.
For triglycerides, median % change from baseline
VYTORIN doses pooled (10/20-10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to rosuvastatin doses pooled (10-40mg).
p<0.05 vs. rosuvastatin 10mg
p<0.05 vs. rosuvastatin 20mg
p<0.05 vs. rosuvastatin 40mg
Intention-to-treat analysis on all SHARP patients ever allocated to VYTORIN or placebo