VYTORIN
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VYTORIN safely and effectively. See full prescribing information for VYTORIN. VYTORIN (ezetimibe/simvastatin) TabletsInitial U.S. Approval: 2004RECENT MAJOR CHANGESDosage and Administration Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products (2.6) 03/2010 Coadministration with Other Drugs (2.7) 03/2010Warnings and Precautions Myopathy/Rhabdomyolysis (5.1) 03/2010INDICATIONS AND USAGEVYTORIN®, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to: reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1) reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. (1.2) Limitations of Use (1.3) No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. VYTORIN has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. DOSAGE AND ADMINISTRATION Dosage range is 10/10 mg/day through 10/80 mg/day. (2.1) Recommended usual starting dose is 10/20 mg/day. (2.1) Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. (2.7, 7.5) DOSAGE FORMS AND STRENGTHS Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80 (3) CONTRAINDICATIONS Hypersensitivity to any component of this medication (4, 6.2) Active liver disease or unexplained persistent elevations of hepatic transaminase levels (4, 5.2) Women who are pregnant or may become pregnant (4, 8.1) Nursing mothers (4, 8.3) WARNINGS AND PRECAUTIONS Patients should be advised 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 CYP3A4 inhibitors, gemfibrozil, cyclosporine, danazol, amiodarone, verapamil, and diltiazem. Predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. (5.1, 8.5, 8.6) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. Patients titrated to the 10/80-mg dose should receive additional liver function tests. (5.2) VYTORIN is not recommended in patients with moderate or severe hepatic impairment. (5.3, 12.3) Side Effects Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck/Schering-Plough Pharmaceuticals at 1-866-637-2501 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8) Interacting Agents Prescribing Recommendations Itraconazole,ketoconazole,erythromycin,clarithromycin,telithromycin, HIV protease inhibitors, nefazodone,fibrates Avoid VYTORIN Cyclosporine, danazol Do not exceed 10/10 mg VYTORIN daily Amiodarone, verapamil Do not exceed 10/20 mg VYTORIN daily Diltiazem Do not exceed 10/40 mg VYTORIN daily Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily) Cyclosporine: Combination increases exposure of ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored. (7.6, 12.3) Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting VYTORIN. Monitor INR frequently until stable upon initiation or alteration of VYTORIN therapy. (7.9) Cholestyramine: Combination decreases exposure of ezetimibe. (2.7, 7.5) USE IN SPECIFIC POPULATIONS Severe renal impairment: Caution should be exercised and the patient should be closely monitored. (2.4, 8.6)
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 VYTORIN INDICATIONS AND USAGE
- 2 VYTORIN DOSAGE AND ADMINISTRATION
- 2.1 Recommended Dosing
- 2.2 Patients with Homozygous Familial Hypercholesterolemia
- 2.3 Patients with Hepatic Impairment
- 2.4 Patients with Renal Impairment
- 2.5 Geriatric Patients
- 2.6 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products
- 2.7 Coadministration with Other Drugs
- 3 DOSAGE FORMS AND STRENGTHS
- 4 VYTORIN CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
- 6 VYTORIN ADVERSE REACTIONS
- 7 DRUG INTERACTIONS
- 8 USE IN SPECIFIC POPULATIONS
- 10 OVERDOSAGE
- 11 VYTORIN DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
- 13 NONCLINICAL TOXICOLOGY
- 14 CLINICAL STUDIES
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
1.1 Primary Hyperlipidemia
VYTORIN is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)
VYTORIN is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Limitations of Use
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. VYTORIN has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. VYTORIN should be taken as a single daily dose in the evening, with or without food. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titration of VYTORIN, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.
2.2 Patients with Homozygous Familial Hypercholesterolemia
The recommended dosage for patients with homozygous familial hypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the evening. 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.
2.3 Patients with Hepatic Impairment
No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.3)].
2.4 Patients with Renal Impairment
No dosage adjustment is necessary in patients with mild or moderate renal impairment. However, for patients with severe renal insufficiency, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Caution should be exercised when VYTORIN is administered to these patients, and they should be closely monitored [see Warnings and Precautions (5.1); Clinical Pharmacology (12.3)].
2.5 Geriatric Patients
No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].
2.6 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products
Because of an increased risk for myopathy, caution should be used when treating Chinese patients with VYTORIN coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1).]
2.7 Coadministration with Other Drugs
[See Warnings and Precautions (5.1) and Drug Interactions (7).]
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)].
Cyclosporine or Danazol
Caution should be exercised when initiating VYTORIN in the setting of cyclosporine. In patients taking cyclosporine or danazol, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. The dose of VYTORIN should not exceed 10/10 mg/day [see Drug Interactions (7.6)].
Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with VYTORIN, the dose should not exceed 10/20 mg/day [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
Diltiazem
The dose of VYTORIN should not exceed 10/40 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
Other Concomitant Lipid-Lowering Therapy
The safety and effectiveness of VYTORIN administered with fibrates have not been established. Therefore, the combination of VYTORIN and fibrates should be avoided [see Warnings and Precautions (5.1) and Drug Interactions (7.2 and 7.8)].
There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Combination therapy with gemfibrozil should be avoided because of an increase in simvastatin exposure with concomitant use. [See Warnings and Precautions (5.1) and Drug Interactions (7.2 and 7.8).]
3 DOSAGE FORMS AND STRENGTHS
- VYTORIN® 10/10, (ezetimibe 10 mg/simvastatin 10 mg tablets) are white to off-white capsule-shaped tablets with code “311” on one side.
- VYTORIN® 10/20, (ezetimibe 10 mg/simvastatin 20 mg tablets) are white to off-white capsule-shaped tablets with code “312” on one side.
- VYTORIN® 10/40, (ezetimibe 10 mg/simvastatin 40 mg tablets) are white to off-white capsule-shaped tablets with code “313” on one side.
- VYTORIN® 10/80, (ezetimibe 10 mg/simvastatin 80 mg tablets) are white to off-white capsule-shaped tablets with code “315” on one side.
4 CONTRAINDICATIONS
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)].
5 WARNINGS AND PRECAUTIONS
5.1 Myopathy/Rhabdomyolysis
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of CK >10 X the upper limit of normal (ULN) was 0.2% for VYTORIN, 0.6% for placebo, 0.0% for ezetimibe, and 0.3% for all simvastatin doses.
Simvastatin, like other statins, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above 10 X ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), uncontrolled hypothyroidism, and renal impairment.
As with other statins, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
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 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. Therapy with VYTORIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
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 other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). The use of VYTORIN concomitantly with these CYP3A4 inhibitors should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN should be suspended during the course of treatment. [See Drug Interactions (7).]
The benefits of the combined use of VYTORIN with the following drugs should be carefully weighed against the potential risks of combinations: gemfibrozil, other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), cyclosporine, danazol, amiodarone, verapamil, or diltiazem.
Caution should be used when prescribing other fibrates with VYTORIN, as these agents can cause myopathy when given alone.
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/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 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with lipid-modifying doses of a niacin-containing product. 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. 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.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.7), Drug Interactions (7), and Clinical Pharmacology (12.3)].
| Interacting Agents | Prescribing Recommendations |
| Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Fibrates  |
Avoid VYTORIN |
| Cyclosporine Danazol |
Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone Verapamil |
Do not exceed 10/20 mg VYTORIN daily |
|
Diltiazem |
Do not exceed 10/40 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart 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.
It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of therapy with VYTORIN is recommended.
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).]
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
- Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
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 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 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 10,189 patients in clinical trials.
Table 2 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.
| Body System/Organ Class Adverse Reaction |
Placebo (%) n=371 |
Ezetimibe 10 mg (%) n=302 |
Simvastatin (%) n=1234 |
VYTORIN (%) 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 |
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
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 γ-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; memory impairment; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]; hepatitis/jaundice; 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.
7 DRUG INTERACTIONS
[See Clinical Pharmacology (12.3).]
VYTORIN
7.1 CYP3A4 Interactions
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 can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of VYTORIN. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
Itraconazole, ketoconazole, and other antifungal azoles
Macrolide antibiotics erythromycin, clarithromycin, and the ketolide antibiotic telithromycin
HIV protease inhibitors
Antidepressant nefazodone
Grapefruit juice in large quantities (>1 quart daily)
Concomitant use of these drugs and any medication labeled as having a strong inhibitory effect on CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN should be suspended during the course of treatment.
7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is increased by gemfibrozil and to a lesser extent by other fibrates [see Warnings and Precautions (5.1)].
7.3 Amiodarone, Verapamil, or Diltiazem
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone, verapamil, or diltiazem with higher doses of VYTORIN [see Warnings and Precautions (5.1)].
7.4 Niacin
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with VYTORIN 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 Cyclosporine or Danazol
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of VYTORIN [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Caution should be exercised when using VYTORIN and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine [see Dosage and Administration (2.7)]. Cyclosporine concentrations should be monitored in patients receiving VYTORIN and cyclosporine [see Clinical Pharmacology (12.3)].
The degree of increase in ezetimibe exposure may be greater in patients with severe renal impairment. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
7.7 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.
7.8 Fibrates
The safety and effectiveness of VYTORIN administered with fibrates have not been established.
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)]. Coadministration of VYTORIN with fibrates is not recommended until use in patients is studied. [See Warnings and Precautions (5.1).]
7.9 Coumarin Anticoagulants
Simvastatin 20-40 mg/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 (10 mg 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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X.
[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, 1000 mg/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 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for 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, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface 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 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.
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, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) 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 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161-351 mg/dL) in the ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149-336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.
| 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 Week 33, 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 40 mg/day has not been studied in adolescents. Also, VYTORIN has not been studied in patients younger than 10 years 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 <10 years 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 (≥65 years) is a predisposing factor for myopathy, VYTORIN should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3).]
8.6 Renal Impairment
Caution should be exercised when VYTORIN is administered to patients with severe renal impairment. [See Dosage and Administration (2.4).]
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, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, 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 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, 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 3.6 g. 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 C24H21F2NO3 and 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:
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMGCoA 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-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C25H38O5 and 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:
VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or 80 mg 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 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe 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 β-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 Apo B, 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) 10 mg/10 mg to 10 mg/80 mg 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 β-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 Cmax value 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 β-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 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, 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 in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-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 β-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 4 hours and declined rapidly to about 10% of peak by 12 hours postdose.
Specific Populations
Geriatric Patients
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, 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 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
Pediatric Patients: [See Pediatric Use (8.4).]
Gender
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, 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 (10 mg 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 CrCl ≤30 mL/min/1.73 m2), 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 (10/20 mg daily for 7 days) on the pharmacokinetics of NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean Cmax and AUC of niacin increased 9% and 22%, respectively. The mean Cmax and 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 Cmax of total ezetimibe (1%), and simvastatin (2%), it increased the mean Cmax of 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 (≥1 g/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
| Coadministered Drug and Dosing Regimen |
Total Ezetimibe |
|
| Change in AUC | Change in Cmax | |
| Cyclosporine-stable dose required (75-150 mg BID) |
↑240% | ↑290% |
| Fenofibrate, 200 mg QD, 14 days |
↑48% | ↑64% |
| Gemfibrozil, 600 mg BID, 7 days |
↑64% | ↑91% |
| Cholestyramine, 4 g BID, 14 days |
↓55% | ↓4% |
| Aluminum & magnesium hydroxide combination antacid, single dose |
↓4% | ↓30% |
| Cimetidine, 400 mg BID, 7 days | ↑6% | ↑22% |
| Glipizide, 10 mg, single dose | ↑4% | ↓8% |
| Statins | ||
| Lovastatin 20 mg QD, 7 days | ↑9% | ↑3% |
| Pravastatin 20 mg QD, 14 days | ↑7% | ↑23% |
| Atorvastatin 10 mg QD, 14 days | ↓2% | ↑12% |
| Rosuvastatin 10 mg QD, 14 days | ↑13% | ↑18% |
| Fluvastatin 20 mg QD, 14 days | ↓19% | ↑7% |
| Coadministered Drug and its Dosage Regimen | Ezetimibe Dosage Regimen |
Change in AUC of Coadministered Drug |
Change in Cmax of Coadministered Drug |
| Warfarin, 25 mg single dose on Day 7 | 10 mg QD, 11 days |
↓2% (R-warfarin) ↓4% (S-warfarin) |
↑3% (R-warfarin) ↑1% (S-warfarin) |
| Digoxin, 0.5 mg single dose | 10 mg QD, 8 days | ↑2% | ↓7% |
| Gemfibrozil, 600 mg BID, 7 days |
10 mg QD, 7 days | ↓1% | ↓11% |
| Ethinyl estradiol & Levonorgestrel QD, 21 days |
10 mg QD, Days 8-14 of 21 day oral contraceptive cycle |
Ethinyl estradiol 0% Levonorgestrel 0% |
Ethinyl estradiol ↓9% Levonorgestrel ↓5% |
| Glipizide, 10 mg on Days 1 and 9 | 10 mg QD, Days 2-9 | ↓3% | ↓5% |
| Fenofibrate, 200 mg QD, 14 days |
10 mg QD, 14 days | ↑11% | ↑7% |
| Cyclosporine, 100 mg single dose Day 7 |
20 mg QD, 8 days | ↑15% | ↑10% |
| Statins | |||
| Lovastatin 20 mg QD, 7 days |
10 mg QD, 7 days | ↑19% | ↑3% |
| Pravastatin 20 mg QD, 14 days |
10 mg QD, 14 days | ↓20% | ↓24% |
| Atorvastatin 10 mg QD, 14 days |
10 mg QD, 14 days | ↓4% | ↑7% |
| Rosuvastatin 10 mg QD, 14 days |
10 mg QD, 14 days | ↑19% | ↑17% |
| Fluvastatin 20 mg QD, 14 days |
10 mg QD, 14 days | ↓39% | ↓27% |
Simvastatin
| Coadministered Drug or Grapefruit Juice | Dosing of Coadministered Drug or Grapefruit Juice | Dosing of Simvastatin |
Geometric Mean Ratio
(Ratio |
||
| AUC | Cmax | ||||
| Avoid taking with VYTORIN [see Warnings and Precautions (5.1)] | |||||
| Telithromycin |
200 mg QD for 4 days | 80 mg | simvastatin acid simvastatin |
12 8.9 |
15 5.3 |
| Nelfinavir |
1250 mg BID for 14 days | 20 mg QD for 28 days | simvastatin acid simvastatin |
6 |
6.2 |
| Itraconazole |
200 mg QD for 4 days | 80 mg | simvastatin acid simvastatin |
13.1 13.1 |
|
| Avoid >1 quart of grapefruit juice with VYTORIN [see Warnings and Precautions (5.1)] | |||||
|
Grapefruit Juice |
200 mL of double-strength TID |
60 mg single dose | simvastatin acid simvastatin |
7 16 |
|
|
Grapefruit Juice |
8 oz (about 237 mL) of single-strength |
20 mg single dose | simvastatin acid simvastatin |
1.3 1.9 |
|
| Avoid taking with VYTORIN. If VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)] | |||||
| Gemfibrozil | 600 mg BID for 3 days | 40 mg | simvastatin acid simvastatin |
2.85 1.35 |
2.18 0.91 |
| Avoid taking with >10/20 mg VYTORIN, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)] | |||||
| Verapamil SR | 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 | 80 mg on Day 10 | simvastatin acid simvastatin |
2.3 2.5 |
2.4 2.1 |
| Avoid taking with >10/40 mg VYTORIN, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)] | |||||
| Diltiazem | 120 mg BID for 10 days | 80 mg on Day 10 | simvastatin acid simvastatin |
2.69 3.10 |
2.69 2.88 |
| Diltiazem | 120 mg BID for 14 days | 20 mg on Day 14 | simvastatin | 4.6 | 3.6 |
| No dosing adjustments required for the following: | |||||
| Fenofibrate | 160 mg QD x14 days | 80 mg QD on Days 8-14 | simvastatin acid simvastatin |
0.64 0.89 |
0.89 0.83 |
| Amlodipine | 10 mg QD x 10 days | 80 mg on Day 10 | simvastatin acid simvastatin |
1.58 1.77 |
1.56 1.47 |
| Propranolol | 80 mg single dose | 80 mg single dose | total inhibitor active inhibitor |
0.79 0.79 |
↓ from 33.6 to 21.1 ng·eq/ml ↓ from 7.0 to 4.7 ng·eq/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 vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in 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 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test.
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in 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 vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
Simvastatin
In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times 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 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/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 15 times (males) and 22 and 25 times (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 vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/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 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), 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 10 mg/kg/day (approximately 2 times the human exposure, based on AUC, at 80 mg/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 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/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 60 mg/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 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/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 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/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 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).
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 ED50 value of 0.5 μg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 μg/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 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/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 5 mg/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, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks 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, 1528 hyperlipidemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), 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, Apo B, 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 Table 7.) The lipid response to VYTORIN was similar in patients with TG levels greater than or less than 200 mg/dL.
| Treatment (Daily Dose) |
N | Total-C | LDL-C | Apo B | HDL-C | TG |
Non-HDL-C |
| Pooled data (All VYTORIN doses) |
609 | -38 | -53 | -42 | +7 | -24 | -49 |
| Pooled data (All simvastatin doses) |
622 | -28 | -39 | -32 | +7 | -21 | -36 |
| Ezetimibe 10 mg | 149 | -13 | -19 | -15 | +5 | -11 | -18 |
| Placebo | 148 | -1 | -2 | 0 | 0 | -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, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥130 mg/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 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 8).
| Simvastatin 20 mg |
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 10/40 mg and 10/80 mg 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 Table 9.)
| Treatment (Daily Dose) |
N | Total-C |
LDL-C |
Apo B |
HDL-C | TG |
Non-HDL-C |
| VYTORIN by dose | |||||||
| 10/10 | 230 | -34 |
-47 |
-37 |
+8 | -26 | -43 |
| 10/20 | 233 | -37 |
-51 |
-40 |
+7 | -25 | -46 |
| 10/40 | 236 | -41 |
-57 |
-46 |
+9 |
-27 | -52 |
| 10/80 | 224 | -43 |
-59 |
-48 |
+8 |
-31 | -54 |
| 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, 788 patients 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 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, VYTORIN lowered LDL-C to a greater degree than atorvastatin (see Table 10).
| Treatment | N | Total-C | LDL-C | Apo B | HDL-C | TG |
Non-HDL-C |
| Week 6 | |||||||
| Atorvastatin 10 mg |
262 | -28 | -37 | -32 | +5 | -23 | -35 |
| VYTORIN10/10 |
263 | -34 |
-46 |
-38 |
+8 |
-26 | -43 |
| VYTORIN 10/20 |
263 | -36 |
-50 |
-41 |
+10 |
-25 | -46 |
| Week 12 | |||||||
| Atorvastatin 20 mg | 246 | -33 | -44 | -38 | +7 | -28 | -42 |
| VYTORIN 10/20 | 250 | -37 |
-50 |
-41 |
+9 | -28 | -46 |
| VYTORIN 10/40 | 252 | -39 |
-54 |
-45 |
+12 |
-31 | -50 |
| Week 18 | |||||||
| Atorvastatin 40 mg | 237 | -37 | -49 | -42 | +8 | -31 | -47 |
| VYTORIN 10/40 |
482 | -40 |
-56 |
-45 |
+11 |
-32 | -52 |
| Week 24 | |||||||
| Atorvastatin 80 mg | 228 | -40 | -53 | -45 | +6 | -35 | -50 |
| VYTORIN 10/80 |
459 | -43 |
-59 |
-49 |
+12 |
-35 | -55 |
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 Table 11.
| Treatment (Daily Dose) |
N | Total-C |
LDL-C |
Apo B |
HDL-C | TG |
Non-HDL-C |
| VYTORIN by dose 10/20 |
476 | -37 |
-52 |
-42 |
+7 | -23 |
-47 |
| 10/40 | 477 | -39 |
-55 |
-44 |
+8 | -27 | -50 |
| 10/80 | 474 | -44 |
-61 |
-50 |
+8 | -30 |
-56 |
| 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, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.
VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for VYTORIN vs. simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -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 1719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-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 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. 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 40 mg. 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 40 mg was produced.
16 HOW SUPPLIED/STORAGE AND HANDLING
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:
NDC 21695-325-30 bottles of 30
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:
NDC 21695-339-30 bottles of 30
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:
NDC 21695-827-30 bottles of 30
Storage
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Keep container tightly closed.
Storage of 10,000, 5000, and 2500 count bottles
Store bottle of 10,000 VYTORIN 10/10 and 10/20, 5000 VYTORIN 10/40, and 2500 VYTORIN 10/80 capsule-shaped tablets at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Store in original container until time of use. When product container is subdivided, repackage into a tightly-closed, light-resistant container. Entire contents must be repackaged immediately upon opening.
Manufactured for:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
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 Technology Singapore Pte. Ltd.
Singapore 637766
U.S. Patent Nos. 5,846,966 and RE37,721
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
17 PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (17.5).]
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 Warnings and Precautions (5.1)]. Patients should also be advised to inform other physicians prescribing a new medication that they are taking VYTORIN.
17.1 Muscle Pain
All patients starting therapy with VYTORIN should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. They 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. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment.
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.
17.5 FDA-Approved Patient Labeling
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, available as a tablet in four strengths:
- VYTORIN 10/10 (ezetimibe 10 mg/simvastatin 10 mg)
- VYTORIN 10/20 (ezetimibe 10 mg/simvastatin 20 mg)
- VYTORIN 10/40 (ezetimibe 10 mg/simvastatin 40 mg)
- VYTORIN 10/80 (ezetimibe 10 mg/simvastatin 80 mg)
VYTORIN is a 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.
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 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 10 years of age.
What should I tell my doctor before and while taking VYTORIN?
Tell your doctor right away if you experience unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage.
The risk of muscle breakdown is greater at higher doses of VYTORIN.
The risk of muscle breakdown is greater in patients with kidney problems.
Taking VYTORIN with certain substances can increase the risk of muscle problems. It is particularly important to tell your doctor if you are taking any of the following:
- cyclosporine
- danazol
- antifungal agents (such as itraconazole or ketoconazole)
- fibric acid derivatives (such as gemfibrozil, bezafibrate, or fenofibrate)
- the antibiotics erythromycin, clarithromycin, and telithromycin
- HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and saquinavir)
- the antidepressant nefazodone
- amiodarone (a drug used to treat an irregular heartbeat)
- verapamil or diltiazem (a drug used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions)
- large quantities of grapefruit juice (>1 quart daily)
- large doses (≥1 g/day) 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 any prescription and nonprescription medicines you are taking or plan to take, including natural or herbal remedies.
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?
Your doctor has prescribed your dose of VYTORIN. The available doses of VYTORIN are 10/10, 10/20, 10/40, and 10/80. The usual daily starting dose is VYTORIN 10/20.
- Take VYTORIN once a day, in the evening, with or without food.
- Try to take VYTORIN as prescribed. 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 may do blood tests to check your liver before you start taking VYTORIN and during treatment.
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; 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 not a 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.
Issued May 2010
9619517
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
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 Technology Singapore Pte. Ltd.
Singapore 637766
U.S. Patent Nos. 5,846,966 and RE37,721
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
This is a representative sample of the packaging. Please see How Supplied section for a complete list of available packaging.
VYTORIN® 10/20
(ezetimibe/simvastatin)
Each tablet contains 10 mg ezetimibe and 20 mg simvastatin.
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.]
Keep container tightly closed.
Rx only
USUAL ADULT DOSAGE: See accompanying circular.
30 Tablets
NDC 21695-325-30
Dist. by:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, U. S. A.
Jointly manuf. by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia, Italy
and
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Product of Singapore.
9732402
30 | No. 3874
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
PRINCIPAL DISPLAY PANEL - Bottle Label 10/40
VYTORIN® 10/40
(ezetimibe/simvastatin)
Each tablet contains 10 mg ezetimibe and 40 mg simvastatin.
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.]
Keep container tightly closed.
30 Tablets
NDC 21695-339-30
Rx only
USUAL ADULT DOSAGE: See accompanying circular.
Dist. by:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, U. S. A.
Manuf. by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia, Italy
Formulated in Italy.
9861900
30 | No. 3875
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
PRINCIPAL DISPLAY PANEL - Bottle Label 10/80
VYTORIN® 10/80
(ezetimibe/simvastatin)
Each tablet contains 10 mg ezetimibe and 80 mg simvastatin.
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.]
Keep container tightly closed.
30 Tablets
NDC 21695-827-30
Rx only
USUAL ADULT DOSAGE: See accompanying circular.
Dist. by:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, U. S. A.
Manuf. by:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Product of Singapore.
9732601
30 | No. 3876
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
VYTORINezetimibe and simvastatin TABLET
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
VYTORINezetimibe and simvastatin TABLET
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
VYTORINezetimibe and simvastatin TABLET
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
