1.  Simvastatin/ezetibine

• A. ORAL
  
  • 1. HYPERCHOLESTEROLEMIA
    
    • a. The oral dosage range of the fixed-dose combination ezetimibe/simvastatin (Vytorin(TM)) for the treatment of hypercholesterolemia is 10/10 milligrams (mg) to 10/80 mg once daily. Ezetimibe/simvastatin should be administered as adjunctive therapy to a cholesterol-lowering diet once daily in the evening, with or without food, generally beginning with the ezetimibe/simvastatin 10/20 mg tablet. In patients requiring smaller reductions in low-density lipoprotein cholesterol (LDL-C), therapy may be initiated at a dose of ezetimibe/simvastatin 10/10 mg once daily. Patients requiring greater reductions in LDL-C (greater than 55%), may be started at a dose of ezetimibe/simvastatin 10/40 mg per day. Dosage should be adjusted according to baseline LDL-C levels and patient response to therapy (Prod Info Vytorin(TM), 2004).
  • 2. HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
    
    • a. For the treatment of homozygous familial hypercholesterolemia, the recommended dose is ezetimibe/simvastatin 10/40 milligrams (mg) or 10/80 mg once daily in the evening, with or without food. Ezetimibe/simvastatin should be utilized as an adjunct to other lipid-lowering therapies (eg, LDL apheresis) or alone, if such treatments are not available (Prod Info Vytorin(TM), 2004).
  • 3. SPECIAL DOSING CONSIDERATIONS
    
    • a. The administration of ezetimibe/simvastatin should occur at least 2 hours before or 4 hours after the administration of BILE ACID SEQUESTRANTS (Prod Info Vytorin(TM), 2004).
    • b. Ezetimibe/simvastatin should not be initiated in patients taking CYCLOSPORINE unless the patient has previously tolerated simvastatin treatment at a dose of 5 milligrams (mg) or higher. The dose of ezetimibe/simvastatin should not exceed 10/10 mg/day (Prod Info Vytorin(TM), 2004).
    • c. In patients taking AMIODARONE or VERAPAMIL concurrently with ezetimibe/simvastatin, the dose should not exceed 10/20 milligrams/day (Prod Info Vytorin(TM), 2004).
• B. BIOEQUIVALENCE
  
  • 1. The fixed-dose combination ezetimibe/simvastatin is bioequivalent to the coadministration of ezetimibe and simvastatin individually (Prod Info Vytorin(TM), 2004).

• A. No dosage adjustment is necessary in patients with mild or moderate renal impairment. However, ezetimibe/simvastatin therapy should not be initiated in patients with severe renal insufficiency unless the patient has previously tolerated simvastatin treatment at a dose of 5 milligrams or higher. Caution should be exercised when these patients are given ezetimibe/simvastatin and they should be closely monitored (Prod Info Vytorin(TM), 2004).

• A. No dosage adjustment is necessary in patients with mild hepatic impairment, however, ezetimibe/simvastatin is not recommended for patients with moderate to severe hepatic impairment (Prod Info Vytorin(TM), 2004).

• A. Data are insufficient for the safe and effective use of ezetimibe/simvastatin in pediatric patients (Prod Info Vytorin(TM), 2004).
• B. Treatment with ezetimibe in children less than 10 years of age is not recommended (Prod Info Vytorin(TM), 2004).
• C. Simvastatin doses greater than 40 milligrams have not been studied in pediatric patients of any age range. Simvastatin has not been studied in children less than 10 years of age or in premenarchal girls (Prod Info Vytorin(TM), 2004).

• A. PEAK RESPONSE :
  
  • 1. Hypercholesterolemia, Oral: 2 weeks (Prod Info Vytorin(TM), 2004).
    • a. Maximal to near maximal response is achieved within two weeks and is maintained during ongoing therapy (Prod Info Vytorin(TM), 2004).

• A. TIME TO PEAK CONCENTRATION :
  
  • 1. Oral, 1 to 12 hours, ezetimibe; 4 hours, simvastatin (Prod Info Vytorin(TM), 2004; Simard & Turgeon, 2003; Prod Info Zetia(TM), 2002).
    • a. Maximum concentrations of 3.4 to 5.5 nanograms/milliliter (ng/mL) were observed at 4 to 12 hours after a single 10 milligram (mg) dose of ezetimibe in fasted adults. The active metabolite, ezetimibe-glucuronide, reached maximum concentrations of 45 to 71 ng/mL at 1 to 2 hr after dosing (Prod Info Zetia(TM), 2002).
    • b. At steady-state doses of 10 or 20 milligrams (mg), maximum concentration (C-max) of ezetimibe was 131 nanograms/milliliter (ng/mL) and time to peak (t-max) was 1 hour in a cohort of healthy volunteers (Simard & Turgeon, 2003).
    • c. A single 20 milligram (mg) dose study in 8 healthy males found a maximum concentration (C-max) of 5.21 nanograms/milliliter (ng/mL) for ezetimibe at 9.88 hours, and a C-max of 61.2 mg/mL at 2.31 hours for the active glucuronide metabolite (Simard & Turgeon, 2003).
    • d. Plasma concentrations of simvastatin peaked at 4 hours and declined rapidly to approximately 10% of the peak by 12 hours postdose (Prod Info Vytorin(TM), 2004).
• B. AREA UNDER THE CURVE
  
  • 1. Area under the curve (AUC) was 86.4 nanograms (ng) x hour/milliliter (hr/mL) for ezetimibe and 636 ng x hr/mL for ezetimibe glucuronide, the active metabolite, in 8 healthy males who received a single 20 milligram dose (Simard & Turgeon, 2003).
  • 2. Area under the curve (AUC) values for ezetimibe were increased approximately 3 to 4-fold and 5 to 6-fold in patients with moderate (Child-Pugh score, 7 to 9) and severe (Child-Pugh score, 10 to 15) hepatic impairment, respectively. Ezetimibe/simvastatin is not recommended in patients with moderate or severe liver impairment, however, no dose adjustments are needed in those with mild hepatic impairment (Prod Info Vytorin(TM), 2004).

• A. BIOAVAILABILITY (F) :
  
  • 1. Oral: less than 5%, simvastatin (Prod Info Vytorin(TM), 2004)
    • a. Because of extensive first pass metabolism, less than 5% of an oral simvastatin dose reaches the general circulation as active inhibitors (Prod Info Vytorin(TM), 2004).
• B. EFFECTS OF FOOD : none (Prod Info Vytorin(TM), 2004).
  • 1. The administration of ezetimibe (10 milligram tablets) with a high-fat or non-fat meal did not affect the extent of absorption of ezetimibe. Plasma profiles of active and total inhibitors of HMG-CoA were not affected by the administration of simvastatin just prior to a low-fat meal (Prod Info Vytorin(TM), 2004).

• 2.3.2.1 DISTRIBUTION SITES
  • A. TOTAL PROTEIN BINDING : ezetimibe, greater than 90%; simvastatin, approximately 95% (Prod Info Vytorin(TM), 2004).
    • 1. Both ezetimibe and its active metabolite, ezetimibe glucuronide, are greater than 90% bound to plasma proteins (Prod Info Vytorin(TM), 2004).
    • 2. Both simvastatin and its beta-hydroxyacid metabolite are approximately 95% bound to plasma proteins (Prod Info Vytorin(TM), 2004).
  • B. OTHER DISTRIBUTION SITES :
    
    • 1. BILE, extensive (ezetimibe) (Bays et al, 2001).
      • a. Following intraduodenal administration, ezetimibe and its glucuronide conjugate appear in portal plasma and bile within minutes (Bays et al, 2001).
    • 2. LIVER, extensive (simvastatin) (Prod Info Vytorin(TM), 2004).
      • a. Liver is the primary site of action and has higher concentrations than non-target tissues (Prod Info Vytorin(TM), 2004).
• 2.3.2.2 DISTRIBUTION KINETICS
  • A. VOLUME OF DISTRIBUTION (Vd) : ezetimibe, 105.3 L (Simard & Turgeon, 2003).

• 2.3.3.1 METABOLISM SITES AND KINETICS
  • A. LIVER, extensive (simvastatin); extensive (ezetimibe) (Prod Info Vytorin(TM), 2004).
    • 1. Simvastatin, a prodrug, is hydrolyzed in the liver to the beta-hydroxyacid, the active inhibitor of HMG-CoA reductase (Prod Info Zocor(R), 2003).
    • 2. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion (Prod Info Vytorin(TM), 2004).
    • 3. Preclinical studies suggest that ezetimibe has no significant effect on drug metabolizing enzymes; it appears to have minimal propensity to interact with cytochrome P450 substrates (Bays et al, 2001).
  • B. SMALL INTESTINE, extensive (ezetimibe) (Prod Info Vytorin(TM), 2004; Miettinen, 2001; Bays et al, 2001).
    • 1. Ezetimibe undergoes extensive glucuronidation in the intestinal wall following absorption (Prod Info Vytorin(TM), 2004; Miettinen, 2001; Bays et al, 2001).
    • 2. Ezetimibe glucuronide, the major active metabolite, undergoes enterohepatic recirculation (Simard & Turgeon, 2003).
• 2.3.3.2 METABOLITES
  • A. Ezetimibe, ezetimibe glucuronide (active); simvastatin, beta-hydroxyacid form (active) (Prod Info Vytorin(TM), 2004).
    • 1. Ezetimibe is rapidly metabolized to ezetimibe glucuronide (Prod Info Vytorin(TM), 2004).
    • 2. The beta-hydroxyacid of simvastatin is the major active metabolite. Other hepatic metabolites include 6- hydroxy, 6-hydroxymethyl, and 6-exo-methylene derivatives (Prod Info Zocor(R), 2003). In addition, several other unidentified metabolites have been found in the bile (Mauro, 1993).

• 2.3.4.1 BREAST MILK
  • A. BREASTFEEDING : UNSAFE
    • 1. It is not known whether ezetimibe/simvastatin is excreted in breast milk. The manufacturer does not recommend the use of ezetimibe/simvastatin in breast feeding because small quantities of another drug in the same class as simvastatin are known to be excreted into breast milk and because of the potential for serious adverse reactions in nursing infants (Prod Info Vytorin(TM), 2004).
• 2.3.4.2 KIDNEY
  • A. RENAL EXCRETION: ezetimibe, 11%; simvastatin, 13% (Prod Info Vytorin(TM), 2004).
    • 1. Approximately 9% of the administered dose was detected as ezetimibe glucuronide (active metabolite) in the urine (Prod Info Vytorin(TM), 2004).
• 2.3.4.3 OTHER
  • A. OTHER EXCRETION :
    
    • 1. FECES, ezetimibe, 78%; simvastatin, 60% (Prod Info Vytorin(TM), 2004).
      • a. Approximately 69% of an administered ezetimibe dose was detected as unchanged drug in the feces (Prod Info Vytorin(TM), 2004).
      • b. For simvastatin, 60% of an oral dose was excreted in feces, this includes absorbed drug equivalents excreted in the bile, as well as any unabsorbed drug (Prod Info Vytorin(TM), 2004).

• 2.3.5.1 PARENT COMPOUND
  • A. ELIMINATION HALF-LIFE : ezetimibe, 22 hours; (Prod Info Vytorin(TM), 2004).
• 2.3.5.2 METABOLITES
  • A. Ezetimibe glucuronide, 22 hours (Prod Info Vytorin(TM), 2004).

• A. CENTRAL NERVOUS SYSTEM EFFECTS
  
  • 1. HEADACHE has been observed in 6.8% of patients following treatment with ezetimibe/simvastatin (Prod Info Vytorin(TM), 2004).
  • 2. ASTHENIA has been observed during simvastatin therapy (Prod Info Vytorin(TM), 2004).
  • 3. FATIGUE has been associated with the use of ezetimibe (Prod Info Vytorin(TM), 2004).

• A. GASTROINTESTINAL EFFECTS
  
  • 1. Gastrointestinal effects associated with ezetimibe or simvastatin therapy include ABDOMINAL PAIN, DIARRHEA, CONSTIPATION, DYSPEPSIA, FLATULENCE, and NAUSEA (Prod Info Vytorin(TM), 2004).

• A. HEPATOTOXICITY
  
  • 1. In three, 12-week trials, persistent ELEVATIONS IN SERUM TRANSAMINASES (eg, alanine aminotransferase) to more than 3 times the upper limit of normal occurred in about 1.7% of patients treated with ezetimibe/simvastatin. This occurrence appeared to be dose related, with an incidence of 2.6% for patients treated with ezetimibe/simvastatin 10/80 milligrams. The elevations in transaminases were primarily asymptomatic and not associated with cholestasis. Serum transaminases returned to pretreatment levels with discontinuation of ezetimibe/simvastatin therapy or with continued treatment. Discontinue therapy if serum transaminase levels rise to 3 times upper limit of normal and are persistent (Prod Info Vytorin(TM), 2004).

• A. OCULAR EFFECTS
  
  • 1. CATARACTS have been reported in patients following the use of simvastatin (Prod Info Vytorin(TM), 2004).

• A. RESPIRATORY EFFECTS
  
  • 1. INFLUENZA and UPPER RESPIRATORY TRACT INFECTION have been reported in 2.6% and 3.9% of patients, respectively, following the use of ezetimibe/simvastatin (Prod Info Vytorin(TM), 2004).
  • 2. COUGHING, PHARYNGITIS, SINUSITIS, and VIRAL INFECTION have been associated with the administration of ezetimibe (Prod Info Vytorin(TM), 2004).

• A. DERMATOLOGIC EFFECTS
  
  • 1. ECZEMA, PRURITUS, and RASH have been reported in patients following treatment with simvastatin (Prod Info Vytorin(TM), 2004).

• A. MUSCULOSKELETAL EFFECTS
  
  • 1. MYALGIA and PAIN IN EXTREMITIES have occurred in 3.5% and 2.3% of patients, respectively, following therapy with ezetimibe/simvastatin (Prod Info Vytorin(TM), 2004).
  • 2. ARTHRALGIA and BACK PAIN have been associated with the administration of ezetimibe (Prod Info Vytorin(TM), 2004).
• B. RHABDOMYOLYSIS
  
  • 1. Rare cases of rhabdomyolysis with acute renal failure have been reported in patients receiving simvastatin. The incidence of myopathy/rhabdomyolysis was less than 0.1% among subjects treated with simvastatin in the Heart Protection Study (n=10,269) (Anon, 2003). Concurrent administration of cyclosporine, gemfibrozil, nicotinic acid, macrolide antibiotics (erythromycin, clarithromycin), mibefradil, nefazodone, itraconazole, or ketoconazole may increase the risk of rhabdomyolysis; the benefits and risks of combined therapy should be carefully weighed (Prod Info Zocor(R), 1998; Tobert, 1988). Simvastatin should be temporarily withheld or stopped in patients with a condition suggestive of myopathy or risk factors for developing acute renal failure (ie, severe infection, hypotension, major surgery, trauma, severe metabolic or endocrine disorders, and uncontrolled seizures) (Prod Info Zocor(R), 2002). Others have NOT observed rhabdomyolysis when simvastatin 10 mg daily was administered to heart transplant patients receiving cyclosporine (Campana et al, 1995; Barbir et al, 1991).
  • 2. The risk of myopathy/rhabdomyolysis is dose related for simvastatin. In clinical trials, the incidence as been approximately 0.02% at 20 milligrams (mg), 0.07% at 40 mg, and 0.3% at 80 mg (Prod Info Vytorin(TM), 2004).

• A. OVERDOSE
  
• B. HYPERSENSITIVITY
  
  • 1. Hypersensitivity reactions, including ANGIOEDEMA and rash have been reported (Prod Info Vytorin(TM), 2004).

• 1. The U.S. Food and Drug Administration's Pregnancy Category X (Prod Info Vytorin(TM), 2004).
• 2. The safety of the use of ezetimibe/simvastatin has not been established in pregnant women. Treatment should be stopped immediately as soon as pregnancy is recognized. Women of childbearing age should only be treated with ezetimibe/simvastatin if they are highly unlikely to conceive and have been informed of the potential hazards (Prod Info Vytorin(TM), 2004).

• A. AMIODARONE
  
• B. AMPRENAVIR
  
• C. ATAZANAVIR
  
• D. BEZAFIBRATE
  
• E. CIPROFIBRATE
  
• F. CLARITHROMYCIN
  
• G. CLOFIBRATE
  
• H. CYCLOSPORINE
  
• I. DIGOXIN
  
• J. ERYTHROMYCIN
  
• K. FENOFIBRATE
  
• L. GEMFIBROZIL
  
• M. INDINAVIR
  
• N. ITRACONAZOLE
  
• O. KETOCONAZOLE
  
• P. NEFAZODONE
  
• Q. NELFINAVIR
  
• R. NIACIN
  
• S. PROPRANOLOL
  
• T. RITONAVIR
  
• U. SAQUINAVIR
  
• V. TIPRANAVIR
  
• W. VERAPAMIL
  
• X. WARFARIN
  

• A. GRAPEFRUIT JUICE
  

• A. LABORATORY PARAMETERS
  
  • 1. Lipid/lipoprotein profile periodically (to include low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides, apolipoprotein B)
• B. PHYSICAL EXAMINATION
  
  • 1. Cholesterol-lowering agents (ie, ezetimibe/simvastatin) are used as an adjunct to dietary restriction of cholesterol and saturated fats, weight reduction in overweight patients, and exercise. Weight reduction, adherence to diet and exercise should be assessed at routine follow-up.

• A. LABORATORY PARAMETERS
  
  • 1. Liver function tests should be performed prior to initiation of therapy and as clinically indicated during treatment. An additional test should be performed prior to titration to an ezetimibe/simvastatin dose of 10/80 milligrams (mg), 3 months following titration to the 10/80 mg dose, and semiannually for the first year of treatment. If an elevation in transaminases occurs, a second liver function evaluation should be performed to confirm the finding. Frequent liver function tests should be performed until the laboratory values return to normal. If increases of transaminases greater than 3 times the upper limit of normal or greater occur and persist, ezetimibe/simvastatin should be stopped (Prod Info Vytorin(TM), 2004).
• B. PHYSICAL EXAMINATION
  
  • 1. Patients should be questioned concerning muscle weakness, myalgias or muscle tenderness. If present, a creatine phosphokinase (CPK) should be obtained. If it is more than 10 times the upper limit of normal with suspected myopathy, discontinuation of ezetimibe/simvastatin is recommended.

• 1. Simvastatin, an HMG-CoA reductase inhibitor, and ezetimibe, a selective cholesterol absorption inhibitor, work in combination employing complementary mechanisms of action to produce dual inhibition of cholesterol absorption and synthesis (Prod Info Vytorin(TM), 2004).
• 2. Ezetimibe inhibits passage of dietary and biliary cholesterol across the brush border of the small intestine, with minimal or no effect on absorption of other soluble food nutrients (Prod Info Zetia(TM), 2002; Miettinen, 2001; Bays et al, 2001). Preliminary studies have indicated no significant effect of the drug on absorption of fat-soluble vitamins (Bays et al, 2001). Following absorption, ezetimibe is glucuronidated in the intestinal wall, and the parent drug and its glucuronide undergo enterohepatic recirculation, a characteristic that limits peripheral exposure (Miettinen, 2001; Bays et al, 2001).
• 3. Simvastatin is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). Inhibition of this enzyme results in lowering of plasma cholesterol by inhibiting the body's synthesis of cholesterol to a small extent, and, more importantly, increasing the number of low- density lipoprotein (LDL) receptors present on hepatic and extrahepatic tissues (Grundy, 1988; Slater & MacDonald, 1988). Simvastatin is effective in lowering total cholesterol, LDL cholesterol, and apolipoprotein B in hypercholesterolemic patients. Simvastatin tends to decrease triglycerides and raise HDL cholesterol (Walker, 1988; Walker, 1989; Stalenhoef et al, 1989; Illingworth & Bacon, 1989; Mol et al, 1986; Simons et al, 1987; Walker & Tobert, 1987; Mol et al, 1988; Molgaard et al, 1988; Olsson et al, 1986; Sirtori et al, 1989; Weisweiler & Schwandt, 1986; Saku et al, 1989; French et al, 1990; Catalano, 1990; Morgan, 1990).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, yes; pediatric, no 
  EFFICACY: Adult, effective
  DOCUMENTATION: Adult, excellent
  

• 2. SUMMARY :

  
   - Ezetimibe/simvastatin is indicated for the 
     treatment of homozygous familial 
     hypercholesterolemia as an adjunct to other 
     lipid-lowering treatments or as monotherapy 
     if such treatments are not available
  

• 3. ADULT :
  
  • a. Combination therapy with simvastatin and ezetimibe was more effective than simvastatin therapy alone in reducing low-density lipoprotein cholesterol (LDL- C) in patients with homozygous familial hypercholesterolemia. In a randomized, double-blind, 12 week study, a subgroup of patients (n=14) with homozygous familial hypercholesterolemia receiving simvastatin therapy (40 milligrams (mg)/day) at baseline received an increase in their simvastatin dose to 80 mg/day which produced a 13% reduction in LDL-C from baseline. A pooled analysis of the concurrent administration of ezetimibe (10 mg/day) and simvastatin (40 or 80 mg/day) showed a 23% reduction in LDL-C from baseline. In addition, an analysis of only those patients who received ezetimibe 10 mg with simvastatin 80 mg daily demonstrated a 29% reduction of LDL-C from baseline (Prod Info Vytorin(TM), 2004).
  • b. In patients with homozygous familial hypercholesterolemia (HoFH), a 12-week course of EZETIMIBE added to atorvastatin or SIMVASTATIN was well tolerated and produced significant additional lowering of low-density lipoprotein cholesterol (LDL- C) compared to that achieved with statin monotherapy. The study had 2 phases. Phase 1 was an open-label, lead-in phase of 6 to 14 weeks in which subjects with HoFH (by genotyping or clinical criteria) received 40 milligrams (mg) of either atorvastatin or simvastatin; phase 2 was a randomized, double-blind study over 12 weeks. In phase 2, patients were randomized into 3 groups: the statin-80 group, which received 80 mg/day of atorvastatin or simvastatin (n=17); the EZE 40 group, which received ezetimibe 10 mg/day plus 1 of the 2 statins given as 40 mg (n=16); and the EZE 80 group, given ezetimibe 10 mg/day plus an 80-mg statin dose (n=17). For analysis, the 2 ezetimibe groups were combined (EZE 40/80; n=33). Approximately, 85% of the total cohort were 18 years of age or older and 15% were between 12 and 17 years old. All subjects were required to follow the National Cholesterol Education Program Step 1 (or stricter) diet. After 12 weeks of treatment, LDL-C was reduced significantly more in the EZE 40/80 group than in the statin-80 group (20.7% versus 6.7%; p=0.007). Proportions of patients who achieved a 15% or greater reduction in LDL-C were 58% and 18% for the EZE 40/80 group and the statin- 80 group, respectively (p=0.001). Similar reductions were associated with EZE 40/80 treatment across sub-groups according to sex, age, race, baseline LDL-C, and receiving LDL apheresis or not. LDL-C was reduced among subjects receiving ezetimibe plus the higher dose statin 80 mg by 27.5% compared with 7.0% for subjects receiving statin 80-mg monotherapy (p=0.0001). For total cholesterol concentrations, reductions were 18.7% and 5.3% for the EZE 40/80 and statin-80 groups, respectively (p less than 0.01). Adverse events occurred in 73% and 65%, respectively of the EZE 40/80 and statin-80 groups; most common were headache, pharyngitis, and upper respiratory tract infection. One patient from each group had elevated liver enzymes (ALT and/or AST greater than 3 times the upper limit of normal); 2 patients in the EZE 40/80 group discontinued due to adverse effects (Gagne et al, 2002).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, yes; pediatric, no
  EFFICACY: Adult, effective
  DOCUMENTATION: Adult, excellent
  

• 2. SUMMARY :

  
   - Ezetimibe/simvastatin is indicated as adjunctive
     therapy to diet for the treatment of primary 
     hypercholesterolemia or mixed hyperlipidemia
  

• 3. ADULT :
  
  • a. In patients with primary hypercholesteremia, simvastatin monotherapy was less effective than combination therapy with simvastatin and ezetimibe in reducing total cholesterol, low-density lipoprotein cholesterol (LDL- C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C). In a double-blind, placebo-controlled, multicenter, 12-week trial, patients (n=1528) with hypercholesterolemia were randomized to one of the following ten treatment groups: placebo, ezetimibe (10 milligrams (mg)), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or ezetimibe/simvastatin ( 10/10 mg, 10/20 mg, 10/40 mg, or 10/80 mg). Significantly lower total cholesterol, LDL-C, Apo B, TG, and non-HDL-C levels were observed in patients in the ezetimibe/simvastatin groups as compared with those receiving all doses of simvastatin. The effects of ezetimibe/simvastatin on HDL-C were similar to the effects seen with simvastatin. Additional analysis showed that, as compared with placebo, ezetimibe/simvastatin significantly increased HDL-C (+0 vs +7, respectively) and decreased LDL- C (-2 vs -53, respectively). The lipid response to ezetimibe/simvastatin was similar in patients with TG levels greater than or less than 200 mg/deciliter (dL) (Prod Info Vytorin(TM), 2004).
  • b. Combination therapy with simvastatin and ezetimibe was more effective than atorvastatin treatment in reducing low-density lipoprotein cholesterol (LDL- C) in patients with primary hypercholesterolemia. In a randomized, double-blind, multicenter, 24 week study, patients (n=788) with primary hypercholesterolemia, who had failed to achieve their target LDL-C goal, received either a combination therapy with ezetimibe/simvastatin or atorvastatin monotherapy at initial doses of 10/10 milligrams (mg)/day, 10/20 mg/day or 10 mg/day, respectively. For all three treatment groups, the statin dose was titrated at 6-week intervals to 80 mg/day. At weeks 6, 12, 18, and 24, the ezetimibe/simvastatin therapy produced greater reductions in LDL-C as compared with atorvastatin. At the end of 24 treatment weeks, ezetimibe/simvastatin 10/80 mg produced greater reductions in LDL-C as compared with atorvastatin 80 mg (-59.4% vs -52.5%, respectively; p less than 0.001) and also produced greater increases in HDL-C (12.3% vs 6.5%, respectively; p less than 0.001) (Ballantyne et al, 2004).
  • c. Limited 2-week studies in patients with hypercholesterolemia have demonstrated greater reductions in low-density lipoprotein (LDL) cholesterol when ezetimibe was combined with a statin compared to statin monotherapy. Falls in LDL cholesterol of 51 to 59% have been achieved with ezetimibe 10 mg daily in combination with lovastatin 20 or 40 milligrams (mg) daily, simvastatin 10 or 20 mg daily, or atorvastatin 10 mg daily; this represents an additional reduction of LDL cholesterol by up to 25% with addition of ezetimibe (Bays et al, 2001; Miettinen, 2001). Lower doses of statins may be possible during combined therapy. In one 2-week study, LDL cholesterol was reduced by 52% with the combination of simvastatin 10 mg once daily plus ezetimibe 10 mg once daily, compared to a reduction of 35% with simvastatin 10 mg daily alone (Miettinen, 2001).