Pronunciation:
(ez ET i mibe & SIM va stat in)(ez ET i mibe & SIM va stat in)

U.S. Brand Names: Vytorin™

Generic Available: No

Use: Used in combination with dietary therapy for the treatment of primary hypercholesterolemia and homozygous familial hypercholesterolemia

Pregnancy Risk Factor: X

Pregnancy Implications: See individual agents.

Lactation: Excretion in breast milk unknown/contraindicated

Contraindications: Hypersensitivity to ezetimibe, simvastatin, or any component of the formulation; acute liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Warnings/Precautions: Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by laboratory assessment. Rhabdomyolysis with acute renal failure has occurred with simvastatin. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses

1 g/day) or during concurrent use with potent CYP3A4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors). Weigh the risk versus benefit when combining any of these drugs with a simvastatin-containing product. Use caution with renal or mild hepatic impairment; not recommended for use with moderate or severe hepatic impairment. Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Stop a few days prior to elective major surgery. Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Safety and efficacy have not been established in patients <10 years of age or premenarcheal girls.

Adverse Reactions: Percentages below refer to combination Vytorin™. Also see individual agents.

1% to 10%:

Central nervous system: Headache (7%)

Neuromuscular & skeletal: Myalgia (4%), pain in extremity (2%)

Overdosage/Toxicology: See individual agents.

Drug Interactions: Substrate of CYP3A4 (major); Inhibits CYP2C8/9 (weak), 2D6 (weak)

Amiodarone: May increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 20 mg/day.

Antacids: Plasma concentrations of simvastatin may be decreased when given with magnesium-aluminum hydroxide containing antacids (reported with atorvastatin).

Antifungals (imidazoles): May increase the levels/effects of simvastatin. Consider therapy modification.

Bile acid sequestrants reduces absorption of ezetimibe and simvastatin. Give

2 hours before or

4 hours after bile acid sequestrants.

Calcium channel blockers (nondihydropyridine) may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 20 mg/day when taking verapamil.

Cyclosporine: Concurrent use may increase the risk of myopathy and rhabdomyolysis; may increase level of ezetimibe also; dose of simvastatin should not exceed 10 mg/day. Consider modification of therapy if possible.

CYP3A4 inhibitors: May increase the levels/effects of simvastatin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Fibric acid derivatives: Increased risk of myopathy and rhabdomyolysis. May increase levels of ezetimibe.

Grapefruit juice may inhibit metabolism of simvastatin via CYP3A4; avoid high dietary intakes of grapefruit juice.

Niacin (

1 g/day): Concurrent use may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 10 mg/day.

Warfarin effects (hypoprothrombinemic response) may be increased; monitor INR closely when simvastatin is initiated, changed, or discontinued.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid excessive ethanol consumption (due to potential hepatic effects).

Food: Simvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of large quantities (>1 quart/day).

Herb/Nutraceutical: St John's wort may decrease simvastatin levels.

Stability: Store at 20°C to 25°C (68°F to 77°F)

Mechanism of Action:

Ezetimibe: Inhibits absorption of cholesterol at the brush border of the small intestine, leading to a decreased delivery of cholesterol to the liver.

Simvastatin: A methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis.

Pharmacodynamics/Kinetics: See individual agents.

Bioavailability: Vytorin™ is equivalent to coadministered ezetimibe and simvastatin.

Dosage: Oral: Adults:

Homozygous familial hypercholesterolemia: Ezetimibe 10 mg and simvastatin 40 mg once daily or ezetimibe 10 mg and simvastatin 80 mg once daily in the evening

Hyperlipidemias: Initial: Ezetimibe 10 mg and simvastatin 20 mg once daily in the evening

Patients who require >55% reduction in LDL-C: Initial: Ezetimibe 10 mg and simvastatin 40 mg once daily

Dosage adjustment with concomitant medications:

Cyclosporine: Patient must demonstrate tolerance to simvastatin

5 mg once daily. Dose should not exceed ezetimibe 10 mg and simvastatin 10 mg once daily.

Fibrates or niacin: Simvastatin dose should not exceed 10 mg/day.

Amiodarone or verapamil: Simvastatin dose should not exceed 20 mg/day.

Dosage adjustment in renal impairment: Dosage adjustment unnecessary in mild to moderate renal dysfunction. In severe dysfunction, start only if patient tolerates 5 mg daily of simvastatin; monitor closely.

Dosage adjustment in hepatic impairment: Dosage adjustment unnecessary in mild hepatic dysfunction.

Monitoring Parameters: Creatine phosphokinase levels due to possibility of myopathy; serum cholesterol (total and fractionated)

Obtain liver function tests prior to initiation, dosage increase, and thereafter when clinically indicated. Patients titrated to the simvastatin 80 mg dose should be tested prior to initiation and 3 months after initiating the 80 mg dose. Thereafter, periodic monitoring (ie, semiannually) is recommended for the first year of treatment. Patients with elevated transaminase levels should have a second (confirmatory) test and frequent monitoring until values normalize. Discontinue if increase in ALT/AST is persistently >3 times ULN.

Dietary Considerations: May be taken with or without food.

Dental Health: Effects on Dental Treatment: No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions: No information available to require special precautions

Mental Health: Effects on Mental Status: May cause dizziness or fatigue; may rarely cause anxiety, depression, insomnia, or memory loss

Mental Health: Effects on Psychiatric Treatment: Rhabdomyolysis with acute renal failure has occurred; risk increased with concurrent use of fluvoxamine, nefazodone, and verapamil

Dosage Forms: Tablet:

10/10: Ezetimibe 10 mg and simvastatin 10 mg

10/20: Ezetimibe 10 mg and simvastatin 20 mg

10/40: Ezetimibe 10 mg and simvastatin 40 mg

10/80: Ezetimibe 10 mg and simvastatin 80 mg