simvastatin/ezetimibe (Vytorin)

Dosing and uses of Vytorin (simvastatin/ezetimibe)

• Adult
• Pediatric

 

Adult dosage forms and strengths

simvastatin/ezetimibe

tablet

• 10mg/10mg
• 10mg/20mg
• 10mg/40mg
• 10mg/80mg

 

Hypercholesterolemia

10 mg/10 mg/day-10 mg/40 mg/day PO qHs

Usual starting dose: 10 mg/20 mg PO qHs

Simvastatin 80 mg/day should only be used for individuals who have been taking a simvastatin dose of 80 mg for 12 months or longer without evidence of myopathy

FDA advises if patients are taking simvastatin 40 mg/day without meeting their LDL goal to switch to a different statin rather than increase to 80 mg/day

 

Dosage modifications

Coadministration with dronedarone, verapamil, or diltiazem: Do not exceed 10 mg/day

Coadministration with amiodarone, amlodipine, or ranolazine: Do not exceed 20 mg/day

Coadministration with lomitapide: Reduce simvastatin dose by 50% and do not exceed 20 mg/day (or 40 mg/day in those previously tolerating 80 mg/day) when initiating lomitapide

Grapefruit juice: Avoid large quantities of grapefruit juice (ie, ≥1 quart/day)

Chinese patients taking lipid-modifying doses of niacin (ie, ≥1 g/day): Increased risk of myopathy with simvastatin 40 mg/day; consider lower dose

Renal impairment

• GFR ≥60 mL/min/1.73 m²: Dose adjustment not necessary
• GFR <60 mL/min/1.73 m²: 10 mg ezetimibe and 20 mg simvastatin PO qDay; may use higher doses with caution

Hepatic impairment

• Mild: Dosage adjustment not required
• Moderate-to-severe: Not recommended

 

Administration

Patient should be placed on standard cholesterol-lowering diet before receiving drug

Administer >2 hr before or >4 hr after bile acid sequestrant (eg, cholestyramine)

 

Pediatric dosage forms and strengths

simvastatin/ezetimibe

tablet

• 10mg/10mg
• 10mg/20mg
• 10mg/40mg

 

Heterozygous Familial Hypercholesterolemia

<10 years: Safety and efficacy not established

10-18 years: 10 mg/10 mg/day-10 mg/40 mg/day PO qHs

Simvastatin 80 mg/day should only be used for individuals who have been taking a simvastatin dose of 80 mg for 12 months or longer without evidence of myopathy  

FDA advises if patients are taking simvastatin 40 mg/day without meeting their LDL goal to switch to a different statin rather than increase to 80 mg/day

 

Vytorin (simvastatin/ezetimibe) adverse (side) effects

1-10%

Headache (6.8%)

Upper respiratory tract infection (3.9%)

Myalgia (3.5%)

Increased ALT (4%)

Influenza (2.6%)

Pain in extremity (2.3%)

 

Postmarketing Reports

Erectile dysfunction

Interstitial lung disease

Rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use

 

Warnings

Contraindications

Hypersensitivity to either component

Active liver disease, or unexplained elevated transaminases

Pregnancy, lactation

Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, posaconazole, voriconazole, HIV protease inhibitors, nefazodone, boceprevir, telaprevir, cobicistat), fibrates (including gemfibrozil), cyclosporine, and danazoL

 

Cautions

Monitor liver function tests before initiating treatment and thereafter when clinically indicated; reports of fatal and non-fatal hepatic failure in patients taking statins

Discontinue if markedly elevated CPK levels occur or myopathy is diagnosed or suspected

Increased HbA1c and fasting serum glucose levels reported with HMG-CoA reductase inhibitors

Avoid use in severe renal impairment

High potential for drug interactions

Simvastatin and myopathy risk

• Dose adjustment required when coadministered with niacin, amiodarone, verapamil, diltiazem, amlodipine, and ranolazine
• Predisposing factors for myopathy include advanced age (>65 years), uncontrolled hypothyroidism, and renal impairment
• Increased risk for myopathy in Chinese patients coadministered niacin >1 g/day
• Risk of myopathy is greater in patients taking simvastatin 80 mg/day, especially in the 1st year of treatment
• Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin
• Risk for myopathy increased when coadministered with other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), colchicine, amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine
• See Contraindications for list of drugs contraindicated because of increased risk for myopathy when coadministered with simvastatin
• See Adult Dosing for dose limitations

 

Pregnancy and lactation

Pregnancy category: X

Lactation: do not take if nursing

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Vytorin (simvastatin/ezetimibe)

Mechanism of action

Simvastatin: HMG-CoA reductase inhibitor, inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

Ezetimibe: Inhibits intestinal absorption of cholesterol at brush border

 

Pharmacokinetics

Simvastatin

• Onset: >3 days; 2 weeks (peak effect)
• Bioavailability: <5%
• Protein binding: 95%
• Peak plasma time: 1.3-2.4 hr
• Excretion: Feces (60%); urine (13%)

Ezetimibe

• Bioavailability: Variable
• Peak plasma time: 4-12 hr
• Excretioin: Feces (78%); urine (11%)
• Half-life: 22 hr
• Metabolism: Undergoes glucuronide conjugation in the small intestine and liver

 

Pharmacogenomics

SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)

Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

• Optivia Biotechnology, Inc (https://optiviabio.com/index.html)