simvastatin/ezetimibe (Vytorin)
Classes: Lipid-Lowering Agents, Statins; HMG-CoA Reductase Inhibitors
Dosing and uses of Vytorin (simvastatin/ezetimibe)
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)