simvastatin/ezetimibe (Rx)

Brand and Other Names:Vytorin
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Dosing & Uses

AdultPediatric

Dosage Forms & 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

Prescribing information 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)

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

Dosage Forms & 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

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Interactions

Interaction Checker

and simvastatin/ezetimibe

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (1)

              • cyclosporine

                cyclosporine, ezetimibe. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Monitor for potential adverse effects of cyclosporine and ezetimibe if coadministered, especially in patients with severe renal impairment.

              Monitor Closely (6)

              • apalutamide

                apalutamide will decrease the level or effect of ezetimibe by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and weakly induces OATP1B1 and may decrease systemic exposure of drugs that are substrates of both UGT and OATP1B1.

              • cholestyramine

                cholestyramine decreases levels of ezetimibe by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2-4 hours.

              • fostemsavir

                fostemsavir will increase the level or effect of ezetimibe by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 transporter. If possible, avoid coadministration or modify dose of OATP1B1/3 substrates coadministered with fostemsavir.

              • glecaprevir/pibrentasvir

                glecaprevir/pibrentasvir will increase the level or effect of ezetimibe by Other (see comment). Use Caution/Monitor. Coadministration with glecaprevir/pibrentasvir may increase plasma concentration of drugs that are substrates of OATP1B1 or OATP1B3

              • letermovir

                letermovir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.

              • sofosbuvir/velpatasvir

                sofosbuvir/velpatasvir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Velpatasvir inhibits OATP1B1, OATP1B3, and OATP2B1 transporters. .

              Minor (5)

              • fenofibrate

                fenofibrate increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • fenofibrate micronized

                fenofibrate micronized increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • fenofibric acid

                fenofibric acid increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • gemfibrozil

                gemfibrozil increases levels of ezetimibe by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • voclosporin

                voclosporin will increase the level or effect of ezetimibe by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.

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              Adverse 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

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              Warnings

              Contraindications

              Hypersensitivity to either component

              Active liver disease, or unexplained elevated transaminases

              Pregnancy, lactation

              Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, posaconazole, voriconazole, HIV protease inhibitors, nefazodone, 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
              • Risk of myopathy is greater in patients taking simvastatin 80 mg/day, especially in the 1st year of treatment
              • Risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid

              Immune-mediated necrotizing myopathy

              • Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported with statin use
              • IMNM is characterized by muscle biopsy showing necrotizing myopathy without significant inflammation improvement with immunosuppressive agents, proximal muscle weakness, and elevated serum creatine kinase, which persist despite discontinuation of statin treatment
              • Treatment with immunosuppressive agents may be required
              • Advice all patients starting therapy or whose dose is being increased, about the risk of myopathy, including rhabdomyolysis
              • Patients should report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing therapy; additional neuromuscular and serologic testing may be necessary
              • Therapy should be discontinued immediately if myopathy is diagnosed or suspected
              • Discontinue therapy if markedly elevated creatine kinase (CK) levels occur or if myopathy diagnosed or suspected
              • Therapy should be temporarily withheld in any patient experiencing an acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis, eg, sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy
              • Consider risk of IMNM carefully prior to initiation of a different statin
              • If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM
              • Additional neuromuscular and serologic testing may be necessary
              • Treatment with immunosuppressive agents may be required
              • Consider risk of IMNM carefully prior to initiation of a different statin
              • If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM

              Coadministration with niacin

              • Myopathy/rhabdomyolysis observed with simvastatin coadministered with lipid-modifying niacin doses (ie, ≥1 g/day); also observed when coadministered with daptomycin
              • Risk of myopathy is greater in Chinese patients, and therefore, coadministration of simvastatin with lipid-modifying niacin doses is not recommended in Chinese patients
              • Unknown if this risk applies to other patients of Asian descent
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              Pregnancy & Lactation

              Pregnancy

              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 use with statins during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero

              Lactation

              Unknown if simvastatin 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 breastfeed

              A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother

              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.

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              Pharmacology

              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 (http://optiviabio.com/index.html)
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              Administration

              Oral 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)

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              Patient Handout

              A Patient Handout is not currently available for this monograph.
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              Formulary

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              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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              Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.