Version July 2025
Dosage guidance:
Dosing: Simvastatin 80 mg is limited to patients who have been taking this dose for >12 consecutive months without evidence of myopathy and are not currently taking or beginning a simvastatin dose-limiting or contraindicated interacting medication. Simvastatin 20 to 40 mg/day is considered a moderate-intensity statin (generally reduces low-density lipoprotein cholesterol [LDL-C] by ~30% to 49%). If patient is unable to achieve LDL-C with 40 mg, do not increase to 80 mg dose. Instead, switch patient to a high-intensity statin (atorvastatin or rosuvastatin). Assess response ~1 to 3 months after initiation of therapy or dose adjustment and every 3 to 12 months thereafter (Ref).
Clinical considerations: Consider combination therapy in patients who do not meet cholesterol treatment goals with dietary modification plus maximally tolerated statin therapy. Refer to individual agents for more information (Ref).
Atherosclerotic cardiovascular disease, primary or secondary prevention: Note: Simvastatin is an alternative to a high-intensity statin for primary prevention in patients at high risk of atherosclerotic cardiovascular disease (ASCVD) or for secondary prevention of ASCVD. May use ezetimibe as an additional agent in patients who do not meet cholesterol treatment goals with dietary modification plus maximally tolerated statin therapy (Ref). See individual agents for more information.
Oral: Initial: Ezetimibe 10 mg/simvastatin 20 to 40 mg once daily in the evening. If low-density lipoprotein-cholesterol (LDL-C) goal (eg, percent reduction or absolute goal) is not met with the initial dose, may consider simvastatin up-titration to a maximum of 40 mg/day or switch to a high-intensity statin (atorvastatin or rosuvastatin) depending on estimated 10-year ASCVD risk (see ACC/AHA ASCVD Risk Estimator Plus online), LDL-C response, and tolerability (Ref).
Familial hypercholesterolemia, homozygous or heterozygous:
Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin. Multiple lipid-lowering agents are warranted in patients who do not meet cholesterol treatment goals with maximally tolerated statin therapy alone (Ref).
Oral: Ezetimibe 10 mg/simvastatin 40 mg once daily in the evening.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
GFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR <60 mL/minute/1.73 m2: Ezetimibe 10 mg and simvastatin 20 mg once daily in the evening (higher doses should be used with caution).
Use is contraindicated in patients with acute liver failure or decompensated cirrhosis.
Refer to adult dosing.
(For additional information see "Ezetimibe and simvastatin: Pediatric drug information")
Dosage guidance:
Dosing: Based on adults, a lower, conservative dosing regimen may be necessary in patient populations predisposed to myopathy, including patients of Chinese descent or those concurrently receiving other lipid-lowering agents (eg, niacin, fibric acid derivatives), amiodarone, amlodipine, diltiazem, dronedarone, ranolazine, or verapamil. Dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks.
Clinical considerations: Lifestyle changes are recommended to be implemented for at least 6 to 12 months before beginning pharmacotherapy (Ref).
Heterozygous familial hypercholesterolemia: Limited data available: Children ≥10 years and Adolescents (males and postmenarchal females): Oral: Initial: Ezetimibe 10 mg and simvastatin 10 to 20 mg once daily in the evening. Reported final dosing range: Ezetimibe 10 mg and simvastatin 10 to 40 mg once daily; maximum dose: Ezetimibe 10 mg and simvastatin 40 mg (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: Muscle symptoms (potential myopathy): Children ≥10 years and Adolescents: Discontinue use until symptoms can be evaluated; check CPK level; based on experience in adult patients, also evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution (symptoms and any associated CPK abnormalities), resume the original or consider a lower dose of simvastatin and retitrate. If muscle symptoms recur, discontinue simvastatin use. After muscle symptom resolution, may then reinitiate a different statin at an initial low dose; gradually increase if tolerated. Based on experience in adult patients, if muscle symptoms or elevated CPK persists for 2 months in the absence of continued statin use, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (Ref).
KDIGO recommendations (Ref): Children and Adolescents: Multidrug regimens (including ezetimibe and simvastatin) are not recommended for pediatric patients with chronic kidney disease, regardless of severity of LDL elevation.
There are no pediatric-specific recommendations; for adults, use is contraindicated in patients with active liver disease or with unexplained transaminase elevations.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
1% to 10%:
Gastrointestinal: Diarrhea (3%)
Hepatic: Increased serum alanine aminotransferase (4%)
Infection: Influenza (2%)
Nervous system: Headache (6%)
Neuromuscular & skeletal: Limb pain (2%), myalgia (4%)
Respiratory: Upper respiratory tract infection (4%)
Frequency not defined:
Hepatic: Increased serum aspartate aminotransferase
Neuromuscular & skeletal: Back pain
Postmarketing:
Cardiovascular: Flushing, vasculitis
Dermatologic: Alopecia, erythema multiforme, lichen planus, pruritus, purpuric rash, skin changes (including changes in nails, changes of hair, cutaneous nodule, dry mucous membranes, skin discoloration, xeroderma), skin photosensitivity, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Elevated glycosylated hemoglobin, increase in fasting plasma glucose
Gastrointestinal: Cholecystitis, cholelithiasis, nausea, pancreatitis, vomiting
Genitourinary: Erectile dysfunction
Hematologic & oncologic: Anemia, eosinophilia, hemolytic anemia, increased erythrocyte sedimentation rate, leukemia, positive ANA titer, thrombocytopenia
Hepatic: Hepatic failure, hepatitis, increased serum transaminases, jaundice
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, angioedema)
Immunologic: Dermatomyositis
Nervous system: Asthenia, chills, depression, dizziness, malaise, paresthesia, peripheral neuropathy
Neuromuscular & skeletal: Arthralgia, arthritis, immune-mediated necrotizing myopathy, increased creatine phosphokinase in blood specimen, lupus-like syndrome, muscle cramps, polymyalgia rheumatica, rhabdomyolysis
Respiratory: Dyspnea, interstitial lung disease
Miscellaneous: Fever
Hypersensitivity to ezetimibe, simvastatin, or any component of this medication; concomitant use of strong CYP3A4 inhibitors (select azole antifungals, macrolide antibiotics, antiviral medications, and nefazodone), cyclosporine, danazol, or gemfibrozil; acute liver failure or decompensated cirrhosis.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Diabetes mellitus: Increases in HbA1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.
• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, discontinue therapy. If an alternate etiology is not identified, do not restart simvastatin. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.
• Myopathy/Rhabdomyolysis: Rhabdomyolysis (rarely fatal) with acute renal failure secondary to myoglobinuria and/or myopathy have been reported. This risk is dose-related and is increased with concomitant use of interacting medications. Consult drug interactions database for more detailed information. If concurrent use is warranted, consider lower starting and maintenance doses of simvastatin. Use caution in patients with inadequately treated hypothyroidism, ≥65 years of age, women, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitor use has also been reported. Myopathy and rhabdomyolysis also have been reported with ezetimibe monotherapy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected; consider treatment with immunosuppressants and additional neuromuscular and serologic testing. Prior to initiating a different HMG-CoA reductase inhibitor consider risk of IMNM; monitor closely.
Disease-related concerns:
• Ethanol: Use caution in patients who consume large amounts of alcohol and/or who have a past history of liver disease.
• Myasthenia gravis: May rarely worsen or precipitate myasthenia gravis (MG); monitor for worsening MG if treatment is initiated (AAN [Narayanaswami 2021]).
• Renal impairment: Avoid use in patients with severe renal impairment (creatinine clearance not defined) unless patient has already tolerated simvastatin at a dose ≥5 mg; use doses of simvastatin >20 mg/day with caution and monitor closely for adverse events (eg, myopathy) in patients with moderate-to-severe renal impairment (ie, CrCl <60 mL/minute/1.73 m2). Initial dosage adjustment is not necessary in mild-to-moderate impairment. Renal impairment may also increase risk for myopathy.
Special populations:
• Children: Coadministration of ezetimibe with simvastatin at dosages of more than 40 mg/day has not been studied in adolescents. Also, ezetimibe/simvastatin has not been studied in patients <10 years of age or in premenarchal girls.
• Chinese patients: Increased risk of myopathy; use with caution. Coadministration of ezetimibe/simvastatin with niacin ≥1 g/day is not recommended in Chinese patients; it is not known if this also applies to other Asian patients.
• Older adult: Use with caution in patients ≥65 years of age; these patients are predisposed to myopathy.
• Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.
Other warnings/precautions:
• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Vytorin: ezetimibe 10 mg and simvastatin 10 mg, ezetimibe 10 mg and simvastatin 20 mg, ezetimibe 10 mg and simvastatin 40 mg, ezetimibe 10 mg and simvastatin 80 mg
Generic: ezetimibe 10 mg and simvastatin 10 mg, ezetimibe 10 mg and simvastatin 20 mg, ezetimibe 10 mg and simvastatin 40 mg, ezetimibe 10 mg and simvastatin 80 mg
Yes
Tablets (Ezetimibe-Simvastatin Oral)
10-10 mg (per each): $11.01 - $11.10
10-20 mg (per each): $11.01 - $11.10
10-40 mg (per each): $11.01 - $11.10
10-80 mg (per each): $11.01 - $11.10
Tablets (Vytorin Oral)
10-10 mg (per each): $16.49
10-20 mg (per each): $16.49
10-40 mg (per each): $16.49
10-80 mg (per each): $16.49
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: May be administered without regard to meals. Administer in the evening for maximal efficacy. Ezetimibe/simvastatin should be taken ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
Oral: May be administered without regard to meals. Administration with the evening meal or at bedtime has been associated with somewhat greater LDL-C reduction. Ezetimibe/simvastatin should be taken ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
Atherosclerotic cardiovascular disease, primary or secondary prevention: As an adjunct to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C), and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.
Familial hypercholesterolemia, homozygous or heterozygous: As an adjunct to diet for the reduction of elevated total-C and LDL-C in patients with heterozygous or homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments.
Limitations of use: Ezetimibe/simvastatin has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
Vytorin may be confused with Vyvanse
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abiraterone Acetate: May increase myopathic (rhabdomyolysis) effects of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Acipimox: May increase myopathic (rhabdomyolysis) effects of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Aldesleukin: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Amiodarone: May increase serum concentration of Simvastatin. Amiodarone may increase active metabolite exposure of Simvastatin. Management: Consider using a non-interacting statin (pravastatin) in patients on amiodarone. If combined, limit the adult simvastatin dose to 20 mg daily and monitor for evidence of simvastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). Risk D: Consider Therapy Modification
AmLODIPine: May increase serum concentration of Simvastatin. Management: Dose of simvastatin should not exceed 20 mg daily if coadministering with amlodipine. If coadministering with simvastatin and amlodipine, close laboratory and clinical monitoring for signs and symptoms of rhabdomyolysis is warranted. Risk D: Consider Therapy Modification
Asciminib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Avacopan: May increase serum concentration of Simvastatin. Management: Limit the simvastatin dose to 10 mg daily (or 20 mg daily for patients who previously tolerated simvastatin 80 mg daily for at least 1 year without evidence of myopathy) in patients treated with avacopan. Monitor for increased simvastatin toxicities. Risk D: Consider Therapy Modification
Azithromycin (Systemic): May increase myopathic (rhabdomyolysis) effects of Simvastatin. Risk C: Monitor
Belumosudil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid coadministration of belumosudil with these substrates of OATP1B1/1B3 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the OATP1B1/1B3 substrate may be required. Risk D: Consider Therapy Modification
Bempedoic Acid: May increase serum concentration of Simvastatin. Management: Avoid coadministration of bempedoic acid with simvastatin doses greater than 20 mg due to the potential for increased simvastatin concentrations and simvastatin-related myopathy. Risk D: Consider Therapy Modification
Bile Acid Sequestrants: May decrease absorption of Ezetimibe. Management: Administer ezetimibe at least 2 hours before or 4 hours after any bile acid sequestrant. Risk D: Consider Therapy Modification
Bulevirtide: Ezetimibe may decrease therapeutic effects of Bulevirtide. Risk X: Avoid
Ceftobiprole Medocaril: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
Ciprofloxacin (Systemic): May increase myopathic (rhabdomyolysis) effects of Simvastatin. Ciprofloxacin (Systemic) may increase serum concentration of Simvastatin. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
Colchicine: May increase myopathic (rhabdomyolysis) effects of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). HMG-CoA Reductase Inhibitors (Statins) may increase serum concentration of Colchicine. Risk C: Monitor
CycloSPORINE (Systemic): May increase serum concentration of Simvastatin. Risk X: Avoid
CYP3A4 Inducers (Moderate): May decrease serum concentration of Simvastatin. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Simvastatin. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase serum concentration of Simvastatin. CYP3A4 Inhibitors (Moderate) may increase active metabolite exposure of Simvastatin. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase active metabolite exposure of Simvastatin. CYP3A4 Inhibitors (Strong) may increase serum concentration of Simvastatin. Risk X: Avoid
CYP3A4 Inhibitors (Weak): May increase serum concentration of Simvastatin. CYP3A4 Inhibitors (Weak) may increase active metabolite exposure of Simvastatin. Risk C: Monitor
Cyproterone: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Dabigatran Etexilate: Simvastatin may increase anticoagulant effects of Dabigatran Etexilate. Risk C: Monitor
Daclatasvir: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Danazol: May increase serum concentration of Simvastatin. Risk X: Avoid
DAPTOmycin: Simvastatin may increase adverse/toxic effects of DAPTOmycin. Risk X: Avoid
Darolutamide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Digoxin: Simvastatin may increase serum concentration of Digoxin. Risk C: Monitor
DilTIAZem: Simvastatin may decrease serum concentration of DilTIAZem. DilTIAZem may increase serum concentration of Simvastatin. Management: Avoid concurrent use of diltiazem with simvastatin when possible. If used together, limit adult doses to simvastatin 10 mg daily and diltiazem 240 mg per day; monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider Therapy Modification
Dinutuximab Beta: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Dronedarone: May increase serum concentration of Simvastatin. Dronedarone may increase active metabolite exposure of Simvastatin. Management: Carefully consider the potential risks and benefits of this combination. If coadministered, limit adult simvastatin dose to 10 mg daily, and monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider Therapy Modification
Elafibranor: May increase adverse/toxic effects of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk of muscle toxicity may be increased. Risk C: Monitor
Elbasvir and Grazoprevir: May increase serum concentration of Simvastatin. Risk C: Monitor
Elexacaftor, Tezacaftor, and Ivacaftor: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Elranatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Eltrombopag: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Encorafenib: May increase serum concentration of Simvastatin. Encorafenib may decrease serum concentration of Simvastatin. Risk C: Monitor
Epcoritamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Erythromycin (Systemic): May increase active metabolite exposure of Simvastatin. Erythromycin (Systemic) may increase serum concentration of Simvastatin. Risk X: Avoid
Etravirine: May decrease serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. Risk C: Monitor
Fenofibrate and Derivatives: May increase adverse/toxic effects of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fenofibrate and Derivatives may increase serum concentration of Ezetimibe. Risk C: Monitor
Fibric Acid Derivatives: May increase adverse/toxic effects of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fibric Acid Derivatives may increase serum concentration of Ezetimibe. Risk X: Avoid
Fosamprenavir: May increase serum concentration of Simvastatin. Risk X: Avoid
Fostamatinib: May increase serum concentration of Simvastatin. Risk C: Monitor
Fostemsavir: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest possible starting statin dose and monitor patients closely for statin-related adverse effects (eg, muscle aches and pains) during coadministration with fostemsavir. Risk D: Consider Therapy Modification
Fusidic Acid (Systemic): May increase adverse/toxic effects of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Risk X: Avoid
Gemfibrozil: May increase myopathic (rhabdomyolysis) effects of Simvastatin. Gemfibrozil may increase serum concentration of Simvastatin. Concentrations of the active simvastatin acid metabolite may also be increased by gemfibrozil. Risk X: Avoid
Gepotidacin: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid
Givinostat: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Glecaprevir and Pibrentasvir: May increase serum concentration of Simvastatin. Risk X: Avoid
Glofitamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Grapefruit Juice: May increase serum concentration of Simvastatin. Risk X: Avoid
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Itraconazole: May increase serum concentration of Simvastatin. Risk X: Avoid
Lacidipine: May increase serum concentration of Simvastatin. Risk C: Monitor
Lanthanum: May decrease serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Administer HMG-CoA reductase inhibitors (eg, statins) at least two hours before or after lanthanum. Risk D: Consider Therapy Modification
Leflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Leniolisib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
Letermovir: May increase serum concentration of Simvastatin. Risk X: Avoid
Levamlodipine: May increase serum concentration of Simvastatin. Management: Limit simvastatin dose to 20 mg daily and monitor closely for signs and symptoms of rhabdomyolysis (eg, creatinine phosphokinase, muscle aches and pains) if coadministering with levamlodipine. Risk D: Consider Therapy Modification
Lomitapide: May increase serum concentration of Simvastatin. Lomitapide may increase active metabolite exposure of Simvastatin. Management: Reduce the recommended simvastatin dose by 50%. Generally, limit the maximum adult simvastatin dose to 20 mg/day. A 40 mg/day dose can be considered in patients who previously received 80 mg/day for at least a year without evidence of muscle toxicity. Risk D: Consider Therapy Modification
Lonafarnib: May increase serum concentration of Simvastatin. Risk X: Avoid
Mosunetuzumab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Niacin: May increase myopathic (rhabdomyolysis) effects of Simvastatin. Niacin may increase serum concentration of Simvastatin. Management: Avoid this combination in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. If coadministered, consider simvastatin dose reductions and monitor closely for signs and symptoms of muscle toxicity. Risk D: Consider Therapy Modification
Nirmatrelvir and Ritonavir: May increase serum concentration of Simvastatin. Management: Discontinue simvastatin at least 12 hours prior to initiating nirmatrelvir and ritonavir, and do not restart simvastatin until 5 days after completing nirmatrelvir and ritonavir treatment. Risk X: Avoid
Pretomanid: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
QuiNINE: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Raltegravir: May increase myopathic (rhabdomyolysis) effects of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Ranolazine: May increase serum concentration of Simvastatin. Management: Carefully consider the potential benefits and risks of this combination. Limit simvastatin to 20 mg daily if coadministered, and monitor closely for signs and symptoms of myopathy or rhabdomyolysis. Risk D: Consider Therapy Modification
Red Yeast Rice: May increase adverse/toxic effects of HMG-CoA Reductase Inhibitors (Statins). Risk X: Avoid
Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase serum concentration of Repaglinide. Risk C: Monitor
Resmetirom: May increase serum concentration of Simvastatin. Management: Limit the simvastatin dose to 20 mg daily during coadministration with resmetirom. Monitor for increased simvastatin adverse effects (eg, myalgias) during coadministration. Risk D: Consider Therapy Modification
Ritlecitinib: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Roxadustat: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Rupatadine: May increase adverse/toxic effects of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Risk C: Monitor
Simeprevir: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor
Spironolactone: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
St John's Wort: May decrease active metabolite exposure of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding the concomitant administration of St John's Wort with atorvastatin, lovastatin and simvastatin in order to avoid the potential for decreased effects statins. If coadministered, monitor for decreased statin efficacy. Risk D: Consider Therapy Modification
Talquetamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tarlatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Teclistamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Teriflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Ticagrelor: May increase serum concentration of Simvastatin. Management: Avoid using doses of simvastatin greater than 40 mg/day with ticagrelor. Monitor for increased systemic effects of simvastatin in patients receiving concurrent ticagrelor. Risk D: Consider Therapy Modification
Tipranavir: May increase serum concentration of Simvastatin. Risk X: Avoid
Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may increase myopathic (rhabdomyolysis) effects of Trabectedin. Risk C: Monitor
Treosulfan: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Trofinetide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider Therapy Modification
Vadadustat: May increase serum concentration of Simvastatin. Management: Initiate simvastatin at 5 mg daily and no not exceed 20 mg daily during coadministration with vadadustat. Monitor patients for simvastatin adverse effects (eg, myopathy) during any combined use. Risk D: Consider Therapy Modification
Verapamil: May increase serum concentration of Simvastatin. Verapamil may increase active metabolite exposure of Simvastatin. Management: Carefully consider the potential risks and benefits of this combination. If coadministered, limit adult simvastatin dose to 10 mg daily, and monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Risk D: Consider Therapy Modification
Vitamin K Antagonists: HMG-CoA Reductase Inhibitors (Statins) may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor
Voclosporin: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Voxilaprevir: May increase serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Risk D: Consider Therapy Modification
Xanomeline: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
See individual agents.
Use is contraindicated in women who may become pregnant.
Use is contraindicated in pregnant women. See individual monographs for additional information.
It is not known if ezetimibe or simvastatin are present in breast milk. Use is contraindicated in breastfeeding women. See individual agents.
Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 3 to 6 months and the diet should be continued during drug therapy. Simvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of grapefruit juice.
Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi 2008; Smith 2003).
Manufacturer's labeling:
Consider neuromuscular and serologic testing if immune-mediated necrotizing myopathy is suspected.
American College of Cardiology/American Heart Association blood cholesterol guideline recommendations (ACC/AHA [Grundy 2019]:
Lipid panel (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides): Baseline lipid panel; fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter. If 2 consecutive low-density lipoprotein levels are <40 mg/dL, consider decreasing the dose.
Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (AST and ALT); measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, yellowing of skin or sclera) during therapy.
CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).
Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.
If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.
Ezetimibe: Inhibits absorption of cholesterol at the brush border of the small intestine, leading to a decreased delivery of cholesterol to the liver. Ezetimibe inhibits the enzyme Niemann-Pick C1-Like1 (NPC1L1), a sterol transporter.
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. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus 2002; Ray 2005).
See individual agents.
Bioavailability: Vytorin is equivalent to coadministered ezetimibe and simvastatin.
