After a comprehensive review of all available data, the FDA is requesting all statin manufacturers to remove the contraindication in the prescribing information against using statins in pregnant patients. Although statin therapy should be discontinued in most pregnant patients, health care providers should consider the ongoing therapeutic needs of the individual patient, especially patients at very high risk of cardiovascular events during pregnancy, such as patients with homozygous familial hypercholesterolemia or those with established cardiovascular disease. Additionally, breastfeeding is still not recommended in patients taking a statin; health care providers should determine whether it is better to temporarily stop statin therapy while breastfeeding or to continue statin therapy and not have the patient breastfeed. If ongoing statin treatment is necessary, infant formula and other alternatives are available. The FDA expects that removing the contraindication will enable health care providers and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke.
Further information is available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy.
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 active liver disease or with unexplained transaminase elevations.
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. Incidences refer to combination, Vytorin. Also see individual agents.
1% to 10%:
Central nervous system: Headache (6%)
Gastrointestinal: Diarrhea (3%)
Hepatic: Increased serum ALT (4%)
Infection: Influenza (2%)
Neuromuscular & skeletal: Myalgia (4%), limb pain (2%), myopathy
Respiratory: Upper respiratory infection (4%)
Hypersensitivity to ezetimibe, simvastatin, or any component of this medication; coadministration with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, or danazol; active liver disease or unexplained persistent elevations in hepatic transaminases; pregnancy or use in women who may become pregnant; breastfeeding.
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, interrupt therapy. If an alternate etiology is not identified, do not restart simvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.
• Myopathy/Rhabdomyolysis: Rhabdomyolysis with acute renal failure secondary to myoglobinuria and/or myopathy have been reported; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, protease inhibitors), cyclosporine, fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day); 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.
• Hepatic impairment: Use is contraindicated with active liver disease and with unexplained transaminase elevations.
• 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.
Concurrent drug therapy issues:
• High potential for interactions: Use is contraindicated in patients taking strong CYP3A4 inhibitors, cyclosporine, danazol, and gemfibrozil (see Drug Interactions); if concurrent use of a contraindicated interacting medication is unavoidable, treatment with simvastatin should be suspended during use or consider the use of an alternative HMG-CoA reductase inhibitor void of CYP3A4 metabolism. Use caution and/or limit dose with amiodarone, amlodipine, diltiazem, ranolazine, verapamil, other fibrates, and lipid-lowering doses of niacin (≥1g/day).
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 - $11.19
10-20 mg (per each): $11.01 - $11.19
10-40 mg (per each): $11.01 - $11.19
10-80 mg (per each): $11.01 - $11.19
Tablets (Vytorin Oral)
10-10 mg (per each): $15.71
10-20 mg (per each): $15.71
10-40 mg (per each): $15.71
10-80 mg (per each): $15.71
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abiraterone Acetate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Amiodarone: May increase serum concentrations of the active metabolite(s) of Simvastatin. Amiodarone may increase the serum concentration 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 the 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 the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Azithromycin (Systemic): May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Risk C: Monitor therapy
Bempedoic Acid: May increase the 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 the absorption of Ezetimibe. Management: Administer ezetimibe at least 2 hours before or 4 hours after any bile acid sequestrant. Risk D: Consider therapy modification
Ciprofloxacin (Systemic): May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Ciprofloxacin (Systemic) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Colchicine. Risk C: Monitor therapy
CycloSPORINE (Systemic): May increase the serum concentration of Simvastatin. Risk X: Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Simvastatin. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Simvastatin. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Risk X: Avoid combination
CYP3A4 Inhibitors (Weak): May increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Cyproterone: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Dabigatran Etexilate: Simvastatin may enhance the anticoagulant effect of Dabigatran Etexilate. Risk C: Monitor therapy
Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Danazol: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
DAPTOmycin: Simvastatin may enhance the adverse/toxic effect of DAPTOmycin. Risk X: Avoid combination
Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Digoxin: Simvastatin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
DilTIAZem: Simvastatin may decrease the serum concentration of DilTIAZem. DilTIAZem may increase the 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
Dronedarone: May increase serum concentrations of the active metabolite(s) of Simvastatin. Dronedarone may increase the serum concentration 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
Elbasvir and Grazoprevir: May increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Encorafenib: May increase the serum concentration of Simvastatin. Encorafenib may decrease the serum concentration of Simvastatin. Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Erythromycin (Systemic): May increase serum concentrations of the active metabolite(s) of Simvastatin. Erythromycin (Systemic) may increase the serum concentration of Simvastatin. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. Risk C: Monitor therapy
Fenofibrate and Derivatives: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fenofibrate and Derivatives may increase the serum concentration of Ezetimibe. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fibric Acid Derivatives: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fibric Acid Derivatives may increase the serum concentration of Ezetimibe. Risk X: Avoid combination
Fosamprenavir: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Fostamatinib: May increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Fostemsavir: May increase the 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 enhance the adverse/toxic effect 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 combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Gemfibrozil may increase the serum concentration of Simvastatin. Concentrations of the active simvastatin acid metabolite may also be increased by gemfibrozil. Risk X: Avoid combination
Glecaprevir and Pibrentasvir: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Itraconazole: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Lacidipine: May increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Lanthanum: May decrease the 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 the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Leniolisib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Lercanidipine: May increase the serum concentration of Simvastatin. Management: Administer lercanidipine in the morning and simvastatin in the evening in patients receiving these drugs in combination. Risk D: Consider therapy modification
Letermovir: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Levamlodipine: May increase the 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 concentrations of the active metabolite(s) of Simvastatin. Lomitapide may increase the serum concentration 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 the serum concentration of Simvastatin. Risk X: Avoid combination
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Niacin: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the 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 the 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 combination
Nirogacestat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pretomanid: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Ranolazine: May increase the 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 enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Risk X: Avoid combination
Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Ritlecitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Roxadustat: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy
Rupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
St John's Wort: May decrease serum concentrations of the active metabolite(s) 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 the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Ticagrelor: May increase the 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 the serum concentration of Simvastatin. Risk X: Avoid combination
Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Risk C: Monitor therapy
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Trofinetide: May increase the 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
Verapamil: May increase serum concentrations of the active metabolite(s) of Simvastatin. Verapamil may increase the serum concentration 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 (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Voxilaprevir: May increase the 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
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.
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