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Simvastatin

Medically reviewed by Drugs.com. Last updated on Jul 29, 2020.

Pronunciation

(sim va STAT in)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Oral:

FloLipid: 20 mg/5 mL (150 mL); 40 mg/5 mL (150 mL) [contains ethylparaben, methylparaben, propylene glycol, propylparaben]

Generic: 20 mg/5 mL (75 mL [DSC])

Tablet, Oral:

Zocor: 5 mg [DSC], 10 mg, 20 mg, 40 mg, 80 mg

Generic: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Brand Names: U.S.

  • FloLipid
  • Zocor

Pharmacologic Category

  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

Simvastatin is 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).

Absorption

Although 85% is absorbed following administration, <5% reaches the general circulation due to an extensive first-pass effect

Metabolism

Hepatic via CYP3A4; extensive first-pass effect

Excretion

Feces (60%); urine (13%)

Onset of Action

Onset of action: >3 days; Peak effect: 2 weeks.

LDL-C reduction: 20 to 40 mg/day: 35% to 41%.

Average HDL-C increase: 5% to 15%.

Average triglyceride reduction: 7% to 30%.

Time to Peak

1.3 to 2.4 hours

Half-Life Elimination

Unknown

Protein Binding

~95%

Special Populations: Renal Function Impairment

Higher systemic exposure may be achieved in patients with severe renal insufficiency.

Special Populations: Elderly

Mean plasma level of HMG-CoA reductase inhibitory activity is increased approximately 45%.

Use: Labeled Indications

Heterozygous familial hypercholesterolemia: To reduce elevated total cholesterol (total-C), LDL-C, apoB, and triglyceride levels, and to increase HDL-C in patients with primary hypercholesterolemia.

Heterozygous familial hypercholesterolemia (pediatrics): To reduce total-C, LDL-C, and apoB levels in boys and postmenarche girls 10 to 17 years of age with heterozygous familial hypercholesterolemia with either LDL-C ≥190 mg/dL, LDL-C ≥160 mg/dL with positive family history of premature cardiovascular disease (CVD), or LDL-C ≥160 mg/dL with 2 or more other CVD risk factors.

Homozygous familial hypercholesterolemia: To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Prevention of atherosclerotic cardiovascular disease:

Primary prevention of atherosclerotic cardiovascular disease: To reduce the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in adults without a history of coronary heart disease (CHD) but who have multiple CHD risk factors.

Secondary prevention in patients with established atherosclerotic cardiovascular disease: To reduce the risk of MI, stroke, revascularization procedures, and angina in patients with a history of CHD.

Off Label Uses

Transplantation, post kidney

Based on the 2013 Kidney Disease: Improving Global Outcomes clinical practice guideline for lipid management in chronic kidney disease, simvastatin is suggested following kidney transplant to reduce cardiovascular events (eg, myocardial infarction, stroke, cardiovascular death) [KDIGO 2013].

Contraindications

Hypersensitivity to simvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil; pregnancy or women who may become pregnant; breastfeeding

Dosing: Adult

Note: Use in conjunction with lifestyle modification (eg, diet and exercise). When choosing to initiate therapy and selecting dose intensity, consider the following: age, baseline LDL-C, 10-year atherosclerotic cardiovascular disease (ASCVD) risk, risk-enhancing factors, potential adverse effects, and drug interactions. Simvastatin is considered a moderate-intensity statin at doses of 20 to 40 mg/day (generally reduces LDL-C by ~30% to 49%). If LDL-C must be lowered ≥50%, select an alternative 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. Safety: Dosing limitation: Simvastatin 80 mg/day is not recommended due to increased risk of myopathy. If patient is unable to achieve LDL-C goal with simvastatin 40 mg/day, switch to a high-intensity statin (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Heterozygous familial hypercholesterolemia (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin. Multiple lipid-lowering therapies may be needed if statin monotherapy is not effective. Referral to a lipid specialist should be considered if treatment goals are not met (ACC/AHA [Grundy 2019]; Rosenson 2020a).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Homozygous familial hypercholesterolemia (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin. Multiple lipid-lowering therapies may be needed if statin monotherapy is not effective. Referral to a lipid specialist should be considered if treatment goals are not met (ACC/AHA [Grundy 2019]; Rosenson 2020a).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Prevention of atherosclerotic cardiovascular disease:

Note: If LDL-C goal (eg, percent reduction or absolute goal) is not met with the initial dose, may consider up-titration to a maximum of 40 mg/day based on estimated 10-year ASCVD risk (see ACC/AHA ASCVD Risk Estimator Plus online), LDL-C response, and tolerability. If LDL-C goal is not met with maximally tolerated dose, consider switching to a high-intensity statin (atorvastatin or rosuvastatin); additional lipid-lowering therapy may be warranted (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Primary prevention:

Patients without diabetes, 40 to 75 years of age, and LDL-C 70 to 189 mg/dL:

ASCVD 10-year risk 5% to <7.5%:

Note: Depending on baseline LDL-C and presence of risk-enhancing factors, consider statin therapy after shared decision-making with patient. Some experts suggest shared decision-making if ASCVD 10-year risk is 5% to 10%; however, in patients with a baseline LDL-C ≥160 mg/dL, statin therapy is usually recommended (Pignone 2020).

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49% (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

ASCVD 10-year risk ≥7.5% to <20%:

Note: Depending on baseline LDL-C and presence of risk-enhancing factors, consider statin therapy after shared decision-making with patient. Some experts suggest initiating moderate-intensity statin therapy in most patients if ASCVD 10-year risk is >10% to <20% and LDL-C is >100 mg/dL (Pignone 2020).

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49%; higher-risk patients with multiple risk-enhancing factors may benefit from high-intensity statin therapy (ie, with atorvastatin or rosuvastatin) to reduce LDL-C by ≥50% (ACC/AHA [Grundy 2019]).

ASCVD 10-year risk ≥20% (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Patients with diabetes:

Age 40 to 75 years without additional ASCVD risk factors:

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49% (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Secondary prevention in patients with established ASCVD (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease) (alternative agent):

Note: Use of simvastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a). Patients with high-risk ASCVD may require additional therapies to achieve LDL-C goal (eg, <70 mg/dL or <50 mg/dL if very high risk) (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]; Rosenson 2020b).

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).

Transplantation, post kidney (alternative agent) (off-label use):

Note: Initiate after transplant regardless of baseline cholesterol levels. Certain immunosuppressive drugs can induce or exacerbate hypercholesterolemia; significant drug interactions between statins and immunosuppressant drugs are frequent; some interactions can increase statin serum concentrations and risk of toxicity (eg, myopathy) (AHA [Wiggins 2016]; Brennan 2020; KDIGO 2013). Consult drug interactions database for more detailed information.

Oral: Initial: 20 mg once daily at bedtime starting 1 to 2 weeks after transplant; increase dose based on response, tolerability, and concomitant drugs up to 40 mg once daily (Brennan 2020).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: 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, verapamil (see the following conservative, maximum adult doses). 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. Lifestyle changes are recommended to be implemented for at least 6 to 12 months before beginning pharmacotherapy (AACE [Jellinger 2017]).

Hyperlipidemia or heterozygous familial hypercholesterolemia (HeFH) and nonfamilial hypercholesterolemia: Note: Limited data available for nonfamilial hypercholesterolemia or other forms of non-HeFH hyperlipidemia.

Begin treatment if, after adequate trial (6 to 12 months) of intensive lifestyle modification emphasizing body weight normalization and diet, the following are present (AACE [Jellinger 2017]):

LDL-C ≥190 mg/dL or

LDL-C remains ≥160 mg/dL and two or more cardiovascular risk factors: Family history of premature atherosclerotic cardiovascular disease (<55 years of age), overweight, obesity, or other elements of insulin resistance syndrome or

LDL-C ≥130 mg/dL and diabetes mellitus (Daniels 2008; NHLBI 2011).

Therapy may also be considered for children 8 to 9 years of age meeting the above criteria or for children with diabetes mellitus and LDL-C ≥130 mg/dL (Daniels 2008).

Children ≥4 years and <10 years: Very limited data available: Oral: Initial: 5 mg once daily in the evening increasing to 10 mg once daily after 4 weeks and to 20 mg once daily after another 4 weeks as tolerated; maximum daily dose: 20 mg/day; most experience is with children at least 8 years of age; in trials, the youngest reported patient was 4 years of age (Ducobu 1992; García-de-la-Puente 2009; Stefanutti 1999; Vuorio 2017).

Children ≥10 years and Adolescents: Oral: Initial: 10 mg once daily in the evening increasing to 20 mg once daily after 6 weeks and to 40 mg once daily after another 6 weeks as tolerated; maximum daily dose: 40 mg/day.

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 ≥4 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 (NHLBI 2011; Stone 2013).

Dosing: Adjustment for Toxicity

Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (ACC/AHA [Stone 2014]).

Mild to moderate muscle symptoms: Discontinue use until symptoms can be evaluated; 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, resume the original or lower dose of simvastatin. If muscle symptoms recur, discontinue simvastatin use. After muscle symptom resolution, may then use a low dose of a different statin; gradually increase if tolerated. In the absence of continued statin use, if muscle symptoms or elevated CPK continues after 2 months, 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 (ACC/AHA [Stone 2014]).

Administration

Suspension: Administer in the evening on an empty stomach. Shake well for at least 20 seconds before administering dose.

Tablets: Administered without regard to meals. Administer in the evening for maximal efficacy.

Dietary Considerations

Generally, patients should be placed on a standard cholesterol-lowering diet and other lifestyle modifications for 3 to 6 months prior to the initiation of drug therapy. The diet should be continued during drug therapy. However, for patients with advanced risk factors (eg, known coronary heart disease), drug therapy may be initiated concurrently with diet modification. 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).

Storage

Suspension: Store at 20°C to 25°C (68°C to 77°F). Do not refrigerate or freeze; protect from heat. Use within 1 month of opening.

Tablets: Store at 5°C to 30°C (41°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

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). Consider therapy modification

AmLODIPine: May increase the serum concentration of Simvastatin. Management: Dose of simvastatin should not exceed 20 mg daily if coadministering with levamlodipine or amlodipine. If coadministering with simvastatin and amlodipine, close laboratory and clincal monitoring for signs and symptoms of rhabdomyolysis is warranted. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Azithromycin (Systemic): May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. 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. Consider therapy modification

Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Consider therapy modification

Bosentan: May decrease the serum concentration of Simvastatin. Monitor therapy

Cilostazol: May increase the serum concentration of Simvastatin. Monitor therapy

Ciprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification

Clarithromycin: May increase the serum concentration of Simvastatin. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Simvastatin. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Simvastatin. Avoid combination

Cyproterone: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid use of statins metabolized by CYP3A4 (eg, simvastatin) and consider avoiding fluvastatin as well in patients receiving high dose cyproterone (300 mg/day). Consider use of pravastatin, rosuvastatin, or pitavastatin if statin therapy is needed. Consider therapy modification

Dabigatran Etexilate: Simvastatin may enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Danazol: May increase the serum concentration of Simvastatin. Avoid combination

DAPTOmycin: Simvastatin may enhance the adverse/toxic effect of DAPTOmycin. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DilTIAZem: Simvastatin may increase 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). Consider therapy modification

Dronedarone: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of dronedarone with simvastatin when possible. If used together, limit adult simvastatin dose to 10 mg daily, and monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Efavirenz: May decrease the serum concentration of Simvastatin. Monitor therapy

Elbasvir: May increase the serum concentration of Simvastatin. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of Simvastatin. Avoid combination

Eslicarbazepine: May decrease the serum concentration of Simvastatin. Monitor therapy

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. Monitor therapy

Fenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Fluconazole: May increase the serum concentration of Simvastatin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin-Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding coadministration of fosphenytoin/phenytoin and statins. If combined, monitor for decreased therapeutic effects of statins if fosphenytoin/phenytoin is initiated/dose increased. Consider therapy modification

Fostamatinib: May increase the serum concentration of Simvastatin. 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. 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. Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Avoid combination

Glecaprevir and Pibrentasvir: May increase the serum concentration of Simvastatin. Avoid combination

Grapefruit Juice: May increase the serum concentration of Simvastatin. Avoid combination

Grazoprevir: May increase the serum concentration of Simvastatin. Monitor therapy

Green Tea: May increase the serum concentration of Simvastatin. Specifically, Simvastatin lactone concentrations may be increased. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May decrease the metabolism of Simvastatin. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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. Consider therapy modification

Letermovir: May increase the serum concentration of Simvastatin. Avoid combination

Levamlodipine: May increase the serum concentration of Simvastatin. Management: Dose of simvastatin should not exceed 20 mg daily if coadministering with levamlodipine or amlodipine. If coadministering with simvastatin and levamlodipine, close laboratory and clincal monitoring for signs and symptoms of rhabdomyolysis is warranted. Consider therapy modification

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. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of Simvastatin. Management: Avoid simvastatin during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Niacin: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin with niacin should be avoided in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. Consider therapy modification

Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: Simvastatin may enhance the adverse/toxic effect of PAZOPanib. Specifically, the risk for ALT/AST elevations may be increased. Monitor therapy

Protease Inhibitors: May increase the serum concentration of Simvastatin. Avoid combination

QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Ranolazine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of ranolazine with simvastatin when possible. If used together, limit simvastatin dose to 20 mg daily and monitor for evidence of simvastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). Consider therapy modification

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Avoid combination

Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider use of noninteracting antilipemic agents (note: pitavastatin concentrations may increase with rifamycin treatment). Monitor for altered HMG-CoA reductase inhibitor effects. Rifabutin and fluvastatin, or possibly pravastatin, may pose lower risk. Consider therapy modification

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. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of Simvastatin. Monitor therapy

St John's Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding the concomitant administration of St Johns Wort with interacting HMG-CoA reductase inhibitors in order to avoid the potential for decreased antilipemic effects. Monitor for decreased effects during concomitant therapy. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Telithromycin: May increase the serum concentration of Simvastatin. Avoid combination

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Ticagrelor: May increase the serum concentration of Simvastatin. Management: Avoid using doses of simvastatin greater than 40 mg/day with ticagrelor. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Management: Avoid concomitant use of OATP1B1/1B3 substrates in patients receiving the Jynarque brand of tolvaptant. Concentrations and effects of the OATP1B1/1B3 substrate would be expected to increase with combined use. Consider therapy modification

Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Monitor therapy

Verapamil: May increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult simvastatin dose to 10 mg daily and monitor closely for signs of simvastatin toxicity (eg, myositis, rhabdomyolysis). Consider therapy modification

Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists. 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. Consider therapy modification

Adverse Reactions

1% to 10%:

Cardiovascular: Atrial fibrillation (6%), edema (3%)

Central nervous system: Headache (3% to 7%), vertigo (5%)

Dermatologic: Eczema (5%)

Gastrointestinal: Abdominal pain (7%), constipation (7%), gastritis (5%), nausea (5%)

Genitourinary: Cystitis (interstitial; Huang 2015)

Hepatic: Increased serum transaminases (≤2%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (>3 x normal; 5%), myalgia (4%)

Respiratory: Upper respiratory infection (9%), bronchitis (7%)

Frequency not defined:

Dermatologic: Skin rash

Endocrine & metabolic: Increased gamma-glutamyl transferase

Gastrointestinal: Diarrhea, dyspepsia, flatulence, gastrointestinal disease

Hepatic: Increased serum alkaline phosphatase

Neuromuscular & skeletal: Asthenia

<1%, postmarketing, and/or case reports: Alopecia, amnesia, anaphylaxis, anemia, angioedema, arthralgia, arthritis, changes in nails, changes of hair, chills, cognitive dysfunction, confusion, depression, dermatomyositis, dizziness, dry mucous membranes, dysgeusia (Tuccori 2011), dyspnea, elevated glycosylated hemoglobin, eosinophilia, erectile dysfunction, erythema multiforme, fever, flushing, forgetfulness, hemolytic anemia, hepatic failure, hepatitis, hypersensitivity reaction, immune-mediated necrotizing myopathy, increase in fasting plasma glucose, increased erythrocyte sedimentation rate, interstitial pulmonary disease, jaundice, leukopenia, lupus-like syndrome, malaise, memory impairment, muscle cramps, myopathy, nodule, nonthrombocytopenic purpura, pancreatitis, paresthesia, peripheral neuropathy, polymyalgia rheumatica, positive ANA titer, pruritus, rhabdomyolysis, skin changes, skin discoloration, skin photosensitivity, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, urticaria, vasculitis, vomiting, xeroderma

Warnings/Precautions

Concerns related to adverse effects:

• Diabetes mellitus: Increases in HbA1c and fasting blood glucose have been reported; however, the benefits of statin therapy far outweigh the risk of dysglycemia.

• Hepatotoxicity: Persistent elevations in serum transaminases have been reported; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Postmarketing reports of fatal and nonfatal hepatic failure have been reported and are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly. If an alternate etiology is not identified, do not restart simvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Myopathy/Rhabdomyolysis: Rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with high doses of simvastatin (80 mg). Concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil is contraindicated due to increased risk of myopathy. Use with caution in patients with uncontrolled hypothyroidism, patients taking other drugs associated with myopathy (eg, colchicine), ≥65 years of age, and women; these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitors use has also been reported. 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 immune-mediated necrotizing myopathy; monitor closely.

Disease-related concerns:

• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Use is contraindicated with active liver disease and with unexplained transaminase elevations.

• Renal impairment: Use with caution in patients with severe renal impairment (creatinine clearance not defined); these patients are predisposed to myopathy. Initial dosage adjustment necessary; monitor closely.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.

Special Populations:

• Chinese patients: Increased risk for myopathy; use with caution. Coadministration of simvastatin with niacin ≥1 g/day is not recommended in Chinese patients; it is not known if this also applies to other Asian patients.

• Elderly: 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; severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy). Based on current research and clinical guidelines, HMG-CoA reductase inhibitors should be continued in the perioperative period for noncardiac and cardiac surgery (ACC/AHA [Fleisher 2014]; ACC/AHA [Hillis 2011]). Perioperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

• Appropriate use: Drug therapy should be only one component of multiple risk factor intervention in patients at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. In patients with CHD or multiple risk factors for CHD, initiate therapy simultaneously with diet.

• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.

Monitoring Parameters

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]):

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Lipid profile (fasting or nonfasting) before initiating treatment. Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter. If 2 consecutive LDL 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 or 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.

Manufacturer's labeling: Consider neuromuscular and serologic testing if immune-mediated necrotizing myopathy is suspected.

Reproductive Considerations

Simvastatin is contraindicated in females who may become pregnant.

Adequate contraception is recommended if an HMG-CoA reductase inhibitor is required in females of reproductive potential. Females planning a pregnancy should discontinue the HMG-CoA reductase inhibitor 1 to 2 months prior to attempting to conceive (AHA/ACC [Grundy 2019]).

Pregnancy Risk Factor

X

Pregnancy Considerations

Simvastatin is contraindicated in pregnant females.

There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data (Godfrey 2012; Lecarpentier 2012). Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long-term outcomes of primary hypercholesterolemia treatment.

Simvastatin should be discontinued immediately if an unplanned pregnancy occurs during treatment.

Patient Education

What is this drug used for?

• It is used to slow the progress of heart disease.

• It is used to lower bad cholesterol and raise good cholesterol (HDL).

• It is used to lower triglycerides.

• It is used to lower the chance of heart attack, stroke, and death in some people.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Abdominal pain

• Nausea

• Constipation

• Common sold symptoms

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Abnormal heartbeat

• Unable to pass urine

• Change in amount of urine passed

• Muscle pain

• Muscle tenderness

• Muscle weakness

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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