Simvastatin

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)

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

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

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% (for each doubling of this dose, LDL-C is lowered ~6%)

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%

Use in Specific Populations

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

Hyperlipidemias:

Dysbetalipoproteinemia: Reduce elevated triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) in patients with primary dysbetalipoproteinemia (Fredrickson type III)

Heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia: To reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and TG, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb)

Heterozygous familial hypercholesterolemia (HeFH) in adolescents: To reduce total-C, LDL-C, and apo B 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 two 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

Hypertriglyceridemia: To reduce elevated serum triglyceride levels in patients with hypertriglyceridemia (Fredrickson type IV)

Limitations of use: Has not been studied in conditions where the major lipid abnormality is elevation of chylomicrons (Fredrickson types I and V)

Prevention of cardiovascular events: To reduce the risk of nonfatal MI, stroke, and total mortality; and to reduce the need for coronary/non-coronary revascularization procedures in patients at high risk of coronary events (eg, patients with coronary heart disease, diabetes, PVD, history of stroke or other cerebrovascular disease)

Use: Off Label

Cardiac risk reduction for noncardiac surgery (perioperative therapy)yes

Based on the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery, perioperative initiation of statins is reasonable for patients undergoing vascular surgery and may be considered in patients with clinical indications according to guideline-directed medical therapy who are undergoing elevated risk procedures. In patients undergoing non-cardiac surgery who are currently receiving a statin, the statin should be continued.

Noncardioembolic stroke/Transient ischemic attack (secondary prevention)yes

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack (TIA), statin therapy with intensive lipid-lowering effects is recommended to reduce the risk of recurrent stroke and future cardiovascular events in patients with ischemic stroke or TIA presumed to be of atherosclerotic origin who have an LDL-C concentration ≥100 mg/dL (with or without evidence for other clinical atherosclerotic cardiovascular disease [ASCVD]) or who have an LDL-C concentration <100 mg/dL (without evidence for other clinical ASCVD).

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

Dosage and Administration

Dosing: Adult

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and the patient's response; adjustments should be made at intervals of 4 weeks or more; doses may need adjusted based on concomitant medications.

Note: Dosing limitation: Simvastatin 80 mg is limited to patients that have been taking this dose for >12 consecutive months without evidence of myopathy and are not currently taking or beginning to take a simvastatin dose-limiting or contraindicated interacting medication. If patient is unable to achieve low-density lipoprotein-cholesterol (LDL-C) goal using the 40 mg dose of simvastatin, increasing to 80 mg dose is not recommended. Instead, switch patient to an alternative LDL-C-lowering treatment providing greater LDL-C reduction.

Homozygous familial hypercholesterolemia: Oral: 40 mg once daily in the evening

Prevention of cardiovascular events (also see ACC/AHA Blood Cholesterol Guideline recommendations), hyperlipidemias: Oral: Initial: 10 to 20 mg once daily in the evening; range: 5 to 40 mg/day

Patients requiring only moderate reduction of LDL-C: May be started at 5 to 10 mg once daily in the evening; adjust to achieve recommended LDL-C goal.

Patients requiring reduction of >40% of LDL-C: May be started at 40 mg once daily in the evening; adjust to achieve recommended LDL-C goal.

Patients with CHD or at high risk for cardiovascular events (patients with diabetes, PVD, history of stroke or other cerebrovascular disease): Dosing should be started at 40 mg once daily in the evening; start simultaneously with diet therapy.

Prevention of cardiovascular disease/reduce the risk of atherosclerotic cardiovascular disease: Oral:

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2018]; ACC/AHA [Stone 2013]):

Note: When choosing to initiate therapy and selecting dose-intensity, consider atherosclerotic cardiovascular disease (ASCVD) risk, risk-enhancing factors, possibility for side effects, and drug interactions.

Primary prevention:

LDL-C ≥190 mg/dL and age 20 to 75 years: High-intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Diabetes, age 40 to 75 years, and an estimated 10-year ASCVD risk <7.5%: Moderate-intensity therapy: 20 to 40 mg once daily

Diabetes, age 40 to 75 years, and an estimated 10-year ASCVD risk ≥7.5%: High-intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

LDL-C 70 to 189 mg/dL, age 40 to 75 years, and an estimated 10-year ASCVD risk ≥7.5%: Moderate- to high-intensity therapy: 20 to 40 mg once daily or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin)

Secondary prevention:

Patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) or is post-CABG (AHA [Kulik 2015]) and:

Age ≤75 years: High-intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Age >75 years: Moderate- to high-intensity therapy: 20 to 40 mg once daily or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin); if moderate-intensity therapy is started and tolerated, increase to a high-intensity statin therapy within 3 months (Rosenson 2019).

US Preventive Services Task Force recommendations (USPSTF 2016): Age 40 to 75 years, no history of CVD, with ≥1 CVD risk factor (dyslipidemia, diabetes, hypertension, or smoking), and calculated 10-year CVD event risk of ≥10%:

Primary prevention:

Low-intensity therapy: 10 mg once daily

Moderate-intensity therapy: 20 to 40 mg once daily

Note: These recommendations do not pertain to patients with very high CVD risk factors (eg, LDL >190 mg/dL, familial hypercholesterolemia) (were excluded from primary prevention trials); use clinical judgement in the treatment of these patients. In patients with a calculated 10-years CVD event risk of 7.5% to 10%, may consider use of a statin based on patient characteristics.

Dosage adjustment for simvastatin with concomitant medications: Note: Patients currently tolerating and requiring a dose of simvastatin 80 mg who require initiation of an interacting drug with a dose cap for simvastatin should be switched to an alternative statin with less potential for drug-drug interaction.

Amiodarone, amlodipine, or ranolazine: Simvastatin dose should not exceed 20 mg/day

Diltiazem, dronedarone, or verapamil: Simvastatin dose should not exceed 10 mg/day

Lomitapide: Reduce simvastatin dose by 50% when initiating lomitapide. Simvastatin dose should not exceed 20 mg/day (or 40 mg daily for those who previously tolerated simvastatin 80 mg daily for ≥1 year without evidence of muscle toxicity).

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

Dosing adjustment for simvastatin with concomitant medications: There are no recommendations in the manufacturer's labeling for patients <18 years. In adolescents ≥18 years, the following have been suggested:

Diltiazem, dronedarone, or verapamil: Maximum simvastatin daily dose: 10 mg/day

Amiodarone or amlodipine: Maximum daily dose: 20 mg/day

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 2013]).

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 2013]).

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

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: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). 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

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 Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. 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). Consider therapy modification

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/day and diltiazem 240 mg/day; avoid Simcor (simvastatin/niacin) because fixed simvastatin doses exceed the maximum. Consider therapy modification

Dronedarone: May increase the serum concentration of Simvastatin. Management: Limit simvastatin to a max of 10 mg/day (in adults). Increase monitoring for signs of simvastatin toxicity (e.g., 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: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

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

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: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). 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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. 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

Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

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, avoid doses of simvastatin greater than 20 mg/day. 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. 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 maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. 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 HbA_1c 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.

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 2018]; ACC/AHA [Stone 2013]):

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.

Pregnancy

Pregnancy Risk Factor

X

Pregnancy Considerations

Simvastatin is contraindicated in pregnant females or those who may become pregnant.

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.

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 2018]).

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.

Frequently reported side effects of this drug

• Headache
• Abdominal pain
• Nausea
• Constipation
• Common sold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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 a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.