Simvastatin (Lexi-Drugs)

Pronunciation

(sim va STAT in)

Brand Names: US

FloLipid; Zocor

Brand Names: Canada

ACT Simvastatin [DSC]; AG-Simvastatin; APO-Simvastatin; Auro-Simvastatin; BCI Simvastatin [DSC]; DOM-Simvastatin; JAMP-Simvastatin; Mar-Simvastatin; MINT-Simvastatin; MYLAN-Simvastatin; PHARMA-Simvastatin; PHL-Simvastatin [DSC]; PMS-Simvastatin; Q-Simvastatin [DSC]; RAN-Simvastatin; RIVA-Simvastatin; SANDOZ Simvastatin; Simvastatin-10; Simvastatin-20; Simvastatin-40; Simvastatin-80; TARO-Simvastatin; TEVA-Simvastatin; Zocor

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: Renal Impairment: Adult

Mild to moderate impairment: No dosage adjustment necessary; simvastatin does not undergo significant renal excretion.

Severe impairment: Initial: 5 mg once daily with close monitoring.

Dosing: Hepatic Impairment: Adult

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

Dosing: Adjustment for Toxicity: Adult

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]).

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 medicationsThere 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: Renal Impairment: Pediatric

There are no pediatric specific recommendations. Simvastatin does not undergo significant renal excretion. Based on experience in adult patients with mild-to-moderate renal impairment, no dosage adjustment necessary; in severe impairment, use with caution.

Dosing: Hepatic Impairment: Pediatric

Contraindicated in patients with active liver disease, including unexplained persistent elevations in hepatic transaminases.

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: Adult

  Cardiac risk reduction for noncardiac surgery (perioperative therapy)Level of Evidence [G]

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)Level of Evidence [G]

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).

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Coronary Artery Bypass Graft Surgery:

“AHA Scientific Statement, Secondary Prevention After Coronary Artery Bypass Graft Surgery,” February 2015

AHA/ACC/HRS, “2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation,” March 2014

Diabetes Mellitus:

AACE/ACE, “Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm- 2019 Executive Summary,” January 2019

American Diabetes Association, “Standards of Medical Care in Diabetes – 2019,” January 2019

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Dyslipidemia:

AACE/ACE, “Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease,” April 2017

ACC/AHA, “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults,” November 2013

AHA/ACC, “Guideline on the management of blood cholesterol,” November 2018

Canadian Cardiovascular Society, “2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult, 2012

NLA, “National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia” Part 1: April 2015; Part 2: December 2015

The Endocrine Society, “Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline,” September 2012

The Kidney Disease: Improving Global Outcomes (KDIGO), “Lipid Management in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2013 Clinical Practice Guideline,” December 2013

Ischemic Heart Disease:

ACC/AHA/AATS/PCNA/SCAI/STS, “2014 Focused Update of the Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” July 2014

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, “2012 Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” November 2012

Stroke:

AHA/ASA, “Guidelines for Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack,” May 2014.

“Guidelines for the Primary Prevention of Stroke,” December 2010

Surgery:

ACC/AHA, “2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery,” August 2014

Administration: Oral

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.

Administration: Pediatric

Oral: May be taken without regard to meals. Administration with the evening meal or at bedtime has been associated with somewhat greater LDL-C reduction

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/Stability

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).

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, nausea, constipation, or common sold symptoms. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), abnormal heartbeat, urinary retention, change in amount of urine passed, muscle pain, muscle tenderness, or muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
  International issues:
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

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.

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.

Geriatric Considerations

Effective and well tolerated in the elderly, although ≥65 years of age is a risk factor for myopathy. The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. According to the ACC/AHA, high-intensity statin doses are indicated for patients <75 years of age with existing clinical atherosclerotic cardiovascular disease (ASCVD); patients without clinical ASCVD if LDL-C is >190 mg/dL; patients without clinical ASCVD who are 40 to 75 years with type 1 or type 2 diabetes and with an estimated 10-year ASCVD risk ≥7.5%. Patients 40 to 75 years of age with a 10-year ASCVD risk >7.5% are candidates for moderate- to high-intensity statin therapy. Patients >75 years of age with existing clinical ASCVD are candidates for moderate-intensity statin doses. There are no data or recommendations on managing patients >75 years of age without clinical ASCVD who have type 1 or 2 diabetes or with a 10-year risk of ASCVD >7.5% (with or without diabetes) (Stone 2013). It is the authors’ belief that pharmacologic treatment be reserved for those whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment. The risks of polypharmacy and life expectancy must also be taken into consideration. It should be noted that the benefits of primary prevention in low-risk older adults remain unclear (Han 2017; Newson 2011), but the benefits of statins for secondary prevention are well documented (Shepherd 2002). While concerning reports of cognitive impairment and dementia with statin use have been published, it should be noted recent research has failed to support this association (Mortensen 2018). Despite this, all reports of cognitive impairment or slowing should be investigated, especially if these complaints come shortly after statin initiation.

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]).

Breast-Feeding Considerations

It is not known if simvastatin is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is contraindicated by the manufacturer.

Briggs’ Drugs in Pregnancy & Lactation
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

Allergy and Idiosyncratic Reactions
Metabolism/Transport Effects

Substrate of CYP3A4 (major), OATP1B1/1B3 (SLCO1B1/1B3); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions 

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: 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 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: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Risk D: Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk 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

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. Risk D: Consider therapy modification

Bosentan: May decrease the serum concentration of Simvastatin. Risk C: 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. Risk D: Consider therapy modification

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

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). Risk D: Consider therapy modification

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

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: 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. Risk D: Consider therapy modification

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

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Simvastatin. Risk X: 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.Risk D: Consider therapy modification

Dabigatran Etexilate: Simvastatin may enhance the anticoagulant effect of Dabigatran Etexilate. Management: Consider an alternative HMG-CoA reductase inhibitor (statin) in patients taking dabigatran who require statin therapy. If used together, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

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). Risk D: Consider therapy modification

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: HMG-CoA Reductase Inhibitors (Statins) may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: 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. Risk D: 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). Risk D: Consider therapy modification

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

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

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

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Risk C: 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. Risk D: Consider therapy modification

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

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

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin, pravastatin, or pitavastatin.Risk C: Monitor therapy

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

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

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

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

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

Fostamatinib: May increase the serum concentration of Simvastatin. Risk C: 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. 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

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

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

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

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

Imatinib: May decrease the metabolism of Simvastatin. Risk C: Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: 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. Risk D: Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification

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

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

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. Risk D: 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. Risk X: 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. Risk D: Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification

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

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

PAZOPanib: HMG-CoA Reductase Inhibitors (Statins) may enhance the hepatotoxic effect of PAZOPanib. Specifically, the risk for increased serum transaminase concentrations may be increased. Management: Simvastatin is specifically implicated in the interaction. There is a lack of data regarding risk with other statins, but caution appears warranted with any statins. Atorvastatin should be avoided due to P-gp inhibition. Risk C: Monitor therapy

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

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

QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification

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: Avoid the concurrent use of ranolazine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day. 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

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. Risk D: 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.Risk C: Monitor therapy

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

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

Simeprevir: May increase the serum concentration of Simvastatin. Risk C: 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. Risk D: Consider therapy modification

St John’s Wort: May decrease the serum concentration 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. Risk D: 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. Risk D: Consider therapy modification

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

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. 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. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Risk D: Consider therapy modification

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

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Risk D: Consider therapy modification

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

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

Food Interactions

Simvastatin serum concentration may be increased when taken with grapefruit juice. Management: Avoid combination.

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.

Reference Range

Treatment goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.

Advanced Practitioners Physical Assessment/Monitoring

Rule out secondary causes of hyperlipidemia prior to initiation. Assess other medicines patient may be taking; alternate therapy or dosage adjustments may be needed. Obtain liver enzyme tests prior to therapy and as needed. Obtain CPK when myopathy is considered or in high-risk patients. Follow-up with lipid panel within 2 to 4 weeks of initiation or titration.

Nursing Physical Assessment/Monitoring

Check ordered labs and report and abnormalities. Monitor for and educate patient to report signs and symptoms of myopathy (muscle pain, weakness, fatigue). Consider dietary assessment and plan for teaching.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

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

Tablet, Oral:

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

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

Dosage Forms: Canada

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

Tablet, Oral:

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

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

Anatomic Therapeutic Chemical (ATC) Classification
  • C10AA01
Generic Available (US)

Yes

Pricing: US

Tablets (Simvastatin Oral)

5 mg (per each): $0.02 – $2.81

10 mg (per each): $0.02 – $2.82

20 mg (per each): $0.04 – $4.92

40 mg (per each): $0.05 – $4.92

80 mg (per each): $0.06 – $4.92

Tablets (Zocor Oral)

5 mg (per each): $4.15

10 mg (per each): $5.54

20 mg (per each): $9.67

40 mg (per each): $9.67

80 mg (per each): $9.67

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.

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).

Pharmacodynamics/Kinetics

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%

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

Protein binding: ~95%

Metabolism: Hepatic via CYP3A4; extensive first-pass effect

Bioavailability: <5%

Half-life elimination: Unknown

Time to peak: 1.3 to 2.4 hours

Excretion: Feces (60%); urine (13%)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Higher systemic exposure may be achieved in patients with severe renal insufficiency.

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

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Assess unusual presentations of muscle weakness or myopathy resulting from lipid therapy such as patient having a difficult time brushing teeth or weakness with chewing. Refer patient back to their physician for evaluation and adjustment of lipid therapy.

Effects on Bleeding

No information available to require special precautions

FDA Approval Date
December 23, 1991
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Rosenson RS, Hayward RA, Lopez-Sendon J. Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 3, 2019.

Rossebo AB, Pederson TR, Boman K, et al, “Intensive Lipid Lowering With Simvastatin and Ezetimibe in Aortic Stenosis,” N Engl J Med, 2008, 359(13):1343-56.[PubMed 18765433 ]

Scandinavian Simvastatin Survival Study, “Randomized Trial of Cholesterol Lowering in 4444 Patients With Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S),” Lancet, 1994, 344(8934):1383-9.[PubMed 7968073]

Sever PS, Dahlof B, Poulter NR, et al, “Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial,” Lancet, 2003, 361(9364):1149-58.[PubMed 12686036]

Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623-1630.[PubMed 12457784]

Shepherd J, Cobbe SM, Ford I, et al, “Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia. West of Scotland Coronary Prevention Study Group,” N Engl J Med, 1995, 333(20):1301-7.[PubMed 7566020]

Smith DJ, Olive KE. Chinese red rice-induced myopathy. South Med J. 2003;96(12):1265-1267.[PubMed 14696880]

Stone NJ, Robinson J, Lichtenstein AH, et al, 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published online ahead of print November 12, 2013].Circulation. 2013; doi: 10.1161/01.cir.0000437738.63853.7a.

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, “Intensive Lowering of LDL Cholesterol With 80 mg versus 20 mg Simvastatin Daily in 12,064 Survivors of Myocardial Infarction: A Double-Blind Randomised Trial,” Lancet, 2010, 376(9753):1658-69.[PubMed 21067805]

Tonelli M, Wanner C; for the Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. Lipid Management in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2013 Clinical Practice Guideline [published online ahead of print]. Ann Intern Med. 2013.[PubMed 24323134]

Tuccori M, Lapi F, Testi A, et al. Drug-induced taste and smell alterations: a case/non-case evaluation of an italian database of spontaneous adverse drug reaction reporting. Drug Saf. 2011;34(10):849-859.[PubMed 21879779]

US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, Grossman DC, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316(19):1997-2007.[PubMed 27838723]

Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20(3):217-219.[PubMed 17555487]

Zocor (simvastatin) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; March 2019.

Brand Names: International

Alkor (EG); Allesta (UA); Antex (PY); Avastinee (HK); Bestatin (TH); Biosim (IN); Cazet (EG); Cholemed (BE); Cholestat (ID); Clinfar (BR); Colesken (MX); Corstat (HK); Cotritev (CR, DO, GT, HN, NI, PA, SV); Covastin (HK, MY, SG); Decrelip (PY); Ecuvas (EC); Esvat (ID); Ethicol (ID); Eucor (TH); Forcad (PH); Husimba (KR); Ifistatin (SG); Klonastin (AR); Lesvatin (ID); Lipaco (MY); Lipecor (KR); Lipex (AU, HR, NZ); Lipidoff (TW); Lipinorm (ID); Liponorm (IT); Lipovas (JP); Lochol (TH); Lodales (FR); Luoqi (CN); Mersivas (ID); Nimicor (CL); Nor-Vastina (CR, DO, GT, HN, NI, PA, SV); Orovas (PH); Priacin (SG); Pulsar AT (CR, DO, GT, HN, NI, PA, SV); Pusarat (MX); Ransim (AU); Rechol (ID); Recol (BD); Rezostatin (TW); Roco (KR); Simaspen (ZA); Simastin (BD); Simaz (LK); Simbado (ID); Simchol (ID); Simlo (MX, ZW); Simovil (IL); Simplaqor (MX); SimStatin (NZ); Simtan (IE); Simtin (SG); Simva (CR, DO, GT, HN, NI, PA, SV); Simvacor (IL, KW, LV, MY, SG); Simvahex (PH); Simvahexal (TW); Simvalord (KR); Simvar (AU); Simvart (KR); Simvast (AE, BH, ET, QA); Simvastan (KR); Simvata (KR); Simvatin (AE, BH, CY, IQ, IR, JO, KR, KW, LB, LY, OM, QA, SA, SY, YE, ZA); Simvaxon (IL); Simver (QA); Simvor (LK, TH, VN); Sinty (TW); Sinvacor (IT); Sivacor (BH); Sivas (KR); Sivastin (IT); Statin (CO); Stavid (ET, MY); Torio (TH); Tulip (MX); Valemia (ID); Vascor (LB, MY, SG); Vasilip (HK); Vasotenal (PE); Vastin (BD); Vidastat (PH); Viscor (QA); Zeid (MX); Zetina (EC); Zimmex (TH); Zimstat (AU); Zocor (AE, AR, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DK, EC, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IT, JM, JO, KE, KR, KW, LB, LK, LR, LU, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NO, PA, PE, PH, PK, PL, PT, QA, RO, SA, SC, SD, SK, SL, SN, SR, SV, TH, TN, TR, TT, TW, TZ, UG, UY, VE, VN, ZM, ZW); Zocor HP (PH); Zocord (AT, SE); Zokor (UA); Zorced (MX); Zostin (BD); Zovast (PH)

Simvastatin (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(sim va STAT in)

Brand Names: US

FloLipid; Zocor

Brand Names: Canada

Zocor

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.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to simvastatin or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this drug, like certain drugs that are used for HIV, infections, or depression. There are many drugs that must not be taken with this drug. Your doctor or pharmacist can tell you if you are taking a drug that must not be taken with this drug.
  • If you have any of these health problems: Active liver disease or a rise in liver enzymes.
  • If you are pregnant or may be pregnant. Do not take this drug if you are pregnant.
  • If you are breast-feeding. Do not breast-feed while you take this drug.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • Follow the diet and workout plan that your doctor told you about.
  • Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
  • Avoid or limit drinking alcohol to less than 3 drinks a day. Drinking too much alcohol may raise your chance of liver disease.
  • Avoid grapefruit and grapefruit juice.
  • If you are Chinese and taking niacin products, talk with your doctor. You could have a greater risk of muscle problems.
  • This drug may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this drug with your other drugs.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • This drug may cause harm to the unborn baby if you take it while you are pregnant.
  • Use birth control that you can trust to prevent pregnancy while taking this drug.
  • If you are pregnant or you get pregnant while taking this drug, call your doctor right away.
What are some side effects that I need to call my doctor about right away?
  • 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:
  • 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.
  • A heartbeat that does not feel normal.
  • Not able to pass urine or change in how much urine is passed.
  • This drug may cause muscle pain, tenderness, or weakness. Sometimes, a very bad muscle problem may happen that may lead to kidney problems. Rarely, deaths have happened in people who get these problems when taking drugs like this one. Call your doctor right away if you have muscle pain, tenderness, or weakness that is not normal (with or without fever or feeling out of sorts). Call your doctor right away if you have muscle signs that last after your doctor has told you to stop taking this drug.
  • Liver problems have happened with drugs like this one. Sometimes, this has been deadly. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
What are some other side effects of this drug?
  • 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.
  • Belly pain.
  • Upset stomach.
  • Constipation.
  • Signs of a common cold.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • Take in the evening.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Tablets:
  • Take with or without food.
  • Liquid (suspension):
  • Take on an empty stomach.
  • Shake well for at least 20 seconds before each use.
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
  • Do not use a household teaspoon or tablespoon to measure this drug. Doing so could lead to the dose being too high.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • All products:
  • Store at room temperature. Do not refrigerate or freeze.
  • Store in a dry place. Do not store in a bathroom.
  • Protect from heat.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
  • Liquid (suspension):
  • After opening, throw away any part not used after 30 days.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Simvastatin (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(sim va STAT in)

Brand Names: US

FloLipid; Zocor

Brand Names: Canada

Zocor

What is this drug used for?
  • It is used to lower bad cholesterol and raise good cholesterol (HDL).
  • It is used to lower triglycerides.
  • It may be given to your child for other reasons. Talk with the doctor.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child takes any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this drug, like certain drugs that are used for HIV, infections, or seizures. There are many drugs that must not be taken with this drug.
  • If your child has any of these health problems: Active liver disease or a rise in liver enzymes.
  • If your child is pregnant:
  • Do not give this drug to your child if she is pregnant.
  • If your child is breast-feeding a baby:
  • Be sure your child does not breast-feed a baby while taking this drug.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Have your child’s blood work checked often. Talk with your child’s doctor.
  • If your child has high blood sugar (diabetes), you will need to watch his/her blood sugar closely.
  • Have your child follow the diet and workout plan your child’s doctor told you about.
  • Do not give your child more of this drug than what the doctor told you to give. Giving more of this drug than you are told may raise the chance of very bad side effects.
  • Alcohol may interact with this drug. Be sure your child does not drink alcohol.
  • Avoid giving your child grapefruit and grapefruit juice.
  • If your child is Chinese and taking niacin products, talk with the doctor. Your child could have a greater risk of muscle problems.
  • This drug may affect how much of some other drugs are in the body. If your child is taking other drugs, talk with the doctor. Your child may need to have blood work checked more closely while taking this drug with other drugs.
  • If your child is or may be sexually active:
  • Have your child use birth control to prevent pregnancy while taking this drug.
  • If your child is pregnant:
  • This drug may cause harm to the unborn baby if your child takes it during pregnancy. If your child is pregnant or gets pregnant while taking this drug, call the doctor right away.
What are some side effects that I need to call my child’s doctor about right away?
  • 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 child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • 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.
  • A heartbeat that does not feel normal.
  • Not able to pass urine or change in how much urine is passed.
  • This drug may cause muscle pain, tenderness, or weakness. Sometimes, a very bad muscle problem may happen that may lead to kidney problems. Rarely, deaths have happened in people who get these problems when taking drugs like this one. Call the doctor right away if your child has muscle pain, tenderness, or weakness that is not normal (with or without fever or feeling out of sorts). Call the doctor right away if your child has muscle signs that last after the doctor has told you to stop giving this drug.
  • Liver problems have happened with drugs like this one. Sometimes, this has been deadly. Call the doctor right away if your child has signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Headache.
  • Belly pain.
  • Upset stomach.
  • Constipation.
  • Signs of a common cold.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • Give in the evening.
  • To gain the most benefit, do not miss giving your child doses.
  • Keep giving this drug to your child as you have been told by your child’s doctor or other health care provider, even if your child feels well.
  • Tablets:
  • Give this drug with or without food.
  • Liquid (suspension):
  • Give on an empty stomach.
  • Shake well for at least 20 seconds before each use.
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
  • Do not use a household teaspoon or tablespoon to measure this drug. Doing so could lead to the dose being too high.
What do I do if my child misses a dose?
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • All products:
  • Store at room temperature. Do not refrigerate or freeze.
  • Store in a dry place. Do not store in a bathroom.
  • Protect from heat.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
  • Liquid (suspension):
  • After opening, throw away any part not used after 30 days.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.