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Special Alerts
HMG-CoA Reductase Inhibitors and Protease Inhibitors: New Contraindications and Dose Limitations
March 2012
The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of updates to the prescribing information regarding use of HMG-CoA reductase inhibitors with protease inhibitors. Use of some of these medications together may increase the risk of myopathy or the more serious rhabdomyolysis, which can damage the kidneys and lead to kidney failure (sometimes fatal). The updates include new contraindications (lovastatin, simvastatin), warnings (atorvastatin), and maximum dose restrictions for specific HMG-CoA reductase inhibitors (atorvastatin, rosuvastatin) when combined with specific protease inhibitors used for the treatment of human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
Lovastatin, simvastatin: Protease inhibitors (including boceprevir and telaprevir) are contraindicated with either lovastatin or simvastatin
Rosuvastatin: With atazanavir ± ritonavir or lopinavir + ritonavir: Rosuvastatin maximum daily dose of 10 mg
Atorvastatin:
With darunavir + ritonavir or fosamprenavir ± ritonavir or saquinavir + ritonavir: Atorvastatin maximum daily dose of 20 mg
With lopinavir + ritonavir: Use lowest daily atorvastatin dose; monitor closely
With nelfinavir: Atorvastatin maximum daily dose of 40 mg
With telaprevir or tipranavir + ritonavir: Avoid concurrent use
Other HMG-CoA reductase inhibitors were reviewed, but did not have adjustments to dosing.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm.
HMG-CoA Reductase Inhibitors: Liver Enzyme Monitoring Requirements Removed and Warning Updates
February 2012
The U.S. Food and Drug Administration (FDA) has approved important labeling changes for HMG-CoA reductase inhibitors.
Routine monitoring of liver enzymes has been removed from the drug labeling. The incidence of serious liver injury associated with the currently marketed HMG-CoA reductase inhibitors is very low and routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury, but may cause interruptions in therapy for patients with isolated increases in ALT levels, placing them at risk for cardiovascular events. Baseline liver function tests are still recommended prior to initiation of HMG-CoA Reductase Inhibitor therapy.
Based upon review of postmarketing events through the AERS database and clinical trials, updated details regarding cognitive adverse events and glycemic regulation have been added to the labels. Although rare, reversible memory impairment (including confusion, forgetfulness, amnesia, and memory loss) can occur with HMG-CoA reductase inhibitors. These cognitive symptoms have been reported at variable times during therapy (1 day to years after initiation) and are reversible with discontinuation; resolution usually occurs within ~3 weeks. Cases have not been associated with fixed or progressive dementia; nor have they been associated with age, specific HMG CoA reductase inhibitor, dose or concomitant medication use.
Additionally, HMG-CoA reductase inhibitors have been associated with increases in glycosylated hemoglobin and fasting plasma glucose. Subgroup analyses of randomized, controlled, clinical trials, an observational study, and meta-analyses have observed an association between new onset diabetes and the use of an HMG CoA reductase inhibitor.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm.
Dose Limitation Revised for Simvastatin (Zocor®) When Administered Concomitantly with Amiodarone
December 2011
The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of revised dose recommendations regarding the concomitant use of simvastatin and amiodarone. The FDA is now recommending a maximum simvastatin dose of 20 mg/day in patients receiving concomitant amiodarone.
The current recommendation represents a change from a previous recommendation (communicated by the FDA in June 2011) to limit the dose of simvastatin to 10 mg when coadministered with amiodarone. This previous recommendation was erroneous as there were no pharmacokinetic or clinical trial data to support that dose limitation.
Manufacturer's labeling for Zocor® and Vytorin® (ezetimibe and simvastatin) was updated in October 2011 to reflect the most current recommendation. Of note, Simcor® (niacin and simvastatin) prescribing information, dated June 2011, lists coadministration with amiodarone as a contraindication.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm283137.htm.
Pronunciation
(sim va STAT in)
Generic Available (U.S.)
Yes
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Used with dietary therapy for the following:
Secondary prevention of cardiovascular events in hypercholesterolemic patients with established coronary heart disease (CHD) or at high risk for CHD: To reduce cardiovascular morbidity (myocardial infarction, coronary/noncoronary revascularization procedures) and mortality; to reduce the risk of stroke
Hyperlipidemias: To reduce elevations in total cholesterol (total-C), LDL-C, apolipoprotein B, triglycerides, and VLDL-C, and to increase HDL-C in patients with primary hypercholesterolemia (elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias); treatment of homozygous familial hypercholesterolemia
Heterozygous familial hypercholesterolemia (HeFH): In adolescent patients (10-17 years of age, females >1 year postmenarche) with HeFH having LDL-C ≥190 mg/dL or LDL-C ≥160 mg/dL with positive family history of premature cardiovascular disease (CVD), or 2 or more CVD risk factors in the adolescent patient
Pregnancy Risk Factor
X
Pregnancy Considerations
Cholesterol biosynthesis may be important in fetal development. Contraindicated in pregnancy. Administer to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards. If pregnancy occurs during treatment, discontinue simvastatin immediately.
Lactation
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Excretion in breast milk is unknown, but would be expected; other medications in this class are excreted in human milk. Breast-feeding is contraindicated.
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, protease inhibitors [including boceprevir and telaprevir], telithromycin), cyclosporine, danazol, and gemfibrozil; pregnancy; breast-feeding
Warnings/Precautions
Concerns related to adverse effects:
• Diabetes mellitus: Increases in Hb A1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.
• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart simvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary.
• Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with high doses (80 mg), concurrent use of other lipid-lowering medications (fibric acid derivatives, or niacin at doses ≥1 g/day), other interacting drugs (eg, moderate-to-strong CYP3A4 inhibitors), age ≥65 years, female gender, uncontrolled hypothyroidism, and renal dysfunction. Use with caution in patients taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. 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). However, based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
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); initial dosage adjustment is necessary; monitor closely. Initial dosage adjustment is not necessary in mild-to-moderate impairment. Renal impairment may also increase risk for myopathy.
Concurrent drug therapy issues:
• High potential for interactions: Concomitant use of simvastatin with some drugs may require cautious use, may not be recommended, may require dosage adjustments, or may be contraindicated. If concurrent use of a contraindicated interacting medication is unavoidable, treatment with simvastatin should be suspended during use or consider the use of an alternative HMG-CoA reductase inhibitor void of CYP3A4 metabolism.
Special Populations:
• Chinese patients: Do not use high dose simvastatin (80 mg) if concurrently taking niacin ≥1 g/day; concomitant use may increase risk of myopathy in Chinese patients.
• Elderly: Use with caution in patients ≥65 years of age; these patients are predisposed to myopathy.
Other warnings/precautions:
• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.
Adverse Reactions
1% to 10%:
Cardiovascular: Atrial fibrillation (6%; placebo 5%), edema (3%; placebo 2%)
Central nervous system: Headache (3% to 7%), vertigo (5%)
Dermatologic: Eczema (5%)
Gastrointestinal: Abdominal pain (7%), constipation (2% to 7%), gastritis (5%), nausea (5%)
Hepatic: Transaminases increased (>3 x ULN; 1%)
Neuromuscular & skeletal: CPK increased (>3 x normal; 5%), myalgia (4%)
Respiratory: Upper respiratory infections (9%), bronchitis (7%)
<1%, postmarketing, and/or case reports: Alkaline phosphatase increased, alopecia, amnesia (reversible), anaphylaxis, anemia, angioedema, arthralgia, arthritis, blood glucose increased, chills, cognitive impairment (reversible), confusion (reversible), depression, dermatomyositis, diabetes mellitus (new onset), diarrhea, dizziness, dryness of skin/mucous membranes, dyspepsia, dyspnea, eosinophilia, erythema multiforme, ESR increased, fever, flatulence, flushing, glycosylated hemoglobin (Hb A1c) increased, GGT increased, hemolytic anemia, hepatic failure, hepatitis, hypersensitivity reaction, jaundice, leukopenia, malaise, memory disturbance (reversible), memory impairment (reversible), muscle cramps, nail changes, nodules, pancreatitis, paresthesia, peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, pruritus, purpura, rash, rhabdomyolysis, skin discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome, thrombocytopenia, toxic epidermal necrolysis, urticaria, vasculitis, vomiting, weakness
Additional class-related events or case reports (not necessarily reported with simvastatin therapy): Alteration in taste, anorexia, anxiety, bilirubin increased, cataracts, cholestatic jaundice, cirrhosis, decreased libido, depression, erectile dysfunction/impotence, facial paresis, fatty liver, fulminant hepatic necrosis, gynecomastia, hepatoma, hyperbilirubinemia, impaired extraocular muscle movement, increased CPK (>10 x normal), interstitial lung disease, ophthalmoplegia, peripheral nerve palsy, psychic disturbance, renal failure (secondary to rhabdomyolysis), thyroid dysfunction, tremor, vertigo
Metabolism/Transport Effects
Substrate of CYP3A4 (major), SLCO1B1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C8 (weak), CYP2C9 (weak), CYP2D6 (weak)
Drug Interactions
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (limit simvastatin adult maximum dose to 20 mg/day, limit immediate-release lovastatin to 40 mg/day, limit extended-release lovastatin to 20 mg/day). Avoid Simcor (simvastatin/niacin). 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
Antacids: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Consider use of HMG-CoA reductase inhibitors posing the least rhabdomyolysis risk (e.g. fluva- or pravastatin), and monitor for signs/symptoms of rhabdomyolysis. Do not use keto- or itraconazole with lova- or simvastatin, or posaconazole with simvastatin. Risk D: Consider therapy modification
ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult product labeling for specific recommendations. Risk C: Monitor therapy
Boceprevir: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Use of cyclosporine with simvastatin, lovastatin, or pitavastatin is contraindicated. U.S. and Canadian recommendations for some statins may differ, see appropriate prescribing information. Monitor closely for myotoxicity with concurrent use. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Use of cyclosporine with simvastatin, lovastatin, or pitavastatin is contraindicated. U.S. and Canadian recommendations for some statins may differ, see appropriate prescribing information. Monitor closely for myotoxicity with concurrent use. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. 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. 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
Danazol: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Concurrent use of simvastatin with danazol is contraindicated. Initiate lovastatin at an adult maximum dose of 10 mg/day, and do not 20 mg/day, when danazol is given concomitantly. Fluvastatin, pravastatin and rosuvastatin may pose lower risk. Risk D: Consider therapy modification
DAPTOmycin: HMG-CoA Reductase Inhibitors 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
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diltiazem: May increase the serum concentration of Simvastatin. Simvastatin may increase the serum concentration of Diltiazem. Management: Avoid concurrent use of diltiazem 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
Dronedarone: May increase the serum concentration of Simvastatin. Management: Consider using lower simvastatin doses; consider limiting simvastatin to a max of 20 mg/day (in adults). Increase monitoring for signs of simvastatin toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification
Efavirenz: May decrease the serum concentration of Simvastatin. Risk C: Monitor therapy
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification
Erythromycin: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. 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: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fusidic Acid: May enhance the adverse/toxic effect of Simvastatin. Specifically, the risk of rhabdomyolysis may be increased. Fusidic Acid may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
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
Grapefruit Juice: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider avoiding concurrent use of GFJ (especially larger amounts) with lovastatin, simvastatin, or atorvastatin. Consider using a lower statin dose or a statin that is less likely to interact when possible. Risk D: Consider therapy modification
Green Tea: May increase the serum concentration of Simvastatin. Specifically, Simvastatin lactone concentrations may be increased. Risk C: Monitor therapy
Imatinib: May decrease the metabolism of Simvastatin. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Lanthanum: HMG-CoA Reductase Inhibitors 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
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Avoid lovastatin or simvastatin with erythro-, clarithro-, or telithromycin. Limit pitavastatin to a 1 mg/day maximum adult dose with erythromycin. Atorvastatin dose adjustments may be required. Increase monitoring for toxicity with any such combination. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Management: This is of greatest concern with niacin doses of 1 g or greater daily. Avoid simvastatin 80 mg in combination with niacin 1 g or greater in Chinese patients. Canadian labeling contraindicates use of niacin with rosuvastatin 40 mg. Risk D: Consider therapy modification
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Protease Inhibitors: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Risk D: Consider therapy modification
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. 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
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. Risk X: Avoid combination
Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. 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
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Telaprevir: May increase the serum concentration of Simvastatin. Risk X: Avoid combination
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. Risk C: Monitor therapy
Trabectedin: HMG-CoA Reductase Inhibitors 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 may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Excessive ethanol consumption has the potential to cause hepatic effects. Management: Avoid or limit ethanol consumption.
Food: Simvastatin serum concentration may be increased when taken with grapefruit juice. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice. Management: Avoid concurrent intake of large quantities of grapefruit juice (>1 quart/day).
Herb/Nutraceutical: St John's wort may decrease simvastatin levels. Management: Avoid St John's wort.
Storage
Tablets should be stored in tightly-closed containers at temperatures between 5°C to 30°C (41°F to 86°F).
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
Pharmacodynamics/Kinetics
Onset of action: >3 days
Peak effect: 2 weeks
Absorption: 85%
Protein binding: ~95%
Metabolism: Hepatic via CYP3A4; extensive first-pass effect
Bioavailability: <5%
Half-life elimination: Unknown
Time to peak: 1.3-2.4 hours
Excretion: Feces (60%); urine (13%)
Dosage
Oral: 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
Children 10-17 years (females >1 year postmenarche): HeFH: 10 mg once daily in the evening; range: 10-40 mg/day (maximum: 40 mg/day)
Dosage adjustment for simvastatin with concomitant amiodarone, amlodipine, diltiazem, ranolazine, or verapamil: Refer to drug-specific dosing in adult dosing section
Adults:
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: 40 mg once daily in the evening
Prevention of cardiovascular events, hyperlipidemias: 10-20 mg once daily in the evening; range: 5-40 mg/day
Patients requiring only moderate reduction of LDL-C may be started at 5-10 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.
Dosage adjustment 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 or verapamil: Simvastatin dose should not exceed 10 mg/day
Dosage adjustment in Chinese patients on niacin doses ≥1 g/day: Use caution with simvastatin doses exceeding 20 mg/day; because of an increased risk of myopathy, do not administer simvastatin 80 mg concurrently.
Dosing adjustment in renal impairment:
Manufacturer's recommendations:
Mild-to-moderate renal impairment: No dosage adjustment necessary; simvastatin does not undergo significant renal excretion
Severe renal impairment: Clcr <30 mL/minute: Initial: 5 mg/day with close monitoring
Alternative recommendation: No dosage adjustment necessary for any degree of renal impairment (Aronoff, 2007)
Administration: Oral
May be administered without regard to meals. Administer in the evening for maximal efficacy.
Monitoring Parameters
Serum cholesterol (total and fractionated) after 4 weeks of therapy and periodically thereafter; baseline CPK (recheck CPK in any patient with symptoms suggestive of myopathy); obtain baseline liver function tests (repeat during therapy if clinically indicated)
Dietary Considerations
May be taken without regard to meals. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
Patient Education
Take at same time each day, in the evening, with or without food. Follow prescribed cholesterol-lowering diet and exercise regimen. Avoid excessive grapefruit juice (>1 quart/day) and alcohol. You will have periodic blood tests to assess effectiveness. Report unusual muscle cramping or weakness, yellowing of skin or eyes, easy bruising or bleeding, or unusual fatigue.
Geriatric Considerations
Effective and well tolerated in the elderly. The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. The National Cholesterol Education Program recommends that all adults maintain a plasma cholesterol <160 mg/dL. In elderly patients with one additional risk factor, goal LDL would be <130 mg/dL. It is the authors' belief that pharmacologic treatment be reserved for those who are unable to obtain a desirable plasma cholesterol concentration by diet alone and for whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment. Age ≥65 years is a risk factor for myopathy.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.
Cardiovascular Considerations
Primary Prevention: HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (≥2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (eg, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html. LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.
Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (Sever, 2003), patients with HTN and at least three other risk factors were randomized to 10 mg daily of atorvastatin or placebo. These patients had a total nonfasting cholesterol <250 mg/dL before treatment. LDL-C levels were 132 mg/dL before treatment and fell to an average of 90 mg/dL in the atorvastatin-treated group. There was a significant reduction in stroke, cardiovascular events, and coronary events in the atorvastatin-treated group as compared to the placebo group. There was no difference in mortality between the groups.
HMG-CoA reductase inhibitors decrease C-reactive protein (CRP), an inflammatory marker and an acute phase reactant. Elevated levels of high sensitive CRP (hsCRP), which detects CRP levels as low as 0.175 mg/L, have been shown to be associated with an increased risk of cardiovascular events. Recently, the JUPITER trial demonstrated that the use of rosuvastatin in healthy patients (men ≥50 years and women ≥60 years) without a history of cardiovascular disease with LDL <130 mg/dL and a hsCRP level ≥2 mg/L reduced the risk of major cardiovascular events (eg, nonfatal MI, stroke, death from cardiovascular causes), The number needed to treat over 5 years to prevent 1 cardiovascular event is 25. Current guidelines do not recommend drug treatment for patients with an LDL <130 mg/dL. However, identification of the patient at higher risk of cardiovascular events within this subgroup using hsCRP is now important given that statins may prevent the occurrence of these serious cardiovascular events (Ridker, 2008).
Secondary Prevention: Secondary prevention trials indicate that “statin” therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations. PROVE IT is a randomized, double-blind trial evaluating hospitalized patients with acute coronary syndrome to determine the effects of intense LDL-C lowering therapy. Four thousand patients with an LDL-C levels of 106 mg/dL were randomized to pravastatin 40 mg daily or atorvastatin 80 mg daily. After 2 years, the combined cardiovascular endpoint (death, MI, unstable angina requiring hospitalization, revascularization and stroke) was ~26% in the pravastatin patients (median LDL-C 95 mg/dL) and ~22% in the atorvastatin treated patients (median LDL-C 62 mg/dL).
LaRosa and colleagues assessed the efficacy and safety of lowering LDL cholesterol <100 mg/dL in patients with stable coronary heart disease (LaRosa, 2005). Ten thousand and one patients with baseline LDL levels <130 mg/dL were randomized to atorvastatin 10 mg or 80 mg daily and followed for a median of 4.9 years. The primary endpoint was the occurrence of the first major cardiovascular event (death from CVD, MI, resuscitation after cardiac arrest, or stroke). A primary event occurred in 434 patients (8.7%) receiving 80 mg daily (mean LDL 77 mg/dL) and 548 patients (10.9%) receiving 10 mg dose (mean LDL 101 mg/dL) (95% CI, 0.69-0.89; p <0.001). There was no mortality difference between the two treatment groups.
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. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus, 2002).
Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness
Mental Health: Effects on Psychiatric Treatment
Rhabdomyolysis with acute renal failure has occurred; risk is increased with concurrent use of fluvoxamine nefazodone and verapamil
Nursing: Physical Assessment/Monitoring
Monitor closely in presence of impaired liver function. Assess risk potential for interactions with other prescriptions or herbal products patient may be taking that may increase risk of myopathy or rhabdomyolysis. Assess cholesterol profile prior to treatment and at regular intervals. Assess LFT prior to initiating therapy and recheck when clinically indicated. Teach proper diet and exercise regimen.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg
Zocor®: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Simvastatin)
5 mg (30): $17.99
10 mg (30): $19.99
20 mg (30): $27.99
40 mg (30): $27.99
80 mg (30): $35.99
Tablets (Zocor)
5 mg (30): $77.30
10 mg (30): $93.99
20 mg (30): $173.99
40 mg (90): $465.99
80 mg (30): $178.99
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International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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