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Simvastatin

Pronunciation

Pronunciation

(sim va STAT in)

Dosage Forms

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

Tablet, Oral:

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

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

Brand Names: U.S.

  • Zocor

Pharmacologic Category

  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus, 2002; Ray, 2005).

Absorption

85%

Metabolism

Hepatic via CYP3A4; extensive first-pass effect

Excretion

Feces (60%); urine (13%)

Onset of Action

>3 days; Peak effect: 2 weeks

Time to Peak

1.3 to 2.4 hours

Half-Life Elimination

Unknown

Protein Binding

~95%

Special Populations: Renal Function Impairment

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

Special Populations: Elderly

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

Use: Labeled Indications

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

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) according to the American College of Cardiology/American Heart Association: To reduce the risk of ASCVD in patients with clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) who are greater than 75 years of age or not a candidate for high-intensity statin therapy; in patients without clinical ASCVD if LDL-C is 190 mg/dL or greater and not a candidate for high-intensity statin therapy; in patients without clinical ASCVD who have type 1 or type 2 diabetes and are between 40 and 75 years of age; in patients with an estimated 10-year ASCVD risk 7.5% or greater and who are between 40 and 75 years of age (Stone, 2013). The American Heart Association (AHA) recommends statin therapy (unless contraindicated) for all coronary artery bypass graft (CABG) surgery patients to help maintain long-term graft patency and help obtain the highest level of physical health and quality of life (AHA [Kulik, 2015]). Specific recommendations from the Kidney Disease: Improving Global Outcomes (KDIGO) organization have also been released for patients with chronic kidney disease (KDIGO [Tonelli, 2013]).

Contraindications

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

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 to 17 years (females >1 year postmenarche): HeFH: 10 mg once daily in the evening; range: 10 to 40 mg/day (maximum: 40 mg/day)

Dosage adjustment for simvastatin with concomitant amiodarone, amlodipine, diltiazem, dronedarone, lomitapide, 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 (also see ACC/AHA Blood Cholesterol Guideline recommendations), hyperlipidemias: 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: ACC/AHA Blood Cholesterol Guideline recommendations to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) (Stone, 2013): Adults ≥21 years:

Primary prevention:

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

Type 1 or 2 diabetes and age 40 to 75 years: Moderate intensity therapy: 20 to 40 mg once daily

Type 1 or 2 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)

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 or not a candidate for high intensity therapy: Moderate intensity therapy: 20 to 40 mg once daily

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, 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)

Dosage adjustment in Chinese patients on niacin doses ≥1 g/day:

US labeling: Use caution with simvastatin doses exceeding 20 mg/day; because of an increased risk of myopathy, do not administer simvastatin 80 mg concurrently.

Canadian labeling: Concomitant use is not recommended in Chinese and other Asian patients.

Dosing adjustment for toxicity:

Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (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 (Stone, 2013).

Dosage adjustment in renal impairment: Manufacturer’s recommendations:

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

Severe impairment: CrCl <30 mL/minute: Initial: 5 mg/day with close monitoring.

Dosage adjustment in hepatic impairment: Use is contraindicated in the setting of active liver disease.

Administration

May be administered without regard to meals. Administer in the evening for maximal efficacy.

Dietary Considerations

May be taken without regard to meals. 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

Tablets should be stored in tightly-closed containers at temperatures between 5°C to 30°C (41°F to 86°F).

Drug Interactions

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

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 lovastatin adult maximum dose to 40 mg/day). Consider therapy modification

AmLODIPine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antacids: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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 full interaction monograph for specific recommendations. Monitor therapy

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

Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors. More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. Consider therapy modification

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

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

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

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

Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

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

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

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

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

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

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

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

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. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diltiazem: Simvastatin may increase the serum concentration of Diltiazem. Diltiazem may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of diltiazem with simvastatin when possible. If used together, limit adult doses to simvastatin 10 mg/day and diltiazem 240 mg/day; avoid Simcor (simvastatin/niacin) because fixed simvastatin doses exceed the maximum. Consider therapy modification

Dronedarone: May increase the serum concentration of Simvastatin. Management: Limit simvastatin to a max of 10 mg/day (in adults). Increase monitoring for signs of simvastatin toxicity (e.g., myositis, rhabdomyolysis). Consider therapy modification

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

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

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

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

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

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. 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. Monitor therapy

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

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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Consider therapy modification

Fusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Avoid combination

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

Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Gemfibrozil may increase the serum concentration of Simvastatin. Concentrations of the active simvastatin acid metabolite may also be increased by gemfibrozil. Avoid combination

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Imatinib: May decrease the metabolism of Simvastatin. Monitor therapy

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Lercanidipine: May increase the serum concentration of Simvastatin. Management: Administer lercanidipine in the morning and simvastatin in the evening in patients receiving these drugs in combination. Consider therapy modification

Lomitapide: May increase the serum concentration of Simvastatin. Management: Reduce the recommended simvastatin dose by 50%. Generally, limit the maximum adult simvastatin dose to 20 mg/day. A 40 mg/day dose can be considered in patients who previously received 80 mg/day for at least a year without evidence of muscle toxicity. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Management: Greatest concern with niacin 1 g/d or greater. Avoid simvastatin 80 mg with niacin 1 g or greater in Chinese patients. Do not exceed 40 mg/d of simva or lovastatin with Niaspan. Use of niacin with rosuvastatin 40 mg is contraindicated (Canadian label). Consider therapy modification

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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: HMG-CoA Reductase Inhibitors may enhance the hepatotoxic effect of PAZOPanib. Specifically, the risk for increased serum transaminase concentrations may be increased. Management: Simvastatin is specifically implicated in this interaction. There is a lack of data regarding the risk with other statins, but caution appears warranted with any statins. Monitor therapy

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

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

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

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

Ranolazine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of ranolazine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day. Consider therapy modification

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. 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. Consider therapy modification

Sacubitril: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

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

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

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Verapamil: May increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. Consider therapy modification

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

Adverse Reactions

Frequency not always defined.

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

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

Dermatologic: Eczema (5%)

Gastrointestinal: Abdominal pain (7%), constipation (2% to 7%), gastritis (5%), nausea (5%)

Genitourinary: Cystitis (interstitial; Huang 2015)

Hepatic: Increased transaminases (>3 x ULN; 1%)

Neuromuscular & skeletal: Increased CPK (>3 x normal; 5%), myalgia (4%)

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

<1% (Limited to important or life-threatening): Alopecia, amnesia (reversible), anaphylaxis, anemia, angioedema, arthralgia, arthritis, chills, cognitive impairment (reversible), confusion (reversible), depression, dermatomyositis, diabetes mellitus (new onset), diarrhea, dizziness, dryness of skin/mucous membranes, dyspepsia, dyspnea, eosinophilia, erythema multiforme, fever, flatulence, flushing, hemolytic anemia, hepatic failure, hepatitis, hypersensitivity reaction, increased alkaline phosphatase, increased blood glucose, increased ESR, increased GGT, increased glycosylated hemoglobin (HbA1c), 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, cataracts, cholestatic jaundice, cirrhosis, decreased libido, depression, erectile dysfunction/impotence, facial paresis, fatty liver, fulminant hepatic necrosis, gynecomastia, hepatoma, hyperbilirubinemia, immune-mediated necrotizing myopathy (IMNM), impaired extraocular muscle movement, increased bilirubin, increased CPK (>10 x normal), interstitial lung disease, ophthalmoplegia, peripheral nerve palsy, psychic disturbance, renal failure (secondary to rhabdomyolysis), thyroid dysfunction, tremor, vertigo

Warnings/Precautions

Concerns related to adverse effects:

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

• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart simvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Immune-mediated necrotizing myopathy (IMNM): IMNM, an autoimmune-mediated myopathy, has been reported (rarely) with HMG-CoA reductase inhibitor therapy. IMNM presents as proximal muscle weakness with elevated CPK levels, which persists despite discontinuation of HMG-CoA reductase inhibitor therapy; additionally, muscle biopsy may show necrotizing myopathy with limited inflammation. Immunosuppressive therapy (eg, corticosteroids, azathioprine) may be used for treatment.

• 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. 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.

• Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

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

Monitoring Parameters

2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013):

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.

Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, ALT); measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.

CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).

Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.

If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.

Manufacturer's labeling: Liver enzyme tests at baseline and repeated when clinically indicated. Measure CPK when myopathy is being considered or may measure CPK periodically in high risk patients (eg, drug-drug interaction). Lipid panel should be analyzed after 4 weeks of therapy and periodically thereafter.

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. 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.

Use of simvastatin is contraindicated in pregnancy. HMG-CoA reductase inhibitors should be discontinued prior to pregnancy (ADA, 2013). If treatment of dyslipidemias is needed in pregnant women or in women of reproductive age, other agents are preferred (Berglund, 2012; Stone, 2013). The manufacturer recommends administration to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards.

Patient Education

• 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, dyspepsia, constipation, rhinitis, rhinorrhea, or pharyngitis. Have patient report immediately to prescriber arrhythmia, urinary retention, oliguria, signs of severe muscle problems, or signs of hepatic impairment (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 healthcare 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.

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