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Niacin and Simvastatin

Pronunciation

(NYE a sin & sim va STAT in)

Index Terms

  • Niacin/Simvastatin
  • Simvastatin and Niacin

Dosage Forms

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

Tablet, variable release, oral:

Simcor:

500/20: Niacin 500 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

500/40: Niacin 500 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]

750/20: Niacin 750 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

1000/20: Niacin 1000 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

1000/40: Niacin 1000 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]

Brand Names: U.S.

  • Simcor [DSC]

Pharmacologic Category

  • Antilipemic Agent, HMG-CoA Reductase Inhibitor
  • Antilipemic Agent, Miscellaneous

Pharmacology

Niacin is a component of two coenzymes which is necessary for tissue respiration, lipid metabolism, and glycogenolysis; inhibits the synthesis of very low density lipoproteins.

Simvastatin is a 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).

Use: Labeled Indications

Reduce total cholesterol, LDL, Apo B, non-HDL, TG, and/or increase HDL in patients with primary hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia in combination with standard cholesterol-lowering diet when simvastatin or niacin monotherapy is inadequate

Simvastatin: 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). 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 niacin, simvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of transaminases; active peptic ulcer disease; arterial bleeding; pregnancy; breast-feeding; concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, protease inhibitors including boceprevir and telaprevir, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, telithromycin, and cobicistat-containing products), amiodarone, cyclosporine, danazol, diltiazem, dronedarone, gemfibrozil, and verapamil

Dosing: Adult

Dosage forms are a fixed combination of niacin extended-release and simvastatin.

Dyslipidemia: Oral:

Initial dose:

Patients naïve to niacin therapy: Niacin 500 mg/simvastatin 20 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin

Patients currently on immediate-release niacin products: Niacin 500 mg/simvastatin 20 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin

Patients currently on simvastatin (20-40 mg daily): Niacin 500 mg/simvastatin 40 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin

Maintenance dose: Niacin 1000-2000 mg/ simvastatin 20-40 mg once daily (maximum daily dose: niacin 2000 mg/simvastatin 40 mg)

Note: If therapy is interrupted for >7 days, reinstitution of therapy should begin with the lowest dose followed by retitration as tolerated. Not for use as initial therapy of dyslipidemias. May be substituted for equivalent dose of niacin extended-release, however, manufacturer does not recommend direct substitution with immediate-release preparations.

Dosage adjustment for simvastatin component with concomitant medications: Amiodarone, amlodipine, or ranolazine: Dose should not exceed niacin 1000 mg/simvastatin 20 mg once daily

Dosing: Renal Impairment

Mild-to-moderate impairment: No dosage adjustment required; use caution.

Severe renal impairment: Use with extreme caution or avoid unless patient already tolerating simvastatin doses ≥10 mg.

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

Discontinue therapy if transaminases >3 times ULN persist or are accompanied by symptoms (nausea, fever, malaise).

Administration

Tablets must be swallowed whole; do not crush or chew. Administer with a low-fat snack at bedtime. To attenuate flushing symptoms, may premedicate with aspirin 325 mg administered 30 minutes before dose; avoid ingestion of hot liquids or alcohol concurrently with niacin (Stone, 2013).

Dietary Considerations

Continue standard cholesterol-lowering diet during therapy. Should be taken with a low-fat snack.

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

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

Alcohol (Ethyl): May enhance the adverse/toxic effect of Niacin. Consider therapy modification

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

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

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

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors. 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

Bile Acid Sequestrants: May decrease the absorption of Niacin. 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

Elbasvir: May increase 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

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

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

HMG-CoA Reductase Inhibitors: Niacin may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. 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 myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin 80 mg with niacin should be avoided and simvastatin doses over 20 mg/day should be used cautiously in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. Consider therapy modification

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

Rosuvastatin: Niacin may enhance the myopathic (rhabdomyolysis) effect of Rosuvastatin. Monitor therapy

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

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

Simvastatin: Niacin may enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin 80 mg with niacin should be avoided and simvastatin doses over 20 mg/day should be used cautiously in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. Consider therapy modification

St John's 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 John's 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

Test Interactions

Niacin: False elevations in some fluorometric determinations of plasma or urinary catecholamines; false-positive urine glucose (Benedict's reagent)

Adverse Reactions

Reactions/percentages reported with combination product; also see individual agents.

>10%: Cardiovascular: Flushing (≤59%)

1% to 10%:

Central nervous system: Headache (5%)

Dermatologic: Pruritus (3%)

Gastrointestinal: Diarrhea (3%), nausea (3%)

Neuromuscular & skeletal: Back pain (3%)

Frequency not defined: Alkaline phosphatase increased, amylase increased, bilirubin increased, creatinine kinase increased, fasting blood glucose increased, GGT increased, LDH increased, phosphorus decreased, platelets decreased, prothrombin time increased, thyroid function test abnormalities, transaminases increased, uric acid increased

Warnings/Precautions

Concerns related to adverse effects:

• Flushing/pruritus: Flushing and pruritus, common adverse effects of niacin, may be attenuated with a gradual increase in dose, administering with food, avoidance of concurrent ingestion of ethanol or hot liquids, and/or by taking aspirin (adults: 325 mg) 30 minutes before dosing (Stone, 2013). Avoid concurrent ingestion of ethanol, hot liquids, or spicy foods to minimize flushing. Flushing associated with extended-release preparation is significantly reduced (Guyton, 2007). Niacin should not be used if patient experiences persistent severe cutaneous symptoms during therapy (Stone, 2013).

• Gastrointestinal effects: May cause gastrointestinal distress, vomiting, diarrhea, or aggravate peptic ulcer; gastrointestinal distress may be attenuated with a gradual increase in dose and administration with food. Use is contraindicated in patients with active peptic ulcer disease; use with caution in patients with a past history of peptic ulcer. Niacin should not be used if patient experiences unexplained abdominal pain or gastrointestinal symptoms or unexplained weight loss during therapy (Stone, 2013).

• Hematologic effects: Dose-related reductions in platelet count and increases of prothrombin time may occur.

• Hepatotoxicity: Cases of severe hepatotoxicity, including fulminant hepatic necrosis, have occurred when immediate release (crystalline) niacin products have been substituted with sustained-release (modified release, timed-release) niacin products at equivalent doses. Patients should be initiated with low doses with titration to achieve desired response. Postmarketing reports of fatal and nonfatal hepatic failure with simvastatin 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. Niacin should not be used if hepatic transaminase elevations >2-3 times upper limit of normal occur during therapy (Stone, 2013).

• Hypophosphatemia: Has been associated with small but statistically significant dose-related reductions in phosphorus levels. Monitor phosphorus levels periodically in patients at risk for hypophosphatemia.

• 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 (simvastatin 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. Discontinue treatment if CK levels rise to >10 times ULN with concomitant muscle symptoms.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with unstable angina or MI. In patients with pre-existing coronary artery disease, the incidence of atrial fibrillation was observed more frequently in those receiving immediate release (crystalline) niacin as compared to placebo (Coronary Drug Project Research Group, 1975). Niacin should not be used if patient experiences new-onset atrial fibrillation during therapy (Stone, 2013).

• Diabetes: Niacin may increase fasting blood glucose, although clinical data suggest increases are generally modest (<5%) (Guyton, 2007). Use niacin with caution in patients with diabetes. Monitor glucose; adjustment of diet and/or hypoglycemic therapy may be necessary. Niacin should not be used if patient experiences persistent hyperglycemia during therapy (Stone, 2013).

• Gout: May be associated with hyperuricemia. Use niacin with caution in patients with gout. Niacin should not be used if patient experiences acute gout during therapy (Stone, 2013).

• Hepatic impairment: Use with caution in patients with a past history of hepatic impairment. Use is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Transaminases should be monitored during therapy; if levels elevated, repeat test (confirmatory) and monitor frequently until transaminases return to normal; therapy should be discontinued if transaminase levels >3 times ULN persist or are accompanied by symptoms (nausea, fever, malaise).

• Renal impairment: Use with caution in renal impairment; use with extreme caution or avoid in severe impairment unless patient already tolerating simvastatin doses ≥10 mg. Renal impairment may also increase risk for myopathy.

Concurrent drug therapy issues:

• High potential for interactions: 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: Concomitant use of niacin (>1 g/day) and simvastatin (>20 mg/day) should be done with caution; 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.

Dosage form specific issues:

• Product interchangeability: Bioavailability of niacin formulations vary (regular release versus extended release) and are not interchangeable; cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted niacin products at equivalent doses. In addition, bioequivalence between different Simcor® dosage strengths has not been evaluated and strengths should not be considered exchangeable.

Other warnings/precautions:

• Alcohol use: Use with caution in patients who consume large amounts of ethanol due to the increased risk of liver dysfunction.

• Appropriate use: Prior to initiation, secondary causes for hypercholesterolemia (eg, poorly controlled diabetes mellitus, hypothyroidism) should be excluded; management with diet and other nonpharmacologic measures (eg, exercise or weight reduction) should be attempted prior to initiation.

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 4-12 weeks after initiation or dose adjustment and every 3-12 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.

Baseline fasting blood glucose or hemoglobin A1c and uric acid before initiation and repeat during uptitration to maintenance dose and every 6 months thereafter.

Pregnancy Risk Factor

X

Pregnancy Considerations

Use is contraindicated in pregnant women. See individual agents.

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 flushing or headache. Have patient report immediately to prescriber prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes),, severe dizziness, passing out, angina, tachycardia, shortness of breath, sweating a lot, urinary retention, change in amount of urine passed, severe muscle pain, or severe 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 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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