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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

Primary hypercholesterolemia/mixed dyslipidemia/hypertriglyceridemia: Reduce total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), or increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia in combination with standard cholesterol-lowering diet when simvastatin or niacin monotherapy is inadequate.

Note: Niacin is no longer considered a primary or secondary agent for dyslipidemias. Although niacin consistently affects surrogate markers, especially LDL-C, it has not been shown to reduce cardiovascular disease outcomes beyond that achieved with statin use and may be associated with harm (ACC 2016; Garg 2017; Wierzbicki 2014). In two large clinical trials, the addition of niacin to patients receiving simvastatin did not reduce cardiovascular morbidity or mortality (Boden 2011; Landray 2014). May consider use in patients with very high triglyceride levels (>500 mg/dL) or in dyslipidemia for patients who do not achieve the desired response or have intolerance to a statin or other alternative therapy (Boden 2014; Flink 2015).

Guideline recommendations: Simvastatin: Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) to reduce the risk of ASCVD in select adult patients (ACC/AHA [Stone 2013]; ADA 2017a; NLA [Jacobson 2015]; USPSTF 2016). Refer to respective guideline for specific recommendations.

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 or women who may become pregnant; breastfeeding; concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, protease inhibitors [including boceprevir and telaprevir], itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, telithromycin, cobicistat-containing products), amiodarone, cyclosporine, danazol, diltiazem, dronedarone, gemfibrozil, verapamil

Dosing: Adult

Primary hypercholesterolemia/mixed dyslipidemia/hypertriglyceridemia: Oral: Note: Niacin is no longer recommended, except in specific clinical situations (eg, high triglyceride levels [>500 mg/dL], if not able to achieve desired response, or intolerance to other therapies) (ACC 2016; Boden 2014; Garg 2017; Landray 2014; Wierzbicki 2014).

Initial dose: Note: Not for use as initial therapy of dyslipidemias. Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and the patient's response.

Patients naïve to niacin ER therapy or currently on immediate-release niacin: Niacin ER 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 to 40 mg daily): Niacin ER 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 ER 1,000 to 2,000 mg/simvastatin 20 to 40 mg once daily (maximum daily dose: niacin ER 2,000 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. May be substituted for equivalent dose of niacin extended-release, however, manufacturer does not recommend direct substitution with immediate-release preparations.

Dosage adjustment with concomitant medications:

Amiodarone, amlodipine, or ranolazine: Maximum: Niacin ER 1,000 mg/simvastatin 20 mg per day

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling (combination has not been studied); use with caution. Also see individual agents.

Severe renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (combination has not been studied). Use with extreme caution or avoid unless patient already tolerating simvastatin doses ≥10 mg. Also see individual agents.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (combination has not been studied). Contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Also see individual agents.

Dosing: Adjustment for Toxicity

Hepatic toxicity: Discontinue use if hepatic transaminase levels rise, particularly to 3 x ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise.

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

Administration

Administer tablets whole; do not break, crush or chew. Administer with a low-fat snack at bedtime. To attenuate flushing symptoms, may premedicate with aspirin 30 minutes before dose; avoid ingestion of alcohol, hot or spicy foods/liquids concurrently with niacin.

Dietary Considerations

Administer with a low-fat snack; avoid alcohol, hot drinks, and spicy foods around the time of administration. 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 (Statins). Monitor therapy

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

Amiodarone: May increase the serum concentration of Simvastatin. Management: Consider using a non-interacting statin (pravastatin) in patients on amiodarone. If combined, limit the simvastatin dose to 20 mg daily and monitor for evidence of simvastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). 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 (Statins). 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 (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

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

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

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 (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

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

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

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. 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 (Statins). Monitor therapy

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

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

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

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

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

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

Glecaprevir and Pibrentasvir: May increase the serum concentration of Simvastatin. Avoid combination

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

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

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

HMG-CoA Reductase Inhibitors (Statins): Niacin may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

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

Imatinib: May decrease the metabolism of Simvastatin. Monitor therapy

Lanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification

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

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

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

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

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

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

Niacin: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin 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 (Statins). Monitor therapy

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

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

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

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

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

QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). 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 (Statins). Monitor therapy

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

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Avoid combination

Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider use of noninteracting antilipemic agents (note: pitavastatin concentrations may increase with rifamycin treatment). Monitor for altered HMG-CoA reductase inhibitor effects. Rifabutin and fluvastatin, or possibly pravastatin, may pose lower risk. Consider therapy modification

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

Rupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Monitor therapy

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

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

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

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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

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 (High risk with Inducers). Monitor therapy

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

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

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

Voxilaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Consider therapy modification

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:

Endocrine & metabolic: Abnormal thyroid function test, decreased serum phosphate, increased amylase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased uric acid

Hematologic & oncologic: Increase in fasting plasma glucose, prolonged prothrombin time, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases

Neuromuscular & skeletal: Increased creatine phosphokinase

Warnings/Precautions

Concerns related to adverse effects:

• Flushing/pruritus: Flushing and pruritus are 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 or spicy foods/liquids, and/or by taking aspirin 30 minutes before dosing. Flushing associated with extended-release preparation is significantly reduced (Guyton 2007). Consider discontinuation if persistent severe cutaneous symptoms occur during therapy.

• 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. Consider discontinuation if unexplained abdominal pain/weight loss or other gastrointestinal symptoms occur during therapy.

• 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. Persistent elevations in serum transaminases have been reported with simvastatin; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Postmarketing reports of fatal and nonfatal hepatic failure with simvastatin have been reported and are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly; if an alternate etiology is not identified, do not restart. Liver enzyme tests should be obtained at baseline and as clinically indicated. Discontinue use if hepatic transaminase levels rise, particularly to 3 x ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise.

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

• Myopathy/rhabdomyolysis: Rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with high doses of simvastatin (80 mg) or niacin (doses ≥1 g/day). Concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil is contraindicated due to increased risk of myopathy. Use with caution in patients with uncontrolled hypothyroidism, patients taking other drugs associated with myopathy (eg, colchicine), ≥ 65 years of age, and women; these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitors use has also been reported. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.

Disease-related concerns:

• 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). Consider discontinuation if new-onset atrial fibrillation occurs during therapy.

• Diabetes: Niacin is associated with new-onset diabetes or worsening glucose tolerance in patients with preexisting diabetes (Garg 2017; Goldie 2016); use with caution in patients with diabetes. Monitor glucose; adjustment of diet and/or hypoglycemic therapy may be necessary. Consider discontinuation if persistent hyperglycemia occurs during therapy.

• Gout: Niacin may be associated with hyperuricemia; use with caution in patients with gout. Consider discontinuation if acute gout occurs during therapy.

• Hepatic impairment: Use with caution in patients with a past history of hepatic impairment; monitor liver function tests. Contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases.

• 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Chinese patients: Increased risk for myopathy in Chinese patients with simvastatin; use with caution. Do not use high dose simvastatin (80 mg) if concurrently taking niacin ≥1 g/day.

• 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, 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 (ACC/AHA [Fleisher 2014]).

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.

Other warnings/precautions:

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

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.

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

Manufacturer's labeling: Platelets/prothrombin time (if on anticoagulants); phosphorus (if predisposed to hypophosphatemia)

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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