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Sitagliptin and Simvastatin

Pronunciation

(sit a GLIP tin & sim va STAT in)

Index Terms

  • Simvastatin and Sitagliptin
  • Sitagliptin Phosphate and Simvastatin

Dosage Forms

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

Tablet, oral:

Juvisync 50/10: Sitagliptin 50 mg and simvastatin 10 mg [DSC]

Juvisync 50/20: Sitagliptin 50 mg and simvastatin 20 mg [DSC]

Juvisync 50/40: Sitagliptin 50 mg and simvastatin 40 mg [DSC]

Juvisync 100/10: Sitagliptin 100 mg and simvastatin 10 mg [DSC]

Juvisync 100/20: Sitagliptin 100 mg and simvastatin 20 mg [DSC]

Juvisync 100/40: Sitagliptin 100 mg and simvastatin 40 mg [DSC]

Brand Names: U.S.

  • Juvisync™ [DSC]

Pharmacologic Category

  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

Simvastatin: 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).

Sitagliptin: Inhibits dipeptidyl peptidase IV (DPP-IV) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-IV enzyme.

Use: Labeled Indications

For use when treatment with both sitagliptin and simvastatin is appropriate:

Sitagliptin: Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise as monotherapy or in combination therapy with other antidiabetic agents

Simvastatin: 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

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

Dosing: Adult

Hyperlipidemia and type 2 diabetes: Oral: Initial dose: Sitagliptin 100 mg and simvastatin 40 mg once daily. Note: Patients already taking simvastatin <40 mg daily (with or without sitagliptin 100 mg daily) can be converted to the comparable equivalent of the combination product. Dose adjustments should be made at intervals of ≥4 weeks.

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas): Reduced dose of insulin and/or insulin secretagogues may be needed.

Dosage adjustment for simvastatin with concomitant medications:

Amiodarone, amlodipine, or ranolazine: Simvastatin dose should not exceed 20 mg daily

Diltiazem, dronedarone, or verapamil: Simvastatin dose should not exceed 10 mg daily

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

Dosage adjustment for simvastatin in Chinese patients on niacin doses ≥1 g/day: Use caution with simvastatin doses of 40 mg daily because of an increased risk of myopathy

Dosing: Renal Impairment

Renal function may be estimated using Cockcroft-Gault formula for dosage adjustment purposes.

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl ≥30 to <50 mL/minute (approximate SCr of >1.7 to ≤3.0 mg/dL [males] or >1.5 to ≤2.5 mg/dL [females]): Initial: Sitagliptin 50 mg and simvastatin 40 mg once daily. Note: Patients already taking simvastatin <40 mg daily (with or without sitagliptin 50 mg daily) can be converted to the comparable equivalent of the combination product.

CrCl <30 mL/minute (approximate SCr of >3.0 mg/dL [males] or >2.5 mg/dL [females]): Use is not recommended.

End-stage renal disease (ESRD): Use is not recommended.

Dosing: Hepatic Impairment

Use is contraindicated.

Administration

Administer in the evening. Do not split or divide tablet.

Dietary Considerations

May be taken with or without food. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

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 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

ACE Inhibitors: DPP-IV Inhibitors may enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

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

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. 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

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

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

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

Digoxin: SITagliptin may increase the serum concentration of Digoxin. 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

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

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

Imatinib: May decrease the metabolism of Simvastatin. Monitor therapy

Insulin: DPP-IV Inhibitors may enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

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

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). 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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

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

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

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

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

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

Sulfonylureas: DPP-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. 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

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. 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

See individual agents.

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 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.

• Hypersensitivity reactions: Rare hypersensitivity reactions, including anaphylaxis, angioedema, and/or severe dermatologic reactions such as Stevens-Johnson syndrome, have been reported with sitagliptin in postmarketing surveillance; discontinue if signs/symptoms of hypersensitivity reactions occur. Events have generally been noted within the first 3 months of therapy, and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use.

• 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.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with sitagliptin use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk.

Disease-related concerns:

• Diabetic ketoacidosis (DKA): Should not be used in patients with DKA due to lack of efficacy in this patient population.

• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease.

• Renal impairment: Use is not recommended in patients with severe renal dysfunction and end-stage renal disease (ESRD) requiring hemodialysis since the appropriate combination dose is not available. Additionally, cases of sitagliptin-induced acute renal failure (some requiring dialysis) have been reported.

• Type 1 diabetes mellitus: Should not be used in patients with type 1 diabetes mellitus (insulin dependent, IDDM) due to lack of efficacy in this patient population

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.

• Insulin: Concomitant use of insulin may increase the risk of hypoglycemia. Monitor blood glucose closely; dosage reduction of insulin may be required.

• Insulin secretagogues: Concomitant use of an insulin secretagogue (eg, sulfonylurea) may increase the risk of hypoglycemia. Monitor blood glucose closely; dosage reduction of secretagogues may be required.

Special populations:

• Chinese patients: Use higher simvastatin dose (40 mg) with caution if concurrently taking niacin ≥1 g/day; concomitant use may increase risk of myopathy in Chinese patients; risk to other Asian populations is not known.

• 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. Simvastatin has not been studied in Fredrickson type I and V hyperlipidemia.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Sitagliptin: HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), serum glucose; renal function (prior to initiation and periodically during treatment)

Simvastatin:

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.

Manufacturer's labeling: Upon initiation or titration, lipid panel should be analyzed after ≥4 weeks of therapy and periodically 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 headache, rhinitis, abdominal pain, or constipation. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), urinary retention, change in amount of urine passed, bruising, bleeding, burning or numbness feeling, dizziness, confusion, memory impairment, depression, sexual dysfunction, tachycardia, arrhythmia, chills, pharyngitis, persistent cough, shortness of breath, insomnia, severe loss of strength and energy, muscle pain, muscle tenderness, muscle weakness, severe joint pain, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

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

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