Medically reviewed on March 25, 2018

Pronunciation

(sit a GLIP tin)

Index Terms

• MK-0431
• Sitagliptin Phosphate

Dosage Forms

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

Tablet, Oral:

Januvia: 25 mg, 50 mg, 100 mg

Brand Names: U.S.

• Januvia

Pharmacologic Category

• Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor

Pharmacology

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.

Absorption

Rapid

Distribution

~198 L

Metabolism

Not extensively metabolized; minor metabolism via CYP3A4 and 2C8 to metabolites (inactive) suggested by in vitro studies

Excretion

Urine 87% (~79% as unchanged drug, 16% as metabolites); feces 13%

Time to Peak

1 to 4 hours

Half-Life Elimination

12.4 hours

Protein Binding

38%

Special Populations: Renal Function Impairment

Plasma AUC levels of sitagliptin were increased approximately 2- and 4-fold in patients with moderate and severe renal impairment, including patients with ESRD on hemodialysis, respectively.

Special Populations: Elderly

Elderly patients had ~19% higher plasma concentration.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent) as monotherapy or combination therapy.

Contraindications

Serious hypersensitivity (eg, anaphylaxis, angioedema) to sitagliptin or any component of the formulation

Dosing: Adult

Diabetes mellitus, type 2: Oral: 100 mg once daily

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

Dosing: Renal Impairment

eGFR ≥45 mL/minute/1.73 m²: No dosage adjustment necessary.

eGFR ≥30 to <45 mL/minute/1.73 m²: 50 mg once daily

eGFR <30 mL/minute/1.73 m²: 25 mg once daily

ESRD requiring hemodialysis or peritoneal dialysis: 25 mg once daily; administer without regard to timing of hemodialysis

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

Oral: Administer without regard to meals.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on American Diabetes Association (ADA) recommendations is an integral part of therapy.

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

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

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

Angiotensin-Converting Enzyme Inhibitors: Dipeptidyl Peptidase-IV Inhibitors may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Digoxin: SITagliptin may increase the serum concentration of Digoxin. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. 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

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

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

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

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

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

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

Sulfonylureas: Dipeptidyl Peptidase-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

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

Adverse Reactions

1% to 10%:

Endocrine & metabolic: Hypoglycemia (1%)

Respiratory: Nasopharyngitis (5%)

Frequency not defined:

Gastrointestinal: Diarrhea, nausea

Renal: Increased serum creatinine

<1%, postmarketing, and/or case reports: Acute pancreatitis (including hemorrhagic or necrotizing forms), acute renal failure (possibly requiring dialysis), anaphylaxis, angioedema, arthralgia, back pain, bullous pemphigoid, constipation, exfoliative dermatitis, headache, hypersensitivity, hypersensitivity vasculitis, increased liver enzymes, limb pain, myalgia, oral mucosa ulcer, pain, pemphigoid, pruritus, renal insufficiency, severe arthralgia, skin rash (including macular), Stevens-Johnson syndrome, stomatitis, urticaria, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-IV inhibitor therapy resumed.

• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.

• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin reactions, such as Stevens-Johnson syndrome, have been reported; 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 dipeptidyl peptidase IV (DPP-IV) inhibitor use.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with 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.

• Renal effects: Worsening renal function, including acute renal failure, sometimes requiring dialysis has been reported.

Disease-related concerns:

• Cardiovascular disease: In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with heart failure. Use sitagliptin with caution in patients at risk for heart failure (eg, history of heart failure or renal impairment) and monitor for signs and symptoms of heart failure during therapy; consider discontinuation if heart failure develops. In a scientific statement from the American Heart Association, sitagliptin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). However, in one large randomized, double-blinded trial in patients with type 2 diabetes and established cardiovascular disease (history of major CAD, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease), the occurrence of the primary composite cardiovascular outcome (cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) with sitagliptin was found to be noninferior to placebo. In addition, the rate of hospitalization for heart failure did not differ between the two groups (Green 2015; McGuire 2016).

• Renal impairment: Use with caution in patients with moderate to severe renal dysfunction and end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis; dosing adjustment required.

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.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with insulin-dependent diabetes mellitus (IDDM) (type 1) or in patients with diabetic ketoacidosis (DKA).

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

Monitoring Parameters

HbA_1c (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 2018a]), serum glucose; renal function prior to initiation and periodically during treatment; signs/symptoms of heart failure

Pregnancy Considerations

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2018c; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2018c; Blumer 2013). Agents other than sitagliptin are currently recommended to treat diabetes in pregnant women (ADA 2018c).

Health care providers are encouraged to enroll women exposed to sitagliptin during pregnancy in the registry (1-800-986-8999).

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, pharyngitis, common cold symptoms, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), 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), skin blisters, skin breakdown, severe joint pain, persistent 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.

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