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Sitagliptin: Drug information

Sitagliptin: Drug information
(For additional information see "Sitagliptin: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Januvia
Brand Names: Canada
  • Januvia
Pharmacologic Category
  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
Dosing: Adult

Note: Due to lack of additive glycemic benefit, use in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist should be avoided (Ref). May require a dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia.

Diabetes mellitus, type 2, treatment

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or who cannot take metformin, particularly in patients close to glycemic goals when avoidance of hypoglycemia and/or weight gain is desirable; use is not associated with improvement in cardiovascular or renal outcomes (Ref).

Oral: 100 mg once daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Oral:

Altered kidney function:

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.

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (13.5% removed during 3- to 4-hour hemodialysis session) (Ref): 25 mg once daily; may administer without regard to timing of dialysis.

Peritoneal dialysis: 25 mg once daily.

Dosing: Hepatic Impairment: Adult

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).

Dosage Forms: US

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

Tablet, Oral:

Januvia: 25 mg, 50 mg, 100 mg

Generic Equivalent Available: US

No

Dosage Forms: Canada

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

Tablet, Oral:

Januvia: 25 mg, 50 mg, 100 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021995s050lbl.pdf#page=27, must be dispensed with this medication.

Administration: Adult

Oral: Administer without regard to meals.

Use: Labeled Indications

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

Medication Safety Issues
Sound-alike/look-alike issues:

Januvia may be confused with Enjuvia, Janumet, Jantoven

SITagliptin may be confused with SAXagliptin, SUMAtriptan

Adverse Reactions (Significant): Considerations
Arthralgia

Arthralgia, including severe and disabling cases, has been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin (Ref). Specific inflammatory joint complications may include polyarthritis, polyarthropathy, rheumatoid arthritis, and severe synovitis (Ref). Patients may or may not exhibit an increase in rheumatoid factors (Ref).

Mechanism: Not well established; one hypothesis includes cytokine-induced inflammation (Ref).

Onset: Varied; onset may occur within 1 day to years after treatment initiation. Symptoms may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumes (Ref).

In one study, most patients who reported arthralgias did so within 3 months of initiation of DPP-4 inhibitors and symptoms resolved within 1 month after discontinuation (Ref).

Risk factors:

• Longer duration of therapy; data is conflicting (Ref).

Dermatologic reactions

Dipeptidyl peptidase-4 (DPP-4) inhibitor use, including sitagliptin, has been associated with development or exacerbation of bullous pemphigoid (Ref). Although most DPP-4 inhibitors have been associated with the development of bullous pemphigoid, vildagliptin is associated with a higher risk (Ref). In addition, severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome or toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms have been reported with sitagliptin (Ref). Other dermatologic reactions that have occurred following sitagliptin use are maculopapular rash and fixed drug eruption (Ref).

Mechanism: Non-dose-related; immunologic.

Bullous pemphigoid: Exact mechanism unknown (Ref). Some skin cells (including keratinocytes) express DPP-4, leading to an increase in cytokine production, tissue differentiation, and collagen metabolism; whether this leads to an alteration in the properties of the epidermal basement membrane is unknown.

Delayed hypersensitivity reactions (including SCARs): Mediated by T-cells (Ref).

Onset:

Bullous pemphigoid: Delayed; median onset of ~6 months (range: 6 to 1,751 days) (Ref). Most cases of bullous pemphigoid typically resolve following discontinuation; some require symptomatic treatment (Ref).

Delayed hypersensitivity reactions: Varied; typically occur days to weeks after drug exposure (Ref).

Risk factors:

• Age; although older age may be a risk factor for the development of bullous pemphigoid, some studies have not shown age to be a factor (Ref).

• Males; some studies have suggested that male patients with diabetes may be at higher risk than female patients (Ref), although a meta-analysis of case-controlled studies did not find sex to be a predisposing risk factor (Ref).

Heart failure

An increased risk of hospitalization due to heart failure (HF) was identified as a potential issue with dipeptidyl peptidase-4 (DPP-4) inhibitors, specifically saxagliptin and alogliptin, following results from the SAVOR TIMI 53 and EXAMINE trials, respectively (Ref). In contrast, the TECOS and CARMELINA trials showed no increased risk of hospitalization due to HF with sitagliptin or linagliptin, respectively, including in patients with preexisting HF (Ref). A meta-analysis of 182 trials found that, overall, use of a DPP-4 inhibitor was not associated with an increased risk of HF (OR: 1.05; 95% CI: 0.96 to 1.15; I2 = 0%); a significantly higher risk of HF was seen with saxagliptin (OR: 1.22; 95% CI: 1.03 to 1.45), but not for other DPP-4 inhibitors (Ref). The American Diabetes Association (ADA) suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF; however, other agents are preferred (ADA 2021). The American Heart Association considers sitagliptin to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: Major) (Ref).

Mechanism: Unknown (Ref).

Onset: Variable; the American Heart Association suggests the impact of DPP-4 inhibitors on myocardial dysfunction may be seen within weeks to ≥1 year (Ref).

Risk factors:

• Presence of risk factors for HF or preexisting HF (Ref)

Hypersensitivity reactions (immediate)

Anaphylaxis and angioedema have been reported with sitagliptin (Ref).

Mechanism: Non-dose-related; immunologic.

Angioedema: Considered a non-mast-cell-mediated process involving impaired catabolism of bradykinin (Ref). Sitagliptin and other dipeptidyl peptidase-4 (DPP-4) inhibitors can inactivate substance P and bradykinin (Ref).

Anaphylaxis: Considered to be an IgE-mediated reaction (Ref).

Onset: Varied; events have generally been noted within the first 3 months of therapy and may occur with the initial dose (Ref).

Risk factors:

• Concomitant use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or p-glycoprotein inhibitors (Ref)

• Hereditary angioedema (Ref)

• History of angioedema with other DPP-4 inhibitors

Pancreatic events

Cases of acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis with some fatalities), chronic pancreatitis, and pancreatic cancer have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists), including sitagliptin (Ref).

Mechanism: Causality has not been firmly established (Ref). DPP-4 inhibitors indirectly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation (Ref).

Risk factors:

• Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis

• Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer (Ref)

• Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesity

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

1% to 10%:

Endocrine & metabolic: Hypoglycemia (1%)

Respiratory: Nasopharyngitis (5%)

Frequency not defined: Gastrointestinal: Diarrhea, nausea

Postmarketing:

Dermatologic: Bullous pemphigoid (García-Díez 2018; Tanaka 2019), skin rash (Nakai 2014), Stevens-Johnson syndrome (Desai 2010), toxic epidermal necrolysis (Desai 2010)

Gastrointestinal: Acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis) (Butler 2013; Elashoff 2011; Scheen 2018), constipation (Williams-Herman 2010), oral mucosa ulcer (Jinbu 2013), stomatitis, vomiting

Hepatic: Increased liver enzymes (Shahbaz 2018)

Hypersensitivity: Anaphylaxis (Desai 2010), angioedema (Arcani 2017; Gosmanov 2012; Skalli 2010), drug reaction with eosinophilia and systemic symptoms (Sin 2012)

Nervous system: Headache (Zaghloul 2018)

Neuromuscular & skeletal: Arthralgia (FDA safety alert; Mascolo 2016), myalgia (Tarapues 2013)

Renal: Acute kidney injury (possibly requiring dialysis) (Shih 2016), interstitial nephritis (Alsaad 2016)

Contraindications

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

Warnings/Precautions

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).

– Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 (Korner 2009; Peterli 2012). A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with sitagliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small but significant reduction in postprandial blood glucose (Shah 2018).

• 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.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with type 1 diabetes.

Metabolism/Transport Effects

Substrate of CYP2C8 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk C: Monitor therapy

Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: 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. Risk D: Consider therapy modification

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

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

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk D: Consider therapy modification

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

Reproductive Considerations

Dipeptidyl peptidase 4 (DPP-4) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)

Pregnancy Considerations

Information related to the use of sitagliptin in pregnancy is limited (Sun 2017).

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).

Agents other than sitagliptin are currently recommended to treat diabetes mellitus during pregnancy (ADA 2021).

Breastfeeding Considerations

It is not known if sitagliptin is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Dietary Considerations

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

Monitoring Parameters

Serum glucose; renal function prior to initiation and periodically during treatment; signs/symptoms of heart failure, hypersensitivity, and/or pancreatitis; development of blisters or erosions.

HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2021):

HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Older adults (≥65 years of age) (ADA 2021): Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).

HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.

Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Classification of hypoglycemia (ADA 2021):

Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.

Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.

Mechanism of Action

Sitagliptin inhibits dipeptidyl peptidase-4 (DPP-4) 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-4 enzyme.

Pharmacokinetics

Absorption: Rapid

Distribution: ~198 L

Protein binding: 38%

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

Bioavailability: ~87%

Half-life elimination: 12.4 hours

Time to peak, plasma: 1 to 4 hours

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

Pharmacokinetics: Additional Considerations

Altered kidney function: 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.

Older adult: Elderly patients had ~19% higher plasma concentration.

Pricing: US

Tablets (Januvia Oral)

25 mg (per each): $20.86

50 mg (per each): $20.86

100 mg (per each): $20.86

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Fazique (CR, DO, GT, HN, MX, NI, PA, SV);
  • Glactiv (JP);
  • Glipita (BD);
  • Inosita (LK);
  • Janaglip (EG);
  • Januvia (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FR, GB, GR, GY, HK, HR, HU, ID, IE, IL, IN, IS, IT, JM, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NL, NO, NZ, PE, PH, PL, PR, PT, QA, RO, RU, SA, SE, SG, SI, SK, SR, TH, TR, TT, TW, TZ, UA, UY, VN, ZA, ZW);
  • Januvia XR (HK);
  • Janvia (BD);
  • Nimegon (BR);
  • Ristaben (CL, EE, IE);
  • Sigtin (TW);
  • Sijatin (TW);
  • Sitagen (LK);
  • Sitalia (BD);
  • Sitap (BD);
  • Sitrg (LK);
  • Sliptin (BD);
  • Tesavel (EE, ES, IE, IT, NL, PL, PT);
  • Xelevia (AR, CZ, DE, DK, EE, ES, FR, GR, HR, HU, IE, IT, LT, MT, NL, PH, PT, RO, SK, TR)


For country code abbreviations (show table)
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