Brand name: Januvia
Drug class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA class: HS502
Chemical name: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate monohydrate
Molecular formula: C₁₆H₁₅F₆N₅O•H₃O₄P•H₂O
CAS number: 654671-77-9

Medically reviewed by Drugs.com on Jun 12, 2023. Written by ASHP.

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.^{1 9 11}

Uses for SITagliptin

Type 2 Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{1 3 4 9}

Used in combination with immediate- or extended-release metformin given separately or as a fixed combination (Janumet or Janumet XR, respectively) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus^{1 11 21 45} when treatment with both sitagliptin and metformin is appropriate.^{11 45}

Used in fixed combination with ertugliflozin (Steglujan) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.⁵⁰

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).^{698 704 705}

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.^{698 704}

May need to initiate therapy with 2 drugs (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target).^{698 704} In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.^{698 704}

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.⁷⁰⁴

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.^{698 699 704 705 706} DPP-4 inhibitors recommended by some experts as one of several classes of drugs for use in combination therapy, particularly in patients with both postprandial and fasting plasma glucose elevations.^{29 698 704}

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^{698 704}

Should not be used in patients with type 1 diabetes mellitus or diabetic ketoacidosis.^{1 10 11 45 50}

SITagliptin Dosage and Administration

General

• Use of combination therapy initially or as maintenance therapy may not be appropriate in all patients; use according to clinician discretion.^{1 11}

• Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.^{1 11}

• Fixed combination of sitagliptin and ertugliflozin: Correct volume depletion prior to initiating.⁵⁰

• Fixed combination of sitagliptin and immediate- or extended-release metformin hydrochloride: Individualize dosage based on patient's current antidiabetic regimen, clinical response, and tolerability.^{11 45}

Administration

Oral Administration

Sitagliptin Monotherapy

Administer orally once daily with or without food.^{1 10}

If a dose is missed, take missed dose as soon as it is remembered and resume regular schedule.¹ If the missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.¹ Do not double dose to replace missed dose.¹

Sitagliptin/Immediate-release Metformin Hydrochloride Fixed Combination

Administer twice daily with meals, increasing dosage gradually to minimize adverse GI effects of metformin hydrochloride component.^{11 13}

If a dose is missed, take missed dose with a meal²³ as soon as it is remembered and resume regular schedule.¹³ If missed dose is not remembered until the time of next dose, skip missed dose and resume regular schedule.¹³ Do not double dose to replace missed dose.¹³

The manufacturer states that tablets of the fixed combination of sitagliptin and immediate-release metformin hydrochloride must not be split or divided before swallowing.¹¹

Sitagliptin/Extended-release Metformin Hydrochloride Fixed Combination

Administer once daily with a meal, preferably the evening meal.⁴⁵

If a dose is missed, take missed dose with food as soon as it is remembered and resume regular schedule.⁴⁵ If missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.⁴⁵ Do not double dose to replace missed dose.⁴⁵

The manufacturer states that tablets of the fixed combination of sitagliptin and extended-release metformin hydrochloride must not be split or divided before swallowing.⁴⁵

Sitagliptin/Ertugliflozin Fixed Combination

Administer orally once daily in the morning with or without food.⁵⁰

If a dose of the fixed combination of sitagliptin and ertugliflozin is missed, take missed dose as soon as it is remembered and resume regular schedule.⁵⁰ If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule.⁵⁰ Do not double dose to replace a missed dose.⁵⁰

Dosage

Available as sitagliptin phosphate (as the monohydrate); dosage expressed in terms of sitagliptin.^{1 11 45 50}

Adults

Type 2 Diabetes Mellitus

Sitagliptin Monotherapy

Oral

100 mg once daily;^{1 10} higher dosages (200 mg daily) did not provide additional glycemic benefit in clinical trials.¹

Sitagliptin/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients not currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of immediate-release metformin hydrochloride twice daily as the fixed combination.¹¹ Increase dosage gradually to reduce adverse GI effects of metformin.¹¹

Patients currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of immediate-release metformin hydrochloride twice daily or 50 mg of sitagliptin and 1 g of immediate-release metformin hydrochloride twice daily as the fixed combination, depending on the patient's existing dosage of metformin hydrochloride.^{11 23}

Patients currently receiving immediate-release metformin hydrochloride 850 mg twice daily: Initially, 50 mg of sitagliptin and 1 g of immediate-release metformin hydrochloride twice daily as the fixed combination.¹¹

Maintain the same total daily dosage of sitagliptin and metformin hydrochloride when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride (Janumet) and the fixed combination of sitagliptin and extended-release metformin hydrochloride (Janumet XR).⁴⁵

Sitagliptin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients not currently receiving metformin hydrochloride: Initially, 100 mg of sitagliptin and 1 g of extended-release metformin hydrochloride once daily.⁴⁵

Patients currently receiving metformin hydrochloride: Initially, 100 mg of sitagliptin and 1 g of extended-release metformin hydrochloride once daily or 100 mg of sitagliptin and 2 g of extended-release metformin hydrochloride once daily, depending on the patient's existing dosage of metformin hydrochloride.⁴⁵

Patients currently receiving immediate-release metformin hydrochloride 850 mg or 1 g twice daily: Initially, 100 mg of sitagliptin and 2 g of extended-release metformin hydrochloride once daily.⁴⁵

Maintain the same total daily dosage of sitagliptin and metformin hydrochloride when transitioning between the fixed combination sitagliptin and immediate-release metformin hydrochloride (Janumet) and the fixed combination of sitagliptin and extended-release metformin hydrochloride (Janumet XR).⁴⁵

Sitagliptin/Ertugliflozin Fixed-combination Therapy

Oral

Initially, 100 mg of sitagliptin and 5 mg of ertugliflozin once daily in the morning.⁵⁰

If well tolerated and additional glycemic control needed, may increase dosage to 100 mg of sitagliptin and 15 mg of ertugliflozin once daily.⁵⁰

Patients currently receiving ertugliflozin: Maintain current ertugliflozin dosage.⁵⁰

Combination Therapy with Sitagliptin and Other Oral Antidiabetic Agents or Insulin Given as Separate Components

Oral

Combination therapy with metformin hydrochloride: Sitagliptin 100 mg once daily has been used.^{5 10 21 24}

Combination therapy with an insulin secretagogue (e.g., sulfonylurea) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.^{1 11 22} Reduced dosage of concomitant insulin secretagogue may be needed to decrease risk of hypoglycemia.^{1 11}

Combination therapy with a thiazolidinedione (e.g., pioglitazone, rosiglitazone) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.^{1 2 10 11}

Combination therapy with insulin with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.^{1 11} Reduced dosage of concomitant insulin may be needed to decrease risk of hypoglycemia.^{1 11}

Prescribing Limits

Adults

Type 2 Diabetes Mellitus

Oral

Sitagliptin monotherapy: Maximum 100 mg daily.²³

Fixed combination of sitagliptin and ertugliflozin: Maximum 100 mg of sitagliptin and 15 mg of ertugliflozin daily.⁵⁰

Fixed combination of sitagliptin and immediate- or extended-release metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily.^{11 23 45}

Special Populations

Hepatic Impairment

Sitagliptin Monotherapy

Oral

No dosage adjustments needed in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).^{1 10 23} Data lacking on use in patients with severe hepatic impairment (Child-Pugh score >9); manufacturer states that such use not recommended.^{1 10}

Sitagliptin/Ertugliflozin Fixed-combination Therapy

Oral

No dosage adjustments needed in patients with mild to moderate hepatic impairment.⁵⁰ Data lacking on use in patients with severe hepatic impairment (Child-Pugh score >9); manufacturer states that such use not recommended.⁵⁰

Sitagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Manufacturer states that use of the fixed combination of sitagliptin and immediate- or extended-release metformin hydrochloride not recommended.^{11 45}

Renal Impairment

Sitagliptin Monotherapy

Oral

eGFR ≥45 mL/minute per 1.73 m²: No dosage adjustment needed.^{1 23 26}

eGFR 30 to <45 mL/minute per 1.73 m²: 50 mg once daily.^{1 26}

eGFR <30 mL/minute per 1.73 m²: 25 mg once daily.^{1 26}

ESRD requiring hemodialysis or peritoneal dialysis: 25 mg once daily.^{1 26} May administer without regard to timing of dialysis.^{1 10 26} (See Absorption: Special Populations, under Pharmacokinetics.)

Sitagliptin/Ertugliflozin Fixed-combination Therapy

Oral

Mild renal impairment: No dosage adjustment or increased monitoring needed.⁵⁰

eGFR 30 to <60 mL/minute per 1.73 m²¹ : Initiation of the fixed combination not recommended.⁵⁰ Continued use not recommended in patients with eGFR persistently between 30 and <60 mL/minute per 1.73 m².⁵⁰

eGFR <30 mL/minute per 1.73 m²: Contraindicated.⁵⁰

Sitagliptin/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Assess renal function (eGFR) prior to initiation of therapy.¹¹

eGFR 30 to <45 mL/minute per 1.73 m²: Not recommended.¹¹

eGFR <30 mL/minute per 1.73 m²: Contraindicated.¹¹

Sitagliptin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Assess renal function (eGFR) prior to initiation of therapy.⁴⁵

eGFR 30–45 mL/minute per 1.73 m²: Initiation of fixed combination of sitagliptin and extended-release metformin hydrochloride not recommended.⁴⁵

If eGFR decreases to <45 mL/minute per 1.73 m² during therapy, weigh benefits of continued use and limit dosage of sitagliptin component to 50 mg once daily.⁴⁵

eGFR <30 mL/minute per 1.73 m²: Contraindicated.⁴⁵

Geriatric Patients

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function.¹ (See Geriatric Use and also see Renal Impairment under Cautions.)

Fixed combination of sitagliptin and ertugliflozin: No dosage adjustment needed based solely on age.⁵⁰ Fixed combination of sitagliptin and ertugliflozin expected to have diminished efficacy in geriatric patients with renal impairment.⁵⁰ (See Geriatric Use and also see Renal Impairment under Cautions.)

Fixed combination of sitagliptin and immediate- or extended-release metformin hydrochloride: Select dosage with caution because of age-related decreases in renal function.¹¹ (See Geriatric Use and also see Renal Impairment under Cautions.)

Cautions for SITagliptin

Contraindications

• Known serious hypersensitivity (e.g., anaphylaxis, angioedema) to sitagliptin or any ingredient in formulation.^{1 11 50}

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported during postmarketing experience with sitagliptin or sitagliptin/metformin.^{1 11 28}

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes in patients with type 2 diabetes mellitus receiving incretin mimetics.^{36 37} FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report.³⁶

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.³⁶ Monitor patients receiving sitagliptin or sitagliptin/metformin for manifestations of pancreatitis, such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back.^{1 11 28}

If pancreatitis suspected, promptly discontinue sitagliptin and initiate appropriate management (e.g., obtain serum and urine amylase, amylase/creatinine clearance ratio, serum electrolytes, calcium, glucose, lipase).^{1 11 28}

Safety and efficacy not established in patients with a history of pancreatitis; unknown whether such patients are at increased risk for pancreatitis with sitagliptin therapy.^{1 11 45 50}

Heart Failure Risk

Association between DPP-4 inhibitor treatment and heart failure observed in cardiovascular outcomes studies conducted with 2 other DPP-4 inhibitors (alogliptin, saxagliptin) in patients with type 2 diabetes mellitus and ASCVD.^{1 11 42 43 44 45 50}

Consider potential risks and benefits of sitagliptin therapy prior to use in patients at risk for heart failure (e.g., history of heart failure or renal impairment).^{1 11 45 50} Monitor patients for manifestations of heart failure.^{1 11 45 50} (See Advice to Patients.) If heart failure develops, institute appropriate evaluation and management according to current standards of care and consider discontinuance of sitagliptin.^{1 11 45 50}

Worsening of Renal Function

Worsening of renal function, including acute renal failure that sometimes required dialysis, reported in some patients during postmarketing experience.^{1 11}

Assess renal function prior to initiation of sitagliptin and periodically thereafter.^{1 11}

Severe Arthralgia

Severe, disabling joint pain reported in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, sitagliptin, saxagliptin).^{1 41} Onset of such symptoms has ranged from 1 day to years following initiation of therapy.^{1 41} Symptoms resolved upon discontinuance of the DPP-4 inhibitor; symptoms recurred in some patients when the same or another DPP-4 inhibitor was restarted.^{1 41}

Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue if appropriate.^{1 41} (See Advice to Patients.)

Concomitant Therapy with Hypoglycemic Agents

Greater incidence of hypoglycemia when sitagliptin used in combination with a sulfonylurea or insulin.^{1 11} May require lower dosage of concomitant insulin secretagogue (e.g., sulfonylurea) or insulin to reduce risk of hypoglycemia.^{1 11}

Dermatologic and Sensitivity Reactions

Risk of hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative dermatitis, Stevens-Johnson syndrome).^{1 11} Onset usually within first 3 months of treatment initiation, but may occur after first dose.^{1 11} (See Contraindications under Cautions.)

If hypersensitivity reactions occur, promptly discontinue drug, assess other potential causes for event, and institute alternative antidiabetic therapy.^{1 11} (See Advice to Patients.)

Use caution in patients with a history of angioedema with other DPP-4 inhibitors; unknown whether such patients will be predisposed to angioedema with sitagliptin.¹

Postmarketing cases of bullous pemphigoid requiring hospitalization reported with DPP-4 inhibitor use.¹ Usually resolved after discontinuation of the DPP-4 inhibitor and treatment with topical or systemic immunosuppressive therapy.¹ Advise patients to report the development of blisters or erosions while receiving sitagliptin.¹ Discontinue drug if bullous pemphigoid is suspected and consider referral to a dermatologist for diagnosis and appropriate treatment.¹

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).^{1 11} (See Advice to Patients.)

Temporary discontinuance of sitagliptin and administration of insulin may be required.¹¹ May reinstitute sitagliptin therapy after acute episode of hyperglycemia has resolved.¹¹

Macrovascular Outcomes

Evidence of macrovascular risk reduction with sitagliptin not conclusively demonstrated in controlled clinical trials.^{1 11 45 50}

Use of Fixed Combinations

When sitagliptin is used in fixed combination with ertugliflozin, metformin hydrochloride, or other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) in addition to those associated with sitagliptin.^{11 45 50}

Specific Populations

Pregnancy

Data lacking on use of sitagliptin in pregnant women.¹ In animal studies, no adverse developmental effects observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at doses ≤30 times the human 100-mg dose (based on AUC).¹ May contact pregnancy registry at 800-986-8999.^{1 11 13 45 50 45 50}

Lactation

Sitagliptin distributed into milk in rats; not known whether distributed into human milk.^{1 11} Use caution.^{1 11}

Pediatric Use

Safety and efficacy of sitagliptin alone or in fixed combination with ertugliflozin or metformin not established in children <18 years of age.^{1 11 13 23 45 50}

Geriatric Use

No substantial differences in safety and efficacy of sitagliptin relative to younger adults, but increased sensitivity cannot be ruled out.¹

Sitagliptin is substantially eliminated by kidneys; assess renal function more frequently in geriatric patients.^{1 11 45 50}

Renal Impairment

Sitagliptin is substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter.^{1 11}

Sitagliptin exposure increased in patients with renal impairment;¹ lower dosages recommended in patients with eGFR less than 45 mL/minute per 1.73 m² and those with end-stage renal disease requiring dialysis.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Sitagliptin monotherapy or add-on therapy with metformin and/or a thiazolidinedione or glimepiride and more commonly than with placebo: Nasopharyngitis,^{1 3 4 10} upper respiratory tract infection,^{1 10} peripheral edema,¹ headache.^{1 10}

Sitagliptin administered concomitantly with ertugliflozin and more commonly than with placebo: Adverse effects similar in type and incidence to those reported with ertugliflozin alone.⁵⁰

Sitagliptin administered concomitantly with metformin and more commonly than with placebo: Diarrhea, upper respiratory infection, headache.¹¹

Sitagliptin administered concomitantly with metformin and glimepiride and more commonly than with placebo: Hypoglycemia, headache.¹¹

Sitagliptin administered concomitantly with insulin and more commonly than with placebo: Hypoglycemia.¹¹

Drug Interactions

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.^{1 10 12}

Drugs Metabolized by Hepatic Microsomal Enzymes

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro or induce CYP3A4.^{1 11} Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.¹

Drugs Secreted by Renal Tubular Cationic Transport

Substrate of organic anion transport system; pharmacokinetic interaction unlikely with substrates of organic cationic transport system.¹

Drugs Affecting or Affected by P-glycoprotein (P-gp) Transport System

Substrate of P-gp transport system.^{1 12} Potential pharmacokinetic interaction (increased absorption and renal clearance of sitagliptin) with P-gp inhibitors.^{1 12 23}

Clinically important pharmacokinetic interactions with P-gp inhibitors unlikely.^{1 12 23} Does not appear to inhibit P-gp transport system.^{1 12} Pharmacokinetic interactions with substrates of P-gp unlikely.¹

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Specific Drugs

SITagliptin Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of sitagliptin is 87%.^{1 23}

Rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally attained ≤3 hours following administration of recommended doses.^{1 23 25}

Fixed-combination tablet containing sitagliptin 50 mg and immediate-release metformin hydrochloride 500 mg or 1 g (Janumet) is bioequivalent to one 50-mg tablet of sitagliptin and one 500-mg or 1-g tablet of metformin hydrochloride, respectively, given simultaneously.¹¹

Onset

Reduction in postprandial plasma glucose excursion: Approximately 60 minutes.^{4 7 23}

Duration

Approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours following administration of ≥50 or ≥100 mg, respectively, of sitagliptin.^{1 9 23 25}

Food

Food does not appear to affect absorption.¹

Special Populations

Renal impairment results in increased plasma AUC.¹ Removed modestly by hemodialysis; time to peak plasma drug concentration increased in a limited number of patients with ESRD requiring hemodialysis.^{1 26}

Moderate hepatic impairment results in increased peak plasma concentrations and AUC; not considered clinically important.^{1 23}

In geriatric patients, modest increases in plasma concentrations compared with younger adults.^{1 11}

No clinically meaningful effect of body mass index, sex, or race on sitagliptin pharmacokinetics.¹

Distribution

Extent

Distributed into milk in rats¹¹ ; not known whether distributed into human milk.¹

Plasma Protein Binding

38%.¹

Elimination

Metabolism

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.^{1 12}

Elimination Route

Eliminated principally by kidneys via active tubular secretion.^{1 25 26} Excreted in urine (87%) mainly as unchanged drug and in feces (13%).^{1 10}

Half-life

12.4 hours.¹

Special Populations

Renal impairment results in increased terminal elimination half-life.²⁶

Stability

Storage

Oral

Tablets

Sitagliptin, fixed combination of sitagliptin and ertugliflozin, and fixed combinations of sitagliptin and immediate- or extended-release metformin: 20–25°C (may be exposed to 15–30°C).^{1 11 45 50}

Actions

• Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).^{1 7 8 9 11 21 24}

• Inhibits DPP-4 selectively with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those from therapeutic dosage.^{1 11}

• Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.^{1 2 3 7 8 9 10 21} Coadministration of sitagliptin and metformin has an additive effect on active GLP-1 concentrations.^{1 11 21}

• GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated) by intracellular signaling pathways involving cyclic 3′,5′-adenosine monophosphate (cAMP).^{1 8 21 24}

• GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.^{1 2 3 7 21 24}

• Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.^{1 4 7 11}

• Sitagliptin usually not associated with hypoglycemia or substantial changes in body weight.^{1 3 4 5 8 9}

Advice to Patients

• When sitagliptin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).^{11 45 50}

• Importance of patient reading medication guide before initiating therapy and each time drug is dispensed.^{1 6 11 13 45 50 51}

• Inform patients of potential risks and advantages of sitagliptin-containing therapy and of alternative therapies.^{1 6 11 45 50}

• Importance of not using sitagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.^{1 6}

• Importance of informing clinician if hypoglycemia occurs, particularly if concomitant therapy with a sulfonylurea antidiabetic agent (i.e., insulin secretagogue) or insulin is used; a lower dosage of the sulfonylurea or insulin may be required in such cases.^{1 6 11 13}

• Risk of acute pancreatitis, which may be severe or fatal.^{1 6 13 28 45 50} Importance of patient advising clinicians about a history of pancreatitis, gallstones, alcoholism, high triglyceride levels, or kidney problems.^{1 6 13 45 51} Importance of discontinuing sitagliptin and promptly notifying clinician if signs or symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting, are present.^{1 6 13 28 45 50}

• Importance of informing patients of the possibility of severe and disabling joint pain.^{1 6 41} Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue therapy without consulting their clinician.^{1 6 41}

• Importance of informing patients about possibility of heart failure with sitagliptin therapy.^{1 6} Importance of patients informing clinicians about a history of heart failure or renal impairment.^{1 6} Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, unusual tiredness, rapid weight gain, edema especially in the feet, ankles, or legs); importance of patients immediately contacting a clinician if manifestations of heart failure occur.^{1 6}

• Importance of instructing patients regarding self-monitoring of blood glucose, periodic HbA_1c monitoring, adherence to meal planning, regular physical exercise, and management of hypoglycemia and hyperglycemia.^{1 6 11 13 50}

• Discuss potential for alterations in dosage requirements in special situations (e.g., fever, trauma, infection, surgery, changes in renal function); importance of informing clinician promptly if such situations occur.^{1 6 13 50} (See Loss of Glycemic Control under Cautions.)

• Risk of allergic reactions (e.g., rash; hives; swelling of face, lips, tongue, throat that may cause difficulty in breathing or swallowing).^{1 6 11 50} If such reactions occur, importance of discontinuing sitagliptin and informing clinicians promptly.^{1 6 11 13 50} (See Dermatologic and Sensitivity Reactions under Cautions.)

  Importance of informing patients that bullous pemphigoid may occur with the use of a DPP-4 inhibitor.^{1 6 11 45 50} Advise patients to promptly inform clinician if skin blisters or erosion (breakdown of outer layer of skin) occurs.^{1 6 11 45 50}

• Importance of swallowing tablets of the fixed combinations of sitagliptin and immediate- or extended-release metformin hydrochloride whole and not cutting, crushing, or chewing them.^{11 45}

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 13}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., allergies, kidney problems).^{1 13 50}

• Importance of informing patients of other important precautionary information.^{1 13 50} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

• Can Victoza and Januvia be used together?

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