Januvia

Generic Name: Sitagliptin Phosphate
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

Special Alerts:

[Posted 09/25/2009] FDA notified healthcare professionals and patients of revisions to the prescribing information for sitagliptin (Januvia) and sitagliptin/metformin (Janumet) to include information on reported cases of acute pancreatitis in patients using these products. Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the Agency between October 2006 and February 2009. It is recommended that healthcare professionals monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin. Sitagliptin has not been studied in patients with a history of pancreatitis. Therefore, it is not known whether these patients are at an increased risk for developing pancreatitis and the medication should be used with caution and with appropriate monitoring in patients with a history of pancreatitis. Considerations for healthcare professionals, information for patients, and a Data Summary are provided. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for sitagliptin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Januvia

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 3 4 9}

Used in combination with metformin hydrochloride as initial therapy for management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 11 21}

Used in combination with metformin, a sulfonylurea, or a thiazolidinedione (e.g., a peroxisome proliferator-activated receptor-_γ [PPAR-_γ] agonist) as second-line therapy for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and metformin, sulfonylurea, or thiazolidinedione monotherapy.^{1 2 5 9 11 22 24} Patients initially receiving an oral antidiabetic agent will eventually require multiple oral antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control because of declining β₂-cell function with disease progression.^{15 16 17 18 19}

Used in combination with metformin and a sulfonylurea as second-line therapy for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and combined therapy with a sulfonylurea and metformin.^{1 22}

Fixed combination with metformin used as second-line therapy in patients who do not achieve adequate glycemic control despite diet, exercise, and monotherapy with sitagliptin or metformin.^{1 11} Fixed combination with metformin also used in those already receiving therapy with sitagliptin and metformin as separate components.¹¹ Safety and efficacy of switching to sitagliptin/metformin fixed combination from antidiabetic agents other than sitagliptin or metformin not established.¹¹

Safety and efficacy of sitagliptin in combination with insulin not established.^{1 6 11}

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.^{1 6 10 11 13 20 21}

Januvia Dosage and Administration

General

• 
  

  Individualize dosage of sitagliptin/metformin hydrochloride in fixed combination based on patient's current antidiabetic regimen, clinical response, and tolerability.¹¹ Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.¹¹

  
  

Administration

Oral Administration

Sitagliptin monotherapy: Administer orally once daily with or without food.^{1 6 10} If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.⁶ If the missed dose is remembered at time of next dose, skip missed dose and resume the regular schedule.⁶ Do not double dose to replace missed dose.⁶

Sitagliptin/metformin hydrochloride fixed combination: Administer twice daily with meals, increasing dosage gradually to minimize GI adverse effects of metformin hydrochloride component.^{11 13} If a dose is missed, take missed dose with a meal²³ as soon as it is remembered followed by resumption of regular schedule.¹³ If missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.¹³ Do not double dose to replace missed dose.¹³

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as sitagliptin phosphate (as the monohydrate); dosage expressed in terms of sitagliptin.¹

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Previously Untreated Patients

Oral

Monotherapy: 100 mg once daily.^{1 10}

Combination therapy with metformin hydrochloride (as separate components): 100 mg of sitagliptin once daily.^{1 21 23}

Patients Transferred to Combination Therapy with Certain Other Antidiabetic Agents Given as Separate Components

Oral

Combination therapy with metformin hydrochloride: 100 mg of sitagliptin once daily.^{1 5 10 24} May continue current dosage of metformin hydrochloride at initiation of sitagliptin.¹ For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with a sulfonylurea: 100 mg of sitagliptin once daily.^{1 22} Dosage of concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.^{1 6} For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with metformin hydrochloride and a sulfonylurea: 100 mg of sitagliptin once daily.^{1 22} Dosage of concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.^{1 6} For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with a thiazolidinedione: 100 mg of sitagliptin once daily.^{1 2 10} May continue current dosage of thiazolidinedione at initiation of sitagliptin.¹ For additional therapy, see Diabetes Mellitus under Uses.

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients inadequately controlled on monotherapy with metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride or 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination, depending on the patient's existing dosage of metformin hydrochloride.^{11 23} Select the tablet strength of the fixed combination that most closely provides the patient's existing dosage of metformin hydrochloride.^{11 23}

Patients inadequately controlled on metformin hydrochloride 850 mg twice daily: 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination.¹¹

Efficacy and safety of transferring patients inadequately controlled on metformin hydrochloride dosage >2 g daily to sitagliptin in fixed combination with metformin hydrochloride not established.²³

Patients inadequately controlled on sitagliptin monotherapy: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride as the fixed combination twice daily.¹¹ If additional glycemic control is needed, increase dosage of the metformin hydrochloride component by administering 50 mg of sitagliptin and 1 g of metformin hydrochloride as the fixed combination twice daily.^{11 23}

For replacement of therapy with the drugs given concurrently as separate tablets, dosage of the fixed combination is based on the patient's current dosages of sitagliptin and metformin hydrochloride.¹¹ Select the tablet strength of the fixed combination that most closely provides patient's existing dosages of sitagliptin and metformin hydrochloride.^{11 23}

Prescribing Limits

Adults

Diabetes Mellitus

Oral

Sitagliptin monotherapy: Maximum 100 mg daily.²³

Fixed combination with metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily (in divided doses).^{11 23}

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).^{1 10 23} Efficacy and safety not established in patients with severe hepatic impairment (Child-Pugh score >9).^{1 10}

Renal Impairment

Sitagliptin Monotherapy

Oral

Moderate renal impairment (Cl_cr of 30 to <50 mL/minute, corresponding to S_cr of >1.7–3 mg/dL in men or >1.5–2.5 mg/dL in women): 50 mg once daily.^{1 23 26}

Severe renal impairment (Cl_cr <30 mL/minute, corresponding to S_cr of >3 mg/dL in men or >2.5 mg/dL in women): 25 mg once daily.^{1 26}

End-stage renal disease requiring hemodialysis or peritoneal dialysis: 25 mg once daily.^{1 26}

May administer without regard to timing of hemodialysis.^{1 10 26} (See Absorption: Special Populations, under Pharmacokinetics.)

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients with renal impairment receiving reduced dosages of sitagliptin should not be switched to the fixed combination of sitagliptin and metformin hydrochloride.¹¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function.^{1 11} (See Geriatric Use and also see Renal Impairment under Cautions.)

Sitagliptin in fixed combination with 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.) Carefully titrate dosage to minimum dosage necessary for adequate glycemic control.¹¹

Cautions for Januvia

Contraindications

• 
  

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

  
  

Warnings/Precautions

Use of Fixed Combinations

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

When used in fixed combination with metformin hydrochloride, consider the cautions, precautions, and contraindications associated with metformin hydrochloride.¹¹

Loss of Glycemic Control

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).^{1 6 11} (See Advice to Patients.)

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

Sensitivity Reactions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Concomitant Antidiabetic Therapy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

In clinical studies, rates of hypoglycemia in patients receiving sitagliptin in combination with metformin or pioglitazone were similar to placebo.^{1 11 21}

In a long-term (52-week) clinical noninferiority study, rates of hypoglycemia with sitagliptin/metformin combination therapy were lower than those observed with glipizide/metformin combination therapy.^{1 24} However, in a 24-week clinical study, rates of hypoglycemia in patients receiving sitagliptin and glimepiride with or without metformin were greater than those in patients receiving glimepiride and metformin.²² For dosage adjustments, see Patients Transferred to Combination Therapy with Certain Other Antidiabetic Agents Given as Separate Components, under Dosage and Administration.

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety of sitagliptin in combination with insulin not established.^{1 6 11}

Specific Populations

Pregnancy

Category B.^{1 11} Pregnancy registry at 800-986-8999.^{1 11 13}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 6 11} Use caution.^{1 11}

Pediatric Use

Safety and efficacy of sitagliptin alone or in fixed combination with metformin not established in children <18 years of age.^{1 6 11 13 23}

Geriatric Use

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

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter because geriatric patients more likely to have decreased renal function.¹

Renal Impairment

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter.¹

Common Adverse Effects

Upper respiratory tract infection,^{1 10} nasopharyngitis,^{1 3 4 10} headache.^{1 6 10}

Interactions for Januvia

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

Inhibitors of p-Glycoprotein Transport System

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

With wide safety margin of sitagliptin, clinically important pharmacokinetic interactions with p-glycoprotein inhibitors unlikely.^{1 12 23} Does not appear to inhibit p-glycoprotein transport system.^{1 12}

Drugs Secreted by Renal Tubular Cationic Transport

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

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Cyclosporine	Increased absorption and plasma concentrations of sitagliptin1 12	Not considered clinically important1 12
Digoxin	Slight increase in plasma concentrations and AUC of digoxin 1 23	Not considered clinically important; no dosage adjustment needed1 23
Hormonal contraceptives, oral	No clinically meaningful effect on pharmacokinetics of norethindrone or ethinyl estradiol1
Metformin	Potential additive effect on active GLP-1 concentrations1 11 21 22 Pharmacokinetic interactions unlikely1 10 11 27	Relevance of these effects to glycemic control in patients with type 2 diabetes mellitus unclear11 23
Simvastatin	Pharmacokinetic interactions unlikely1
Sulfonylureas	Minimal additional risk of hypoglycemia when sitagliptin added to glimepiride therapy (limited data)1 22 Pharmacokinetic interactions unlikely1 23	Reduced dosage of sulfonylurea may be required to reduce risk of hypoglycemia1 23
Thiazolidinediones	Pharmacokinetic interactions unlikely1
Warfarin	Pharmacokinetic interactions unlikely1

Januvia Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 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 metformin hydrochloride 500 mg or 1 g (Janumet) 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 end-stage renal disease 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}

Distribution

Extent

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

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

20–25°C (may be exposed to 15–30°C).^{1 11 13}

Actions

• 
  

  Inhibits dipeptidyl peptidase-4 (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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

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

  
  


• 
  

  Importance of patient reading patient information leaflet before initiating therapy and each time drug is dispensed.^{1 6 13}

  
  


• 
  

  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}

  
  


• 
  

  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} (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} If such reactions occur, importance of discontinuing sitagliptin and informing clinicians promptly.^{1 6 11 13} (See Sensitivity Reactions under Cautions.)

  
  


• 
  

  Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 6 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).^{6 13}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 6 13} (See Cautions.)

  
  

Preparations

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

Sitagliptin Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of sitagliptin)	Januvia	Merck
		50 mg (of sitagliptin)	Januvia	Merck
		100 mg (of sitagliptin)	Januvia	Merck

Sitagliptin Phosphate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg (of sitagliptin) with Metformin Hydrochloride 500 mg	Janumet (with povidone)	Merck
		50 mg (of sitagliptin) with Metformin Hydrochloride 1 g	Janumet (with povidone)	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Janumet 50-1000MG Tablets (MERCK SHARP & DOHME): 60/$216.00 or 180/$618.99

Janumet 50-500MG Tablets (MERCK SHARP & DOHME): 60/$217.00 or 180/$629.95

Januvia 100MG Tablets (MERCK SHARP & DOHME): 30/$216.00 or 90/$619.94

Januvia 25MG Tablets (MERCK SHARP & DOHME): 90/$645.98 or 270/$1,825.92

Januvia 50MG Tablets (MERCK SHARP & DOHME): 30/$220.99 or 90/$635.94

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck. Januvia (sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2007 Oct.

2. Rosenstock J, Brazg R, Andryuk PJ et al. Efficacy and safety of dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006; 28:1556-68. [PubMed 17157112]

3. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006; 49:2564-71. [PubMed 17001471]

4. Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006; 29:2632-7. [PubMed 17130196]

5. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29:2638-43. [PubMed 17130197]

6. Merck. Januvia (sitagliptin phosphate) tablets patient information. Whitehouse Station, NJ; 2007 Oct.

7. Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91:4612-9. [PubMed 16912128]

8. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhbitors in type 2 diabetes. Lancet. 2006; 368:1696-705. [PubMed 17098089]

9. Anon. Sitagliptin (Januvia) for type 2 diabetes. Med Lett Drugs Ther. 2007; 49:1-3.

10. Merck. Product information form for AHFS drug information: Januvia (sitagliptin phosphate) tablets. Whitehouse Station, NJ; 2006.

11. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2008 Jan.

12. Krishna R, Bergman A, Larson P et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007; 47:165-74. [PubMed 17244767]

13. Merck. Janumet (sitagliptin phosphate) tablets patient information. Whitehouse Station, NJ; 2008 Jan.

14. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. [PubMed 16873813]

15. Hirsch IB, Bergenstal RM, Parkin CG et al. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005; 23(2):78-86.

16. Buse J. Combining insulin and oral agents. Am J Med. 2000; 108(Suppl 6A):23S-32S. [IDIS 446200] [PubMed 10764847]

17. Florence JA, Yeager BF. Treatment of type 2 diabetes mellitus. Am Fam Physician. 1999; 59:2835-44. [IDIS 428714] [PubMed 10348076]

18. Bastyr EJ, Johnson ME, Trautman ME et al. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther. 1999; 21:1703-4. [IDIS 438022] [PubMed 10566566]

19. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. [IDIS 430576] [PubMed 10454950]

20. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2004; 27(Suppl 1):S94-102.

21. Goldstein BJ, Feinglos MN, Lunceford JK et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30:1979-87. [PubMed 17485570]

22. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety of the didpeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007; 9:733-45. [PubMed 17593236]

23. Merck, North Wales, PA: personal communication.

24. Nauck MA, Meininger G, Sheng G et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007; 9:194-205. [PubMed 17300595]

25. Bergman A, Stevens C, Zhou YY et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a didpeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006; 28:55-72. [PubMed 16490580]

26. Bergman AJ, Cote J, Yi B et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007; 30:1862-4. [PubMed 17468348]

27. Herman GA, Bergman A, Yi B et al. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006; 22:1939-47. [PubMed 17022853]

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• Januvia Prescribing Information (FDA)


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