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Sitagliptin (Januvia): Drug Monograph

    Brand Names
    • Januvia
    Drug Class
    • Dipeptidyl peptidase-4 (DPP-4) inhibitor
    Indications
    • Improve glycemic control in adults with type 2 diabetes mellitus along with diet and exercise
    • Important limitations of use:
      • Should not be used in patients with type1 diabetes or for the treatment of diabetic ketoacidosis
      • Has not been studied in patients with a history of pancreatitis
    Dosing

    (Adult)

    • General Notes: 
      • May be taken with or without food
    • Type 2 Diabetes Mellitus
      • 100 mg by mouth once daily


    (Pediatrics)

    • None
    Renal Dosing
    • Moderate, CrCl ≥30<50 mL/min:
      • Limit to 50 mg once daily
    • Severe, CrCl <30 mL/min:
      • Limit to 25 mg once daily
    • ESRD requiring hemodialysis/peritoneal dialysis:
      • 25 mg once daily; administer without regard to timing of dialysis
    Hepatic Dosing
    • None
    Dosage Forms
    • Tablets:  25 mg, 50 mg, 100 mg
    Black Box Warnings
    • None
    Contraindications
    • History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
    Warnings
    • Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis  
    • Acute renal failure, sometimes requiring dialysis          
    • Increased risk of hypoglycemia when sitagliptin is added to an insulin secretagogue or insulin therapy
    • Serious allergic and hypersensitivity reactions
    • No clinical studies establishing conclusive evidence of macrovascular risk reduction
    Adverse Reactions
    • Upper respiratory tract infection
    • Nasopharyngitis
    • Headache
    • Hypoglycemia
    • Joint pain
    Overdose
    • No dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.
    Antidote
    • None
    Drug Interactions
    • CYP450 Enzymes:
      • Substrate (minor) of CYP2C8 and CYP3A4
    • Transporters:
      • Minor substrate of P-gp
    • Other: Potential interaction with digoxin likely due to competitive inhibition of P-gp
    Special Populations
    • Pregnancy: Pregnancy Category B
    • Labor and Delivery: None
    • Nursing Mothers: It is unknown whether sitagliptin is excreted in human milk.
    • Renal Impairment: Dosage adjustment necessary for moderate and severe impairment, and for end-stage renal disease.
    • Hepatic Impairment: None
    • Pediatric Patients: Safety and effectiveness in pediatric patients under 18 years of age have not been established.
    • Geriatric Patients: No overall differences in safety of effectiveness were observed between subjects 65 years and over and younger subjects.  This drug is known to be substantially excreted by the kidney.  Due to decreased renal function in some elderly patients, care should be taken in dose selection.
    Pregnancy Rating
    • Category B
    Breastfeeding
    • It is unknown whether sitagliptin is excreted in human milk.
    Chemical Structure


    • Scientific Name: 7-[(3R)-3-amino-1-oxo-4-(2, 4, 5-trifluorophenyl)butyl]-5,6,7,8-tetraphydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
    • Empirical Formula: C16H15F6N5O∙H3PO4∙H2O
    • Molecular Weight: 523.32
    Mechanism of Action
    • Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) that are released by the intestine throughout the day, and levels are increased in response to a meal.
    Pharmacodynamics
    • General: DPP-4 inhibition by sitagliptin is known to result in a 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations.  The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
    Pharmacokinetics
    • Absorption:
      • The absolute bioavailability is approximately 87%.
      • A high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
    • Distribution:
      • The mean volume of distribution at steady state is approximately 198 liters.
      • The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
    • Metabolism:
      • Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
      • In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
    • Elimination:
      • Following administration of an oral [14C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing.
      • The apparent terminal t1/2 following a 100mg oral dose of sitagliptin was approximately 12.4 hours.
      • Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.  Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin.
      • Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
    • Special Populations
      • Renal Insufficiency: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of sitagliptin (50mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80mL/min), moderate (30 to <50mL/min), and severe (<30mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses.  Compared to normal healthy control subjects, an approximate 1.1-to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3-to 4-hour hemodialysis session starting 4 hours post dose).  To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring dialysis.
      • Hepatic Insufficiency: In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100mg dose of sitagliptin. These differences are not considered to be clinically meaningful.  No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic insufficiency. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
      • Body Mass Index (BMI): No dosage adjustment is necessary based on BMI.  Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
      • Gender:No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
      • Geriatric:No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
      • Pediatric:Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.
      • Race:No dosage adjustment is necessary based on race.  Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
    • Drug Interactions
      • In Vitro Assessment of Drug Interactions: Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4.  Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin.  Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways. Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
      • In Vivo Assessment of Drug Interactions
      • Effects of Sitagliptin on Other Drugs: In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).
      • Digoxin:Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25mg digoxin concomitantly with 100mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
      • Metformin:Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
      • Sulfonylureas:Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin.  Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride), which, like glyburide, are primarily eliminated by CYP2C9.
      • Simvastatin:Single-dose pharmacokinetics of simvastatin,  a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin.  Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
      • Thiazolidinediones:Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that sitagliptin is not an inhibitor of CYP2C8-mediated metabolism.
      • Warfarin:Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics  (as assessed by measurement of prothrombin INR) of a single dose of warfarin.  Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
      • Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
      • Effects of Other Drugs on Sitagliptin: Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications.
      • Metformin:Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
      • Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin.  Co-administration of a single 100mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29%and 68%, respectively.  These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful.  The renal clearance of sitagliptin was also not meaningfully altered.   Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
    Pharmacogenetics
    • None
    Counseling Points
    • Tell patients of the potential risks and benefits of sitagliptin and of alternative modes of therapy
    • Tell patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.
    • Persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Promptly discontinue sitagliptin and contact their physician if persistent severe abdominal pain occurs.
    • Incidence of hypoglycemia is increased when sitagliptin is added to a sulfonylurea or insulin. To decrease risk of hypoglycemia, a lower dose of the sulfonylurea or insulin may be required.
    • If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking sitagliptin and seek medical advice promptly. 
    • Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels.
    • Adjustment on dosage based on changes in renal function tests over time may be needed.
    References
    • Sitagliptin (Januvia).  Product Insert.  Merck & Co, Inc.  Whitehouse Station, NJ.  2010.

MESH Terms & Keywords

  • Sitagliptin, Januvia, Dipeptidyl, Pepidase-4, DPP-4 Inhibitor