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
Brands: Januvia, Janumet

Introduction

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

Uses for Sitagliptin Phosphate

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 to improve glycemic control in patients with type 2 diabetes mellitus.^{1 3 4 9}

Slideshow: Can Prescription Drugs Lead to Weight Gain?

Used in combination with metformin (given separately or as the fixed combination) as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus^{1 11 21} when treatment with both sitagliptin and metformin is appropriate.¹¹

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione [peroxisome proliferator-activated receptor-_γ agonist]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with one or more oral antidiabetic agents and/or insulin.^{1 2 5 9 11}

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.^{1 10 11}

Sitagliptin Phosphate 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

  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}

Administration

Oral Administration

Sitagliptin Monotherapy

Administer orally once daily with or without food.^{1 6 10}

Swallow tablets whole; do not split, crush, or chew.^{1 6}

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 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 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

Diabetes Mellitus

Monotherapy

Oral

100 mg once daily.^{1 10}

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients not currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of 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 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.²³

Patients currently receiving 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 switching therapy from oral antidiabetic agents other than sitagliptin or metformin hydrochloride specifically to the fixed combination of sitagliptin and metformin hydrochloride not established.¹¹

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

Oral

Combination therapy with metformin hydrochloride: Sitagliptin 50 mg twice daily or 100 mg once daily has been used.^{1 5 21 24}

Combination therapy with an insulin secretagogue (e.g., sulfonylurea): 100 mg of sitagliptin once daily has been used.^{1 22} Reduced dosage of concomitant insulin secretagogue may be needed to decrease risk of hypoglycemia.^{1 6}

Combination therapy with metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea): 100 mg of sitagliptin once daily has been used.^{1 22} Reduced dosage of concomitant insulin secretagogue may be needed to decrease risk of hypoglycemia.^{1 6}

Combination therapy with a thiazolidinedione (e.g., pioglitazone, rosiglitazone): 100 mg of sitagliptin once daily has been used.^{1 2 10}

Combination therapy with metformin hydrochloride and a thiazolidinedione: 100 mg of sitagliptin once daily has been used.¹

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 6}

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 Sitagliptin Phosphate

Contraindications

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

Warnings/Precautions

Acute Pancreatitis

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.

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

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}

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

Unknown whether history of pancreatitis increases risk for pancreatitis with sitagliptin therapy.^{1 11}

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}

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}

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

Loss of Glycemic Control

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 sitagliptin therapy after acute episode of hyperglycemia has resolved.¹¹

Macrovascular Outcomes

Evidence of macrovascular risk reduction with sitagliptin or any other antidiabetic agent not conclusively demonstrated in controlled clinical trials.¹

Use of Fixed Combinations

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

Sitagliptin monotherapy or add-on therapy with metformin and/or a thiazolidinedione or glimepiride: Nasopharyngitis,^{1 3 4 10} upper respiratory tract infection,^{1 10} peripheral edema,¹ headache.^{1 6 10}

Sitagliptin/metformin fixed combination: Diarrhea, upper respiratory infection, headache.¹¹

Sitagliptin in combination with metformin and glimepiride: Hypoglycemia, headache.¹¹

Sitagliptin in combination with insulin: Hypoglycemia.¹¹

Interactions for Sitagliptin Phosphate

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}

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 needed but monitor digoxin appropriately1 23
Hormonal contraceptives, oral	No clinically meaningful effect on pharmacokinetics of norethindrone or ethinyl estradiol1
Insulin	Risk of hypoglycemia increased when sitagliptin added to insulin therapy1 11	Reduced dosage of insulin may be required to reduce risk of hypoglycemia1
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	Risk of hypoglycemia increased when sitagliptin added to glimepiride therapy1 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

Sitagliptin Phosphate 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 not using sitagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.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} Importance of advising clinicians about a history of pancreatitis, gallstones, alcoholism, high triglyceride levels, or kidney problems.^{6 13} Importance of discontinuing sitagliptin and promptly notifying clinician if signs or symptoms of pancreatitis (e.g., nausea, vomiting, anorexia, persistent severe abdominal pain sometimes radiating to the back) are present.^{6 13 28}

• Importance of patient reading medication guide 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 advising patient not to split, crush, or chew sitagliptin tablets before swallowing.^{1 6} Importance of informing clinician if unable to swallow sitagliptin tablets whole.⁶

• 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	Merck
		50 mg (of sitagliptin) with Metformin Hydrochloride 1 g	Janumet	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2013. 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 &amp; DOHME): 60/$224.99 or 180/$645.95

Janumet 50-500MG Tablets (MERCK SHARP &amp; DOHME): 60/$220.99 or 180/$639.96

Januvia 100MG Tablets (MERCK SHARP &amp; DOHME): 30/$235.00 or 90/$672.99

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

Januvia 50MG Tablets (MERCK SHARP &amp; DOHME): 30/$228.98 or 90/$659.99