Sitagliptin Phosphate

Pronunciation: (SYE-ta-GLIP-tin FOS-fate)
Class: Antidiabetic agent

Trade Names

Januvia
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg

Pharmacology

Sitagliptin is a dipeptidyl peptidase-4 inhibitor that is thought to act in type 2 diabetes by slowing the inactivation of incretin hormones.

Pharmacokinetics

Absorption

Sitagliptin is rapidly absorbed, with 100 mg reaching a C _max of 950 nM in 1 to 4 h. The bioavailability is approximately 87%.

Distribution

Vd is approximately 198 L. Plasma protein binding is 38%.

Metabolism

Metabolism by CYP3A4 and, to a lesser degree, CYP2C8.

Elimination

Terminal half-life is approximately 12.4 h. Approximately 13% is excreted in feces and 87% in urine via active tubular secretion (79% as unchanged drug). Sitagliptin is a substrate for organic anion transport.

Special Populations

Renal Function Impairment

Plasma AUC levels of sitagliptin were increased approximately 2- and 4-fold in patients with moderate and severe renal impairment, including patients with ESRD on hemodialysis, respectively. Dosage adjustment is required.

Hepatic Function Impairment

Mean AUC and C _max of sitagliptin increased approximately 21% and 13%, respectively, in patients with moderate hepatic impairment. However, no dosage adjustment is necessary. There is no clinical experience in patients with severe hepatic impairment.

Elderly

Elderly patients had an approximate 19% higher plasma concentration; no dosage adjustment is required.

Gender/Race/BMI

No clinically meaningful effects on the pharmacokinetics of sitagliptin were observed.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus as monotherapy or as combination therapy.

Contraindications

None well documented.

Dosage and Administration

Adults

PO 100 mg once daily.

Renal Function Impairment
Adults Moderate renal impairment (CrCl 30 to less than 50 mL/min)

PO 50 mg once daily.

Severe renal impairment (CrCl less than 30 mL/min) or ESRD requiring hemodialysis or peritoneal dialysis

PO 25 mg once daily. Administer without regard to the timing of hemodialysis.

General Advice

• May be taken with or without food.
• When used in combination with a sulfonylurea, a lower dose of the sulfonylurea may be required to reduce the risk of hypoglycemia.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Cyclosporine

Sitagliptin plasma concentrations may be increased modestly (approximately 68%), which is not expected to be clinically important.

Digoxin

Digoxin plasma concentrations may be increased slightly (approximately 18%); no dosage adjustment is recommended.

Sulfonylurea (eg, tolbutamide)

A lower dose of the sulfonylurea may be needed to reduce the risk of hypoglycemia.

Adverse Reactions

CNS

Headache (1%).

EENT

Nasopharyngitis (5%).

GI

Diarrhea (3%); abdominal pain (2%); nausea (1%); acute pancreatitis, hepatic enzyme elevations (postmarketing).

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, angioedema, cutaneous vasculitis, exfoliative skin conditions (including Stevens-Johnson syndrome), rash, and urticaria (postmarketing)

Respiratory

Upper respiratory tract infection (5%).

Precautions

Monitor Periodically monitor blood glucose and glycosylated Hgb. Assess renal function prior to initiation of therapy and periodically thereafter. Observe patients carefully for signs and symptoms of pancreatitis.

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hypersensitivity

Anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome, have occurred.

Renal Function

Dosage adjustments are required in patients with moderate or severe renal impairment and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Pancreatitis

Acute pancreatitis, both fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported.

Type 1 diabetes/diabetic ketoacidosis

Do not use sitagliptin in these settings.

Overdosage

Symptoms

Mean increases in QTc interval of 8 msec, which were not considered clinically important, were observed at a dose of 800 mg. There is no experience with doses above 800 mg.

Patient Information

• Inform patients that acute pancreatitis has been reported during postmarketing use of sitagliptin. Inform patients that 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. Instruct patients to promptly discontinue sitagliptin and contact their health care provider if persistent abdominal pain occurs.
• Educate patient, family, or caregiver regarding type 2 diabetes and its management.
• Instruct patient that this drug is not a substitute for diet and exercise and to follow prescribed regimen.
• Emphasize the importance of regular daily blood glucose monitoring and periodic glycosylated Hgb tests.
• Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake in the event that either occurs.
• Instruct patient to report hypoglycemic or hyperglycemic episodes to a health care provider.
• Advise patient that during periods of stress (eg, fever, trauma, infection, surgery), medication requirements may change and to seek medical advice promptly.
• Inform patients that the incidence of hypoglycemia is increased when sitagliptin is added to a sulfonylurea or insulin, and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
• Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin. 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, advise patients to stop taking sitagliptin and seek medical advice promptly.

Copyright © 2009 Wolters Kluwer Health.