Sitagliptin

Uses

Monotherapy: Sitagliptin is used for an adjunct to diet and exercise to improve glycemic control in patients with type ll diabetes mellitus.

Combination with Metformin: Sitagliptin is used for patients with type 2 diabetes mellitus to improve glycemic control in combination with Metformin as initial therapy or when the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with a Sulfonylurea: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with a sulfonylurea when treatment with the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with a Thiazolidinediones: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with a thiazolidinedi- one when treatment with the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with Metformin and a Sulfonylurea: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with Metformin and a sulfonylurea when dual therapy with these agents, with diet and exercise, does not provide adequate glycemic control.

Sitagliptin is also used to associated treatment for these conditions: Type 2 Diabetes Mellitus

How Sitagliptin works

Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIP. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. Reduced inhibition of incretins increase insulin synthesis and decrease glucagon release in a manner dependant on glucose concentrations. These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c).

Dosage

Sitagliptin dosage

The recommended dose of Sitagliptin is 100 mg once daily as monotherapy or as combination therapy with Metformin, a sulfonylurea, a thiazolidinedione, or Metformin plus a sulfonylurea. Sitagliptin can be taken with or without food.

Elderly: No dosage adjustment is required based solely on age. The drug is excreted by the kidney. As elderly patients are more likely to have decreased renal function, caution should be taken in dose selection in the elderly.

Pediatric use: There is no data on use of Sitagliptin in patients younger than 18 years of age and therefore not recommended.

Side Effects

The most common adverse reactions are; upper respiratory tract infection, nasopharyngitis and headache. Hypoglycemia may occur in patients treated with the combination of Sitagliptin and sulfonylurea and add-on to insulin.

Toxicity

Animal studies in pregnancy have shown no adverse effects on the mother or offspring at normal doses, however these results are not always applicable to humans. There is currently a voluntary registry of fetal exposure. Animal studies at 100 times the maximum recommended human dose resulted in an increase in rib malformations. Sitagliptin is excreted in the milk of rats but it is not known if it would also be expressed in human breast milk. Because many drugs are expressed in human breast milk, the risk and benefit of prescribing the medication must be considered. There is currently a lack of safety and effectiveness data in pediatric patients. No differences in safety and efficacy were observed in geriatric patients compared to younger patients, however caution should be used in this population as they are more likely to have reduced renal function. Sitagliptin has also been associated with a 34% relative risk increase for all cause infection. There was no significant difference in patient response across sex, age, race, ethnicity, and BMI.

Precaution

Sitagliptin should not be used in patients with type l diabetes or for the treatment of diabetic ketoacidosis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating Sitagliptin and periodically thereafter. When used with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. There have been post marketing reports of serious allergic and hypersensitivity reactions in patients treated with Sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop Sitagliptin, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. There have been no clinical studies establishing conclusive evidence of macrovascular risk.

Interaction

Co-administration of Digoxin and Sitagliptin may slightly increase the mean peak drug concentration of Digoxin. But no dosage adjustment of Digoxin or Sitagliptin is recommended.

Food Interaction

• Take with or without food.

[Moderate] GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes.

Hypoglycemia most frequently occurs during acute consumption of alcohol.

Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise.

The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion.

By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia.

Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis.

Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan.

Alcohol should not be consumed on an empty stomach or following exercise.

Sitagliptin Drug Interaction

Moderate: insulin glargine, furosemideUnknown: aspirin, aspirin, aspirin, amoxicillin / clavulanate, rosuvastatin, apixaban, omega-3 polyunsaturated fatty acids, metformin, empagliflozin, atorvastatin, metoprolol, metoprolol, omega-3 polyunsaturated fatty acids, acetaminophen, clopidogrel, cyanocobalamin, ascorbic acid, cholecalciferol

Sitagliptin Disease Interaction

Major: pancreatitisModerate: renal dysfunction

Volume of Distribution

198L.

Elimination Route

Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokinetics. Sitagliptin reaches maximum plasma concentration in 2 hours.

Half Life

Approximately 12.4 hours. Other studies have reported a half life of approximately 11 hours.

Clearance

350mL/min.

Elimination Route

Approximately 79% of sitagliptin is excreted in the urine as the unchanged parent compound. 87% of the dose is eliminated in the urine and 13% in the feces.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy Category B. Safety of Sitagliptin in pregnant women has not been established. Sitagliptin should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus.

Nursing Mothers: It is not known whether Sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sitagliptin is administered to a nursing woman.

Contraindication

History of a serious hypersensitivity reaction to Sitagliptin, such as anaphylaxis or angioedema.

Special Warning

Renal Insufficiency-

• Mild renal insufficiency (creatinine clearance [CrCl] >50 mL/min, approximately corresponding to serum creatinine levels of >1.7 mg/dL in men and >1.5 mg/dL in women), no dosage adjustment for Sitagliptin is required.
• Moderate renal insufficiency (CrCl >30 to 1.7 to 1.5 to
• Severe renal insufficiency (CrCl 3.0 mg/dL in men and > 2.5 mg/dL in women) or with end -stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of hemodialysis. Concomitant Use with a Sulfonylurea- When Sitagliptin is used in combination with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

Hepatic Insufficiency: No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. Sitagliptin has not been studied in patients with severe hepatic insufficiency.

Acute Overdose

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were 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 periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.

Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.

Storage Condition

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

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