Ertugliflozin And Sitagliptin

Uses

Ertugliflozin is a SGLT2 inhibitor used to treat type 2 diabetes mellitus.

Ertugliflozin as a monotherapy is indicated to improve the glycemic control in adult patients with type 2 diabetes. Ertugliflozin, in combination with metformin hydrochloride, is indicated to improve glycemic control in patients with diabetes type 2 who are not controlled on a regimen of ertugliflozin or metformin or in patients who are already treated with both ertugliflozin and metformin. The administration of ertugliflozin in combination with sitagliptin is indicated to improve glycemic control in adult patients with type 2 diabetes when treatment with ertugliflozin and sitagliptin is appropriate. It is pointed out that the use of ertugliflozin has to be an adjunct therapy to the use of diet and exercise. The type 2 diabetes mellitus is characterized by insulin resistance in muscle and liver, which results in the elevation of glucose levels in blood, or by presence of insulin deficiency. The insulin resistance is related to genetic factors, obesity, sedentary lifestyle or/and aging. This increase in the blood glucose can cause severe damage to kidney, eyes and vascular system.

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.

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

How Ertugliflozin And Sitagliptin works

As part of a normal process, the glucose from the blood is filtered for excretion and reabsorbed in the glomerulus so less than one percent of this glucose is excreted in the urine. The reabsorption is mediated by the sodium-dependent glucose cotransporter (SGLT), mainly the type 2 which is responsible for 90% of the reabsorbed glucose. Ertugliflozin is a small inhibitor of the SGLT2 and its activity increases glucose excretion, reducing hyperglycemia without the requirement of excessive insulin secretion.

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

Ertugliflozin And 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

The reports from clinical trials have portrait ertugliflozin to be well tolerated and abscent of significant side effects. Carcinogenic studies have been performed and it has been reported an increased incidence of adrenal medullary pheochromocytoma; possibly related to carbohydrate malabsorption leading to altered calcium homeostasis. There were no reported cases of mutagenesis or impairment in fertility.

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.

Volume of Distribution

After oral administration of ertugliflozin, the apparent volume of distribution was reported to be 215.3 L. The steady-state volume of distribution after intravenous administration of etrugliflozin is 85.53 L.

198L.

Elimination Route

Preclinical studies showed that ertugliflozin is well absorbed and had an oral bioavailability of 70-90%. The reported Tmax occurred at 0.5-1.5 hours after dosage. Following oral administration, the Cmax and AUC appeared to be dose proportional.Administration of 15 mg reported values of Cmax and AUC of 268 ng/ml and 1193 ng h/ml respectively.

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

The terminal elimination half-life of ertugliflozin is 11-17 hours.

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

Clearance

The apparent total plasma clearance rate after oral administration of ertugliflozin is 178.7 ml/min and the systemic total plasma clearance after intravenous administration is reported to be 187.2 ml/min.

350mL/min.

Elimination Route

The total recovery of ertugliflozin was 91% and this elimination route is distributed in a ratio of 50% in the urine and 41% in feces. The recovery of the administered dose was achieved approximately 168 hours after initial administration. Urine elimination occurred very rapidly and 80% of the dosage recovered in urine was obtained after 24 hours. The eliminated dose in urine was composed of seven different major metabolites and the unchanged ertugliflozin as a minor metabolite. The elimination rate in feces was depending on the bowel movements of each patient but 98.5% of the eliminated dose in feces was obtained after 168 hours of initial dosage. This eliminated dose was formed mainly by unchanged ertugliflozin and three other minor metabolites.

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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