Sigletic (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

Manufactured By

Pharmaceutical Works “Polpharma”, SA (Poland)

Or

Pharmacare, PLC Co. (Palestine)

Quality Control Release

Pharmaceutical Works “POLPHARMA”, SA (Poland)

Or

PHARMACARE PREMIUM, Ltd. (Malta)

Contact Information

AKRIKHIN AO (Russia)

ATC Code

A10BH01 (Sitagliptin)

Active Substance

Sitagliptin (Rec.INN registered by WHO)

Dosage Forms

	Sigletic	Film-coated tablets, 25 mg: 10, 14, 28 or 56 pcs.
		Film-coated tablets, 50 mg: 14, 15, 28 or 56 pcs.
		Film-coated tablets, 100 mg: 10, 14, 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex; the core of the tablets on the cross-section is white or almost white.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, sodium stearyl fumarate.

Film coating composition: polyvinyl alcohol, macrogol 3350, talc, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

10 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (2) – carton packs.
14 pcs. – blisters (4) – carton packs.

Film-coated tablets light orange in color, round, biconvex, engraved “50” on one side; the core of the tablets on the cross-section is white or almost white.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, sodium stearyl fumarate.

Film coating composition: polyvinyl alcohol, macrogol 3350, talc, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

14 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (2) – carton packs.
14 pcs. – blisters (4) – carton packs.
15 pcs. – blisters (1) – carton packs.

Film-coated tablets light brown in color, round, biconvex; the core of the tablets on the cross-section is white or almost white.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, sodium stearyl fumarate.

Film coating composition: polyvinyl alcohol, macrogol 3350, talc, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

10 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (1) – carton packs.
14 pcs. – blisters (2) – carton packs.
14 pcs. – blisters (4) – carton packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

Pharmacological Action

The drug Sigletic is an orally active, highly selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, intended for the treatment of type 2 diabetes mellitus. Sitagliptin differs in chemical structure and pharmacological action from glucagon-like peptide-1 (GLP-1) analogues, insulin, sulfonylurea derivatives, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues. By inhibiting DPP-4, Sitagliptin increases the concentration of two incretin hormones: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).

Incretin hormones are secreted in the intestine throughout the day, and their concentration increases in response to food intake. Incretins are part of the internal physiological system regulating glucose homeostasis. At normal or elevated blood glucose concentrations, incretin hormones promote increased insulin synthesis and its secretion by pancreatic beta-cells through intracellular signaling mechanisms associated with cyclic adenosine monophosphate (cAMP).

GLP-1 also helps suppress the increased secretion of glucagon by pancreatic alpha-cells. The decrease in glucagon concentration against the background of increased insulin concentration leads to a reduction in glucose production by the liver, which ultimately results in decreased glycemia. This mechanism of action differs from that of sulfonylurea derivatives, which stimulate insulin release even at low blood glucose concentrations, which carries the risk of sulfonylurea-induced hypoglycemia not only in patients with type 2 diabetes but also in healthy individuals.

At low blood glucose concentrations, the listed effects of incretins on insulin release and decreased glucagon secretion are not observed. GLP-1 and GIP do not affect glucagon release in response to hypoglycemia. Under physiological conditions, incretin activity is limited by the DPP-4 enzyme, which rapidly hydrolyzes incretins into inactive products.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By increasing incretin concentrations, Sitagliptin enhances glucose-dependent insulin release and contributes to decreased glucagon secretion. In patients with type 2 diabetes and hyperglycemia, these changes in insulin and glucagon secretion lead to a reduction in glycated hemoglobin HbA_1c concentration and a decrease in plasma glucose levels measured fasting and after a glucose tolerance test or meal. In patients with type 2 diabetes, a single dose of sitagliptin leads to inhibition of DPP-4 enzyme activity for 24 hours, resulting in a 2-3 fold increase in circulating incretin concentrations of GLP-1 and GIP, an increase in plasma insulin and C-peptide concentrations, a decrease in plasma glucagon concentration, a reduction in fasting glycemia, and a reduction in glycemia after a glucose load or meal.

Effect on Blood Pressure

In a randomized, placebo-controlled, crossover study involving patients with arterial hypertension, the combined use of antihypertensive drugs (one or more from the list: ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta-blockers, diuretics) with sitagliptin was generally well tolerated by patients. In this category of patients, sitagliptin demonstrated a slight hypotensive effect: at a daily dose of 100 mg, Sitagliptin reduced the mean 24-hour ambulatory systolic blood pressure by 2 mm Hg compared to the placebo group. No hypotensive effect was observed in patients with normal blood pressure.

Effect on Cardiac Electrophysiology

In a randomized, placebo-controlled, crossover study in healthy volunteers, sitagliptin was administered as a single dose of 100 mg or 800 mg (8 times the recommended dose), or placebo. After administration of the recommended therapeutic dose of 100 mg, no effect of the drug on the QT interval duration was observed either at the time of its maximum plasma concentration or at other checkpoints throughout the study. After administration of 800 mg, the maximum placebo-corrected mean change from baseline in QT interval duration at 3 hours after drug administration was 8.0 msec. This slight increase was assessed as clinically insignificant. After the 800 mg dose, the maximum plasma concentration of sitagliptin was approximately 11 times higher than the corresponding value after the therapeutic dose of 100 mg.

Sitagliptin Cardiovascular Safety Assessment Study (TECOS)

In the sitagliptin cardiovascular safety assessment study (TECOS), patients received sitagliptin 100 mg daily (or 50 mg/day if the baseline estimated glomerular filtration rate (eGFR) was ≥30 ml/min/1.73 m² and <50 ml/min/1.73 m²) or placebo, which were added to standard therapy according to existing national standards for defining target HbA_1c levels and controlling cardiovascular risk factors. At the end of the median follow-up period of 3 years, in patients with type 2 diabetes, the use of sitagliptin in addition to standard treatment did not increase the risk of major adverse cardiovascular events (hazard ratio 0.98; 95% confidence interval, 0.89-1.08; p<0.001 for non-inferiority) or the risk of hospitalization for heart failure (hazard ratio 1.00; 95% confidence interval 0.83-1.20; p=0.98 for risk difference), compared to standard treatment without the additional use of sitagliptin.

Pharmacokinetics

Absorption

The pharmacokinetics of sitagliptin have been comprehensively described in healthy individuals and patients with type 2 diabetes. In healthy individuals, after oral administration of 100 mg sitagliptin, rapid absorption of the drug is noted, with C_max reached within 1 to 4 hours after administration. AUC increases proportionally to the dose and in healthy subjects is 8.52 µmol/L×h after oral administration of 100 mg, C_max was 950 nmol/L. The plasma AUC of sitagliptin increased by approximately 14% after the next dose of 100 mg of the drug upon reaching steady state after the first dose. Intra- and inter-subject coefficients of variation for sitagliptin AUC were insignificant.

The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of sitagliptin with a high-fat meal has no effect on pharmacokinetics, sitagliptin can be administered regardless of food intake.

Distribution

The mean V_d at steady state after a single 100 mg dose of sitagliptin in healthy volunteers is approximately 198 L. The fraction of sitagliptin bound to plasma proteins is relatively low at 38%.

Metabolism

Only a small portion of the administered drug is metabolized. After administration of ¹⁴C-labeled sitagliptin orally, approximately 16% of the radioactive sitagliptin was excreted as its metabolites. Traces of 6 metabolites of sitagliptin were detected, likely lacking DPP-4 inhibitory activity. In vitro studies have shown that the primary isoenzymes involved in the limited metabolism of sitagliptin are CYP3A4 and CYP2C8.

Excretion

Approximately 79% of sitagliptin is excreted unchanged by the kidneys. After oral administration of ¹⁴C-labeled sitagliptin to healthy volunteers, approximately 100% of the administered sitagliptin was excreted: 13% via the intestine. 87% by the kidneys – within one week after drug administration. The mean T_1/2 of sitagliptin after oral administration of 100 mg is approximately 12.4 hours; renal clearance is approximately 350 ml/min.

Elimination of sitagliptin occurs primarily by renal excretion via active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The involvement of hOAT-3 in the transport of sitagliptin has not been studied clinically. Sitagliptin is also a substrate for P-glycoprotein, which may also participate in the renal elimination of sitagliptin. However, cyclosporine, a P-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Pharmacokinetics in Special Patient Populations

Renal impairment. An open-label study of sitagliptin at a dose of 50 mg/day was conducted to investigate its pharmacokinetics in patients with varying degrees of severity of chronic renal impairment compared to a control group of healthy volunteers. The study included patients with mild, moderate, and severe renal impairment, as well as patients with end-stage chronic kidney disease (CKD) requiring dialysis. Furthermore, the effect of renal impairment on the pharmacokinetics of sitagliptin in patients with type 2 diabetes and mild, moderate, or severe renal impairment (including patients with end-stage CKD) was assessed using population pharmacokinetic analyses.

An increase in the plasma AUC of sitagliptin by approximately 1.2-fold and 1.6-fold compared to the control group was noted in patients with mild renal impairment (eGFR from ≥60 ml/min/1.73 m² to <90 ml/min/1.73 m²) and in patients with moderate renal impairment (eGFR from ≥45 ml/min/1.73 m² to <60 ml/min/1.73 m²), respectively. Since this increase is not clinically significant, dose adjustment in these patients is not required. An approximately two-fold increase in the plasma AUC of sitagliptin was noted in patients with moderate renal impairment (eGFR from ≥30 ml/min/1.73 m² to <60 ml/min/1.73 m²) and an approximately four-fold increase in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²), including patients with end-stage CKD requiring dialysis. Sitagliptin was minimally removed during hemodialysis: only 13.5% of the administered dose was removed from the body during a 3-4 hour dialysis session started 4 hours after drug administration. Therefore, to achieve therapeutic plasma concentrations of sitagliptin (similar to those in patients with normal renal function) in patients with eGFR <45 ml/min/1.73 m², lower doses are recommended.

Hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh score 7-9), the mean AUC and C_max of sitagliptin after a single 100 mg dose increased by approximately 21% and 13%, respectively, compared to the control group of healthy volunteers. Therefore, no dose adjustment of the drug is required for mild and moderate hepatic impairment. There are no clinical data on the use of sitagliptin in patients with severe hepatic impairment (Child-Pugh score greater than 9). However, since Sitagliptin is primarily excreted by the kidneys, no significant change in the pharmacokinetics of sitagliptin is expected in patients with severe hepatic impairment.

Elderly patients. Patient age did not have a clinically significant impact on the pharmacokinetic parameters of sitagliptin. Compared to young patients, in elderly patients (65-80 years), the concentration of sitagliptin is approximately 19% higher. No dose adjustment of the drug based on age is required.

Indications

Sigletic is indicated for use in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control.

As monotherapy

• In patients who have not achieved adequate control with diet and exercise alone, and for whom metformin is unsuitable due to contraindications or intolerance.

As dual oral therapy in combination with

• Metformin, when diet and exercise combined with metformin alone do not provide adequate glycemic control;
• A sulfonylurea, when diet and exercise combined with the maximum tolerated dose of a sulfonylurea do not provide adequate glycemic control, and when metformin is unsuitable due to contraindications or intolerance;
• Peroxisome proliferator-activated receptor gamma (PPARγ) agonists (i.e., thiazolidinediones), when the use of PPARγ agonists is acceptable, and when diet and exercise combined with PPARγ agonists alone do not provide adequate glycemic control.

As triple oral therapy in combination with

• A sulfonylurea and metformin, when diet and exercise combined with dual therapy with these drugs do not provide adequate glycemic control;
• PPARγ agonists and metformin, when the use of PPARγ agonists is acceptable, and when diet and exercise combined with dual therapy with these drugs do not provide adequate glycemic control.

In combination with insulin

Sigletic is also prescribed as an add-on therapy to insulin (with or without metformin), when diet and exercise combined with a stable dose of insulin do not provide adequate glycemic control.

ICD codes

Dosage Regimen

Sigletic is taken orally, regardless of meals.

The dose is 100 mg of sitagliptin once daily. When used in combination with metformin and/or PPARγ agonists, the dose of metformin and/or PPARγ agonists should be maintained, and Sigletic should be taken concomitantly with them.

When Sigletic is used in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of hypoglycemia.

If a dose of Sigletic is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Special Patient Groups

Patients with Renal Impairment

When considering the use of sitagliptin in combination with another antidiabetic medicinal product, its conditions of use in patients with renal impairment should be checked.

For patients with mild (eGFR ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²) and moderate (eGFR ≥45 mL/min/1.73 m² to <60 mL/min/1.73 m²) renal impairment, no dose adjustment is required.

For patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²) the dose of Sigletic is 50 mg once daily.

For patients with severe renal impairment (eGFR ≥15 mL/min/1.73 m² to <30 mL/min/1.73 m²) or end-stage renal disease (eGFR <15 mL/min/1.73 m²) including patients requiring hemodialysis or peritoneal dialysis, the dose of Sigletic is 25 mg once daily. Therapy can be administered without regard to the timing of dialysis.

Due to the dose adjustment based on renal function, assessment of renal function is recommended prior to initiation of Sigletic and periodically during therapy.

Patients with Hepatic Impairment

For patients with mild or moderate hepatic impairment, no dose adjustment is required. The use of Sigletic has not been studied in patients with severe hepatic impairment and caution should be exercised in such cases.

However, since Sitagliptin is primarily excreted by the kidneys, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Elderly Patients

No dose adjustment is required in elderly patients.

Children

The use of sitagliptin in children under 18 years of age is contraindicated.

Adverse Reactions

Serious adverse reactions have been reported, including pancreatitis and hypersensitivity reactions. Hypoglycemia was reported when used in combination with sulfonylureas (4.7%-13.8%) and insulin (9.6%).

Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequency is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and unknown (cannot be estimated from the available data).

Table 1. Frequency of adverse reactions identified in placebo-controlled clinical trials of sitagliptin monotherapy and from post-marketing experience

* Adverse reactions have been identified from post-marketing surveillance.

^†See section 4.4.

^‡See below TECOS Cardiovascular Safety Outcome Study.

Description of Selected Adverse Reactions

In addition to the drug-related adverse events described above, adverse events noted regardless of causality and occurring in at least 5% or more of patients receiving Sitagliptin included upper respiratory tract infection and nasopharyngitis. Other adverse events noted regardless of causality, which occurred more frequently in patients receiving Sitagliptin (did not reach the 5% level but occurred with a frequency greater than 0.5% more in the sitagliptin groups than in the control group), were osteoarthritis and limb pain.

Some adverse reactions were observed more frequently in studies of sitagliptin combined with other hypoglycemic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycemia (frequency “very common” with sulfonylurea and metformin combinations), influenza (“common” with insulin (with or without metformin)), nausea and vomiting (“common” with metformin), flatulence (“common” with metformin or pioglitazone), constipation (“common” with sulfonylurea and metformin combination), peripheral edema (“common” with pioglitazone or pioglitazone and metformin combination), somnolence and diarrhea (“uncommon” with metformin), and dry mouth (“uncommon” with insulin (with or without metformin)).

Cardiovascular Safety Outcome Study (TECOS)

The Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) included 7332 patients treated with Sitagliptin 100 mg daily (or 50 mg daily if baseline estimated eGFR was ≥30 and <50 mL/min/1.73 m²) and 7339 patients receiving placebo in the intent-to-treat population.

Both treatments were added to usual care, based on national standards for HbA_1c and cardiovascular risk factors. The overall incidence of serious adverse events in patients receiving Sitagliptin was similar to that in patients receiving placebo.

In the intent-to-treat population among patients taking insulin and/or sulfonylureas at study start, the incidence of severe hypoglycemia was 2.7% in patients receiving Sitagliptin and 2.5% in patients receiving placebo; among patients not taking insulin and/or sulfonylureas at study start, the incidence of severe hypoglycemia was 1.0% in patients receiving Sitagliptin and 0.7% in patients receiving placebo.

The incidence of adjudication-confirmed pancreatitis was 0.3% in patients receiving Sitagliptin and 0.2% in patients receiving placebo.

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions via the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to sitagliptin or to any of the excipients;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age.

Use in Pregnancy and Lactation

Pregnancy

There are no reliable data on the use of sitagliptin in pregnant women. Animal studies have shown reproductive toxicity at high doses. The potential risk to humans is unknown.

Due to the lack of data on the medical use of Sigletic during pregnancy, its use in pregnant women is contraindicated.

Breastfeeding Period

It is not known whether Sitagliptin passes into human breast milk. An animal study showed passage of sitagliptin into breast milk. Sigletic should not be used during lactation.

Fertility

Animal data do not indicate an effect of sitagliptin therapy on male and female reproductive function. Human data are lacking.

Use in Hepatic Impairment

For patients with mild or moderate hepatic impairment, no dose adjustment is required. The use of Sigletic has not been studied in patients with severe hepatic impairment and caution should be exercised in such cases.

However, since Sitagliptin is primarily excreted by the kidneys, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Use in Renal Impairment

When considering the use of sitagliptin in combination with another antidiabetic medicinal product, its conditions of use in patients with renal impairment should be checked.

For patients with mild (eGFR ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²) and moderate (eGFR ≥45 mL/min/1.73 m² to <60 mL/min/1.73 m²) renal impairment, no dose adjustment is required.

For patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²), the dose of Sigletic is 50 mg once daily.

For patients with severe renal impairment (eGFR ≥15 mL/min/1.73 m² to <30 mL/min/1.73 m²) or end-stage renal disease (eGFR <15 mL/min/1.73 m²) including patients requiring hemodialysis or peritoneal dialysis, the dose of Sigletic is 25 mg once daily. Therapy can be administered without regard to the timing of dialysis.

Due to the dose adjustment based on renal function, assessment of renal function is recommended prior to initiation of Sigletic and periodically during therapy.

Pediatric Use

The use of sitagliptin in children under 18 years of age is contraindicated.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

General Instructions

Sigletic should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Acute Pancreatitis

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. After discontinuation of sitagliptin, clinical manifestations of pancreatitis usually resolve (with or without supportive care), but cases of necrotizing or hemorrhagic pancreatitis and/or fatal outcome have been reported very rarely. If pancreatitis is suspected, use of Sigletic and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Sigletic should not be restarted. Caution should be exercised when using the drug in patients with a history of pancreatitis.

Hypoglycemia When Used in Combination with Other Hypoglycemic Medicinal Products

In clinical trials of sitagliptin as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycemia (i.e., metformin and/or PPARγ agonists), the rates of hypoglycemia reported with sitagliptin were similar to those in patients taking placebo. Hypoglycemia was observed when Sitagliptin was used in combination with insulin or sulfonylureas. Therefore, to reduce the risk of hypoglycemia, a reduction in the dose of the sulfonylurea derivative or insulin may be considered.

Renal Impairment

Sitagliptin is excreted by the kidneys. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower doses are recommended in patients with a glomerular filtration rate <45 mL/min, as well as in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

When considering the use of sitagliptin in combination with another hypoglycemic medicinal product, its conditions of use in patients with renal impairment should be monitored.

Hypersensitivity Reactions

During post-marketing experience, reports of serious hypersensitivity reactions in patients treated with Sitagliptin have been received. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome. The onset of these reactions occurred within the first 3 months after initiation of therapy, with some reports received after the first dose. If a hypersensitivity reaction is suspected, Sigletic should be discontinued. Other potential causes for the event should be assessed, and alternative therapy for diabetes should be instituted.

Bullous Pemphigoid

During post-marketing experience, reports of bullous pemphigoid in patients taking DPP-4 inhibitors, including Sitagliptin, have been received. If bullous pemphigoid is suspected, Sigletic should be discontinued.

Sodium

Sigletic contains less than 1 mmol sodium (23 mg) per dose, that is to say, essentially ‘sodium-free’.

Effect on Ability to Drive and Use Machines

Sitagliptin has no or negligible influence on the ability to drive and use machines. However, when driving or operating machines, it should be taken into account that dizziness and drowsiness may occur.

In addition, patients should be advised to take precautions to avoid hypoglycemia while driving, particularly when Sitagliptin is used in combination with sulfonylurea derivatives or insulin.

Overdose

Symptoms: In controlled clinical studies, single doses of up to 800 mg sitagliptin were administered to healthy volunteers. Minimal changes in the QT interval, not considered clinically significant, were observed in one study at the 800 mg dose of sitagliptin. Doses higher than 800 mg/day have not been studied in humans. In Phase I clinical studies of multiple doses, no treatment-related adverse reactions were noted with sitagliptin at daily doses up to 400 mg for 28 days.

Treatment: In the event of an overdose, it is reasonable to institute 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 poorly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. There is no experience with peritoneal dialysis of sitagliptin.

Drug Interactions

Effect of Other Medicinal Products on Sitagliptin

The clinical data described below indicate that the risk of clinically significant interactions with co-administered medicinal products is low.

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with a contribution from CYP2C8. In patients with normal renal function, metabolism, including that mediated by CYP3A4, plays a minor role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease. For this reason, potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, clarithromycin, could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or end-stage renal disease. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been evaluated in a clinical study.

In vitro transport studies showed that Sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3-mediated transport of sitagliptin was blocked in vitro by probenecid, although the risk of clinically significant interaction is considered low. Co-administration with OAT3 inhibitors has not been studied in vivo.

Metformin: Co-administration of a twice-daily dose of 1000 mg metformin with 50 mg sitagliptin did not significantly alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent P-glycoprotein inhibitor, on the pharmacokinetics of sitagliptin. Co-administration of a single oral 100 mg dose of sitagliptin and a single oral 600 mg dose of cyclosporine increased the AUC and C_max of sitagliptin by approximately 29% and 68%, respectively. These changes in the pharmacokinetics of sitagliptin were not considered clinically significant. Renal clearance of sitagliptin was not significantly altered. Therefore, significant interaction with other P-glycoprotein inhibitors was not expected.

Effect of Sitagliptin on Other Medicinal Products

Digoxin: Sitagliptin had a slight effect on plasma concentrations of digoxin. Following administration of 0.25 mg digoxin in combination with 100 mg sitagliptin daily for 10 days, the plasma digoxin AUC increased on average by 11%, and the plasma C_max increased on average by 18%. No adjustment of the digoxin dose is necessary. However, patients at risk of digoxin toxicity should be monitored appropriately when Sitagliptin and digoxin are co-administered.

In vitro data indicate that Sitagliptin does not inhibit or stimulate CYP450 isoenzymes. In clinical studies, Sitagliptin did not significantly alter the pharmacokinetic properties of metformin, glibenclamide (glyburide), simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity to cause interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and the organic cation transporter (OCT).

Sitagliptin may be a weak inhibitor of P-glycoprotein in vivo.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.