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Pharmacodynamics: General: In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology: In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100 mg, JANUVIA 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours post-dose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.
In patients with type 2 diabetes administered JANUVIA 100 mg (N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Clinical Studies: There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.
In patients with type 2 diabetes, treatment with JANUVIA produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
Monotherapy: A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of JANUVIA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug wash-out period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the 24-week study 741 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or JANUVIA.
Treatment with JANUVIA at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 1). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving JANUVIA 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with JANUVIA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given JANUVIA, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. The effect of JANUVIA on lipid endpoints was similar to placebo. Body weight did not increase from baseline with JANUVIA therapy in either study, compared to a small reduction in patients given placebo. (See Table 1.)
Click on icon to see table/diagram/imageAdditional Monotherapy Study: A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of JANUVIA in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of JANUVIA and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of JANUVIA were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with JANUVIA relative to those on placebo. In addition, the reductions in A1C and FPG with JANUVIA compared to placebo were generally similar to those observed in other monotherapy studies. (See Pharmacokinetics as follows.)
Combination Therapy: Add-on Combination Therapy with Metformin: A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
In combination with metformin, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 2). Rescue glycemic therapy was used in 5% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups. (See Table 2.)
Click on icon to see table/diagram/imageInitial Combination Therapy with Metformin: A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of JANUVIA once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.
Initial therapy with the combination of JANUVIA and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to JANUVIA alone (Table 3, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: JANUVIA 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo. (See Table 3 and Figure 1.)
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Click on icon to see table/diagram/imageInitial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.
Active-Controlled Study vs Glipizide in Combination with Metformin: The efficacy of JANUVIA was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of JANUVIA 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.
After 52 weeks, JANUVIA and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 4). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of JANUVIA to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%). (See Table 4 and Figure 2.)
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Click on icon to see table/diagram/imageThe incidence of hypoglycemia in the JANUVIA group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with JANUVIA exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).
Add-on Combination Therapy with Pioglitazone: A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.
In combination with pioglitazone, JANUVIA provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 5). Rescue therapy was used in 7% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change. (See Table 5.)
Click on icon to see table/diagram/imageAdd-on Combination Therapy with Glimepiride, with or without Metformin: A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
In combination with glimepiride, with or without metformin, JANUVIA provided significant improvements in A1C and FPG compared to placebo (Table 6). In the entire study population (patients on JANUVIA in combination with glimepiride and patients on JANUVIA in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with JANUVIA 100 mg and 27% of patients treated with placebo. In this study, patients treated with JANUVIA had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. (See Use with Medications Known to Cause Hypoglycemia under Precautions; Clinical Trials Experience under Adverse Reactions.) (See Table 6.)
Click on icon to see table/diagram/imageAdd-on Combination Therapy with Insulin (with or without Metformin): A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA as add-on to stable dose insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.
The median daily insulin dose at baseline was 42 units in the patients treated with JANUVIA and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 7). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with JANUVIA. (See Use with Medications Known to Cause Hypoglycemia under Precautions; Clinical Trials Experience under Adverse Reactions.) (See Table 7.)
Click on icon to see table/diagram/imageIn another 24-week, randomized, double-blind, placebo-controlled study designed to assess the insulin-sparing efficacy of JANUVIA as add-on combination therapy, 660 patients with inadequate glycemic control on insulin glargine with or without metformin (≥1500 mg per day) were randomized to the addition of either 100 mg of JANUVIA (N=330) or placebo (N=330), administered once daily while undergoing intensification of insulin therapy. Baseline HbA1c was 8.74% and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. Glycemic endpoints measured included HbA1c and FPG.
At Week 24, the increase in daily insulin dose was 20% smaller in patients treated with JANUVIA (19 IU/day) than in patients treated with placebo (24 IU/day). The difference in insulin dose (-5 IU/day) was statistically significant (p=0.009). The reduction in HbA1c in patients treated with JANUVIA and insulin (with or without metformin) was -1.31% compared to -0.87% in patients treated with placebo and insulin (with or without metformin), a difference of -0.45% [95% CI: -0.60, -0.29]. The reduction in FPG in patients treated with JANUVIA and insulin (with or without metformin) was -55.5 mg/dL compared to -44.8 mg/dL in patients treated with placebo and insulin (with or without metformin), a difference of -10.7 mg/dL [95% CI: -17.2, -4.3]. The incidence of symptomatic hypoglycemia was 25.2% in patients treated with JANUVIA and insulin (with or without metformin) and 36.8% in patients treated with placebo and insulin (with or without metformin). The difference in incidence of hypoglycemia (-11.6%) was statistically significant (p=0.001). The difference was mainly due to a higher percentage of patients in the placebo group experiencing 3 or more episodes of hypoglycemia (9.4 vs. 19.1%). There was no difference in the incidence of severe hypoglycemia.
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized study in 14,671 patients in the intention-to-treat population with an HbA1c of ≥6.5 to 8.0% with established CV disease who received JANUVIA (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m2) or placebo (7,339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR <30 mL/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥75 years of age and 3,324 patients with renal impairment (eGFR <60 mL/min/1.73 m2).
Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the sitagliptin and placebo groups was 0.29% (0.01), 95% CI (-0.32, -0.27); p<0.001. Patients in the sitagliptin group received fewer antihyperglycemic agents than did those in the placebo group (hazard ratio 0.72; 95% CI, 0.68 to 0.77; p≤0.001) and, among patients not on insulin at study entry, were less likely to start chronic insulin therapy (hazard ratio 0.70; 95% CI, 0.63 to 0.79; p<0.001).
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.
After a median follow up of 3 years, JANUVIA, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared to usual care without JANUVIA in patients with type 2 diabetes (see Table 8).
Click on icon to see table/diagram/imageJANUVIA in Pediatric Patients with Type 2 Diabetes and Inadequate Glycemic Control: A 54-week, double-blind study was conducted to evaluate the efficacy and safety of JANUVIA 100 mg once daily in pediatric patients (10 to 17 years of age) with type 2 diabetes who were not on anti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5% to 10%) or were on a stable dose of insulin for at least 12 weeks (with HbA1c 7% to 10%). Patients were randomized to JANUVIA 100 mg or placebo once daily for 20 weeks.
Mean baseline HbA1c was 7.5%. Treatment with JANUVIA 100 mg did not provide significant improvement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with JANUVIA (N=95) was 0.0% compared to 0.2% in patients treated with placebo (N=95), a difference of -0.2% (95% CI: -0.7, 0.3).
Pharmacokinetics: The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption: The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.
Distribution: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism: Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Excretion: Following administration of an oral [14C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Special Populations: Renal Impairment: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of JANUVIA (50 mg dose) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on hemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate or severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.
Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m2 to <90 mL/min/1.73 m2) and patients with moderate renal impairment (eGFR ≥45 mL/min/1.73 m2 to <60 mL/min/1.73 m2), respectively. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
Plasma AUC levels of sitagliptin were increased approximately 2-fold in patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <45 mL/min/1.73 m2) and approximately 4-fold in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), including patients with ESRD on hemodialysis. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours post-dose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with eGFR <45 mL/min/1.73 m2. (See Patients with Renal Impairment under Dosage & Administration.)
Hepatic Impairment: In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild or moderate hepatic impairment.
There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI. Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Gender: No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Geriatric: No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Pediatric: The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in pediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted AUC of sitagliptin in plasma was approximately 18% lower compared to adult patients with type 2 diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference based on the flat PK/PD relationship between the dose of 50 mg and 100 mg in adults.
No studies with sitagliptin have been performed in pediatric patients <10 years of age.
Race: No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
Drug Interactions: In Vitro Assessment of Drug Interactions: Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions: Effects of Sitagliptin on Other Drugs: In clinical studies, as described previously, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).
Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA is not an inhibitor of CYP2C8-mediated metabolism.
Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Effects of Other Drugs on Sitagliptin: Clinical data described previously suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications.
Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
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