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Generic Name
Sitagliptin
Brand Names
Brynovin, Januvia, Steglujan, Zituvio
FDA approval date: October 16, 2006
Classification: Dipeptidyl Peptidase 4 Inhibitor
Form: Tablet, Solution
What is Brynovin (Sitagliptin)?
BRYNOVIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use BRYNOVIN is not recommended in patients with type 1 diabetes. BRYNOVIN has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using BRYNOVIN. [see Warnings and Precautions.
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Related Clinical Trials
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Targeting Macrophage Migration Inhibitory Factor: A Phase 2 and Pharmacodynamic Study of Sitagliptin in Patients With Progressive Grade 4 Gliomas
Summary: The purpose of this study is to evaluate whether treating glioblastoma patients with sitagliptin can improve immune response against the tumor by targeting specific immune cells called myeloid-derived suppressor cells (MDSCs) that suppress your body's natural immune response against cancer. Sitagliptin is an investigational drug for this condition that works by inhibiting an enzyme called dipeptid...
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Brand Information
BRYNOVIN (Sitagliptin Hydrochloride Oral)
1INDICATIONS & USAGE
BRYNOVIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use
BRYNOVIN is not recommended in patients with type 1 diabetes.
2DOSAGE FORMS & STRENGTHS
BRYNOVIN oral solution 25 mg/mL is supplied as a clear, colorless to nearly colorless aqueous solution in an amber glass bottle.
3CONTRAINDICATIONS
BRYNOVIN is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin or any of the excipients in BRYNOVIN. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported
4ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the labeling:
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
* Intent-to-treat population
* Intent-to-treat population.
In a 24-week trial of initial therapy with sitagliptin in combination with pioglitazone, there were no adverse reactions reported in ≥5% of patients and more commonly than in patients given pioglitazone alone.
* Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population.
In a pooled analysis of the two monotherapy trials, the add-on to metformin trial, and the add-on to pioglitazone trial, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with sitagliptin 100 mg and 0.9% in patients treated with placebo.
Gastrointestinal Adverse Reactions
In a pooled analysis of the two monotherapy trials, the add-on to metformin trial, and the add-on to pioglitazone trial, the incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin was as follows: abdominal pain (sitagliptin 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3%, 2.3%).
Pancreatitis
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control).
Vital Sign and Electrocardiogram (ECG) Changes
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with sitagliptin.
Laboratory Tests
Across clinical trials, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical trials, with a mean baseline WBC count of approximately 6,600 cells/microL) is not considered to be clinically relevant. In a 12-week trial of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin (0.12 mg/dL [0.04]) and in patients treated with placebo (0.07 mg/dL [0.07]). The clinical significance of this added increase in serum creatinine relative to placebo is not known.
4.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of sitagliptin as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
5OVERDOSAGE
In the event of an overdose with BRYNOVIN, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures dictated by the patient’s clinical status.
6DESCRIPTION
BRYNOVIN (sitagliptin) oral solution contains sitagliptin hydrochloride (HCl), an orally-active inhibitor of the DPP-4 enzyme.
Sitagliptin HCl is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water; very slightly soluble in ethanol; and practically insoluble in n-Heptane.
7CLINICAL STUDIES
Overview of Clinical Trials
The effectiveness of BRYNOVIN has been established for glycemic control in patients with type 2 diabetes mellitus based on adequate and well-controlled trials of sitagliptin tablets, referenced below as “sitagliptin”. There were approximately 5,200 patients with type 2 diabetes mellitus randomized in nine double-blind, placebo-controlled clinical safety and efficacy trials conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these trials, the ethnic/racial distribution was approximately 59% white, 20% Hispanic or Latino, 10% Asian, 6% Black or African American, 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 trial of 52-weeks duration was conducted in 1,172 patients with type 2 diabetes mellitus who had inadequate glycemic control on metformin.
In patients with type 2 diabetes mellitus, treatment with sitagliptin produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
The effectiveness of BRYNOVIN has been established for glycemic control in patients with type 2 diabetes mellitus based on adequate and well-controlled trials of sitagliptin tablets, referenced below as “sitagliptin”. There were approximately 5,200 patients with type 2 diabetes mellitus randomized in nine double-blind, placebo-controlled clinical safety and efficacy trials conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these trials, the ethnic/racial distribution was approximately 59% white, 20% Hispanic or Latino, 10% Asian, 6% Black or African American, 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 trial of 52-weeks duration was conducted in 1,172 patients with type 2 diabetes mellitus who had inadequate glycemic control on metformin.
In patients with type 2 diabetes mellitus, treatment with sitagliptin produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
7.1Monotherapy
A total of 1,262 patients with type 2 diabetes mellitus participated in two double-blind, placebo-controlled trials, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of sitagliptin monotherapy. In both monotherapy trials, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout 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 trial, 521 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg, and in the 24-week trial 741 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg. Patients who failed to meet specific glycemic goals during the trials were treated with metformin rescue, added on to placebo or sitagliptin.
* Intent-to-treat population using last observation on trial prior to metformin rescue therapy.
A multinational, randomized, double-blind, placebo-controlled trial was also conducted to assess the safety and tolerability of sitagliptin in 91 patients with type 2 diabetes mellitus and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of sitagliptin and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg of sitagliptin daily. In this trial, the safety and tolerability of sitagliptin were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with sitagliptin relative to those on placebo. In addition, the reductions in A1C and FPG with sitagliptin compared to placebo were generally similar to those observed in other monotherapy trials.
7.2Combination Therapy
Add-on Combination Therapy with MetforminA total of 701 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin. Patients already on metformin HCl (N=431) at a dosage of at least 1,500 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 HCl (at a dosage of at least 1,500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue.
In combination with metformin, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 7). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
In combination with metformin, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 7). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
Table 7: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Add-on Combination Therapy with Metformin in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy.
Initial Combination Therapy with MetforminA total of 1,091 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial trial 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 trial 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 sitagliptin once daily, 500 mg or 1,000 mg of metformin HCl twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1,000 mg of metformin HCl twice daily. Patients who failed to meet specific glycemic goals during the trial were treated with glyburide (glibenclamide) rescue.
Initial therapy with the combination of sitagliptin and metformin HCl provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 8, 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 trial entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin HCl 500 mg bid, -1.1%; metformin HCl 1,000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin HCl 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin HCl 1,000 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.
Initial therapy with the combination of sitagliptin and metformin HCl provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 8, 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 trial entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin HCl 500 mg bid, -1.1%; metformin HCl 1,000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin HCl 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin HCl 1,000 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.
Table 8:Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to glyburide (glibenclamide) rescue therapy.
Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Adult Patients with Type 2 Diabetes Mellitus*
Initial 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 Trial vs Glipizide in Combination with Metformin
The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes mellitus. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin HCl monotherapy (dosage of ≥1,500 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 sitagliptin 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 dosage was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dosage of glipizide after the titration period was 10 mg.
After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 9). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the trial (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).
Table 9: Glycemic Parameters in a 52-Week Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin (Intent-to-Treat Population)*
* The intent-to-treat analysis used the patients’ last observation in the trial prior to discontinuation.
Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin (Per Protocol Population)*
* The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.
The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32%). Patients treated with sitagliptin 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 mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin 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 dosage 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 sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.
In combination with pioglitazone, sitagliptin provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 10). Rescue therapy was used in 7% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.
A total of 353 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin 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 dosage 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 sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.
In combination with pioglitazone, sitagliptin provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 10). Rescue therapy was used in 7% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.
Table 10: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Add-on Combination Therapy with Pioglitazone in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to metformin rescue therapy.
Initial Combination Therapy with Pioglitazone
A total of 520 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind trial designed to assess the efficacy of sitagliptin as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at trial entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) 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 100 mg of sitagliptin in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this trial.
Table 11: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Combination with Pioglitazone as Initial Therapy in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial.
Add-on Combination Therapy with Metformin and Rosiglitazone
A total of 278 patients with type 2 diabetes mellitus participated in a 54-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin and rosiglitazone. Patients on dual therapy with metformin HCl ≥1,500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl ≥1,500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin HCl ≥1,500 mg/day and rosiglitazone ≥4 mg/day in a dosage titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trial were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.
In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.
A total of 278 patients with type 2 diabetes mellitus participated in a 54-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin and rosiglitazone. Patients on dual therapy with metformin HCl ≥1,500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl ≥1,500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin HCl ≥1,500 mg/day and rosiglitazone ≥4 mg/day in a dosage titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trial were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.
In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.
Table 12: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin and Rosiglitazone in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to glipizide (or other sulfonylurea) rescue therapy.
Add-on Combination Therapy with Glimepiride, with or without Metformin
A total of 441 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin 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 HCl (≥1,500 mg per day). After a dosage-titration and dosage-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 sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue.
In combination with glimepiride, with or without metformin, sitagliptin provided significant improvements in A1C and FPG compared to placebo (Table 13). In the entire trial population (patients on sitagliptin in combination with glimepiride and patients on sitagliptin 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 sitagliptin 100 mg and 27% of patients treated with placebo. In this trial, patients treated with sitagliptin 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 Warnings and Precautions (5.4); Adverse Reactions (6.1)].
A total of 441 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin 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 HCl (≥1,500 mg per day). After a dosage-titration and dosage-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 sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue.
In combination with glimepiride, with or without metformin, sitagliptin provided significant improvements in A1C and FPG compared to placebo (Table 13). In the entire trial population (patients on sitagliptin in combination with glimepiride and patients on sitagliptin 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 sitagliptin 100 mg and 27% of patients treated with placebo. In this trial, patients treated with sitagliptin 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 Warnings and Precautions (5.4); Adverse Reactions (6.1)].
Table 13:Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin as Add-On Combination Therapy with Glimepiride, with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy.
Add-on Combination Therapy with Insulin (with or without Metformin)
A total of 641 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin as add-on to insulin therapy (with or without metformin). The racial distribution in this trial was approximately 70% white, 18% Asian, 7% Black or African American, and 5% other groups. Approximately 14% of the patients in this trial were Hispanic or Latino. Patients entered a 2- week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl (≥1,500 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 sitagliptin or placebo, administered once daily. Patients were on a stable dosage of insulin prior to enrollment with no changes in insulin dosage 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 dosage as rescue therapy.
The median daily insulin dosage at baseline was 42 units in the patients treated with sitagliptin and 45 units in the placebo-treated patients. The median change from baseline in daily dosage of insulin was zero for both groups at the end of the trial. In combination with insulin (with or without metformin), sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 14). 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 sitagliptin. [See Warnings and Precautions (5.4); Adverse Reactions (6.1)].
A total of 641 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin as add-on to insulin therapy (with or without metformin). The racial distribution in this trial was approximately 70% white, 18% Asian, 7% Black or African American, and 5% other groups. Approximately 14% of the patients in this trial were Hispanic or Latino. Patients entered a 2- week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl (≥1,500 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 sitagliptin or placebo, administered once daily. Patients were on a stable dosage of insulin prior to enrollment with no changes in insulin dosage 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 dosage as rescue therapy.
The median daily insulin dosage at baseline was 42 units in the patients treated with sitagliptin and 45 units in the placebo-treated patients. The median change from baseline in daily dosage of insulin was zero for both groups at the end of the trial. In combination with insulin (with or without metformin), sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 14). 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 sitagliptin. [See Warnings and Precautions (5.4); Adverse Reactions (6.1)].
Table 14: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin as Add-on Combination Therapy with Insulin in Adult Patients with Type 2 Diabetes Mellitus*
* Intent-to-treat population using last observation on trial prior to rescue therapy.
Maintenance of BRYNOVIN During Initiation and Titration of Insulin Glargine
A total of 746 patients with type 2 diabetes mellitus (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of continuing sitagliptin during the initiation and up- titration of insulin glargine. Patients who were on a stable dosage of metformin HCl (≥1,500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the trial. Those on metformin and sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4–8-week run-in period in which they were maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued. At randomization patients were randomized either to continue sitagliptin or to discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dosage of 10 units subcutaneously in the evening. Patients were instructed to uptitrate their insulin dosage in the evening based on fasting blood glucose measurements to achieve a target of 72-100 mg/dL.
At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 15). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dosage between arms.
A total of 746 patients with type 2 diabetes mellitus (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of continuing sitagliptin during the initiation and up- titration of insulin glargine. Patients who were on a stable dosage of metformin HCl (≥1,500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the trial. Those on metformin and sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4–8-week run-in period in which they were maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued. At randomization patients were randomized either to continue sitagliptin or to discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dosage of 10 units subcutaneously in the evening. Patients were instructed to uptitrate their insulin dosage in the evening based on fasting blood glucose measurements to achieve a target of 72-100 mg/dL.
At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 15). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dosage between arms.
Table 15: Change from Baseline in A1C and FPG at Week 30 in the Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine Trial
*Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing Week 30 data.
8HOW SUPPLIED/STORAGE AND HANDLING
BRYNOVIN (sitagliptin) oral solution 25 mg/mL is supplied as a clear colorless, to nearly colorless aqueous solution in an amber glass bottle with a child resistant closure.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Pancreatitis
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 BRYNOVIN and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (.
Heart Failure
Inform patients of the signs and symptoms of heart failure. Before initiating BRYNOVIN, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (.
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Inform patients that the incidence of hypoglycemia is increased when BRYNOVIN is added to insulin or a sulfonylurea. Explain to patients receiving BRYNOVIN in combination with these medications the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (.
Inform patients of the signs and symptoms of heart failure. Before initiating BRYNOVIN, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (.
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Inform patients that the incidence of hypoglycemia is increased when BRYNOVIN is added to insulin or a sulfonylurea. Explain to patients receiving BRYNOVIN in combination with these medications the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (.
Hypersensitivity Reactions
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, patients must stop taking BRYNOVIN and seek medical advice promptly [see Warnings and Precautions (.
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, patients must stop taking BRYNOVIN and seek medical advice promptly [see Warnings and Precautions (.
Severe and Disabling Arthralgia
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (.
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (.
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (.
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (.
Manufactured for: Azurity Pharmaceuticals, Inc.
Woburn, MA 01801
Woburn, MA 01801
BRYNOVIN is a registered trademark of Azurity Pharmaceuticals, Inc.
10SPL MEDGUIDE SECTION
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 01/2025
11PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
BRYNOVIN (Sitagliptin) Oral Solution 25 mg/mL - Carton Label
NDC 24338-017-01
120 mL
Rx only
BRYNOVIN (Sitagliptin) Oral Solution 25 mg/mL - Bottle Label
NDC 24338-017-01
120 mL
Rx only
