Limitations of Use

NESINA is not recommended for use in patients with type 1 diabetes mellitus.

2.1 Recommended Dosage

• The recommended dosage of NESINA is 25 mg taken orally once daily. Do not split tablets.
• NESINA may be taken with or without food [see Clinical Pharmacology (12.3)].
• Instruct patients if a dose is missed, not to double their next dose.

2.2 Patients with Renal Impairment

• Assess renal function prior to initiation of NESINA and periodically thereafter [see Use in Specific Populations (8.6)].
• No dose adjustment of NESINA is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min).
• The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).
• The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). NESINA may be administered without regard to the timing of dialysis. NESINA has not been studied in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.1 Pancreatitis

Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 6 (0.2%) patients treated with NESINA 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with NESINA and in 7 (0.3%) of patients treated with placebo.

It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using NESINA.

After initiation of NESINA, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated.

5.2 Heart Failure

In the EXAMINE trial which enrolled patients with type 2 diabetes mellitus and recent acute coronary syndrome, 106 (3.9%) of patients treated with NESINA and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure.

Consider the risks and benefits of NESINA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of NESINA.

5.3 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA [see Adverse Reactions (6.2)]. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes mellitus. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.

5.4 Hepatic Effects

There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)].

In glycemic control trials in patients with type 2 diabetes mellitus, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with NESINA 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with NESINA and in 1.8% of patients treated with placebo.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.

5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.

5.6 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.7 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving NESINA. If bullous pemphigoid is suspected, NESINA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

6.1 Clinical 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.

A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with NESINA, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator. The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes mellitus was seven years, the mean body mass index (BMI) was 31 kg/m2 (49% of patients had a BMI ≥30 kg/m2), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to NESINA was 49 weeks with 3,348 subjects treated for more than one year.

In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with NESINA 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with NESINA 25 mg compared to 8.4% with placebo or 6.2% with active comparator.

Adverse reactions reported in ≥4% of adult patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during the postmarketing use of NESINA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus

Hepatobiliary Disorders: fulminant hepatic failure

Immune System Disorders: hypersensitivity reactions including anaphylaxis

Investigations: hepatic enzyme elevations

Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis

Renal and Urinary Disorders: tubulointerstitial nephritis

Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid

7.1 Insulin Secretagogues and Insulin

Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of NESINA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of NESINA have not been established in pediatric patients.

Effectiveness of NESINA was not demonstrated in a 52 week, randomized, double-blind, placebo-controlled trial (NCT02856113) in 151 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.

8.5 Geriatric Use

Of the total number of patients (N=9052) in clinical safety and efficacy trials treated with NESINA, 2,257 (24.9%) patients were 65 years and older and 386 (4.3%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients.

8.6 Renal Impairment

A total of 602 adult patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m2) and 4 patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m2 or <15 mL/min/1.73 m2, respectively) at baseline were treated with NESINA in clinical trials in patients with type 2 diabetes mellitus.

In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline.

The recommended dose is 12.5 mg once daily in patients with moderate renal impairment and 6.25 mg once daily in patients with severe renal impairment, as well as in patients with ESRD requiring dialysis. NESINA may be administered without regard to the timing of the dialysis.

8.7 Hepatic Impairment

No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) [see Clinical Pharmacology (12.3)]. NESINA has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering NESINA to patients with liver disease [see Warnings and Precautions (5.4)].

12.1 Mechanism of Action

Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of NESINA has been studied in healthy subjects and in patients with type 2 diabetes mellitus. The pharmacokinetics of NESINA was similar in healthy subjects and in patients with type 2 diabetes mellitus. After multiple-dose administration up to 400 mg for 14 days in patients with type 2 diabetes mellitus, accumulation of alogliptin was minimal with an increase in total [e.g., area under the plasma concentration curve (AUC)] and peak (i.e., Cmax) alogliptin exposures of 34% and 9%, respectively. Total and peak exposure to alogliptin increased proportionally across single doses and multiple doses of alogliptin ranging from 25 mg to 400 mg. The intersubject coefficient of variation for alogliptin AUC was 17%.

Drug Interaction Studies

Clinical Studies

Effects of Alogliptin on the Pharmacokinetics of Other Drugs

In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of NESINA is recommended based on results of the described pharmacokinetic studies.

Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs

* Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR).

** Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail.

Effects of Other Drugs on the Pharmacokinetics of Alogliptin

There are no clinically meaningful changes in the pharmacokinetics of alogliptin when NESINA is administered concomitantly with the drugs described below (Figure 2).

Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin

In Vitro Studies

Effect of Alogliptin on CYP Enzymes

Alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Overview of Clinical Trials in Adults with Type 2 Diabetes Mellitus

NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin).

A total of 14,053 patients with type 2 diabetes mellitus were randomized in 11 double-blind, placebo- or active-controlled clinical safety and efficacy trials conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to trial medication was 70% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino. Patients had an overall mean age of 57 years (range 21 to 91 years).

In patients with type 2 diabetes mellitus, treatment with NESINA produced clinically meaningful and statistically significant improvements in hemoglobin A1c (A1C) compared to placebo. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with NESINA appears to be related to the degree of A1C elevation at baseline.

NESINA had similar changes from baseline in serum lipids compared to placebo.

14.2 Patients with Inadequate Glycemic Control on Diet and Exercise

A total of 1,768 patients with type 2 diabetes mellitus participated in three double-blind trials to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three trials had a four week, single-blind, placebo run-in period followed by a 26 week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy.

In a 26 week, double-blind, placebo-controlled trial, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy.

Improvements in A1C were not affected by gender, age or baseline body mass index (BMI).

The mean change in body weight with NESINA was similar to placebo.

In a 26 week, double-blind, active-controlled trial, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.

In a 26 week, double-blind, placebo-controlled trial, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; NESINA 12.5 mg twice daily; NESINA 25 mg daily; or NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin.

14.3 Combination Therapy

Add-On Therapy to Metformin

A total of 2081 patients with type 2 diabetes mellitus participated in two 26 week, double-blind, placebo-controlled trials to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both trials, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy.

In the first 26 week, placebo-controlled trial, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose.

The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin.

Table 6. Glycemic Parameters at Week 26 in a Placebo-Controlled Trial of NESINA as Add-On Therapy to Metformin in Adults with Type 2 Diabetes Mellitus*

	NESINA 25 mg + Metformin	Placebo + Metformin
* Intent-to-treat population using last observation on trial † Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose ‡ p<0.001 compared to placebo
A1C (%)	N=203	N=103
Baseline (mean)	7.9	8.0
Change from baseline (adjusted mean†)	-0.6	-0.1
Difference from placebo (adjusted mean† with 95% confidence interval)	-0.5‡ (-0.7, -0.3)	˗
% of patients (n/N) achieving A1C ≤7%	44% (92/207)‡	18% (19/104)
FPG (mg/dL)	N=204	N=104
Baseline (mean)	172	180
Change from baseline (adjusted mean†)	-17	0
Difference from placebo (adjusted mean† with 95% confidence interval)	-17‡ (-26, -9)	˗

In the second 26 week, double-blind, placebo-controlled trial, a total of 1,554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of NESINA alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.

Table 7. Glycemic Parameters in a 26 Week Trial of NESINA, Pioglitazone and NESINA in Combination with Pioglitazone when Added to Metformin in Adults with Type 2 Diabetes Mellitus*

	Placebo	NESINA 25 mg	Pioglitazone 15 mg	Pioglitazone 30 mg	Pioglitazone 45 mg	NESINA 25 mg + Pioglitazone 15 mg	NESINA 25 mg + Pioglitazone 30 mg	NESINA 25 mg + Pioglitazone 45 mg
* Intent-to-treat population using last observation in the trial † Least squares means adjusted for treatment, geographic region, metformin dose and baseline value ‡ p≤0.01 when compared to corresponding doses of pioglitazone and NESINA alone
A1C (%)	N=126	N=123	N=127	N=123	N=126	N=127	N=124	N=126
Baseline (mean)	8.5	8.6	8.5	8.5	8.5	8.5	8.5	8.6
Change from baseline (adjusted mean†)	-0.1	-0.9	-0.8	-0.9	-1.0	-1.3‡	-1.4‡	-1.6‡
Difference from pioglitazone (adjusted mean† with 95% confidence interval)	-	-	-	-		-0.5‡ (-0.7, -0.3)	-0.5‡ (-0.7, -0.3)	-0.6‡ (-0.8, -0.4)
Difference from NESINA (adjusted mean† with 95% confidence interval)	-	-	-	-	-	-0.4‡ (-0.6, -0.1)	-0.5‡ (-0.7, -0.3)	-0.7‡ (-0.9, -0.5)
Patients (%) achieving A1C ≤7%	6% (8/129)	27% (35/129)	26% (33/129)	30% (38/129)	36% (47/129)	55% (71/130)‡	53% (69/130)‡	60% (78/130)‡
FPG (mg/dL)	N=129	N=126	N=127	N=125	N=129	N=130	N=126	N=127
Baseline (mean)	177	184	177	175	181	179	179	178
Change from baseline (adjusted mean†)	7	-19	-24	-29	-32	-38‡	-42‡	-53‡
Difference from pioglitazone (adjusted mean† with 95% confidence interval)	-	-	-	-	-	-14‡ (-24, -5)	-13‡ (-23, -3)	-20‡ (-30, -11)
Difference from NESINA (adjusted mean† with 95% confidence interval)	-	-	-	-	-	-19‡ (-29, -10)	-23‡ (-33, -13)	-34‡ (-44, -24)

Figure 3. Change from Baseline in A1C at Week 26 with NESINA and Pioglitazone Alone and NESINA in Combination with Pioglitazone When Added to Metformin in Adults with Type 2 Diabetes Mellitus

14.4 Cardiovascular Safety Trial

A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of NESINA. The trial compared the risk of major adverse cardiovascular events (MACE) between NESINA (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes mellitus and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued.

Eligible patients were adults with type 2 diabetes mellitus who had inadequate glycemic control at baseline (e.g., HbA1c >6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of NESINA was based on estimated renal function at baseline per dosage and administration recommendations [see Dosage and Administration (2.2)]. The average time between an acute coronary syndrome event and randomization was approximately 48 days.

The mean age of the population was 61 years. Most patients were male (68%), White (73%), and were recruited from outside of the United States (86%). Asian and Black or African American patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers. Hypertension (83%) and renal impairment (27% with an eGFR ≤60 mL/min/1.73 m2) were prevalent co-morbid conditions. Use of medications to treat diabetes mellitus (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, renin-angiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to NESINA and placebo at baseline. During the trial, medications to treat diabetes mellitus and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines.

The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The trial was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to trial drug was 526 days and 95% of the patients were followed to trial completion or death.

Table 12 shows the trial results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint. The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3.

The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and NESINA overlap throughout the duration of the trial. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 MACE per 100 PY), decreased from day 60 to the end of the first year (8.4 per 100 PY) and was lowest after one year of follow-up (5.2 per 100 PY).

Figure 4. Observed Cumulative Rate of MACE in EXAMINE

The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to NESINA and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on NESINA and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Pancreatitis

Inform patients that acute pancreatitis has been reported during use of NESINA. Educate 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 NESINA and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating NESINA, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare providers 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 (5.2)].

Hypersensitivity Reactions

Inform patients that allergic reactions have been reported during use of NESINA. Instruct patients if symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should discontinue NESINA and seek medical advice promptly [see Warnings and Precautions (5.3)].

Hepatic Effects

Inform patients that postmarketing reports of liver injury, sometimes fatal, have been reported during use of NESINA. Instruct patients if signs or symptoms of liver injury occur, patients should discontinue NESINA and seek medical advice promptly [see Warnings and Precautions (5.4)].

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with NESINA. Educate patients about the risks, symptoms and appropriate management of hypoglycemia [see Warnings and Precautions (5.5)].

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 (5.6)].

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 (5.7)].

Dosage

Instruct patients to take NESINA only as prescribed. Instruct patients if a dose is missed, not to double their next dose.