PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 2.5 mg

30 Tablets NDC 0310-6100-30
onglyza®
(saxagliptin) tablets
2.5 mg
DISPENSE WITH MEDICATION GUIDE
Rx only
AstraZeneca

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].

1.2 Limitations of Use

ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1.2)

4 CONTRAINDICATIONS

ONGLYZA is contraindicated in patients with a history of a serious hypersensitivity reaction to ONGLYZA, such as anaphylaxis, angioedema, or exfoliative skin conditions [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)].

History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to ONGLYZA. (4)

6 ADVERSE REACTIONS

The following serious adverse reactions are described below or elsewhere in the prescribing information:

•

Pancreatitis [see Warnings and Precautions (5.1)]

•

Heart Failure [see Warnings and Precautions (5.2)]

•

Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3)]

•

Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

•

Severe and disabling arthralgia [see Warnings and Precautions (5.5)]

•

Bullous pemphigoid [see Warnings and Precautions (5.6)]

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.

Adverse Reactions in Efficacy Trials

The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies (14)]. These data shown in the table reflect exposure of 882 patients to ONGLYZA and a mean duration of exposure to ONGLYZA of 21 weeks. The mean age of these patients was 55 years, 1.4 % were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR≥60mL/min/1.73 m2) in 91% of these patients.

Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of ONGLYZA. These adverse reactions occurred more commonly on ONGLYZA than on placebo and occurred in at least 5% of patients treated with ONGLYZA.

Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with ONGLYZA 5 mg and More Commonly than in Patients Treated with Placebo

	% of Patients
	ONGLYZA 5 mg N=882	Placebo N=799
The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.
Upper respiratory tract infection	7.7	7.6
Urinary tract infection	6.8	6.1
Headache	6.5	5.9

In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo.

In the add-on to TZD trial, the incidence of peripheral edema was higher for ONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add- on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide.

The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received ONGLYZA did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of ONGLYZA on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is not known.

Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of subjects receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 subjects treated with ONGLYZA 2.5 mg or at least 2 subjects treated with ONGLYZA 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%).

Adverse Reactions with Concomitant Use with Insulin

In the add-on to insulin trial [see Clinical Studies (14.1)], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1)].

Hypoglycemia

Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

In the add-on to glyburide study, the overall incidence of reported hypoglycemia was higher for ONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and 0.7% for placebo [see Warnings and Precautions (5.3)]. The incidence of reported hypoglycemia for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given ONGLYZA 5 mg plus metformin and 4% in patients given metformin alone.

In the active-controlled trial comparing add-on therapy with ONGLYZA 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with ONGLYZA 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was reported in none of the ONGLYZA-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).

In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for ONGLYZA 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was higher with ONGLYZA 5 mg (5.3%) versus placebo (3.3%).

In the add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for ONGLYZA 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the ONGLYZA-treated patients and in none of the placebo-treated patients [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. None of these events in patients who received ONGLYZA required hospitalization or were reported as life-threatening by the investigators. One ONGLYZA-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

Renal Impairment

In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8280) of ONGLYZA- treated subjects and 5.1% (422/8212) of placebo-treated subjects. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the ONGLYZA versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73 m2 for ONGLYZA-treated patients and a mean decrease of 2.4 mL/min/1.73 m2 for placebo-treated patients. More subjects randomized to ONGLYZA (421/5227, 8.1%) compared to subjects randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min/1.73 m2 (i.e., normal or mild renal impairment) to ≤50 mL/min/1.73 m2 (i.e., moderate or severe renal impairment). The proportions of subjects with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment.

Infections

In the unblinded, controlled, clinical trial database for ONGLYZA to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 ONGLYZA- treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with ONGLYZA until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of ONGLYZA that remained stable throughout ONGLYZA treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with ONGLYZA use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to ONGLYZA use.

There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in an ONGLYZA-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of ONGLYZA therapy. There have been no spontaneous reports of opportunistic infections associated with ONGLYZA use.

Vital Signs

No clinically meaningful changes in vital signs have been observed in patients treated with ONGLYZA.

Laboratory Tests

Absolute Lymphocyte Counts

There was a dose-related mean decrease in absolute lymphocyte count observed with ONGLYZA. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when ONGLYZA 5 mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for ONGLYZA 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the ONGLYZA 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to ONGLYZA although some patients had recurrent decreases upon rechallenge that led to discontinuation of ONGLYZA. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage.

In the SAVOR trial mean decreases of approximately 84 cells/microL with ONGLYZA relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on ONGLYZA and placebo, respectively.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of ONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of ONGLYZA. 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.

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Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

•

Pancreatitis

•

Severe and disabling arthralgia

•

Bullous pemphigoid

•

Rhabdomyolysis

Adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo are upper respiratory tract infection, urinary tract infection, and headache. (6.1)

Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. (6.1)

7 DRUG INTERACTIONS

7.1 Strong Inhibitors of CYP3A4/5 Enzymes

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of ONGLYZA should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

 Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with ONGLYZA significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dosage to 2.5 mg once daily. (2.3, 7.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited data with ONGLYZA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [see Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal Data

In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed

in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.

In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC.

8.2 Lactation

Risk Summary

There is no information regarding the presence of ONGLYZA in human milk, the effects on the breastfed infant, or the effects on milk production.

Saxagliptin is present in the milk of lactating rats [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ONGLYZA and any potential adverse effects on the breastfed infant from ONGLYZA or from the underlying maternal condition.

Data

Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations.

8.4 Pediatric Use

Safety and effectiveness of ONGLYZA in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of ONGLYZA in pediatric patients have not been performed.

8.5 Geriatric Use

In the seven, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, a total of 4751 (42.0%) of the 11301 patients randomized to ONGLYZA were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects ≥65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

In a 12-week randomized placebo-controlled trial, ONGLYZA 2.5 mg was administered to 85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage renal disease (ESRD) (n=19) [see Clinical Studies (14)]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with ONGLYZA 2.5 mg and 22% among subjects treated with placebo. Four ONGLYZA-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals. ONGLYZA tablets must not be split or cut.

2.2 Dosage in Patients with Renal Impairment

No dosage adjustment for ONGLYZA is recommended for patients with eGFR ≥45mL/min/1.73 m2.

The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with eGFR <45mL/min/1.73 m2 (which includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.

Because the dosage of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter.

2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors

The dosage of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or

with Insulin

When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia [see Warnings and Precautions (5.3)].

Recommended dosage is 2.5 mg or 5 mg once daily taken regardless of meals. (2.1)

Patients eGFR <45 mL/min/1.73 m2 (with moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals. (2.2)

Assess renal function before starting ONGLYZA and periodically thereafter. (2.2)

2.5 mg daily is recommended for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1)

3 DOSAGE FORMS AND STRENGTHS

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ONGLYZA (saxagliptin) 5 mg tablets are pink, biconvex, round, film-coated tablets with “5” printed on one side and “4215” printed on the reverse side, in blue ink.

•

ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets with “2.5” printed on one side and “4214” printed on the reverse side, in blue ink.

Tablets: 5 mg and 2.5 mg. (3)

10 OVERDOSAGE

In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy subjects at doses up to 400 mg daily for 2 weeks (80-times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours).

11 DESCRIPTION

Saxagliptin is an orally-active inhibitor of the DPP-4 enzyme.

Saxagliptin monohydrate is described chemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C18H25N3O2•H2O and the molecular weight is 333.43. The structural formula is:


Saxagliptin monohydrate is a white to light yellow or light brown, non- hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).

Each film-coated tablet of ONGLYZA for oral use contains either 2.79 mg saxagliptin hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and iron oxides.

12 CLINICAL PHARMACOLOGY

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, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive 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.

12.2 Pharmacodynamics

In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits 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 glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8-times the MRHD).

12.3 Pharmacokinetics

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.

No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time- dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Absorption

The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. ONGLYZA may be administered with or without food.

Distribution

The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Metabolism

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1)].

Excretion

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.

Specific Populations

Renal Impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage.

The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73 m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.

Hepatic Impairment

In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.

Body Mass Index

No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.

Gender

No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Geriatric

No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Race and Ethnicity

No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

The metabolism of saxagliptin is primarily mediated by CYP3A4/5.

In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp.

In Vivo Assessment of Drug Interactions

Table 2: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin

Coadministered Drug	Dosage of Coadministered Drug*	Dosage of Saxagliptin*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUC†	C****max
Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ‡ Results exclude one subject. § The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin.
No dosing adjustments required for the following:
Metformin	1000 mg	100 mg	saxagliptin 5-hydroxy saxagliptin	0.98 0.99	0.79 0.88
Glyburide	5 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	0.98 ND	1.08 ND
Dapagliflozin	10 mg single dose	5 mg single dose	saxagliptin 5-hydroxy saxagliptin	↓1% ↑9%	↓7% ↑6%
Pioglitazone‡	45 mg QD for 10 days	10 mg QD for 5 days	saxagliptin 5-hydroxy saxagliptin	1.11 ND	1.11 ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for 5 days	10 mg QD for 7 days	saxagliptin 5-hydroxy saxagliptin	1.05 1.06	0.99 1.02
Simvastatin	40 mg QD for 8 days	10 mg QD for 4 days	saxagliptin 5-hydroxy saxagliptin	1.12 1.02	1.21 1.08
Diltiazem	360 mg LA QD for 9 days	10 mg	saxagliptin 5-hydroxy saxagliptin	2.09 0.66	1.63 0.57
Rifampin§	600 mg QD for 6 days	5 mg	saxagliptin 5-hydroxy saxagliptin	0.24 1.03	0.47 1.39
Omeprazole	40 mg QD for 5 days	10 mg	saxagliptin 5-hydroxy saxagliptin	1.13 ND	0.98 ND
Aluminum hydroxide + magnesium hydroxide + simethicone	aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	0.97 ND	0.74 ND
Famotidine	40 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	1.03 ND	1.14 ND
Limit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors [seeDrug Interactions (7.1)** andDosage and Administration (2.3)]:**
Ketoconazole	200 mg BID for 9 days	100 mg	saxagliptin 5-hydroxy saxagliptin	2.45 0.12	1.62 0.05
Ketoconazole	200 mg BID for 7 days	20 mg	saxagliptin 5-hydroxy saxagliptin	3.67 ND	2.44 ND

ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting

Table 3: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs

				AUC*	C****max
AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. † Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. ‡ Results include all subjects.
Coadministered Drug	Dosage of Coadministered Drug†	Dosage of Saxagliptin†	Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00
No dosing adjustments required for the following:
Metformin	1000 mg	100 mg	metformin	1.20	1.09
Glyburide	5 mg	10 mg	glyburide	1.06	1.16
Pioglitazone‡	45 mg QD for 10 days	10 mg QD for 5 days	pioglitazone hydroxy-pioglitazone	1.08 ND	1.14 ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for 5 days	10 mg QD for 7 days	digoxin	1.06	1.09
Simvastatin	40 mg QD for 8 days	10 mg QD for 4 days	simvastatin simvastatin acid	1.04 1.16	0.88 1.00
Diltiazem	360 mg LA QD for 9 days	10 mg	diltiazem	1.10	1.16
Ketoconazole	200 mg BID for 9 days	100 mg	ketoconazole	0.87	0.84
Ethinyl estradiol and Norgestimate	ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days	5 mg QD for 21 days	ethinyl estradiol norelgestromin norgestrel	1.07 1.10 1.13	0.98 1.09 1.17

ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1165-times (females) the 5 mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females) the 5 mg/day clinical dose, based on AUC.

Mutagenesis

Saxagliptin was not mutagenic or clastogenic in a battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.

Impairment of Fertility

Saxagliptin administered to rats had no effect on fertility or the ability to maintain a litter at exposures up to 603-times and 776-times the 5 mg clinical dose in males and females, based on AUC.

13.2 Animal Toxicology and/or Pharmacology

Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the 5 mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the 5 mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

ONGLYZA (saxagliptin) tablets have markings on both sides and are available in the strengths and packages listed in Table 16.

Table 16: ONGLYZA Tablet Presentations

Tablet Strength	Film-Coated Tablet Color/Shape	Tablet Markings	Package Size	NDC Code
5 mg	pink biconvex, round	“5” on one side and “4215” on the reverse, in blue ink	Bottles of 30 Bottles of 90	0310-6105-30 0310-6105-90
2.5 mg	pale yellow to light yellow biconvex, round	“2.5” on one side and “4214” on the reverse, in blue ink	Bottles of 30 Bottles of 90	0310-6100-30 0310-6100-90

Storage and Handling

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read FDA-approved patient labeling (Medication Guide).

Medication Guide

Healthcare providers should instruct their patients to read the Medication Guide before starting ONGLYZA therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens.

Patients should be informed of the potential risks and benefits of ONGLYZA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

Pancreatitis

Patients should be informed that acute pancreatitis has been reported during postmarketing use of ONGLYZA. Before initiating ONGLYZA, patients should be questioned about other risk factors for pancreatitis, such as a history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed 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. Patients should be instructed to promptly discontinue ONGLYZA and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].

Heart Failure

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

Hypersensitivity Reactions

Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during postmarketing use of ONGLYZA. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking ONGLYZA and seek medical advice promptly.

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 (5.5)].

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 (5.6)].

Missed Dose

Patients should be informed that if they miss a dose of ONGLYZA they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day.

Administration Instructions

Patients should be informed that ONGLYZA tablets must not be split or cut.

Laboratory Tests

Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C, with a goal of decreasing these levels toward the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust their dose based on changes in renal function tests over time.

ONGLYZA is a registered trademark of the AstraZeneca group of companies.

Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850