HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ONGLYZA safely and effectively. See full prescribing information for
`ONGLYZA.
`
`ONGLYZA (saxagliptin) tablets, for oral use
`Initial U.S. Approval: 2009
`
`-------------------------- RECENT MAJOR CHANGES --------------------------
`Warnings and Precautions
`Pancreatitis (5.1)
`Heart Failure (5.2)
`
`4/2016
`4/2016
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`ONGLYZA is a dipeptidyl peptidase-4 (DPP4) inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus. (1.1, 14)
`Limitation of use:
`Not used for the treatment of type 1 diabetes mellitus or diabetic
`
`ketoacidosis. (1.2)
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`Recommended dosage is 2.5 mg or 5 mg once daily taken regardless of
`
`meals. (2.1)
`Patients with moderate or severe renal impairment, or end-stage renal
`disease (CrCl ≤50 mL/min): 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)
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Tablets: 5 mg and 2.5 mg. (3)
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`History of a serious hypersensitivity reaction (e.g., anaphylaxis,
`
`angioedema, exfoliative skin conditions) to ONGLYZA. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Pancreatitis: If pancreatitis is suspected, promptly discontinue
`
`ONGLYZA. (5.1)
`Heart Failure: Consider the risks and benefits of ONGLYZA in patients
`who have known risk factors for heart failure. Monitor patients for signs
`and symptoms. (5.2)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Monotherapy and Combination Therapy
`1.2 Limitation of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Dosage in Patients with Renal Impairment
`2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5
`Inhibitors
`2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or
`with Insulin
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Heart Failure
`5.3 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`5.4 Hypersensitivity Reactions
`5.5 Severe and Disabling Arthralgia
`5.6 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`Hypoglycemia: In add-on to sulfonylurea, add-on to insulin, and add-on
`to metformin plus sulfonylurea trials, confirmed hypoglycemia was
`more common in patients treated with ONGLYZA compared to placebo.
`When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a
`lower dose of insulin secretagogue or insulin may be required to
`minimize the risk of hypoglycemia. (5.3, 6.1)
`Hypersensitivity-Related Events (e.g., urticaria, facial edema): More
`common in patients treated with ONGLYZA than in patients treated
`with placebo; and postmarketing reports of serious hypersensitivity
`reactions such as anaphylaxis, angioedema, and exfoliative skin
`conditions. Promptly discontinue ONGLYZA, assess for other potential
`causes, institute appropriate monitoring and treatment, and initiate
`alternative treatment for diabetes. (5.4, 6.1, 6.2)
`Arthralgia: Severe and disabling arthralgia has been reported in patients
`taking DPP4 inhibitors. Consider as a possible cause for severe joint
`pain and discontinue drug if appropriate. (5.5)
`Macrovascular Outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`ONGLYZA or any other antidiabetic drug. (5.6)
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`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)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------ DRUG INTERACTIONS ------------------------------
`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)
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`No adequate and well-controlled studies in pregnant women. (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 4/2016
`
`7.1 Strong Inhibitors of CYP3A4/5 Enzymes
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Glycemic Efficacy Trials
`14.2 Renal Impairment
`14.3 Cardiovascular Safety Trial
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
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`

`
`FULL PRESCRIBING INFORMATION
`
`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 Limitation 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.
`
`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 mild renal impairment (creatinine clearance
`[CrCl] >50 mL/min).
`
`The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with moderate or severe renal
`impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] 50 mL/min)
`[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. Renal function can be estimated from serum
`creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula [see Clinical
`Pharmacology (12.3)].
`
`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)].
`
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`3 DOSAGE FORMS AND STRENGTHS
`
` 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.
`
`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)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pancreatitis
`There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. In a cardiovascular outcomes
`trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for
`ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving
`ONGLYZA compared to 9 of 8173 (0.1%) receiving placebo. Preexisting risk factors for pancreatitis were identified in
`88% (15/17) of those patients receiving ONGLYZA and in 100% (9/9) of those patients receiving placebo.
`
`After initiation of ONGLYZA, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected,
`promptly discontinue ONGLYZA and initiate appropriate management. It is unknown whether patients with a history of
`pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA.
`
`5.2 Heart Failure
`In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD
`(SAVOR trial), more patients randomized to ONGLYZA (289/8280, 3.5%) were hospitalized for heart failure compared
`to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart
`failure was higher in the ONGLYZA group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior
`history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure,
`irrespective of treatment assignment.
`
`Consider the risks and benefits of ONGLYZA prior to initiating treatment in patients at a higher risk for heart failure.
`Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of
`heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to
`current standards of care and consider discontinuation of ONGLYZA.
`
`5.3 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause
`hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a
`sulfonylurea or with insulin [see Adverse Reactions (6.1)]. Therefore, a lower dose of the insulin secretagogue or insulin
`may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA [see Dosage and
`Administration (2.4)].
`
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`5.4 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA. These
`reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the
`first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose.
`
`If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event,
`and institute alternative treatment for diabetes [see Adverse Reactions (6.2)].
`
`Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is
`unknown whether such patients will be predisposed to angioedema with ONGLYZA.
`
`5.5 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP4 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 DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain
`and discontinue drug if appropriate.
`
`5.6 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or
`any other antidiabetic drug.
`
`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)]
`
`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/1.73m2) in 91% of these patients.
`
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`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
`
`Upper respiratory tract infection
`
`Urinary tract infection
`
`Headache
`
`% of Patients
`
`ONGLYZA 5 mg
`N=882
`
`Placebo
`N=799
`
`7.7
`
`6.8
`
`6.5
`
`7.6
`
`6.1
`
`5.9
`
`* 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.
`
`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%).
`
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`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/1.73m2 for ONGLYZA-treated patients and a mean decrease of 2.4 mL/min/1.73m2 for placebo-
`treated patients. More subjects randomized to ONGLYZA (421/5227, 8.1%) compared to subjects randomized to placebo
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`
`(344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min (i.e., normal or mild renal impairment) to ≤50 mL/min
`(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.
`
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`
`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.
`
` Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
`Contraindications (4) and Warnings and Precautions (5.4)].
` Acute pancreatitis [see Warnings and Precautions (5.1)].
`Severe and disabling arthralgia [see Warnings and Precautions (5.5)].
`
`
`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)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category B
`There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not
`always predictive of human response, ONGLYZA, like other antidiabetic medications, should be used during pregnancy
`only if clearly needed.
`
`Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of
`organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240
`mg/kg, or approximately 1503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the
`maximum recommended human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed
`at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor
`skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the
`MRHD.
`
`Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was
`neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100
`and 10 times the MRHD (saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the
`MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated
`maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in
`maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting
`in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was
`limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental
`toxicity in these litters was limited to fetal body weight decrements of 7%, and a low incidence of delayed ossification of
`the fetal hyoid.
`
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`Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in
`male and female offspring only at maternally toxic doses (exposures 1629 and 53 times saxagliptin and its active
`metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin
`at any dose.
`
`Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
`
`8.3 Nursing Mothers
`Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. It is not
`known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be
`exercised when ONGLYZA is administered to a nursing woman.
`
`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).
`
`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 DPP4 enzyme.
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`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