`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`• When used with an insulin secretagogue (e.g., sulfonylurea), a lower
`
`
`dose of the insulin secretagogue may be required to reduce the risk of
`
`hypoglycemia. (5.2)
`
`There have been postmarketing reports of serious hypersensitivity
`
`
`reactions in patients treated with ONGLYZA such as anaphylaxis,
`
`angioedema, and exfoliative skin conditions. In such cases, promptly
`
`
`
`discontinue ONGLYZA, assess for other potential causes, institute
`
`appropriate monitoring and treatment, and initiate alternative treatment
`
`for diabetes. (5.3, 6.2)
`
`
`There have been no clinical studies establishing conclusive evidence of
`
`macrovascular risk reduction with ONGLYZA or any other antidiabetic
`
`
`
`drug. (5.4)
`
`-------------------------------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)
`
`
`Hypoglycemia was reported more commonly in patients treated with the
`
`
`combination of ONGLYZA and sulfonylurea than in patients treated
`
`
`with the combination of placebo and sulfonylurea. (6.1)
`Hypersensitivity-related events (e.g., urticaria, facial edema) were
`reported more commonly in patients treated with ONGLYZA than in
`
`patients treated with placebo. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`
`Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)
`
`
`•
`significantly increases saxagliptin concentrations. Recommend limiting
`
`ONGLYZA dose to 2.5 mg once daily. (2.3, 7.1)
`
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`There are no adequate and well-controlled studies in pregnant women.
`
`•
`(8.1)
`Safety and effectiveness of ONGLYZA in pediatric patients below the
`
`
`
`age of 18 have not been established. (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide
`
`
`•
`
`Revised: 11/2011
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`17
`
`
`
`Pediatric Use
`8.4
`
`
`Geriatric Use
`8.5
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2
`Animal Toxicology
`
`CLINICAL STUDIES
`
`
`14.1 Monotherapy
`
`
`14.2 Combination Therapy
`
`
`14.3 Renal Impairment
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1
`Instructions
`
`
`17.2
`Laboratory Tests
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed
`
`11/2011
`11/2011
`
`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
`Initial U.S. Approval: 2009
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage
`
`Important Limitations of Use (1.2)
`
`
`Contraindications (4)
`
`Warnings and Precautions
`
`
`11/2011
`
`Pancreatitis (5.1)
`
`
`11/2011
`Hypersensitivity Reactions (5.3)
`
`
`---------------------------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 in multiple clinical settings. (1.1, 14)
`
`
`
`Important limitations of use:
`
`
`Should not be used for the treatment of type 1 diabetes mellitus or
`
`•
`diabetic ketoacidosis. (1.2)
`
`
`Has not been studied in patients with a history of pancreatitis. (1.2, 5.1)
`
`
`
`
`•
`------------------------DOSAGE AND ADMINISTRATION----------------------
`
`The recommended dose is 2.5 mg or 5 mg once daily taken regardless of
`
`
`
`•
`meals. (2.1)
`2.5 mg daily is recommended for patients with moderate or severe renal
`
`impairment, or end-stage renal disease (CrCl ≤50 mL/min). Assess renal
`
`
`function prior to initiation of 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-----------------------
`
`There have been postmarketing reports of acute pancreatitis. If
`
`•
`pancreatitis is suspected, promptly discontinue ONGLYZA. (5.1)
`
`
`
`
`•
`
`
`•
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1
`Monotherapy and Combination Therapy
`
`
`1.2
`Important Limitations of Use
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Recommended Dosing
`
`
`2.2
`Patients with Renal Impairment
`
`
`2.3
`Strong CYP3A4/5 Inhibitors
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Pancreatitis
`
`
`5.2
`Use with Medications Known to Cause Hypoglycemia
`
`
`5.3
`Hypersensitivity Reactions
`
`
`5.4
`Macrovascular Outcomes
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`7.1
`Strong Inhibitors of CYP3A4/5 Enzymes
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`6
`
`
`7
`
`8
`
`Reference ID: 3044277
`
`1
`
`2.0
`
`Approved
`
`v
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`1
`
`1.1
`
`
`INDICATIONS AND USAGE
`
`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 in multiple clinical settings. [See Clinical Studies (14).]
`
`
`
`
`1.2
`
`Important Limitations of Use
`
`ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic
`
`
`ketoacidosis, as it would not be effective in these settings.
`
`
`ONGLYZA has not been studied in patients with a history of pancreatitis. It is unknown whether
`patients with a history of pancreatitis are at an increased risk for the development of pancreatitis
`while using ONGLYZA. [See Warnings and Precautions (5.1).]
`
`
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`
`
`
`The recommended dose of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals.
`
`2.2
`
`
`
`Patients with Renal Impairment
`
`
`
`No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment
`
`
`
`(creatinine clearance [CrCl] >50 mL/min).
`
`
`The dose of ONGLYZA is 2.5 mg once daily 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 (14.3)]. ONGLYZA
`
`
`should be administered following hemodialysis. ONGLYZA has not been studied in patients
`undergoing peritoneal dialysis.
`
`Because the dose 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
`
`2
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
`

`

`
`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
`
`Strong CYP3A4/5 Inhibitors
`
`
`The dose 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).]
`
`
`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
`
`
`History of a serious hypersensitivity reaction to ONGLYZA, such as anaphylaxis, angioedema,
`
`or exfoliative skin conditions. [See Warnings and Precautions (5.3) and Adverse Reactions
`
`(6.2).]
`
`
`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`Pancreatitis
`
`There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After
`
`initiation of ONGLYZA, patients should be observed carefully for signs and symptoms of
`pancreatitis. If pancreatitis is suspected, ONGLYZA should promptly be discontinued and
`
`appropriate management should be initiated. It is unknown whether patients with a history of
`
`
`pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA.
`
`3
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
`

`

`
`
`
`5.2
`
`
`
`Use with Medications Known to Cause Hypoglycemia
`
`
`Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the
`
`insulin secretagogue may be required to reduce the risk of hypoglycemia when used in
`
`combination with ONGLYZA. [See Adverse Reactions (6.1).]
`
`
`5.3
`
`
`
`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.
`
`
`5.4
`
`Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`
`reduction with ONGLYZA or any other antidiabetic drug.
`
`6
`
`6.1
`
`
`ADVERSE REACTIONS
`
`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.
`
`
`
`Monotherapy and Add-On Combination Therapy
`
`
`In two placebo-controlled monotherapy trials of 24-weeks duration, patients were treated with
`
`ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo. Three 24-week, placebo-
`
`
`controlled, add-on combination therapy trials were also conducted: one with metformin, one with
`
`4
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
`

`

`
`
`a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials,
`
`patients were randomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg
`
`daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy
`trials and in the add-on combination trial with metformin.
`
`In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the
`
`
`two monotherapy trials, the add-on to metformin trial, the add-on to thiazolidinedione (TZD)
`
`trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated
`
`
`with ONGLYZA 2.5 mg and ONGLYZA 5 mg was similar to placebo (72.0% and 72.2% versus
`
`70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%,
`
`
`and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively.
`
`The most common adverse events (reported in at least 2 patients treated with ONGLYZA 2.5 mg
`
`or at least 2 patients 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%). The adverse reactions in this pooled
`
`analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated
`
`
`with ONGLYZA 5 mg, and more commonly than in patients treated with placebo are shown in
`Table 1.
`
`Table 1:
`
`
`
`Adverse Reactions (Regardless of Investigator Assessment of
`
`Causality) in Placebo-Controlled Trials* Reported in ≥5% of
`
`Patients Treated with ONGLYZA 5 mg and More Commonly than
`
`
`in Patients Treated with Placebo
`
`
`Placebo
`ONGLYZA 5 mg
`N=799
`N=882
`61 (7.6)
`68 (7.7)
`Upper respiratory tract infection
`
`
`49 (6.1)
`60 (6.8)
`Urinary tract infection
`47 (5.9)
`57 (6.5)
`Headache
`* 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.
`
`Number (%) of Patients
`
`
`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.
`
`
`5
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
`

`

`
`In this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with
`ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequently compared to placebo
`
`
`
`
`included: sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7%
`
`versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus
`1.3%).
`
`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 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 saxagliptin
`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.
`
`Use in Renal Impairment
`
`
`ONGLYZA 2.5 mg was compared to placebo in a 12-week trial in 170 patients with type 2
`
`diabetes and moderate or severe renal impairment or end-stage renal disease (ESRD). The
`
`incidence of adverse events, including serious adverse events and discontinuations due to
`
`adverse events, was similar between ONGLYZA and placebo.
`
`Adverse Reactions Associated with ONGLYZA Coadministered with Metformin in
`
`Treatment-Naive Patients with Type 2 Diabetes
`
`
`Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality)
`
`in ≥5% of patients participating in an additional 24-week, active-controlled trial of
`
`
`coadministered ONGLYZA and metformin in treatment-naive patients.
`
`6
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
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`

`
`
`
`
`Table 2:
`
`Initial Therapy with Combination of ONGLYZA and Metformin in
`Treatment-Naive Patients: Adverse Reactions Reported (Regardless
`of Investigator Assessment of Causality) in ≥5% of Patients Treated
`
`with Combination Therapy of ONGLYZA 5 mg Plus Metformin
`(and More Commonly than in Patients Treated with Metformin
`
`Alone)
`
`
`
`Number (%) of Patients
`
`
`Metformin*
`ONGLYZA 5 mg + Metformin*
`
`
`N=328
`N=320
`17 (5.2)
`24 (7.5)
`Headache
`
`
`13 (4.0)
`22 (6.9)
`Nasopharyngitis
`* Metformin was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.
`
`
`
`
`
`Hypoglycemia
`
`
`Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent
`
`glucose measurement was not required. 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. The
`
`incidence of reported hypoglycemia for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus
`
`placebo given as monotherapy was 4.0% 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 4.0% 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).
`
`During 12 weeks of treatment in patients with moderate or severe renal impairment or ESRD, the
`
`
`overall incidence of reported hypoglycemia was 20% among patients treated with ONGLYZA
`
`
`
`2.5 mg and 22% among patients treated with placebo. Four ONGLYZA-treated patients (4.7%)
`
`7
`
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`
`Approved
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`v
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`

`
`
`and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic
`hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL).
`
`
`
`
`
`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 saxagliptin-treated patient in this pooled analysis discontinued due to
`generalized urticaria and facial edema.
`
`Infections
`
`In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6
`(0.12%) reports of tuberculosis among the 4959 saxagliptin-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 saxagliptin
`
`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 saxagliptin that remained stable throughout saxagliptin 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 saxagliptin
`
`use. Causality has not been estimated and there are too few cases to date to determine whether
`
`
`tuberculosis is related to saxagliptin use.
`
`
`There has been one case of a potential opportunistic infection in the unblinded, controlled
`
`clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne
`
`fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no
`
`spontaneous reports of opportunistic infections associated with saxagliptin use.
`
`8
`
`Reference ID: 3044277
`
`2.0
`
`Approved
`
`v
`
`

`

`
`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 saxagliptin 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 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.
`
`Platelets
`
`ONGLYZA did not demonstrate a clinically meaningful or consistent effect on platelet count in
`
`the six, double-blind, controlled clinical safety and efficacy trials.
`
`
`6.2
`
`Postmarketing Experience
`
`Additional adverse reactions have been identified during postapproval use of ONGLYZA.
`
`Because these reactions are reported voluntarily from a population of uncertain size, it is
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`generally not possible to reliably estimate their frequency or establish a causal relationship to
`
`
`
`drug exposure.
`
`
`
`
`
`
`
`
`• Hypersensitivity reactions
`
`conditions. [See Contraindications (4) and Warnings and Precautions (5.3).]
`
`• Acute pancreatitis. [See Indications and Usage (1.2) and Warnings and Precautions (5.1).]
`
`
`
`
`
`including anaphylaxis, angioedema, and exfoliative skin
`
`7
`
`7.1
`
`
`DRUG INTERACTIONS
`
`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
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`
`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.
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`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.
`
`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 have not been established.
`
`8.5
`
`
`
`Geriatric Use
`
`
`In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, 634 (15.3%)
`
`of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years
`
`and over. No overall differences in safety or effectiveness were observed between patients ≥65
`
`
`years old and the younger patients. While this clinical experience has not identified differences
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`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).]
`
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`
`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.
`
`(1S,3S,5S)-2-[(2S)-2-Amino-2-(3-
`
`is described chemically as
`Saxagliptin monohydrate
`hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
`(1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-
`monohydrate
`or
`
`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:
`
`
`
`
`
`
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`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 DPP4 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 DPP4 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 DPP4 enzyme
`
`
`activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 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.
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`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