`•
`
`
`•
`
`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. (5.2, 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. (5.3, 6.1, 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)
`
`
`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-----------------------------
`
`
`
`
`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 PATI ENT C O UNSELING I NF O R M AT I O N a nd Med ica tion
`
`
`
`
`Guide.
`
`
`•
`
`
`Revised: 05/2013
`
`
`
`
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`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 and/or Pharmacology
`
`CLINICAL STUDIES
`
`
`
`14.1 Monotherapy
`
`
`14.2 Combination Therapy
`
`
`14.3 Renal Impairment
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`16
`
`17
`
`*Sections or subsections omitted from the full prescribing information
`
`
`
`are not listed
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
` 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
`
`
` ---------------------------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)
`
`
`
`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----------------------
`
`
`
`
`
`
`
`
`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-----------------------
`
`Acute Pancreatits (postmarketing reports): If pancreatitis is suspected,
`
`
`•
`
`
`promptly discontinue ONGLYZA. (5.1)
`
`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.
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`Monotherapy and Combination Therapy
`1.1
`
`
`1.2
`Important Limitations of Use
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Recommended Dosage
`2.1
`
`
`2.2
`Dosage in Patients with Renal Impairment
`
`
`2.3
`Dosage Adjustment with Concomitant Use of Strong
`
`
`CYP3A4/5 Inhibitors
`
`Concomitant Use with an Insulin Secretagogue (e.g.,
`2.4
`
`
`Sulfonylurea) or with Insulin
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`
`Pancreatitis
`5.1
`
`5.2
`Hypoglycemia with Concomitant Use of Sulfonylurea or
`
`
`
`Insulin
`
`
`Hypersensitivity Reactions
`5.3
`
`
`5.4
`Macrovascular Outcomes
`
`ADVERSE REACTIONS
`
`
`
`Clinical Trials Experience
`6.1
`
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`
`Strong Inhibitors of CYP3A4/5 Enzymes
`7.1
`
`
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`Reference ID: 3314070
`
`
`
` 1
`
`
`
`
` 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 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 (14.3)]. ONGLYZA should be administered following hemodialysis. ONGLYZA has not
`
`
` been studied in patients undergoing peritoneal dialysis.
`
`
`2
`
`
`Reference ID: 3314070
`
`
`
`
`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 (5.2).]
`
`
`
` 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 (5.3) and Adverse Reactions (6.2).]
`
`
`
`3
`
`
`Reference ID: 3314070
`
`
`
`
` 5
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 5.1
`
`
`
` 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.
`
`
`
` 5.2
`
`
`
` 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).]
`
`
`
`
` 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.
`
`
`
`4
`
`
`Reference ID: 3314070
`
`
`
`
` 6
`
`
`
`
`
` ADVERSE REACTIONS
`
`
`
` 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 with Monotherapy and with 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
`
` 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. The 10 mg dosage is not an approved
`
`
`
` dosage.
`
`
`
`
` 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% 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.
`
`5
`
`
`Reference ID: 3314070
`
`
`
`
`
`
`
` 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
`
` Nu mber (% ) of P a t ient s
`P la cebo
`O NGL YZA 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.
`
`
`
`
`
`
` 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 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 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.
`
`
`
`
`6
`
`
`Reference ID: 3314070
`
`
`
`
`
`
` 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.
`
`
`
` Adverse Reactions in Patients with 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 with Concomitant Use with Insulin
`
`In the add-on to insulin trial [see Clinical Studies (14.2)], 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)].
`
`
`
`
`
`Adverse Reactions with Concomitant Use 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.
`
`
`
`Table 2:
`
`
`Initial Therapy with Combination of ONGLYZA and Metformin in
`
`
`
`
`Treatment-Naive Patients: Adverse Reactions Reported in ≥5% of
`
`
`
`
`Patients Treated with Combination Therapy of ONGLYZA 5 mg
`
`
`Plus Metformin (and More Commonly than in Patients Treated
`
`
`
`
`
`with Metformin Alone)
`
`
`
`
`
`
`Nu mber (% ) of P a t ien t s
`
`M et for min *
`O NGL YZA 5 mg + M etfor min*
`
`
`
` 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.
`
`
`
`
`
`
`7
`
`Reference ID: 3314070
`
`
`
`
`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 (5.2)]. 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).
`
`
`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%)
`
`
`
`
`and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic
`
`
`
`hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL).
`
`
`
`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
`
`
`
`
`8
`
`
`Reference ID: 3314070
`
`
`
`
`was reported in 1.6% of the ONGLYZA-treated patients and in none of the placebo-treated
`
`
`
`
`
`
`patients [see Warnings and Precautions (5.2)].
`
`
`
`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.
`
`
`
`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.
`
`
`
`9
`
`
`Reference ID: 3314070
`
`
`
`
` 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.
`
`
`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 postapproval 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.
`
` including anaphylaxis, angioedema, and exfoliative skin
`• Hypersensitivity reactions
`
`
`
` conditions. [See Contraindications (4) and Warnings and Precautions (5.3).]
`
`
`
`
`
`10
`
`
`Reference ID: 3314070
`
`
`
`
` • Acute pancreatitis. [See Indications and Usage (1.2) and Warnings and Precautions (5.1).]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` 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
`
`
`11
`
`
`Reference ID: 3314070
`
`
`
`
` 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 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 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
`
`
` in responses between the elderly and younger patients, greater sensitivity of some older
`
`
`
` individuals cannot be ruled out.
`
`12
`
`
`Reference ID: 3314070
`
`
`
`
` 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).]
`
`
`
` 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.
`
`
`
`(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:
`
`
`
`
`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
`
`
`
`
`
`13
`
`
`Reference ID: 3314070
`
`
`
`
`soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol
`
`
`
`400 (PEG 400).
`
`
`Each film-coated tablet of ON