`
`
`
`
`
`
`
`
`
`
`
`
`
`
`--------------------------- 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)
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`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)
`
`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)
`
`
`Bullous Pemphigoid: There have been postmarketing reports of bullous
`
`
`pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors.
`
`
`
`
`Tell patients to report development of blisters or erosions. If bullous
`
`pemphigoid is suspected, discontinue ONGLYZA. (5.6)
`
`
`
`• Macrovascular Outcomes: There have been no clinical studies
`
`
`
`establishing conclusive evidence of macrovascular risk reduction with
`
`
`ONGLYZA. (5.7)
`
`
`
`------------------------------ 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)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide
`
`
`Revised: 2/2017
`
` 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 -------------------------
`
`
`
`
`
`Dosage and Administration (2.2)
`2/2017
`
`
`Warnings and Precautions
`
`
`Pancreatitis (5.1)
`
`
`Heart Failure (5.2)
`
`
`Bullous Pemphigoid (5.6)
`
`
`Macrovascular Outcomes (5.7)
`
`
`
`
`
`
`
`
`
`4/2016
`
`4/2016
`
`1/2017
`
`2/2017
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------
`
`
`
`
`Recommended dosage is 2.5 mg or 5 mg once daily taken regardless of
`
`
`
`
`
`•
`
`meals. (2.1)
`
`Patients eGFR <45 mL/min/1.73 m2 (with moderate or severe renal
`
`
`
`
`
`impairment, or end-stage renal disease): Recommended dosage is 2.5 mg
`
`once daily regardless of meals. (2.2)
`
`
`
`
`Assess renal function before starting ONGLYZA and periodically
`
`thereafter. (2.2)
`
`
`
`2.5 mg daily is recommended for patients also taking strong cytochrome
`
`
`
`
`P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1)
`
`•
`
`
`
`•
`
`
`•
`
`
`--------------------- 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)
`
`
`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 Bullous Pemphigoid
`
`
`
`5.7 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`Reference ID: 4062021
`
`
`7.1 Strong Inhibitors of CYP3A4/5 Enzymes
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`
`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.
`
`
`
`
`
`
` 1
`
`Novo Nordisk Exhibit 2403
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`
`
`
`
`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 eGFR ≥45mL/min/1.73 m2 .
`
`
`
`
`
`
`
` The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with eGFR <45mL/min/1.73 m2 (which
`
`
`
`
`
`
`includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis)
`
`
`
`[see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. ONGLYZA should be administered following
`
`
`
`
`hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.
`
`
`
`
`
`Because the dosage of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is
`
`
`recommended prior to initiation of ONGLYZA and periodically thereafter.
`
`
`
`
`
` 2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors
`
` The dosage of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5)
`inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
`
`
` saquinavir, and telithromycin) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
` 2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`
`
` When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of
`
`
`
` the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia [see Warnings and Precautions
`
`
` (5.3)].
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 4062021
`
`
`2
`
`
`Novo Nordisk Exhibit 2403
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`• 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)].
`
` 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.
`
`
`
`
`
`Reference ID: 4062021
`
`
`3
`
`Novo Nordisk Exhibit 2403
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`
`
`
`
`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 Bullous Pemphigoid
`
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In
`reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of
`
`
`
`the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving ONGLYZA. If bullous
`
`
`
`
`
`
`pemphigoid is suspected, ONGLYZA should be discontinued and referral to a dermatologist should be considered for
`
`
`
`
`diagnosis and appropriate treatment.
`
`
`
` 5.7 Macrovascular Outcomes
`
`
` There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA.
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
` The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`
`
`
`
`
`
` • Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`
` • Heart Failure [see Warnings and Precautions (5.2)]
`
`
`
` • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3)]
`
`
`
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`
`
`
`
`
` • Severe and disabling arthralgia [see Warnings and Precautions (5.5)]
`
`
`
`
`
` • Bullous pemphigoid [see Warnings and Precautions (5.6)]
`
`
`
` 6.1 Clinical Trials Experience
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
`
`
`
`
`
`
`
`
` of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
`
` in practice.
`
`
`
`Adverse Reactions in Efficacy Trials
`
`
`The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies (14)]. These data
`
`shown in the table reflect exposure of 882 patients to ONGLYZA and a mean duration of exposure to ONGLYZA of 21
`
`
`
`
`weeks. The mean age of these patients was 55 years, 1.4 % were 75 years or older and 48.4% were male. The population
`
`
`4
`
`
`
`
`
`Reference ID: 4062021
`
`Novo Nordisk Exhibit 2403
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`IPR2023-00724
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`
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`
`
`
`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.
`
`
`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%).
`
`
`
`
`Reference ID: 4062021
`
`
`5
`
`
`Novo Nordisk Exhibit 2403
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`
`
`
`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
`
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`reflect true hypoglycemia.
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`
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`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,
`
`
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`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
`
`
`
`
`
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`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%
`
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`versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive
`
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`patients given ONGLYZA 5 mg plus metformin and 4% in patients given metformin alone.
`
`
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`In the active-controlled trial comparing add-on therapy with ONGLYZA 5 mg to glipizide in patients inadequately
`
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`controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with
`
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`ONGLYZA 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia
`
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`
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`(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).
`
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`
`
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`In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for ONGLYZA 5 mg and 19.9%
`
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`for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose
`
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`≤50 mg/dL) was higher with ONGLYZA 5 mg (5.3%) versus placebo (3.3%).
`
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`
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`
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`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)].
`
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`Hypersensitivity Reactions
`
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`Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were
`
`
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`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
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`urticaria and facial edema.
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`Renal Impairment
`
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`In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum
`
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`creatinine compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8280) of ONGLYZA-
`
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`
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`treated subjects and 5.1% (422/8212) of placebo-treated subjects. The most frequently reported adverse reactions included
`
`
`
`
`
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`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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`Reference ID: 4062021
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`(344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min/1.73 m2 (i.e., normal or mild renal impairment) to ≤50
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`mL/min/1.73 m2 (i.e., moderate or severe renal impairment). The proportions of subjects with renal adverse reactions
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`increased with worsening baseline renal function and increased age, regardless of treatment assignment.
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`Infections
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`In the unblinded, controlled, clinical trial database for ONGLYZA to date, there have been 6 (0.12%) reports of
`
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`tuberculosis among the 4959 ONGLYZA-treated patients (1.1 per 1000 patient-years) compared to no reports of
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`tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing.
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`The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred
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`in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had
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`recently visited Indonesia. The duration of treatment with ONGLYZA until report of tuberculosis ranged from 144 to 929
`
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`days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had
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`lymphopenia prior to initiation of ONGLYZA that remained stable throughout ONGLYZA treatment. The final patient
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`had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have
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`been no spontaneous reports of tuberculosis associated with ONGLYZA use. Causality has not been estimated and there
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`are too few cases to date to determine whether tuberculosis is related to ONGLYZA use.
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`There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in
`
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`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.
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`Vital Signs
` No clinically meaningful changes in vital signs have been observed in patients treated with ONGLYZA.
`
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`
` 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
`
`
`
`
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`
`
` 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
`
`
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`
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`rechallenge that led to discontinuation of ONGLYZA. The decreases in lymphocyte count were not associated with
`
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`
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`clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage.
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`In the SAVOR trial mean decreases of approximately 84 cells/microL with ONGLYZA relative to placebo was observed.
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`The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤750 cells/microL was 1.6%
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`(136/8280) and 1.0% (78/8212) on ONGLYZA and placebo respectively.
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`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
`
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`lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
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`Reference ID: 4062021
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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` 6.2 Postmarketing Experience
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` 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
`
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`
` establish a causal relationship to drug exposure.
`
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` • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
`
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` Contraindications (4) and Warnings and Precautions (5.4)].
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` • Pancreatitis [see Warnings and Precautions (5.1)].
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` • Severe and disabling arthralgia [see Warnings and Precautions (5.5)].
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` • Bullous pemphigoid [see Warnings and Precautions (5.6)]
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` 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
`
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`
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` Pharmacology (12.3)].
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` 8 USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
`
` Risk Summary
` Limited data with ONGLYZA in pregnant women are not sufficient to determine a drug-associated risk for major birth
`
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`
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` defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
` [see Clinical Considerations].
`
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` No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to
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` pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and
` postnatal period. [see Data].
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` The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c
`
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`
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` greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated
` background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated
`
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`
`
` background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
`
` respectively.
`
`
`Clinical Considerations
` Disease-associated maternal and/or embryo/fetal risk
`
`
`
` Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous
`
`
`
` abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for
`
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` major birth defects, stillbirth, and macrosomia related morbidity.
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`Reference ID: 4062021
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`8
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
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`Data
`
`
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`Animal Data
`
`
`In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of
`
`
`organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed
`
`
`
`
`
`
`in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC.
`
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`Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
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`In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats
`
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`administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical
`
`dose, based on AUC.
`
`
` 8.2 Lactation
`
` Risk Summary
` There is no information regarding the presence of ONGLYZA in human milk, the effects on the breastfed infant, or the
`
` effects on milk production.
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`
`
` Saxagliptin is present in the milk of lactating rats [see Data]. The developmental and health benefits of breastfeeding
`
`
`
`
`
`
`
`
` should be considered along with the mother’s clinical need for ONGLYZA and any potential adverse effects on the
` breastfed infant from ONGLYZA or from the underlying maternal condition.
`
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`
`
` Data
`
` Saxagliptin is secreted in the milk of lactating rats at approximately a