`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` insulin and use in congestive heart failure NYHA Class I and II
`
`
`
`
`
`
` may increase risk. Consider the risks and benefits of OSENI prior
` to initiating treatment in patients at risk for heart failure. Monitor
`
`
`
`
`
`
` patients at risk for heart failure for signs and symptoms. If heart
`
`
`
`
` failure develops, evaluate and manage according to current
`
`
` standards of care and consider discontinuation of OSENI. (5.1)
`
` • Acute pancreatitis: There have been postmarketing reports of
`
`
`
` acute pancreatitis. If pancreatitis is suspected, promptly
`
`
` discontinue OSENI. (5.2)
`
`
`
` • Hypersensitivity: There have been postmarketing reports of
`
` serious hypersensitivity reactions in patients treated with alogliptin
`
` such as anaphylaxis, angioedema and severe cutaneous adverse
`
`
`
` reactions, including Stevens-Johnson syndrome. In such cases,
`
`
`
`
` promptly discontinue OSENI, assess for other potential causes,
`
`
`
`
`institute appropriate monitoring and treatment and initiate
` alternative treatment for diabetes. (5.3)
`
`
`
` • Hepatic effects: Postmarketing reports of hepatic failure,
` sometimes fatal. Causality cannot be excluded. If liver injury is
`
`
` detected, promptly interrupt OSENI and assess patient for
`
`
`
`
`
` probable cause, then treat cause if possible, to resolution or
`
` stabilization. Do not restart OSENI if liver injury is confirmed and
`
`
`
` no alternative etiology can be found. Use with caution in patients
`
`
` with liver disease. (5.4)
`
`
`
`
`
` • Edema: Dose-related edema may occur. (5.5)
`
`
`
` • Fractures: Increased incidence in female patients. Apply current
`
` standards of care for assessing and maintaining bone health. (5.6)
`
` • Bladder cancer: May increase the risk of bladder cancer. Do not
`
`
`
`
` use in patients with active bladder cancer. Use caution when
`
`
` using in patients with a prior history of bladder cancer. (5.7)
`
`
`
`
`
` • Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea)
`
`
`
` or insulin is used in combination with OSENI, a lower dose of
`
`
` insulin secretagogue or insulin may be required to minimize the
`
` risk of hypoglycemia. (5.8)
`
`
`
`
`
` • Macular edema: Postmarketing reports. Recommend regular eye
` exams in all patients with diabetes according to current standards
`
`
`
`
`
`
` of care with prompt evaluation for acute visual changes. (5.9)
` • Arthralgia: Severe and disabling arthralgia has been reported in
`
`
` patients taking DPP-4 inhibitors. Consider as a possible cause for
`
`
` severe joint pain and discontinue if appropriate. (5.10)
`
`
` • 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 OSENI.
`
`
`
` (5.11)
` • Macrovascular outcomes: There have been no clinical studies
`
`
`
` establishing conclusive evidence of macrovascular risk reduction
`
`
` with OSENI. (5.12)
` -----------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`
`
` The most common adverse reactions (4% or greater incidence) are
` nasopharyngitis, back pain and upper respiratory tract infection. (6.1)
`
`
`
`
`
`
`
`
` To report SUSPECTED ADVERSE REACTIONS, contact Takeda
` Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at
`
`
`
` 1-800-FDA-1088 or www.fda.gov/medwatch.
` ------------------------------DRUG INTERACTIONS-----------------------------­
`
`
`
` • Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone
` concentrations. Limit the pioglitazone dose to 15 mg daily. (2.3, 7.1)
`
`
`
`
` • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone
`
` concentrations. (7.2)
` • Topiramate may decrease pioglitazone concentrations. (7.3)
`
`
`
`
` -----------------------USE IN SPECIFIC POPULATIONS---------------------­
` • Females and Males of Reproductive Potential: Advise premenopausal
`
`
`
` females of the potential for an unintended pregnancy. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and
`
` Medication Guide
`
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 12/2017
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`
`
`OSENI safely and effectively. See full prescribing information for
`
`
`
`OSENI.
`
`OSENI (alogliptin and pioglitazone) tablets, for oral use
`
`
`
`
`Initial U.S. Approval: 2013
`
`
`WARNING: CONGESTIVE HEART FAILURE
`
`
`
`See full prescribing information for complete boxed warning
`
`
`
`• Thiazolidinediones, including pioglitazone, cause or
`
`
`
`exacerbate congestive heart failure in some patients. (5.1)
`
`• After initiation of OSENI and after dose increases, monitor
`
`
`
`
`
`patients carefully for signs and symptoms of heart failure
`
`
`(e.g., excessive, rapid weight gain, dyspnea and/or
`
`
`
`
`
`edema). If heart failure develops, it should be managed
`
`
`
`
`
`
`according to current standards of care and
`
`
`discontinuation or dose reduction of pioglitazone in OSENI
`
`
`must be considered. (5.1)
`
`
`
`• OSENI is not recommended in patients with symptomatic
`
`
`
`
`
`
`heart failure. (5.1)
`
`
`
`
`
`• Initiation of OSENI in patients with established New York
`
`
`
`
`
`
`Heart Association (NYHA) Class III or IV heart failure is
`contraindicated. (4, 5.1)
`
`
`---------------------------RECENT MAJOR CHANGES-----------------------------­
`
`
` Warnings and Precautions
`
` 12/2016
` Urinary Bladder Tumors (5.7)
`
`
` 12/2016
`
`
` Bullous Pemphigoid (5.11)
` -----------------------------INDICATIONS AND USAGE----------------------------­
`
`
` OSENI is a dipeptidyl peptidase-4 inhibitor and thiazolidinedione
`
`
` combination product indicated as an adjunct to diet and exercise to
`
`
` improve glycemic control in adults with type 2 diabetes mellitus. (1.1)
`
`
`
` Important Limitations of Use: Not for treatment of type 1 diabetes or
`
`
`
`
` diabetic ketoacidosis. (1.1)
`
`
` ---------------------------DOSAGE AND ADMINISTRATION---------------------­
`
`
`
`
`
`
` • Individualize the starting dose of OSENI based on the patient’s current
` regimen and concurrent medical condition but do not exceed a daily
`
`
`
`
` dose of alogliptin 25 mg and pioglitazone 45 mg. (2.1)
`
`
`
`
` • Can be taken with or without food. (2.1)
`
` • Limit initial dose of pioglitazone to 15 mg once daily in patients with
`
`
` NYHA Class I or II heart failure. (2.1)
`
`
`
` • Adjust dose if moderate renal impairment. (2.2)
`
`
`Creatinine
`Clearance
`(mL/min)
`
`
`
`Degree of Renal
`Impairment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Moderate
`
`
`
` ≥30 to <60
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Recommended Dosing
`
`12.5 mg/15 mg,
`
`
` 12.5 mg/30 mg or
`
`12.5 mg/45 mg once daily
`
`
`
`
` • OSENI is not recommended for patients with severe renal impairment
`
`
`
`
` or end-stage renal disease (ESRD) requiring dialysis. (2.2)
` • The maximum recommended dose of pioglitazone is 15 mg once daily
`
`
`
`in patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil). (2.3,
`
` 7.1)
` ----------------------DOSAGE FORMS AND STRENGTHS----------------------­
`
` Tablets:
`
`
`
`
` 25 mg alogliptin and 15 mg pioglitazone, 25 mg alogliptin and 30 mg
`
`
` pioglitazone, 25 mg alogliptin and 45 mg pioglitazone. (3)
`
`
`
` 12.5 mg alogliptin and 15 mg pioglitazone, 12.5 mg alogliptin and 30 mg
`
`
`
` pioglitazone, 12.5 mg alogliptin and 45 mg pioglitazone. (3)
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS--------------------------------­
`
`
`
`
` • History of a serious hypersensitivity reaction to alogliptin or
` pioglitazone, components of OSENI, such as anaphylaxis, angioedema
`
`
`
`
` or severe cutaneous adverse reactions. (4)
` • Do not initiate OSENI in patients with established NYHA Class III or IV
`
`
`
` heart failure. (4)
` -----------------------WARNINGS AND PRECAUTIONS---------------------­
`
`
`
`
` • Congestive heart failure: Fluid retention may occur and can
` exacerbate or lead to congestive heart failure. Combination use with
`
`
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
` Page 2 of 45
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Strong CYP2C8 Inhibitors
`
`
`
`
`7.2 CYP2C8 Inducers
`
`
`
`
`7.3 Topiramate
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic 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
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: CONGESTIVE HEART FAILURE
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`1.1 Monotherapy and Combination Therapy
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommendations for All Patients
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`2.3 Coadministration with Strong CYP2C8 Inhibitors
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Congestive Heart Failure
`
`
`
`5.2 Pancreatitis
`
`
`
`5.3 Hypersensitivity Reactions
`
`
`
`5.4 Hepatic Effects
`
`
`
`5.5 Edema
`
`
`
`5.6 Fractures
`
`
`
`5.7 Urinary Bladder Tumors
`
`
`
`5.8 Use with Medications Known to Cause Hypoglycemia
`
`
`
`5.9 Macular Edema
`
`
`
`5.10 Severe and Disabling Arthralgia
`
`
`
`
`5.11 Bullous Pemphigoid
`
`
`
`5.12 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`6.2 Laboratory Abnormalities
`
`
`
`
`6.3 Postmarketing Experience
`
`
`
`
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` Page 3 of 45
`
`
`
` WARNING: CONGESTIVE HEART FAILURE
`
`
`
`
`
`
` • Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or
`
` exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
`
`
`
`
` • After initiation of OSENI and after dose increases, monitor patients carefully for signs and
`
` symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If
`
`
` heart failure develops, it should be managed according to current standards of care and
`
` discontinuation or dose reduction of pioglitazone in OSENI must be considered [see
`
`
`
` Warnings and Precautions (5.1)].
` • OSENI is not recommended in patients with symptomatic heart failure [see Warnings and
`
`
`Precautions (5.1)].
`
`
`
`
` Initiation of OSENI in patients with established New York Heart Association (NYHA) Class
`
` III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and
`
`
`
`Precautions (5.1)].
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1 Monotherapy and Combination Therapy
`
`
`
`
`OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type
`
`
`
`
`2 diabetes mellitus when treatment with both alogliptin and pioglitazone is appropriate [see Clinical
`
`
`Studies (14)].
`
`Important Limitations of Use
`
`
`
`
`
`
`OSENI is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it
`
`would not be effective in these settings.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`2.1 Recommendations for All Patients
`
`
`
`OSENI should be taken once daily and can be taken with or without food. The tablets must not be
`
`split before swallowing.
`
`
`
`
`The recommended starting dose for OSENI (alogliptin and pioglitazone):
`
`
`
`
`for patients inadequately controlled on diet and exercise is 25 mg/15 mg or 25 mg/30 mg,
`•
`
`
`for patients inadequately controlled on metformin monotherapy is 25 mg/15 mg or 25 mg/30 mg,
`•
`
`
`
`
`
`for patients on alogliptin who require additional glycemic control is 25 mg/15 mg or 25 mg/30 mg,
`•
`
`
`
`
`for patients on pioglitazone who require additional glycemic control is 25 mg/15 mg, 25 mg/30
`•
`
`mg or 25 mg/45 mg as appropriate based upon current therapy,
`
`
`
`
`
`for patients switching from alogliptin coadministered with pioglitazone, OSENI may be initiated at
`
`
`the dose of alogliptin and pioglitazone based upon current therapy,
`
`
`
`for patients with congestive heart failure (NYHA Class I or II) is 25 mg/15 mg.
`•
`
`
`
`The OSENI dose can be titrated up to a maximum of 25 mg/45 mg once daily based on glycemic
`
`
`response as determined by hemoglobin A1c (A1C).
`
`
`
`
`
`After initiation of OSENI or with dose increase, monitor patients carefully for adverse reactions related
`
`
`to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and
`
`
`
`symptoms of congestive heart failure) [see Boxed Warning and Warnings and Precautions (5.1)].
`
`
`•
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

` 2.2 Patients with Renal Impairment
`
`
`
`
`
`
` No dose adjustment of OSENI is necessary for patients with mild renal impairment (creatinine
` clearance [CrCl] ≥60 mL/min).
`
`
` The dose of OSENI is 12.5 mg/15 mg, 12.5 mg/30 mg or 12.5 mg/45 mg once daily for patients with
`
`
`
`
` moderate renal impairment (CrCl ≥30 to <60 mL/min).
`
`
`
`
`
`
` OSENI is not recommended for patients with severe renal impairment or ESRD [see Use in Specific
`
`
`
` Populations (8.6) and Clinical Pharmacology (12.3)]. Coadministration of pioglitazone and alogliptin
`
`
`
`
` 6.25 mg once daily based on individual requirements may be considered in these patients.
`
`
`
` Because there is a need for dose adjustment based upon renal function, assessment of renal function
`
`
`
` is recommended prior to initiation of OSENI therapy and periodically thereafter.
`
`
`
`
`
` 2.3 Coadministration with Strong CYP2C8 Inhibitors
`
`
` Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone
`
`
`
` exposure approximately three-fold. Therefore, the maximum recommended dose of OSENI is
` 25 mg/15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see
`
`
`
`
` Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
` Page 4 of 45
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
` 25 mg/15 mg tablets are yellow, round, biconvex, and film-coated, with both “A/P” and “25/15”
`•
`
` printed on one side.
` 25 mg/30 mg tablets are peach, round, biconvex, and film-coated, with both “A/P” and “25/30”
`
` printed on one side.
` 25 mg/45 mg tablets are red, round, biconvex, and film-coated, with both “A/P” and “25/45”
`
`
` printed on one side.
` 12.5 mg/15 mg tablets are pale yellow, round, biconvex, and film-coated, with both “A/P” and
`
`
`
` “12.5/15” printed on one side.
` 12.5 mg/30 mg tablets are pale peach, round, biconvex, and film-coated, with both “A/P” and
`
`
`
` “12.5/30” printed on one side.
` 12.5 mg/45 mg tablets are pale red, round, biconvex, and film-coated, with both “A/P” and
`
`
`
` “12.5/45” printed on one side.
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
` History of a serious hypersensitivity reaction to alogliptin or pioglitazone, components of OSENI, such
` as anaphylaxis, angioedema or severe cutaneous adverse reactions.
`
`
` Do not initiate in patients with NYHA Class III or IV heart failure [see Boxed Warning].
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Congestive Heart Failure
`
`
`
`
`
` Consider the risks and benefits of OSENI prior to initiating treatment in patients at risk for heart
` failure, such as those with a prior history of heart failure and a history of renal impairment, and
`
`
`
`
`
`
` observe these patients for signs and symptoms of congestive heart failure. Patients should be
` advised of the characteristic symptoms of congestive heart failure and should be instructed to
`
`
`
`immediately report such symptoms. If congestive heart failure develops, it should be managed
`
`
` according to current standards of care and consider discontinuation of OSENI.
`
`
`
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
`
` Page 5 of 45
`
`
`
`
`
`
`
` Alogliptin
`
`
`
` In the EXAMINE trial which enrolled patients with type 2 diabetes and recent acute coronary
`
`
`
`
` syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with
`
`
`
`
` placebo were hospitalized for congestive heart failure.
`
`
`
` Pioglitazone
` Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or
`
`
`
` in combination with other antidiabetic medications and is most common when pioglitazone is used in
` combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure [see
`
`
`
`
` Boxed Warning, Contraindications (4) and Adverse Reactions (6.1)].
`
`
` 5.2 Pancreatitis
` Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In
`
`
` glycemic control trials in patients with type 2 diabetes, acute pancreatitis was reported in six (0.2%)
` patients treated with alogliptin 25 mg and two (<0.1%) patients treated with active comparators or
`
`
`
`
`
`placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and
`high cardiovascular (CV) risk), acute pancreatitis was reported in ten (0.4%) patients treated with
`
`
`
`alogliptin and in seven (0.3%) patients treated with placebo.
`
`
`
`It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while
`
`
`
`using OSENI.
`
`After initiation of OSENI, patients should be observed for signs and symptoms of pancreatitis. If
`
`
`pancreatitis is suspected, OSENI should promptly be discontinued and appropriate management
`
`
`
`
`
`
`
`should be initiated.
`
`5.3 Hypersensitivity Reactions
`
`
`
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse
`
`
`
`reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected,
`
`
`
`
`
`discontinue OSENI, assess for other potential causes for the event and institute alternative treatment
`
`
`
`
`
`for diabetes [see Adverse Reactions (6.3)]. Use caution in patients with a history of angioedema with
`
`
`
`
`
`another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be
`
`
`predisposed to angioedema with OSENI.
`
`5.4 Hepatic Effects
`
`
`
`There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking
`
`
`
`
`
`pioglitazone or alogliptin, although some of the reports contain insufficient information necessary to
`
`establish the probable cause [see Adverse Reactions (6.3)].
`
`
`
`In glycemic control trials of alogliptin in patients with type 2 diabetes, serum alanine aminotransferase
`
`
`(ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of
`
`
`
`patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or
`
`
`placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and
`high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper
`
`
`limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients
`
`
`
`
`
`treated with placebo.
`
`Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive
`
`
`heart failure, both of which may cause liver test abnormalities, and they may also have other forms of
`
`
`
`
`
`liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (ALT,
`
`
`
`
`aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin) and assessing the patient
`
`
`
`
`is recommended before initiating OSENI therapy. In patients with abnormal liver tests, OSENI should
`
`
`
`be initiated with caution.
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

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` Page 6 of 45
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` Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including
` fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if
`
`
`
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`
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`
`
` the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the
` reference range), OSENI treatment should be interrupted and an investigation done to establish the
`
`
`
`
`
`
` probable cause. OSENI should not be restarted in these patients without another explanation for the
` liver test abnormalities.
`
` 5.5 Edema
`
`
`
` Pioglitazone
`
`
` In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone
`
`
` than in placebo-treated patients and is dose-related [see Adverse Reactions (6.1)]. In postmarketing
`
`
`
`
`
` experience, reports of new onset or worsening of edema have been received.
`
`
`
`
`
` OSENI should be used with caution in patients with edema. Because thiazolidinediones, including
`
`
` pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure,
`
`
` OSENI should be used with caution in patients at risk for congestive heart failure. Patients treated
`
`
`
`
`
`
` with OSENI should be monitored for signs and symptoms of congestive heart failure [see Boxed
`
`
`
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`
`
`
`
` Warning, Warnings and Precautions (5.1) and Patient Counseling Information (17)].
`
`
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`
`
` 5.6
` Fractures
` Pioglitazone
`
`In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with
` type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605),
`
`
`
`
`
`
`force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean
`
`
`
`
`
`
`follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for
`
` pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of
`
`
`
`
`
`
`
`treatment and persisted during the course of the study. The majority of fractures observed in female
` patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the
`
`
`
` incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%).
`
`
`
`
`The risk of fracture should be considered in the care of patients, especially female patients, treated
` with pioglitazone and attention should be given to assessing and maintaining bone health according
`
`
`to current standards of care.
` 5.7 Urinary Bladder Tumors
`
`
`Pioglitazone
` Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see
`
`
`
`
`
`Nonclinical Toxicology (13.1)]. In addition, during the three year PROactive clinical trial, 14 patients
`
`
`
`out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo
`
`
`were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was
`
`
`less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on
`
`
`
`pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of
`
`
`patients was observed for up to 10 additional years, with little additional exposure to pioglitazone.
`
`
`
`
`During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer
`
`
`
`did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–
`
`1.72]).
`
`
`Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among
`
`
`
`
`
`
`observational studies; some did not find an increased risk of bladder cancer associated with
`
`pioglitazone, while others did.
`
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

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` Page 7 of 45
` A large prospective10 year observational cohort study conducted in the United States found no
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`statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to
`
`
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`pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89–1.26]).
`
`
`
`
`A retrospective cohort study conducted with data from the United Kingdom found a statistically
`significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI:
`
`1.22–2.19]).
`
`
`Associations between cumulative dose or cumulative duration of exposure to pioglitazone and
`
`
`bladder cancer were not detected in some studies including the 10 year observational study in the
`
`
`
`
`
`U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies
`
`preclude conclusive interpretations of the observational data.
`
`Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are
`
`
`
`insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.
`
`
`
`Consequently, OSENI should not be used in patients with active bladder cancer and the benefits of
`
`glycemic control versus unknown risks for cancer recurrence with OSENI should be considered in
`
`
`patients with a prior history of bladder cancer.
`
`
`
`5.8 Use with Medications Known to Cause Hypoglycemia
`
`
`Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia.
`
`
`Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of
`
`hypoglycemia when used in combination with OSENI.
`
`
`5.9 Macular Edema
`
`Pioglitazone
`
`
`Macular edema has been reported in postmarketing experience in diabetic patients who were taking
`
`
`
`
`pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased
`
`
`visual acuity, but others were diagnosed on routine ophthalmologic examination.
`
`
`
`
`Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had
`
`
`
`
`improvement in their macular edema after discontinuation of their thiazolidinedione.
`
`
`
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`Patients with diabetes should have regular eye exams by an ophthalmologist according to current
`
`
`
`
`
`
`
`standards of care. Patients with diabetes who report any visual symptoms should be promptly
`
`
`
`
`
`referred to an ophthalmologist, regardless of the patient's underlying medications or other physical
`findings [see Adverse Reactions (6.1)].
`
`
`
`
`
`
`
`5.10 Severe and Disabling Arthralgia
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
`
`
`
`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 DPP-4
`
`
`
`
`inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`
`appropriate.
`
`
`5.11 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 OSENI. If bullous pemphigoid is suspected,
`OSENI should be discontinued and referral to a dermatologist should be considered for diagnosis and
`
`appropriate treatment.
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

` 5.12 Macrovascular Outcomes
`
`
` There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`
`
` with OSENI.
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` Page 8 of 45
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` 6 ADVERSE REACTIONS
`
`
` The following serious adverse reactions are described below or elsewhere in the prescribing
` information:
`
`
` • Congestive Heart Failure [see Warnings and Precautions (5.1)]
`
`
` • Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`
` • Hepatic Effects [see Warnings and Precautions (5.4)]
`
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.10)]
`
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.11)]
`
`
`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.
`
`
`Alogliptin and Pioglitazone
`
`
`Over 1500 patients with type 2 diabetes have received alogliptin coadministered with pioglitazone in
`
`
`
`
`
`four large, randomized, double-blind, controlled clinical trials. The mean exposure to OSENI was
`
`
`
`
`
`
`29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two
`
`
`
`
`placebo-controlled studies of 16 to 26 weeks in duration and two active-controlled studies of
`
`
`
`
`26 weeks and 52 weeks in duration. In the OSENI arm, the mean duration of diabetes was
`
`
`
`
`
`
`
`
`approximately six years, the mean body mass index (BMI) was 31 kg/m2 (54% of patients had a BMI
`
`
`
`
`
`≥30 kg/m2), and the mean age was 54 years (16% of patients ≥65 years of age).
`
`
`
`
`
`
`
`
`
`In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions
`
`
`
`
`
`
`was 65% in patients treated with OSENI compared to 57% treated with placebo. Overall
`
`
`
`
`discontinuation of therapy due to adverse reactions was 2.5% with OSENI compared to 2.0% with
`
`
`
`
`
`
`placebo, 3.7% with pioglitazone or 1.3% with alogliptin.
`
`
`
`
`
`
`
`Adverse reactions reported in ≥4% of patients treated with OSENI and more frequently than in
`
`
`
`
`
`
`
`patients who received alogliptin, pioglitazone or placebo are summarized in Table 1.
`
`
`
`
`
`
`Reference ID: 4198901
`
`Novo Nordisk Exhibit 2430
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
`
` Page 9 of 45
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` Placebo
`N=153
`
`
`6 (3.9)
`
`5 (3.3)
`
`
`
` Pioglitazone‡
`N=949
`
`
`37 (3.9)
`
`32 (3.4)
`
` Table 1. Adverse Reactions Reported in ≥4% of Patients Treated with OSENI and More
`
`
`
`
`
` Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Placebo
`
`
`
`
`Number of Patients (%)
`
`
` Alogliptin†
`
` OSENI*
`N=1533
`N=446
`
`
`
`
`75 (4.9)
`21 (4.7)
`
`
`64 (4.2)
`9 (2.0)
`
`
`
`
`Nasopharyngitis
`
`Back Pain
`
`Upper Respiratory Tract
`
`Infection
`
`
`
`*OSENI – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg
`
`
`
`
`combined with pioglitazone 15 mg, 30 mg and 45 mg
`†Alogliptin – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg
`
`
`
`
`
`
`
`
`‡Pioglitazone – includes data pooled for patients receiving pioglitazone 15 mg, 30 mg and
`
`
`
`
`
`
`
`
`
`45 mg
`
`
`63 (4.1)
`
`
`19 (4.3)
`
`
`26 (2.7)
`
`
`5 (3.3)
`
`
`
` Alogliptin Add-On Therapy to a Thiazolidinedione
`
`
`
`
`
` In addition, in a 26 week, placebo-controlled, double-blind study, patients inadequately controlled on
`a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on
` alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently
`
`
`
`
`
`
`
`
`than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%).
` Hypoglycemia
`
`
`
` In a 26 week, placebo-controlled factorial study with alogliptin in combination with pioglitazone on
`
` background therapy with metformin, the incidence of subjects reporting hypoglycemia was