`
`
`
`
`
`
`
`
`
` 4/2016
`
`
`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
` NESINA safely and effectively. See full prescribing information for
`
`
`
` NESINA.
`
` NESINA (alogliptin) tablets, for oral use
`
` Initial U.S. Approval: 2013
`
`
`
`---------------------------RECENT MAJOR CHANGES--------------------------­
`
`
` Indications and Usage (1.1)
` 4/2016
`
` Dosage and Administration
` Patients with Renal Impairment (2.2)
`
` Warnings and Precautions
`
`
` Pancreatitis (5.1)
`
`
` 4/2016
` Heart Failure (5.2)
`
` 4/2016
`
`
`
`
` 4/2016
` Hepatic Effects (5.4)
` Bullous Pemphigoid (5.7)
`
` 12/2016
`
`
` ----------------------------INDICATIONS AND USAGE---------------------------­
`
`
`
`
` NESINA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an
` adjunct to diet and exercise to improve glycemic control in adults with
`
`
`
`
` type 2 diabetes mellitus. (1.1, 14)
` Important Limitations of Use: Not for treatment of type 1 diabetes or
`
`
`
` diabetic ketoacidosis. (1.1)
`
` ------------------------DOSAGE AND ADMINISTRATION----------------------­
` The recommended dose in patients with normal renal function or
`
`
`
`•
`
` mild renal impairment is 25 mg once daily. (2.1)
`
`
`
` Can be taken with or without food. (2.1)
`
`
`
` Adjust dose if moderate or severe renal impairment or end-stage
`
`
` renal disease (ESRD). (2.2)
`
`
`
`
`Creatinine
`Clearance
`
`(mL/min)
` ≥30 to <60
`
`
`
`•
`
`•
`
`
`
`
`
`
`
`Degree of Renal
`
`
`Impairment
`
` Moderate
`
`
`Recommended Dosing
`
`
` 12.5 mg once daily
`
`
`
` Severe/ESRD
`
`
`
` <30
`
`
`
` 6.25 mg once daily
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`Tablets: 25 mg, 12.5 mg and 6.25 mg (3)
`------------------------------CONTRAINDICATIONS-------------------------------­
`
`
`History of a serious hypersensitivity reaction to alogliptin-containing
`
`
`
`
`
`products, such as anaphylaxis, angioedema or severe cutaneous
`
`
`adverse reactions. (4)
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`1.1 Monotherapy and Combination Therapy
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosing
`
`
`2.2 Patients with Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Pancreatitis
`
`
`5.2 Heart Failure
`
`
`5.3 Hypersensitivity Reactions
`
`
`5.4 Hepatic Effects
`
`
`5.5 Use with Medications Known to Cause Hypoglycemia
`
`
`5.6 Severe and Disabling Arthralgia
`
`
`
`5.7 Bullous Pemphigoid
`
`
`5.8 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`
`
`Reference ID: 4025807
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`Acute pancreatitis: There have been postmarketing reports of
`
`
`•
`acute pancreatitis. If pancreatitis is suspected, promptly
`
`
`
`
`discontinue NESINA. (5.1)
`
`Heart failure: Consider the risks and benefits of NESINA prior to
`
`
`initiating treatment in patients at risk for heart failure. If heart
`
`
`
`failure develops, evaluate and manage according to current
`
`
`standards of care and consider discontinuation of NESINA (5.2).
`
`
`Hypersensitivity: There have been postmarketing reports of
`
`
`serious hypersensitivity reactions in patients treated with NESINA
`
`
`
`such as anaphylaxis, angioedema and severe cutaneous adverse
`
`
`
`
`reactions, including Stevens-Johnson syndrome. In such cases,
`
`
`
`
`promptly discontinue NESINA, 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 NESINA and assess patient for
`
`
`
`
`probable cause, then treat cause if possible, to resolution or
`
`
`stabilization. Do not restart NESINA if liver injury is confirmed and
`
`
`
`
`no alternative etiology can be found. (5.4)
`
`
`
`Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea)
`
`
`
`
`or insulin is used in combination with NESINA, a lower dose of the
`
`
`
`insulin secretagogue or insulin may be required to minimize the
`
`
`risk of hypoglycemia. (5.5)
`
`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 drug if appropriate. (5.6)
`
`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
`
`
`NESINA. (5.7)
`
`
`• Macrovascular outcomes: There have been no clinical studies
`
`
`
`
`establishing conclusive evidence of macrovascular risk reduction
`
`with NESINA or any other antidiabetic drug. (5.8)
`
`
`
`
`
`----------------------------ADVERSE REACTIONS--------------------------------­
`The most common adverse reactions (4% or greater incidence) are
`
`
`
`
`
`
`nasopharyngitis, headache 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.
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide
`
`
`
`
`Revised: 12/2016
`
`
`
`Lactation
`8.2
`
`
`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
`
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Patients with Inadequate Glycemic Control on Diet and
`
`
`Exercise
`
`14.2 Combination Therapy
`
`
`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
`
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
` Page 2 of 31
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
` 1.1 Monotherapy and Combination Therapy
`
`
`
`NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type
`
`
`2 diabetes mellitus [see Clinical Studies (14)].
`
`
`
`Important Limitations of Use
`
`
`
`
`
`
`
`NESINA 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 Dosing
`
`
`
`
`
`
`
`The recommended dose of NESINA is 25 mg once daily. NESINA may be taken with or without food.
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`No dose adjustment of NESINA is necessary for patients with mild renal impairment (creatinine
`
`
`clearance [CrCl] ≥60 mL/min).
`
`
`
`
`
`
`The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to
`
`<60 mL/min).
`
`
`
`
`The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to
`
`
`
`
`
`
`<30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis).
`
`
`
`
`NESINA may be administered without regard to the timing of dialysis. NESINA has not been studied
`
`
`in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6), Clinical
`
`
`Pharmacology (12.3)].
`
`
`
`
`Because there is a need for dose adjustment based upon renal function, assessment of renal function
`
`is recommended prior to initiation of NESINA therapy and periodically thereafter.
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`25 mg tablets are light red, oval, biconvex, film-coated, with “TAK ALG-25” printed on one side.
`•
`
`
`
`12.5 mg tablets are yellow, oval, biconvex, film-coated, with “TAK ALG-12.5” printed on one
`•
`
`side.
`
`
`6.25 mg tablets are light pink, oval, biconvex, film-coated, with “TAK ALG-6.25” printed on one
`
`side.
`
`
`•
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis,
`
`angioedema or severe cutaneous adverse reactions.
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 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 6 (0.2%)
`
`
`patients treated with NESINA 25 mg and 2 (<0.1%) patients treated with active comparators or
`placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
` Page 3 of 31
`
`high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with
`
`
`NESINA and in 7 (0.3%) of patients treated with placebo.
`
`
`It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while
`
`using NESINA.
`
`
`After initiation of NESINA, patients should be observed for signs and symptoms of pancreatitis. If
`
`pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management
`
`should be initiated.
`
`
`5.2 Heart Failure
`
`
`
`In the EXAMINE trial which enrolled patients with type 2 diabetes and recent acute coronary
`
`syndrome, 106 (3.9%) of patients treated with NESINA and 89 (3.3%) of patients treated with placebo
`
`
`were hospitalized for congestive heart failure.
`
`
`Consider the risks and benefits of NESINA 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 heart failure during therapy. Patients should be
`
`
`
`
`advised of the characteristic symptoms of heart failure and should be instructed to immediately report
`
`
`such symptoms. If heart failure develops, evaluate and manage according to current standards of
`
`
`care and consider discontinuation of NESINA.
`
`
`
`5.3 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`
`
`NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse
`
`
`
`
`
`reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected,
`
`
`discontinue NESINA, assess for other potential causes for the event and institute alternative
`
`
`
`
`treatment for diabetes [see Adverse Reactions (6.2)]. 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 NESINA.
`
`
`5.4 Hepatic Effects
`
`
`
`
`There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking
`
`NESINA, although some of the reports contain insufficient information necessary to establish the
`
`probable cause [see Adverse Reactions (6.2)].
`
`
`
`
`In glycemic control trials 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 NESINA 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 NESINA and in 1.8% of patients treated
`
`with placebo.
`
`
`
`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
`
`
`the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests
`persist or worsen, NESINA should be interrupted and investigation done to establish the probable
`
`
`
`
`
`cause. NESINA should not be restarted in these patients without another explanation for the liver test
`
`abnormalities.
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
` Page 4 of 31
`
`
`
`
`
` 5.5 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 NESINA.
`
`
`
` 5.6 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.
`
`
`5.7 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 NESINA. If bullous pemphigoid is suspected,
`
`
`
`NESINA should be discontinued and referral to a dermatologist should be considered for diagnosis
`
`
`and appropriate treatment.
`
`
`
`5.8 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`
`
`
`with NESINA or any other antidiabetic drug.
`
`
`
`6 ADVERSE REACTIONS
`
`
`The following serious adverse reactions are described below or elsewhere in the prescribing
`
`
`information:
`
`
`
`
`• Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`• Heart Failure [see Warnings and Precautions (5.2)]
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`
`
`• Hepatic Effects [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
`
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
`
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.7)]
`
`
`
`
`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.
`
`
`
`A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled
`
`
`
`
`
`clinical trials of whom 9052 subjects were treated with NESINA, 3469 subjects were treated with
`
`
`
`
`
`placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven
`years, the mean body mass index (BMI) was 31 kg/m2 (49% of patients had a BMI ≥30 kg/m2), and
`
`
`
`
`
`
`
`
`the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to NESINA was
`
`
`
`
`
`
`
`
`
`49 weeks with 3348 subjects treated for more than one year.
`
`
`In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions
`
`
`
`
`
`
`was 73% in patients treated with NESINA 25 mg compared to 75% with placebo and 70% with active
`
`
`
`
`
`
`
`comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with NESINA
`
`
`
`
`
`25 mg compared to 8.4% with placebo or 6.2% with active comparator.
`
`
`
`
`
`
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

` Page 5 of 31
`
`
`
` Adverse reactions reported in ≥4% of patients treated with NESINA 25 mg and more frequently than
`
`
`
`
`
`
`
` in patients who received placebo are summarized in Table 1.
`
`
`
`
`
`
`
` Table 1. Adverse Reactions Reported in ≥4% Patients Treated with NESINA 25 mg and More
`
`
`
`
`
`
`
` Frequently Than in Patients Given Placebo in Pooled Studies
`Number of Patients (%)
`
`
`
`
`
`
`Nasopharyngitis
`
`Upper Respiratory Tract Infection
`
`
`
`
`Headache
`
`
`NESINA
`
`25 mg
`
`N=6447
`
`309 (4.8)
`
`287 (4.5)
`
`
`278 (4.3)
`
`
`Placebo
`
`
`N=3469
`
`152 (4.4)
`
`121 (3.5)
`
`
`101 (2.9)
`
`
`
`Active
`
`Comparator
`
`N=2257
`
`113 (5.0)
`
`113 (5.0)
`
`121 (5.4)
`
`
`
`
` Hypoglycemia
`
` Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs
`
` and symptoms of hypoglycemia.
` In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with
`
`
`
`
`
`
`
`
` NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or
`
`
` insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy
`
`
`
` study comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was
`
`
`
` 5.4% with NESINA compared to 26% with glipizide (Table 2).
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`Table 2. Incidence and Rate of Hypoglycemia* in Placebo and Active-Controlled Studies when
`
` NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or
`
`
`
`
`
` Compared to Glipizide or Metformin
`
`
`Add-On to Glyburide
`
`(26 Weeks)
`
`
`
`
`
` Page 6 of 31
`
`
`
`
`
`Placebo
`
`
`
`
`
`N=99
` 11 (11.1)
`
`1 (1)
`
`NESINA 25 mg
`
`
`
`N=198
` 19 (9.6)
`
`
`0
`
`
`NESINA 25 mg
`
`
`N=129
`
` 35 (27)
`1 (0.8)
`
`
`NESINA 25 mg
`
`
`
`N=207
`
` 0
`
`0
`
`NESINA 25 mg
`
`
`N=199
`
`14 (7.0)
`
`
`
` 0
`
`
`Placebo
`
`
`N=129
`
` 31 (24)
`
`2 (1.6)
`
`
`Placebo
`
`
`
`N=104
`
` 3 (2.9)
`
`
`0
`
`Placebo
`
`
`N=97
`
`5 (5.2)
`
`
` 1 (1)
`
`
`
`NESINA 25 mg
`
`
`Glipizide
`
`
`N=222
`12 (5.4)
`
`
`0
`
`NESINA 25 mg
`
`
`
`N=112
`
`
`2 (1.8)
`
`
`0
`
`
`N=219
`57 (26)
`
`
`3 (1.4)
`Metformin 500 mg
`
`twice daily
`
`
`N=109
`
`
`2 (1.8)
`
`
`0
`
` Overall (%)
`
`†
`
`Severe (%)
`
`
`Add-On to Insulin (± Metformin)
`
`(26 Weeks)
`
`
` Overall (%)
`
`†
`
`Severe (%)
`Add-On to Metformin
`
`(26 Weeks)
`
`
` Overall (%)
`
`†
`
`Severe (%)
`
`Add-On to Pioglitazone
`(± Metformin or Sulfonylurea)
`
`
`
`(26 Weeks)
`
`Overall (%)
`
`†
`
`Severe (%)
`
`
`Compared to Glipizide
`
`(52 Weeks)
`
`
`Overall (%)
`
`†
`
`Severe (%)
`Compared to Metformin
`
`
`
`(26 Weeks)
`
`
`
`
`
`Overall (%)
`†
`
`Severe (%)
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

` Add-On to Metformin Compared to Glipizide
`
`
` (52 Weeks)
`
`
`
`
`
`
`
`
`
` Page 7 of 31
`
`
`
`NESINA 25 mg
`
`
`
`N=877
`
`Glipizide
`
`
`
`N=869
`
`
`Overall (%)
`†
`
`
`4 (0.5)
`0
`
`Severe (%)
`
`*Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic
`
`
`
`
`hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population.
`
`†
`
`
`
`Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting
`
`depressed level or loss of consciousness or seizure.
`
`
`
`207 (23.8)
`
`
`12 (1.4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients
`
`
`
`
`
`
`
` receiving NESINA and 6.5% in patients receiving placebo. Serious adverse reactions of
` hypoglycemia were reported in 0.8% of patients treated with NESINA and in 0.6% of patients treated
`
`
`
` with placebo.
` Renal Impairment
`
` In glycemic control trials in patients with type 2 diabetes, 3.4% of patients treated with NESINA and
`
`
`
`
`
`
` 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly
` reported adverse reactions were renal impairment (0.5% for NESINA and 0.1% for active
`
`
`
`
`
`
`
` comparators or placebo), decreased creatinine clearance (1.6% for NESINA and 0.5% for active
`
`
` comparators or placebo) and increased blood creatinine (0.5% for NESINA and 0.3% for active
`
`
`
`
` comparators or placebo) [see Use in Specific Populations (8.6)].
`
`
` In the EXAMINE trial of high CV risk type 2 diabetes patients, 23% of patients treated with NESINA
`
`
`
`
` and 21% of patients treated with placebo had an investigator reported renal impairment adverse
`
`
`
`
`
` reaction. The most commonly reported adverse reactions were renal impairment (7.7% for NESINA
`
` and 6.7% for placebo), decreased glomerular filtration rate (4.9% for NESINA and 4.3% for placebo)
`
`
` and decreased renal clearance (2.2% for NESINA and 1.8% for placebo). Laboratory measures of
`
`
`
`
` renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in
`
`
`
` 21.1% of patients treated with NESINA and 18.7% of patients treated with placebo. Worsening of
`
`
`
`
`
`
` chronic kidney disease stage was seen in 16.8% of patients treated with NESINA and in 15.5% of
`
`
`
`
` patients treated with placebo.
`
`
` 6.2 Postmarketing Experience
`
`
`
` The following adverse reactions have been identified during the postmarketing use of NESINA.
`
` Because these reactions are reported voluntarily from a population of uncertain size, it is not always
`
`
` possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
` Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and
`
`
`
`
`
`
` severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme
` elevations, fulminant hepatic failure, severe and disabling arthralgia, bullous pemphigoid, and
`
`
`
`
`
`
`
`
` diarrhea, constipation, nausea, and ileus [see Warnings and Precautions (5.1, 5.3, 5.4, 5.6, 5.7)].
`
`
`
`
`
`
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
` NESINA is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No
`
` significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with
`
`
`
` renally excreted drugs [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
` Page 8 of 31
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
` 8.1 Pregnancy
` Risk Summary
`
`
` Limited data with NESINA in pregnant women are not sufficient to determine a drug-associated risk
`
`
` for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly
`
`
`
`
`
` controlled diabetes in pregnancy [see Clinical Considerations].
`
`
`
`
` No adverse developmental effects were observed when alogliptin was administered to pregnant rats
`
`
`
`
`
`
`
`
`
`and rabbits during organogenesis at exposures 180- and 149-times the 25 mg clinical dose,
`
`
`
`
`
`respectively, based on plasma drug exposure (AUC) [see Data].
`
`
`
`
`The estimated background risk of major birth defects is 6-10% in women with pre-gestational
`
`
`
`
`
`diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10.
`
`
`
`
`The estimated background risk of miscarriage for the indicated population is unknown. In the U.S.
`
`
`
`
`general population, the estimated background risk of major birth defects and miscarriage in clinically
`
`
`
`recognized pregnancies is 2-4% and 15-20%, respectively.
`
`
`Clinical Considerations
`
`
`Disease-associated maternal and/or embryo/fetal risk
`
`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-
`
`
`
`eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly
`
`
`controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related
`
`morbidity.
`
`Data
`
`Animal Data
`
`
`
`
`Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause
`
`
`
`
`
`
`adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180
`
`
`
`
`times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental
`
`
`
`
`transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
`
`No adverse developmental outcomes were observed in offspring when alogliptin was administered to
`
`
`
`
`
`pregnant rats during gestation and lactation at doses up to 250 mg/kg (~ 95 times the 25 mg clinical
`
`
`dose, based on AUC).
`
`
`
`8.2 Lactation
`
`Risk Summary
`
`There is no information regarding the presence of alogliptin in human milk, the effects on the
`
`
`
`
`
`
`
`
`breastfed infant, or the effects on milk production. Alogliptin is present in rat milk: however, due to
`
`
`species specific differences in lactation physiology, animal lactation data may not reliably predict
`
`
`
`levels in human milk. The developmental and health benefits of breastfeeding should be considered
`
`
`
`along with the mother’s clinical need for NESINA and any potential adverse effects on the breastfed
`
`
`
`
`infant from NESINA or from the underlying maternal condition.
`
`
`8.4 Pediatric Use
`
`
`
`
`
`Safety and effectiveness of NESINA in pediatric patients have not been established.
`
`
`8.5 Geriatric Use
`
`
`
`
`
`Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with NESINA,
`
`
`
`
`
`
`
`2257 (24.9%) patients were 65 years and older and 386 (4.3%) patients were 75 years and older. No
`
`
`
`
`
`overall differences in safety or effectiveness were observed between patients 65 years and over and
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
` Page 9 of 31
`
` 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.
`
`
` 8.6 Renal Impairment
` A total of 602 patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m2) and 4
`
`
`
`
`
`
`patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m2 or
`
`<15 mL/min/1.73 m2, respectively) at baseline were treated with NESINA in clinical trials in patients
`
`
`
`
`with type 2 diabetes. Reductions in HbA1c were generally similar in this subgroup of patients. The
`
`
`overall incidence of adverse reactions was generally balanced between NESINA and placebo
`
`treatments in this subgroup of patients.
`
`
`In the EXAMINE trial of high CV risk type 2 diabetes patients, 694 patients had moderate renal
`
`
`
`
`impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The
`
`
`
`overall incidences of adverse reactions, serious adverse reactions and adverse reactions leading to
`
`
`
`
`study drug discontinuation were generally similar between the treatment groups.
`
`8.7 Hepatic Impairment
`
`
`No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh
`
`
`
`
`Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to
`
`subjects with normal hepatic function in a pharmacokinetic study. NESINA has not been studied in
`
`
`
`
`
`
`patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering
`
`NESINA to patients with liver disease [see Warnings and Precautions (5.3)].
`
`
`
`
`
`
`10 OVERDOSAGE
`
`
`The highest doses of NESINA administered in clinical trials were single doses of 800 mg to healthy
`
`
`
`
`subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32
`
`
`
`
`
`
`
`
`
`times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious
`
`
`
`
`
`adverse reactions were observed at these doses.
`
`
`
`In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and
`
`
`supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be
`
`
`reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.
`
`
`
`Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the
`
`
`
`drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is
`
`
`not known if NESINA is dialyzable by peritoneal dialysis.
`
`
`
`
`11 DESCRIPTION
`
`
`NESINA tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable
`
`
`
`inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
`
`
`Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3­
`
`
`aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
` monobenzoate. It has a molecular formula of C18H21N5O2•C7H6O2 and a molecular weight of 461.51
`
`
` daltons. The structural formula is:
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4025807
`
`Novo Nordisk Exhibit 2426
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
` Page 10 of 31
`
`
`
`O
`
`CN
`
`H3C
`
`N
`
`N
`
`•
`
`HO2C
`
`O
`
`( Z)
`
`N
`
`(R)
`
`NH2
`
`Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the
`
`
`aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol,
`
`
`
`slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.
`
`
`
`
`Each NESINA tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is equivalent to
`
`
`
`
`
`
`
`25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following inactive ingredients: mannitol,
`
`
`
`
`
`
`
`
`
`microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate.
`
`
`In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide,
`
`
`
`
`ferric oxide (red or yellow) and polyethylene glycol, and is marked with printing ink (Gray F1).
`
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and
`
`
`
`
`glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small
`
`
`
`
`intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells
`
`
`
`in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme
`
`within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic
`
`
`
`
`
`glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the
`
`
`
`insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of
`
`
`the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and
`
`
`
`postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes
`
`
`
`mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at
`
`
`
`
`concentrations approximating therapeutic exposures.
`
`
`12.2 Pharmacodynamics
`
`
`Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of DPP-4
`
`
`
`
`
`within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of
`
`
`
`
`
`
`
`
`12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or
`
`
`
`
`
`
`
`
`equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold
`
`
`
`
`
`
`
`
`greater with NESINA (