HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`These highlights do not include all the information needed to
`
`
`
`
`use KAZANO safely and effectively. See full prescribing
`
`
`information for KAZANO.
`
`
`
`
`
`
`
`KAZANO (alogliptin and metformin HCl) tablets, for oral use
`
`
`Initial U.S. Approval: 2013
`
`WARNING: LACTIC ACIDOSIS
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`• Postmarketing cases of metformin-associated lactic acidosis
`
`
`have resulted in death, hypothermia, hypotension, and
`
`
`resistant bradyarrhythmias. Symptoms included malaise,
`
`
`
`myalgias, respiratory distress, somnolence, and abdominal
`
`
`pain. Laboratory abnormalities included elevated blood
`
`
`
`lactate levels, anion gap acidosis, increased lactate/pyruvate
`
`
`
`ratio; and metformin plasma levels generally greater than
`
`
`5 mcg/mL. (5.1)
`
`• Risk factors include renal impairment, concomitant use of
`
`
`certain drugs, age ≥65 years old, radiological studies with
`
`
`
`contrast, surgery and other procedures, hypoxic states,
`
`
`
`
`excessive alcohol intake, and hepatic impairment. Steps to
`
`reduce the risk of and manage metformin-associated lactic
`
`
`
`acidosis in these high risk groups are provided in the Full
`
`Prescribing Information. (5.1)
`
`
`• If lactic acidosis is suspected, discontinue KAZANO and
`
`
`
`institute general supportive measures in a hospital setting.
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`•
`
`
`•
`
`
`5/2016
`
`
`5/2016
`
`5/2016
`
`
`-------------------------WARNINGS AND PRECAUTIONS------------------------­
`• Lactic acidosis: See boxed warning. (5.1)
`
`
`
`• Acute pancreatitis: There have been postmarketing reports of acute
`
`pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`KAZANO. (5.2)
`
`• Heart failure: Consider the risks and benefits of KAZANO 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 KAZANO (5.3).
`
`
`
`• 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 KAZANO, assess for other potential causes, institute
`
`
`
`appropriate monitoring and treatment and initiate alternative
`
`treatment for diabetes. (5.4)
`
`• Hepatic effects: Postmarketing reports of hepatic failure, sometimes
`
`
`
`
`
`fatal. Causality cannot be excluded. If liver injury is detected,
`
`
`
`
`
`promptly interrupt KAZANO and assess patient for probable cause,
`
`
`
`then treat cause if possible, to resolution or stabilization. Do not
`
`
`
`restart KAZANO if liver injury is confirmed and no alternative etiology
`
`
`can be found. (5.5)
`
`• Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`
`Monitor hematologic parameters annually. (5.6)
`
`
`• Hypoglycemia: When used with an insulin secretagogue (e.g.,
`
`
`
`sulfonylurea) or with insulin, a lower dose of the insulin secretagogue
`
`
`or insulin may be required to reduce the risk of hypoglycemia. (5.7)
`
`
`
`
`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. (5.8)
`
`
`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 KAZANO. (5.9)
`
`
`
`• Macrovascular outcomes: There have been no clinical studies
`
`
`
`
`establishing conclusive evidence of macrovascular risk reduction with
`
`KAZANO or any other antidiabetic drug. (5.10)
`
`
`
`
`-----------------------------ADVERSE REACTIONS---------------------------------­
`The most common adverse reactions (4% or greater incidence) are
`
`
`
`
`
`upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension,
`
`
`
`headache, back pain and urinary tract infection. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Takeda
`
`
`
`Pharmaceuticals at 1-877-TAKEDA-7 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`--------------------------------DRUG INTERACTIONS-------------------------------­
`
`• Carbionic anhydrase inhibitors may increase risk of lactic acidosis.
`
`
`
`Consider more frequent monitoring. (7.1)
`
`
`
`• Drugs that reduce metformin clearance (such as ranolazine,
`
`
`
`
`
`
`
`
`vandetanib, dolutegravir, and cimetidine), may increase the
`
`
`accumulation of metformin. Consider the benefits and risks of
`
`
`
`
`concomitant use. (7.2)
`
`• Alcohol can potentiate the effect of metformin on lactate metabolism.
`
`
`
`Warn patients against excessive alcohol intake. (7.3)
`
`
`--------------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`• Females and Males of Reproductive Potential: Advise
`
`premenopausal females of the potential for an unintended
`
`pregnancy. (8.3)
`
`• Pediatrics: Safety and effectiveness of KAZANO in patients below the
`
`
`
`
`
`
`age of 18 have not been established. (8.4)
`
`
`• Geriatric Use: Assess renal function more frequently. (8.5)
`
`
`
`
`
`• Hepatic Impairment: Avoid use in patients with hepatic impairment.
`
`
`
`
`(8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide
`
`
`ENT MAJOR CHANGES-------------------------­
`--------------------------REC
`
`Boxed Warni
`12/2016
`ng
`
`
`
`d Usage (Indications an 1.1)
`4/2016
`
`
`Administrati
`on
`Dosage and
`
`
`
`ndations for
` Use in Renal Impairment (2.2)
`Recomme
`
`ation f or Io
`dinated Contrast Imaging
`Discontinu
`ures (2.3)
`Proced
`
`
`Contraindications (4)
`
`
`Warnings and Precautions
`
`
`
`12/2016
`Lactic Acidosis (5.1)
`
`
`4/2016
`Pancreatitis (5.2)
`
`
`4/2016
`Heart Failure (5.3)
`
`
`
`4/2016
`Hepatic Effects (5.5)
`
`
`
`12/2016
`Bullous Pemphigoid (5.9)
`
`
`---------------------------INDICATIONS AND USAGE--------------------------­
`
`
`KAZANO is a dipeptidyl-peptidase-4 (DPP-4) inhibitor and a
`
`
`
`biguanide 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 based on the patient’s current
`•
`
`
`regimen. (2.1)
`
`
`
`
`• Give twice daily with food. (2.1)
`
`• Adjust the dosing based on effectiveness and tolerability while
`
`
`
`not exceeding the maximum recommended daily dose of 25 mg
`
`
`
`alogliptin and 2000 mg metformin HCl. (2.1)
`
`
`
`
`• Prior to initiation, assess renal function with estimated glomerular
`
`filtration rate (eGFR) (2.2)
`o Do not use in patients with eGFR below 60 mL/min/1.73 m2 .
`
`
`
`
`
`
`• KAZANO may need to be discontinued at time of, or prior to,
`
`
`
`
`
`
`iodinated contrast imaging procedures. (2.3)
`
`---------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Tablets: 12.5 mg alogliptin and 500 mg metformin HCl, 12.5 mg
`
`
`
`
`alogliptin and 1000 mg metformin HCl. (3)
`
`
`
`
`----------------------------CONTRAINDICATIONS-------------------------------­
`
`• Severe renal impairment: eGFR below 30 mL/min/1.73 m2. (4)
`
`
`
`
`• Metabolic acidosis, including diabetic ketoacidosis. (4)
`
`
`• History of a serious hypersensitivity reaction to alogliptin or
`
`
`
`
`
`
`metformin, components of KAZANO, such as anaphylaxis,
`
`
`
`angioedema or severe cutaneous adverse reactions. (4)
`
`
`____________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`Revised: 2/2017
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`Page 2 of 35
`
`
`
`
`
`
`7.1 Carbonic Anhydrase Inhibitors
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`7.2 Drugs that Reduce Metformin Clearance
`
`WARNING: LACTIC ACIDOSIS
`
`
`
`7.3 Alcohol
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`
`7.4
`Insulin Secretagogues and Insulin
`
`1.1 Monotherapy and Combination Therapy
`
`
`
`
`
`
`7.5 The Use of Metformin with Other Drugs
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`2.1 Recommendations for All Patients
`
`
`
`
`
`
`8.1 Pregnancy
`
`2.2 Recommendations for Use in Renal Impairment
`
`
`
`
`
`
`
`8.2 Lactation
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`8.4 Pediatric Use
`
`4 CONTRAINDICATIONS
`
`
`
`
`8.5 Geriatric Use
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`8.6 Renal Impairment
`
`5.1 Lactic Acidosis
`
`
`
`
`
`8.7 Hepatic Impairment
`
`5.2 Pancreatitis
`
`
`
`10 OVERDOSAGE
`
`
`5.3 Heart Failure
`
`
`
`11 DESCRIPTION
`
`
`5.4 Hypersensitivity Reactions
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`5.5 Hepatic Effects
`
`
`
`
`
`
`12.1 Mechanism of Action
`
`5.6 Vitamin B12 Levels
`
`
`
`
`
`
`12.2 Pharmacodynamics
`
`
`
`5.7 Use with Medications Known to Cause Hypoglycemia
`
`
`
`12.3 Pharmacokinetics
`
`
`
`
`5.8 Severe and Disabling Arthralgia
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`5.9 Bullous Pemphigoid
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`5.10 Macrovascular Outcomes
`
`14 CLINICAL STUDIES
`
`
`6 ADVERSE REACTIONS
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`6.2 Laboratory Abnormalities
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`6.3 Postmarketing Experience
`
`
`are not listed.
`
`
`7 DRUG INTERACTIONS
`
`____________________________________________________________________________________________________________________________________
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
` Page 3 of 35
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`Postmarketing cases of metformin-associated lactic acidosis have resulted in death,
`
`hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin­
`
`associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms
`
`such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
`
`Metformin-associated lactic acidosis was characterized by elevated blood lactate
`
`levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or
`
`
`ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally
`
`
`
`
`
`greater than 5 mcg/mL [see Warnings and Precautions (5.1)].
`
`
`
`
`Risk factors for metformin-associated lactic acidosis include renal impairment,
`
`
`concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as
`
`
`
`topiramate), age 65 years old or greater, having a radiological study with contrast,
`
`
`surgery and other procedures, hypoxic states (e.g., acute congestive heart failure),
`
`
`excessive alcohol intake, and hepatic impairment.
`
`
`Steps to reduce the risk of and manage metformin-associated lactic acidosis in these
`
`
`high risk groups are provided in the Full Prescribing Information [see Dosage and
`
`
`
`Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug
`
`Interactions (7), and Use in Specific Populations (8.6, 8.7)].
`
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue
`
`
`KAZANO and institute general supportive measures in a hospital setting. Prompt
`
`
`
`hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1 Monotherapy and Combination Therapy
`
`KAZANO 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 metformin is appropriate [see Clinical
`
`Studies (14)].
`
`Important Limitations of Use
`
`
`
`
`
`
`
`
`
`KAZANO 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 Recommendations for All Patients
`
`
`
`
`• Healthcare providers should individualize the starting dose of KAZANO based on the patient’s
`
`current regimen.
`
`
`• KAZANO should be taken twice daily with food with gradual dose escalation to reduce the
`
`
`
`gastrointestinal (GI) side effects due to metformin. KAZANO tablets must not be split before
`
`swallowing.
`
`
`
`• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum
`
`
`
`recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl.
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
` Page 4 of 35
`
`
`
`
`
`
`
` • The following doses are available:
`
`
`
`
`
` 12.5 mg alogliptin and 500 mg metformin HCl
`
` 12.5 mg alogliptin and 1000 mg metformin HCl
`
`
` 2.2 Recommendations for Use in Renal Impairment
`
`
`
`
` Assess renal function prior to initiation of KAZANO and periodically thereafter.
`
`
`
`
`
`
`KAZANO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below
`30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
`
`KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m2 because
`
`
`these patients require a lower daily dosage of alogliptin than what is available in the fixed combination
`
`KAZANO product.
`
`
`Discontinuation for Iodinated Contrast Imaging Procedures
`2.3
`
`
`
`
`
`Discontinue KAZANO at the time of, or prior to, an iodinated contrast imaging procedure in patients
` with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease,
`
`alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re­
`
`
`evaluate eGFR 48 hours after the imaging procedure; restart KAZANO if renal function is stable [see
`
`
`
`Warnings and Precautions (5.1)].
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`• 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with “12.5/500” debossed on
`
`one side and “322M” debossed on the other side
`
`
`• 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with “12.5/1000” debossed
`
`on one side and “322M” debossed on the other side
`
`
`
`4 CONTRAINDICATIONS
`
`
`KAZANO is contraindicated in patients with:
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should
`
`
`
`
`
`be treated with insulin.
`
`• History of a serious hypersensitivity reaction to alogliptin or metformin, components of KAZANO,
`
`
`
`
`
`
`
`
`such as anaphylaxis, angioedema or severe cutaneous adverse reactions.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1
`Lactic Acidosis
`
`
`Lactic Acidosis
`
`
`There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
`
`
`
`These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,
`
`
`
`myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia,
`hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin­
`
`
`associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than
`
`5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased
`
`
`
`
`lactate:pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL. Metformin
`
`decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic
`
`
`acidosis, especially in patients at risk.
`If metformin-associated lactic acidosis is suspected, general supportive measures should be
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
` Page 5 of 35
`
`
`
`
`
` instituted promptly in a hospital setting, along with immediate discontinuation of KAZANO. In
`
`
`
`KAZANO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis
`
`
`is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride
`
`
`
`is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions).
`
`Hemodialysis has often resulted in reversal of symptoms and recovery.
`
`
`
`
`Educate patients and their families about the symptoms of lactic acidosis and if these symptoms
`
`
`
`
`
`occur instruct them to discontinue KAZANO and report these symptoms to their healthcare provider.
`
`
`
`For each of the known and possible risk factors for metformin-associated lactic acidosis,
`
`
`
`recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided
`
`below:
`
`Renal Impairment
`The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with
`
`
`
`
`significant renal impairment. The risk of metformin accumulation and metformin-associated lactic
`acidosis increases with the severity of renal impairment because metformin is substantially excreted
`
`
`
`by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage
`
`
`
`and Administration (2.2), Clinical Pharmacology (12.3)]:
`
`
`
`• Before initiating KAZANO, obtain an eGFR.
`• KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see
`
`
`
`Contraindications (4)].
`• KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m2
`
`
`
`because these patients require a lower dosage of alogliptin than what is available in the fixed
`combination KAZANO product.
`
`• Obtain an eGFR at least annually in all patients taking KAZANO. In patients at increased risk
`
`
`
`
`
`
`for the development of renal impairment (e.g., the elderly), renal function should be assessed
`
`more frequently.
`
`Drug Interactions
`The concomitant use of KAZANO with specific drugs may increase the risk of metformin-associated
`
`
`
`
`
`
`
`
`lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere
`
`
`with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore,
`
`
`
`consider more frequent monitoring of patients.
`
`Age 65 or Greater
`
`
`
`The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly
`
`
`
`
`
`patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger
`
`
`
`patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations
`
`
`(8.5)].
`
`
`Radiological Studies with Contrast
`
`Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an
`
`
`
`acute decrease in renal function and the occurrence of lactic acidosis. Stop KAZANO at the time of,
`
`
`or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and
`60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in
`
`
`
`
`patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after
`
`
`
`
`
`
`the imaging procedure, and restart KAZANO if renal function is stable.
`
`Surgery and Other Procedures
`
`
`
`
`Withholding of food and fluids during surgical or other procedures may increase the risk for volume
`
`
`
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`
`
` Page 6 of 35
`
` depletion, hypotension and renal impairment. KAZANO should be temporarily discontinued while
`
`
`
`patients have restricted food and fluid intake.
`
`
`Hypoxic States
`
`
`
`
`Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting
`
`
`of acute congestive heart failure (particularly when accompanied by hypoperfusion and
`
`
`
`hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other
`conditions associated with hypoxemia have been associated with lactic acidosis and may also
`
`
`
`
`cause prerenal azotemia. When such events occur, discontinue KAZANO.
`
`Excessive Alcohol Intake
`
`
`
`
`Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of
`
`
`
`metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while
`
`
`receiving KAZANO.
`
`Hepatic Impairment
`
`Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis.
`
`
`
`
`This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore,
`
`
`
`
`avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease.
`
`
`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 6 (0.2%)
`
`patients treated with alogliptin 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
`high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) patients treated with
`
`alogliptin and in 7 (0.3%) patients treated with placebo.
`
`
`It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while
`
`using KAZANO.
`
`
`
`
`After initiation of KAZANO, patients should be observed for signs and symptoms of pancreatitis. If
`
`
`
`pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management
`
`should be initiated.
`
`
`5.3 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 alogliptin and 89 (3.3%) of patients treated with
`
`placebo were hospitalized for congestive heart failure.
`
`
`
`
`
`Consider the risks and benefits of KAZANO 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 KAZANO.
`
`
`5.4 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 KAZANO, 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
`
`
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

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` Page 7 of 35
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` angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether
`
`
`
`
` such patients will be predisposed to angioedema with KAZANO.
` 5.5 Hepatic Effects
`
`
`
`
`
`
`
` There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking
` alogliptin, although some of the reports contain insufficient information necessary to establish the
`
`
`
` probable cause [see Adverse Reactions (6.3)].
` 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 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.
`
`
`
`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, KAZANO should be interrupted and investigation done to establish the probable
`
`
`
`
`
`cause. KAZANO should not be restarted in these patients without another explanation for the liver
`
`test abnormalities.
`5.6 Vitamin B12 Levels
`
`
`
`In controlled, 29-week clinical trials of immediate-release metformin, a decrease to subnormal levels
`
`
`
`of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in
`
`
`
`approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from
`
`
`
`the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be
`
`
`
`
`rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of
`
`
`
`
`
`hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent
`
`
`abnormalities should be appropriately investigated and managed. Certain individuals (those with
`
`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing
`
`
`
`
`subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to
`
`
`
`
`
`
`three-year intervals may be useful.
`
`
`5.7 Use with Medications Known to Cause Hypoglycemia
`
`
`
`
`Alogliptin
`
`
`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 KAZANO.
`
`Metformin Hydrochloride
`
`
`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use
`
`
`but could occur when caloric intake is deficient, when strenuous exercise is not compensated by
`
`caloric supplementation or during concomitant use with other glucose-lowering agents (such as
`
`sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients and those with
`
`
`adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic
`
`
`effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β­
`
`
`
`
`
`adrenergic blocking drugs.
`
`5.8 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
`
`
`
`
`
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

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` Page 8 of 35
`
` 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.
` 5.9 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 DPP-4 inhibitor. Tell patients to report
`
`
`development of blisters or erosions while receiving KAZANO. If bullous pemphigoid is suspected,
`
`
`
`KAZANO should be discontinued and referral to a dermatologist should be considered for diagnosis
`
`
`and appropriate treatment.
`
`
`5.10 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`
`
`
`
`with KAZANO 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 (5.2)]
`
`
`• Heart Failure [see Warnings and Precautions (5.3)]
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`
`
`
`• Hepatic Effects [see Warnings and Precautions (5.5)]
`
`
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.8)]
`
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.9)]
`
`
`
`
`
`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 Metformin Hydrochloride
`
`
`
`
`
`
`Over 2700 patients with type 2 diabetes have received alogliptin coadministered with metformin in
`
`
`
`
`
`
`
`four large, randomized, double-blind controlled clinical trials. The mean exposure to KAZANO was 58
`
`
`
`
`weeks, with more than 1400 subjects treated for more than one year. These included two 26 week
`
`
`
`placebo-controlled studies, one 52 week active control study and an interim analysis of a 104 week
`
`
`
`
`
`
`active-controlled study. In the KAZANO arm, the mean duration of diabetes was approximately six
`years, the mean body mass index (BMI) was 31 kg/m2 (56% of patients had a BMI ≥30 kg/m2) and the
`
`
`
`mean age was 55 years (18% of patients ≥65 years of age).
`
`
`
`
`
`
`
`In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions
`
`
`
`
`
`
`was 74% in patients treated with KAZANO compared to 75% treated with placebo. Overall
`
`
`
`
`
`discontinuation of therapy due to adverse reactions was 6.2% with KAZANO compared to 1.9% in
`
`
`
`
`placebo, 6.4% in metformin and 5.0% in alogliptin.
`
`Adverse reactions reported in ≥4% of patients treated with KAZANO and more frequently than in
`
`
`
`
`
`patients who received alogliptin, metformin or placebo are summarized in Table 1.
`
`
`
`
`
`
`
`Reference ID: 4055915
`
`Novo Nordisk Exhibit 2428
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

` Page 9 of 35
`
`
`
`
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`
`
` Table 1. Adverse Reactions Reported in ≥4% of Patients Treated with KAZANO and More
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo
` Number of Patients (%)
`
`
`Alogliptin†
`
` Metformin‡
`N=222
`N=1592
`
`
`
`KAZANO*
`
`N=2794
`
`
`
`
`
`
` Placebo
`N=106
`
`
`
`
`
`224 (8.0)
`
`
`6 (2.7)
`
`
`105 (6.6)
`
`
`3 (2.8)
`
`
`Upper respiratory tract
`
`infection
`
`
`
`
`
`2 (1.9)
`93 (5.8)
`7 (3.2)
`191 (6.8)
`Nasopharyngitis
`
`
`
`
`
`3 (2.8)
`105 (6.6)
`4 (1.8)
`155 (5.5)
`Diarrhea
`
`
`
`
`
`6 (5.7)
`96 (6.0)
`5 (2.3)
`154 (5.5)
`Hypertension
`
`
`
`
`
`3 (2.8)
`74 (4.6)
`11 (5.0)
`149 (5.3)
`Headache
`
`
`
`
`
`1 (0.9)
`72 (4.5)
`1 (0.5)
`119 (4.3)
`Back pain
`
`
`
`
`
`2 (1.9)
`59 (3.7)
`4 (1.8)
`116 (4.2)
`Urinary tract infection
`*KAZANO – includes data pooled for patients receiving alogliptin 25 and 12.5 mg
`
`
`
`
`
` combined with various dose of metformin
`
`
`†Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg
`
`
`
`
`
`‡Metformin – includes data pooled for patients receiving variou