`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` ADLYXIN safely and effectively. See full prescribing information for
` ADLYXIN.
`
`
` ADLYXIN (lixisenatide) injection, for subcutaneous use
`
`
`
` Initial U.S. Approval: 2016
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
` ADLYXIN is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as
`
`
`
`
`
` an adjunct to diet and exercise to improve glycemic control in adults with type
`
`
`
`
`
`
`
`
`
`
`
`
` 2 diabetes mellitus (1).
`
`
`
`
`
` Limitations of Use (1):
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Has not been studied in patients with chronic pancreatitis or a history of
`
`
`
`
`
`
`
`
`
`unexplained pancreatitis. Consider other antidiabetic therapies in patients
`
`
`
`
`with a history of pancreatitis.
`
`
`
`
`
`
`
`
`
`• Not for treatment of type 1 diabetes or diabetic ketoacidosis.
`
`
`
`
`
`
`
`
`
`
`• Has not been studied in combination with short acting insulin.
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Has not been studied in patients with gastroparesis and is not recommended
`
`
`
`
`
`in patients with gastroparesis.
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Initiate at 10 mcg once daily for 14 days. On Day 15, increase dosage to 20
`
`
`
`mcg once daily (2.1).
`
`
`
`
`
`
`
`
`
`
`
`• Administer once daily within one hour before the first meal of the day
`
`
`(2.2).
`
`
`
`
`
`
`
`
`
`
`• Inject subcutaneously in the abdomen, thigh or upper arm (2.2).
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
`
`
`
`
`
`• Injection: 50 mcg/mL in 3 mL in green prefilled pen (for 14 pre-set doses;
`
`
`
`
`
`10 mcg per dose) (3).
`
`
`
`
`
`
`
`
`
`
`
`• Injection: 100 mcg/mL in 3 mL in burgundy prefilled pen (for 14 pre-set
`
`
`
`
`
`
`doses; 20 mcg per dose) (3).
`
`
`
`
`
`• Never share ADLYXIN pen between patients, even if the needle is changed
`
`
`
`
`
`
`
`
`
`(5.3).
`
`• Hypoglycemia with Concomitant use of Sulfonylurea or Basal Insulin:
`
`
`
`
`
`
`
`
`
`
`When ADLYXIN is used with a sulfonylurea or basal insulin, consider
`
`
`
`
`
`
`
`
`
`
`lowering the dose of the sulfonylurea or basal insulin to reduce the risk of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hypoglycemia. (5.4).
`• Acute Kidney Injury: Monitor renal function in patients with renal
`
`
`
`
`
`
`
`
`
`
`impairment reporting severe adverse gastrointestinal reactions. ADLYXIN
`
`
`
`is not recommended in patients with end stage renal disease (5.5).
`
`
`
`
`
`
`
`
`
`• Immunogenicity: Patients may develop antibodies to lixisenatide. If there is
`
`
`
`
`
`
`
`
`
`
`worsening glycemic control or failure to achieve targeted glycemic control,
`
`
`
`
`
`
`
`significant injection site reactions or allergic reactions, alternative
`
`
`
`
`
`
`
`antidiabetic therapy should be considered (5.6).
`
`
`
`
`
`
`• Macrovascular Outcomes: Clinical studies have not shown macrovascular
`
`
`risk reduction with ADLYXIN or any other antidiabetic drug (5.7).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`The most common adverse reactions (≥5%) of patients treated with
`
`
`
`
`
`
`
`
`
`
`ADLYXIN are nausea, vomiting, headache, diarrhea, dizziness, and
`
`
`
`
`
`hypoglycemia (6.1).
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
`
`
`at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• ADLYXIN delays gastric emptying which may impact absorption of
`
`
`
`
`
`
`
`
`
`
`concomitantly administered oral medications. Oral medications that are
`
`
`
`
`particularly dependent on threshold concentrations for efficacy, such as
`
`
`
`
`
`
`
`
`
`antibiotics, or medications for which a delay in effect is undesirable, such
`
`
`
`
`
`
`
`
`
`
`as acetaminophen, should be administered 1 hour before ADLYXIN (7.1,
`
`
`
`
`
`
`
`
`12.3).
`
`• Oral contraceptives should be taken at least 1 hour before ADLYXIN
`
`
`
`
`
`
`
`
`
`
`
`
`administration or 11 hours after the dose of ADLYXIN (7.1, 12.3).
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`Pregnancy: ADLYXIN should be used during pregnancy only if the potential
`
`
`
`
`
`
`
`
`
`
`
`benefit justifies the potential risk to the fetus (8.1).
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`
`
`
`
`
`Hypersensitivity to ADLYXIN or any product components. Hypersensitivity
`
`
`
`
`
`
`
`
`reactions including anaphylaxis have occurred with ADLYXIN (4).
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`
`
`• Anaphylaxis and Serious Hypersensitivity Reactions: Discontinue
`
`
`
`
`
`
`
`ADLYXIN and promptly seek medical advice (5.1).
`
`• Pancreatitis: Discontinue promptly if pancreatitis is suspected. Do not
`
`
`
`
`
`
`
`
`
`restart if pancreatitis is confirmed. Consider other antidiabetic therapies in
`
`
`
`
`
`
`
`
`
`patients with a history of pancreatitis (5.2).
`
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 7/2016
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1 INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Instructions
`
`
`
`2.2 Important Administration Instructions
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Anaphylaxis and Serious Hypersensitivity Reactions
`
`
`
`
`
`5.2 Pancreatitis
`
`
`5.3 Never Share ADLYXIN Pen Between Patients
`
`
`
`
`
`
`5.4 Hypoglycemia with Concomitant Use of Sulfonylurea or Basal
`
`
`
`
`
`
`
`
`
`Insulin
`
`5.5 Acute Kidney Injury
`
`
`
`
`5.6 Immunogenicity
`
`
`5.7 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Immunogenicity
`
`
`
`7 DRUG INTERACTIONS
`
`7.1 Delayed Gastric Emptying Effects on Oral Medications
`
`
`
`
`
`
`
`7.2 Dosage Adjustment of Sulfonylurea or Basal Insulin with
`
`
`
`
`
`
`
`
`
`Concomitant Use with ADLYXIN
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`8.6 Renal Impairment
`
`
`
`8.7 Patients with Gastroparesis
`
`
`
`
`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 Monotherapy
`
`14.2 Add-on Combination Therapy to Metformin (Alone or in
`
`
`
`
`
`
`
`
`Combination with Sulfonylurea)
`
`
`
`14.3 Add-on Combination Therapy to a Sulfonylurea (Alone or in
`
`
`
`
`
`
`
`
`
`Combination with Metformin)
`
`
`
`14.4 Add-on Treatment to Pioglitazone (Alone or in Combination with
`
`
`
`
`
`
`
`
`
`
`Metformin)
`
`14.5 Add on to Basal Insulin (Alone or in Combination with Oral
`
`
`
`
`
`
`
`
`
`Antidiabetics)
`
`14.6 ELIXA Cardiovascular Outcome Study
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`16.2 Storage and Handling
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`
`
`
`
`
`
`
`listed.
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`ADLYXIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`
`
`with type 2 diabetes mellitus.
`
`
`Limitations of Use:
`
`
`
`• ADLYXIN has not been studied in patients with chronic pancreatitis or a history of
`
`
`
`
`
`
`
`
`
`
`unexplained pancreatitis. Consider other antidiabetic therapies in patients with a history
`
`of pancreatitis [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`
`• ADLYXIN is not a substitute for insulin. ADLYXIN is not indicated for use in patients
`
`
`
`
`
`
`with type 1 diabetes mellitus or for treatment of diabetic ketoacidosis.
`
`
`
`
`• The concurrent use of ADLYXIN with short acting insulin has not been studied and is
`
`
`not recommended.
`• ADLYXIN has not been studied in patients with gastroparesis and is not recommended in
`
`
`
`
`patients with gastroparesis.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Instructions
`
`
`
`
`
`
`• The starting dose of ADLYXIN is 10 mcg subcutaneously once daily for 14 days.
`
`
`
`Increase the dose to the maintenance dose of 20 mcg once daily starting on Day 15.
`
`•
`
`
`Instruct patients and caregivers on the preparation and use of the pen prior to first use of
`ADLYXIN. Training should include a practice injection.
`
`
`
`Inspect ADLYXIN visually before use. It should appear clear and colorless. Do not use
`
`
`
`
`
`
`
`
`ADLYXIN if particulate matter or coloration is seen.
`
`
`
`
`• Administer ADLYXIN by subcutaneous injection in the abdomen, thigh or upper arm
`
`
`once daily.
`
`
`
`
`
`• Rotate injections sites with each dose. Do not use the same site for each injection.
`
`
`
`
`
`
`
`
`Instruct patients to administer an injection of ADLYXIN within one hour before the first
`
`•
`
`
`
`
`
`
`
`
`
`
`
`meal of the day preferably the same meal each day. If a dose is missed, administer
`ADLYXIN within one hour prior to the next meal.
`
`
`
`
`
`
`
`
`
`
`Instruct patients to protect the pen from light by keeping it in its original packaging and
`
`to discard pen 14 days after its first use.
`
`
`•
`
`
`•
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`ADLYXIN is a clear solution for subcutaneous injection available as:
`
`
`
`
`
`
`
`• 50 mcg/mL in 3 mL solution in a green single-patient use prefilled pen (for 14 doses; 10
`
`
`mcg/dose)
`
`Reference ID: 3964775
`
`
`
`2.2 Important Administration Instructions
`
`
`
`•
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
`
`
` • 100 mcg/mL in 3 mL solution in a burgundy single-patient use prefilled pen (for 14
`
`doses; 20 mcg/dose)
`
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`
`
`ADLYXIN is contraindicated in patients with known hypersensitivity to lixisenatide or to any
`
`
`
`
`
`
`
`component of ADLYXIN. Hypersensitivity reactions including anaphylaxis have occurred with
`
`
`
`ADLYXIN [see Warnings and Precautions (5.1) and Adverse reactions (6.1)].
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Anaphylaxis and Serious Hypersensitivity Reactions
`
`
`
`
`
`
`
`
`
`
`
`
`In clinical trials of ADLYXIN, there have been cases of anaphylaxis determined to be related to
`
`ADLYXIN (frequency of 0.1% or 10 cases per 10,000 patient-years). Other serious
`
`hypersensitivity reactions including angioedema also occurred [see Adverse Reactions (6.1)].
`
`
`
`Inform and closely monitor patients with a history of anaphylaxis or angioedema with another
`
`GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will
`
`
`be predisposed to anaphylaxis with ADLYXIN. ADLYXIN is contraindicated in patients with
`known hypersensitivity to lixisenatide [see Contraindications (4)]. If a hypersensitivity reaction
`
`
`
`
`
`
`
`occurs, the patient should discontinue ADLYXIN and promptly seek medical attention.
`
`
`
`5.2 Pancreatitis
`
`
`
`
`Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has
`
`
`
`
`
`
`
`
`
`
`been reported postmarketing in patients treated with GLP-1 receptor agonists. In clinical trials of
`
`
`
`
`
`
`
`
`
`
`ADLYXIN, there were 21 cases of pancreatitis among ADLYXIN-treated patients and 14 cases
`
`
`
`in comparator-treated patients (incidence rate of 21 vs. 17 per 10,000 patient-years). ADLYXIN
`
`
`
`
`cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5),
`
`
`
`
`
`
`
`
`
`
`and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a
`
`
`history of cholelithiasis or alcohol abuse.
`
`
`
`
`
`
`After initiation of ADLYXIN, observe patients carefully for signs and symptoms of pancreatitis
`
`(including persistent severe abdominal pain, sometimes radiating to the back and which may or
`
`
`may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue
`
`
`ADLYXIN and initiate appropriate management. If pancreatitis is confirmed, do not restart
`
`
`
`
`
`
`ADLYXIN. Consider antidiabetic therapies other than ADLYXIN in patients with a history of
`
`pancreatitis.
`
`
`
`
`5.3 Never Share ADLYXIN Pen Between Patients
`
`
`
`
`
`
`
`
`
`ADLYXIN pens should never be shared between patients, even if the needle is changed. Pen-
`
`sharing poses a risk for transmission of blood-borne pathogens.
`
`
`
`5.4 Hypoglycemia with Concomitant Use of Sulfonylurea or Basal Insulin
`
`
`
`
`Patients receiving ADLYXIN in combination with basal insulin or a sulfonylurea have an
`
`
`
`
`
`increased risk of hypoglycemia. In patients receiving sulfonylurea with or without metformin,
`
`14.5% patients on ADLYXIN reported symptomatic hypoglycemia compared to 10.6% for those
`on placebo. In patients receiving basal insulin with or without metformin, 28.3% patients on
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
`
`
`
`ADLYXIN reported symptomatic hypoglycemia compared to 23.0% for those on placebo. In
`
`patients receiving basal insulin with sulfonylurea, 47.2% patients on ADLYXIN reported
`
`
`symptomatic hypoglycemia compared to 21.6% for those on placebo. Reduction in the dose of
`
`
`
`
`sulfonylurea or basal insulin may be necessary. [see Adverse Reactions (6.1) and Drug
`
`
`
`
`
`Interactions (7.2)].
`
`
`5.5 Acute Kidney Injury
`
`
`Acute kidney injury and worsening of chronic renal failure, which may sometimes require
`
`
`
`
`
`
`hemodialysis has been reported postmarketing in patients treated with GLP-1 receptor agonists.
`
`
`
`
`
`
`Some of these events were reported in patients without known underlying renal disease. A
`
`majority of the reported events occurred in patients who had experienced nausea, vomiting,
`
`diarrhea, or dehydration.
`
`
` Monitor renal function when initiating or escalating doses of ADLYXIN in patients with renal
`
`
`
`
`
`
`
`
`
`
`
`
`
` impairment and in patients reporting severe gastrointestinal reactions. ADLYXIN is not
` recommended in patients with end stage renal disease [see Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`
`
`
`5.6 Immunogenicity
`
`Patients may develop antibodies to lixisenatide following treatment with ADLYXIN. A pooled
`
`
`
`
`
`
`
`
`analysis of studies of lixisenatide-treated patients showed that 70% were antibody positive at
`
`
`
`
`
`
`
`
`Week 24. In the subset of patients (2.4 %) with the highest antibody concentrations
`
`(>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic
`
`
`
`
`
`
`
`
`reactions and injection site reactions occurred in antibody positive patients. [see Warnings and
`
`
`
`
`Precautions (5.1), Adverse Reactions (6.2)].
`
`
`
`
`If there is worsening glycemic control or failure to achieve targeted glycemic control, significant
`
`
`
`
`
`
`
`
`injection site reactions or allergic reactions, alternative antidiabetic therapy should be considered
`
`
`
`
`
`
`[see Adverse Reactions (6.1)].
`
`
`5.7 Macrovascular Outcomes
`
`Clinical studies have not shown macrovascular risk reduction with ADLYXIN or any other
`
`
`
`
`
`
`antidiabetic drug [see Clinical Studies (14)].
`
`
`
`
`6 ADVERSE REACTIONS
`
`The following serious reactions are described below or elsewhere in the prescribing information:
`
`• Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions
`
`
`
`
`(5.1)]
`
`• Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Hypoglycemia with Concomitant Use of Sulfonylurea or Basal Insulin [see Warnings
`
`
`
`
`and Precautions (5.4)]
`
`
`• Renal Failure [see Warnings and Precautions (5.5)]
`
`
`
`
`
`Immunogenicity [see Warnings and Precautions (5.6)]
`
`
`
`
`•
`
`6.1 Clinical Trials Experience
`
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`Pool of Placebo-Controlled Trials
`
`
`The data in Table 1 are derived from the placebo-controlled trials [see Clinical Studies (14)].
`
`
`
`
`
`
`
`
`
`
`
`
`These data reflect exposure of 2869 patients to ADLYXIN and a mean duration of exposure to
`
`
`
`
`
`
`
`
`
`
`ADLYXIN of 21.7 weeks. Across the treatment arms, the mean age of patients was 56.1 years,
`
`
`
`2.3% were 75 years or older and 48.2% were male. The population in these studies was 63.7%
`
`
`
`
`
`
`
`White, 2.6% Black or African American, 32.0% Asian; 18.9% were of Hispanic or Latino
`
`
`
`
`ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean
`
`HbA1c of 8.1%. At baseline, 11.2% of the population reported retinopathy. Baseline estimated
`renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m2) in 95.3% of the
`
`
`pooled study populations.
`
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of
`
`ADLYXIN in the pool of placebo-controlled trials. These adverse reactions were not present at
`
`
`
`
`
`
`baseline, occurred more commonly on ADLYXIN than on placebo, and occurred in at least 5%
`
`
`
`
`
`
`
`
`of patients treated with ADLYXIN.
`
`
`
`
`
`
`Table 1: Adverse Reactions Reported in ≥5% of ADLYXIN-Treated Patients with Type 2 Diabetes Mellitus
`
`
`
`
`
`
`
`
`and Occurring More Frequently Compared to Placebo
`
`
`
`
`
`
`Placebo
`
`(N=1639)
`
`6%
`
`2%
`
`
` 6%
`6%
`
`
` 4%
`
`ADLYXIN
`
`(N=2869)
`
`25%
`
`10%
`
` 9%
`
`8%
`
`
` 7%
`
`Adverse reaction
`
`Nausea
`
`Vomiting
`
`
` Headache
`Diarrhea
`
` Dizziness
`
`
`*hypoglycemia is discussed separately
`
`Gastrointestinal Adverse Reactions
`
`In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more
`
`frequently among patients receiving ADLYXIN than placebo (placebo 18.4%, ADLYXIN
`
`
`
`
`
`
`39.7%). More patients receiving ADLYXIN (4.3%) discontinued treatment due to
`
`
`
`
`
`gastrointestinal adverse reactions than patients receiving placebo (0.5%). Investigators graded
`
`
`the severity of gastrointestinal adverse reactions occurring on ADLYXIN as “mild” in 64.2% of
`
`
`
`
`
`
`cases, “moderate” in 32.3% of cases, or “severe” in 3.5% of cases. The majority of these adverse
`
`
`
`
`
`
`
`
`
`
`
`reactions occurred during the first 3 weeks after starting treatment.
`
`
`
`
`
`
`
`
`
`In addition to the reactions in Table 1, the following adverse reactions were reported in >2% of
`
`
`patients and more frequently in ADLYXIN-treated patients than placebo (frequencies listed,
`
`
`
`
`
`
`respectively, as: placebo; ADLYXIN): dyspepsia (0.2%, 3.2%), constipation (1.8%, 2.8%),
`
`
`
`
`
`
`abdominal distension (0.9%, 2.2%), abdominal pain upper (0.9%, 2.2%), abdominal pain (1.5%,
`2.0%).
`
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`Hypoglycemia
`
`
`
`
`
`
`
`
`
`
` Symptomatic hypoglycemia was defined as an event with clinical symptoms that were
`
`
` considered to result from a hypoglycemic episode with an accompanying plasma glucose <60
`
`
`
`
`
` mg/dL or associated with prompt recovery after oral carbohydrate, intravenous glucose, or
`
`
`
`
`
`
`
`
`
`
`
` glucagon administration if no plasma glucose value was available.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were
`
`considered to result from hypoglycemia in which the patient required the assistance of another
`
`person, associated with a plasma glucose level below 36 mg/dL or, associated with prompt
`
`
`recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma
`
`
`glucose was available.
`
`
`
`
`
`
`Table 2 summarizes the incidence of symptomatic hypoglycemia and severe hypoglycemia in
`
`
`
`seven placebo-controlled efficacy/safety studies.
`
`Table 2: Incidence (%) of Symptomatic Hypoglycemia and Severe Hypoglycemia in Patients with Type 2
`
`
`
`
`
`Diabetes Mellitus During the 24-week Main Treatment Period
`
`
`
`
`
`
`Background therapy
`
`Monotherapy#
`
` Symptomatic (%)
`
`
`Severe (%)
`With Metformin
`
`
` Symptomatic (%)
`
`
`Severe (%)
`With Sulfonylurea +/- metformin
`
`
`
` Symptomatic (%)
`
`
`Severe (%)
`With Pioglitazone +/- metformin
`
`
`
` Symptomatic (%)
`
`
`Severe (%)
`With Basal insulin +/- metformin
`
`
`
`
` Symptomatic (%)
`Severe (%)
`
`
` With Basal insulin +/- sulfonylurea
`Symptomatic (%)
`
`
`
`Severe (%)
`
`With Insulin Glargine and metformin +/­
`
`thiazolidinedione
`
`
`Symptomatic (%)
`
`Severe (%)
` # 12-week treatment duration
`
`
`
`
` Injection site reactions
`
`ADLYXIN
`
`N=239
`
`
` 2
`
`0
`N=946
`
`
` 3
`
`0
`N=656
`
`
` 15
`
`0.2
`N=323
`
`
` 3
`
`0
`N=374
`
`
` 28
`1
`
`N=108
`
`47
`
`
`0
`N=223
`
`
`22
`
`
`0.4
`
`
`
`Placebo
`
`N=122
`
`
` 2
`
`0
`N=432
`
`
` 1
`
`0
`N=377
`
`
` 11
`
`0
`N=161
`
`
` 1
`
`0
`N=213
`
`
` 23
`0
`
`N=111
`
`22
`
`
`0
`N=223
`
`
`14
`
`
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`
`Injections site reactions (e.g., pain, pruritus and erythema) were reported more frequently in
`
`
`
`
`ADLYXIN-treated patients (4%) than placebo treated patients (2 %).
`
`
`
`Anaphylaxis and Hypersensitivity
`
`In the ADLYXIN development program anaphylaxis cases were adjudicated. Anaphylaxis was
`
`
`
`
`
`
`
`
`
`defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system
`
`
`
`
`
`
`
`
`
`
`
`involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be
`
`present but were not required for the case definition. More cases adjudicated as meeting the
`
`
`
`
`
`
`definition for anaphylaxis occurred in ADLYXIN-treated patients (incidence rate of 0.2% or 16
`
`
`
`
`
`cases per 10,000 patient years) than placebo treated patient (incidence rate of 0.1% or 7 cases per
`
`
`
`
`
`
`
`
`
`
`
`10,000 patient years).
`
`
`Allergic reactions (such as anaphylactic reaction, angioedema and urticaria) adjudicated as
`
`
`
`
`
`
`
`
`possibly related to the study medication were observed more frequently in ADLYXIN-treated
`
`
`
`
`
`
`
`patients (0.4%) than placebo-treated patient (0.2%) [see Warnings and Precautions (5.1)].
`
`
`
`6.2 Immunogenicity
`
`In the pool of 9 placebo-controlled studies, 70% of patients exposed to lixisenatide tested
`
`
`positive for anti-lixisenatide antibodies during the trials. In the subset of patients (2.4%) with the
`
`
`
`
`
`
`
`
`highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed.
`
`
`A higher incidence of allergic reactions and injection site reactions occurred in antibody positive
`
`
`patients. [see Warnings and Precautions (5.6)]
`
`
`
`Anti-lixisenatide antibody characterization studies have demonstrated the potential for
`
`
`
`
`
`
`development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but their
`
`
`incidence has not been fully determined and the clinical significance of these antibodies is not
`
`
`
`
`currently known.
`
`
`No information regarding the presence of neutralizing antibodies is currently available.
`
`
`
`
`
`
`
`The detection of antibody formation is highly dependent on the sensitivity and specificity of the
`
`
`
`
`assay. Additionally, the observed incidence of antibody (including neutralizing antibody)
`
`
`positivity in an assay may be influenced by several factors including assay methodology, sample
`
`
`
`handling, timing of sample collection, concomitant medications, and underlying disease. For
`
`these reasons, the incidence of antibodies to lixisenatide cannot be directly compared with the
`
`
`incidence of antibodies with other products.
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`
` 7.1 Delayed Gastric Emptying Effects on Oral Medications
`
`
`
`
`
`
` ADLYXIN delays gastric emptying which may reduce the rate of absorption of orally
`
`
`
` administered medications. Use caution when coadministering oral medications that have a
`
`
`
`
`
`
` narrow therapeutic ratio or that require careful clinical monitoring. These medications should be
`
`
`
` adequately monitored when concomitantly administered with ADLYXIN. If such medications
`
` are to be administered with food, patients should be advised to take them with a meal or snack
`
` when ADLYXIN is not administered.
`
`
`
`
`
`
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`
`
`
`
` Oral medications that are particularly dependent on threshold concentrations for efficacy, such as
`
`
`
`
`
`
`
`
`
` antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen,
` should be administered at least 1 hour before ADLYXIN injection [see Clinical Pharmacology
`
`
`
`
`(12.3)].
`
`
`
`
`
`Patients taking oral contraceptives should be advised to take them at least 1 hour before
`
`ADLYXIN administration or at least 11 hours after the dose of ADLYXIN [see Clinical
`
`
`
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`7.2 Dosage Adjustment of Sulfonylurea or Basal Insulin with Concomitant Use with
`
`ADLYXIN
`
`
`
`
`
`
`When ADLYXIN is added to a sulfonylurea or basal insulin, there is a potential risk of
`
`
`hypoglycemia. A reduction of the concomitantly administered sulfonylurea or basal insulin may
`
`
`be necessary. [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`Risk Summary
`
`
`
`
`
`
`
`
`
`
`
`The limited available data with lixisenatide in pregnant women are not sufficient to inform a
`
`
`
`
`
`
`
`
`
`
`drug-associated risk of major birth defects and miscarriage. There are risks to the mother and
`fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
`
`
`
`
`Based on animal reproduction studies, there may be risks to the fetus from exposure to
`
`
`lixisenatide during pregnancy. ADLYXIN should be used during pregnancy only if the potential
`
`
`
`
`
`
`benefit justifies the potential risk to the fetus.
`
`Lixisenatide administered to pregnant rats and rabbits during organogenesis was associated with
`
`
`
`
`
`
`
`
`
`
`visceral closure and skeletal defects at systemic exposures that decreased maternal food intake
`
`
`
`
`
`
`
`
`
`
`
`and weight gain during gestation, and that are 1-time and 6-times higher than the 20 mcg/day
`clinical dose, respectively, based on plasma 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 a
`
`
`
`
`
`
`
`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, stillbirth and delivery complications. Poorly
`
`
`
`
`
`
`
`
`
`
`
`
`controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia
`
`
`related morbidity.
`
`
`Data
`Animal Data
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
`
`
`
`
`
` In pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during
` organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g.,
`
`
`
`
`
`
` microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. Impaired
`
` ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and
`
`
`
` pelvis) were observed at ≥5 mcg/kg/day, resulting in systemic exposure that is 1-time the
`
`
`
`
`
`
` 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food
`
`
`
`
`
`
`
`
`
`
` consumption, and motor activity were observed concurrent with the adverse fetal findings, which
`
` confounds the interpretation of relevance of these malformations to the human risk assessment.
`
` Placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in
`
`
`
`
`
`
`
`
`
`
`
`
` fetal/maternal plasma of 0.1%.
`
`
`
`
`
`In pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during
`
`
`organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal
`
`
`
`
`malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-
`
`
`
`
`
`
`
`
`
`
`
`
`
`times the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight,
`food consumption, and motor activity were observed concurrent with the fetal findings, which
`
`
`
`
`
`
`
`
`
`confounds the interpretation of relevance of these malformations to the human risk assessment.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in
`
`
`
`fetal/maternal plasma of ≤0.3%. In a second study in pregnant rabbits, no drug-related
`malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg
`
`
`administered during organogenesis, resulting in systemic exposures up to 9-times the clinical
`
`exposure at 20 mcg/day, based on plasma AUC.
`
`
`
`
`In pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day
`
`6 through lactation, decreases in maternal body weight, food consumption, motor activity were
`
`
`
`
`observed at all doses. Skeletal malformations and increased pup mortality were observed at 400
`mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose, based on mcg/m2 .
`
`8.2 Lactation
`
`
`Risk Summary
` There is no information regarding the presence of ADLYXIN in human milk, the effects on the
`
`
`
`
`
`
`
` breastfed infant, or the effects on milk production. However, lixisenatide is present in rat milk
` [see Data]. The developmental and health benefits of breastfeeding should be considered along
`
`
`
`
`
`
`
`
`
`
`
` with the mother’s clinical need for lixisenatide and any potential adverse effects on the breastfed
`infant from lixisenatide or from the underlying maternal condition.
`
`
`Data
`Animal Data
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A study in lactating rats showed low (9.4%) transfer of lixisenatide and its metabolites into milk
`
`
`
`
`
`
`
`
`and negligible (0.01%) levels of unchanged lixisenatide peptide in the gastric contents of
`
`
`weaning offspring.
`
`
`8.4 Pediatric Use
`
`
`
`
`
`
`
`
`
`
`
`Safety and effectiveness of ADLYXIN have not been established in pediatric patients below 18
`
`
`
`years of age.
`
`
`8.5 Geriatric Use
`
`
`
`
`
`Reference ID: 3964775
`
`Novo Nordisk Exhibit 2455
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
`In Phase 2 and 3controlled clinical studies of ADLYXIN, a total of 1837 (25%) of the patients
`
`
`
`
`exposed to the study medication were 65 years of age and over and 288 (4%) were 75 years of
`
`
`
`
`age and over. No overall differences were observed in