HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`BYETTA safely and effectively. See full prescribing information for
`BYETTA.
`
`BYETTA (exenatide) Injection
`Initial U.S. Approval: 2005
`-------------------------- RECENT MAJOR CHANGES --------------------------
`2/2015
`Warnings and Precautions (5.1)
`--------------------------- INDICATIONS AND USAGE --------------------------
`BYETTA (exenatide) 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 (1.1, 14).
`Important Limitations of Use
`Not a substitute for insulin. BYETTA should not be used for the
`
`treatment of type 1 diabetes or diabetic ketoacidosis (1.2).
`Concurrent use with prandial insulin has not been studied and cannot be
`
`recommended (1.2).
`Has not been studied in patients with a history of pancreatitis. Consider
`
`other antidiabetic therapies in patients with a history of pancreatitis
`(1.2).
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`Inject subcutaneously within 60 minutes prior to morning and evening
`
`meals (or before the two main meals of the day, approximately 6 hours
`or more apart) (2.1).
`Initiate at 5 mcg per dose twice daily; increase to 10 mcg twice daily
`
`after 1 month based on clinical response (2.1).
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`BYETTA is supplied as 250 mcg/mL exenatide in:
`5 mcg per dose, 60 doses, 1.2 mL prefilled pen
`
`10 mcg per dose, 60 doses, 2.4 mL prefilled pen
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`History of severe hypersensitivity to exenatide or any product
`
`components (4.1).
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Never share a BYETTA pen between patients, even if the needle is
`
`changed (5.1).
`Pancreatitis: Postmarketing reports with exenatide, including fatal and
`
`non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue BYETTA
`promptly. BYETTA should not be restarted. Consider other antidiabetic
`therapies in patients with a history of pancreatitis (5.2).
`Hypoglycemia: Increased risk when BYETTA is used in combination
`with medications known to cause hypoglycemia (e.g., insulin or insulin
`secretagogue). Consider reducing the dose of insulin or insulin
`secretagogue (5.3).
`
`
`
`2
`
`3
`4
`
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Type 2 Diabetes Mellitus
`1.2
`Important Limitations of Use
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Hypersensitivity
`WARNINGS AND PRECAUTIONS
`5.1 Never Share a BYETTA Pen Between Patients
`5.2 Acute Pancreatitis
`5.3 Use with Medications Known to Cause Hypoglycemia
`5.4 Renal Impairment
`5.5 Gastrointestinal Disease
`5.6
`Immunogenicity
`5.7 Hypersensitivity
`5.8 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Orally Administered Drugs
`7.2 Warfarin
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`
`6
`
`7
`
`8
`
`Reference ID: 3706632
`
`
`
`
`
`
`
`
`Renal Impairment: Postmarketing reports with exenatide, sometimes
`requiring hemodialysis and kidney transplantation. BYETTA should not
`be used in patients with severe renal impairment or end-stage renal
`disease and should be used with caution in patients with renal
`transplantation. Caution should be applied when initiating BYETTA or
`escalating the dose of BYETTA in patients with moderate renal failure
`(5.4, 8.6, 12.3).
`Severe Gastrointestinal Disease: Use of BYETTA is not recommended
`in patients with severe gastrointestinal disease (e.g., gastroparesis) (5.5).
`Hypersensitivity: Postmarketing reports with exenatide of
`hypersensitivity reactions (e.g., anaphylaxis and angioedema). The
`patient should discontinue BYETTA and other suspect medications and
`promptly seek medical advice (5.7).
` Macrovascular outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`BYETTA or any other antidiabetic drug (5.8).
`------------------------------ ADVERSE REACTIONS -----------------------------
` Most common (≥5%) and occurring more frequently than placebo in
`clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery,
`dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually
`decreases over time (5.3, 6).
`Postmarketing reports with exenatide of increased international
`normalized ratio (INR) with concomitant use of warfarin, sometimes
`with bleeding (6.2, 7.2).
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 and www.byetta.com or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`------------------------------ DRUG INTERACTIONS -----------------------------
` May impact absorption of orally administered medications (7.1, 12.3).
` Warfarin: Postmarketing reports of increased INR sometimes associated
`with bleeding. Monitor INR frequently until stable upon initiation or
`
`alteration of BYETTA therapy (6.2, 7.2).
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: Based on animal data, BYETTA may cause fetal harm.
`
`BYETTA should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus. To report drug exposure during
`pregnancy call 1-800-633-9081 (8.1).
`Nursing Mothers: Caution should be exercised when BYETTA is
`
`administered to a nursing woman (8.3).
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 2/2015
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.3
`Reproductive and Developmental Toxicology
`14 CLINICAL STUDIES
`14.1
`Monotherapy
`14.2
`Combination Therapy with Oral Antihyperglycemic
`Medicines
`14.3
`Combination with Insulin Glargine
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1
`How Supplied
`16.2
`Storage and Handling
`17
`PATIENT COUNSELING INFORMATION
`17.1
`Never Share a BYETTA Pen Between Patients
`17.2
`Risk of Pancreatitis
`17.3
`Risk of Hypoglycemia
`17.4
`Risk of Renal Impairment
`
`1
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`17.5
`17.6
`
`Risk of Hypersensitivity Reactions
`Use in Pregnancy
`
`17.7
`
`Instructions
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
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`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1 Type 2 Diabetes Mellitus
`BYETTA (exenatide) 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
`1.2
`BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of type 1
`diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
`
`The concurrent use of BYETTA with prandial insulin has not been studied and cannot be
`recommended.
`
`Based on postmarketing data BYETTA has been associated with acute pancreatitis, including
`fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been studied in
`patients with a history of pancreatitis. It is unknown whether patients with a history of
`pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic
`therapies should be considered in patients with a history of pancreatitis.
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`BYETTA should be initiated at 5 mcg administered twice daily (BID) at any time within the 60-
`minute period before the morning and evening meals (or before the two main meals of the day,
`approximately 6 hours or more apart). BYETTA should not be administered after a meal. Based
`on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month
`of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side
`effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh,
`abdomen, or upper arm. Do not mix BYETTA with insulin. Do not transfer BYETTA from the
`pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or
`intramuscular injection of BYETTA.
`
`Use BYETTA only if it is clear, colorless and contains no particles.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL
`exenatide in the following packages:
`
` 5 mcg per dose, 60 doses, 1.2 mL prefilled pen
`
`3
`
`
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` 10 mcg per dose, 60 doses, 2.4 mL prefilled pen
`CONTRAINDICATIONS
`4
`4.1 Hypersensitivity
`BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide
`or to any of the product components.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Never Share a BYETTA Pen Between Patients
`BYETTA pens must never be shared between patients, even if the needle is changed. Pen-
`sharing poses a risk for transmission of blood-borne pathogens.
`
`5.2 Acute Pancreatitis
`Based on postmarketing data, BYETTA has been associated with acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of
`BYETTA, and after dose increases, observe patients carefully for signs and symptoms of
`pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back,
`which may or may not be accompanied by vomiting). If pancreatitis is suspected, BYETTA
`should promptly be discontinued and appropriate management should be initiated. If
`pancreatitis is confirmed, BYETTA should not be restarted. Consider antidiabetic
`therapies other than BYETTA in patients with a history of pancreatitis.
`5.3 Use with Medications Known to Cause Hypoglycemia
`The risk of hypoglycemia is increased when BYETTA is used in combination with a
`sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower
`dose of the sulfonylurea to reduce the risk of hypoglycemia.
`
`When BYETTA is used in combination with insulin, the dose of insulin should be evaluated. In
`patients at increased risk of hypoglycemia consider reducing the dose of insulin [see Adverse
`Reactions (6.1)]. The concurrent use of BYETTA with prandial insulin has not been studied and
`cannot be recommended. It is also possible that the use of BYETTA with other glucose-
`independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia.
`
`For additional information on glucose-dependent effects see Mechanism of Action (12.1).
`
`5.4 Renal Impairment
`BYETTA should not be used in patients with severe renal impairment (creatinine clearance <30
`mL/min) or end-stage renal disease and should be used with caution in patients with renal
`transplantation [see Use in Specific Populations (8.6)]. In patients with end-stage renal disease
`
`Reference ID: 3706632
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`receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal
`side effects. Because BYETTA may induce nausea and vomiting with transient hypovolemia,
`treatment may worsen renal function. Caution should be applied when initiating or escalating
`doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment (creatinine
`clearance 30-50 mL/min).
`
`There have been postmarketing reports of altered renal function, including increased serum
`creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes
`requiring hemodialysis or kidney transplantation. Some of these events occurred in patients
`receiving one or more pharmacologic agents known to affect renal function or hydration status,
`such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or
`diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or
`diarrhea, with or without dehydration. Reversibility of altered renal function has been observed
`in many cases with supportive treatment and discontinuation of potentially causative agents,
`including BYETTA. Exenatide has not been found to be directly nephrotoxic in preclinical or
`clinical studies.
`
`5.5 Gastrointestinal Disease
`BYETTA has not been studied in patients with severe gastrointestinal disease, including
`gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse reactions,
`including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in patients
`with severe gastrointestinal disease.
`
`
`
`Immunogenicity
`5.6
` Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody
`levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week placebo-
`controlled studies and the 30-week comparator-controlled study of BYETTA. In 3%, 4%, 1%,
`and 1% of these patients, respectively, antibody formation was associated with an attenuated
`glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic
`control, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1)].
`
`5.7 Hypersensitivity
`There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis
`and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the
`patient should discontinue BYETTA and other suspect medications and promptly seek medical
`advice [see Adverse Reactions (6.2)].
`
`5.8 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with BYETTA or any other antidiabetic drug.
`
`Reference ID: 3706632
`
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`
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`ADVERSE REACTIONS
`6
`6.1 Clinical Trial 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.
`
`Hypoglycemia
`Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in six placebo-
`controlled clinical trials.
`
`Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as
`Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled
`Clinical Trials*
`
`BYETTA
`5 mcg BID
`
`BYETTA
`10 mcg BID
`
`77
`5.2%
`0.21
`0.0%
`
`110
`4.5%
`0.13
`0.0%
`
`125
`14.4%
`0.64
`0.0%
`
`245
`19.2%
`0.78
`0.4%
`
`not evaluated
`not evaluated
`not evaluated
`not evaluated
`
`78
`3.8%
`0.52
`0.0%
`
`113
`5.3%
`0.12
`0.0%
`
`129
`35.7%
`1.61
`0.0%
`
`241
`27.8%
`1.71
`0.0%
`
`121
`10.7%
`0.98
`0.0%
`
`Placebo
`BID
`
`Monotherapy (24 Weeks)
`N
`
`% Overall
`
`Rate (episodes/patient-year)
`
`% Severe
`
`With Metformin (30 Weeks)
`N
`
`% Overall
`
`Rate (episodes/patient-year)
`
`% Severe
`
`With a Sulfonylurea (30 Weeks)
`123
`N
`
`3.3%
`% Overall
`
`0.07
`Rate (episodes/patient-year)
`
`0.0%
`% Severe
`
`With Metformin and a Sulfonylurea (30 Weeks)
`N
`247
`
`% Overall
`12.6%
`
`Rate (episodes/patient-year)
`0.58
`
`% Severe
`0.0%
`
`With a Thiazolidinedione (16 Weeks)
`N
`
`% Overall
`
`Rate (episodes/patient-years)
`
`% Severe
`
`
`77
`1.3%
`0.03
`0.0%
`
`113
`5.3%
`0.12
`0.0%
`
`112
`7.1%
`0.56
`0.0%
`
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`Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as
`Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled
`Clinical Trials*
`
`BYETTA
`BYETTA
`Placebo
`10 mcg BID
`5 mcg BID
`BID
`With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks)†
`
` N
`122
`not evaluated
`137
`% Overall
`29.5%
`not evaluated
`24.8%
`
`Rate (episodes/patient-years)
`1.58
`not evaluated
`1.61
`
`% Severe
`0.8%
`not evaluated
`0.0%
`
`* A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood
`glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms
`consistent with hypoglycemia requiring the assistance of another person and associated with either a documented
`blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia.
`† When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by
`20% in patients with an HbA1c ≤8.0% to minimize the risk of hypoglycemia. See Table 9 for insulin dose titration
`algorithm.
`N = number of Intent-to-Treat subjects in each treatment group.
`Immunogenicity
`Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of
`BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or
`sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked
`at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low
`titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA1c) in these
`patients was generally comparable to that observed in the 534 patients (56%) without antibody
`titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these
`patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27
`(3% overall) had a glycemic response comparable to that of patients without antibodies [see
`Warnings and Precautions (5.6)].
`
`In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 36
`patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in
`these patients was generally comparable to that observed in the 69 patients (60%) without
`antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these
`patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5%
`overall) had a glycemic response comparable to that of patients without antibodies [see Warnings
`and Precautions (5.6)].
`
`In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer
`antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally
`comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3
`patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an
`
`Reference ID: 3706632
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`attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic
`response comparable to that of patients without antibodies [see Warnings and Precautions (5.6)].
`
`Antibodies to exenatide were not assessed in the 30-week placebo-controlled trial of BYETTA
`used in combination with insulin glargine.
`
`In the 30-week comparator-controlled trial of BYETTA used in combination with insulin
`glargine and metformin, 60 patients (20%) had low titer antibodies to exenatide at 30 weeks. The
`level of glycemic control in these patients was generally comparable to that observed in the 234
`patients (77%) without antibody titers. An additional 10 patients (3%) had higher titer antibodies
`at 30 weeks. Of these patients, 2 (1% overall) had an attenuated glycemic response to BYETTA;
`the remaining 8 (3% overall) had a glycemic response comparable to that of patients without
`antibodies [see Warnings and Precautions (5.5)].
`
`Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were
`tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-
`emergent cross-reactive antibodies were observed across the range of titers.
`
`Other Adverse Reactions
`Monotherapy
`For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2
`summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and
`occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.
`
`Table 2: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used
`as Monotherapy (excluding Hypoglycemia)*
`Monotherapy
`Placebo BID
`N = 77
`%
`0
`0
`0
`
`All BYETTA BID
`N = 155
`%
`8
`4
`3
`
`Nausea
`Vomiting
`Dyspepsia
`*In a 24-week placebo-controlled trial.
`BID = twice daily.
`
`Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more
`frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most
`frequently reported adverse reaction associated with BYETTA, nausea, occurred in a dose-
`dependent fashion.
`
`Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headache
`and nausea. No placebo-treated patients withdrew due to adverse reactions.
`
`Reference ID: 3706632
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`Combination Therapy
`Add-On to Metformin and/or Sulfonylurea
`In the three 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea,
`adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more
`frequently in BYETTA-treated patients compared with placebo-treated patients [see Warnings
`and Precautions (5.3)] are summarized in Table 3.
`
`Table 3: Treatment-Emergent Adverse Reactions ≥2% Incidence and Greater
`Incidence with BYETTA Treatment used with Metformin and/or a Sulfonylurea
`(excluding Hypoglycemia)*
`
`Nausea
`Vomiting
`Diarrhea
`Feeling Jittery
`Dizziness
`Headache
`Dyspepsia
`Asthenia
`Gastroesophageal Reflux Disease
`Hyperhidrosis
`* In three 30-week placebo-controlled clinical trials.
`BID = twice daily.
`
`Placebo BID
`N = 483
`%
`18
`4
`6
`4
`6
`6
`3
`2
`1
`1
`
`All BYETTA BID
`N = 963
`%
`44
`13
`13
`9
`9
`9
`6
`4
`3
`3
`
`Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more
`frequently than with placebo included decreased appetite. Nausea was the most frequently
`reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the
`frequency and severity decreased over time in most of the patients who initially experienced
`nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported
`no new types of adverse reactions than those observed in the 30-week controlled trials.
`
`The most common adverse reactions leading to withdrawal for BYETTA-treated patients were
`nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to
`nausea and none due to vomiting.
`
`Add-On to Thiazolidinedione with or without Metformin
`For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or
`without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an
`incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with
`placebo-treated patients.
`
`Reference ID: 3706632
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`Table 4: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used
`with a Thiazolidinedione (TZD), with or without Metformin (MET) (excluding
`Hypoglycemia)*
`With a TZD or TZD/MET
`
`Nausea
`Vomiting
`Dyspepsia
`Diarrhea
`Gastroesophageal Reflux Disease
`* In a 16-week placebo-controlled clinical trial.
`BID = twice daily.
`
`Placebo
`N = 112
`%
`15
`1
`1
`3
`0
`
`All BYETTA BID
`N = 121
`%
`40
`13
`7
`6
`3
`
`Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more
`frequently than with placebo included decreased appetite. Chills (n=4) and injection-site
`reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an
`injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events
`(chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No
`serious adverse events were reported in the placebo arm.
`
`The most common adverse reactions leading to withdrawal for BYETTA-treated patients were
`nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
`
`Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione (Placebo-
`Controlled)
`For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or
`without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding
`hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-
`treated patients compared with placebo-treated patients.
`
`Table 5: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used
`with Insulin Glargine with or without Oral Antihyperglycemic Medications (excluding
`Hypoglycemia)*
`With Insulin Glargine
`
`Placebo
`N = 122
`%
`8
`4
`8
`4
`2
`2
`1
`
`All BYETTA BID
`N = 137
`%
`41
`18
`18
`14
`10
`7
`5
`
`Nausea
`Vomiting
`Diarrhea
`Headache
`Constipation
`Dyspepsia
`Asthenia
`
`Reference ID: 3706632
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`Table 5: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used
`with Insulin Glargine with or without Oral Antihyperglycemic Medications (excluding
`Hypoglycemia)*
`With Insulin Glargine
`
`Abdominal Distension
`Decreased Appetite
`Flatulence
`Gastroesophageal Reflux Disease
`* In a 30-week placebo-controlled clinical trial.
`BID = twice daily.
`
`Placebo
`N = 122
`%
`1
`0
`1
`1
`
`All BYETTA BID
`N = 137
`%
`4
`3
`2
`2
`
`The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated
`patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to
`nausea or vomiting.
`
`6.2 Postmarketing Experience
`The following additional adverse reactions have been reported during postapproval use of
`BYETTA. Because these events are reported voluntarily from a population of uncertain size, it is
`generally not possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
`Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular
`or papular rash, angioedema, anaphylactic reaction [see Warnings and Precautions (5.7)].
`
`Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use
`sometimes associated with bleeding [see Drug Interactions (7.2)].
`
`Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal
`distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic
`and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1.2) and
`Warnings and Precautions (5.2)].
`
`Neurologic: dysgeusia; somnolence
`
`Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal
`impairment, worsened chronic renal failure or acute renal failure (sometimes requiring
`hemodialysis), kidney transplant and kidney transplant dysfunction [see Warnings and
`Precautions (5.4)].
`
`Skin and Subcutaneous Tissue Disorders: alopecia
`
`Reference ID: 3706632
`
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`DRUG INTERACTIONS
`7
`7.1 Orally Administered Drugs
`The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of
`orally administered drugs. BYETTA should be used with caution in patients receiving oral
`medications that have narrow therapeutic index or require rapid gastrointestinal absorption [see
`Adverse Reactions (6.2)]. For oral medications that are dependent on threshold concentrations for
`efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at
`least 1 hour before BYETTA injection. If such drugs are to be administered with food, patients
`should be advised to take them with a meal or snack when BYETTA is not administered [see
`Clinical Pharmacology (12.3)].
`
`7.2 Warfarin
`There are postmarketing reports of increased INR sometimes associated with bleeding, with
`concomitant use of warfarin and BYETTA [see Adverse Reactions (6.2)]. In a drug interaction
`study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In
`patients taking warfarin, prothrombin time should be monitored more frequently after initiation
`or alteration of BYETTA therapy. Once a stable prothrombin time has been documented,
`prothrombin times can be monitored at the intervals usually recommended for patients on
`warfarin.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`
`Pregnancy Category C
`There are no adequate and well-controlled studies of BYETTA use in pregnant women. In
`animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased
`number of neonatal deaths. BYETTA should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`
`Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and
`throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760
`mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the
`maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology
`(13.3)].
`
`In developmental toxicity studies, pregnant animals received exenatide subcutaneously during
`organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or
`260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications
`from exposures 12 times the human exposure resulting from the maximum recommended dose of
`
`Reference ID: 3706632
`
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`20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460,
`or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal
`growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure
`resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical
`Toxicology (13.3)].
`
`Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through
`lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were
`observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the
`human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC
`[see Nonclinical Toxicology (13.3)].
`
`Pregnancy Registry
`A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed
`to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-
`633-9081.
`
`8.3 Nursing Mothers
`It is not known whether exenatide is excreted in human milk. However, exenatide is present at
`low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following
`subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and
`because of the potential for clinically significant adverse reactions in nursing infants from
`exenatide, a decision should be made whether to discontinue nursing or discontinue the drug,
`taking into account these potential risks against the glycemic benefits to the lactating woman.
`Caution should be exercised when BYETTA is administered to a nursing woman.
`
`8.4 Pediatric Use
`Safety and effectiveness of BYETTA have not been established in pediatric patients.
`
`8.5 Geriatric Use
`Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that
`age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology
`(12.3)]. BYETTA was studied in 282 p