10/2009
`
`10/2009
`
`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------------------------
`Indications and Usage
`10/2009
` Monotherapy and Combination Therapy (1.1)
` Important Limitations of Use
`History of Pancreatitis (1.2)
`Warnings and Precautions
` Pancreatitis (5.1)
`
` Renal Impairment (5.3)
`
` Macrovascular Outcomes (5.7)
`
`---------------------------INDICATIONS AND USAGE---------------------------
`BYETTA 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.
`Important Limitations of Use
`• BYETTA is not a substitute for insulin. BYETTA should not be used in
`patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
`(1.2).
`• The concurrent use of BYETTA with insulin has not been studied and
`cannot be recommended (1.2).
`• BYETTA 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-----------------------
`• Pancreatitis: Postmarketing reports, including fatal and non-fatal
`hemorrhagic or necrotizing pancreatitis. Discontinue BYETTA promptly.
`
`2
`
`3
`4
`
`BYETTA should not be restarted. Consider other antidiabetic therapies in
`patients with a history of pancreatitis (5.1).
`• Hypoglycemia: Increased risk when BYETTA is used in combination with
`a sulfonylurea. Consider reducing the sulfonylurea dose (5.2).
`• Renal Impairment: Postmarketing reports, 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 (5.3).
`• Severe Gastrointestinal Disease: Use of BYETTA is not recommended in
`patients with severe gastrointestinal disease (e.g., gastroparesis) (5.4).
`• Hypersensitivity: Postmarketing reports of hypersensitivity reactions (e.g.
`anaphylaxis and angioedema). The patient should discontinue BYETTA
`and other suspect medications and promptly seek medical advice (5.6).
`• There have been no clinical studies establishing conclusive evidence of
`macrovascular risk reduction with BYETTA or any other antidiabetic drug
`(5.7).
`-----------------------------ADVERSE REACTIONS-------------------------------
`• Most common (≥5%) and occurring more frequently than placebo in
`clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery,
`dizziness, headache, dyspepsia. Nausea usually decreases over time (5.2;
`6).
`• Postmarketing reports of increased international normalized ratio (INR)
`with concomitant use of warfarin, sometimes with bleeding (6.2).
`To report SUSPECTED ADVERSE REACTIONS contact Amylin
`Pharmaceuticals, Inc. and Eli Lilly and Company at 1-800-868-1190 and
`www.byetta.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`------------------------------DRUG INTERACTIONS------------------------------
`• Warfarin: Postmarketing reports of increased INR sometimes associated
`with bleeding. Monitor INR frequently until stable upon initiation or
`alteration of BYETTA therapy (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 FDA-
`approved patient labeling.
`
`Revised: 10/2009
`
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`8.6
`Hepatic Impairment
`8.7
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment of
`13.1
`Fertility
`
`Reproductive and Developmental Toxicology
`13.3
`14 CLINICAL STUDIES
`14.1 Monotherapy
`14.2
`Combination Therapy
`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.
`
`Page 1 of 26
`
`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
`5 WARNINGS AND PRECAUTIONS
`5.1
`Acute Pancreatitis
`5.2
`Hypoglycemia
`5.3
`Renal Impairment
`5.4
`Gastrointestinal Disease
`5.5
`Immunogenicity
`5.6
`Hypersensitivity
`5.7
`Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1
`Clinical Trial Experience
`6.2
`Post-Marketing 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
`
`MPI EXHIBIT 1021 PAGE 1
`
`MPI EXHIBIT 1021 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0001
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`1.1 Type 2 Diabetes Mellitus
`BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus.
`
`1.2 Important Limitations of Use
`BYETTA is not a substitute for insulin. BYETTA should not be used in patients with type 1
`diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these
`settings.
`
`The concurrent use of BYETTA with 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.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`BYETTA should be initiated at 5 mcg administered twice daily 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. 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
`10 mcg per dose, 60 doses, 2.4 mL prefilled pen
`
`Page 2 of 26
`
`MPI EXHIBIT 1021 PAGE 2
`
`MPI EXHIBIT 1021 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0002
`
`

`

`4 CONTRAINDICATIONS
`
`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 Acute Pancreatitis
`Based on postmarketing data BYETTA has been associated with acute pancreatitis,
`ncluding fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of
`BYETTA, and after dose increases, observe patients carefully for signs and symptoms of
`ancreatitis (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
`nitiated. If pancreatitis is confirmed, BYETTA should not be restarted. Consider
`ntidiabetic therapies other than BYETTA in patients with a history of pancreatitis.
`
`i p ia
`
`5.2 Hypoglycemia
`The risk of hypoglycemia is increased when BYETTA is used in combination with a
`sulfonylurea (hypoglycemia can also occur when other antidiabetic agents are 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. 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).
`
`5.3 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
`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 mcg to 10 mcg in patients with moderate renal impairment (creatinine
`clearance 30 to 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
`
`Page 3 of 26
`
`MPI EXHIBIT 1021 PAGE 3
`
`MPI EXHIBIT 1021 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0003
`
`

`

`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.
`
`5.4 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.
`
`5.5 Immunogenicity
`Patients may develop antibodies to exenatide following treatment with BYETTA, consistent with
`the potentially immunogenic properties of protein and peptide pharmaceuticals. In a small
`proportion of patients, the formation of antibodies to exenatide at high titers could result in
`failure to achieve adequate improvement in glycemic control. If there is worsening glycemic
`control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be
`considered [see Adverse Reactions (6.1)].
`
`5.6 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)].
`
`5.7 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with BYETTA or any other antidiabetic drug.
`
`6 ADVERSE REACTIONS
`
`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
`
`Page 4 of 26
`
`MPI EXHIBIT 1021 PAGE 4
`
`MPI EXHIBIT 1021 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0004
`
`

`

`Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in five placebo-
`controlled clinical trials.
`
`Table 1:
`
`Incidence (%) and Rate of Hypoglycemia When BYETTA was Used as Monotherapy or With
`Concomitant Antidiabetic Therapy in Five Placebo-Controlled Clinical Trials*
`BYETTA
`5 mcg twice daily
`
`10 mcg twice daily
`
`77
`1.3%
`0.03
`
`0.0%
`
`113
`5.3%
`0.12
`
`Immunogenicity
`
`Page 5 of 26
`
`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%
`
`Dose not studied
`Dose not studied
`Dose not studied
`
`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
`
`Placebo twice daily
`Monotherapy (24 Weeks)
`N
`% Overall
`Rate
`(episodes/patient­
`year)
`% Severe
`With Metformin (30 Weeks)
`N
`% Overall
`Rate
`(episodes/patient­
`year)
`0.0%
`% Severe
`With a Sulfonylurea (30 Weeks)
`N
`123
`% Overall
`3.3%
`Rate
`0.07
`(episodes/patient­
`year)
`0.0%
`% Severe
`With Metformin and a Sulfonylurea (30 Weeks)
`N
`247
`% Overall
`12.6%
`Rate
`0.58
`(episodes/patient­
`year)
`0.0%
`% Severe
`With a Thiazolidinedione (16 Weeks)
`N
`112
`% Overall
`7.1%
`Rate
`0.56
`(episodes/patient­
`years)
`0.0%
`Dose not studied
`0.0%
`% Severe
`* For the 30-week trials, a hypoglycemia episode was recorded if the patient reported symptoms consistent with
`hypoglycemia and was recorded as severe if the subject required the assistance of another person to treat the
`event. For the other trials, a hypoglycemic episode was recorded if a patient reported signs or symptoms of
`hypoglycemia or had a blood glucose value consistent with hypoglycemia regardless of associated symptoms or
`treatment and was recorded as severe if the subject required the assistance of another person to treat the event.
`The requirement for assistance had to be accompanied by a blood glucose measurement of <50 mg/dL or
`prompt recovery after administration of oral carbohydrate.
`N = The number of Intent-to-Treat subjects in each treatment group.
`
`MPI EXHIBIT 1021 PAGE 5
`
`MPI EXHIBIT 1021 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0005
`
`

`

`In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, 38% of
`patients had low titer antibodies to exenatide at 30 weeks. For this group, the level of glycemic
`control (hemoglobin A1c [HbA1c]) was generally comparable to that observed in those without
`antibody titers. An additional 6% of patients had higher titer antibodies at 30 weeks. In about
`half of this 6% (3% of the total patients given BYETTA in the 30-week controlled studies), the
`glycemic response to BYETTA was attenuated; the remainder had a glycemic response
`comparable to that of patients without antibodies.
`
`In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 9% of
`patients had higher titer antibodies at 16 weeks. In the 24-week trial of BYETTA used as
`monotherapy, 3% of patients had higher titer antibodies at 24 weeks. Compared with patients
`who did not develop antibodies to BYETTA, on average the glycemic response in patients with
`higher titer antibodies was attenuated [see Warnings and Precautions (5.5)].
`
`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)*
`Placebo BID
`N = 77
`%
`0
`0
`0
`
`Monotherapy
`
`Nausea
`Vomiting
`Dyspepsia
`* In a 24-week placebo-controlled trial.
`
`BID = twice daily.
`
`
`All BYETTA BID
`N = 155
`%
`8
`4
`3
`
`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.
`
`Combination Therapy
`
`Add-on to metformin and/or sulfonylurea
`
`Page 6 of 26
`
`MPI EXHIBIT 1021 PAGE 6
`
`MPI EXHIBIT 1021 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0006
`
`

`

`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 (5.2)] 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)*
`Placebo BID
`All BYETTA BID
`N = 483
`N = 963
`%
`%
`18
`44
`4
`13
`6
`13
`4
`9
`6
`9
`6
`9
`3
`6
`2
`4
`1
`3
`
`Nausea
`Vomiting
`Diarrhea
`Feeling Jittery
`Dizziness
`Headache
`Dyspepsia
`Asthenia
`Gastroesophageal Reflux
`Disease
`1
`Hyperhidrosis
`* In three 30-week placebo-controlled clinical trials.
`
`BID = twice daily.
`
`
`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.
`
`Page 7 of 26
`
`MPI EXHIBIT 1021 PAGE 7
`
`MPI EXHIBIT 1021 PAGE 7
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0007
`
`

`

`Table 4:
`
`Treatment-Emergent Adverse Reactions ≥2% Incidence With BYETTA Used With a
`Thiazolidinedione, With or Without Metformin (Excluding Hypoglycemia)*
`Placebo
`All BYETTA BID
`With a TZD or
`N = 112
`N = 121
`TZD/MET
`%
`%
`15
`40
`Nausea
`1
`13
`Vomiting
`1
`7
`Dyspepsia
`3
`6
`Diarrhea
`Gastroesophageal
`0
`3
`Reflux Disease
`In a 16-week placebo-controlled clinical 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. 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.
`
`6.2 Post-Marketing Experience
`The following additional adverse reactions have been reported during post-approval 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 (5.6)].
`
`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 Limitations of Use (1.2) and
`Warnings and Precautions (5.1)].
`
`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
`
`Page 8 of 26
`
`MPI EXHIBIT 1021 PAGE 8
`
`MPI EXHIBIT 1021 PAGE 8
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0008
`
`

`

`hemodialysis), kidney transplant and kidney transplant dysfunction [see Warnings and
`Precautions (5.3)].
`
`7 DRUG INTERACTIONS
`
`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.
`
`8 USE IN SPECIFIC POPULATIONS
`
`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
`
`Page 9 of 26
`
`MPI EXHIBIT 1021 PAGE 9
`
`MPI EXHIBIT 1021 PAGE 9
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0009
`
`

`

`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
`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 2-4 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
`
`Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry 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 patients 65 years of age or older and in 16 patients
`75 years of age or older. No differences in safety or effectiveness were observed between these
`patients and younger patients. Because elderly patients are more likely to have decreased renal
`function, care should be taken in dose selection in the elderly based on renal function.
`
`Page 10 of 26
`
`MPI EXHIBIT 1021 PAGE 10
`
`MPI EXHIBIT 1021 PAGE 10
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0010
`
`

`

`8.6 Renal Impairment
`BYETTA is not recommended for use in patients with end-stage renal disease or severe renal
`impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with
`renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal
`impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating
`or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal
`impairment (creatinine clearance 30 to 50 mL/min) [see Clinical Pharmacology (12.3)].
`
`8.7 Hepatic Impairment
`No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic
`hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is
`not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`
`In a clinical study of BYETTA, three patients with type 2 diabetes each experienced a single
`overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses
`included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations.
`One of the three patients experienced severe hypoglycemia requiring parenteral glucose
`administration. The three patients recovered without complication. In the event of overdose,
`appropriate supportive treatment should be initiated according to the patient’s clinical signs and
`symptoms.
`
`11 DESCRIPTION
`
`BYETTA (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma
`suspectum. Exenatide differs in chemical structure and pharmacological action from insulin,
`sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides,
`thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4
`inhibitors.
`
`Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula
`C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for
`exenatide is shown below.
`
`H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu
`-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
`
`BYETTA is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge
`that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms
`(mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a
`tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for
`
`Page 11 of 26
`
`MPI EXHIBIT 1021 PAGE 11
`
`MPI EXHIBIT 1021 PAGE 11
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1021-0011
`
`

`

`injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses
`of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice
`daily administration (BID).
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion
`and exhibit other antihyperglycemic actions following their release into the circulation from the
`gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by
`the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows
`gastric emptying.
`
`The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has
`been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in
`both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta
`cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
`Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose
`concentrations.
`
`BYETTA improves glycemic control by reducing fasting and postprandial glucose
`concentrations in patients with type 2 diabetes through the actions described below.
`
`Glucose-dependent insulin secretion: BYETTA has acute effects on pancreatic beta-cell
`responsiveness to glucose leading to insulin release predominantly in the presence of elevated
`glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease
`and approach euglycemia. However, BYETTA does not impair the normal glucagon response to
`hypoglycemia.
`
`First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the
`first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the
`“first-phase insulin