` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` TANZEUM safely and effectively. See full prescribing information for
`
` TANZEUM.
`
` TANZEUM (albiglutide) for injection, for subcutaneous use
` Initial U.S. Approval: 2014
`
`
`
`
`
`
`
`
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`See full prescribing information for complete boxed warning.
`
`
`
`• Carcinogenicity of albiglutide could not be assessed in rodents,
`
`
`
`but other glucagon-like peptide-1 (GLP-1) receptor agonists have
`caused thyroid C-cell tumors in rodents at clinically relevant
`
`
`
`exposures. Human relevance of GLP-1 receptor-agonist-induced
`
`
`C-cell tumors in rodents has not been determined. It is unknown
`whether TANZEUM causes thyroid C-cell tumors, including
`
`
`
`medullary thyroid carcinoma (MTC), in humans. (5.1, 13.1)
`
`
`
`• TANZEUM is contraindicated in patients with a personal or
`
`
`
`
`family history of MTC or in patients with Multiple Endocrine
`
`
`
`Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding
`
`
`
`
`the potential risk of MTC and symptoms of thyroid tumors. (4.1,
`
`
`5.1)
`
`
`
`
`
`
`
`
`-----------------------------RECENT MAJOR CHANGES -----------------------------­
`
`
`
`
`Contraindications (4)
`8/2017
`
`
`Warnings and Precautions (5.4)
`8/2017
`
`
`
`Warnings and Precautions, Acute Kidney Injury (5.5)
`12/2017
`
`
`
`
`
`
`
` ----------------------------- INDICATIONS AND USAGE------------------------------­
`
`
`
` TANZEUM is a 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:
`
` • Not recommended as first-line therapy for patients inadequately controlled
`
`
`
`
` on diet and exercise. (1, 5.1)
`
`
`
`
`
` • Has not been studied in patients with a history of pancreatitis. Consider
`
`
` other antidiabetic therapies in patients with a history of pancreatitis. (1, 5.2)
`
`
` • Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1)
`
`
`
`
`
` • Not for patients with pre-existing severe gastrointestinal disease. (1)
`
`
` • Has not been studied in combination with prandial insulin. (1)
`
`
`
`
` -------------------------DOSAGE AND ADMINISTRATION -------------------------­
`
`
`
` • Administer once weekly at any time of day, without regard to meals. (2.1)
`
`
`
` • Inject subcutaneously in the abdomen, thigh, or upper arm. (2.1)
`
`
`
`
`
`
` • Initiate at 30 mg subcutaneously once weekly. Dose can be increased to
`
`
`
` 50 mg once weekly in patients requiring additional glycemic control. (2.1)
`
`
` • If a dose is missed, administer within 3 days of missed dose. (2.1)
`
`
`
`
`
` • See Full Prescribing Information and Patient Instructions for Use for
`
`
`
`
`
`
`
` reconstitution of lyophilized powder and administration. (2.4, 2.5, 17)
`
`
`
`
` ----------------------- DOSAGE FORMS AND STRENGTHS------------------------­
`
`
` For injection: 30 mg or 50 mg in a single-dose Pen. (3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-------------------------------- CONTRAINDICATIONS --------------------------------­
`
`
`• TANZEUM is contraindicated in patients with a personal or family history
`
`
`
`
`
`
`
`of medullary thyroid carcinoma or in patients with Multiple Endocrine
`
`
`
`Neoplasia syndrome type 2. (4)
`
`
`• TANZEUM is contraindicated in patients with a prior serious
`
`
`
`
`
`
`hypersensitivity reaction to albiglutide or any of the product components.
`
`
`
`(4, 5.4)
`
`
` ------------------------- WARNINGS AND PRECAUTIONS -------------------------­
`
` • Thyroid C-Cell Tumors: See Boxed Warning. (5.1)
`
`
`
`• Acute Pancreatitis: Discontinue promptly if suspected. Do not restart if
`
`
`
`
`
`
`confirmed. Consider other antidiabetic therapies in patients with a history
`
`
`
`
`of pancreatitis. (5.2)
`
`
`• Hypoglycemia: Can occur when used in combination with insulin
`
`
`
`
`
`
`
`secretagogues (e.g., sulfonylureas) or insulin. Consider lowering
`
`
`
`
`sulfonylurea or insulin dosage when starting TANZEUM. (5.3)
`
`
`• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`
`
`
`
`angioedema) have occurred. Discontinue TANZEUM and promptly seek
`
`
`
`
`
`
`medical advice. (5.4)
`
`
`• Acute Kidney Injury: Postmarketing cases of worsening renal function and
`
`
`
`
`
`
`
`
`acute renal injury, some requiring hemodialysis, have occurred. Monitor
`
`
`
`renal function in patients with renal impairment reporting severe adverse
`
`
`
`
`gastrointestinal reactions and advise patients to avoid fluid depletion. (5.5)
`
`
`
`
`
`
`• Macrovascular Outcomes: There have been no clinical trials establishing
`
`
`
`
`
`conclusive evidence of macrovascular risk reduction with TANZEUM.
`
`
`
`(5.6)
`
`-------------------------------- ADVERSE REACTIONS --------------------------------­
`
`
`Adverse reactions reported in ≥5% of patients treated with TANZEUM
`
`
`
`
`
`
`
`and more frequently than in patients on placebo were upper respiratory
`
`
`
`
`tract infection, diarrhea, nausea, injection site reaction, cough, back pain,
`
`
`
`
`
`arthralgia, sinusitis, and influenza. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`
`GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`
`-------------------------------- DRUG INTERACTIONS---------------------------------­
`
`
`TANZEUM delays gastric emptying. May impact absorption of concomitantly
`
`
`
`administered oral medications. (7)
`
`------------------------- USE IN SPECIFIC POPULATIONS -------------------------­
`
`
`
`• Pregnancy: TANZEUM may cause fetal harm; only use if potential benefit
`
`
`
`
`
`justifies potential risk to fetus. (8.1)
`
`
`
`• Acute Kidney Injury: No dosage adjustment recommended. Monitor renal
`
`
`
`
`
`function in patients with renal impairment reporting severe adverse
`
`
`gastrointestinal reactions. (5.5, 8.6)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`Revised: 12/2017
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g.,
`
`
`
`Sulfonylurea) or with Insulin
`
`
`
`2.3 Reconstitution of the Lyophilized Powder
`
`
`
`Important Administration Instructions
`2.4
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Thyroid C-Cell Tumors
`
`
`5.2 Acute Pancreatitis
`
`5.3 Hypoglycemia with Concomitant Use of Insulin
`
`
`
`Secretagogues or Insulin
`
`
`
`5.4 Hypersensitivity Reactions
`
`
`5.5 Acute Kidney Injury
`
`
`
`5.6 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`Reference ID: 4198143
`
`
`
`
`
`6.2
`Immunogenicity
`
`
`Postmarketing Experience
`6.3
`
`
`7 DRUG INTERACTIONS
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal 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 Toxicity
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Monotherapy
`
`1
`
`
`Novo Nordisk Exhibit 2436
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`IPR2023-00724
`Page 00001
`
`

`

`
`
`14.2 Combination Therapy
`
`
`14.3 Type 2 Diabetes Mellitus Patients with Renal Impairment
`
`
`
`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.
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`• Carcinogenicity of albiglutide could not be assessed in rodents, but other glucagon-like
`
`
`peptide-1 (GLP-1) receptor agonists have caused thyroid C-cell tumors in rodents at
`clinically relevant exposures. Human relevance of GLP-1 receptor-agonist-induced C-
`
`cell tumors in rodents has not been determined. It is unknown whether TANZEUM
`
`
`causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in
`humans [see Warnings and Precautions (5.1), Nonclinical Toxicology (13.1)].
`
`
`
`
`• TANZEUM is contraindicated in patients with a personal or family history of MTC or
`
`
`
`
`in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel
`
`
`patients regarding the potential risk of MTC with the use of TANZEUM and inform
`them of the symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea,
`
`
`persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid
`
`ultrasound monitoring is of uncertain value for early detection of MTC in patients
`treated with TANZEUM [see Contraindications (4.1), Warnings and Precautions (5.1)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`
`with type 2 diabetes mellitus [see Clinical Studies (14)].
`
`
`
`Limitations of Use:
`
`
`• TANZEUM is not recommended as first-line therapy for patients inadequately controlled on
`
`
`diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to
`
`humans. Prescribe TANZEUM only to patients for whom the potential benefits are
`
`considered to outweigh the potential risk [see Warnings and Precautions (5.1)].
`
`
`
`• TANZEUM has not been studied in patients with a history of pancreatitis [see Warnings and
`
`
`
`Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of
`
`
`
`pancreatitis.
`• TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for
`
`
`the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin
`
`
`
`in these patients.
`
`• TANZEUM has not been studied in patients with severe gastrointestinal disease, including
`
`
`
`severe gastroparesis. The use of TANZEUM is not recommended in patients with pre­
`
`existing severe gastrointestinal disease [see Adverse Reactions (6.1)].
`
`
`
`
`• TANZEUM has not been studied in combination with prandial insulin.
`
`
`
`
`
`Reference ID: 4198143
`
`2
`
`
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
`
`
` 2
`
` DOSAGE AND ADMINISTRATION
` 2.1
`
`
` Dosage
`
`
`
`
`
`
` The recommended dosage of TANZEUM is 30 mg once weekly given as a subcutaneous
`
` injection in the abdomen, thigh, or upper arm region. The dosage may be increased to 50 mg
`
` once weekly if the glycemic response is inadequate.
`
`
` TANZEUM may be administered at any time of day without regard to meals. Instruct patients to
`
`
` administer TANZEUM once a week on the same day each week. The day of weekly
`
`
`
`
` administration may be changed if necessary as long as the last dose was administered 4 or more
`
`
` days before.
` If a dose is missed, instruct patients to administer as soon as possible within 3 days after the
`
`
`
` missed dose. Thereafter, patients can resume dosing on their usual day of administration. If it is
`
`
` more than 3 days after the missed dose, instruct patients to wait until their next regularly
` scheduled weekly dose.
`
`
`
`
` Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
` 2.2
` When initiating TANZEUM, consider reducing the dosage of concomitantly administered insulin
`
`
`
`
` secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings
`
` and Precautions (5.3)].
`
` Reconstitution of the Lyophilized Powder
`
`
` 2.3
`
` The lyophilized powder contained within the Pen must be reconstituted prior to administration.
` See Patient Instructions for Use for complete administration instructions with illustrations. The
`
`
`
`
`
`
`
` instructions may also be found at www.TANZEUM.com. Instruct patients as follows:
` Pen Reconstitution
`
`
`
` a) Hold the Pen body with the clear cartridge pointing up to see the [1] in the number window.
`
` b) To reconstitute the lyophilized powder with the diluent in the Pen, twist the clear cartridge on
`
`
` the Pen in the direction of the arrow until the Pen is felt/heard to “click” into place and the
`
`
`
`
` [2] is seen in the number window. This mixes the diluent with the lyophilized powder.
` c) Slowly and gently rock the Pen side-to-side 5 times to mix the reconstituted solution of
`
`
`
`
`
`
` TANZEUM. Advise the patient to not shake the Pen hard to avoid foaming.
` d) Wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen to ensure that the
`
`
`
`
` reconstituted solution is mixed.
` Preparing Pen for Injection
`
` e) Slowly and gently rock the Pen side-to-side 5 additional times to mix the reconstituted
`
`
` solution.
`
` f) Visually inspect the reconstituted solution in the viewing window for particulate matter. The
`
`
`
`
`
`
` reconstituted solution will be yellow in color. After reconstitution, use TANZEUM within
`
`
` 8 hours.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4198143
`
`
`3
`
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` g) Holding the Pen upright, attach the needle to the Pen by pushing it straight down until there
`
`
`
`
` is a click and the needle snaps into place. Gently tap the clear cartridge to bring large bubbles
`
` to the top.
` See Dosage and Administration (2.5) for important administration instructions, including the
`
` injection procedure.
`
` Alternate Method of Reconstitution (Healthcare Professional Use Only)
`
` The Patient Instructions for Use provide directions for the patient to wait 15 minutes for the 30­
`
`
` mg Pen and 30 minutes for the 50-mg Pen after the lyophilized powder and diluent are mixed to
`
`
` ensure reconstitution.
`
` Healthcare professionals may utilize the following alternate method of reconstitution. Because
`
`
` this method relies on appropriate swirling and visual inspection of the solution, it should only be
` performed by healthcare professionals.
`
` a) Follow Step A (Inspect Your Pen and Mix Your Medication) in the Instructions for
`
`
` Use. Make sure you have:
`
`
`
` Inspected the Pen for [1] in the number window and expiration date.
`
`
`•
`
` • Twisted the clear cartridge until [2] appears in the number window and a “click”
`
`
`
` is heard. This combines the medicine powder and liquid in the clear cartridge.
`
`
`b) Hold the Pen with the clear cartridge pointing up and maintain this orientation
`
`
` throughout the reconstitution.
` c) Gently swirl the Pen in small circular motions for at least one minute. Avoid
`
`
`
` shaking as this can result in foaming, which may affect the dose.
` d) Inspect the solution, and if needed, continue to gently swirl the Pen until all the
`
`
`
`
`
` powder is dissolved and you see a clear yellow solution that is free of particles. A
` small amount of foam, on top of the solution at the end of reconstitution, is normal.
`
` • For 30-mg Pen: Complete dissolution usually occurs within 2 minutes but may
`
`
`
`
`
` take up to 5 minutes, as confirmed by visual inspection, for a clear yellow
`
`
`
`
`
` solution free of particles.
`
`
` • For 50-mg Pen: Complete dissolution usually occurs within 7 minutes but may
`
`
`
`
` take up to 10 minutes.
`
` e) After reconstitution, continue to follow the steps in the Instructions for Use, starting
`
`
` at Step B: Attach the Needle.
` 2.4
`
` Important Administration Instructions
` Instruct patients as follows:
`
`
`
` • The pen should be used within 8 hours of reconstitution prior to attaching the needle.
`
` • After attaching the supplied needle, remove air bubbles by slowly twisting the Pen until you
`
`
`
` see the [3] in the number window. At the same time, the injection button will be
`
`
`
` automatically released from the bottom of the Pen.
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4198143
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
` • Use immediately after the needle is attached and primed. The product can clog the needle if
`
`
`
` allowed to dry in the primed needle.
` • After subcutaneously inserting the needle into the skin in the abdomen, thigh, or upper arm
`
`
`
`
`
` region, press the injection button. Hold the injection button until you hear a “click” and then
`
`
` hold the button for 5 additional seconds to deliver the full dose.
` When using TANZEUM with insulin, instruct patients to administer as separate injections and to
`
`
`
`
`
` never mix the products. It is acceptable to inject TANZEUM and insulin in the same body region
` but the injections should not be adjacent to each other.
`
`
` When injecting in the same body region, advise patients to use a different injection site each
` week. TANZEUM must not be administered intravenously or intramuscularly.
`
`
`
`
`
`
`
`
`
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
` TANZEUM is supplied as follows:
`
` • For injection: 30-mg lyophilized powder in a single-dose Pen (pen injector) for
`
`
` reconstitution.
` • For injection: 50-mg lyophilized powder in a single-dose Pen (pen injector) for
`
`
` reconstitution.
`
`
`
`
`
` CONTRAINDICATIONS
`
`
` 4
` Medullary Thyroid Carcinoma
`
`
`•
` TANZEUM is contraindicated in patients with a personal or family history of medullary thyroid
`
`
`
` carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
`
`
` [see Warnings and Precautions (5.1)].
`
`
`
`
` Hypersensitivity
`
`•
` TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to
`
`
`
`albiglutide or to any of the product components. Serious hypersensitivity reactions including
`angioedema have been reported with TANZEUM [see Warnings and Precautions (5.4)].
`
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`Risk of Thyroid C-Cell Tumors
`5.1
`
`Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of
`drug-clearing, anti-drug antibodies [see Nonclinical Toxicology (13.1)]. Other GLP-1 receptor
`
`
`
`agonists have caused dose-related and treatment–duration-dependent thyroid C-cell tumors
`
`
`(adenomas or carcinomas) in rodents. Human relevance of GLP-1 receptor-agonist-induced C-
`
`
`cell tumors in rodents has not been determined. It is unknown whether TANZEUM causes
`thyroid C-cell tumors, including MTC, in humans [see Boxed Warning, Contraindications (4.1)].
`
`
`Across 8 Phase III clinical trials [see Clinical Studies (14)], MTC was diagnosed in 1 patient
`
`
`
`
`
`receiving TANZEUM and 1 patient receiving placebo. Both patients had markedly elevated
`
`
`serum calcitonin levels at baseline. Cases of MTC in patients treated with liraglutide, another
`
`
`Reference ID: 4198143
`
`
`5
`
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`
`
`
`
` GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports
`
`
`
` are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor
`
` agonist use in humans.
` TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients
`
`
` with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TANZEUM
` and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or
`
`
` persistent hoarseness).
` Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early
`
`
` detection of MTC in patients treated with TANZEUM. Such monitoring may increase the risk of
`
`
` unnecessary procedures due to the low specificity of serum calcitonin testing for MTC and a
` high background incidence of thyroid disease. Significantly elevated serum calcitonin may
`
`
`
`
`
`
` indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum
` calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients
`
` with thyroid nodules noted on physical examination or neck imaging should also be further
`
` evaluated.
` Acute Pancreatitis
` 5.2
`
`
`
` In clinical trials, acute pancreatitis has been reported in association with TANZEUM.
`
` Across 8 Phase III clinical trials [see Clinical Studies (14)], pancreatitis adjudicated as likely
`
`
`
`
` related to therapy occurred more frequently in patients receiving TANZEUM (6 of 2,365 [0.3%])
`
`
` than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,062 [0.1%]).
` After initiation of TANZEUM, 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
` TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted.
`
`
` TANZEUM has not been studied in patients with a history of pancreatitis to determine whether
`
` these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in
`
`
` patients with a history of pancreatitis.
` 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
`
`
`
`
`
` The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin
` secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of
`
`
` sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Dosage and
`
` Administration (2.2), Adverse Reactions (6.1)].
`
`
`
` 5.4 Hypersensitivity Reactions
` Serious hypersensitivity reactions (including angioedema and generalized pruritus and rash with
`
`
`
`dyspnea) have been reported with TANZEUM. If hypersensitivity reactions occur, discontinue
`
`
`
`use of TANZEUM; treat promptly per standard of care, and monitor until signs and symptoms
`resolve. Do not use in patients with a previous hypersensitivity reaction to TANZEUM [see
`
`
`
`Contraindications (4)].
`
`
`
`
`
`
`
`
`
`Reference ID: 4198143
`
`
`6
`
`
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`IPR2023-00724
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`

`

` Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use
`
`
`
`caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor
`agonist because it is unknown whether such patients will be predisposed to these reactions with
`
`TANZEUM.
`
`
`
`Acute Kidney Injury
`5.5
`
`There have been postmarketing cases of worsening renal function and acute kidney injury in
`
`patients treated with TANZEUM, some of which required hemodialysis. Some of the
`
`
`
`postmarketing events were reported in the absence of gastrointestinal adverse reactions and in
`
`
`patients without known underlying renal disease.
`In a trial of TANZEUM in patients with renal impairment [see Clinical Studies (14.3)], the
`
`
`
`frequency of such gastrointestinal reactions increased as renal function declined [see Use in
`
`Specific Populations (8.6)]. Because these reactions may worsen renal function, use caution
`
`
`when initiating or escalating doses of TANZEUM in patients with renal impairment and/or in
`
`
`
`
`those reporting severe gastrointestinal symptoms. Advise patients treated with TANZEUM of the
`potential risk of dehydration in relation to gastrointestinal side effects and to take precautions to
`avoid fluid depletion [see Use in Specific Populations (8.6)].
`
`
`
`5.6 Macrovascular Outcomes
`
`
`There have been no clinical trials establishing conclusive evidence of macrovascular risk
`
`reduction with TANZEUM.
`
`
`
`ADVERSE REACTIONS
`6
`
`The following serious reactions are described below or elsewhere in the prescribing information:
`
`
`
`• Risk of Thyroid C-Cell Tumors [see Warnings and Precautions (5.1)]
`
`
`
`
`• Acute Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
`
`• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and
`
`
`
`Precautions (5.3)]
`
`
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`
`
`
`
`• Renal Impairment [see Warnings and Precautions (5.5)]
`
`
`
`
`6.1
`Clinical Trials Experience
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`observed in the clinical trials of a drug cannot be directly compared with 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 4 placebo-controlled trials. TANZEUM was used as
`monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies (14)]. These data
`
`
`reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM
`
`
`
`
`
`of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or
`
`
`older and 53% of participants were male. The population in these studies was 48% white, 13%
`7
`
`
`Reference ID: 4198143
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
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`

`

` African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had
`
`
`
`
` type 2 diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of
`the population in these studies reported peripheral neuropathy and 4% reported retinopathy.
` Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2)
`
`
`
`
`in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in
`
`
`
`
`9%.
`
`Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of
`
`TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at
`baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5%
`
`
`of patients treated with TANZEUM.
`
`
`
`Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of Patients
`
`Treated with TANZEUMa
`
`
`
`
`TANZEUM
`Placebo
`
`
`
`
`
`(n = 923)
`(n = 468)
`
`
`
`%
`Adverse Reaction
`%
`
`
`
`
`14.2
`Upper respiratory tract infection
`13.0
`
`
`
`13.1
`Diarrhea
`10.5
`
`
`
`11.1
`Nausea
`9.6
`
`Injection site reactionb
`
`
`10.5
`2.1
`
`
`
`6.9
`6.2
`Cough
`
`
`
`6.7
`5.8
`Back pain
`
`
`
`6.6
`6.4
`Arthralgia
`
`
`
`6.2
`5.8
`Sinusitis
`
`
`
`5.2
`3.2
`Influenza
` a Adverse reactions reported include those occurring with the use of glycemic rescue
`
`
`
`
`
` medications which included metformin (17% for placebo and 10% for TANZEUM) and
`
` insulin (24% for placebo and 14% for TANZEUM).
`
`b See below for other events of injection site reactions reported.
`
`
`Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal
`
`
`complaints occurred more frequently among patients receiving TANZEUM (39%) than patients
`
`
`
`receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following
`
`
`
`gastrointestinal adverse reactions also occurred more frequently in patients receiving
`
`TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal
`
`reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus
`
`3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported
`reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions
`
`
`
`
`
`as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases.
`
`Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or
`
`
`
`placebo.
`
`Injection Site Reactions: In the pool of placebo-controlled trials, injection site reactions occurred
`
`
`more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term “injection
`
`
`
`site reaction” (see Table 1), the following other types of injection site reactions also occurred
`
`
`
`more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus
`
`
`
`8
`
`Reference ID: 4198143
`
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`IPR2023-00724
`Page 00008
`
`

`

`TANZEUM ), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM),
`
`injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site
`
`hypersensitivity (0% versus 0.8% for placebo versus TANZEUM), and injection site hemorrhage
`
`
`(0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the
`
`
`
`frequently reported reactions. The majority of injection site reactions were judged as “mild” by
`investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on
`TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%),
`
`
`experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to
`
`be “moderate” or “severe” (27% versus 6%), and required local or systemic treatment for the
`
`reactions (36% versus 11%).
`
`
`Pool of Placebo- and Active-Controlled Trials
`
`
`The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2
`
`
`
`
`
`diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of
`
`
`TANZEUM as monotherapy, as add-on therapy to oral antidiabetic agents, and as add-on therapy
`to basal insulin [see Clinical Studies (14)]. In this pool, a total of 2,116 patients with type 2
`
`
`
`diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of
`
`
`
`patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was
`
`
`75 years or older and 51% of participants were male. Forty-eight percent of patients were white,
`
`15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the
`
`
`population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline,
`
`
`21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline
`estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of
`
`
`
`
`the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the
`
`
`
`
`population.
`
`In the pool of placebo- and active-controlled trials, the types and frequencies of common adverse
`
`
`
`
`reactions excluding hypoglycemia were similar to those listed in Table 1.
`
`
`Other Adverse Reactions
`
`Hypoglycemia: The proportion of patients experiencing at least one documented symptomatic
`
`
`
`
`hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one
`severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies (14)] is
`
`
`shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to
`
`sulfonylurea or insulin [see Warnings and Precautions (5.3)].
`
`
`
`Reference ID: 4198143
`
`
`9
`
`
`Novo Nordisk Exhibit 2436
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
`In Combination with
`
`
`Insulin Glargine (26 Weeks)
`
`Documented symptomatic
`
`Severe
`
` Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa
`
`
`
`
`TANZEUM
`Monotherapyb
`
`
`
`Placebo
`30 mg Weekly
`
`
`
`
`
`n = 101
`(52 Weeks)
`n = 101
`Documented symptomaticc
`
`
`
`2%
`2%
`Severed
`
`
`
`-
`-
`In Combination with Metformin Trial
`Placebo
`TANZEUM
`
`
`
`(104 Weeks)e
`
`
`
`
`
`n = 101
`n = 302
`
`
`
`Documented symptomatic
`4%
`3%
`
`
`
`Severe
`-
`-
`
`
`In Combination with Pioglitazone ±
`Placebo
`TANZEUM
`
`
`
`
`
`
`
`
`n = 151
`Metformin (52 Weeks)
`n = 150
`
`
`
`Documented symptomatic
`1%
`3%
`
`
`
`Severe
`1%
`-
`In Combination with Metformin and
`Placebo
`TANZEUM
`
`
`
`
`
`
`
`
`n = 115
`Sulfonylurea (52 Weeks)
`n = 271
`
`
`
`Documented symptomatic
`7%
`13%
`
`
`
`Severe
`-
`0.4%
`
`Insulin Lispro
`TANZEUM
`
`
`
`
`n = 281
`n = 285
`
`
`
`
`30%
`16%
`
`
`0.7%
`-
`Insulin Glargine
`TANZEUM
`
`
`
`
`
`
`n = 241
`n = 504
`
`
`27%
`17%
`
`
`0.4%
`0.4%
`Sitagliptin
`TANZEUM
`
`
`
`
`
`
`n = 246
`n = 249
`
`
`6%
`10%
`
`
`0.8%
`-
`
`In Combination with
`
`
`
`Metformin ± Sulfonylurea (52 Weeks)
`
`Documented symptomatic
`
`Severe
`In Combination with OADs in Renal
`
`
`Impairment (26 Weeks)
`
`Documented symptomatic
`
`Severe
` OAD = Oral antidiabetic agents.
`
`a Data presented are to the primary endpoint and include only events occurring on-therapy with
`
`
`
`
`
`randomized me