`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
` These highlights do not include all the information needed to use
`
` TRULICITY safely and effectively. See full prescribing information
`
`
`
`
`
` for TRULICITY.
`
`
`
` TRULICITY (dulaglutide) injection, for subcutaneous use
`
` Initial U.S. Approval: 2014
`
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`
`
`
`
`• Dulaglutide causes thyroid C-cell tumors in rats. It is unknown
`
`
`
`whether TRULICITY causes thyroid C-cell tumors, including
`
`
`
`medullary thyroid carcinoma (MTC), in humans as the human
`
`relevance of dulaglutide-induced rodent thyroid C-cell tumors
`
`has not been determined (5.1, 13.1).
`
`
`
`
`• TRULICITY is contraindicated in patients with a personal or
`
`
`
`
`
`
`family history of MTC and 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, 5.1).
`
`
`--------------------------- RECENT MAJOR CHANGES -------------------------­
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`08/2017
`Hypersensitivity Reactions (5.4)
`
`
`
`---------------------------- INDICATIONS AND USAGE --------------------------­
`
`
`
`
`
`TRULICITY® 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.
`
`
`
`Limitations of Use:
`
`
`• Not recommended as first-line therapy for patients inadequately
`
`
`
`controlled on diet and exercise (1.1, 5.1).
`
`
`
`• Has not been studied in patients with a history of pancreatitis.
`
`
`
`Consider another antidiabetic therapy (1, 5.2).
`
`
`
`
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`
`
`
`• Not for patients with pre-existing severe gastrointestinal disease.
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`• Administer once weekly at any time of day (2.1).
`
`
`
`
`•
`Inject subcutaneously in the abdomen, thigh, or upper arm (2.1).
`
`
`
`
`
`
`•
`Initiate at 0.75 mg subcutaneously once weekly. Dose can be
`
`
`
`
`
`
`
`increased to 1.5 mg once weekly for additional glycemic control
`
`
`
`
`
`
`
`(2.1).
`
`If a dose is missed, administer if there are at least 3 days (72 hours)
`
`
`
`
`
`
`
`until the next scheduled dose (2.1).
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`
`•
`Injection: 0.75 mg/0.5 mL solution in a single-dose pen (3)
`
`
`
`
`
`
`•
`Injection: 1.5 mg/0.5 mL solution in a single-dose pen (3)
`
`
`
`
`
`
`
`•
`Injection: 0.75 mg/0.5 mL solution in a single-dose prefilled syringe
`
`
`
`
`
`(3)
`
`Injection: 1.5 mg/0.5 mL solution in a single-dose prefilled syringe
`
`
`
`
`
`
`(3)
`
`
`•
`
`
`•
`
`
`1
`------------------------------- CONTRAINDICATIONS -----------------------------­
`
`
`
`
`• TRULICITY 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, 5.1).
`
`• TRULICITY is contraindicated in patients with a prior serious
`
`
`
`
`
`hypersensitivity reaction to TRULICITY or any of the product
`
`
`
`
`
`
`components (4, 5.4).
`
`------------------------ WARNINGS AND PRECAUTIONS----------------------­
`
`
`
`
`
`• Thyroid C-cell Tumors: See Boxed Warning (5.1).
`
`
`
`
`• Pancreatitis: Has been reported in clinical trials. Discontinue
`
`
`
`promptly if pancreatitis is suspected. Do not restart if pancreatitis is
`
`
`
`confirmed. Consider other antidiabetic therapies in patients with
`
`
`history of pancreatitis (5.2).
`
`
`• Hypoglycemia: When TRULICITY is used with an insulin
`
`
`
`
`secretagogue (e.g., a sulfonylurea) or insulin, consider lowering the
`
`
`
`dose of the sulfonylurea or insulin to reduce the risk of
`
`
`
`
`
`hypoglycemia (5.3).
`
`
`• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`
`
`
`anaphylactic reactions and angioedema) have occurred.
`
`
`Discontinue TRULICITY and promptly seek medical advice (5.4).
`
`
`
`
`
`• Acute Kidney Injury: Monitor renal function in patients with renal
`
`
`
`
`
`impairment reporting severe adverse gastrointestinal reactions (5.5).
`
`
`
`• Severe Gastrointestinal Disease: Use may be associated with
`
`
`gastrointestinal adverse reactions, sometimes severe. Has not been
`
`
`
`studied in patients with severe gastrointestinal disease and is not
`
`recommended in these patients (5.6).
`
`• Macrovascular outcomes: There have been no studies establishing
`
`
`conclusive evidence of macrovascular risk reduction with
`
`
`TRULICITY (5.7).
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`
`The most common adverse reactions, reported in ≥5% of patients
`
`
`
`
`
`treated with TRULICITY are: nausea, diarrhea, vomiting, abdominal
`
`
`
`
`pain, and decreased appetite (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
`
`
`
`and Company at 1-800-LillyRx (1-800-545-5979) or FDA at
`
`
`
`
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------- DRUG INTERACTIONS ------------------------------
`
`
`
`
`
`Dulaglutide slows gastric emptying and may impact absorption of
`
`
`
`
`concomitantly administered oral medications (7.1, 12.3).
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS---------------------­
`
`
`• Pregnancy: TRULICITY should be used during pregnancy only if the
`
`
`
`
`
`
`potential benefit justifies the potential risk to fetus (8.1).
`
`
`
`
`• Renal Impairment: No dosage adjustment recommended. Monitor
`
`
`renal function in patients with renal impairment reporting severe
`
`adverse gastrointestinal reactions (5.5, 8.7).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved Medication Guide.
`
`
`Revised: 06/2018
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Limitations of Use
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage
`
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g.,
`
`
`Sulfonylurea) or with Insulin
`
`
`Important Administration Instructions
`2.3
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Risk of Thyroid C-cell Tumors
`
`
`5.2 Pancreatitis
`
`
`5.3 Hypoglycemia with Concomitant Use of Insulin
`
`
`Secretagogues or Insulin
`
`
`5.4 Hypersensitivity Reactions
`
`
`
`5.5 Acute Kidney Injury
`
`
`5.6 Severe Gastrointestinal Disease
`
`Reference ID: 4284895
`
`
`
`5.7 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`
`
`6.1 Clinical Studies Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Oral Medications
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`8.7 Renal Impairment
`
`
`8.8 Gastroparesis
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`Novo Nordisk Exhibit 2446
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`
` 12.3 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Monotherapy
`
`
`14.2 Combination Therapy
`
`
`14.3 Moderate to Severe Chronic Kidney Disease
`
`
`
`
`
`2
`
`
`
`
`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
`
`
`
`
`
`
`
`• In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the
`
`
`
`
`incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether
`
`
`
`TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human
`
`
`
`
`
`
`
`relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and
`
`
`Precautions (5.1), and Nonclinical Toxicology (13.1)].
`
`
`
`
`• TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple
`
`
`
`
`
`
`
`Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of
`
`
`TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea,
`
`
`
`
`
`
`
`persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain
`
`
`
`
`
`
`
`value for early detection of MTC in patients treated with TRULICITY [see Contraindications (4) and Warnings
`
`and Precautions (5.1)].
`
`
`1
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`TRULICITY® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`diabetes mellitus.
`
`
`1.1 Limitations of Use
`
`
`
`
`
`• TRULICITY is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet
`
`
`
`
`and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe TRULICITY
`
`only to patients for whom the potential benefits outweigh the potential risk [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`• TRULICITY 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.
`
`
`
`
`
`• TRULICITY should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic
`
`
`
`
`
`ketoacidosis. TRULICITY is not a substitute for insulin.
`
`
`
`
`
`
`• TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis.
`The use of TRULICITY is not recommended in patients with pre-existing severe gastrointestinal disease [see
`
`
`Warnings and Precautions (5.6)].
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Dosage
`
`
`
`
`The recommended initiating dose of TRULICITY is 0.75 mg once weekly. The dose may be increased to 1.5 mg
`
`
`
`
`
`once weekly for additional glycemic control. The maximum recommended dose is 1.5 mg once weekly.
`
`
`
`
`
`
`
`
`Administer TRULICITY once weekly, any time of day, with or without food. TRULICITY should be injected
`
`
`
`subcutaneously in the abdomen, thigh, or upper arm.
`
`
`If a dose is missed, instruct patients to administer as soon as possible if there are at least 3 days (72 hours) until the
`
`
`
`
`next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the
`
`
`
`next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing
`
`schedule.
`
`
`
`
`The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more
`
`days before.
`
`
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`
`
`When initiating TRULICITY, 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)].
`
`
`
`2.3
`
`
`Important Administration Instructions
`
`
`
`Prior to initiation of TRULICITY, patients should be trained by their healthcare professional on proper injection
`
`technique. Training reduces the risk of administration errors such as improper injection site, needle sticks, and incomplete
`
`Reference ID: 4284895
`
`Novo Nordisk Exhibit 2446
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
`3
`
`
`
`
`
`
`
` dosing. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. The
`
`
`
` instructions can also be found at www.trulicity.com.
` When using TRULICITY with insulin, instruct patients to administer as separate injections and to never mix the
`
`
`
`
`
`
`
`
` products. It is acceptable to inject TRULICITY 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. TRULICITY must
` not be administered intravenously or intramuscularly.
`
`
`
`
` TRULICITY solution should be visually inspected for particulate matter and discoloration prior to administration.
` DOSAGE FORMS AND STRENGTHS
`
`
`
` • Injection: 0.75 mg/0.5 mL solution in a single-dose pen
`
`
`
`
`
`
` • Injection: 1.5 mg/0.5 mL solution in a single-dose pen
`
`
`
`
`
`
` • Injection: 0.75 mg/0.5 mL solution in a single-dose prefilled syringe
`
`
`
`
`
` • Injection: 1.5 mg/0.5 mL solution in a single-dose prefilled syringe
`
`
`
`
` CONTRAINDICATIONS
`
` Medullary Thyroid Carcinoma
`
`
`
`
` TRULICITY 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
` •
`
`
`
` TRULICITY is contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the
`
` product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been
`
`
`
` reported with TRULICITY [see Warnings and Precautions (5.4)].
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Risk of Thyroid C-cell Tumors
`
`
`
` In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the
`
`
` incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology (13.1)].
`
`
`
`
`
` Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats
`
`
`
` at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary
`
`
`
`
`
` thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not
`
`
`
`
`
` been determined.
`
`
`
`
`
`
` One case of MTC was reported in a patient treated with TRULICITY. This patient had pretreatment calcitonin levels
` approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another 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.
`
`
`
`
`
`
`
`
` TRULICITY 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 TRULICITY and inform them of symptoms of thyroid
`
`
`
`
`
`
` tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
` Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in
`
`
`
`
`
`
` patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test
`
`
`
`
` specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin
`
`
`
`
`
` value 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.
`
`
` 5.2 Pancreatitis
` In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions
`
`
`
`
`
`
`
`
`
`
`
`
`
` were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years).
` An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4
`
`
`
`
`
` cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).
`
`
`
`
`
`
` After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis, including persistent
`
`
`
`
` severe abdominal pain. If pancreatitis is suspected, promptly discontinue TRULICITY. If pancreatitis is confirmed,
`
`
`
` TRULICITY should not be restarted. TRULICITY has not been evaluated in patients with a prior history of 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 TRULICITY is used in combination with insulin secretagogues (e.g.,
`
`
`
`
` sulfonylureas) or insulin. 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
` 4
`
`
` •
`
`Reference ID: 4284895
`
`Novo Nordisk Exhibit 2446
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`4
`
`
`
`
`5.4 Hypersensitivity Reactions
`
`
`There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and
`
`
`
`
`
`
`angioedema in patients treated with TRULICITY [see Adverse Reactions (6.2)]. If a hypersensitivity reaction occurs,
`
`discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in
`
`
`
`patients with a previous hypersensitivity reaction to TRULICITY [see Contraindications (4)].
`
`Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with
`
`
`
`
`a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients
`
`
`will be predisposed to anaphylaxis with TRULICITY.
`
`
`5.5 Acute Kidney Injury
`
`
`In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of
`
`acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these
`
`
`
`events were reported in patients without known underlying renal disease. A majority of reported events occurred in
`
`
`
`
`
`
`patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal
`
`
`
`
`
`
`
`function, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal
`
`
`
`function in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Use in Specific
`
`
`
`Populations (8.7)].
`
`
`5.6 Severe Gastrointestinal Disease
`
`
`
`
`
`
`Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe [see Adverse
`
`
`
`
`
`
`Reactions (6.1)]. TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe
`
`
`
`gastroparesis, and is therefore not recommended in these patients.
`
`
`5.7 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`TRULICITY.
`6
`
`
`ADVERSE REACTIONS
`
`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)]
`
`
`
`• 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)]
`
`
`• Acute Kidney Injury [see Warnings and Precautions (5.5)]
`
`
`
`
`• Severe Gastrointestinal Disease [see Warnings and Precautions (5.6)]
`
`
`6.1 Clinical Studies Experience
`
`
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
`
`
`
`
`clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect
`
`the rates observed in practice.
`
`Pool of Placebo-controlled Trials
`
`
`The data in Table 1 are derived from the placebo-controlled trials [see Clinical Studies (14)].
`
`
`
`
`
`
`These data reflect exposure of 1670 patients to TRULICITY and a mean duration of exposure to TRULICITY of 23.8
`
`
`
`
`
`
`
`
`weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were
`
`
`
`
`
`
`male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic
`
`
`
`
`
`
`
`or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%.
`
`
`At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired
`(eGFR ≥60mL/min/1.73 m2) in 96.0% of the pooled study populations.
`
`
`
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of TRULICITY in the
`
`
`
`
`
`pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on
`
`
`
`
`TRULICITY than on placebo, and occurred in at least 5% of patients treated with TRULICITY.
`
`
`
`
`
`Table 1: Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of TRULICITY-Treated Patients
`
`
`
`
`
`
`
`
`Adverse Reaction
`TRULICITY 0.75 mg
`Placebo
`TRULICITY 1.5 mg
`
`
`
`
`
`
`
`
`
` (N=568)
` (N=836)
`
` (N=834)
`
`%
`%
`%
`
`
`
`5.3
`12.4
`21.1
`
`
`
`6.7
`12.6
`8.9
`
`
`
`2.3
`6.0
`12.7
`
`
`
`4.9
`6.5
`9.4
`
`
`
`1.6
`4.9
`8.6
`
`
`
`
`Nausea
`
`Diarrheaa
`
`Vomitingb
`
`Abdominal Painc
`
`Decreased Appetite
`
`
`Reference ID: 4284895
`
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`
`a
`
` b
`
`
`
` c
`
`
` d
`
`
`4.1
`
`4.2
`
`
`
`
`5
`
`5.8
`
`5.6
`
`
`
`
`
`
`
`
`2.3
`Dyspepsia
`
`
`2.6
`Fatigued
`
`
`
`
` Includes diarrhea, fecal volume increased, frequent bowel movements.
`
` Includes retching, vomiting, vomiting projectile.
`
`
`
`
`
`
`
`
`Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain.
` Includes fatigue, asthenia, malaise.
`
`
` Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.
`
`
`Gastrointestinal Adverse Reactions
`
`
`In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients
`
`
`
`
`
`receiving TRULICITY than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving TRULICITY
`
`
`
`
`
`
`0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than
`
`
`
`
`
`
`patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on
`
`
`
`
`
`
`
`0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cases, respectively, or “severe” in 7% and 11% of cases, respectively.
`
`
`
`
`
`
`In addition to the reactions in Table 1, the following adverse reactions were reported more frequently in TRULICITY-
`
`
`treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%,
`
`
`
`
`
`
`
`3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%,
`
`
`
`
`
`
`
`1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).
`
`
`
`
`
`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 6 placebo- and active-controlled trials evaluating the use of TRULICITY as monotherapy and add-on
`
`
`
`
`
`
`therapy to oral medications or insulin.[see Clinical Studies (14)]. In this pool, a total of 3342 patients with type 2 diabetes
`
`
`
`
`
`
`
`were treated with TRULICITY for a mean duration of 52 weeks. The mean age of patients was 56 years, 2% were 75
`
`
`
`
`
`
`
`
`years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11%
`
`
`
`
`
`
`Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and
`
`
`
`
`
`
`
`had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal
`
`
`function was normal or mildly impaired (eGFR ≥60 ml/min/1.73 m2) in 95.7% of the TRULICITY population.
`
`
`
`
`
`
`
`
`
`
`
`
`In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding
`
`
`hypoglycemia, were similar to those listed in Table 1.
`
`Other Adverse Reactions
`Hypoglycemia
`
`Table 2 summarizes the incidence of documented symptomatic (≤70 mg/dL glucose threshold) and severe
`
`
`
`
`
`hypoglycemia in the placebo-controlled clinical studies.
`
`
`
`Table 2: Incidence (%) of Documented Symptomatic and Severe Hypoglycemia Adverse Reactions in Placebo-
`
`
`
`
`
`Controlled Trials
`
`
`
`TRULICITY 0.75 mg
`
`
`
`
`Placebo
`
`
`
`Add-on to Metformin
`
`(26 weeks)
`
`Documented symptomatic
`
`
`Severe
`
`Add-on to Metformin + Pioglitazone
`
`(26 weeks)
`
`Documented symptomatic
`
`
`Severe
`
`Add-on to Glimepiride
`
`N=60
`(24 weeks)
`
`
`1.7%
`Documented symptomatic
`
`
`0
`Severe
`
`
`In Combination with Insulin Glargine ± Metformin
`
`
`
`
`N=150
`
`(28 weeks)
`
`
`30.0%
`
`Documented symptomatic
`
`
`N=177
`
`1.1%
`
`0
`
`
`N=141
`
`1.4%
`
`0
`
`
`Reference ID: 4284895
`
`TRULICITY 1.5 mg
`
`
`
`
`N=302
`
`2.6%
`
`0
`
`
`N=280
`
`4.6%
`
`0
`
`
`-
`-
`-
`
`
`
`
`
`-
`-
`
`
`
`
`N=304
`
`5.6%
`
`0
`
`
`N=279
`
`5.0%
`
`0
`
`
`N=239
`
`11.3%
`
`0
`
`
`N=150
`
`35.3%
`
`
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`
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` 0
`
`-
`
`
`
`6
`
`
`
` 0.7%
`
`
`
` Severe
`
`Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin [see
`
`
`
`Warnings and Precautions (5.3)]. In a 78-week clinical trial, documented symptomatic hypoglycemia occurred in 39% and
`
`
`
`40% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe
`
`
`
`
`
`
`
`
`hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-
`
`
`
`
`
`administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when
`
`TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred
`
`
`
`
`
`
`
`in 2.4% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with prandial
`
`
`
`
`
`
`
`insulin.
`
`
`Heart Rate Increase and Tachycardia Related Adverse Reactions
`TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The
`
`
`
`
`
`
`long-term clinical effects of the increase in HR have not been established [see Warnings and Precautions (5.7)].
`
`
`
`
`
`
`Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus
`
`
`
`
`
`tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY
`
`
`
`
`
`1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and
`
`
`
`1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus
`
`
`
`
`
`
`tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in
`
`
`
`
`
`
`
`
`
`
`0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.
`
`
`
`
`
`
`
`
`Immunogenicity
`
`Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) TRULICITY-treated patients developed anti-drug
`
`
`
`
`antibodies (ADAs) to the active ingredient in TRULICITY (i.e., dulaglutide).
`
`
`
`Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population)
`
`
`had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against
`
`
`
`
`
`native GLP-1.
`
`The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally,
`
`
`
`
`the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several
`
`
`factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and
`
`underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the
`
`
`incidence of antibodies of other products.
`
`Hypersensitivity
`
`Systemic hypersensitivity adverse reactions sometimes severe (e.g., severe urticaria, systemic rash, facial edema,
`
`
`
`
`
`lip swelling) occurred in 0.5% of patients on TRULICITY in the four Phase 2 and five Phase 3 studies.
`
`
`
`
`
`Injection-site Reactions
`
`In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5%
`
`
`
`
`
`
`of TRULICITY-treated patients and in 0.0% of placebo-treated patients.
`
`
`PR Interval Prolongation and Adverse Reactions of First Degree Atrioventricular (AV) Block
`
`
`
`
`
`A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated patients in
`
`
`
`
`contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first degree AV block
`
`
`
`
`
`
`
`
`occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo,
`
`
`
`
`
`
`
`TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220
`
`
`
`
`
`milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY
`
`
`
`
`
`
`
`
`
`
`
`1.5 mg, respectively.
`
`
`
`Amylase and Lipase Increase
`
`Patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to
`
`
`
`20%, while placebo-treated patients had mean increases of up to 3%.
`
`
`
`6.2 Postmarketing Experience
`
`
`The following additional adverse reactions have been reported during post-approval use of TRULICITY. 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.
`
`
`• Anaphylactic reactions, angioedema [see Contraindications (4), Warnings and Precautions (5.6), Patient
`
`
`
`
`Counseling Information (17)].
`
`• Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring
`
`
`
`hemodialysis [see Warnings and Precautions (5.5) and Patient Counseling Information (17)].
`
`
`
`
`Reference ID: 4284895
`
`Novo Nordisk Exhibit 2446
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`7
`
`DRUG INTERACTIONS
`7
`
`
`7.1 Oral Medications
`
`
`TRULICITY slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly
`
`
`
`
`
`administered oral medications. Caution should be exercised when oral medications are concomitantly administered with
`
`
`TRULICITY. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when
`
`
`
`
`
`concomitantly administered with TRULICITY. In clinical pharmacology studies, TRULICITY did not affect the absorption of
`
`
`
`
`
`the tested, orally administered medications to a clinically relevant degree [see Clinical Pharmacology (12.3)].
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`
`8.1 Pregnancy
`