HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`MOUNJARO safely and effectively. See full prescribing
`information for MOUNJARO.
`MOUNJARO® (tirzepatide) Injection, for subcutaneous use
`Initial U.S. Approval: 2022
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`(cid:1)(cid:1) Tirzepatide causes thyroid C-cell tumors in rats. It is
`unknown whether MOUNJARO causes thyroid C-cell
`tumors, including medullary thyroid carcinoma (MTC), in
`humans as the human relevance of tirzepatide-induced
`rodent thyroid C-cell tumors has not been determined (5.1,
`13.1).
`(cid:1) MOUNJARO 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, 5.1).
`
` --------------------------- RECENT MAJOR CHANGES --------------------------
`Contraindications (4)
`04/2023
`Warnings and Precautions
`Hypersensitivity Reactions (5.4)
`04/2023
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`MOUNJARO® is a glucose-dependent insulinotropic polypeptide (GIP)
`receptor and glucagon-like peptide-1 (GLP-1) receptor agonist
`indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus. (1)
`Limitations of Use:
`(cid:1) Has not been studied in patients with a history of pancreatitis (1,
`5.2)
`Is not indicated for use in patients with type 1 diabetes mellitus (1)
`
`(cid:1)
` ------------------------ DOSAGE AND ADMINISTRATION -----------------------
`The recommended starting dosage is 2.5 mg injected
`(cid:1)
`subcutaneously once weekly (2.1)
`(cid:1) After 4 weeks, increase to 5 mg injected subcutaneously once
`weekly (2.1)
`If additional glycemic control is needed, increase the dosage in
`2.5 mg increments after at least 4 weeks on the current dose.
`The maximum dosage is 15 mg subcutaneously once weekly (2.1).
`(cid:1)
`(cid:1) Administer once weekly at any time of day, with or without meals.
`(2.2)
`Inject subcutaneously in the abdomen, thigh, or upper arm. (2.2)
`(cid:1)
`(cid:1) Rotate injection sites with each dose.
` ----------------------DOSAGE FORMS AND STRENGTHS ---------------------
`Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL
`in single-dose pen or single-dose vial (3)
`
`(cid:1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage
`2.2
`Important Administration Instructions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`
`Reference ID: 5216931
`
`1
`
` ------------------------------- CONTRAINDICATIONS ------------------------------
`(cid:1) Personal or family history of medullary thyroid carcinoma or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (4,
`5.1)
`(cid:1) Known serious hypersensitivity to tirzepatide or any of the
`excipients in MOUNJARO (4, 5.4)
`
` ------------------------ WARNINGS AND PRECAUTIONS -----------------------
`(cid:1) Pancreatitis: Has been reported in clinical trials. Discontinue
`promptly if pancreatitis is suspected. (5.2)
`(cid:1) Hypoglycemia with Concomitant Use of Insulin Secretagogues or
`Insulin: Concomitant use with an insulin secretagogue or insulin
`may increase the risk of hypoglycemia, including severe
`hypoglycemia. Reducing dose of insulin secretagogue or insulin
`may be necessary. (5.3)
`(cid:1) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`anaphylaxis and angioedema) have been reported. Discontinue
`MOUNJARO if suspected and promptly seek medical advice. (5.4)
`(cid:1) Acute Kidney Injury: Monitor renal function in patients with renal
`impairment reporting severe adverse gastrointestinal reactions.
`(5.5)
`(cid:1) 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)
`(cid:1) Diabetic Retinopathy Complications in Patients with a History of
`Diabetic Retinopathy: Has not been studied in patients with non-
`proliferative diabetic retinopathy requiring acute therapy,
`proliferative diabetic retinopathy, or diabetic macular edema.
`Monitor patients with a history of diabetic retinopathy for
`progression. (5.7)
`(cid:1) Acute Gallbladder Disease: Has occurred in clinical trials. If
`cholelithiasis is suspected, gallbladder studies and clinical follow-
`up are indicated. (5.8)
`
` ------------------------------- ADVERSE REACTIONS ------------------------------
`(cid:10)(cid:18)(cid:15)(cid:1)(cid:21)(cid:23)(cid:26)(cid:27)(cid:1)(cid:13)(cid:23)(cid:21)(cid:21)(cid:23)(cid:22)(cid:1)(cid:11)(cid:14)(cid:29)(cid:15)(cid:25)(cid:26)(cid:15)(cid:1)(cid:25)(cid:15)(cid:11)(cid:13)(cid:27)(cid:19)(cid:23)(cid:22)(cid:26)(cid:4)(cid:1)(cid:25)(cid:15)(cid:24)(cid:23)(cid:25)(cid:27)(cid:15)(cid:14)(cid:1)(cid:19)(cid:22)(cid:1)(cid:33)(cid:8)(cid:2)(cid:1)(cid:23)(cid:16)(cid:1)(cid:24)(cid:11)(cid:27)(cid:19)(cid:15)(cid:22)(cid:27)(cid:26)(cid:1)
`treated with MOUNJARO are: nausea, diarrhea, decreased appetite,
`vomiting, constipation, dyspepsia, and abdominal pain. (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 ------------------------------
`MOUNJARO delays gastric emptying and has the potential to impact
`the absorption of concomitantly administered oral medications. (7.2)
` ------------------------ USE IN SPECIFIC POPULATIONS -----------------------
`(cid:1) Pregnancy: Based on animal study, may cause fetal harm. (8.1)
`Females of Reproductive Potential: Advise females using oral
`contraceptives to switch to a non-oral contraceptive method, or add
`a barrier method of contraception for 4 weeks after initiation and for
`4 weeks after each dose escalation. (7.2, 8.3, 12.3)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`(cid:1)
`
`Revised: (cid:19)(cid:26)/(cid:21)(cid:19)(cid:21)(cid:22)
`
`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
`
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`5.7 Diabetic Retinopathy Complications in Patients with a
`History of Diabetic Retinopathy
`5.8 Acute Gallbladder Disease
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Concomitant Use with an Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
`7.2 Oral Medications
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`FULL PRESCRIBING INFORMATION
`
`2
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.6 Immunogenicity
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Overview of Clinical Studies
`14.2 Monotherapy Use of MOUNJARO in Adult Patients with
`Type 2 Diabetes Mellitus
`14.3 MOUNJARO Use in Combination with Metformin,
`Sulfonylureas, and/or SGLT2 Inhibitors in Adult Patients
`with Type 2 Diabetes Mellitus
`14.4 MOUNJARO Use in Combination with Basal Insulin with or
`without Metformin in Adult Patients with Type 2 Diabetes
`Mellitus
`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 prescr bing information
`are not listed.
`
`(cid:1)(cid:1)
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent
`thyroid C-cell tumors at clinically relevant exposures. It is unknown whether MOUNJARO causes thyroid
`C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-
`induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and
`Nonclinical Toxicology (13.1)].
`(cid:1) MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with
`Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients
`regarding the potential risk for MTC with the use of MOUNJARO 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 MOUNJARO [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`1
`MOUNJARO® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
`Limitations of Use
`(cid:1) MOUNJARO has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
`(cid:1) MOUNJARO is not indicated for use in patients with type 1 diabetes mellitus.
`
`2
`2.1
`(cid:1)
`
`(cid:1)
`(cid:1)
`
`(cid:1)
`(cid:1)
`
`DOSAGE AND ADMINISTRATION
`Dosage
`The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. The 2.5 mg
`dosage is for treatment initiation and is not intended for glycemic control.
`After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
`If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the
`current dose.
`The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
`If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the
`missed dose. If more than 4 days have passed, 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.
`
`Reference ID: 5216931
`
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`3
`
`(cid:1)
`
`2.2
`(cid:1)
`(cid:1)
`
`The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least
`3 days (72 hours).
`Important Administration Instructions
`Prior to initiation, train patients and caregivers on proper injection technique [see Instructions for Use].
`Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe
`capable of measuring a 0.5 mL dose).
`Administer MOUNJARO once weekly, any time of day, with or without meals.
`(cid:1)
`Inject MOUNJARO subcutaneously in the abdomen, thigh, or upper arm.
`(cid:1)
`(cid:1) Rotate injection sites with each dose.
`Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use
`(cid:1)
`MOUNJARO if particulate matter or discoloration is seen.
`(cid:1) When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject
`MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Injection: Clear, colorless to slightly yellow solution in pre-filled single-dose pens or single-dose vials, each available in the
`following strengths:
`2.5 mg/0.5 mL
`(cid:1)
`5 mg/0.5 mL
`(cid:1)
`7.5 mg/0.5 mL
`(cid:1)
`10 mg/0.5 mL
`(cid:1)
`12.5 mg/0.5 mL
`(cid:1)
`15 mg/0.5 mL
`(cid:1)
`
`CONTRAINDICATIONS
`4
`MOUNJARO is contraindicated in patients with:
`A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia
`(cid:1)
`syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
`Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. Serious hypersensitivity
`reactions, including anaphylaxis and angioedema, have been reported with MOUNJARO [see Warnings and
`Precautions (5.4)].
`
`(cid:1)
`
`WARNINGS AND PRECAUTIONS
`5
`Risk of Thyroid C-Cell Tumors
`5.1
`In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of
`thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see
`Nonclinical Toxicology (13.1)]. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary
`thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been
`determined.
`MOUNJARO 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 MOUNJARO 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 MOUNJARO. 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
`values 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.
`
`Reference ID: 5216931
`
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`4
`
`Pancreatitis
`5.2
`Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients
`treated with GLP-1 receptor agonists.
`In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 MOUNJARO-treated patients (0.23
`patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of
`exposure). MOUNJARO has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a
`history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO.
`After initiation of MOUNJARO, 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, discontinue MOUNJARO and initiate appropriate management.
`5.3
`Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
`Patients receiving MOUNJARO in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an
`increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1), Drug Interactions (7.1)].
`The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered
`insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and
`educate them on the signs and symptoms of hypoglycemia.
`5.4
`Hypersensitivity Reactions
`Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with
`MOUNJARO. If hypersensitivity reactions occur, discontinue use of MOUNJARO; treat promptly per standard of care, and
`monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity reaction to
`tirzepatide or any of the excipients in MOUNJARO [see Contraindications (4), Adverse Reactions (6.2)].
`Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in patients with a history of
`angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown whether such patients will be
`predisposed to these reactions with MOUNJARO.
`5.5
`Acute Kidney Injury
`MOUNJARO has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea
`[see Adverse Reactions (6.1)]. These events may lead to dehydration, which if severe could cause acute kidney injury.
`In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and
`worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported
`in patients without known underlying renal disease. A majority of the reported events occurred in patients who had
`experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of
`MOUNJARO in patients with renal impairment reporting severe gastrointestinal adverse reactions.
`5.6
`Severe Gastrointestinal Disease
`Use of MOUNJARO has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse
`Reactions 6.1]. MOUNJARO has not been studied in patients with severe gastrointestinal disease, including severe
`gastroparesis, and is therefore not recommended in these patients.
`5.7
`Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy
`Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.
`MOUNJARO has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy,
`proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be
`monitored for progression of diabetic retinopathy.
`5.8
`Acute Gallbladder Disease
`Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist
`trials and postmarketing.
`In MOUNJARO placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic, and
`cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients. If
`cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.
`
`
`
`Reference ID: 5216931
`
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`5
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`(cid:1) Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
`Pancreatitis [see Warnings and Precautions (5.2)]
`(cid:1)
`(cid:1) Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]
`(cid:1) Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`Acute Kidney Injury [see Warnings and Precautions (5.5)]
`(cid:1)
`Severe Gastrointestinal Disease [see Warnings and Precautions (5.6)]
`(cid:1)
`(cid:1) Diabetic Retinopathy Complications [see Warnings and Precautions (5.7)]
`Acute Gallbladder Disease [see Warnings and Precautions (5.8)]
`(cid:1)
`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 to rates in the clinical trials of another drug and may not reflect the rates observed
`in practice.
`Pool of Two Placebo-Controlled Clinical Trials
`The data in Table 1 are derived from 2 placebo-controlled trials [1 monotherapy trial (SURPASS-1) and 1 trial in
`combination with basal insulin with or without metformin (SURPASS-5)] in adult patients with type 2 diabetes mellitus [see
`Clinical Studies (14.2, 14.4)]. These data reflect exposure of 718 patients to MOUNJARO and a mean duration of
`exposure to MOUNJARO of 36.6 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 54%
`were male. The population was 57% White, 27% Asian, 13% American Indian or Alaska Native, and 3% Black or African
`American; 25% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average
`of 9.1 years with a mean HbA1c of 8.1%. As assessed by baseline fundoscopic examination, 13% of the population had
`retinopathy. At baseline, eGFR was (cid:33)(cid:9)(cid:6) mL/min/1.73 m2 in 53%, 60 to 90 mL/min/1.73 m2 in 39%, 45 to
`60 mL/min/1.73 m2 in 7%, and 30 to 45 mL/min/1.73 m2 in 1% of patients.
`Pool of Seven Controlled Clinical Trials
`Adverse reactions were also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in seven
`controlled clinical trials which included two placebo-controlled trials (SURPASS-1 and -5), three trials of MOUNJARO in
`combination with metformin, sulfonylureas, and/or SGLT2 Inhibitors (SURPASS-2, -3, -4) [see Clinical Studies (14.3)] and
`two additional trials conducted in Japan. In this pool, a total of 5119 adult patients with type 2 diabetes mellitus were
`treated with MOUNJARO for a mean duration of 48.1 weeks. The mean age of patients was 58 years, 4% were 75 years
`or older and 58% were male. The population was 65% White, 24% Asian, 7% American Indian or Alaska Native, and 3%
`Black or African American; 38% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes
`mellitus for an average of 9.1 years with a mean HbA1c of 8.3%. As assessed by baseline fundoscopic examination, 15%
`of the population had retinopathy. At baseline, eGFR was (cid:33)(cid:9)(cid:6) mL/min/1.73 m2 in 52%, 60 to 90 mL/min/1.73 m2 in 40%,
`45 to 60 mL/min/1.73 m2 in 6%, and 30 to 45 mL/min/1.73 m2 in 1% of patients.
`Common Adverse Reactions
`Table 1 shows common adverse reactions, not including hypoglycemia, associated with the use of MOUNJARO in the
`pool of placebo-controlled trials. These adverse reactions occurred more commonly on MOUNJARO than on placebo and
`occurred in at least 5% of patients treated with MOUNJARO.
`
`Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials Reported in (cid:6)(cid:3)(cid:2)(cid:1)(cid:5)(cid:4)(cid:1)MOUNJARO-treated Adult
`Patients with Type 2 Diabetes Mellitus
`Placebo
`MOUNJARO
`MOUNJARO
`10 mg
`(N=235)
`5 mg
`(N=240)
`%
`(N=237)
`%
`%
`12
`15
`12
`13
`5
`10
`
`Nausea
`Diarrhea
`Decreased Appetite
`
`4
`9
`1
`
`Adverse Reaction
`
`Reference ID: 5216931
`
`MOUNJARO
`15 mg
`(N=241)
`%
`18
`17
`11
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`6
`
`9
`5
`5
`2
`Vomiting
`7
`6
`6
`1
`Constipation
`5
`8
`8
`3
`Dyspepsia
`5
`5
`6
`4
`Abdominal Pain
`Note: Percentages reflect the number of patients who reported at least 1 occurrence of the adverse reaction.
`
`In the pool of seven clinical trials, the types and frequency of common adverse reactions, not including hypoglycemia,
`were similar to those listed in Table 1.
`Gastrointestinal Adverse Reactions
`In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients
`receiving MOUNJARO than placebo (placebo 20.4%, MOUNJARO 5 mg 37.1%, MOUNJARO 10 mg 39.6%, MOUNJARO
`15 mg 43.6%). More patients receiving MOUNJARO 5 mg (3.0%), MOUNJARO 10 mg (5.4%), and MOUNJARO 15 mg
`(6.6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). The
`majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation and decreased over time.
`The following gastrointestinal adverse reactions were reported more frequently in MOUNJARO-treated patients than
`placebo-treated patients (frequencies listed, respectively, as: placebo; 5 mg; 10 mg; 15 mg): eructation (0.4%, 3.0%,
`2.5%, 3.3%), flatulence (0%, 1.3%, 2.5%, 2.9%), gastroesophageal reflux disease (0.4%, 1.7%, 2.5%, 1.7%), abdominal
`distension (0.4%, 0.4%, 2.9%, 0.8%).
`Other Adverse Reactions
`Hypoglycemia
`Table 2 summarizes the incidence of hypoglycemic events in the placebo-controlled trials.
`
`Table 2: Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Adult Patients with Type 2 Diabetes
`Mellitus
`MOUNJARO
`5 mg
`%
`
`MOUNJARO
`10 mg
`%
`
`MOUNJARO
`15 mg
`%
`
`Placebo
`
`%
`
`N=115
`1
`0
`
`N=121
`0
`0
`
`N=119
`0
`0
`
`N=120
`0
`0
`
`Monotherapy
`(40 weeks)*
`Blood glucose <54 mg/dL
`Severe hypoglycemia**
`Add-on to Basal Insulin with or
`without Metformin
`N=120
`N=119
`N=116
`N=120
`(40 weeks)*
`14
`19
`16
`13
`Blood glucose <54 mg/dL
`1
`2
`0
`0
`Severe hypoglycemia**
`* Reflects the study treatment period. Data include events occurring during 4 weeks of treatment-free safety follow up. Events
`after introduction of a new glucose-lowering treatment are excluded.
`** Episodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative
`actions.
`Hypoglycemia was more frequent when MOUNJARO was used in combination with a sulfonylurea [see Clinical Studies
`(14)]. In a clinical trial up to 104 weeks of treatment, when administered with a sulfonylurea, hypoglycemia (glucose level
`<54 mg/dL) occurred in 13.8%, 9.9%, and 12.8%, and severe hypoglycemia occurred in 0.5%, 0%, and 0.6% of patients
`treated with MOUNJARO 5 mg, 10 mg, and 15 mg, respectively.
`Heart Rate Increase
`In the pool of placebo-controlled trials, treatment with MOUNJARO resulted in a mean increase in heart rate of 2 to 4
`beats per minute compared to a mean increase of 1 beat per minute in placebo-treated patients. Episodes of sinus
`(cid:27)(cid:11)(cid:13)(cid:18)(cid:31)(cid:13)(cid:11)(cid:25)(cid:14)(cid:19)(cid:11)(cid:4)(cid:1)(cid:11)(cid:26)(cid:26)(cid:23)(cid:13)(cid:19)(cid:11)(cid:27)(cid:15)(cid:14)(cid:1)(cid:30)(cid:19)(cid:27)(cid:18)(cid:1)(cid:11)(cid:1)(cid:13)(cid:23)(cid:22)(cid:13)(cid:23)(cid:21)(cid:19)(cid:27)(cid:11)(cid:22)(cid:27)(cid:1)(cid:19)(cid:22)(cid:13)(cid:25)(cid:15)(cid:11)(cid:26)(cid:15)(cid:1)(cid:16)(cid:25)(cid:23)(cid:21)(cid:1)(cid:12)(cid:11)(cid:26)(cid:15)(cid:20)(cid:19)(cid:22)(cid:15)(cid:1)(cid:19)(cid:22)(cid:1)(cid:18)(cid:15)(cid:11)(cid:25)(cid:27)(cid:1)(cid:25)(cid:11)(cid:27)(cid:15)(cid:1)(cid:23)(cid:16)(cid:1)(cid:33)(cid:7)(cid:8)(cid:1)(cid:12)(cid:15)(cid:11)(cid:27)(cid:26)(cid:1)(cid:24)(cid:15)(cid:25)(cid:1)(cid:21)(cid:19)(cid:22)(cid:28)(cid:27)(cid:15)(cid:4)(cid:1)(cid:11)(cid:20)(cid:26)(cid:23)(cid:1)(cid:30)(cid:15)(cid:25)(cid:15)(cid:1)
`
`Reference ID: 5216931
`
`Novo Nordisk Exhibit 2475
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`7
`
`reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg,
`respectively. For patients enrolled in Japan, these episodes were reported in 7% (3/43), 7.1% (3/42), 9.3% (4/43), and
`23% (10/43) of patients treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. The clinical relevance
`of heart rate increases is uncertain.
`Hypersensitivity Reactions
`Hypersensitivity reactions have been reported with MOUNJARO in the pool of placebo-controlled trials, sometimes severe
`(e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2% of MOUNJARO-treated patients compared
`to 1.7% of placebo-treated patients.
`In the pool of seven clinical trials, hypersensitivity reactions occurred in 106/2,570 (4.1%) of MOUNJARO-treated patients
`with anti-tirzepatide antibodies and in 73/2,455 (3.0%) of MOUNJARO-treated patients who did not develop anti-
`tirzepatide antibodies [see Clinical Pharmacology (12.6)].
`Injection Site Reactions
`In the pool of placebo-controlled trials, injection site reactions were reported in 3.2% of MOUNJARO-treated patients
`compared to 0.4% of placebo-treated patients.
`In the pool of seven clinical trials, injection site reactions occurred in 119/2,570 (4.6%) of MOUNJARO-treated patients
`with anti-tirzepatide antibodies and in 18/2,455 (0.7%) of MOUNJARO-treated patients who did not develop anti-
`tirzepatide antibodies [see Clinical Pharmacology (12.6)].
`Acute Gallbladder Disease
`In the pool of placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic and cholecystectomy)
`was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients.
`Laboratory Abnormalities
`Amylase and Lipase Increase
`In the pool of placebo-controlled clinical trials, treatment with MOUNJARO resulted in mean increases from baseline in
`serum pancreatic amylase concentrations of 33% to 38% and serum lipase concentrations of 31% to 42%. Placebo-
`treated patients had a mean increase from baseline in pancreatic amylase of 4% and no changes were observed in
`lipase. The clinical significance of elevations in lipase or amylase with MOUNJARO is unknown in the absence of other
`signs and symptoms of pancreatitis.
`6.2
`Postmarketing Experience
`The following adverse reactions have been reported during post-approval use of MOUNJARO. Because these reactions
`are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
`establish a causal relationship to drug exposure.
`Hypersensitivity: anaphylaxis, angioedema
`Gastrointestinal: ileus
`
`DRUG INTERACTIONS
`7
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`7.1
`When initiating MOUNJARO, consider reducing the dose of concomitantly administered insulin secretagogues (e.g.,
`sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].
`7.2
`Oral Medications
`MOUNJARO delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly
`administered oral medications. Caution should be exercised when oral medications are concomitantly administered with
`MOUNJARO.
`Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow
`therapeutic index (e.g., warfarin) when concomitantly administered with MOUNJARO.
`Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method
`of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO. Hormonal
`contraceptives that are not administered orally should not be affected [see Use in Specific Populations (8.3) and Clinical
`Pharmacology (12.2, 12.3)].
`
`Reference ID: 5216931
`
`Novo Nordisk Exhibit 2475
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

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`8
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`Available data with MOUNJARO use in pregnant women are insufficient to evaluate for a drug-related risk of major birth
`defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with
`poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may
`be risks to the fetus from exposure to tirzepatide during pregnancy. MOUNJARO should be used during pregnancy only if
`the potential benefit justifies the potential risk to the fetus.
`In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred
`at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth
`reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals
`coincided with pharmacological effects on maternal weight and food consumption (see Data).
`The estimated background risk of major birth defects is 6(cid:34)10% in women with pre-gestational diabetes with an HbA1c
`>7% and has been reported to be as high as 20(cid:34)25% in women with an HbA1c >10%. The estimated background risk of
`miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of
`major birth defects and miscarriage in clinically recognized pregnancies is 2(cid:34)4% and 15(cid:34)20%, respectively.
`Clinical Considerations
`Disease-Associated Maternal and/or Embryo/Fetal Risk
`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous
`abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth
`defects, stillbirth, and macrosomia-related morbidity.
`Data
`Animal Data
`In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tir