HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ZEPBOUND safely and effectively. See full prescribing
`information for ZEPBOUND.
`ZEPBOUND® (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.
`• In rats, tirzepatide causes thyroid C-cell tumors. It is
`unknown whether ZEPBOUND 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).
`• ZEPBOUND 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).
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`ZEPBOUND® is a glucose-dependent insulinotropic polypeptide (GIP)
`receptor and glucagon-like peptide-1 (GLP-1) receptor agonist
`indicated as an adjunct to a reduced-calorie diet and increased
`physical activity for chronic weight management in adults with an initial
`body mass index (BMI) of:
`•
`30 kg/m2 or greater (obesity) or
`•
`27 kg/m2 or greater (overweight) in the presence of at least one
`weight-related comorbid condition (e.g., hypertension,
`dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or
`cardiovascular disease). (1)
`Limitations of Use:
`• Coadministration with other tirzepatide-containing products or any
`GLP-1 receptor agonist is not recommended. (1)
`• The safety and efficacy of coadministration with other products for
`weight management have not been established. (1)
`• ZEPBOUND has not been studied in patients with a history of
`pancreatitis. (1)
`
`•
`
` ------------------------ DOSAGE AND ADMINISTRATION -----------------------
`• The recommended starting dosage is 2.5 mg injected
`subcutaneously once weekly. (2.2)
`• After 4 weeks, increase to 5 mg injected subcutaneously once
`weekly. (2.2)
`Increase the dosage in 2.5 mg increments after at least 4 weeks
`on the current dose. (2.2)
`• The recommended maintenance dosages are 5 mg, 10 mg, or
`15 mg injected subcutaneously once weekly. (2.2)
`• Consider treatment response and tolerability when selecting the
`maintenance dosage. (2.2)
`• The maximum dosage is 15 mg subcutaneously once weekly. (2.2)
`• Administer once weekly at any time of day, with or without meals.
`(2.4)
`Inject subcutaneously in the abdomen, thigh, or upper arm. (2.4)
`•
`• Rotate injection sites with each dose. (2.4)
`
` ----------------------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)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`
`Reference ID: 5355063
`
`1
` ------------------------------- CONTRAINDICATIONS ------------------------------
`• Personal or family history of medullary thyroid carcinoma or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (4)
`• Known serious hypersensitivity to tirzepatide or any of the
`excipients in ZEPBOUND (4)
`
` ------------------------ WARNINGS AND PRECAUTIONS -----------------------
`• Severe Gastrointestinal Disease: Use has been associated with
`gastrointestinal adverse reactions, sometimes severe. Has not
`been studied in patients with severe gastrointestinal disease and is
`not recommended in these patients. (5.2)
`• Acute Kidney Injury: Monitor renal function in patients reporting
`adverse reactions that could lead to volume depletion. (5.3)
`• Acute Gallbladder Disease: Has been reported in clinical trials. If
`cholecystitis is suspected, gallbladder studies and clinical follow-up
`are indicated. (5.4)
`• Acute Pancreatitis: Has been reported in clinical trials. Discontinue
`promptly if pancreatitis is suspected. Do not restart if pancreatitis is
`confirmed. (5.5)
`• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`anaphylaxis, angioedema) have been reported postmarketing with
`tirzepatide. If suspected, advise patients to promptly seek medical
`attention and discontinue ZEPBOUND. (5.6)
`• Hypoglycemia: 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. Inform all patients of the risk of hypoglycemia
`and educate them on the signs and symptoms of hypoglycemia.
`(5.7)
`• Diabetic Retinopathy Complications in Patients with Type 2
`Diabetes Mellitus: 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. (5.8)
`• Suicidal Behavior and Ideation: Monitor for depression or suicidal
`thoughts. Discontinue ZEPBOUND if symptoms develop. (5.9)
`
` ------------------------------- ADVERSE REACTIONS ------------------------------
`The most common adverse reactions, reported in ≥5% of patients
`treated with ZEPBOUND are: nausea, diarrhea, vomiting, constipation,
`abdominal pain, dyspepsia, injection site reactions, fatigue,
`hypersensitivity reactions, eructation, hair loss, gastroesophageal
`reflux disease. (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 ------------------------------
`ZEPBOUND delays gastric emptying and has the potential to impact
`the absorption of concomitantly administered oral medications. (7.2)
`
` ------------------------ USE IN SPECIFIC POPULATIONS -----------------------
`• Pregnancy: May cause fetal harm. When pregnancy is recognized,
`discontinue ZEPBOUND. (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. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`Revised: 03/2024
`
`2.2 Recommended Dosage
`2.3 Recommendations Regarding Missed Dose
`2.4
`Important Administration Instructions
`3 DOSAGE FORMS AND STRENGTHS
`
`

`

`2
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.6 Immunogenicity
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Weight Management Studies in Adults with Overweight or
`Obesity
`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.
`
`
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-Cell Tumors
`5.2 Severe Gastrointestinal Disease
`5.3 Acute Kidney Injury
`5.4 Acute Gallbladder Disease
`5.5 Acute Pancreatitis
`5.6 Hypersensitivity Reactions
`5.7 Hypoglycemia
`5.8 Diabetic Retinopathy Complications in Patients with Type 2
`Diabetes Mellitus
`5.9 Suicidal Behavior and Ideation
`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
`
`
`
`Reference ID: 5355063
`
`

`

`3
`
`•
`
`FULL PRESCRIBING INFORMATION
`WARNING: RISK OF THYROID C-CELL TUMORS
`In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at
`clinically relevant exposures. It is unknown whether ZEPBOUND 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)].
`• ZEPBOUND 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 ZEPBOUND 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 ZEPBOUND [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`1
`ZEPBOUND® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
`management in adults with an initial body mass index (BMI) of:
`•
`30 kg/m2 or greater (obesity) or
`•
`27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension,
`dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease).
`Limitations of Use
`• ZEPBOUND contains tirzepatide. Coadministration with other tirzepatide-containing products or with any glucagon-
`like peptide-1 (GLP-1) receptor agonist is not recommended.
`• The safety and efficacy of ZEPBOUND in combination with other products intended for weight management, including
`prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
`• ZEPBOUND has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.5)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Patient Selection
`2.1
`Select adult patients for ZEPBOUND treatment as an adjunct to a reduced-calorie diet and increased physical activity for
`chronic weight management based on their BMI. Table 1 presents a chart for determining BMI based on height and
`weight. BMI is calculated by dividing weight (in kilograms) by height (in meters) squared.
`
`
`
`
`Reference ID: 5355063
`
`

`

`Table 1: BMI Conversion Chart
`
`4
`
`(lb)
`
`125
`
`130
`
`135
`
`140
`
`145
`
`150
`
`155
`
`160
`
`165
`
`170
`
`175
`
`180
`
`185
`
`190
`
`195
`
`200
`
`205
`
`210
`
`215
`
`220
`
`225
`
`Weight
`
`(kg)
`
`56.8
`
`59.1
`
`61.4
`
`63.6
`
`65.9
`
`68.2
`
`70.5
`
`72.7
`
`75.0
`
`77.3
`
`79.5
`
`81.8
`
`84.1
`
`86.4
`
`88.6
`
`90.9
`
`93.2
`
`95.5
`
`97.7
`
`100.0
`
`102.3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Height
`
`(in)
`
`(cm)
`
`
`
`58
`
`147.3
`
`26
`
`
`
`27
`
`26
`
`
`
`28
`
`27
`
`
`
`29
`
`28
`
`
`
`30
`
`29
`
`
`
`31
`
`30
`
`
`
`32
`
`31
`
`
`
`34
`
`32
`
`
`
`35
`
`33
`
`
`
`36
`
`34
`
`
`
`37
`
`35
`
`
`
`38
`
`36
`
`
`
`39
`
`37
`
`
`
`40
`
`38
`
`
`
`41
`
`39
`
`
`
`42
`
`40
`
`
`
`43
`
`41
`
`
`
`44
`
`43
`
`
`
`45
`
`44
`
`
`
`46
`
`45
`
`
`
`47
`
`46
`
`59
`
`60
`
`61
`
`149.9
`
`152.4
`
`154.9
`
`25
`
`24
`
`24
`
`25
`
`25
`
`26
`
`26
`
`27
`
`27
`
`26
`
`28
`
`27
`
`27
`
`29
`
`28
`
`27
`
`30
`
`29
`
`28
`
`31
`
`30
`
`29
`
`32
`
`31
`
`30
`
`33
`
`32
`
`31
`
`34
`
`33
`
`32
`
`35
`
`34
`
`33
`
`36
`
`35
`
`34
`
`37
`
`36
`
`35
`
`38
`
`37
`
`36
`
`39
`
`38
`
`37
`
`40
`
`39
`
`38
`
`41
`
`40
`
`38
`
`42
`
`41
`
`39
`
`43
`
`42
`
`40
`
`44
`
`43
`
`41
`
`62
`
`63
`
`64
`
`157.5
`
`160.0
`
`162.6
`
`23
`
`22
`
`22
`
`24
`
`23
`
`22
`
`25
`
`24
`
`23
`
`25
`
`24
`
`26
`
`25
`
`27
`
`26
`
`25
`
`28
`
`27
`
`26
`
`28
`
`28
`
`27
`
`29
`
`28
`
`28
`
`30
`
`29
`
`28
`
`31
`
`30
`
`29
`
`32
`
`31
`
`30
`
`33
`
`32
`
`31
`
`34
`
`33
`
`32
`
`35
`
`34
`
`33
`
`36
`
`34
`
`33
`
`36
`
`35
`
`34
`
`37
`
`36
`
`35
`
`38
`
`37
`
`36
`
`39
`
`38
`
`37
`
`40
`
`39
`
`38
`
`65
`
`66
`
`67
`
`165.1
`
`167.6
`
`170.2
`
`21
`
`20
`
`20
`
`22
`
`21
`
`20
`
`23
`
`22
`
`21
`
`23
`
`23
`
`22
`
`24
`
`23
`
`23
`
`24
`
`24
`
`25
`
`24
`
`26
`
`25
`
`24
`
`27
`
`26
`
`25
`
`27
`
`27
`
`26
`
`28
`
`27
`
`27
`
`29
`
`28
`
`27
`
`30
`
`29
`
`28
`
`31
`
`30
`
`29
`
`32
`
`31
`
`30
`
`32
`
`31
`
`30
`
`33
`
`32
`
`31
`
`34
`
`33
`
`32
`
`35
`
`34
`
`33
`
`36
`
`35
`
`34
`
`36
`
`35
`
`34
`
`68
`
`69
`
`70
`
`172.7
`
`175.3
`
`177.8
`
`19
`
`18
`
`18
`
`20
`
`19
`
`19
`
`21
`
`20
`
`19
`
`21
`
`21
`
`20
`
`22
`
`21
`
`21
`
`23
`
`22
`
`22
`
`24
`
`23
`
`22
`
`24
`
`23
`
`24
`
`24
`
`25
`
`24
`
`24
`
`26
`
`25
`
`24
`
`27
`
`26
`
`25
`
`27
`
`27
`
`26
`
`28
`
`27
`
`27
`
`29
`
`28
`
`27
`
`30
`
`29
`
`28
`
`30
`
`29
`
`29
`
`31
`
`30
`
`29
`
`32
`
`31
`
`30
`
`33
`
`32
`
`31
`
`33
`
`32
`
`31
`
`71
`
`72
`
`73
`
`180.3
`
`182.9
`
`185.4
`
`17
`
`17
`
`17
`
`18
`
`18
`
`17
`
`19
`
`18
`
`18
`
`20
`
`19
`
`19
`
`20
`
`20
`
`19
`
`21
`
`20
`
`20
`
`22
`
`21
`
`20
`
`22
`
`22
`
`21
`
`23
`
`22
`
`22
`
`23
`
`22
`
`24
`
`23
`
`24
`
`24
`
`23
`
`25
`
`24
`
`24
`
`26
`
`25
`
`24
`
`27
`
`26
`
`25
`
`27
`
`26
`
`26
`
`28
`
`27
`
`26
`
`29
`
`28
`
`27
`
`29
`
`28
`
`28
`
`30
`
`29
`
`28
`
`31
`
`30
`
`29
`
`74
`
`75
`
`76
`
`188.0
`
`190.5
`
`193.0
`
`16
`
`16
`
`15
`
`17
`
`16
`
`16
`
`17
`
`17
`
`16
`
`18
`
`18
`
`17
`
`19
`
`18
`
`18
`
`19
`
`19
`
`18
`
`20
`
`19
`
`19
`
`21
`
`20
`
`20
`
`21
`
`21
`
`20
`
`22
`
`21
`
`21
`
`23
`
`22
`
`21
`
`23
`
`22
`
`23
`
`23
`
`24
`
`23
`
`24
`
`24
`
`25
`
`24
`
`26
`
`25
`
`26
`
`26
`
`27
`
`26
`
`28
`
`27
`
`28
`
`27
`
`
`
`Recommended Dosage
`2.2
`• The recommended starting dosage of ZEPBOUND is 2.5 mg injected subcutaneously once weekly. The 2.5 mg
`dosage is for treatment initiation and is not intended for chronic weight management.
`• After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
`• The dosage may be increased in 2.5 mg increments, after at least 4 weeks on the current dose.
`• The recommended maintenance dosages of ZEPBOUND in adults are 5 mg, 10 mg, or 15 mg injected
`subcutaneously once weekly.
`• Consider treatment response and tolerability when selecting the maintenance dosage. If patients do not tolerate a
`maintenance dosage, consider a lower maintenance dosage.
`• The maximum dosage of ZEPBOUND is 15 mg injected subcutaneously once weekly.
`
`2.3
`•
`
`Recommendations Regarding Missed Dose
`If a dose is missed, instruct patients to administer ZEPBOUND 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.
`• 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
`2.4
`• Prior to initiation of ZEPBOUND, train patients and caregivers on proper injection technique. Refer to the
`accompanying Instructions for Use for complete administration instructions with illustrations.
`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).
`
`•
`
`
`
`Reference ID: 5355063
`
`

`

`•
`
`Inspect ZEPBOUND visually before use. It should appear clear and colorless to slightly yellow. Do not use
`ZEPBOUND if particulate matter or discoloration is seen.
`• Administer ZEPBOUND once weekly at any time of day, with or without meals.
`•
`Inject ZEPBOUND subcutaneously in the abdomen, thigh, or upper arm.
`• Rotate injection sites with each dose.
`
`5
`
`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
`•
`5 mg/0.5 mL
`•
`7.5 mg/0.5 mL
`•
`10 mg/0.5 mL
`•
`12.5 mg/0.5 mL
`•
`15 mg/0.5 mL
`
`CONTRAINDICATIONS
`4
`ZEPBOUND is contraindicated in patients with:
`• A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions (5.1)].
`• Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND. Serious hypersensitivity
`reactions, including anaphylaxis and angioedema, have been reported with tirzepatide [see Warnings and Precautions
`(5.6) and Adverse Reactions (6.2)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Risk of Thyroid C-Cell Tumors
`5.1
`In 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 ZEPBOUND causes thyroid C-cell tumors, including MTC, in humans as human relevance
`of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.
`ZEPBOUND 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 ZEPBOUND 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 ZEPBOUND. 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.
`
`Severe Gastrointestinal Disease
`5.2
`Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse
`Reactions (6.1)]. In clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients
`receiving ZEPBOUND (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1%). ZEPBOUND has not been studied in
`patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these
`patients.
`
`Acute Kidney Injury
`5.3
`Use of ZEPBOUND has been associated with acute kidney injury, which can result from dehydration due to
`gastrointestinal adverse reactions to ZEPBOUND; including nausea, vomiting, and diarrhea [see Adverse Reactions
`(6.1)].
`
`
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`Reference ID: 5355063
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`

`

`6
`
`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 in patients reporting adverse reactions to
`ZEPBOUND that could lead to volume depletion.
`
`Acute Gallbladder Disease
`5.4
`Treatment with ZEPBOUND and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder
`disease.
`In clinical trials of ZEPBOUND, cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% of placebo-
`treated patients, cholecystitis was reported in 0.7% of ZEPBOUND-treated patients and 0.2% of placebo-treated patients,
`and cholecystectomy was reported in 0.2% of ZEPBOUND-treated patients and no placebo-treated patients. Acute
`gallbladder events were associated with weight reduction. If cholecystitis is suspected, gallbladder diagnostic studies and
`appropriate clinical follow-up are indicated.
`
`Acute Pancreatitis
`5.5
`Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients
`treated with GLP-1 receptor agonists or tirzepatide.
`In clinical trials of tirzepatide for a different indication, 14 events of acute pancreatitis were confirmed by adjudication in 13
`tirzepatide-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). In ZEPBOUND clinical trials, 0.2% of ZEPBOUND-treated patients had acute
`pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of placebo-treated patients
`(0.15 patients per 100 years of exposure). ZEPBOUND 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 ZEPBOUND.
`After initiation of ZEPBOUND, observe patients carefully for signs and symptoms of pancreatitis (including persistent
`severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If
`pancreatitis is suspected, discontinue ZEPBOUND and initiate appropriate management. If the diagnosis of pancreatitis is
`confirmed, ZEPBOUND should not be restarted.
`
`Hypersensitivity Reactions
`5.6
`There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients
`treated with tirzepatide. In ZEPBOUND clinical trials, 0.1% of ZEPBOUND-treated patients had severe hypersensitivity
`reactions compared to no placebo-treated patients. If hypersensitivity reactions occur, advise patients to promptly seek
`medical attention and discontinue use of ZEPBOUND. Do not use in patients with a previous serious hypersensitivity
`reaction to tirzepatide or any of the excipients in ZEPBOUND [see Contraindications (4) and Adverse Reactions (6.2)].
`Serious hypersensitivity reactions, including 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 ZEPBOUND.
`
`Hypoglycemia
`5.7
`ZEPBOUND lowers blood glucose and can cause hypoglycemia.
`In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was
`reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients. In this trial, patients taking
`ZEPBOUND in combination with an insulin secretagogue (e.g., sulfonylurea) had increased risk of hypoglycemia (10.3%)
`compared to ZEPBOUND-treated patients not taking a sulfonylurea (2.1%). There is also increased risk of hypoglycemia
`in patients treated with tirzepatide in combination with insulin [see Drug Interactions (7.1)].
`Hypoglycemia has also been associated with ZEPBOUND and GLP-1 receptor agonists in adults without type 2 diabetes
`mellitus [see Adverse Reactions (6.1)].
`Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In patients
`with diabetes mellitus, monitor blood glucose prior to starting ZEPBOUND and during ZEPBOUND treatment. The risk of
`hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin
`secretagogue) or insulin.
`
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`Reference ID: 5355063
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`

`Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus
`5.8
`Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.
`Tirzepatide 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.
`
`Suicidal Behavior and Ideation
`5.9
`Suicidal behavior and ideation have been reported in clinical trials with other chronic weight management products.
`Monitor patients treated with ZEPBOUND for the emergence or worsening of depression, suicidal thoughts or behaviors,
`and/or any unusual changes in mood or behavior. Discontinue ZEPBOUND in patients who experience suicidal thoughts
`or behaviors. Avoid ZEPBOUND in patients with a history of suicidal attempts or active suicidal ideation.
`
`7
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
`• Severe Gastrointestinal Disease [see Warnings and Precautions (5.2)]
`• Acute Kidney Injury [see Warnings and Precautions (5.3)]
`• Acute Gallbladder Disease [see Warnings and Precautions (5.4)]
`• Acute Pancreatitis [see Warnings and Precautions (5.5)]
`• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
`• Hypoglycemia [see Warnings and Precautions (5.7)]
`• Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus [see Warnings and Precautions (5.8)]
`• Suicidal Behavior and Ideation [see Warnings and Precautions (5.9)]
`
`Clinical Trials Experience
`6.1
`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.
`ZEPBOUND was evaluated for safety in 2 randomized, double-blind, placebo-controlled trials that included 2519 adult
`patients with overweight or obesity treated with ZEPBOUND for up to 72 weeks and a 4-week off drug follow-up period
`[see Clinical Studies (14.1)]. The mean age of patients was 47 years and 37% were male. The population was 72% White,
`12% Asian, 8% Black or African American, and 7% American Indian or Alaska Native; 51% identified as Hispanic or
`Latino ethnicity. Baseline characteristics included an average BMI of 37.4 kg/m2, 29% with a BMI ≥40 kg/m2, 41% with
`hypertension, 37% with dyslipidemia, 25% with type 2 diabetes mellitus, 7% with obstructive sleep apnea, and 4% with
`cardiovascular disease.
`Across both trials, 4.8%, 6.3%, and 6.7% of patients treated with 5 mg, 10 mg, and 15 mg of ZEPBOUND, respectively,
`permanently discontinued treatment as a result of adverse reactions compared to 3.4% of patients treated with placebo.
`The majority of patients who discontinued ZEPBOUND due to adverse reactions did so during the first few months of
`treatment due to gastrointestinal adverse reactions.
`Common Adverse Reactions
`Table 2 shows common adverse reactions associated with the use of ZEPBOUND in the placebo-controlled trials for
`chronic weight management. These adverse reactions occurred more commonly with ZEPBOUND than with placebo and
`occurred in at least 2% of patients treated with ZEPBOUND.
`
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`8
`
`Table 2: Adverse Reactions (≥2% and Greater than Placebo) in ZEPBOUND-Treated Adults with Obesity or
`Overweight for Chronic Weight Management
`
`ZEPBOUND
`ZEPBOUND
`
`Placebo
`5 mg
`10 mg
`
`(N=958)
`(N=630)
`(N=948)
`
`%
`%
`%
`Adverse Reaction
`8
`25
`29
`Nausea
`8
`19
`21
`Diarrheaa
`2
`8
`11
`Vomiting
`5
`17
`14
`Constipationb
`5
`9
`9
`Abdominal Painc
`4
`9
`9
`Dyspepsia
`2
`6
`8
`Injection Site Reactionsd
`3
`5
`6
`Fatiguee
`3
`5
`5
`Hypersensitivity Reactions
`1
`4
`5
`Eructation
`1
`5
`4
`Hair Loss
`2
`4
`4
`Gastroesophageal Reflux Disease
`2
`3
`3
`Flatulence
`2
`3
`3
`Abdominal Distension
`2
`4
`5
`Dizziness
`0
`1
`1
`Hypotensionf
`a
`Includes diarrhea, frequent bowel movements.
`b
`Includes constipation, feces hard.
`c
`Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.
`d
`Includes multiple related adverse event terms, such as injection site bruising, injection site erythema, injection site pruritus,
`injection site pain, injection site rash, injection site reaction.
`Includes asthenia, fatigue, lethargy, malaise.
`Includes blood pressure decreased, hypotension, orthostatic hypotension.
`
`ZEPBOUND
`15 mg
`(N=941)
`%
`28
`23
`13
`11
`10
`10
`8
`7
`5
`5
`5
`5
`4
`4
`4
`2
`
`e
`f
`
`Gastrointestinal Adverse Reactions
`In ZEPBOUND clinical trials, gastrointestinal adverse reactions occurred more frequently among patients receiving
`ZEPBOUND (5 mg 56%, 10 mg 56%, 15 mg 56%) than placebo (30%). More patients receiving ZEPBOUND 5 mg (1.9%),
`ZEPBOUND 10 mg (3.3%), and ZEPBOUND 15 mg (4.3%) discontinued treatment due to gastrointestinal adverse
`reactions than patients receiving placebo (0.5%). The majority of nausea, vomiting, and/or diarrhea events occurred
`during dose escalation and decreased over time.
`Hypotension
`In ZEPBOUND clinical trials, hypotension occurred more frequently among patients taking ZEPBOUND (1.6%) than
`patients taking placebo (0.1%). Hypotension was more frequently seen in ZEPBOUND-treated patients on concomitant
`antihypertensive therapy (2.2%) compared to ZEPBOUND-treated patients not on antihypertensive therapy (1.2%).
`Hypotension also occurred in association with gastrointestinal adverse events and dehydration.
`Hypersensitivity Reactions
`In ZEPBOUND clinical trials, immediate hypersensitivity reactions (within one day after drug administration) occurred in
`2.1% of ZEPBOUND-treated patients compared to 0.4% of placebo-treated patients, while non-immediate hypersensitivity
`reactions occurred in 3.5% of ZEPBOUND-treated patients compared to 2.7% of placebo-treated patients. Among
`ZEPBOUND-treated patients, hypersensitivity reactions were more frequent in those with anti-tirzepatide antibodies
`(6.2%) compared to those who did not develop anti-tirzepatide antibodies (3%) [see Clinical Pharmacology (12.6)]. The
`majority of the hypersensitivity reactions in trials were skin reactions (e.g., rash, itching).
`
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`

`9
`
`Injection Site Reactions
`In ZEPBOUND-treated patients in clinical trials, injection site reactions were more frequent in those with anti-tirzepatide
`antibodies (11.3%) compared to those who did not develop anti-tirzepatide antibodies (1%) [see Clinical Pharmacology
`(12.6)].
`Hair Loss
`Hair loss adverse reactions in ZEPBOUND-treated patients were associated with weight reduction. In ZEPBOUND clinical
`trials, hair loss was reported more frequently in female than male patients in the ZEPBOUND (7.1% female versus 0.5%
`male) and placebo (1.3% female versus 0% male) treatment groups. No ZEPBOUND-treated patients and one placebo-
`treated patient discontinued study treatment due to hair loss.
`Other Adverse Reactions
`Acute Kidney Injury
`In clinical trials, acute kidney injury was reported in 0.5% of ZEPBOUND-treated patients compared to 0.2% of placebo-
`treated patients.
`Acute Gallbladder Disease
`In clinical trials of ZEPBOUND, cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% of placebo-
`treated patients, cholecystitis was reported in 0.7% of ZEPBOUND-treated patients and 0.2% of placebo-treated patients,
`and cholecystectomy was reported in 0.2% of ZEPBOUND-treated patients and no placebo-treated patients.
`Hypoglycemia
`In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was
`reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients.
`In a trial of ZEPBOUND in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic
`capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of ZEPBOUND-treated patients versus
`no placebo-treated patients.
`Heart Rate Increase
`In ZEPBOUND clinical trials, treatment with ZEPBOUND resulted in a mean increase in heart rate of 1 to 3 beats per
`minute compared to no increase in placebo-treated patients.
`Laboratory Abnormalities
`Amylase and Lipase Increase
`In clinical trials, treatment with ZEPBOUND resulted in mean increases from baseline in serum pancreatic amylase
`concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from
`baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of
`elevations in amylase or lipase with ZEPBOUND is unknown in the absence of other signs and symptoms of pancreatitis.
`
`Postmarketing Experience
`6.2
`The following adverse reactions have been reported during post-approval use of tirzepatide, the active ingredient in
`ZEPBOUND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always
`possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.
`Hypersensitivity: anaphylaxis, angioedema
`Gastrointestinal: ileus
`
`7
`
`DRUG INTERACTIONS
`
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`7.1
`ZEPBOUND lowers blood glucose. When initiating ZEPBOUND, consider reducing the dose of concomitantly
`administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and
`Precautions (