`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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: 11/2023
`
`
`
`
`
`
` 2.2 Recommended Dosage
`
`
` 2.3 Recommendations Regarding Missed Dose
`
`
` 2.4
` Important Administration Instructions
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------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 (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: 5274616
`
`

`

`
`
` 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: 5274616
`
`

`

`
`
` 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)].
`
`
`
`
`
`
`
` 1
` INDICATIONS AND USAGE
`
`
`
`
`
`
` 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: 5274616
`
`

`

`
`
` 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
`
` 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
`
`
`
` (kg)
`
`
`
` 56.8
`
`
`
` 59.1
`
`
`
` 61.4
`
`
`
` 63.6
`
`
`
` 65.9
`
`
`
` 68.2
`
`
`
` 70.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Height
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` (in)
`
` (cm)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 58
`
`
`
` 147.3
`
`
`
` 26
`
`
`
` 27
`
`
`
` 28
`
`
`
` 29
`
`
`
` 30
`
`
`
` 31
`
`
`
` 32
`
`
`
` 34
`
`
`
` 35
`
`
`
` 36
`
`
`
` 37
`
`
`
` 38
`
`
`
` 39
`
`
`
` 40
`
`
`
` 41
`
`
`
` 42
`
` 40
`
`
`
` 43
`
` 41
`
`
`
` 44
`
` 43
`
`
`
` 45
`
` 44
`
`
`
` 46
`
` 45
`
`
`
` 47
`
` 46
`
`
`
` 59
`
` 60
`
`
`
` 149.9
`
` 152.4
`
`
`
` 25
`
` 24
`
`
`
` 26
`
` 25
`
`
`
` 27
`
` 26
`
`
`
` 28
`
` 27
`
`
`
` 29
`
` 28
`
`
`
` 30
`
` 29
`
`
`
` 31
`
` 30
`
`
`
` 32
`
` 31
`
`
`
` 33
`
` 32
`
`
`
` 34
`
` 33
`
`
`
` 35
`
` 34
`
`
`
` 36
`
` 35
`
`
`
` 37
`
` 36
`
`
`
` 38
`
` 37
`
`
`
` 39
`
` 38
`
`
`
` 39
`
`
`
` 40
`
`
`
` 41
`
`
`
` 42
`
`
`
`
`
` 43
`
`
`
`
`
` 44
`
`
`
` 61
`
`
`
` 154.9
`
`
`
`
`
` 24
`
`
`
`
`
` 25
`
`
`
`
`
` 26
`
`
`
`
`
` 27
`
`
`
`
`
` 27
`
`
`
`
`
` 28
`
`
`
`
`
` 29
`
`
`
`
`
` 30
`
`
`
`
`
` 31
`
`
`
`
`
` 32
`
`
`
`
`
` 33
`
`
`
`
`
` 34
`
`
`
`
`
` 35
`
`
`
`
`
` 36
`
`
`
`
`
` 37
`
`
`
`
`
` 38
`
`
`
`
`
` 39
`
`
`
`
`
` 40
`
`
`
`
`
` 41
`
`
`
` 42
`
`
`
` 43
`
`
`
`
`
` 62
`
`
`
`
`
` 157.5
`
`
`
` 23
`
`
`
` 24
`
`
`
` 25
`
`
`
` 26
`
`
`
` 27
`
` 26
`
`
`
` 27
`
` 27
`
`
`
` 28
`
` 28
`
`
`
` 29
`
` 28
`
`
`
` 30
`
` 29
`
`
`
` 31
`
` 30
`
`
`
` 32
`
` 31
`
`
`
` 33
`
` 32
`
`
`
` 34
`
` 33
`
`
`
` 35
`
` 34
`
`
`
` 36
`
` 35
`
`
`
` 37
`
` 36
`
`
`
` 38
`
` 36
`
`
`
` 38
`
` 37
`
`
`
` 39
`
` 38
`
`
`
` 40
`
` 39
`
`
`
` 41
`
` 40
`
`
`
` 63
`
` 64
`
`
`
` 160.0
`
` 162.6
`
`
`
` 22
`
` 22
`
`
`
` 23
`
` 22
`
`
`
` 24
`
` 23
`
`
`
` 25
`
` 24
`
`
`
` 25
`
`
`
` 26
`
`
`
` 27
`
`
`
` 28
`
`
`
`
`
` 28
`
`
`
`
`
` 29
`
`
`
`
`
` 30
`
`
`
`
`
` 31
`
`
`
`
`
` 32
`
`
`
`
`
` 33
`
`
`
`
`
` 34
`
`
`
`
`
` 34
`
`
`
`
`
` 35
`
`
`
`
`
` 36
`
`
`
`
`
` 37
`
`
`
`
`
` 38
`
`
`
`
`
` 39
`
`
`
`
`
` 65
`
`
`
`
`
` 165.1
`
`
`
`
`
` 21
`
`
`
`
`
` 22
`
`
`
`
`
` 23
`
`
`
`
`
` 23
`
`
`
`
`
` 24
`
`
`
`
`
` 25
`
`
`
`
`
` 26
`
`
`
`
`
` 27
`
`
`
` 28
`
`
`
` 28
`
`
`
` 29
`
`
`
` 30
`
`
`
` 31
`
` 30
`
`
`
` 32
`
` 31
`
`
`
` 33
`
` 32
`
`
`
` 33
`
` 32
`
`
`
` 34
`
` 33
`
`
`
` 35
`
` 34
`
`
`
` 36
`
` 35
`
`
`
` 37
`
` 36
`
`
`
` 38
`
` 36
`
`
`
` 66
`
` 67
`
`
`
` 167.6
`
` 170.2
`
`
`
` 20
`
` 20
`
`
`
` 21
`
` 20
`
`
`
` 22
`
` 21
`
`
`
` 23
`
` 22
`
`
`
` 23
`
` 23
`
`
`
` 24
`
` 24
`
`
`
` 25
`
` 24
`
`
`
` 26
`
` 25
`
`
`
` 27
`
` 26
`
`
`
` 27
`
` 27
`
`
`
` 28
`
` 27
`
`
`
` 29
`
` 28
`
`
`
` 29
`
`
`
` 30
`
`
`
` 31
`
`
`
`
`
` 31
`
`
`
`
`
` 32
`
`
`
`
`
` 33
`
`
`
`
`
` 34
`
`
`
`
`
` 35
`
`
`
`
`
` 35
`
`
`
`
`
` 68
`
`
`
`
`
` 172.7
`
`
`
`
`
` 19
`
`
`
`
`
` 20
`
`
`
`
`
` 21
`
`
`
`
`
` 21
`
`
`
`
`
` 22
`
`
`
`
`
` 23
`
`
`
`
`
` 24
`
`
`
`
`
` 24
`
`
`
`
`
` 25
`
`
`
`
`
` 26
`
`
`
`
`
` 27
`
`
`
`
`
` 27
`
`
`
`
`
` 28
`
`
`
`
`
` 29
`
`
`
`
`
` 30
`
`
`
` 30
`
`
`
` 31
`
`
`
` 32
`
`
`
` 33
`
`
`
` 34
`
` 33
`
`
`
` 34
`
` 33
`
`
`
` 69
`
`
`
` 175.3
`
`
`
` 18
`
` 18
`
`
`
` 19
`
` 19
`
`
`
` 20
`
` 19
`
`
`
` 21
`
` 20
`
`
`
` 21
`
` 21
`
`
`
` 22
`
` 22
`
`
`
` 23
`
` 22
`
`
`
` 24
`
` 23
`
`
`
` 24
`
` 24
`
`
`
` 25
`
` 24
`
`
`
` 26
`
` 25
`
`
`
` 27
`
` 26
`
`
`
` 27
`
` 27
`
`
`
` 28
`
` 27
`
`
`
` 29
`
` 28
`
`
`
` 30
`
` 29
`
`
`
` 30
`
` 29
`
`
`
` 31
`
` 30
`
`
`
` 32
`
` 31
`
`
`
` 32
`
`
`
` 32
`
`
`
` 70
`
` 71
`
`
`
` 177.8
`
` 180.3
`
`
`
` 17
`
`
`
` 18
`
`
`
` 19
`
`
`
` 20
`
`
`
`
`
` 20
`
`
`
`
`
` 21
`
`
`
`
`
` 22
`
`
`
`
`
` 22
`
`
`
`
`
` 23
`
`
`
`
`
` 24
`
`
`
`
`
` 24
`
`
`
`
`
` 25
`
`
`
`
`
` 26
`
`
`
`
`
` 27
`
`
`
`
`
` 27
`
`
`
`
`
` 28
`
`
`
`
`
` 29
`
`
`
`
`
` 29
`
`
`
`
`
` 30
`
`
`
`
`
` 31
`
`
`
`
`
` 31
`
`
`
`
`
` 72
`
`
`
`
`
` 182.9
`
`
`
`
`
` 17
`
`
`
`
`
` 18
`
`
`
`
`
` 18
`
`
`
`
`
` 19
`
`
`
` 20
`
`
`
` 20
`
`
`
` 21
`
`
`
` 22
`
`
`
` 22
`
` 22
`
`
`
` 23
`
` 22
`
`
`
` 24
`
` 23
`
`
`
` 24
`
` 24
`
`
`
` 25
`
` 24
`
`
`
` 26
`
` 25
`
`
`
` 27
`
` 26
`
`
`
` 27
`
` 26
`
`
`
` 28
`
` 27
`
`
`
` 29
`
` 28
`
`
`
` 29
`
` 28
`
`
`
` 30
`
` 29
`
`
`
` 31
`
` 30
`
`
`
` 73
`
` 74
`
`
`
` 185.4
`
` 188.0
`
`
`
` 17
`
` 16
`
`
`
` 17
`
` 17
`
`
`
` 18
`
` 17
`
`
`
` 19
`
` 18
`
`
`
` 19
`
` 19
`
`
`
` 20
`
` 19
`
`
`
` 20
`
` 20
`
`
`
` 21
`
` 21
`
`
`
` 21
`
`
`
` 22
`
`
`
` 23
`
`
`
` 23
`
`
`
`
`
` 24
`
`
`
`
`
` 24
`
`
`
`
`
` 25
`
`
`
`
`
` 26
`
`
`
`
`
` 26
`
`
`
`
`
` 27
`
`
`
`
`
` 28
`
`
`
`
`
` 28
`
`
`
`
`
` 29
`
`
`
`
`
` 75
`
`
`
`
`
` 190.5
`
`
`
`
`
` 16
`
`
`
`
`
` 16
`
`
`
`
`
` 17
`
`
`
`
`
` 18
`
`
`
`
`
` 18
`
`
`
`
`
` 19
`
`
`
`
`
` 19
`
`
`
`
`
` 20
`
`
`
`
`
` 21
`
`
`
`
`
` 21
`
`
`
`
`
` 22
`
`
`
`
`
` 23
`
`
`
` 23
`
`
`
` 24
`
`
`
` 24
`
`
`
` 25
`
`
`
` 26
`
` 25
`
`
`
` 26
`
` 26
`
`
`
` 27
`
` 26
`
`
`
` 28
`
` 27
`
`
`
` 28
`
` 27
`
`
`
` 76
`
`
`
` 193.0
`
`
`
` 15
`
`
`
` 16
`
`
`
` 16
`
`
`
` 17
`
`
`
` 18
`
`
`
` 18
`
`
`
` 19
`
`
`
` 20
`
`
`
` 20
`
`
`
` 21
`
`
`
` 21
`
`
`
` 22
`
`
`
` 23
`
`
`
` 23
`
`
`
` 24
`
`
`
` 24
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.2
` Recommended Dosage
`
`
`
`
`
`
` • 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.
` 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.
`
`
`
`
`
`
` •
`
`
`
`
`
`
`
`Reference ID: 5274616
`
`

`

` 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 available in pre-filled single-dose pens of 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
`
`
`
`
`
`
`
`
` 4
`
`
` CONTRAINDICATIONS
` 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
`
`
`
` 5.1
`
`
` Risk of Thyroid C-Cell Tumors
` 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.
`
`
`
`
`
`
`
`
` 5.2
`
`
` Severe Gastrointestinal Disease
`
` 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)].
` 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.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5274616
`
`

`

` 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.
`
`
`
`
`
`
`
`
`
`
` 6
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
` 5.6
`
`
` Hypersensitivity Reactions
` 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.
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 5274616
`
`

`

` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)
`
`
`
`
`
` %
` %
` %
`
` 8
` 25
`
`
` 29
`
` 8
`
` 19
`
` 21
`
` 2
`
` 11
`
` 8
`
` 5
` 17
`
` 14
`
`
` 5
`
`
` 9
` 9
`
` 4
`
` 9
`
` 9
`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
`
` Diarrheaa
`
` Vomiting
` Constipationb
`
`
` Abdominal Painc
`
` Dyspepsia
`
`
`
`
`
`Reference ID: 5274616
`
`
`
`
`
` ZEPBOUND
`
`
` 15 mg
` (N=941)
`
`
` %
`
` 28
`
` 23
`
` 13
`
` 11
`
` 10
`
` 10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
` Injection Site Reactionsd
`
` 3
`
` Fatiguee
`
` 3
` Hypersensitivity Reactions
`
` 1
`
` Eructation
`
` 1
`
`
` Hair Loss
`
` 2
` Gastroesophageal Reflux Disease
`
` 2
`
` Flatulence
`
` 2
` Abdominal Distension
`
`
` 2
`
` Dizziness
`
` 0
` Hypotensionf
`
`
`
` Includes diarrhea, frequent bowel movements.
`
`a
`
`
`
`
` Includes constipation, feces hard.
`b
`
`
`
` Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.
`c
`
`
` Includes multiple related adverse event terms, such as injection site bruising, injection site erythema, injection site pruritus,
`
`
`d
` injection site pain, injection site rash, injection site reaction.
`
`
` Includes asthenia, fatigue, lethargy, malaise.
`
` Includes blood pressure decreased, hypotension, orthostatic hypotension.
`
`
`
`
`
`
` 8
`
`
`
`
`
`
` 6
`
` 5
`
` 5
`
` 4
`
` 5
`
` 4
`
` 3
`
` 3
`
` 4
`
` 1
`
`
` 8
`
` 6
`
` 5
`
` 5
`
` 4
`
` 4
`
` 3
`
` 3
`
` 5
`
` 1
`
`
` 8
`
` 7
`
` 5
`
` 5
`
` 5
`
` 5
`
` 4
`
` 4
`
` 4
`
` 2
`
`
`
`
`e
`
`f
`
` Gastroin