Zepbound: Package Insert / Prescribing Info

2.1 Patient Selection

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.

Table 1: BMI Conversion Chart

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).

2.4 Important Administration Instructions

• 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).
• 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.

5.1 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.

5.3 Acute Kidney Injury

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.

5.4 Acute Gallbladder Disease

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.

5.5 Acute Pancreatitis

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.

5.7 Hypoglycemia

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.

5.8 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus

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.

5.9 Suicidal Behavior and Ideation

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.

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.

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.

6.2 Postmarketing Experience

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

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

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 (5.7)].

7.2 Oral Medications

ZEPBOUND 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 ZEPBOUND.

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 ZEPBOUND.

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 with ZEPBOUND and for 4 weeks after each dose escalation. 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)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of ZEPBOUND have not been established in pediatric patients.

8.5 Geriatric Use

In ZEPBOUND clinical trials, 226 (9%) ZEPBOUND-treated patients were 65 years of age or older, and 13 (0.5%) ZEPBOUND-treated patients were 75 years of age or older at baseline.

No overall differences in safety or effectiveness of ZEPBOUND have been observed between patients 65 years of age and older and younger adult patients.

8.6 Renal Impairment

No dosage adjustment of ZEPBOUND is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no change in tirzepatide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion [see Warnings and Precautions (5.3)].

8.7 Hepatic Impairment

No dosage adjustment of ZEPBOUND is recommended for patients with hepatic impairment. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no change in tirzepatide PK was observed [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It contains a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1.

GLP-1 is a physiological regulator of appetite and caloric intake. Nonclinical studies suggest the addition of GIP may further contribute to the regulation of food intake.

12.2 Pharmacodynamics

Tirzepatide lowers body weight with greater fat mass loss than lean mass loss. Tirzepatide decreases calorie intake, and the effects are likely mediated by affecting appetite.

Tirzepatide stimulates insulin secretion in a glucose-dependent manner and reduces glucagon secretion. Tirzepatide increases insulin sensitivity, as demonstrated in a hyperinsulinemic euglycemic clamp study in patients with type 2 diabetes mellitus after 28 weeks of treatment. These effects can lead to a reduction of blood glucose.

Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time.

12.3 Pharmacokinetics

The pharmacokinetics of tirzepatide is similar between healthy subjects and patients with overweight or obesity. Steady-state plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose-proportional manner.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials.

During the 72-week treatment period with anti-drug antibodies (ADA) sampling in the chronic weight management studies [see Clinical Studies (14)], 64.5% (1591/2467) of ZEPBOUND-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 40% and 16.5% of ZEPBOUND-treated patients showed cross-reactivity to native GIP or native GLP-1, respectively.

Of the ZEPBOUND-treated patients, 2.8% and 2.7% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.8% and 0.1% developed neutralizing antibodies against native GIP or GLP-1, respectively.

There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of ZEPBOUND. More ZEPBOUND-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies [see Adverse Reactions (6.1)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the MRHD of 15 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. A statistically significant increase in thyroid C-cell adenomas was observed in male rats (≥0.5 mg/kg) and female rats (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in male and female rats at all doses examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly was not tumorigenic.

Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay.

In fertility and early embryonic development studies, male and female rats were administered twice weekly subcutaneous doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight.

14.1 Weight Management Studies in Adults with Overweight or Obesity

Results

The proportions of patients who discontinued study drug in Study 1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg ZEPBOUND-treated groups, respectively, and 26.4% for the placebo-treated group. The proportions of patients who discontinued study drug in Study 2 were 9.3% and 13.8% for the 10 mg and 15 mg ZEPBOUND-treated groups, respectively, and 14.9% for the placebo-treated group.

For Studies 1 and 2, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving ≥5% weight reduction from baseline to Week 72 (see Table 3).

After 72 weeks of treatment, ZEPBOUND resulted in a statistically significant reduction in body weight compared with placebo, and greater proportions of patients treated with ZEPBOUND 5 mg, 10 mg, and 15 mg achieved at least 5% weight reduction compared to placebo. Among patients treated with ZEPBOUND 10 mg and 15 mg, greater proportions of patients achieved at least 10%, 15%, and 20% weight reduction compared to placebo (see Table 3). A reduction in body weight was observed with ZEPBOUND irrespective of age, sex, race, ethnicity, baseline BMI, and glycemic status.

Table 3: Changes in Body Weight at Week 72 in Studies 1 and 2

Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; N = number of patients randomly assigned to study drug.
a The intention-to-treat population includes all randomly assigned patients. For Study 1 at Week 72, body weight was missing for 21.6%, 10.2%, 10.5%, and 9.4% of patients randomly assigned to placebo, ZEPBOUND 5 mg, 10 mg, and 15 mg, respectively. For Study 2 at Week 72, body weight was missing for 11.1%, 4.8%, and 8.4% of patients randomly assigned to placebo, ZEPBOUND 10 mg, and 15 mg, respectively. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19).
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c Analyzed using logistic regression adjusted for baseline value.
d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate.
e Not controlled for type I error rate.
	Study 1				Study 2
Intention-to-Treat (ITT) Populationa	Placebo N = 643	ZEPBOUND 5 mg N = 630	ZEPBOUND 10 mg N = 636	ZEPBOUND 15 mg N = 630	Placebo N = 315	ZEPBOUND 10 mg N = 312	ZEPBOUND 15 mg N = 311
Body Weight
Baseline mean (kg)	104.8	102.9	105.8	105.6	101.7	100.9	99.6
% Change from baselineb	-3.1	-15.0	-19.5	-20.9	-3.2	-12.8	-14.7
% Difference from placebob (95% CI)		-11.9 (-13.4, _10.4)d	-16.4 (_17.9, -14.8)d	-17.8 (_19.3, -16.3)d		-9.6 (-11.1, -8.1)d	-11.6 (-13.0, -10.1)d
% of Patients losing ≥5% body weight	34.5	85.1	88.9	90.9	32.5	79.2	82.8
% Difference from placebo (95% CI)		50.3 (44.3, 56.2)c,d	54.6 (49.1, 60.0)c,d	56.4 (50.9, 62.0)c,d		46.8 (39.5, 54.1)c,d	50.4 (43.1, 57.8)c,d
% of Patients losing ≥10% body weight	18.8	68.5	78.1	83.5	9.5	60.5	64.8
% Difference from placebo (95% CI)		49.3 (43.6, 54.9)c,e	59.5 (54.2, 64.9)c,d	64.8 (59.6, 70.1)c,d		51.0 (44.4, 57.7)c,d	55.3 (48.6, 62.0)c,d
% of Patients losing ≥15% body weight	8.8	48.0	66.6	70.6	2.7	39.7	48.0
% Difference from placebo (95% CI)		38.7 (33.6, 43.7)c,e	58.1 (53.2, 63.0)c,d	62.0 (57.2, 66.8)c,d		37.0 (31.1, 42.9)c,d	45.4 (39.4, 51.4)c,d
% of Patients losing ≥20% body weight	3.1	30.0	50.1	56.7	1.0	21.5	30.8
% Difference from placebo (95% CI)		26.6 (22.4, 30.7)c,e	47.3 (42.7, 51.9)c,d	53.8 (49.3, 58.3)c,d		20.5 (15.7, 25.4)c,d	29.7 (24.3, 35.0)c,d

The cumulative frequency distributions of change in body weight are shown in Figure 1 for Study 1 and Figure 2 for Study 2. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight reduction. For example, note that the vertical line arising from -10% in Figure 1 intersects the ZEPBOUND 15 mg and placebo curves at approximately 83.5%, and 18.8%, respectively, which correspond to the values shown in Table 3.

Figure 1: Changes in Body Weight (%) from Baseline to Week 72 in Study 1

Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values.

Figure 2: Changes in Body Weight (%) from Baseline to Week 72 in Study 2

Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values.

The time courses of weight reduction with ZEPBOUND and placebo from baseline through Week 72 are depicted in Figure 3 for Study 1 and Figure 4 for Study 2.

Figure 3: Change from Baseline (%) in Body Weight in Study 1

Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least-squares mean ± standard error at Week 72 hybrid imputation (HI).

Figure 4: Change from Baseline (%) in Body Weight in Study 2

Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least squares mean ± standard error at Week 72 hybrid imputation (HI).

16.1 How Supplied

ZEPBOUND is a clear, colorless to slightly yellow solution available in cartons containing 4 pre-filled single-dose pens,1 single-dose vial, or 4 single-dose vials as follows:

16.2 Storage and Handling

• Store ZEPBOUND in a refrigerator at 2°C to 8°C (36°F to 46°F).
• If needed, each single-dose pen or single-dose vial can be stored unrefrigerated at temperatures not to exceed 30°C (86°F) for up to 21 days. If ZEPBOUND is stored at room temperature, it should not be returned to the refrigerator.
• Discard if not used within 21 days after removing from the refrigerator.
• Do not freeze ZEPBOUND. Do not use ZEPBOUND if frozen.
• Store ZEPBOUND in the original carton to protect from light.

Risk of Thyroid C-Cell Tumors

Inform patients that ZEPBOUND causes thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Severe Gastrointestinal Adverse Reactions

Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.2)].

Acute Kidney Injury

Advise patients treated with ZEPBOUND of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.3)].

Acute Gallbladder Disease

Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.4)].

Acute Pancreatitis

Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue ZEPBOUND promptly and contact their healthcare provider if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.5)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported with use of tirzepatide. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking ZEPBOUND and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)].

Hypoglycemia

Inform patients of the risk of hypoglycemia and educate patients on the signs and symptoms of hypoglycemia. Advise patients on insulin or insulin secretagogue therapy that they may have an increased risk of hypoglycemia when using ZEPBOUND and to report signs and/or symptoms of hypoglycemia to their healthcare provider [see Warnings and Precautions (5.7)].

Diabetic Retinopathy Complications

Inform patients with type 2 diabetes mellitus to contact their healthcare provider if changes in vision are experienced during treatment with ZEPBOUND [see Warnings and Precautions (5.8)].

Suicidal Behavior and Ideation

Advise patients to report emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients that if they experience suicidal thoughts or behaviors, they should stop taking ZEPBOUND [see Warnings and Precautions (5.9)].

Pregnancy

Advise a pregnant patient of the potential risk to a fetus. Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with ZEPBOUND. Advise patients that there will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPBOUND during pregnancy [see Use in Specific Populations (8.1)].

Contraception

Use of ZEPBOUND may reduce the efficacy of oral hormonal contraceptives. 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 with ZEPBOUND and for 4 weeks after each dose escalation [see Drug Interactions (7.2), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].

Administration

Instruct patients how to prepare and administer the correct dose of ZEPBOUND and assess their ability to inject subcutaneously to ensure the proper administration of ZEPBOUND. 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) [see Dosage and Administration (2.4)].

Missed Doses

Inform patients if a dose is missed, it should be administered as soon as possible within 4 days after the missed dose. If more than 4 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule [see Dosage and Administration (2.3)].

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

ZEP-0003-USPI-20240523