Drug Safety-related Labeling Changes (SrLC)

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ZEPBOUND (NDA-217806)

(TIRZEPATIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/25/2026 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6)]. In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 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%). Similar rates of severe gastrointestinal adverse reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND clinical trials for OSA. Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists.

ZEPBOUND is not recommended in patients with severe gastroparesis.

5.5 Acute Pancreatitis

Additions and/or revisions underlined:

…

After initiation of ZEPBOUND, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue ZEPBOUND and initiate appropriate management.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus, intestinal obstruction, severe constipation including fecal impaction

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Pancreatitis

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

…

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 ZEPBOUND vials to always use a new syringe and needle for each injection. Use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL or 0.6 mL dose).Inform patients and their caregiver(s) which ZEPBOUND presentation (e.g., vial, prefilled single-dose pen, single-patient-use KwikPen) they will receive and ensure they receive training appropriate for that specific presentation. If the prescribed ZEPBOUND presentation changes, ensure patients and caregivers receive appropriate training and instruct them to consult the Instructions for Use for the newly prescribed presentation. Advise caregivers that ZEPBOUND KwikPen is not recommended for self-administration by those with visual impairment unless their healthcare provider determines the patient can properly administer [see Dosage and Administration (2.4)].

MEDICATION GUIDE

Additions and/or revisions underlined

…

What are the possible side effects of ZEPBOUND? ZEPBOUND may cause serious side effects, including:

…

• dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Tell your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away.

…

• inflammation of your pancreas (pancreatitis). Stop using ZEPBOUND and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without nausea or vomiting. Sometimes you may feel the pain from your abdomen to your back.

…

01/20/2026 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Never Share a ZEPBOUND KwikPen Between Patients

Newly added information

Never share ZEPBOUND KwikPen between patients, even if the pen needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Never Share a ZEPBOUND KwikPen Between Patients

Advise patients that they must never share a ZEPBOUND KwikPen with another person, even if the pen needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.11)].

…

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 ZEPBOUND vials to always use a new syringe and needle for each injection. Use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL or 0.6 mL dose). Notify the patient of which ZEPBOUND presentation they will be receiving and ensure training is appropriate for the specific ZEPBOUND presentation. Advise patients to refer to the IFU in case of any change in the presentation. Advise caregivers that ZEPBOUND KwikPen is not recommended for self-administration by those with visual impairment unless their healthcare provider determines the patient can properly administer [see Dosage and Administration (2.4)].

…

 

MEDICATION GUIDE

Additions and/or revisions underlined:

Do not share your ZEPBOUND KwikPen or needles with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

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How should I use ZEPBOUND?

…

• A caregiver may give you ZEPBOUND injections or you may self-inject if a healthcare provider determines that it is appropriate.

• Self-injection is not recommended for people who are visually impaired.

…

 

How should I store ZEPBOUND?

…

• Store multi-dose vial or single-patient-use KwikPen in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature [up to 86°F (30°C)]. Throw away the multi-dose vial or single-patient-use KwikPen after a total of 30 days at room temperature, 30 days after first use, or after taking 4 weekly doses, even if it still has medicine in it.

…

What are the ingredients in ZEPBOUND?

Active ingredient: tirzepatide

Inactive ingredients: sodium chloride, sodium phosphate dibasic heptahydrate, and water for injection. Benzyl alcohol, glycerin, and phenol are also inactive ingredients in the multi-dose vial and single-patient-use KwikPen. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH.

01/07/2026 (SUPPL-37)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

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 ZEPBOUND vials to always use a new syringe and needle for each injection. Use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL or 0.6 mL dose) [see Dosage and Administration (2.4)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

How should I use ZEPBOUND?

…

• If using ZEPBOUND vials, always use a new syringe and needle for each injection.

  …

  How should I store ZEPBOUND?

• Store ZEPBOUND in the original carton to protect it from light.

• Do not freeze ZEPBOUND. Do not use ZEPBOUND if frozen.

• Store single-dose pen and single-dose vial in the refrigerator between 36°F to 46°F (2°C to 8°C). If needed, each single-dose pen or single-dose vial can be stored at room temperature up to 86°F (30°C) for up to 21 days. If single-dose pen or single-dose vial is stored at room temperature, it should not be returned to the refrigerator. Throw away single-dose pen or single-dose vial if not used within 21 days after removing from the refrigerator.

• Store multi-dose vial in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature [up to 86°F (30°C)]. Throw away the multi-dose vial after a total of 30 days at room temperature, 30 days after first use, or after taking 4 weekly doses, even if it still has medicine in it.

  …

             

09/25/2025 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Acute Kidney Injury Due to Volume Depletion

Additions and/or revisions underlined:

… Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion, especially during dosage initiation and escalation of ZEPBOUND.

6 Adverse Reactions

Additions and/or revisions underlined:

…

• Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.3)]

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6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Acute Pancreatitis

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 a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 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). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA (Studies 5 and 6) was 0.84 patients per 100 years for ZEPBOUND and 0 for placebo-treated patients.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus

…

Renal: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

In a single-dose clinical lactation study, the concentration of tirzepatide in breast milk was found to be either undetectable or low compared to the maternal administered dose (see Data). There are no available data on the effects of tirzepatide on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEPBOUND and any potential adverse effects on the breastfed infant from ZEPBOUND or from the underlying maternal condition.

Data

Following subcutaneous administration of a single 5 mg dose to 11 healthy lactating adult females, the concentration of tirzepatide in breast milk was found to be undetectable (limit of detection in breast milk 4 ng/mL) in 164/171 samples assayed. The cumulative amount of tirzepatide detected in the remaining 7 breast milk samples over the 28-day sampling window was equivalent to less than 0.02% of the maternal administered dose, with the last measurable concentrations occurring 5 days post-dose. The AUC of tirzepatide in breast milk could not be calculated, due to insufficient quantifiable concentrations.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Kidney Injury Due to Volume Depletion

Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings and Precautions (5.3)].

…

Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus

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)].

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MEDICATION GUIDE

Additions and/or revisions underlined:

…

How should I use ZEPBOUND?

…

• Inject ZEPBOUND under the skin (subcutaneously) of your stomach (abdomen), thigh, or another person should inject in the back of the upper arm. Do not inject ZEPBOUND into a muscle (intramuscularly) or vein (intravenously).

  …

• If you take too much ZEPBOUND, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.

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What are the possible side effects of ZEPBOUND?

ZEPBOUND may cause serious side effects, including:

…

• dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration.

  …

           

12/20/2024 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

… Similar rates of severe gastrointestinal adverse reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND clinical trials for OSA.

…

5.4 Acute Gallbladder Disease

Additions and/or revisions underlined:

…

In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 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. Similar rates of cholelithiasis were reported in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND trials for OSA. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

5.5 Acute Pancreatitis

Additions and/or revisions underlined:

… In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 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). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA (Studies 5 and 6) was 0.84 patients per 100 years for ZEPBOUND and 0 for placebo-treated patients.

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. Continuation of ZEPBOUND after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient’s health care provider.

5.6 Hypersensitivity Reactions

Additions and/or revisions underlined:

… In a pool of two ZEPBOUND clinical studies for weight reduction (Studies 1 and 2), 0.1% of ZEPBOUND-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. Similar rates of severe hypersensitivity reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND trials for OSA.

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6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Adverse Reactions in Patients with Obstructive Sleep Apnea

ZEPBOUND was evaluated in 2 randomized, double-blind, placebo-controlled trials (Study 5 and Study 6) that included a total of 467 adult patients with moderate to severe OSA and obesity [see Clinical Studies (14.2)]. Study 5 enrolled 234 patients who were unable or unwilling to use Positive Airway Pressure (PAP) therapy and Study 6 enrolled 235 patients who were on PAP therapy. The adverse reactions observed with ZEPBOUND 10 mg or 15 mg administered subcutaneously once weekly were similar to those reported in the two pooled placebo controlled clinical trials for weight reduction (Study 1 and Study 2).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

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In a pool of two fixed dose ZEPBOUND clinical studies for weight reduction (Study 1 and Study 2), 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.

…

ZEPBOUND clinical studies in OSA (Study 5 and Study 6) did not include sufficient numbers of patients age 65 years or older to determine whether they respond differently from younger adult patients. Other reported clinical experience with tirzepatide has not identified differences in responses between the elderly and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

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What is ZEPBOUND?

• ZEPBOUND is an injectable prescription medicine that may help adults with:

  • obesity, or some adults with overweight who also have weight-related medical problems, to lose excess body weight and keep the weight off.

  • moderate to severe obstructive sleep apnea (OSA) and obesity to improve their OSA.

    …

               

10/18/2024 (SUPPL-15)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

. . .

Before using ZEPBOUND, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had problems with your pancreas or kidneys.

• have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food.

• have a history of diabetic retinopathy.

• are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).

. . .

How should I use ZEPBOUND?

• Read the Instructions for Use that comes with ZEPBOUND.

• Use ZEPBOUND exactly as your healthcare provider tells you to. A healthcare provider should show you how to prepare to inject your dose of ZEPBOUND before injecting the first time.

• Use ZEPBOUND with a reduced-calorie diet and increased physical activity.

10/18/2024 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation

Newly added subsection:

ZEPBOUND delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking ZEPBOUND, including whether modifying preoperative fasting recommendations or temporarily discontinuing ZEPBOUND could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking ZEPBOUND.

6 Adverse Reactions

Additions and revisions underlined:

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 Adverse Reactions [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)]

• Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10)]

6.2 Postmarketing Experience

Newly added information:

Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Pulmonary Aspiration During General Anesthesia or Deep Sedation

Inform patients that ZEPBOUND may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking ZEPBOUND [see Warnings and Precautions (5.10)].

10/18/2024 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Gastrointestinal Adverse Reactions

Subsection title revised

Additions and revisions underlined:

Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In a pool of two ZEPBOUND clinical trials (Studies 1 and 2), 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

03/28/2024 (SUPPL-3)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underline:

…

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)].

…