Tirzepatide

ZEPBOUND ® is indicated in combination with a reduced-calorie diet and increased physical activity: to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition. to treat moderate to severe obstructive sleep apnea (OSA) in adults with obesity. ZEPBOUND is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated in combination with a reduced-calorie diet and increased physical activity: to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition. ( 1 ) to treat moderate to severe obstructive sleep apnea (OSA) in adults with obesity. ( 1 ) Limitations of Use: Coadministration with other tirzepatide-containing products or with any GLP-1 receptor agonist is not recommended. ( 1 ) 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.

Injection: Clear, colorless to slightly yellow solution in pre-filled single-dose pens, single-dose vials, multi-dose vials, or single-patient-use KwikPens, each available in the following strengths. The multi-dose vials and single-patient-use KwikPen each contain 4 doses: Single-dose Pen or Vial 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 Multi-dose Vial (4 doses per vial) Dose per Injection Total Strength per Total Volume Strength per mL 2.5 mg/0.6 mL 10 mg/2.4 mL 4.17 mg/mL 5 mg/0.6 mL 20 mg/2.4 mL 8.33 mg/mL 7.5 mg/0.6 mL 30 mg/2.4 mL 12.5 mg/mL 10 mg/0.6 mL 40 mg/2.4 mL 16.7 mg/mL 12.5 mg/0.6 mL 50 mg/2.4 mL 20.8 mg/mL 15 mg/0.6 mL 60 mg/2.4 mL 25 mg/mL Single-Patient-Use KwikPen (4 doses per KwikPen) Dose per Injection Total Strength per Total Volume Strength per mL 2.5 mg 10 mg/2.4 mL 4.17 mg/mL 5 mg 20 mg/2.4 mL 8.33 mg/mL 7.5 mg 30 mg/2.4 mL 12.5 mg/mL 10 mg 40 mg/2.4 mL 16.7 mg/mL 12.5 mg 50 mg/2.4 mL 20.8 mg/mL 15 mg 60 mg/2.4 mL 25 mg/mL Injection: Single-dose pen or single-dose vial: 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, or 15 mg/0.5 mL ( 3 ) Multi-dose vial or single-patient-use KwikPen ® : 10 mg/2.4 mL (4.17 mg/mL) for four 2.5 mg/0.6 mL doses, 20 mg/2.4 mL (8.33 mg/mL) for four 5 mg/0.6 mL doses, 30 mg/2.4 mL (12.5 mg/mL) for four 7.5 mg/0.6 mL doses, 40 mg/2.4 mL (16.7 mg/mL) for four 10 mg/0.6 mL doses, 50 mg/2.4 mL (20.8 mg/mL) for four 12.5 mg/0.6 mL doses, or 60 mg/2.4 mL (25 mg/mL) for four 15 mg/0.6 mL ( 3 )

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 )] . 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 )

Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. ZEPBOUND is not recommended in patients with severe gastroparesis. ( 5.2 ) Acute Kidney Injury Due to Volume Depletion: 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 observed in patients treated with GLP-1 receptor agonists, or ZEPBOUND. Discontinue if pancreatitis is suspected. ( 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 insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin or insulin secretagogue 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: Monitor patients with a history of diabetic retinopathy for progression. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) Never share a ZEPBOUND KwikPen between patients, even if the pen needle is changed. ( 5.10 )

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 Adverse Reactions 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.

5.3 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, or ZEPBOUND [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal adverse reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion, especially during dosage initiation and escalation of ZEPBOUND.

5.4 Acute Gallbladder Disease Treatment with ZEPBOUND and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. 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 Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, or ZEPBOUND [see Adverse Reactions ( 6 )] . 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.

5.6 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. 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. 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/m 2 (Study 2), 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 )] . […]

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 Due to Volume Depletion [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 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] 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.

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. Adverse Reactions in Patients for Weight Reduction and Long-Term Maintenance Pool of Placebo – Controlled Weight Reduction Trials in Adults with Obesity or Overweight, with or without Type 2 Diabetes (Study 1 and Study 2) ZEPBOUND was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 2,519 adult patients with obesity or overweight treated with ZEPBOUND for up to 72 weeks and a 4-week off drug follow-up period (Study 1 and Study 2) [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/m 2 , 29% with a BMI ≥40 kg/m 2 , 41% with hypertension, 37% with dyslipidemia, 25% with type 2 diabetes mellitus, 7% with obstructive sleep apnea, and 4% with cardiovascular (CV) 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 1 shows common adverse reactions associated with the use of ZEPBOUND in the pool of two placebo-controlled trials for weight reduction (Study 1 and Study 2). These adverse reactions occurred more commonly with ZEPBOUND than with placebo and occurred in at least 2% of patients treated with ZEPBOUND. Table 1: Adverse Reactions (≥2% and Greater than Placebo) in ZEPBOUND-Treated Adults with Obesity or Overweight in Weight Reduction and Long-term Maintenance Trials (Study 1 and Study 2) 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. e Includes asthenia, fatigue, lethargy, malaise. f Includes blood pressure decreased, hypotension, orthostatic hypotension. Adverse Reaction Placebo (N=958) % ZEPBOUND 5 mg (N=630) % ZEPBOUND 10 mg (N=948) % ZEPBOUND 15 mg (N=941) % Nausea 8 25 29 28 Diarrhea a 8 19 21 23 Vomiting 2 8 11 13 Constipation b 5 17 14 11 Abdominal Pain c 5 9 9 10 Dyspepsia 4 9 9 10 Injection Site Reactions d 2 6 8 8 Fatigue e 3 5 6 7 Hypersensitivity Reactions 3 5 5 5 Eructation 1 4 5 5 Hair Loss 1 5 4 5 Gastroesophageal Reflux Disease 2 4 4 5 Flatulence 2 3 3 4 Abdominal Distension 2 3 3 4 Dizziness 2 4 5 4 Hypotension f 0 1 1 2 In a clinical trial for weight reduction that included an intensive lifestyle intervention lead-in period (Study 3), 287 patients were treated with ZEPBOUND for up to 72 weeks. In a randomized withdrawal trial (Study 4), 783 patients were treated with ZEPBOUND for up to 36 weeks, and 335 of these patients were treated for up to 88 weeks [see Clinical Studies ( 14.1 )] . In Study 3, 10% of ZEPBOUND-treated patients and 2% of placebo-treated patients discontinued drug due to adverse reactions. In Study 4, 7% of patients discontinued ZEPBOUND treatment before randomized withdrawal at Week 36 due to adverse reactions. In Study 3 and Study 4, adverse reactions were similar to those reported in the two pooled ZEPBOUND clinical trials (Study 1 and Study 2). Gastrointestinal Adverse Reactions In a pool of Study 1 and 2, 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. 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. Hypotension In a pool of Study 1 and 2, 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 a pool of Study 1 and 2, 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). […]

ZEPBOUND delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. ( 7.2 )

7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) ZEPBOUND lowers blood glucose. When initiating ZEPBOUND, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) 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 )] .

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 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPBOUND (tirzepatide) during pregnancy. Pregnant patients exposed to ZEPBOUND and healthcare providers are encouraged to register by calling 1-844-524-0039 or emailing at MILEregistry@thermofisher.com. To learn more please call or visit https://pregnancyregistry.lilly.com/zepbound. Risk Summary Weight loss offers no benefit to a pregnant patient and may cause fetal harm. Advise pregnant patients that weight loss is not recommended during pregnancy and to discontinue ZEPBOUND when a pregnancy is recognized (see Clinical Considerations) . Available data with tirzepatide in pregnant patients are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those with obesity or overweight, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Animal Data In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide [0.03-, 0.07-, and 0.5-fold the maximum recommended human dose (MRHD) of 15 mg once weekly based on AUC] during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F 1 pups from F 0 maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females.

8.2 Lactation Risk Summary 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.

8.3 Females and Males of Reproductive Potential Contraception Use of ZEPBOUND may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. 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 ) and Clinical Pharmacology ( 12.2 , 12.3 )] .

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

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

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 )] .

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. Both GIP receptors and GLP-1 receptors are found in areas of the brain involved in appetite regulation. Animal studies show that tirzepatide distributes to and activates neurons in brain regions involved in regulation of appetite and food intake.