Tirzepatide

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Recommended Dose Escalation Schedule The recommended starting dosage is 2.5 mg injected subcutaneously once weekly for 4 weeks. Increase the dosage in 2.5 mg increments after at least 4 weeks until recommended maintenance dosage is achieved. ( 2.1 ) Consider treatment response and tolerability when selecting the maintenance dosage. ( 2.1 ) Recommended Maintenance and Maximum Dosage Weight Reduction and Long-Term Maintenance: 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly. ( 2.2 ) Obstructive Sleep Apnea: 10 mg or 15 mg injected subcutaneously once weekly. ( 2.2 ) Maximum Recommended Dosage: 15 mg injected subcutaneously once weekly. ( 2.2 ) Administration Instructions Refer to the Full Prescribing Information for additional important administration instructions about ZEPBOUND presentations. ( 2.4 ) 2.1 Recommended Dose Escalation Schedule The recommended starting dosage of ZEPBOUND for all indications is 2.5 mg injected subcutaneously once weekly for 4 weeks. The 2.5 mg dosage is for treatment initiation and is not approved as a maintenance dosage. Follow the dosage escalation below for all indications to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.2 )] . Consider treatment response and tolerability when selecting the maintenance dosage. If patients do not tolerate a maintenance dosage, consider a lower maintenance dosage. 2.2 Recommended Maintenance and Maximum Dosage Recommended Maintenance Dosage Weight Reduction and Long-Term Maintenance The recommended maintenance dosage is 5 mg, 10 mg, or 15 mg, injected subcutaneously once weekly. OSA The recommended maintenance dosage is 10 mg or 15 mg injected subcutaneously once weekly. Maximum Recommended Dosage The maximum dosage of ZEPBOUND for all indications 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 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. Prior to initiation, train patients and their caregiver(s) on proper injection technique for the prescribed ZEPBOUND presentation [see Instructions for Use ] . After training, a patient may self-inject ZEPBOUND if the healthcare provider determines that it can be properly administered, except for the following: ZEPBOUND KwikPen is not recommended for self-administration by those who are visually impaired. Instruct patients using ZEPBOUND vials to 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) and always use a new syringe and needle for each injection. 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 in combination with a reduced-calorie diet and increased physical activity. Administer ZEPBOUND once weekly at any time of day, with or without meals. Inject ZEPBOUND subcutaneously in the abdomen, thigh, or another person should inject in the back of the upper arm. Rotate injection sites with each dose.

6 ADVERSE REACTIONS 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 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). Injection Site Reactions In ZEPBOUND-treated patients in a pool of Study 1 and 2, injection site reactions were more frequent in those with anti-tirzepatide antibodies (11.3%) compared to those who did not develop anti-tirzepatide antibodies (1%) [see Clinical Pharmacology ( 12.6 )] . Hair Loss Hair loss adverse reactions in ZEPBOUND-treated patients were associated with weight reduction. In a pool of Study 1 and 2, hair loss was reported more frequently in female than male patients in the ZEPBOUND (7.1% female versus 0.5% male) and placebo (1.3% female versus 0% male) treatment groups. No ZEPBOUND-treated patients and one placebo-treated patient discontinued study treatment due to hair loss. Other Adverse Reactions Acute Kidney Injury In a pool of Study 1 and 2, acute kidney injury was reported in 0.5% of ZEPBOUND-treated patients compared to 0.2% of placebo-treated patients. Acute Gallbladder Disease In a pool of Study 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. Hypoglycemia In Study 2, a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m 2 , hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients. In Study 1, a trial of ZEPBOUND in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of ZEPBOUND-treated patients versus no placebo-treated patients. Heart Rate Increase In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in a mean increase in heart rate of 1 to 3 beats per minute compared to no increase in placebo-treated patients. Dysesthesia In a pool of Study 1 and 2, dysesthesia occurred more frequently among patients receiving ZEPBOUND (5 mg 0.2%, 10 mg 0.2%, 15 mg 0.4%) than placebo (0.1%). Dysgeusia In a pool of Study 1 and 2, dysgeusia was reported by 0.4% of ZEPBOUND-treated patients and no placebo-treated patients. Dry Mouth In a pool of Study 1 and 2, dry mouth or dry throat was reported by 1% of ZEPBOUND-treated patients and 0.1% of placebo-treated patients. Laboratory Abnormalities Amylase and Lipase Increase In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in mean increases from baseline in serum pancreatic amylase concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with ZEPBOUND is unknown in the absence of other signs and symptoms of pancreatitis. 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). 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. Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus, intestinal obstruction, severe constipation including fecal impaction Hypersensitivity: anaphylaxis, angioedema Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis

12.3 Pharmacokinetics The pharmacokinetics of tirzepatide is similar between healthy subjects, patients with overweight or obesity, and patients with OSA and obesity. Steady-state plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose-proportional manner. Absorption Following subcutaneous administration, the median time (range) to maximum plasma concentration of tirzepatide is 24 hours (8 to 72 hours). The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm. Distribution The mean [coefficient of variation (CV)%] apparent steady-state volumes of distribution of tirzepatide following subcutaneous administration in patients with overweight or obesity and patients with OSA and obesity are approximately 9.7 L (29%) and 11.8 L (37%), respectively. Tirzepatide is highly bound to plasma albumin (99%). Elimination The apparent population mean clearance of tirzepatide in patients with overweight or obesity and patients with OSA and obesity is approximately 0.06 L/h (CV% ~ 20%). The elimination half-life is approximately 5-6 days in patients with overweight or obesity, and in patients with OSA and obesity. Metabolism Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid, and amide hydrolysis. Excretion The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces. Specific Populations The intrinsic factors of age (18 to 84 years), sex, race (71% White, 11% Asian, 9% American Indian or Alaska Native, and 8% Black or African American), ethnicity, or body weight do not have a clinically relevant effect on the PK of tirzepatide. Patients with Renal Impairment Renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. Data from clinical studies have also shown that renal impairment in patients with overweight or obesity does not impact the pharmacokinetics of tirzepatide [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment Hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies Potential for Tirzepatide to Influence the Pharmacokinetics of Other Drugs In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters. ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Drug Interactions ( 7.2 )] . The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses. Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (C max ) was reduced by 55%, and the median peak plasma concentration (t max ) occurred 1 hour later. After coadministration at Week 6 with tirzepatide 15 mg, there was no meaningful impact on acetaminophen C max and t max . Overall acetaminophen exposure (AUC 0 -24hr ) was not influenced. Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean C max of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%, 66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in t max of 2.5 to 4.5 hours was observed.