FOUNDAYO

1 INDICATIONS AND USAGE FOUNDAYO TM 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. FOUNDAYO™ is a 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 ) Limitations of Use Concomitant use with another GLP-1 receptor agonist is not recommended. ( 1 ) Limitations of Use Concomitant use with another GLP-1 receptor agonist is not recommended.

2 DOSAGE AND ADMINISTRATION Take FOUNDAYO orally once daily, with or without food. ( 2.1 ) Swallow tablets whole. Do not break, crush, or chew. ( 2.1 ) Do not take more than one tablet per day. ( 2.1 ) Starting dosage is 0.8 mg once daily. After at least 30 days, increase dosage to 2.5 mg once daily. ( 2.1 ) After at least 30 days on the 2.5 mg dosage, increase dosage to 5.5 mg once daily. ( 2.1 ) Dosage may be increased to the next dosage level (9 mg, 14.5 mg, or 17.2 mg once daily) after at least 30 days on the current dosage, based on treatment response and tolerability. ( 2.1 ) Maximum dosage is 17.2 mg once daily. ( 2.1 ) 2.1 Recommended Dosage and Administration Recommended Administration Take FOUNDAYO orally once daily, with or without food. Swallow tablets whole. Do not break, crush, or chew. Do not take more than one tablet per day. Recommended Dosage Escalation Follow the FOUNDAYO starting dosage and escalation described below to reduce the risk of gastrointestinal (GI) adverse reactions [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6 )] . The starting dosage is 0.8 mg orally once daily. After at least 30 days on the 0.8 mg dosage, increase the dosage to 2.5 mg once daily. After at least 30 days on the 2.5 mg dosage, increase the dosage to 5.5 mg once daily. The dosage may be increased to the next dosage level (9 mg, 14.5 mg, or 17.2 mg once daily) after at least 30 days on the current dosage, based on treatment response and tolerability. The maximum dosage of FOUNDAYO is 17.2 mg once daily. 2.2 Dosage Modification for Concomitant Use with CYP3A4 Inhibitors and CYP3A4 Inducers FOUNDAYO dosage modification may be required to manage interactions with some concomitant medications [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Strong CYP3A4 Inhibitors Avoid strong CYP3A4 inhibitors that also inhibit OATP1B when taking FOUNDAYO. The maximum dosage of FOUNDAYO is 9 mg once daily when used concomitantly with a strong CYP3A4 inhibitor [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Strong and Moderate CYP3A4 Inducers Avoid strong CYP3A4 inducers when taking FOUNDAYO. Monitor FOUNDAYO effectiveness when concomitantly using moderate CYP3A4 inducers and escalate FOUNDAYO dosage as needed [see Dosage and Administration ( 2.1 , 2.3 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 2.3 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Advise patients not to double up the next dose. If 7 or more consecutive doses are missed, reinitiate dosage escalation at a lower dosage to reduce the risk of gastrointestinal adverse reactions [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6 )] .

5 WARNINGS AND PRECAUTIONS Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including FOUNDAYO. Discontinue if pancreatitis is suspected. ( 5.2 ) Severe Gastrointestinal Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. FOUNDAYO is not recommended in patients with severe gastroparesis. ( 5.3 ) Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.4 ) Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dosage 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. ( 5.5 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists. If suspected, advise the patient to promptly seek medical attention and discontinue FOUNDAYO. ( 5.6 ) Diabetic Retinopathy Complications in Patients with Type 2 Diabetes: Has not been studied in patients with diabetic retinopathy and/or macular edema requiring acute treatment. Monitor patients with a history of diabetic retinopathy for progression. ( 5.7 ) Acute Gallbladder Disease : Has been reported in clinical trials. If cholecystitis is suspected, gallbladder studies and clinical follow-up are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia and 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 ) 5.1 Risk of Thyroid C-Cell Tumors In products with GLP-1 receptor agonist activity that are pharmacologically active in rats and mice, rodent thyroid C-cell tumors (adenomas and carcinomas) have been observed at clinically relevant exposures and are considered GLP-1 receptor-dependent effects in rodents. Orforglipron is not pharmacologically active in rats or mice and did not produce tumors in rodents [see Nonclinical Toxicology ( 13.1 )] . While orforglipron is pharmacologically active at the human GLP-1 receptor, the human relevance of GLP-1 receptor-dependent thyroid C-cell tumors observed in rodents has not been determined [see Nonclinical Toxicology ( 13.1 )] . Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. FOUNDAYO 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 FOUNDAYO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with FOUNDAYO. 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 Acute Pancreatitis Acute pancreatitis has been reported in patients treated with FOUNDAYO. Fatal and non-fatal hemorrhagic or necrotizing pancreatitis have been observed in patients treated with GLP-1 receptor agonists [see Adverse Reactions ( 6 )] . After initiation of FOUNDAYO, obse…

4 CONTRAINDICATIONS FOUNDAYO 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 orforglipron or any of the excipients in FOUNDAYO. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with GLP-1 receptor agonists [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.2 )] . Personal or family history of MTC or in patients with MEN 2 ( 4 ) Known serious hypersensitivity to orforglipron or any of the excipients in FOUNDAYO ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: The maximum dosage of FOUNDAYO is 9 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. Avoid concomitant use with strong CYP3A4 inhibitors that also inhibit OATP1B. ( 7.1 ) CYP3A4 Inducers: Avoid concomitant use with strong CYP3A4 inducers. Monitor FOUNDAYO effectiveness and escalate dosage as needed when used concomitantly with moderate CYP3A4 inducers. ( 7.1 ) Simvastatin: Do not exceed simvastatin 20 mg once daily when used concomitantly with FOUNDAYO. ( 7.2 ) FOUNDAYO delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. ( 7.3 ) 7.1 Effect of Other Drugs on FOUNDAYO Table 2 includes clinically relevant interactions where concomitant use of other drugs affects FOUNDAYO. Table 2: Clinically Relevant Effects of Other Drugs on FOUNDAYO Strong CYP3A4 Inhibitors Intervention The maximum dosage of FOUNDAYO is 9 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. Avoid concomitant use of FOUNDAYO with strong CYP3A4 inhibitors that also inhibit OATP1B (e.g., ritonavir) [see Dosage and Administration ( 2.2 )] . Clinical Impact CYP3A4 inhibitors increase FOUNDAYO exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of FOUNDAYO-associated adverse reactions. Strong CYP3A4 inhibitors that also clinically inhibit OATP1B are expected to significantly increase plasma concentrations of FOUNDAYO, which may increase the risk of FOUNDAYO-associated adverse reactions [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )] . Strong CYP3A4 Inducers Intervention Avoid concomitant use of FOUNDAYO with strong CYP3A4 inducers. Clinical Impact Induction of CYP3A4 decreases FOUNDAYO exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of FOUNDAYO. Moderate CYP3A4 Inducers Intervention Monitor FOUNDAYO effectiveness and escalate dosage as needed when used concomitantly with moderate CYP3A4 inducers [see Dosage and Administration ( 2.1 )] . Clinical Impact Induction of CYP3A4 decreases FOUNDAYO exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of FOUNDAYO. 7.2 Effect of FOUNDAYO on Other Drugs Table 3 includes clinically relevant interactions where concomitant use of FOUNDAYO affects other drugs. Table 3: Clinically Relevant Effects of FOUNDAYO on Other Drugs Simvastatin Intervention Do not exceed simvastatin 20 mg once daily when concomitantly used with FOUNDAYO. Clinical Impact Use of FOUNDAYO with simvastatin increased exposure of the active metabolite simvastatin acid two-fold [see Clinical Pharmacology ( 12.3 )] . A two-fold increase in simvastatin acid exposure at the highest simvastatin dose could be clinically meaningful. Insulin or Insulin Secretagogue (e.g., Sulfonylurea) Intervention When initiating FOUNDAYO, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) [see Warnings and Precautions ( 5.5 )] . Clinical Impact FOUNDAYO stimulates insulin release in the presence of elevated blood glucose concentrations which could increase the risk for hypoglycemia when used in combination with insulin or insulin secretagogues. 7.3 Effect of FOUNDAYO on Oral Medications FOUNDAYO delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Clinical Pharmacology ( 12.3 )] . Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 30 days after initiation with FOUNDAYO and for 30 days after each dose escalation. Hormonal contraceptives that are not administered orally should not be affected.

8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FOUNDAYO (orforglipron) during pregnancy. Pregnant patients exposed to FOUNDAYO and healthcare providers are encouraged to contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979). Risk Summary Weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus and discontinue FOUNDAYO. There are no adequate and well-controlled studies of FOUNDAYO during pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to orforglipron during pregnancy. Imbalances in malformations have been reported in rats and rabbits at low multiples of clinical exposure with GLP-1 receptor agonists active in those species. Orforglipron is not pharmacologically active in rats and rabbits. In animal reproduction studies, oral administration of orforglipron to pregnant monkeys during organogenesis at doses lower than the maximum recommended human dose (MRHD) did not result in embryofetal effects. Higher dose levels and exposures could not be evaluated in monkeys due to dose limiting effects on body weight (see Data) . In a rabbit dose-range finding study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures 14 times the clinical exposure at the MRHD resulted in external malformations and decreases in fetal and placental weights in the absence of maternal toxicity (see Data) . In the definitive rabbit study, oral administration of orforglipron to pregnant rabbits during organogenesis at exposures up to 6 times the clinical exposure at the MRHD did not result in embryofetal effects (see Data) . 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. The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Appropriate weight gain relative to 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 Embryofetal development was evaluated in pregnant monkeys administered orforglipron orally during organogenesis (gestation days 20 to 50) at doses of 0.15 and 0.7 mg/kg/day resulting in systemic exposures lower than the human exposure at the MRHD of 17.2 mg FOUNDAYO, based on AUC. No effects on pregnancy outcome, placental weight, fetal viability, fetal body weight, fetal measurements or external, visceral or skeletal evaluations were observed. Exposure in monkeys was lower than exposure at the MRHD. Higher dose levels and exposures cannot be achieved in pregnant monkeys due to on-target body weight effects. Orforglipron is not pharmacologically active in rabbits. In a rabbit dose-range finding study, orforglipron was administered orally once daily during organogenesis (gestation days 7 to 19) at dose levels of 2, 20, and 200 mg/kg/day. These doses resulted in exposures that were approximately 0.03, 0.8 and 14 times, respectively, the clinical exposure at the MRHD, based on AUC. Statistically significant decreases in fetal and placental weights and external malformations in 2 fetuses from 2 dams were observed at 200 mg/kg/day. In the definitive rabbit study, orforglipron was given orally once daily during organogenesis (gestation days 7 to 19) at dose levels of 4, 40, and 200 mg/kg/day resulting in exposures approximately 0.06, 1.4, and 6.2 times the clinical exposure at the MRHD, respectively, based on AUC. No embryofetal effects were observed in the definitive rabbit study at any dose level. Orforglipron is not p…

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 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Severe Gastrointestinal Reactions [see Warnings and Precautions ( 5.3 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.4 )] Hypoglycemia [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with Type 2 Diabetes [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions, reported in ≥5% of patients treated with FOUNDAYO, are nausea, constipation, diarrhea, vomiting, dyspepsia, abdominal pain, headache, abdominal distension, fatigue, eructation, gastroesophageal reflux disease, flatulence, and hair loss. ( 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. The safety of FOUNDAYO has been established 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 based on adequate and well-controlled trials of an investigational orforglipron formulation (Trials 1 and 2), referred to in this section as FOUNDAYO [see Clinical Studies ( 14 )] . This section of labeling presents safety data from administration of the investigational orforglipron formulation shown as equivalent dosages of once daily FOUNDAYO [see Dosage and Administration ( 2.1 )] . Adverse Reactions in Patients in Weight Management Clinical Trials Pool of Two Placebo-Controlled Clinical Trials: FOUNDAYO was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 3155 adult patients with obesity or overweight treated with FOUNDAYO once daily for up to 72 weeks and a 2-week off-drug follow-up period (Trial 1 and Trial 2) [see Clinical Studies ( 14 )] . The mean age of patients was 49 years and 41% were male. The population was 60% White, 25% Asian, 8% Black or African American, and 0.3% American Indian or Alaska Native; 35% identified as Hispanic or Latino ethnicity. At baseline, patients had an average BMI of 36.5 kg/m 2 , 51% with a BMI ≥35 kg/m 2 , 50% with hypertension, 49% with dyslipidemia, 31% with type 2 diabetes, 11% with obstructive sleep apnea, 3% with coronary artery disease, and 3% with cerebrovascular disease. Across both trials, 8% of patients treated with FOUNDAYO (5.5 mg, 6%; 9 mg, 9%; and 17.2 mg, 10%) once daily permanently discontinued treatment as a result of adverse reactions compared to 3% of patients receiving placebo. The majority of patients (5%) who discontinued FOUNDAYO due to adverse reactions did so due to gastrointestinal adverse reactions. Common Adverse Reactions Table 1 shows common adverse reactions associated with the use of once daily FOUNDAYO in the pool of two placebo-controlled trials for weight management (Trials 1 and 2). These adverse reactions occurred more commonly with once daily FOUNDAYO than with placebo and occurred in at least 5% of patients treated with FOUNDAYO. Table 1: Adverse Reactions Reported in ≥5% of FOUNDAYO-treated Adult Patients with Obesity or Overweight (With or Without Type 2 Diabetes) in Pool of Placebo-Controlled Trials…