Orforglipron

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.

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 )] .

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, 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 FOUNDAYO and initiate appropriate management. 5.3 Severe Gastrointestinal Reactions Use of FOUNDAYO has been associated with gastrointestinal adverse reactions, sometimes severe. In clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients treated with orforglipron (approximately 3%) than patients who received placebo (1%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists [see Adverse Reactions ( 6 )] . FOUNDAYO is not recommended in patients with severe gastroparesis. 5.4 Acute Kidney Injury Due to Volume Depletion There have been reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists or FOUNDAYO. 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 )] . Monitor renal function in patients reporting adverse reactions to FOUNDAYO that could lead to volume depletion, especially during dosage initiation and escalation of FOUNDAYO. 5.5 Hypoglycemia FOUNDAYO lowers blood glucose and can cause hypoglycemia. In a trial of adults with type 2 diabetes and BMI ≥27 kg/m 2 (Trial 2), hypoglycemia (plasma glucose <54 mg/dL) was reported in 2% of patients treated with orforglipron versus 0.2% of patients receiving placebo. One patient treated with orforglipron and no patients receiving placebo reported severe hypoglycemia in Trial 2. In Trial 2, 7% of patients treated with orforglipron once daily in combination with sulfonylurea reported hypoglycemia compared with 0.5% of patients not taking a sulfonylurea [see Adverse Reactions ( 6.1 )] . There is also increased risk of hypoglycemia in patients treated with FOUNDAYO in combination with insulin [see Drug Interactions ( 7.2 )] . Hypoglycemia has also been associated with FOUNDAYO and GLP-1 receptor agonists in adults without type 2 diabetes [see Adverse Reactions ( 6.1 )] . Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In patients with diabetes, monitor blood glucose prior to starting FOUNDAYO and during FOUNDAYO treatment. The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogue). 5.6 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists [see Adverse Reactions ( 6.2 )] . If hypersensitivity reactions occur, advise the patient to promptly seek medical attention and discontinue use of FOUNDAYO. FOUNDAYO is contraindicated in patients with a prior serious hypersensitivity reaction to orforglipron or to any of the excipients in FOUNDAYO. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with FOUNDAYO. 5.7 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Temporary worsening of diabetic retinopathy has been reported with rapid improvement in glucose control. FOUNDAYO 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 of diabetic retinopathy. 5.8 Acute Gallbladder Disease Treatment with FOUNDAYO and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. In a pool of two clinical trials for weight reduction (Trials 1 and 2), cholelithiasis was reported in 1% of patients treated w

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 )

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.

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 (Trials 1 and 2) a Includes other related terms. Adverse Reaction Placebo (N=1,576) % FOUNDAYO 5.5 mg once daily (N=1,051) % FOUNDAYO 9 mg once daily (N=1,055) % FOUNDAYO 17.2 mg once daily (N=1,049) % Nausea 10 26 34 35 Constipation 9 20 27 24 Diarrhea 11 21 23 25 Vomiting 4 13 21 24 Dyspepsia 4 12 16 13 Abdominal pain a 7 13 14 14 Headache 7 8 9 9 Abdominal distension 3 7 9 8 Fatigue a 4 6 7 9 Eructation 1 6 8 8 Gastroesophageal reflux disease 2 6 6 7 Flatulence 2 5 6 6 Hair loss a 2 4 4 5 Gastrointestinal Adverse Reactions In a pool of Trials 1 and 2, gastrointestinal adverse reactions occurred more frequently among patients treated with once daily FOUNDAYO 5.5 mg (60%), 9 mg (68%), and 17.2 mg (69%) than placebo (37%). More patients treated with once daily FOUNDAYO 5.5 mg (3%), 9 mg (6%), and 17.2 mg (6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.7%). Of the FOUNDAYO-treated patients who reported GI adverse reactions, 60%, 36%, and 4% reported mild or moderate or severe adverse reactions, respectively. The incidence of nausea, vomiting, and diarrhea was higher during the FOUNDAYO dosage escalation period and decreased over time. Hypoglycemia In Trial 2, a trial of patients with type 2 diabetes and BMI ≥27 kg/m 2 , hypoglycemia (glucose <54 mg/dL) was reported in 2% of FOUNDAYO-treated patients versus 0.2% of placebo-treated patients. One patient treated with FOUNDAYO 5.5 mg once daily, and no patients receiving placebo reported severe hypoglycemia in Trial 2. In this trial, 7% of patients taking FOUNDAYO in combination with sulfonylurea reported hypoglycemia compared with 0.5% of patients not taking sulfonylurea. In Trial 1, a trial of FOUNDAYO in adults with BMI ≥27 kg/m 2 without type 2 diabetes, there was no systematic capturing of hypoglycemia, but glucose <54 mg/dL was reported in 0.6% of FOUNDAYO-treated patients and no placebo-treated patients. No patients in Trial 1 reported severe hypoglycemia. Other Adverse Reactions Acute Pancreatitis In a pool of Trials 1 and 2, 6 events of acute pancreatitis were confirmed by adjudication in 6 FOUNDAYO-treated patients (0.14 patients per 100 years of exposure) versus 2 events in 1 placebo-treated patient (0.04 patients per 100 years of exposure). Acute Kidney Injury In a pool of Trials 1 and 2, acute kidney injury was reported in 0.2% of FOUNDAYO-treated patients compared to 0.05% of placebo-treated patients. Hypotension In a pool of Trials 1 and 2, hypotension occurred more frequently among patients taking FOUNDAYO (2%) than patients taking placebo (0.5%). Hypotension was more frequently seen in FOUNDAYO-treated patients on concomitant antihypertensive therapy (4%) compared to FOUNDAYO-treated patients not on antihypertensive therapy (1%). Acute Gallbladder Disease In a pool of Trials 1 and 2, cholelithiasis was reported in 1% of FOUNDAYO-treated patients and 0.7% of placebo-treated patients, and acute cholecystitis was reported in 0.4% of FOUNDAYO-treated patients and 0.3% of placebo-treated patients. Tachycardia In a pool of Trials 1 and 2, tachycardia (tachycardia, heart rate increased, and sinus tachycardia) was reported in 3% of patients treated with FOUNDAYO and 0.9% receiving placebo. Treatment with FOUNDAYO resulted in a mean increase in heart rate of 4 to 5 beats per minute from baseline compared to 0.5 beat per minute with placebo. Hair Loss Hair loss adverse reactions in FOUNDAYO-treated patients were associated with weight reduction. In a pool of Trials 1 and 2, hair loss was reported more frequently in female than male patients in the FOUNDAYO (7% female versus 0.9% male) and placebo (3% female versus 0.7% male) treatment groups. Dizziness In a pool of Trials 1 and 2, dizziness was reported in 4% of FOUNDAYO-treated patients and 3% of placebo-treated patients. Dysgeusia In a pool of Trials 1 and 2, dysgeusia was reported in 0.9% of FOUNDAYO-treated patients and 0.3% of placebo-treated patients. Dysesthesia

Mechanism of Action FOUNDAYO is a GLP-1 receptor agonist that binds to and activates the human GLP-1 receptor. GLP-1 is a physiological regulator of appetite and caloric intake. GLP-1 receptors are present in brain regions that regulate appetite. In animal studies, orforglipron distributed to and activated neurons in brain regions that regulate appetite and food intake.