Foundayo Drug Information

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. Limitations of Use Concomitant use with another GLP-1 receptor agonist is not recommended.

Limitations of Use Concomitant use with another GLP-1 receptor agonist is not recommended.

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 . 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.

Dosage Modification for

Concomitant Use with CYP3A4 Inhibitors and CYP3A4 Inducers FOUNDAYO dosage modification may be required to manage interactions with some concomitant medications . 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 . 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 .

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 .

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 . This section of labeling presents safety data from administration of the investigational orforglipron formulation shown as equivalent dosages of once daily FOUNDAYO . 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) . 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 In a pool of Trials 1 and 2, dysesthesia was reported in 0.3% and 1% of patients treated with FOUNDAYO 9 mg, and 17.2 mg, respectively, and 0.1% of patients receiving placebo. No patients taking FOUNDAYO 5.5 mg reported dysesthesia. Hypersensitivity Reactions In a pool of Trials 1 and 2, hypersensitivity reactions, including anaphylactic reaction, occurred in 0.5% of FOUNDAYO-treated patients compared to 0.3% of placebo-treated patients.

Laboratory Abnormalities Amylase and Lipase Increase In a pool of Trials 1 and 2, treatment with FOUNDAYO resulted in mean increases from baseline in serum pancreatic amylase concentrations of 16% to 20% and serum lipase concentrations of 26% to 31%, compared to mean increases from baseline in serum pancreatic amylase of 3% and serum lipase of 4% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with FOUNDAYO is unknown in the absence of other signs and symptoms of pancreatitis.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of GLP-1 receptor agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: 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 and Urinary Disorders: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis

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) . Clinical Impact CYP3A4 inhibitors increase FOUNDAYO exposure , 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 . Strong CYP3A4 Inducers Intervention Avoid concomitant use of FOUNDAYO with strong CYP3A4 inducers.

Clinical Impact Induction of CYP3A4 decreases FOUNDAYO exposure , 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 . Clinical Impact Induction of CYP3A4 decreases FOUNDAYO exposure , which may reduce the effectiveness of FOUNDAYO.

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 . 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) . 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.

Effect of

FOUNDAYO on Oral Medications FOUNDAYO delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications . 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.

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 pharmacologically active in rats. In a pre- and post-natal study in rats, orforglipron was administered orally once daily from implantation through lactation at doses of 5, 30, and 200 mg/kg/day, which resulted in exposures that were approximately 2.9, 4.5, and 13 times the clinical exposure at the MRHD, respectively, based on AUC. No effects were noted at any dose level in the F0 maternal rats or the F1 pups in the pre- and post-natal development study in rats.

In a tissue distribution study, orforglipron-derived radioactivity was not distributed to fetal tissues in pregnant rats.

Pediatric Use Safety and effectiveness of FOUNDAYO have not been established in pediatric patients.

is contraindicated in patients with: A personal or family history of MTC or in patients with MEN 2 . 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 . Personal or family history of MTC or in patients with MEN 2 Known serious hypersensitivity to orforglipron or any of the excipients in FOUNDAYO

In the event of an overdose, consider contacting Poison Control (1-800-222-1222) or a medical toxicologist for latest recommendations. Initiate appropriate supportive treatment according to the patient's clinical signs and symptoms. A period of observation and treatment for these symptoms may be necessary, considering the half-life of orforglipron .