TRULICITY

WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., 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 TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).

5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY. Discontinue if pancreatitis is suspected ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion ( 5.5 ). Severe Gastrointestinal Adverse Reactions: Use may be associated with gastrointestinal adverse reactions, sometimes severe. TRULICITY is not recommended in patients with severe gastroparesis ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 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 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). 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. TRULICITY 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 TRULICITY 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 TRULICITY. 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, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY [see Adverse Reactions ( 6.1 )] . After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue TRULICITY and initiate appropriate management. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving TRULICITY in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7 )]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY. 5.5 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, including TRULICITY [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to TRULICITY that could lead to volume depletion, especially during dosage initiation and escalation of TRULICITY. 5.6 Severe Gastrointestinal Adverse Reactions Use of TRULICITY has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving TRULICITY (0.75 mg 2.2%, 1.5 mg 4.3%) than placebo (1.4%). TRULICITY is not recommended in patients with severe gastroparesis. 5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1%, placebo 1%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation TRULICITY delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking TRULICITY, including whether modifying preoperative fasting recommendations or temporarily discontinuing TRULICITY could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking TRULICITY.

6 ADVERSE REACTIONS The following serious 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 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [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 (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 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 studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than placebo -treated patients (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%). Adult Dose Ranging Trial for TRULICITY 3 mg and 4.5 mg Doses Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 adult patients with type 2 diabetes mellitus treated with TRULICITY 1.5 mg, 3 mg, or 4.5 mg subcutaneously once weekly as an add-on to metformin [see Clinical Studies ( 14.3 )] . The adverse reaction profile is consistent with previous clinical trials in adults. Table 2: Adverse Reactions That Occurred in ≥5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks a a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) % Nausea 13.4 15.6 16.4 Diarrhea 7.0 11.4 10.7 Vomiting 5.6 8.3 9.3 Dyspepsia 2.8 5.0 2.6 Other Adverse Reactions in Adults Hypoglycemia Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies in adult patients with type 2 diabetes mellitus: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Add-on to Metformin (26 weeks) N=177 N=302 N=304 Hypoglycemia with a glucose level <54 mg/dL 0 0.3 0.7 Severe hypoglycemia 0 0 0 Add-on to Metformin + Pioglitazone (26 weeks) N=141 N=280 N=279 Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0 Severe hypoglycemia 0 0 0 Add-on to Glimepiride (24 weeks) N=60 - N=239 Hypoglycemia with a glucose level <54 mg/dL 0 - 3.3 Severe hypoglycemia 0 - 0 In Combination with Insulin Glargine ± Metformin (28 weeks) N=150 - N=150 Hypoglycemia with a glucose level <54 mg/dL 9.3 - 14.7 Severe hypoglycemia 0 - 0.7 Add-on to SGLT2i ± Metformin (24 weeks) N=140 N=141 N=142 Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7 0.7 Severe hypoglycemia 0 0.7 0 Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues. In a 78-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine. In the clinical trial with adult patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on to metformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, and incidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively. Cholelithiasis and Cholecystitis In a cardiovascular outcomes trial in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors with a median follow up of 5.4 years [see Clinical Studies 14.5 ] , cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. Heart Rate Increase and Tachycardia-Related Adverse Reactions In adult patients, TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Hypersensitivity Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of adult patients on TRULICITY in clinical studies. Injection-site Reactions In the placebo-controlled studies in adults, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated adult patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first-degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Acute Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1,000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1,000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1,000 patient years). Based on an analysis of adjudicated events in a clinical trial evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitis occurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patients exposed to TRULICITY 4.5 mg (0.5%). Amylase and Lipase Increase Adult patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%. Adverse Reactions in the Clinical Trial of Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus TRULICITY was administered to 150 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 41.3 weeks [ see Clinical Studies ( 14.6 ) ]. The mean age was 14.5 years and 71% of patients were female. Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2 . The safety profile in pediatric patients treated with TRULICITY 0.75 mg and 1.5 mg subcutaneously once-weekly was consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of injection site reactions. In pediatric patients, the incidence of injection site reactions was 3.9% (2 patients) in the TRULICITY 0.75 mg group, 3.8% (2 patients) in the TRULICITY 1.5 mg group, and 2.0% (1 patient) in the placebo group. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy, cholestasis, elevation of liver enzymes, hepatitis Hypersensitivity: anaphylactic reactions, angioedema Neurologic : dysgeusia, dysesthesia 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 Skin and Subcutaneous Tissue: alopecia

<table width="100%"><caption>Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in &#x2265;5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus </caption><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph>^a Includes diarrhea, fecal volume increased, frequent bowel movements. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph>^b Includes retching, vomiting, vomiting projectile. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph>^c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph>^d Includes fatigue, asthenia, malaise. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph> Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. </paragraph></td></tr></tfoot><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=568)</content> <content styleCode="bold">%</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 0.75 mg</content> <content styleCode="bold">(N=836)</content> <content styleCode="bold">%</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 1.5 mg</content> <content styleCode="bold">(N=834)</content> <content styleCode="bold">%</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">5.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">12.4 </td><td align="center" valign="top" styleCode="Botrule Rrule">21.1 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Diarrhea^a</td><td align="center" valign="top" styleCode="Botrule Rrule">6.7 </td><td align="center" valign="top" styleCode="Botrule Rrule">8.9 </td><td align="center" valign="top" styleCode="Botrule Rrule">12.6 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Vomiting^b</td><td align="center" valign="top" styleCode="Botrule Rrule">2.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">6.0 </td><td align="center" valign="top" styleCode="Botrule Rrule">12.7 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Abdominal Pain^c</td><td align="center" valign="top" styleCode="Botrule Rrule">4.9 </td><td align="center" valign="top" styleCode="Botrule Rrule">6.5 </td><td align="center" valign="top" styleCode="Botrule Rrule">9.4 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased Appetite </td><td align="center" valign="top" styleCode="Botrule Rrule">1.6 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.9 </td><td align="center" valign="top" styleCode="Botrule Rrule">8.6 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dyspepsia </td><td align="center" valign="top" styleCode="Botrule Rrule">2.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.1 </td><td align="center" valign="top" styleCode="Botrule Rrule">5.8 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Fatigue^d</td><td align="center" valign="top" styleCode="Botrule Rrule">2.6 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.2 </td><td align="center" valign="top" styleCode="Botrule Rrule">5.6 </td></tr></tbody></table>

<table width="100%"><caption>Table 2: Adverse Reactions That Occurred in &#x2265;5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks^a</caption><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph>^a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. </paragraph></td></tr></tfoot><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 1.5 mg</content> <content styleCode="bold">(N=612)</content> <content styleCode="bold">%</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 3 mg</content> <content styleCode="bold">(N=616)</content> <content styleCode="bold">%</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 4.5 mg</content> <content styleCode="bold">(N=614)</content> <content styleCode="bold">%</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">13.4 </td><td align="center" valign="top" styleCode="Botrule Rrule">15.6 </td><td align="center" valign="top" styleCode="Botrule Rrule">16.4 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Diarrhea </td><td align="center" valign="top" styleCode="Botrule Rrule">7.0 </td><td align="center" valign="top" styleCode="Botrule Rrule">11.4 </td><td align="center" valign="top" styleCode="Botrule Rrule">10.7 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Vomiting </td><td align="center" valign="top" styleCode="Botrule Rrule">5.6 </td><td align="center" valign="top" styleCode="Botrule Rrule">8.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">9.3 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dyspepsia </td><td align="center" valign="top" styleCode="Botrule Rrule">2.8 </td><td align="center" valign="top" styleCode="Botrule Rrule">5.0 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.6 </td></tr></tbody></table>

<table width="100%"><caption>Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials </caption><col width="26.068%" align="left"/><col width="24.644%" align="left"/><col width="24.644%" align="left"/><col width="24.644%" align="left"/><tbody><tr><td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"/><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 0.75 mg</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">TRULICITY 1.5 mg</content></td></tr><tr><td colspan="4" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Add-on to Metformin</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">(26 weeks)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">N=177</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=302</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=304</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hypoglycemia with a glucose level &lt;54 mg/dL </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.3 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Severe hypoglycemia </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="4" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Add-on to Metformin + Pioglitazone</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">(26 weeks)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">N=141</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=280</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=279</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hypoglycemia with a glucose level &lt;54 mg/dL </td><td align="center" valign="middle" styleCode="Botrule Rrule">1.4 </td><td align="center" valign="middle" styleCode="Botrule Rrule">2.1 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Severe hypoglycemia </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="4" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Add-on to Glimepiride</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">(24 weeks)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">N=60</content></td><td align="center" valign="middle" styleCode="Botrule Rrule">- </td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=239</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hypoglycemia with a glucose level &lt;54 mg/dL </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">- </td><td align="center" valign="middle" styleCode="Botrule Rrule">3.3 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Severe hypoglycemia </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">- </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="4" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">In Combination with Insulin Glargine &#xB1; Metformin</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">(28 weeks)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">N=150</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">-</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=150</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hypoglycemia with a glucose level &lt;54 mg/dL </td><td align="center" valign="middle" styleCode="Botrule Rrule">9.3 </td><td align="center" valign="middle" styleCode="Botrule Rrule">- </td><td align="center" valign="middle" styleCode="Botrule Rrule">14.7 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Severe hypoglycemia </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">- </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td></tr><tr><td colspan="4" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Add-on to SGLT2i &#xB1; Metformin</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">(24 weeks)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">N=140</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=141</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">N=142</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hypoglycemia with a glucose level &lt;54 mg/dL </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Severe hypoglycemia </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr></tbody></table>