Trulicity

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 11/29/2022
Drug Description

What is Trulicity and how is it used?

Trulicity is a prescription medicine used to treat the symptoms of Diabetes Melltus Type 2. Trulicity may be used alone or with other medications.

Trulicity belongs to a class of drugs called Antidiabetics, Glucagon-like Peptide-1 Agonists.

It is not known if Trulicity is safe and effective in children.

What are the possible side effects of Trulicity?

Trulicity may cause serious side effects including:

  • severe pain in your upper stomach, spreading to your back,
  • nausea,
  • vomiting,
  • swelling or a lump in your neck,
  • trouble swallowing,
  • a horse voice,
  • shortness of breath,
  • headache,
  • hunger,
  • weakness,
  • sweating,
  • confusion,
  • irritability,
  • dizziness,
  • fast heart rate,
  • feeling jittery,
  • little or no urination,
  • swelling of your feet or ankles, and
  • tiredness

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Trulicity include:

  • nausea,
  • vomiting,
  • stomach pain,
  • diarrhea, and
  • loss of appetite

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Trulicity. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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 , and Nonclinical Toxicology].
  • 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 and WARNINGS AND PRECAUTIONS].

DESCRIPTION

TRULICITY contains dulaglutide, a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase-IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons.

TRULICITY is a clear, colorless, sterile solution. Each 0.5 mL of TRULICITY solution contains 0.75 mg or 1.5 mg of dulaglutide. Each single-dose pen contains 0.5 mL of solution and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg), trisodium citrate dihydrate (1.37 mg), in water for injection.

Indications

INDICATIONS

TRULICITY® is indicated

Limitations Of Use

  • TRULICITY has not been studied in patients with a history of pancreatitis [see WARNINGS AND PRECAUTIONS]. Consider otherantidiabetic therapies in patients with a history of pancreatitis.
  • TRULICITY should not be used in patients with type 1 diabetes mellitus.
  • TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and is thereforenot recommended in these patients [see WARNINGS AND PRECAUTIONS].

QUESTION

______________ is another term for type 2 diabetes. See Answer
Dosage

DOSAGE AND ADMINISTRATION

Dosage

  • The recommended initiating dose of TRULICITY is 0.75 mg injected subcutaneously once weekly.
  • Increase the dose to 1.5 mg once weekly for additional glycemic control.
  • If additional glycemic control is needed, increase the dose to 3 mg once weekly after at least 4 weeks on the 1.5 mg dose.
  • If additional glycemic control is needed, increase the dose to the maximum dose of 4.5 mg once weekly after at least 4 weeks onthe 3 mg dose.
  • If a dose is missed, instruct patients to administer as soon as possible if there are at least 3 days (72 hours) until the nextscheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose onthe regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
  • The day of weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before.

Important Administration Instructions

  • Administer TRULICITY once weekly, any time of day, with or without food.
  • Inject TRULICITY subcutaneously in the abdomen, thigh, or upper arm.
  • Rotate injection sites with each dose.
  • Inspect TRULICITY visually before use. It should appear clear and colorless. Do not use TRULICITY if particulate matter orcoloration is seen.
  • When using TRULICITY with insulin, administer as separate injections and never mix. It is acceptable to inject TRULICITYand insulin in the same body region, but the injections should not be adjacent to each other.

HOW SUPPLIED

Dosage Forms And Strengths

Injection

TRULICITY is a clear and colorless solution available as:

  • 0.75 mg/0.5 mL solution in a single-dose pen
  • 1.5 mg/0.5 mL solution in a single-dose pen
  • 3 mg/0.5 mL solution in a single-dose pen
  • 4.5 mg/0.5 mL solution in a single-dose pen

TRULICITY (dulaglutide) injection is a clear and colorless solution supplied in single-dose pens. Each TRULICITY single-dosepen is packaged in a cardboard outer carton.

Carton Of 4 Single-Dose Pens
  • 0.75 mg/0.5 mL solution in a single-dose pen (NDC 0002-1433-80)
  • 1.5 mg/0.5 mL solution in a single-dose pen (NDC 0002-1434-80)
  • 3 mg/0.5 mL solution in a single-dose pen (NDC 0002-2236-80)
  • 4.5 mg/0.5 mL solution in a single-dose pen (NDC 0002-3182-80)

Storage And Handling

  • Store TRULICITY in the refrigerator at 36°F to 46°F (2°C to 8°C).
  • If needed, each single-dose pen can be kept at room temperature, not to exceed 86°F (30°C) for a total of 14 days.
  • Do not freeze TRULICITY. Do not use TRULICITY if it has been frozen.
  • Protect TRULICITY from light. Storage of TRULICITY in the original carton is recommended until time of administration.

Manufuctured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Revised: Jun 2022.

Side Effects

SIDE EFFECTS

The following serious reactions are described below or elsewhere in the prescribing information:

  • Risk of Thyroid C-cell Tumors [see WARNINGS AND PRECAUTIONS]
  • Pancreatitis [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Acute Kidney Injury [see WARNINGS AND PRECAUTIONS] Severe Gastrointestinal Disease [see WARNINGS AND PRECAUTIONS]
  • Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see WARNINGS AND PRECAUTIONS]
  • Acute Gallbladder Disease [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of adrug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Pool Of 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 1670 patients exposed to TRULICITY with amean duration of exposure of 23.8 weeks [see Clinical Studies]. The mean age of patients was 56 years, 1% were 75 years orolder and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic orLatino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of thepopulation reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m2 ) in96%.

Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated patients and more commonlythan placebo in a pool of placebo-controlled trials.

Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials Occurring in ≥5% of TRULICITY-Treated Patients

Adverse Reaction Placebo
(N=568)
%
TRULICITY 0.75 mg
(N=836)
%
TRULICITY 1.5 mg
(N=834)
%
Nausea 5.3 12.4 21.1
Diarrheaa 6.7 8.9 12.6
Vomitingb 2.3 6.0 12.7
Abdominal Painc 4.9 6.5 9.4
Decreased Appetite 1.6 4.9 8.6
Dyspepsia 2.3 4.1 5.8
Fatigued 2.6 4.2 5.6
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.

Gastrointestinal Adverse Reactions

In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receivingTRULICITY than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving TRULICITY 0.75 mg (1.3%)and TRULICITY 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo(0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 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% ofcases, respectively.

The following adverse reactions were reported more frequently in TRULICITY-treated patients than placebo (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%).

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 1842patients treated with Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly as an add-on to metformin. The adverse reaction profile isconsistent with previous clinical trials.

Table 2: Adverse Reactions Occurring in ≥5% of Patients Receiving TRULICITY 1.5 mg, 3 mg, or 4.5 mg in a Clinical Trial through 36 Weeksa

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
a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.

Other Adverse Reactions

Hypoglycemia

Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies: 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 toactively administer carbohydrate, glucagon, or other resuscitative actions.

Table 3: Incidence (%) of Hypoglycemia 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 withnon-secretagogues. In a 78-week clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients whenTRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-weekclinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients whenTRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence ofhypoglycemia in patients treated in combination with basal insulin glargine.

In the clinical trial with patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on tometformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, andincidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively.

Cholelithiasis and Cholecystitis

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 inTRULICITY-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

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 wasreported 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 withplacebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitantincrease 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 patients on TRULICITY in clinical studies.

Injection-site Reactions

In the placebo-controlled studies, 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 reaction of First-Degree Atrioventricular (AV) Block

A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated patients in contrast to amean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first-degree AV block occurred morefrequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg andTRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Amylase and Lipase Increase

Patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, whileplacebo-treated patients had mean increases of up to 3%.

Immunogenicity

In clinical studies, 64 (1.6%) TRULICITY-treated patients developed anti-drug antibodies (ADAs) to the active ingredient inTRULICITY (i.e., dulaglutide).

Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) haddulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observedincidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assaymethodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, theincidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events arereported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish acausal relationship to drug exposure.

SLIDESHOW

Type 2 Diabetes: Signs, Symptoms, Treatments See Slideshow
Drug Interactions

DRUG INTERACTIONS

Oral Medications

TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oralmedications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higherdoses of TRULICITY [see DOSAGE AND ADMINISTRATION]. The delay is largest after the first dose and diminishes withsubsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see CLINICAL PHARMACOLOGY]. There is limited experience with theuse of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg.

Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered withTRULICITY.

Concomitant Use With An Insulin Secretagogue (e.g., Sulfonylurea) Or With Insulin

When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such assulfonylureas) or insulin to reduce the risk of hypoglycemia [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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]. 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 isunknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as thehuman 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 study. This patient had pretreatment calcitoninlevels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitoninlevels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated withliraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficientto 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 patientsregarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass inthe neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patientstreated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity forserum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicateMTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, thepatient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also befurther evaluated.

Pancreatitis

In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactionswere reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). Ananalysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).

Based on an analysis of adjudicated events in a clinical study evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitisoccurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patientsexposed to TRULICITY 4.5 mg (0.5%).

After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis, including persistent severeabdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected,promptly discontinue TRULICITY. If pancreatitis is confirmed, TRULICITY should not be restarted. TRULICITY has not beenevaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history ofpancreatitis.

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 increasedrisk of hypoglycemia, including severe hypoglycemia [see ADVERSE REACTIONS and DRUG INTERACTIONS].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulinsecretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on thesigns and symptoms of hypoglycemia.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema inpatients treated with TRULICITY [see ADVERSE REACTIONS]. If a hypersensitivity reaction occurs, discontinue TRULICITY;treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previoushypersensitivity reaction to TRULICITY [see CONTRAINDICATIONS].

Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history ofangioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed toanaphylaxis with TRULICITY.

Acute Kidney Injury

In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of acute renalfailure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported inpatients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea,vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalatingdoses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severeadverse gastrointestinal reactions [see Use In Specific Populations].

Severe Gastrointestinal Disease

Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe [see ADVERSE REACTIONS].TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is thereforenot recommended in these patients.

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 establishedcardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated withTRULICITY 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 retinopathyat baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY1%, placebo 1%).

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with ahistory of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials andpostmarketing. In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for priorcholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placeborespectively. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)

  • Inform patients that TRULICITY causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of thisfinding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistenthoarseness, dysphagia, or dyspnea) to their physician [see BOX WARNING and WARNINGS AND PRECAUTIONS].
  • Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompaniedby vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TRULICITY promptly, and tocontact their physician, if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].
  • Inform patients that the risk of hypoglycemia may be increased when TRULICITY is used in combination with an insulinsecretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see WARNINGS AND PRECAUTIONS].
  • Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluiddepletion. Inform patients treated with TRULICITY of the potential risk for worsening renal function and explain the associatedsigns and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see WARNINGS AND PRECAUTIONS].
  • Inform patients that serious hypersensitivity reactions have been reported with use of TRULICITY. Advise patients on thesymptoms of hypersensitivity reactions and instruct them to stop taking TRULICITY and seek medical advice promptly if suchsymptoms occur [see WARNINGS AND PRECAUTIONS].
  • Inform patients to contact their physician if changes in vision are experienced during treatment with TRULICITY [see WARNINGS AND PRECAUTIONS].
  • Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasisor cholecystitis is suspected for appropriate clinical follow-up [see WARNINGS AND PRECAUTIONS].
  • Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use In SpecificPopulations].
  • Inform patients if a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, they should administerit as soon as possible and then resume their usual once weekly dosing schedule. If a dose is missed and the next regularlyscheduled dose is due in 1 or 2 days, inform the patient to not administer the missed dose and instead resume TRULICITY withthe next regularly scheduled dose [see DOSAGE AND ADMINISTRATION].
  • Advise patients treated with TRULICITY of the potential risk of gastrointestinal side effects [see ADVERSE REACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05, 0.5, 1.5, and 5 mg/kg (0.2-,3-, 8-, and 24-fold the MRHD of 4.5 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. In rats,dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomasand/or carcinomas) compared to controls, at ≥3-fold the MRHD based on AUC. A statistically significant increase in C-celladenomas was observed in rats receiving dulaglutide at ≥0.5 mg/kg. Numerical increases in thyroid C-cell carcinomas occurred at5 mg/kg (24 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statisticalsignificance.

A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1, and 3 mg/kgadministered by subcutaneous injection twice weekly. Dulaglutide did not produce increased incidences of thyroid C-cellhyperplasia or neoplasia at any dose.

Dulaglutide is a recombinant protein; no genotoxicity studies have been conducted.

Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see BOX WARNING and WARNINGS AND PRECAUTIONS].

In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on spermmorphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (55-fold the MRHD based onAUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean numberof corpora lutea, implantation sites, and viable embryos were observed at ≥4.9 mg/kg (≥13-fold the MRHD based on AUC), whichoccurred in the presence of decreased maternal food consumption and body weight gain.

Use In Specific Populations

Pregnancy

Risk Summary

Limited data with TRULICITY in pregnant women are not sufficient to determine a drug-associated risk for major birth defects andmiscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy [see Clinical Considerations]. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide duringpregnancy. TRULICITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In pregnant rats administered dulaglutide during organogenesis, early embryonic deaths, fetal growth reductions, and fetalabnormalities occurred at systemic exposures at least 6-times human exposure at the maximum recommended human dose (MRHD)of 4.5 mg/week. In pregnant rabbits administered dulaglutide during organogenesis, major fetal abnormalities occurred at 5-timeshuman exposure at the MRHD. Adverse embryo/fetal effects in animals occurred in association with decreased maternal weight andfood consumption attributed to the pharmacology of dulaglutide [see Data].

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and hasbeen reported to be as high as 20–25% in women with an HbA1c >10%. The estimated background risk of miscarriage for theindicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects andmiscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryo/fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions,preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, andmacrosomia-related morbidity.

Data

Animal Data

Pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide every 3 days during organogenesis had systemicexposures 2-, 6-, and 18-times human exposure at the maximum recommended human dose (MRHD) of 4.5 mg/week, respectively,based on plasma area under the time-concentration curve (AUC) comparison. Reduced fetal weights associated with decreasedmaternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg.Irregular skeletal ossifications and increases in post-implantation loss also were observed at 4.89 mg/kg.

In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide every 3 days during organogenesis, systemicexposures in pregnant rabbits were 0.5-, 2-, and 5-times human exposure at the MRHD, based on plasma AUC comparison. Fetalvisceral malformation of lung lobular agenesis and skeletal malformations of the vertebrae and/or ribs were observed in conjunctionwith decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg.

In a prenatal-postnatal study in F0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day fromimplantation through lactation, systemic exposures in pregnant rats were 1-, 2-, and 7-times human exposure at the MRHD, basedon plasma AUC comparison. F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower meanbody weight from birth through postnatal day 63 for males and postnatal day 84 for females. F1 offspring from F0 maternal ratsreceiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputialseparation. Females had decreased startle response. These physical findings may relate to the decreased size of the offspring relativeto controls as they appeared at early postnatal assessments but were not observed at a later assessment. F1 female offspring of the F0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative toconcurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred inconjunction with decreased F0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at1.63 mg/kg. The human relevance of these memory deficits in the F1 female rats is not known.

Lactation

Risk Summary

There are no data on the presence of dulaglutide in human milk, the effects on the breastfed infant, or the effects on milk production.The presence of dulaglutide in milk of treated lactating animals was not determined. The developmental and health benefits ofbreastfeeding should be considered along with the mother's clinical need for TRULICITY and any potential adverse effects on thebreastfed infant from TRULICITY or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of TRULICITY have not been established in pediatric patients. TRULICITY is not recommended for use inpediatric patients younger than 18 years.

Geriatric Use

In the glycemic control trials [see Clinical Studies] , 620 (18.6%) TRULICITY-treated patients were 65 years of age or olderand 65 (1.9%) TRULICITY-treated patients were 75 years of age or older at baseline. In the TRULICITY 1.5 mg treatment arm ofthe REWIND trial [see Clinical Studies] , a total of 2619 (52.9%) patients were 65 years of age or older, and 484 (9.8%)patients were 75 years of age or older at baseline.

No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.

Renal Impairment

TRULICITY has been studied in patients with varying degrees of renal function, including a dedicated study in patients withmoderate to severe chronic kidney disease. No overall differences in safety or effectiveness were observed in these studiesaccording to renal function [see Clinical Studies].

In a clinical pharmacology study in subjects with renal impairment, including end-stage renal disease (ESRD), no clinically relevantchange in dulaglutide pharmacokinetics (PK) was observed. In the 52-week study in patients with type 2 diabetes and moderate tosevere renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to that demonstrated inprevious clinical studies [see CLINICAL PHARMACOLOGY].

No dose adjustment is recommended in patients with renal impairment including end-stage renal disease (ESRD). Monitor renalfunction in patients with renal impairment reporting severe adverse gastrointestinal reactions. Use TRULICITY with caution inpatients with ESRD [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Hepatic Impairment

In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutidePK was observed [see CLINICAL PHARMACOLOGY]. However, there is limited clinical experience in patients with mild, moderate,or severe hepatic impairment; therefore, use TRULICITY with caution in these patient populations.

Gastroparesis

Dulaglutide slows gastric emptying. TRULICITY has not been studied in patients with preexisting gastroparesis. Use TRULICITYwith caution in patients with gastroparesis.

Overdose & Contraindications

OVERDOSE

Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderategastrointestinal events (e.g., nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care(including frequent plasma glucose monitoring) should be initiated according to the patient's clinical signs and symptoms.

CONTRAINDICATIONS

TRULICITY is contraindicated in patients with:

  • Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrometype 2 (MEN 2) [see WARNINGS AND PRECAUTIONS].
  • Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactionsincluding anaphylactic reactions and angioedema have been reported with TRULICITY [see WARNINGS AND PRECAUTIONS].
Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology toendogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled toadenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.

Pharmacodynamics

TRULICITY lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetesmellitus. The reduction in fasting and postprandial glucose can be observed after a single dose.

Fasting And Postprandial Glucose

In a clinical pharmacology study in patients with type 2 diabetes mellitus, treatment with once weekly TRULICITY resulted in areduction of fasting and 2-hour PPG concentrations, and postprandial serum glucose incremental AUC, when compared to placebo(-25.6 mg/dL, -59.5 mg/dL, and -197 mg*h/dL, respectively); these effects were sustained after 6 weeks of dosing with the 1.5 mgdose.

First- And Second-Phase Insulin Secretion

Both first- and second-phase insulin secretion were increased in patients with type 2 diabetes treated with TRULICITY comparedwith placebo.

Insulin And Glucagon Secretion

TRULICITY stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with TRULICITY 0.75 mgand 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptideconcentration by 0.09 and 0.07 nmol/L, respectively, in a monotherapy study. In the same study, fasting glucagon concentration wasreduced by 1.71 and 2.05 pmol/L from baseline with TRULICITY 0.75 mg and 1.5 mg, respectively.

Gastric Motility

Dulaglutide causes a delay of gastric emptying. The delay in gastric emptying is dose-dependent but is attenuated with adequatedose escalation to higher doses of TRULICITY. The delay is largest after the first dose and diminishes with subsequent doses.

Cardiac Electrophysiology (QTc)

The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study. Dulaglutide did not produce QTcprolongation at doses of 4 and 7 mg. The maximum recommended dose is 4.5 mg once weekly.

Pharmacokinetics

The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Followingsubcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady state ranges from 24 to 72 hours,with a median of 48 hours. After reaching steady state, the accumulation ratio was approximately 1.56. Steady-state plasmadulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneousadministration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.

Absorption

The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0.75 mg and 1.5 mgdoses was 65% and 47%, respectively. Absolute subcutaneous bioavailability for 3 mg and 4.5 mg doses were estimated to besimilar to 1.5 mg although this has not been specifically studied. Dulaglutide concentrations increased approximately proportional todose from 0.75 mg to 4.5 mg.

Distribution

Apparent population mean central volume of distribution was 3.09 L and the apparent population mean peripheralvolume of distribution was 5.98 L.

Metabolism

Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.

Elimination

The apparent population mean clearance of dulaglutide was 0.142 L/h. The elimination half-life of dulaglutide wasapproximately 5 days.

Specific Populations

The intrinsic factors of age, gender, race, ethnicity, body weight, or renal or hepatic impairment do not have a clinically relevanteffect on the PK of dulaglutide as shown in Figure 1.

Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; C = maximum concentration; ESRD =end-stage renal disease; PK = pharmacokinetics.

Note: Reference values for weight, age, gender, and race comparisons are 93 kg, 56 years old, male, and white, respectively;reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function from the respectiveclinical pharmacology studies. The weight values shown in the plot (70 and 120 kg) are the 10 and 90 percentiles of weight in thePK population.

Figure 1: Impact of intrinsic factors on dulaglutide pharmacokinetics.

Impact of intrinsic factors on dulaglutide pharmacokinetics. - Illustration
Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; Cmax = maximum concentration; ESRD =end-stage renal disease; PK = pharmacokinetics.
Note: Reference values for weight, age, gender, and race comparisons are 93 kg, 56 years old, male, and white, respectively;reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function from the respectiveclinical pharmacology studies. The weight values shown in the plot (70 and 120 kg) are the 10th and 90th percentiles of weight in thePK population.

Renal

Dulaglutide systemic exposure was increased by 20, 28, 14 and 12% for mild, moderate, severe, and ESRD renalimpairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 13, 23, 20 and 11%, respectively ( Figure 1 ). Additionally, in a 52 week clinical study in patients with type 2 diabetes and moderate to severe renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to thatdemonstrated in previous clinical studies [see WARNINGS AND PRECAUTIONS and Use In Specific Population].

Hepatic

Dulaglutide systemic exposure decreased by 23, 33 and 21% for mild, moderate and severe hepatic impairment groups,respectively, compared to subjects with normal hepatic function, and Cmax was decreased by a similar magnitude ( Figure 1 ) [see Use In Specific Populations].

Drug Interactions

The potential effect of co-administered medications on the PK of dulaglutide 1.5 mg and vice versa was studied in several single-and multiple-dose studies in healthy subjects, patients with type 2 diabetes mellitus, and patients with hypertension.

Potential For Dulaglutide To Influence The Pharmacokinetics Of Other Drugs

Dulaglutide slows gastric emptying and, as a result, may reduce the extent and rate of absorption of orally co-administeredmedications. In clinical pharmacology studies, dulaglutide at a dose of 1.5 mg did not affect the absorption of the tested orallyadministered medications to any clinically relevant degree. The delay in gastric emptying is dose-dependent but is attenuated withthe recommended dose escalation to higher doses of TRULICITY [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].The delay is largest after the first dose and diminishes with subsequent doses. PK measures indicating the magnitude of theseinteractions are presented in Figure 2.

Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; C = maximum concentration; PK =pharmacokinetics.

Note: Reference group is co-administered medication given alone.

Figure 2: Impact of dulaglutide 1.5 mg on the pharmacokinetics of co-administered medications.

Impact of dulaglutide 1.5 mg on the pharmacokinetics of co-administered medications. - Illustration
Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; Cmax = maximum concentration; PK =pharmacokinetics.
Note: Reference group is co-administered medication given alone.
Potential For Co-Administered Drugs To Influence The Pharmacokinetics Of Dulaglutide

In a clinical pharmacology study, the co-administration of a single dose of 1.5 mg dulaglutide with steady-state dose of 100 mgsitagliptin caused an increase in dulaglutide AUC and Cmax of approximately 38% and 27%, which is not considered clinicallyrelevant.

Animal Toxicology And/Or Pharmacology

Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5 mg/kg/twice weekly of dulaglutide (1-, 3-, and 13-fold the MRHD basedon AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses withoutmicroscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals includedincreased interlobular ductal epithelium without active ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/withoutinflammation (≥1.5 mg/kg), and increased neutrophilic inflammation of the acinar pancreas (5 mg/kg).

Treatment of monkeys for 12 months with 8.15 mg/kg/twice weekly of dulaglutide (nearly 200-fold the MRHD based on AUC)demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutidetreatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in totalamylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.

Clinical Studies

Glycemic Control Trials In Adults With Type 2 Diabetes Mellitus

TRULICITY has been studied as monotherapy and in combination with metformin, sulfonylurea, metformin and sulfonylurea,metformin and thiazolidinedione, sodium-glucose co-transporter-2 inhibitors (SGLT2i) with or without metformin, basal insulinwith or without metformin, and prandial insulin with or without metformin. TRULICITY has also been studied in patients with type2 diabetes mellitus and moderate to severe renal impairment.

Dose escalation was performed in one study with TRULICITY doses up to 4.5 mg added to metformin. All other clinical studiesevaluated TRULICITY 0.75 mg and 1.5 mg without dose escalation; patients were initiated and maintained on either 0.75 mg or1.5 mg for the duration of the trials.

In patients with type 2 diabetes mellitus, TRULICITY produced reductions from baseline in HbA1c compared to placebo. Nooverall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration ofdiabetes).

Monotherapy

In a double-blind study with primary endpoint at 26 weeks, 807 patients inadequately treated with diet and exercise, or with diet andexercise and one antidiabetic agent used at submaximal dose, were randomized to TRULICITY 0.75 mg once weekly, TRULICITY1.5 mg once weekly, or metformin 1500 to 2000 mg/day following a two-week washout. Seventy-five percent (75%) of the randomized population were treated with one antidiabetic agent at the screening visit. Most patients previously treated with anantidiabetic agent were receiving metformin (~90%) at a median dose of 1000 mg daily and approximately 10% were receiving asulfonylurea.

Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years. Forty-four percent were male. The White,Black and Asian race accounted for 74%, 7% and 8% of the population, respectively. Twenty-nine percent of the study populationwere from the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in reduction in HbA1c from baseline at 26-weeks ( Table 4 ).The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and metformin excluded the pre-specified non-inferiority margin of 0.4%.

Table 4: Results at Week 26 in a Trial of TRULICITY as Monotherapya

26-Week Primary Time Point
TRULICITY 0.75 mg TRULICITY 1.5 mg Metformin 1500-2000 mg
Intent-to-Treat (ITT) Population (N) 270 269 268
HbA1c (%) (Mean)
Baseline 7.6 7.96 7.6
Change from baselineb -0.7 -1.8 -0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 164 161
Change from baselineb -26 -29 -24
Body Weight (kg) (Mean)
Baseline 91.8 92.7 92.4
Change from baselineb -1.4 -2.3 -2.2
Abbreviation: HbA1c = hemoglobin A1c.
a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy aretreated as missing. At Week 26, primary efficacy was missing for 10%, 12% and 14% of individuals randomized to TRULICITY 0.75 mg,TRULICITY 1.5 mg and metformin, respectively.
b Least-squares mean adjusted for baseline value and other stratification factors.
Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included265 individuals in each of the treatment arms.

Combination Therapy

Add-on to Metformin

In this placebo-controlled, double-blind study with primary endpoint at 52 weeks, 972 patients were randomized to placebo,TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in theplacebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the study), all as add-on to metformin.Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemicstabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White,Black and Asian were 53%, 4% and 27%, respectively; and 24% of the study population were in the US.

At the 26-week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, TRULICITY0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%,62% and 39% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a meanweight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin,respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo,TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared toplacebo (at 26 weeks) and compared to sitagliptin (at 26 and 52 weeks), all in combination with metformin ( Table 5 and Figure 3 ).

Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformin a

52-Week Primary Time Point
TRULICITY 0.75 mg TRULICITY 1.5 mg Sitagliptin 100 mg
Intent-to-Treat (ITT) Population (N) 281 279 273
HbA1c (%) (Mean)
Baseline 8.2 8.1 8.0
Change from baselineb -0.9 -1.1 -0.4
Difference from sitagliptinb (95% CI) -0.5 (-0.7, -0.3) -0.7 (-0.9, -0.5) -
Percentage of patients HbA1c <7.0% 49## 59## 33
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline 174 173 171
Change from baselineb -30 -41 -14
Difference from sitagliptinb (95% CI) -15 (-22, -9) -27 (-33, -20) -
Body Weight (kg) (Mean)
Baseline 85.5 86.5 85.8
Change from baselineb -2.7 -3.1 -1.5
Difference from sitagliptinb (95% CI) -1.2 (-1.8, -0.6) -1.5 (-2.1, -0.9) -
Abbreviations: HbA1c = hemoglobin A1c.
a All ITT patients randomized after the dose-finding portion of the study. Last observation carried forward (LOCF) was used to impute missingdata. At Week 52 primary efficacy was missing for 15%, 19%, and 20% of individuals randomized to TRULICITY 0.75 mg, TRULICITY1.5 mg and sitagliptin, respectively.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included276, 277, and 270 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively.
Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to sitagliptin, assessed only for HbA1c.
## p<0.001 TRULICITY compared to sitagliptin, assessed only for HbA1c <7.0%.

Figure 3:Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF)

Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF)- Illustration

TRULICITY 3 mg And 4.5 mg Add-On To Metformin

In this parallel-arm, double-blind study with primary endpoint at 36 weeks, a total of 1842 patients were randomized 1:1:1 toTRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, all as add-on to metformin (NCT03495102).

Following randomization, all patients received TRULICITY 0.75 mg once weekly. The dose was increased every 4 weeks to thenext higher dose until the patients reached the assigned study dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on theassigned study dose for the duration of the study.

Patients had a mean age of 57.1 years; a mean duration of type 2 diabetes of 7.6 years; 51.2% were male; race: White, Black, andAsian were 85.8%, 4.5%, and 2.4%, respectively; and 27.6% of the study population was in the US.

At 36 weeks, treatment with TRULICITY 4.5 mg resulted in a statistically significant reduction in HbA1c and in body weightcompared to TRULICITY 1.5 mg ( Table 6 and Figure 4 ).

Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformina

36-Week Primary Time Point
TRULICITY 1.5 mg TRULICITY 3 mg TRULICITY 4.5 mg
Intent-to-Treat (ITT) Population (N) 612 616 614
HbA1c (%) (Mean)
Baseline 8.6 8.6 8.6
Change from baselineb -1.5 -1.6 -1.8
Difference from 1.5 mgb (95% CI) -0.1 (-0.2, 0.0) -0.2 (-0.4, -0.1) ^
Percentage of patients HbA1c <7.0%c 50 56 62
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 185 184 183
Change from baselineb -45 -46 -51
Difference from 1.5 mgb (95% CI) - 2 (-7, 3) -6 (-11, -2)
Body Weight (kg) (Mean)
Baseline 95.5 96.3 95.4
Change from baselineb -3.0 -3.8 -46
Difference from 1.5 mgb (95% CI) -0.9 (-1.4, -0.4) -1.6 (-2.2, -1.1) ^^1
Abbreviations: HbA1c = hemoglobin A1c
a Intent-to-treat population. At Week 36, primary efficacy was missing for 7%, 7%, and 6% of individuals treated with TRULICITY 1.5 mg,TRULICITY 3 mg, and TRULICITY 4.5 mg, respectively.
b Least-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation.
c Patients with missing HbA1c data at Week 36 were considered as not achieving HbA1c target.
^ p=0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.
^^ p<0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.

Figure 4: Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI)

 Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI)- Illustration

Add-On To Sulfonylurea

In this 24-week placebo-controlled, double-blind study, 299 patients were randomized to and received placebo or once weeklyTRULICITY 1.5 mg, both as add-on to glimepiride. Patients had a mean age of 58 years; mean duration of type 2 diabetes of 8years; 44% were male; race: White, Black, and Asian were 83%, 4%, and 2%, respectively; and 24% of the study population were inthe US.

At 24 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared toplacebo ( Table 7 ).

Table 7: Results at Week 24 of TRULICITY Compared to Placebo as Add-On to Glimepiridea

24-Week Primary Time Point
Placebo TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N) 60 239
HbA1c (%) (Mean)
Baseline 8.4 8.4
Change from baselineb -0.3 -1.3
Difference from placebob (95% CI) -1.1 (-1.4, -0.7)
Percentage of patients HbA1c <7.0%c 17 50
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 175 178
Change from baselineb 2 -28
Difference from placebob (95% CI) -30 (-44, -15)
Body Weight (kg) (Mean)
Baseline 89.5 84.5
Change from baselineb -0.2 -0.5
Difference from placebob (95% CI) -0.4 (-1.2, 0.5)
Abbreviations: HbA1c = hemoglobin A1c.
a Intent-to-treat population. Data post-onset of rescue therapy are treated as missing. At Week 24 primary efficacy was missing for 10% and 12%of individuals randomized to TRULICITY 1.5 mg and placebo, respectively.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to thebaseline values, was used to model a wash-out of the treatment effect for subjects having missing Week 24 data.
c Patients with missing HbA1c data at Week 24 were considered as non-responders.
p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.

Add-On To Metformin And Thiazolidinedione

In this placebo-controlled study with primary endpoint at 26 weeks, 976 patients were randomized to and received placebo,TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximallytolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignmentwas open-label while the treatment assignments to placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg were blinded. After 26weeks, patients in the placebo treatment group were randomized to either TRULICITY 0.75 mg once weekly or TRULICITY1.5 mg once weekly to maintain study blind. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks ofthe lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years;58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the study population were in theUS.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared toplacebo (at 26 weeks) and compared to exenatide at 26 weeks ( Table 8 and Figure 5 ). Over the 52-week study period, the percentageof patients who required glycemic rescue was 8.9% in the TRULICITY 0.75 mg once weekly + metformin and pioglitazonetreatment group, 3.2% in the TRULICITY 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in theexenatide BID + metformin and pioglitazone treatment group.

Table 8: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin andThiazolidinedionea

26-Week Primary Time Point
Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Exenatide 10 mcg BID
Intent-to-Treat (ITT) Population (N) 141 280 279 276
HbA1c (%) (Mean)
Baseline 8.1 8.1 8.1 8.1
Change from baselineb -0.5 -1.3 -1.5 -1.0
Difference from placebob (95% CI) - -0.8
(-1.0, -0.7)
-1.1
(-1.2, -0.9)
-
Difference from exenatideb (95% CI) - -0.3
(-0.4, -0.2)
-0.5
(-0.7, -0.4)
-
Percentage of patients HbA1c <7.0% 43 66**,## 78**,## 52
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 166 159 162 164
Change from baselineb -5 -34 -42 -24
Difference from placebob (95% CI) - -30
(-36, -23)
-38
(-45, -31)
-
Difference from exenatideb (95% CI) - -10
(-15, -5)
-18
(-24, -13)
-
Body Weight (kg) (Mean)
Baseline 94.1 95.5 96.2 7.4
Change from baselineb 1.2 0.2 -1.3 -1.1
Difference from placebob (95% CI) - -1.0
(-1.8, -0.3)
-2.5
(-3.3, -1.8)
-
Difference from exenatideb (95% CI) - 1.3
(0.6, 1.9)
-0.2
(-0.9, 0.4)
-
Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c.
a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy aretreated as missing. At Week 26, primary efficacy was missing for 23%, 10%, 7% and 12% of individuals randomized to placebo, TRULICITY0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included119, 269, 271 and 266 individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.
Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to placebo, assessed only for HbA1c.
Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to exenatide, assessed only for HbA1c.
** p<0.001 TRULICITY compared to placebo, assessed only for HbA1c <7.0%.
## p<0.001 TRULICITY compared to exenatide, assessed only for HbA1c <7.0%.

Figure 5: Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF

  Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF- Illustration

Combination Therapy With SGLT2i, With Or Without Metformin

In this 24-week placebo-controlled, double-blind study, 423 patients were randomized to and received TRULICITY 0.75 mg,TRULICITY 1.5 mg, or placebo, as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4%without metformin). Trulicity was administered once weekly, and SGLT2i was administered according to the local country label.Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9.4 years; 50% were male; race: White, Black, and Asianwere 89%, 3%, and 0.2%, respectively; and 21% of the study population was in the US.

At 24 weeks, treatment with once weekly TRULICITY 0.75 mg and 1.5 mg resulted in a statistically significant reduction frombaseline in HbA1c compared to placebo ( Table 9 ).

The mean baseline body weight was 90.5, 91.1, and 92.9 kg in the placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg groups,respectively. The mean changes from baseline in body weight at Week 24 were -2.0, -2.5, and -2.9 kg for placebo, TRULICITY0.75 mg, and TRULICITY 1.5 mg, respectively. The difference from placebo (95% CI) was -0.9 kg (-1.7, -0.1) for TRULICITY1.5 mg.

Table 9: Results at Week 24 of TRULICITY as Add-on to SGLT2ia

24-Week Primary Time Point
Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N) 140 141 142
HbA1c (%) (Mean)
Baseline 8.1 8.1 8.0
Change from baselineb -0.6 -1.2 -1.3
Difference from placebob (95% CI) - -0.7
(-0.8, -0.5)
-0.8
(-0.9, -0.6)
Percentage of patients HbA1c <7.0%c 31 59 67
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 153 162 161
Change from baselineb -6 -25 -30
Difference from placebob (95% CI) - -19
(-25, -13)
-24
(-30, -18)
Abbreviations: HbA1c = hemoglobin A1c;
SGLT2i = sodium-glucose co-transporter-2 inhibitors.
a Intent-to-treat population. At Week 24, primary efficacy was missing for 3%, 4%, and 6% of individuals treated with placebo, TRULICITY0.75 mg, and TRULICITY 1.5 mg, respectively.
b Least-squares mean adjusted for baseline value and other stratification factors. Placebo multiple imputation, using baseline and 24-week valuesfrom the placebo arm, was applied to model a washout of the treatment effect for patients missing 24-week values (HbA1c, fasting serumglucose, and body weight).
c Patients with missing HbA1c data at Week 24 were considered as non-responders.
p<0.001 for superiority of TRULICITY compared to placebo, overall type I error controlled.

Add-On To Metformin And Sulfonylurea

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52weeks, 807 patients were randomized to and received TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, orinsulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred aftera 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses ofmetformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.

Patients randomized to insulin glargine were started on a dose of 10 units once daily. Insulin glargine dose adjustments occurredtwice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weeklytitration through Week 8 of study treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24%of patients were titrated to goal at the 52-week primary endpoint. The dose of glimepiride could be reduced or discontinued afterrandomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced ordiscontinued in 28%, 32%, and 29% of patients randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine.

Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asianwere 71%, 1% and 17%, respectively; and 0% of the study population were in the US.

Treatment with TRULICITY once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combinationwith metformin and sulfonylurea ( Table 10 ). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg,respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.

Table 10: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin andSulfonylureaa

52-Week Primary Time Point
TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine
Intent-to-Treat (ITT) Population (N) 272 273 262
HbA1c (%) (Mean)
Baseline 8.1 8.2 8.1
Change from baselineb -0.8 -1.1 -0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 165 163
Change from baselineb -16 -27 -32
Difference from insulin glargineb (95% CI) 16 (9, 23) 5 (-2, 12) -
Body Weight (kg) (Mean)
Baseline 86.4 85.2 87.6
Change from baselineb -1.3 -1.9 -1.4
Difference from insulinb (95% CI) -2.8
(-3.4, -2.2)
-3.3
(-3.9, -2.7)
-
Abbreviations: HbA1c = hemoglobin A1c.
a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy aretreated as missing. At Week 52, primary efficacy was missing for 17%, 13% and 12% of individuals randomized to TRULICITY 0.75 mg,TRULICITY 1.5 mg and glargine, respectively.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included267, 263 and 259 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.

Combination Therapy With Basal Insulin, With Or Without Metformin

In this 28-week placebo-controlled, double-blind study, 300 patients were randomized to placebo or once weekly TRULICITY1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). Patients had a mean age of 60 years; mean durationof type 2 diabetes of 13 years; 58% were male; race: White, Black, and Asian were 94%, 4%, and 0.3%, respectively; and 20% ofthe study population was in the US.

The mean starting dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receivingTRULICITY 1.5 mg. At randomization, the initial insulin glargine dose in patients with HbA1c <8.0% was reduced by 20%.

At 28 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared toplacebo ( Table 11 ).

Table 11: Results at Week 28 of TRULICITY Compared to Placebo as Add-On to Basal Insulina

28-Week Primary Time Point
Placebo TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N) 150 150
HbA1c (%) (Mean)
Baseline 8.3 8.4
Change from baselineb -0.7 -1.4
Difference from placebob (95% CI) -0.7 (-0.9, -0.5)
Percentage of patients HbA1c <7.0%c 33 67
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 156 157
Change from baselineb -30 -44
Difference from placebob (95% CI) -14 (-23, -4)
Body Weight (kg) (Mean)
Baseline 92.6 93.3
Change from baselineb 0.8 -1.3
Difference from placebob (95% CI) -2.1 (-2.9, -1.4)
Abbreviations: HbA1c = hemoglobin A1c.
a Intent-to-treat population. At Week 28, primary efficacy was missing for 12% and 8% of individuals randomized to placebo and TRULICITY1.5 mg, respectively.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect tobaseline values, was used to model a wash-out of the treatment effect for subjects having missing Week 28 data.
c Patients with missing HbA1c data at Week 28 were considered as non-responders.
p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.
p≤0.005 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.

Combination Therapy With Prandial Insulin, With Or Without Metformin

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26weeks, 884 patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; duringthe initial 2 weeks of the lead-in period, patients continued their pre-study insulin regimen but could be initiated and/or up-titratedon metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization.

At randomization, patients discontinued their pre-study insulin regimen and were randomized to TRULICITY 0.75 mg once weekly,TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, withor without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine wastitrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fastingglucose goal at the 26-week primary timepoint.

Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asianwere 79%, 10% and 4%, respectively; and 33% of the study population were in the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference inobserved effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specifiednon-inferiority margin of 0.4% ( Table 12 ).

Table 12: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lisproa

26-Week Primary Time Point
TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine
Intent-to-Treat (ITT) Population (N) 293 295 296
HbA1c (%) (Mean)
Baseline 8.4 8.5 8.5
Change from baselineb -1.6 -1.6 -1.4
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 150 157 154
Change from baselineb 4 -5 -8
Difference from insulin glargineb (95% CI) 32 (24, 41) 24 (15, 32) -
Body Weight (kg) (Mean)
Baseline 91.7 91.0 90.8
Change from baselineb 0.2 -0.9 2.3
Difference from insulin glargineb (95% CI) -2.2
(-2.8, -1.5)
-3.2
(-3.8, -2.6)
-
Abbreviation: HbA1c = hemoglobin A1c
a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy aretreated as missing. At Week 26, primary efficacy was missing for 14%, 15%, and 14% of individuals randomized to TRULICITY 0.75 mg,TRULICITY 1.5 mg and glargine, respectively.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included275, 273 and 276 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.

Moderate To Severe Chronic Kidney Disease

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26weeks, a total of 576 patients with type 2 diabetes were randomized and treated to compare TRULICITY 0.75 mg and 1.5 mg withinsulin glargine (NCT01621178).

Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinuedand had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulindose for 3 weeks prior to randomization. At randomization, patients discontinued their pre-study insulin regimen and patients wererandomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all incombination with prandial insulin lispro. For patients randomized to insulin glargine, the initial insulin glargine dose was based onthe basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL.

Patients had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asianwere 69%, 16%, and 3%, respectively; and 32% of the study population were in the US. At baseline, overall mean eGFR was38 mL/min/1.73 m2 , 30% of patients had eGFR <30 mL/min/1.73 m2 , and 45% of patients had macroalbuminuria. Patients on over70 units/day of basal insulin were excluded from the study.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks from baseline. Thedifference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Mean fasting plasma glucose increased in the TRULICITY arms ( Table 13 ).

Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulinglargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 kg in the TRULICITY 0.75 mg,TRULICITY 1.5 mg, and insulin glargine arms, respectively.

Table 13: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro, inPatients with Moderate to Severe Chronic Kidney Diseasea

26-Week Primary Time Point
TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine
Intent-to-Treat Population (N) 190 192 194
HbA1c (%) (Mean)
Baseline 8.6 8.6 8.6
Change from baselineb -0.9 -1.0 -1.0
Difference from insulin glargineb (95% CI) 0.0
(-0.2, 0.3)
-0.1
(-0.3, 0.2)
Percentage of patients HbA1c <8.0% 73 75 74
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 167 161 170
Change from baselineb 6 14 -23
Difference from insulin glargineb (95% CI) 30 (16, 43) 37 (24, 50)
Abbreviation: HbA1c = hemoglobin A1c
a Intent-to-treat population (all randomized and treated subjects) was used in the analysis regardless of discontinuation of study drug or initiationof rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group.
b Least-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors.

Cardiovascular Outcomes Trial In Adults With Type 2 Diabetes Mellitus And Cardiovascular Disease Or MultipleCardiovascular Risk Factors

The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. In thisstudy, 9901 adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular riskfactors were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. The median follow-up duration was 5.4years. The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events(MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% withno lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV riskfactors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one ofthe following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary,carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at leastone of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%).Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomizedtrial population.

At baseline, demographic and disease characteristics were balanced between treatment groups. Patients had a mean age of 66 years;46% were female; race: White, Black, and Asian were 76%, 7%, and 4%, respectively.

The median baseline HbA1c was 7.2%. The mean duration of type 2 diabetes was 10.5 years and the mean BMI was 32.3 kg/m2.

At baseline, 50.5% of patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73m2), 21.6% had moderate renalimpairment (eGFR ≥30 but <60 mL/min/1.73m2), and 1.1% of patients had severe renal impairment (eGFR <30 mL/min/1.73m2)out of 9713 patients whose eGFR were available.

At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs.The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin(23.9%). At baseline, CV disease and risk factors were managed with ACE inhibitors or angiotensin receptor blockers (81.5%), betablockers (45.6%), calcium channel blockers (34.4%), diuretics (46.5%), statin therapy (66.1%), antithrombotic agents (58.7%), andaspirin (51.7%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standardof care treatment targets with respect to blood glucose, lipids, and blood pressure, and manage patients recovering from an acutecoronary syndrome or stroke event per local treatment guidelines.

For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type I error was controlled acrossmultiple tests. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatalMI, or non-fatal stroke (HR: 0.88, 95% CI 0.79, 0.99). Refer to Figure 6 and Table 14.

Vital status was available for 99.7% of subjects in the trial. A total of 1128 deaths were recorded during the REWIND trial. Amajority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups(4.4% in patients treated with TRULICITY and 5.0% in patients treated with placebo). There were 536 all-cause deaths (10.8%) inthe dulaglutide group compared to 592 deaths (12.0%) in the placebo group.

Figure 6:KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial

 KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial- Illustration

Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Study ObservationTime of 5.4 years a

Time to First Occurrence of: TRULICITY
N=4949
Placebo
N=4952
Hazard Ratio (95% CI)b
Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death (MACE)d 594 (12.0%) 663 (13.4%) 0.88
(0.79, 0.99)c
  Cardiovascular death d,e 317 (6.4%) 346 (7.0%) 0.91
(0.78, 1.06)
  Non-fatal myocardial infarction d,e 205 (4.1%) 212 (4.3%) 0.96
(0.79, 1.16)
  Non-fatal stroke d,e 135 (2.7%) 175 (3.5%) 0.76
(0.61, 0.95)
Fatal or non-fatal myocardial infarction d,e 223 (4.5%) 231 (4.7%) 0.96
(0.79, 1.15)
Fatal or non-fatal stroke d,e 158 (3.2%) 205 (4.1%) 0.76
(0.62, 0.94)
a All randomized patients.
b Cox-proportional hazards model with treatment as a factor. Type I error was controlled for the primary and secondary endpoints.
c p=0.026 for superiority (2-sided).
d Number and percentage of patients with events.
e Results for components of MACE, fatal and non-fatal stroke, and fatal and non-fatal MI are listed descriptively for supportive purposes. Nostatistical significance should be inferred since these CIs are not adjusted for multiplicity.

Medication Guide

PATIENT INFORMATION

TRULICITY®
(TRU-li-si-tee)
(dulaglutide) injection, for subcutaneous use

Read this Medication Guide before you start using TRULICITY and each time you get a refill. There may be new information. Thisinformation does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about TRULICITY?

TRULICITY may cause serious side effects, including:

  • Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck,hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rats or mice,TRULICITY and medicines that work like TRULICITY caused thyroid tumors, including thyroid cancer. It is not known ifTRULICITY will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.
  • Do not use TRULICITY if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma(MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

What is TRULICITY?

  • TRULICITY is an injectable prescription medicine that is used:
    • along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes mellitus.
    • to reduce the risk of major cardiovascular events such as death, heart attack, or stroke in adults with type 2 diabetes mellituswith known heart disease or multiple cardiovascular risk factors.
  • It is not known if TRULICITY can be used in people who have had pancreatitis.
  • TRULICITY is not for use in people with type 1 diabetes.
  • TRULICITY is not recommended for use in people with severe stomach or intestinal problems.
  • It is not known if TRULICITY is safe and effective for use in children. TRULICITY should not be used in children under 18years of age.

Do not use TRULICITY if:

  • you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have anendocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • you have had a serious allergic reaction to dulaglutide or any of the ingredients in TRULICITY. See the end of this MedicationGuide for a complete list of ingredients in TRULICITY. Symptoms of a serious allergic reaction include:
    • swelling of your face, lips, tongue or throat
    • problems breathing or swallowing
    • severe rash or itching
    • fainting or feeling dizzy
    • very rapid heartbeat

Before using TRULICITY, tell your healthcare provider about all of your medical conditions, including if you:

  • have or have had problems with your pancreas, kidneys or liver.
  • have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digestingfood.
  • have a history of diabetic retinopathy.
  • are pregnant or plan to become pregnant. It is not known if TRULICITY will harm your unborn baby. Tell your healthcareprovider if you become pregnant while using TRULICITY.
  • are breastfeeding or plan to breastfeed. It is not known if TRULICITY passes into your breast milk. You and your healthcareprovider should decide if you should breastfeed while taking TRULICITY.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins,and herbal supplements. TRULICITY may affect the way some medicines work, and some medicines may affect the wayTRULICITY works.

Before using TRULICITY, tell your healthcare provider if you are taking other medicines to treat diabetes including insulinor sulfonylureas which could increase your risk of low blood sugar. Talk to your healthcare provider about low blood sugar andhow to manage it.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use TRULICITY?

  • Read the Instructions for Use that comes with TRULICITY.
  • Use TRULICITY exactly as your healthcare provider tells you to.
  • TRULICITY is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.
  • Use TRULICITY 1 time each week on the same day each week at any time of the day.
  • You may change the day of the week as long as your last dose was given 3 or more days before.
  • If you miss a dose of TRULICITY, take the missed dose as soon as possible if there are at least 3 days (72 hours) until your nextscheduled dose. If there are less than 3 days remaining, skip the missed dose and take your next dose on the regularly scheduledday. Do not take 2 doses of TRULICITY within 3 days of each other.
  • TRULICITY may be taken with or without food.
  • Do not mix insulin and TRULICITY together in the same injection.
  • You may give an injection of TRULICITY and insulin in the same body area (such as, your stomach area), but not right next toeach other.
  • Change (rotate) your injection site with each weekly injection.Do not use the same site for each injection.
  • If you take too much TRULICITY, call your healthcare provider or go to the nearest emergency room right away.

What are the possible side effects of TRULICITY?

TRULICITY may cause serious side effects, including:

  • See “ What is the most important information I should know about TRULICITY?
  • Inflammation of your pancreas (pancreatitis). Stop using TRULICITY and call your healthcare provider right away if youhave severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain fromyour abdomen to your back.
  • Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use TRULICITY with anothermedicine that can cause low blood sugar, such as a sulfonylurea or insulin.
  • Signs and symptoms of low blood sugar may include:
    • dizziness or light-headedness
    • sweating
    • confusion or drowsiness
    • headache
    • blurred vision
    • slurred speech
    • shakiness
    • fast heartbeat
    • anxiety, irritability, or mood changes
    • hunger
    • weakness
    • feeling jittery
  • Serious allergic reactions. Stop using TRULICITY and get medical help right away if you have any symptoms of a seriousallergic reaction including:
    • swelling of your face, lips, tongue or throat
    • problems breathing or swallowing
    • severe rash or itching
    • fainting or feeling dizzy
    • very rapid heartbeat
  • Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss offluids (dehydration) which may cause kidney problems to get worse.
  • Severe stomach problems. Other medicines like TRULICITY may cause severe stomach problems. It is not known ifTRULICITY causes or worsens stomach problems.
  • Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with TRULICITY.
  • Gallbladder problems. Gallbladder problems have happened in some people who take TRULICITY. Tell your healthcareprovider right away if you get symptoms of gallbladder problems, which may include:
    • pain in your upper stomach (abdomen)
    • diarrhea
    • fever
    • yellowing of skin or eyes (jaundice)
    • clay-colored stools

The most common side effects of TRULICITY may include:

  • nausea
  • diarrhea
  • vomiting
  • stomach (abdominal) pain
  • decreased appetite

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possibleside effects of TRULICITY.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of TRULICITY.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRULICITY for acondition for which it was not prescribed. Do not give TRULICITY to other people, even if they have the same symptoms youhave. It may harm them.

This Medication Guide summarizes the most important information about TRULICITY. If you would like more information, talkwith your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRULICITY that iswritten for health professionals.

What are the ingredients in TRULICITY?

Active ingredient: dulaglutide

Inactive ingredients: citric acid anhydrous, mannitol, polysorbate 80, trisodium citrate dihydrate, in water for injection TRULICITY is a registered trademark of Eli Lilly and Company.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

INSTRUCTIONS FOR USE

TRULICITY®
(TRU-li-si-tee)
(dulaglutide)
injection, for subcutaneous use
0.75 mg/0.5 mL Single-Dose Pen
use 1 time each week (once weekly)

0.75 mg/0.5 mL Single-Dose Pen - Illustration

Information About TRULICITY Single-Dose Pen

Please read this Instructions for Use and the Medication Guide carefully and completely before using your TRULICITYSingle-Dose Pen. Talk to your healthcare provider about how to inject TRULICITY the right way.

TRULICITY Single-Dose Pen (Pen) is a disposable, prefilled medicine delivery device. Each Pen contains 1 dose ofTRULICITY (0.75 mg/0.5 mL). Each Pen should only be used 1 time.

TRULICITY is used 1 time each week. You may want to mark your calendar to remind you when to take your next dose.

Before You Get Started

Expiration Date - Illustration

Remove

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject.

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject- Illustration

Check

Check the Pen label to makesure you have the right medicineand it has not expired.

Check the Pen label to makesure you have the right medicineand it has not expired - Illustration

Inspect

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.- Illustration

Prepare

Wash your hands.

Wash your hands - Illustration

Choose Your Injection Site

Choose Your Injection Site Illustration

  • Your healthcare provider can help you choose the injectionsite that is best for you.
  • You may inject the medicine into your stomach (abdomen) orthigh.
  • Another person may give you the injection in your upper arm.
  • Change (rotate) your injection site each week. You may usethe same area of your body, but be sure to choose a differentinjection site in that area.

Parts of the Pen - Illustration

Step 1 Uncap the Pen

 Uncap the Pen- Illustration

Lock - IllustrationMake sure the Pen is locked.

  • Pull the Base Cap straight off and throw it away in yourhousehold trash.

Do not put the Base Cap back on — this could damagethe needle.

Do not touch the needle.

Step 2 Place and Unlock

Place and Unlock- Illustration

  • Place the Clear Base flat and firmly against your skin atthe injection site.

Unlock - IllustrationUnlock by turning the Lock Ring.

Step 3 Press and Hold

Press and Hold - Illustration

Warning - IllustrationContinue holding the Clear Base firmly against yourskin until you hear a second click. This happens when theneedle starts retracting in about 5-10 seconds.

  • Press and hold the green Injection Button. You will hear aloud click.
  • Remove the Pen from your skin.

You will know your injection is complete when the gray plungeris visible.

Important Information

Disposal of Pen

Storage and Handling

Commonly Asked Questions

Other Information

Where to Learn More

Disposing of Your Used Pens

Disposing of Your Used Pens - Illustration

  • Put your used Pens in a FDA-cleared sharps disposal container right awayafter use. Do not throw away (dispose of) Pens in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use ahousehold container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, withoutsharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container
  • When your sharps disposal container is almost full, you will need to followyour community guidelines for the right way to dispose of your sharpsdisposal container. There may be state or local laws about how you shouldthrow away used needles and syringes. For more information about safesharps disposal, and for specific information about sharps disposal in thestate that you live in, go to the FDA's website at:http://www.fda.gov/safesharpsdisposal.
  • Do not recycle your used sharps disposal container.

Storage and Handling

  • Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • You may store your Pen at room temperature below 86°F (30°C) for up to a total of 14 days.
  • Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
  • Storage of your Pen in the original carton is recommended. Protect your Pen from direct heat and light.
  • The Pen has glass parts. Handle it carefully. If you drop it on a hard surface, do not use it. Use a new Pen for your injection.
  • Keep your TRULICITY Pen and all medicines out of the reach of children.

Commonly Asked Questions

What if I see air bubbles in my Pen?

Air bubbles are normal.

What if I unlock the Pen and press the green Injection Button before pulling off the Base Cap?

Do not remove the Base Cap. Throw away the Pen and get a new Pen.

What if there is a drop of liquid on the tip of the needle when I remove the Base Cap?

A drop of liquid on the tip of the needle is normal.

Do I need to hold the Injection Button down until the injection is complete?

This is not necessary, but it may help you keep the Pen steady and firm against your skin.

I heard more than 2 clicks during my injection—2 louder clicks and 1 soft one. Did I get my complete injection?

Some patients may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove thePen from your skin until you hear the second louder click.

What if there is a drop of liquid or blood on my skin after my injection?

This is normal.

I am not sure if my Pen worked the right way.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible (see step 3). Alsocontact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidentalneedle stick.

Other Information

  • If you have vision problems, do not use your Pen without help from a person trained to use the TRULICITY Pen.

Where to Learn More

  • If you have any questions or problems with your TRULICITY Single-Dose Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.
  • For more information about TRULICITY Single-Dose Pen, visit our website at: www.trulicity.com.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

INSTRUCTIONS FOR USE

TRULICITY®
(TRU-li-si-tee)
(dulaglutide)
injection, for subcutaneous use
1.5 mg/0.5 mL Single-Dose Pen
use 1 time each week (once weekly)

 1.5 mg/0.5 mL Single-Dose P- Illustration

Information About TRULICITY Single-Dose Pen

Please read this Instructions for Use and the Medication Guide carefully and completely before using your TRULICITYSingle-Dose Pen. Talk to your healthcare provider about how to inject TRULICITY the right way.

  • TRULICITY Single-Dose Pen (Pen) is a disposable, prefilled medicine delivery device. Each Pen contains 1 dose ofTRULICITY (1.5 mg/0.5 mL). Each Pen should only be used 1 time.
  • TRULICITY is used 1 time each week. You may want to mark your calendar to remind you when to take your next dose.

Before You Get Started

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject- Illustration

Remove

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject.

Check the Pen label to make sure youhave the right medicine and it has not expired- Illustration

Check

Check the Pen label to make sure youhave the right medicine and it has not expired.

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it - Illustration

Inspect

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.

Wash your hands- Illustration

Prepare

Wash your hands.

Expiration Date - Illustration

Choose Your Injection Site

Choose Your Injection Site - Illustration

  • Your healthcare provider can help you choose the injectionsite that is best for you.
  • You may inject the medicine into your stomach (abdomen) orthigh.
  • Another person may give you the injection in your upper arm.
  • Change (rotate) your injection site each week. You may usethe same area of your body, but be sure to choose a differentinjection site in that area.

Parts of the Pen - Illustration

Step 1 Uncap the Pen

Uncap the Pen- Illustration

Lock - IllustrationMake sure the Pen is locked.

  • Pull the Base Cap straight off and throw it awayin your household trash.

Do not put the Base Cap back on — this coulddamage the needle.

Do not touch the needle.

Step 2 Place and Unlock

Place and Unlock - Illustration

  • Place the Clear Base flat and firmly against yourskin at the injection site.

Unlock - IllustrationUnlock by turning the Lock Ring.

Step 3 Press and Hold

Press and Hold - Illustration

  • Press and hold the green Injection Button. Youwill hear a loud click.

    Warning - IllustrationContinue holding the Clear Base firmlyagainst your skin until you hear a second click.This happens when the needle starts retracting inabout 5-10 seconds.

  • Remove the Pen from your skin.

You will know your injection is complete when the gray plunger isvisible.

Important Information

Disposal of Pen

Storage and Handling

Commonly Asked Questions

Other Information

Where to Learn More

Disposing of Your Used Pens

Disposing of Your Used Pens - Illustration

  • Put your used Pens in a FDA-cleared sharps disposal container right awayafter use. Do not throw away (dispose of) Pens in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use ahousehold container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, without sharpsbeing able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container
  • When your sharps disposal container is almost full, you will need to followyour community guidelines for the right way to dispose of your sharpsdisposal container. There may be state or local laws about how you shouldthrow away used needles and syringes. For more information about safesharps disposal, and for specific information about sharps disposal in thestate that you live in, go to the FDA's website at:http://www.fda.gov/safesharpsdisposal.
  • Do not recycle your used sharps disposal container.

Storage and Handling

  • Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • You may store your Pen at room temperature below 86°F (30°C) for up to a total of 14 days.
  • Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
  • Storage of your Pen in the original carton is recommended. Protect your Pen from direct heat and light.
  • The Pen has glass parts. Handle it carefully. If you drop it on a hard surface, do not use it. Use a new Pen for your injection.
  • Keep your TRULICITY Pen and all medicines out of the reach of children.

Commonly Asked Questions

What if I see air bubbles in my Pen?

Air bubbles are normal.

What if I unlock the Pen and press the green Injection Button before pulling off the Base Cap?

Do not remove the Base Cap. Throw away the Pen and get a new Pen.

What if there is a drop of liquid on the tip of the needle when I remove the Base Cap?

A drop of liquid on the tip of the needle is normal.

Do I need to hold the Injection Button down until the injection is complete?

This is not necessary, but it may help you keep the Pen steady and firm against your skin.

I heard more than 2 clicks during my injection—2 louder clicks and 1 soft one. Did I get my complete injection?

Some patients may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove thePen from your skin until you hear the second louder click.

What if there is a drop of liquid or blood on my skin after my injection?

This is normal.

I am not sure if my Pen worked the right way.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible (see step 3). Alsocontact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidentalneedle stick.

Other Information

  • If you have vision problems, do not use your Pen without help from a person trained to use the TRULICITY Pen.

Where to Learn More

  • If you have any questions or problems with your TRULICITY Single-Dose Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.
  • For more information about TRULICITY Single-Dose Pen, visit our website at: www.trulicity.com.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

INSTRUCTIONS FOR USE

TRULICITY®
(TRU-li-si-tee)
(dulaglutide
injection, for subcutaneous use
3 mg/0.5 mL Single-Dose Pen
use 1 time each week (once weekly)

3 mg/0.5 mL Single-Dose Pen - Illustration

Information About TRULICITY Single-Dose Pen

Please read this Instructions for Use and the Medication Guide carefully and completely before using your TRULICITYSingle-Dose Pen. Talk to your healthcare provider about how to inject TRULICITY the right way.

  • TRULICITY Single-Dose Pen (Pen) is a disposable, prefilled medicine delivery device. Each Pen contains 1 dose ofTRULICITY (3 mg/0.5 mL). Each Pen should only be used 1 time.
  • TRULICITY is used 1 time each week. You may want to mark your calendar to remind you when to take your next dose.

Before You Get Started

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject.- Illustration

Remove

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject.

Check the Pen label to makesure you have the right medicineand it has not expired. Expiration Date - Illustration

Check

Check the Pen label to makesure you have the right medicineand it has not expired. Expiration Date

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.- Illustration

Inspect

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.

Wash your hands. - Illustration

Prepare

Wash your hands.

Expiration Date- Illustration

Choose Your Injection Site

Choose Your Injection Site- Illustration

  • Your healthcare provider can help you choose the injection sitethat is best for you.
  • You may inject the medicine into your stomach (abdomen) orthigh.
  • Another person may give you the injection in your upper arm.
  • Change (rotate) your injection site each week. You may use thesame area of your body, but be sure to choose a differentinjection site in that area.

Parts of the Pen - Illustration

Step 1 Uncap the Pen

Uncap the Pen- Illustration

Lock - IllustrationMake sure the Pen is locked.

  • Pull the Base Cap straight off and throw it away inyour household trash.
  • Do not put the Base Cap back on — this coulddamage the needle.
  • Do not touch the needle.

Step 2 Place and Unlock

Place and Unlock - Illustration

  • Place the Clear Base flat and firmly against your skinat the injection site.

Unlock - IllustrationUnlock by turning the Lock Ring.

Step 3 Press and Hold

Press and Hold- Illustration

  • Press and hold the green Injection Button. You willhear a loud click.

    Warning - IllustrationContinue holding the Clear Base firmly againstyour skin until you hear a second click. Thishappens when the needle starts retracting in about 5-10 seconds.

  • Remove the Pen from your skin.

Important Information

Disposal of Pen

  • Storage and Handling
  • Commonly Asked Questions
  • Other Information
  • Where to Learn More

Disposing of Your Used Pens

Disposing of Your Used Pens- Illustration

  • Put your used Pens in a FDA-cleared sharps disposal container rightaway after use. Do not throw away (dispose of) Pens in yourhousehold trash.
  • If you do not have a FDA-cleared sharps disposal container, you mayuse a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, withoutsharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
  • When your sharps disposal container is almost full, you will need tofollow your community guidelines for the right way to dispose of yoursharps disposal container. There may be state or local laws about howyou should throw away used needles and syringes. For moreinformation about safe sharps disposal, and for specific informationabout sharps disposal in the state that you live in, go to the FDA'swebsite at: http://www.fda.gov/safesharpsdisposal.
  • Do not recycle your used sharps disposal container.

Storage and Handling

  • Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • You may store your Pen at room temperature below 86°F (30°C) for a total of 14 days.
  • Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
  • Storage of your Pen in the original carton is recommended. Protect your Pen from direct heat and light. The Pen has glass parts. Handle it carefully. If you drop it on a hard surface, do not use it. Use a new Pen for your injection.
  • Keep your TRULICITY Pen and all medicines out of the reach of children.

Commonly Asked Questions

What if I see air bubbles in my Pen?

Air bubbles are normal.

What if I unlock the Pen and press the green Injection Button before pulling off the Base Cap?

Do not remove the Base Cap. Throw away the Pen and get a new Pen.

What if there is a drop of liquid on the tip of the needle when I remove the Base Cap?

A drop of liquid on the tip of the needle is normal.

Do I need to hold the Injection Button down until the injection is complete?

This is not necessary, but it may help you keep the Pen steady and firm against your skin.

I heard more than 2 clicks during my injection—2 louder clicks and 1 soft one. Did I get my complete injection?

Some people may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove thePen from your skin until you hear the second louder click.

What if there is a drop of liquid or blood on my skin after my injection?

This is normal.

I am not sure if my Pen worked the right way.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible (see step 3). Alsocontact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidentalneedle stick.

Other Information

  • If you have vision problems, do not use your Pen without help from a person trained to use the TRULICITY Pen.

Where to Learn More

  • If you have any questions or problems with your TRULICITY Single-Dose Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.
  • For more information about TRULICITY Single-Dose Pen, visit our website at: www.trulicity.com.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

INSTRUCTIONS FOR USE

TRULICITY®
(TRU-li-si-tee)
(dulaglutide)
injection, for subcutaneous use
4.5 mg/0.5 mL Single-Dose Pen
use 1 time each week (once weekly)

4.5 mg/0.5 mL Single-Dose Pen- Illustration
4.5 mg/0.5 mL Single-Dose Pen- Illustration

Information About TRULICITY Single-Dose Pen

Please read this Instructions for Use and the Medication Guide carefully and completely before using your TRULICITYSingle-Dose Pen. Talk to your healthcare provider about how to inject TRULICITY the right way.

  • TRULICITY Single-Dose Pen (Pen) is a disposable, prefilled medicine delivery device. Each Pen contains 1 dose ofTRULICITY (4.5 mg/0.5 mL). Each Pen should only be used 1 time.
  • TRULICITY is used 1 time each week. You may want to mark your calendar to remind you when to take your next dose.

Before You Get Started

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject. - Illustration

Remove

Remove the Pen from therefrigerator. Leave the Base Cap on until youare ready to inject.

Check the Pen label to makesure you have the right medicineand it has not expired. Expiration Date- Illustration

Check

Check the Pen label to makesure you have the right medicineand it has not expired. Expiration Date

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it - Illustration

Inspect

Check the Pen to make sure thatit is not damaged and inspect themedicine to make sure it is notcloudy, discolored or hasparticles in it.

Wash your hands- Illustration

Prepare

Wash your hands.

Expiration Date - Illustration

Choose Your Injection Site

Choose Your Injection Site - Illustration

  • Your healthcare provider can help you choose the injection sitethat is best for you.
  • You may inject the medicine into your stomach (abdomen) orthigh.
  • Another person may give you the injection in your upper arm.
  • Change (rotate) your injection site each week. You may use thesame area of your body, but be sure to choose a differentinjection site in that area.

Parts of the Pen - Illustration

Step 1 Uncap the Pen

Uncap the Pen- Illustration

Lock - IllustrationMake sure the Pen is locked.

Do not touch the needle.

  • Pull the Base Cap straight off and throw it away inyour household trash.

    Do not put the Base Cap back on — this coulddamage the needle.

Step 2 Place and Unlock

Place and Unlock - Illustration

  • Place the Clear Base flat and firmly against yourskin at the injection site.

Unlock - IllustrationUnlock by turning the Lock Ring.

Step 3 Press and Hold

Press and Hold - Illustration

  • Press and hold the green Injection Button. Youwill hear a loud click.

    Warning - IllustrationContinue holding the Clear Base firmlyagainst your skin until you hear a second click.This happens when the needle starts retracting inabout 5-10 seconds.

  • Remove the Pen from your skin.

Important Information

  • Disposal of Pen
  • Storage and Handling
  • Commonly Asked Questions
  • Other Information
  • Where to Learn More

Disposing of Your Used Pens

Disposing of Your Used Pens - Illustration

  • Put your used Pens in a FDA-cleared sharps disposal container rightaway after use. Do not throw away (dispose of) Pens in yourhousehold trash.
  • If you do not have a FDA-cleared sharps disposal container, you mayuse a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, withoutsharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
  • When your sharps disposal container is almost full, you will need tofollow your community guidelines for the right way to dispose of yoursharps disposal container. There may be state or local laws about howyou should throw away used needles and syringes. For moreinformation about safe sharps disposal, and for specific informationabout sharps disposal in the state that you live in, go to the FDA'swebsite at: http://www.fda.gov/safesharpsdisposal.
  • Do not recycle your used sharps disposal container.

Storage and Handling

  • Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • You may store your Pen at room temperature below 86°F (30°C) for a total of 14 days.
  • Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
  • Storage of your Pen in the original carton is recommended. Protect your Pen from direct heat and light.
  • The Pen has glass parts. Handle it carefully. If you drop it on a hard surface, do not use it. Use a new Pen for your injection.
  • Keep your TRULICITY Pen and all medicines out of the reach of children.

Commonly Asked Questions

What if I see air bubbles in my Pen?

Air bubbles are normal.

What if I unlock the Pen and press the green Injection Button before pulling off the Base Cap?

Do not remove the Base Cap. Throw away the Pen and get a new Pen.

What if there is a drop of liquid on the tip of the needle when I remove the Base Cap?

A drop of liquid on the tip of the needle is normal.

Do I need to hold the Injection Button down until the injection is complete?

This is not necessary, but it may help you keep the Pen steady and firm against your skin.

I heard more than 2 clicks during my injection—2 louder clicks and 1 soft one. Did I get my complete injection?

Some people may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove thePen from your skin until you hear the second louder click.

What if there is a drop of liquid or blood on my skin after my injection?

This is normal.

I am not sure if my Pen worked the right way.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible (see step 3). Alsocontact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidentalneedle stick.

Other Information

  • If you have vision problems, do not use your Pen without help from a person trained to use the TRULICITY Pen.

Where to Learn More

  • If you have any questions or problems with your TRULICITY Single-Dose Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.
  • For more information about TRULICITY Single-Dose Pen, visit our website at: www.trulicity.com.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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