TRULICITY

Dulaglutide is a human glucagon-like peptide-1 (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 (Chinese hamster ovary) culture.

GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1.

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 (dulaglutide) injection is a clear, colorless, sterile, preservative-free solution for subcutaneous use.

Each single-dose pen contains a 0.5 mL solution of 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg of dulaglutide and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg for 0.75 mg and 1.5 mg; 0.125 mg for 3 mg and 4.5 mg), and trisodium citrate dihydrate (1.37 mg), in water for injection.

Type two diabetes treatment.

Medically supervised use: date of pancreatic infection, stomach or intestinal disorder, visible infectious retrograde disease, liver or kidney diseases, during pregnancy or breastfeeding.

TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1.

Dulaglutide activates the

GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl 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. 12.2 Pharmacodynamics TRULICITY lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus.

The reduction in fasting and postprandial glucose can be observed after a single dose.

In a clinical pharmacology study in patients with type 2 diabetes mellitus, treatment with once weekly TRULICITY resulted in a reduction 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 mg dose.

• and Second-Phase Insulin Secretion Both first.

• and second-phase insulin secretion were increased in patients with type 2 diabetes treated with TRULICITY compared with placebo.

TRULICITY stimulates glucose-dependent insulin secretion and reduces glucagon secretion.

Treatment with

TRULICITY 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a monotherapy trial.

In the same trial, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with TRULICITY 0.75 mg and 1.5 mg, respectively.

Dulaglutide causes a delay of gastric emptying.

The delay in gastric emptying is dose-dependent but is attenuated with adequate dose escalation to higher doses of TRULICITY.

The delay is largest after the first dose and diminishes with subsequent doses.

Electrophysiology (QTc) The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study.

Dulaglutide did not produce

QTc prolongation at doses of and 7 mg. The maximum recommended dose is 4.5 mg once weekly. 12.3 Pharmacokinetics The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus.

Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady state ranges from to 72 hours, with a median of 48 hours.

After reaching steady state, the accumulation ratio was approximately 1.56.

Steady-state plasma dulaglutide concentrations were achieved between and 4 weeks following once weekly administration.

Site of subcutaneous administration (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 mg doses was 65% and 47%, respectively.

Absolute subcutaneous bioavailability for 3 mg and 4.5 mg doses were estimated to be similar to 1.5 mg although this has not been specifically studied.

Dulaglutide concentrations increased approximately proportional to dose 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 peripheral volume of distribution was 5.98 L. Elimination The apparent population mean clearance of dulaglutide was 0.142 L/h.

The elimination half-life of dulaglutide was approximately 5 days.

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

The intrinsic factors of age (≥ 65 years), sex, race, ethnicity, body weight, or renal or hepatic impairment did not have a clinically relevant effect on the PK of dulaglutide as shown in Figure 1.

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

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 respective clinical pharmacology studies.

The weight values shown in the plot (70 and 120 kg) are the 10 th and 90 th percentiles of weight in the PK population.

Figure 1: Impact of intrinsic factors on dulaglutide pharmacokinetics.

Figure 1 Pediatric Patients A population pharmacokinetic analysis was conducted for dulaglutide 0.75 mg and 1.5 mg using data from 128 pediatric patients 10 years of age and older with type 2 diabetes mellitus.

AUC in pediatric patients was approximately 37% lower than that in adult patients.

However, this difference was not determined to be clinically meaningful.

Dulaglutide systemic exposure was increased by and 12% for mild, moderate, severe, and ESRD renal impairment sub-groups, respectively, compared to subjects with normal renal function.

The corresponding values for increase in

C max were and 11%, respectively ( Figure 1 ).

Additionally, in a 52 week clinical trial in patients with type 2 diabetes mellitus and moderate to severe renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies.

Dulaglutide systemic exposure decreased by and 21% for mild, moderate and severe hepatic impairment groups, respectively, compared to subjects with normal hepatic function, and C max was decreased by a similar magnitude ( Figure 1 ) .

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-administered medications.

In clinical pharmacology studies, dulaglutide at a dose of 1.5 mg did not affect the absorption of the tested orally administered medications to any clinically relevant degree.

The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY.

PK measures indicating the magnitude of these interactions are presented in Figure 2.

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

Reference group is co-administered medication given alone.

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

Figure 2 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 mg sitagliptin caused an increase in dulaglutide AUC and C max of approximately 38% and 27%, which is not considered clinically relevant. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies.

In glycemic control trials in adults with type 2 diabetes mellitus (monotherapy and combination therapy) , during a treatment period ranging from to 104 weeks, 64/3,907 (1.6%) of TRULICITY-treated patients developed anti-dulaglutide antibodies (referred to as anti-drug-antibodies (ADA)).

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

There was no identified clinically significant effect of ADA on pharmacokinetics, pharmacodynamics, safety, or effectiveness of TRULICITY over the to 104 week treatment duration in the trials in adults with type 2 diabetes mellitus.

During the 26-week controlled period of the glycemic control trial in pediatric patients 10 years of age or older with type 2 diabetes mellitus, 4/101 (4%) of TRULICITY-treated pediatric patients developed ADA.

Of the 4 pediatric patients that developed ADA, 1 patient (1% of the overall population) developed dulaglutide-neutralizing antibodies and 3 patients (3% of the overall population) developed antibodies against native GLP-1.

During the 52-week postbaseline period of the same trial (through safety follow-up), 6/103 (6%) of TRULICITY-treated patients developed ADA.

Of the 6 patients that developed ADA, 1 patient (1% of the overall population) developed dulaglutide-neutralizing antibodies and 4 patients (4% of the overall population) developed antibodies against native GLP-1.

Because of the low occurrence of

ADA, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of TRULICITY is unknown in pediatric patients.

Dolgletaide is anti-peptide 1's, human glycagon increases glucose-based insulin and slows the stomach drain, helping to control blood sugar levels.

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The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors Pancreatitis Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Hypersensitivity Reactions Acute Kidney Injury Severe Gastrointestinal Disease Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy Acute Gallbladder Disease Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks.

The mean age of patients was 56 years, 1% were 75 years or older and 53% were male.

The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity.

At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy.

Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%.

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

Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise.

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

Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%).

A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%).

Investigators graded the severity of

GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively.

The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than placebo -treated patients (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).

Adult Dose Ranging Trial for

TRULICITY 3 mg and 4.5 mg Doses Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 adult patients with type 2 diabetes mellitus treated with TRULICITY 1.5 mg, 3 mg, or 4.5 mg subcutaneously once weekly as an add-on to metformin.

The adverse reaction profile is consistent with previous clinical trials in adults.

Table 2: Adverse Reactions That Occurred in ≥5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks a a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.

TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) % Nausea 13.4 15.6 16.4 Diarrhea 7.0 11.4 10.7 Vomiting 5.6 8.3 9.3 Dyspepsia 2.8 5.0 2.6 Other Adverse Reactions in Adults Hypoglycemia Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies in adult patients with type 2 diabetes mellitus: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Add-on to Metformin (26 weeks) N=177 N=302 N=304 Hypoglycemia with a glucose level <54 mg/dL 0 0.3 0.7 Severe hypoglycemia 0 0 0 Add-on to Metformin + Pioglitazone (26 weeks) N=141 N=280 N=279 Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0 Severe hypoglycemia 0 0 0 Add-on to Glimepiride (24 weeks) N=60.

• N=239 Hypoglycemia with a glucose level <54 mg/dL 0.

• 3.3 Severe hypoglycemia 0.

• 0 In Combination with Insulin Glargine ± Metformin (28 weeks) N=150.

• N=150 Hypoglycemia with a glucose level <54 mg/dL 9.3.

• 14.7 Severe hypoglycemia 0.

• 0.7 Add-on to SGLT2i ± Metformin (24 weeks) N=140 N=141 N=142 Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7 0.7 Severe hypoglycemia 0 0.7 0 Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues.

In a 78-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea.

Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea.

In a 52-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin.

Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin.

Refer to

Table for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine.

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

In a cardiovascular outcomes trial in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy.

Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively.

Heart Rate Increase and Tachycardia-Related Adverse Reactions In adult patients, TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm).

Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY.

Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of adult patients on TRULICITY in clinical studies.

In the placebo-controlled studies in adults, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients.

PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated adult patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients.

The adverse reaction of first-degree

AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively).

On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Amylase and Lipase Increase Adult patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%.

Adverse Reactions in the Clinical Trial of Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus TRULICITY was administered to 150 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 41.3 weeks.

The mean age was 14.5 years and 71% of patients were female.

Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race.

Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity.

At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2.

The safety profile in pediatric patients treated with TRULICITY 0.75 mg and 1.5 mg subcutaneously once-weekly was consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of injection site reactions.

In pediatric patients, the incidence of injection site reactions was 3.9% (2 patients) in the TRULICITY 0.75 mg group, 3.8% (2 patients) in the TRULICITY 1.5 mg group, and 2.0% (1 patient) in the placebo group. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of TRULICITY.

Because these events are reported voluntarily from a population of uncertain size, it is ge.

Overdoses have been reported in clinical studies.

Effects associated with these overdoses were primarily mild or moderate gastrointestinal 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.

is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) .

Serious hypersensitivity reaction to dulaglutide or to any of the product components.

Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY.

Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components.

Recommended starting dosage is 0.75 mg injected subcutaneously once weekly.

Increase dosage to 1.5 mg once weekly for additional glycemic control.

If additional glycemic control is needed, increase dosage in 1.5 mg increments after at least 4 weeks on the current dosage.

Maximum recommended dosage is 4.5 mg injected subcutaneously once weekly.

If additional glycemic control is needed, increase dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage.

If a dose is missed, administer the missed dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose.

Administer once weekly at any time of day with or without food.

Inject subcutaneously in the abdomen, thigh, or upper arm. 2.1 Adult Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly.

Increase the dosage to 1.5 mg once weekly for additional glycemic control.

If additional glycemic control is needed, increase the dosage in 1.5 mg increments after at least 4 weeks on the current dosage.

The maximum recommended dosage is 4.5 mg injected subcutaneously once weekly. 2.2 Pediatric Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly.

If additional glycemic control is needed, increase the dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage. 2.3 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to administer the dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose.

If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the 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 the new day of administration. 2.4 Important Administration Instructions Prior to initiation, train patients and caregivers on proper injection technique.

TRULICITY once weekly, any time of day, with or without food.

TRULICITY subcutaneously in the abdomen, thigh, or upper arm.

Rotate injection sites with each dose.

TRULICITY visually before use.

It should appear clear and colorless.

Do not use

TRULICITY if particulate matter or coloration is seen.

When using

TRULICITY with insulin, administer as separate injections and never mix.

It is acceptable to inject

TRULICITY and insulin in the same body region, but the injections should not be adjacent to each other.

50090-6571 NDC: 50090-6571-0.5 mL in a SYRINGE / 4 in a CARTON.

Risk Summary Limited data with

TRULICITY in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.

There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy.

Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy.

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 fetal abnormalities 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-times human exposure at the MRHD.

Adverse embryo/fetal effects in animals occurred in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >10%.

The estimated background risk of miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

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, and macrosomia-related morbidity.

Pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide every 3 days during organogenesis had systemic exposures 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 decreased maternal 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, systemic exposures in pregnant rabbits were 0.5-, 2-, and 5-times human exposure at the MRHD, based on plasma AUC comparison.

Fetal visceral malformation of lung lobular agenesis and skeletal malformations of the vertebrae and/or ribs were observed in conjunction with 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 F 0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, systemic exposures in pregnant rats were 1-, 2-, and 7-times human exposure at the MRHD, based on plasma AUC comparison.

F 1 pups from F 0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through postnatal day for males and postnatal day for females.

F 1 offspring from F 0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputial separation.

Females had decreased startle response.

These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment.

F 1 female offspring of the F 0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during of 2 trials in the memory evaluation portion of the Biel water maze.

These findings occurred in conjunction with decreased F 0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg. The human relevance of these memory deficits in the F 1 female rats is not known.

The safety and effectiveness of

TRULICITY as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years of age and older with type 2 diabetes mellitus have been established.

Use of

TRULICITY for this indication is supported by a 26-week, multicenter, randomized, double-blind, parallel arm, placebo-controlled trial in 154 pediatric patients 10 years of age and older with type 2 diabetes mellitus.

TRULICITY-treated pediatric patients reported a higher incidence of injection site-related reactions compared to TRULICITY-treated adults.

TRULICITY have not been established in pediatric patients less than 10 years of age.

In the adult glycemic control trials, 620 (19%) of TRULICITY-treated patients were 65 years of age or older and 65 (2%) of TRULICITY-treated patients were 75 years of age or older at baseline.

In the

TRULICITY 1.5 mg treatment arm of the REWIND trial (cardiovascular outcomes trial in adults with type 2 diabetes mellitus and cardiovascular disease or multiple cardiovascular risk factors) , 2,619 (53%) patients were 65 years of age or older, and 484 (10%) patients were 75 years of age or older at baseline.

No overall differences in safety or effectiveness for TRULICITY have been observed between patients 65 years of age and older and younger adult patients.