Dulaglutide

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# Black Box Warning

# Overview
Dulaglutide is a glucagon-like peptide-1 receptor agonist that is FDA approved for the treatment of glycemic control in adults with type 2 diabetes mellitus.. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include (abdominal pain, decrease in appetite, diarrhea, nausea, vomiting.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- DulaglutideTM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Dulaglutide is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans.
- Prescribe dulaglutide only to patients for whom the potential benefits outweigh the potential risk .
- Dulaglutide has not been studied in patients with a history of pancreatitis . Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. dulaglutide is not a substitute for insulin.
- Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of dulaglutide is not recommended in patients with pre-existing severe gastrointestinal disease
- The concurrent use of dulaglutide and basal insulin has not been studied.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Dulaglutide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dulaglutide in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Dulaglutide in pediatric patients.

# Contraindications
- Dulaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) .
- Dulaglutide is contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components

# Warnings
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  Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether dulaglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.
- One case of MTC was reported in a patient treated with dulaglutide. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
- Dulaglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of dulaglutide and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
- Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with dulaglutide. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
- In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis related adverse reactions were reported in patients exposed to dulaglutide versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analyses of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to dulaglutide (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).
- After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted. dulaglutide has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting .
- Systemic hypersensitivity reactions were observed in patients receiving dulaglutide in clinical trials. If a hypersensitivity reaction occurs, the patient should discontinue dulaglutide and promptly seek medical advice.
- In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients 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 escalating doses of dulaglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
- Use of dulaglutide may be associated with gastrointestinal adverse reactions, sometimes severe . Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with dulaglutide or any other antidiabetic drug.

# Adverse Reactions

## Clinical Trials Experience
- 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
- Renal impairment
- Severe Gastrointestinal Disease
- 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.
- The data in TABLE 1 are derived from the placebo-controlled trials .
- These data reflect exposure of 1670 patients to dulaglutide and a mean duration of exposure to dulaglutide of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies 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 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR 60mL/min/1.73 m2) in 96.0% of the pooled study populations.
- Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of dulaglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on dulaglutide than on placebo, and occurred in at least 5% of patients treated with dulaglutide.
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 receiving dulaglutide than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving dulaglutide 0.75 mg (1.3%) and dulaglutide 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 dulaglutide 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.
- In addition to the reactions in TABLE 1, the following adverse reactions were reported more frequently in dulaglutide-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%).
- The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of dulaglutide as monotherapy and add-on therapy to oral medications or insulin.In this pool, a total of 3342 patients with type 2 diabetes were treated with dulaglutide for a mean duration of 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR 60 ml/min/1.73 m2) in 95.7% of the dulaglutide population.
- In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in TABLE 1.
- TABLE 2 summarizes the incidence of documented symptomatic (70 mg/dL glucose threshold) and severe hypoglycemia in the placebo-controlled clinical studies.
- Hypoglycemia was more frequent when dulaglutide was used in combination with a sulfonylurea or insulin . Documented symptomatic hypoglycemia occurred in 39% and 40% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin.
- Dulaglutide 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have not been established
- Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to dulaglutide. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 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, dulaglutide 0.75 mg and dulaglutide 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 patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) dulaglutide treated patients developed anti-drug antibodies (ADAs) to the active ingredient in dulaglutide (i.e., dulaglutide).
- Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-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 observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.
- Systemic hypersensitivity adverse reactions sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on dulaglutide in the four Phase 2 and five Phase 3 studies.
- In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of dulaglutide-treated patients and in 0.0% of placebo-treated patients.
- A mean increase from baseline in PR interval of 2-3 milliseconds was observed in dulaglutide-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with dulaglutide than placebo (0.9%, 1.7% and 2.3% for placebo, dulaglutide 0.75 mg and dulaglutide 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, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Patients exposed to dulaglutide 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%.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dulaglutide in the drug label.

# Drug Interactions
- Dulaglutide slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with dulaglutide. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with dulaglutide. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested, orally administered medications to a clinically relevant degree

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of dulaglutide in pregnant women. The risk of birth defects, loss, or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes to maintain good metabolic control before conception and throughout pregnancy.
- dulaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.
- In pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide on Gestation Days 6, 9, 12, and 15 (organogenesis), 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, a systemic exposure 14-fold the MRHD based on AUC. Irregular skeletal ossifications and increases in post implantation loss also were observed at 4.89 mg/kg, a systemic exposure 44-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide on Gestation Days 7, 10, 13, 16, and 19 (organogenesis), fetal 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, a systemic exposure 13-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- 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 from implantation through lactation, F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through post-natal day 63 for males and post-natal day 84 for females. F1 offspring from F0 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. 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 to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg, a systemic exposure 16-fold the MRHD based on AUC. *The human relevance of these memory deficits in the F1 female rats is not known.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dulaglutide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Dulaglutide during labor and delivery.

### Nursing Mothers
- It is not known whether dulaglutide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for clinical adverse reactions from dulaglutide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue dulaglutide, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness of dulaglutide have not been established in pediatric patients. dulaglutide is not recommended for use in pediatric patients younger than 18 years.

### Geriatic Use
- In the pool of placebo- and active-controlled trials , 620 (18.6%) dulaglutide-treated patients were 65 years of age and over and 65 dulaglutide-treated patients (1.9%) patients were 75 years of age and over. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

### Gender
There is no FDA guidance on the use of Dulaglutide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Dulaglutide with respect to specific racial populations.

### Renal Impairment
- In the four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) dulaglutide-treated patients had mild renal impairment (eGFR 60 but <90 mL/min/1.73 m2), 171 (4.3%) dulaglutide-treated patients had moderate renal impairment (eGFR 30 but <60 mL/min/1.73 m2) and no dulaglutide-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. In a clinical pharmacology study in subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed .
- There is limited clinical experience in patients with severe renal impairment or ESRD. dulaglutide should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored

### Hepatic Impairment
- There is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Therefore, dulaglutide should be used with caution in these patient populations.
- In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dulaglutide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Dulaglutide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Subcutaneous

### Monitoring
There is limited information regarding Monitoring of Dulaglutide in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Dulaglutide in the drug label.

# Overdosage
- 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.

# Pharmacology

## Mechanism of Action
- Dulaglutide contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). 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.

## Structure
- 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.
Dulaglutide is a clear, colorless, sterile solution. Each 0.5 mL of dulaglutide solution contains 0.75 mg or 1.5 mg of dulaglutide. Each single-dose pen or prefilled syringe 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.

## Pharmacodynamics
- Dulaglutide 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.
- Fasting and Postprandial Glucose
- In a clinical pharmacology study in adults with type 2 diabetes mellitus, treatment with once weekly dulaglutide 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.
- First- and Second-Phase Insulin Secretion
- Both first-and second-phase insulin secretion were increased in patients with type 2 diabetes treated with dulaglutide compared with placebo.
- Insulin and Glucagon Secretion
- Dulaglutide stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a Phase 3 monotherapy study. In the same study, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with dulaglutide 0.75 mg and 1.5 mg, respectively.
- Gastric Motility
- Dulaglutide causes a delay of gastric emptying. 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 QTc prolongation at supratherapeutic doses of 4 and 7 mg.

## 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 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady state, the mean peak plasma concentration (Cmax) and total systemic exposure (AUC) of dulaglutide were 114 ng/mL (range 56 to 231 ng/mL) and 14,000 ng*h/mL (range 6940 to 26,000 ng*h/mL), respectively; accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 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.
- Distribution 
- The mean volumes of distribution after subcutaneous administration of dulaglutide 0.75 mg and 1.5 mg to steady state were approximately 19.2 L (range 14.3 to 26.4 L) and 17.4 L (range 9.3 to 33 L), respectively.
- Metabolism 
- Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.
- Elimination 
- The mean apparent clearance at steady state of dulaglutide is approximately 0.111 L/h for the 0.75 mg dose, and 0.107 L/h for the 1.5 mg dose. The elimination half-life of dulaglutide for both doses is approximately 5 days.
- Specific Populations
- No dose adjustment of dulaglutide is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment. The effects of intrinsic factors on the PK of dulaglutide are shown in Figure1
- Renal 
- Dulaglutide systemic exposure was increased by 20, 28, 14 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 Cmax were 13, 23, 20 and 11%, respectively (FIGURE 1).
- 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).
- Drug Interactions
- The potential effect of co-administered medications on the PK of dulaglutide 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 did not affect the absorption of the tested orally administered medications to any clinically relevant degree.
- Pharmacokinetic (PK) measures indicating the magnitude of these interactions are presented in FIGURE 2. No dose adjustment is recommended for any of the evaluated co-administered medications
- Potential for Co-administered Drugs to Influence the Pharmacokinetics of Dulaglutide
- In a clinical pharmacology study, the coadministration of a single dose of dulaglutide (1.5 mg) with steady-state sitagliptin (100 mg) caused an increase in dulaglutide AUC and Cmax of approximately 38% and 27%, which is not considered clinically relevant.

## Nonclinical Toxicology
- A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05, 0.5, 1.5, and 5.0 mg/kg (0.5-, 7-, 20-, and 58-fold the MRHD of 1.5 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 (adenomas and/or carcinomas) compared to controls, at 7-fold the MRHD based on AUC. A statistically significant increase in C-cell adenomas was observed in rats receiving dulaglutide at 0.5 mg/kg). Numerical increases in thyroid C-cell carcinomas occurred at 5 mg/kg (58 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statistical significance.
- A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1.0, and 3.0 mg/kg administered by subcutaneous injection twice weekly. *Dulaglutide did not produce increased incidences of thyroid C-cell hyperplasia 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 .
- In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on sperm morphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (130-fold the MRHD based on AUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean number of corpora lutea, implantation sites, and viable embryos were observed at 4.9 mg/kg (32-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.
- Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5.0 mg/kg/twice weekly of dulaglutide (3-, 8-, and 30-fold the MRHD based on AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals included increased interlobular ductal epithelium without active ductal cell proliferation (0.5 mg/kg), increased acinar atrophy with/without inflammation (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 500-fold the MRHD based on AUC) demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutide treatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in total amylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.
- Add-on to Metformin
- In this 104-week placebo-controlled, double-blind study (52-week primary endpoint), 972 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo 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 glycemic stabilization 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, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62%, 39% for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, dulaglutide 0.75 mg, dulaglutide 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, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52), all in combination with metformin (TABLE 4 and FIGURE 4).
- Add-on to Metformin and Thiazolidinedione
- In this 52-week placebo-controlled study (26-week primary endpoint), 976 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either dulaglutide 0.75 mg once weekly or dulaglutide 1.5 mg once weekly to maintain study blind. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the 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 4 weeks 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 the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks (TABLE 5 and FIGURE 4). Over the 52-week study period, the percentage of patients who required glycemic rescue was 8.9% in the dulaglutide 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the dulaglutide 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group.
- Add-on to Metformin and Sulfonylurea
- In this 78-week (52-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 807 patients were randomized to dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin 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 U once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration 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 after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to dulaglutide 0.75 mg, dulaglutide 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 Asian were 71%, 1% and 17%, respectively; and 0% of the study population were in the US.
- Treatment with dulaglutide once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea (TABLE 6). The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.
- Add-on to Prandial Insulin, with or without Metformin
- In this 52-week (26-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 884 patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-study insulin regimen but could be initiated and/or up-titrated on 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 dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose 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 Asian were 79%, 10% and 4%, respectively; and 33% of the study population were in the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.

# Clinical Studies
There is limited information regarding Clinical Studies of Dulaglutide in the drug label.

# How Supplied
- Each dulaglutide single-dose pen or prefilled syringe 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)
- Carton of 4 Prefilled Syringes
- 0.75 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1431-80)
- 1.5 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1432-80)

## Storage
- Store dulaglutide in the refrigerator at 36F to 46F (2C to 8C). Do not use dulaglutide beyond the expiration date.
- If needed, each single-dose pen or prefilled syringe can be kept at room temperature, not to exceed 86F (30C) for a total of 14 days.
- Do not freeze dulaglutide. Do not use dulaglutide if it has been frozen.
- Dulaglutide must be protected from light. Storage of dulaglutide in the original carton is recommended until time of administration.
- Discard the dulaglutide single-dose pen or prefilled syringe after use in a puncture-resistant container.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Inform patients that dulaglutide causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician .
- Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.
- Instruct patients to discontinue dulaglutide promptly, and to contact their physician, if persistent severe abdominal pain occurs .
- The risk of hypoglycemia may be increased when dulaglutide is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating dulaglutide therapy, particularly when concomitantly administered with a sulfonylurea or insulin
- Patients treated with dulaglutide should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion, Inform *patients treated with dulaglutide of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs.
- Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking dulaglutide and seek medical advice promptly.
- Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant.
- Prior to initiation of dulaglutide, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations.
- Inform patients of the potential risks and benefits of dulaglutide and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly.
- Each weekly dose of dulaglutide can be administered at any time of day, with or without food. The day of once weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. *Thereafter, patients can resume their usual once weekly dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume dulaglutide with the next regularly scheduled dose.
- Advise patients treated with dulaglutide of the potential risk of gastrointestinal side effects
- Instruct patients to read the Medication Guide and the Instructions for Use before starting dulaglutide therapy and review them each time the prescription is refilled. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating long-term glycemic control.

# Precautions with Alcohol
- Alcohol-Dulaglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Trulicity

# Look-Alike Drug Names
There is limited information regarding Dulaglutide Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price