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Dulaglutide

Class: Incretin Mimetics
Chemical Name: 7-37-Glucagon-like peptide I [8-glycine,22-glutamic acid,36-glycine] (synthetic human) fusion protein with peptide (synthetic 16-amino acid linker) fusion protein with immunoglobulin G4 (synthetic human Fc fragment), dimer
Molecular Formula: C2646H4044N704O836S18
CAS Number: 923950-08-7
Brands: Trulicity

Warning(s)

  • Risk of Thyroid C-Cell Tumors
  • Dulaglutide causes dose- and treatment duration-dependent thyroid C-cell tumors in male and female rats.1 11

  • Unknown whether dulaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as relevance to humans could not be ruled out by clinical or nonclinical studies.1 11

  • Contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).1

REMS:

FDA approved a REMS for dulaglutide to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of dulaglutide and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antidiabetic agent; long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic).1 2 3 4 17

Uses for Dulaglutide

Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1

Used alone or as add-on therapy with metformin, the combination of metformin and a sulfonylurea, the combination of metformin and a thiazolidinedione, and prandial insulin with or without metformin.1 2 3 4 5 6 7

Not recommended as first-line therapy for patients inadequately controlled on diet and exercise alone because of potential thyroid C-cell tumor risk and risk of acute pancreatitis.1 13 (See Risk of Thyroid C-Cell Tumors under Cautions.)

Safety and efficacy not established in patients with a history of pancreatitis; consider other antidiabetic agents.1 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Not recommended for use in patients with severe GI disease, including severe gastroparesis.1

Safety and efficacy in combination with basal insulin not established.1

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

Dulaglutide Dosage and Administration

General

  • Perform regular monitoring (e.g., blood glucose determinations, HbA1c) to determine therapeutic response.1

Administration

Administer by sub-Q injection using a prefilled injection pen.1 11

If a dose is missed, administer it as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose, followed by resumption of the regular weekly schedule.1 If less than 3 days remain before the next scheduled dose, skip the missed dose and resume the regular schedule with the next scheduled dose.1

Administer dulaglutide and insulin as separate injections in patients receiving both medications; do not mix insulin and dulaglutide.1 11 May inject dulaglutide and insulin in the same body regions; do not administer injections adjacent to each other.1 11

Sub-Q Administration

Administer by sub-Q injection once weekly, on the same day each week, at any time of day without regard to meals.1 If changing the day of weekly administration, allow at least 3 days to elapse between doses.1

Administer into abdomen, thigh, or upper arm; rotate sites.1 11 12

Dosage

Adults

Diabetes Mellitus
Sub-Q

Initially, 0.75 mg once weekly.1 May increase dosage to 1.5 mg once weekly if glycemic response is inadequate.1

Special Populations

No special population dosage recommendations.1

Use caution when initiating dulaglutide or escalating dosage in patients with renal impairment.1 (See Renal Effects under Cautions.)

Cautions for Dulaglutide

Contraindications

  • Personal or family history of MTC.1

  • MEN 2.1

  • Prior serious hypersensitivity to dulaglutide or any component in the formulation.1

Warnings/Precautions

Warnings

Risk of Thyroid C-Cell Tumors

Thyroid C-cell tumors found in rats and mice receiving GLP-1 receptor agonists at clinically relevant exposures.1 11 18 Dulaglutide causes dose- and treatment duration-dependent thyroid C-cell tumors in male and female rats after lifetime exposure.1 Unknown whether dulaglutide causes thyroid C-cell tumors, including MTC, in humans; relevance to humans could not be ruled out by clinical or nonclinical studies.1

Very elevated serum calcitonin values may suggest MTC; such values generally exceed 50 ng/mL in patients with MTC.1 Uncertain value of routine monitoring of serum calcitonin; if serum calcitonin is found elevated, refer patient to endocrinologist for further evaluation.1 Role of monitoring serum calcitonin concentrations or thyroid ultrasound examinations for the purpose of early detection of MTC unknown.1 Refer patients with thyroid nodules noted on physical examination or neck imaging to an endocrinologist.1

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions (severe urticaria, systemic rash, facial edema, lip swelling) reported.1 Discontinue dulaglutide if hypersensitivity reaction occurs.1

Other Warnings and Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis reported during clinical trials.1 FDA is evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics (exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, linagliptin).14 15 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report.14 15

FDA states that at this time clinicians should continue to follow the recommendations in the prescribing information for incretin mimetics.14 15 Manufacturer states that if pancreatitis is suspected, promptly discontinue dulaglutide.1 If pancreatitis is confirmed, do not restart dulaglutide.1

Efficacy and safety not established in patients with a history of pancreatitis; consider other antidiabetic agents in such patients.1

Use with Drugs Known to Cause Hypoglycemia

Patients receiving dulaglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin have an increased risk of hypoglycemia.1 A lower dosage of the concomitant insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.1

Renal Effects

Acute renal failure and worsening of chronic renal failure (sometimes requiring hemodialysis) reported with GLP-1 receptor agonists during postmarketing experience.1 Some patients did not have known underlying renal disease.1 Most events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration.1 Because such adverse GI effects may worsen renal function, use caution when initiating dulaglutide or escalating dosage in patients with renal impairment.1 11

GI Effects

Adverse GI effects, sometimes severe, associated with dulaglutide use.1

Dulaglutide not studied in patients with severe GI disease, including severe gastroparesis; use not recommended in such patients.1

Macrovascular Outcomes

Evidence of macrovascular risk reduction with dulaglutide or any other antidiabetic agent not conclusively demonstrated in controlled clinical trials.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether dulaglutide distributed into milk in humans.1 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. 1

Hepatic Impairment

Limited experience in patients with hepatic impairment; use caution.1 No clinically important changes in systemic exposure in patients with hepatic impairment.1

Renal Impairment

No substantial differences in safety and efficacy in patients with mild or moderate renal impairment.1 Limited experience in patients with severe renal impairment or end-stage renal disease; use caution and monitor renal function in those experiencing severe adverse GI effects.1 10 (See Renal Effects under Cautions.)

Common Adverse Effects

Nausea,1 diarrhea,1 vomiting,1 abdominal pain/discomfort,1 decreased appetite,1 dyspepsia,1 fatigue.1

Interactions for Dulaglutide

Orally Administered Drugs

Possible altered rate and extent of absorption of concomitantly administered oral drugs; use caution with concomitantly administered oral drugs.1

Adequately monitor concentrations of oral drugs with a narrow therapeutic index when such drugs are administered concomitantly with dulaglutide.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

No substantial change in acetaminophen peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Atorvastatin

Decreased AUC and peak plasma concentration of atorvastatin1 10

Clinical relevance not known; no dosage adjustment necessary1 10

Digoxin

No substantial change in digoxin peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Lisinopril

No substantial change in lisinopril peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Metformin

No substantial change in metformin peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Metoprolol

No substantial change in metoprolol peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Hormonal contraceptives, oral

No substantial change in ethinyl estradiol or norelgestromin peak plasma concentration or overall AUC1

No dosage adjustment necessary1

Sitagliptin

Increased dulaglutide AUC and peak plasma concentration; no change in sitagliptin AUC and peak plasma concentration1 10

No dosage adjustment of either drug necessary1 10

Warfarin

No change in overall AUC of R- or S-warfarin1

No dosage adjustment necessary1

Dulaglutide Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability 65 and 47% following 0.75- and 1.5-mg doses, respectively.1

Peak plasma dulaglutide concentration at steady state achieved in 24–72 hours (median 48 hours).1 Steady-state concentrations achieved at 2–4 weeks with once-weekly administration.1

Special Populations

In patients with mild, moderate, or severe hepatic impairment, AUC decreased by 23, 33, or 21%, respectively.1 10

In patients with mild, moderate, or severe renal impairment or end-stage renal disease, AUC increased by 20, 28, 14, or 12%, respectively.1 10

Elimination

Metabolism

Presumed to be metabolized into component amino acids by general protein catabolism pathways.1 Resistant to degradation by dipeptidyl peptidase-4 (DPP-4).2 3 4

Half-life

Approximately 5 days.1

Stability

Storage

Parenteral

Injection

2–8°C in original carton; do not freeze.1

After dispensing, may be stored at room temperature up to 30°C for up to 14 days.1

Actions

  • Two disulfide-linked chains, each containing a glucagon-like peptide (GLP-1) analog molecule covalently fused to the Fc portion of a modified human IgG4 heavy chain by a small peptide linker; resistant to degradation by dipeptidyl peptidase-4 (DPP-4) due to structural modifications.1 2 9 Each GLP-1 analog is 90% homologous to human GLP-1 (7–37).1 2

  • Increases insulin release in the presence of elevated glucose concentrations.1 2 3 4

  • Suppresses glucagon secretion.1 2 3 4

  • Delays gastric emptying, reducing postprandial glucose concentrations.1 2 3 4

Advice to Patients

  • Importance of patients reading the medication guide prior to initiating therapy and each time the prescription is refilled. 1 11

  • Importance of informing patients that dulaglutide causes benign and malignant thyroid C-cell tumors in rats and that relevance of this finding to humans is unknown.1 11 Patients should report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, dyspnea) to their clinician.1 11

  • Importance of informing patients of the possibility of acute pancreatitis with dulaglutide therapy.1 11 Importance of patients informing clinicians if they have a history of pancreatitis.1 11 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patients discontinuing dulaglutide and promptly notifying clinician if such signs or symptoms occur.1 11

  • Importance of informing patients of risk of hypoglycemia, particularly if concomitant therapy with an insulin secretagogue (e.g., sulfonylurea) or insulin is used.1 11 Importance of reviewing signs, symptoms, and management of hypoglycemia.1 11

  • Importance of informing patients of possibility of hypersensitivity reactions.1 11 Patients should be instructed to discontinue dulaglutide and promptly seek medical advice if symptoms of hypersensitivity occur.1 11

  • Importance of informing patients of potential risk of adverse GI effects and possibility of dehydration due to such adverse effects; advise patients to take precautions to avoid fluid depletion.1 11 Importance of informing patients of potential risk of worsening renal function, which may require dialysis in some cases.1 11

  • Importance of patients reading the manufacturer's instructions for use before starting dulaglutide therapy.1 11 Importance of instructing patients regarding proper use, storage, and disposal of injection pen.1 11 After dispensing, store pens in refrigerator, or at room temperature for up to 14 days; protect injection pens from light and do not freeze.1 12

  • Importance of informing patients not to take an extra dose of dulaglutide to make up for a missed dose.1 If a dose is missed, patients should take the dose as soon as possible if there are at least 3 days (72 hours) until the next dose; the next dose can be taken on their usual weekly day.1 11 If there are less than 3 days until the next dose, the missed dose should be skipped and patients should take the next dose on their usual weekly day.1 11

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 11

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., pancreatitis).1 11

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dulaglutide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use only

0.75 mg/0.5 mL

Trulicity (available as prefilled single-use injection pen)

Lilly

1.5 mg/0.5 mL

Trulicity (available as prefilled single-use injection pen)

Lilly

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Eli Lilly and Company. Trulicity (dulaglutide) injection, solution prescribing information. Indianapolis, IN; 2015 Mar.

2. Umpierrez G, Tofé Povedano S, Pérez Manghi F et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014; 37:2168-76. [PubMed 24842985]

3. Nauck M, Weinstock RS, Umpierrez GE et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care. 2014; 37:2149-58. [PubMed 24742660]

4. Wysham C, Blevins T, Arakaki R et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014; 37:2159-67. [PubMed 24879836]

5. Giorgino F, Benroubi M, Sun JH, et al. Efficacy and safety of once weekly dulaglutide vs insulin glargine in combination with metformin and glimepiride in type 2 diabetes patients (AWARD-2). Presented at EASD annual meeting. Vienna: 2014 Sep 16–19. Abstract 38.

6. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125469Orig1s000: Statistical review(s). From FDA website. Accessed 2014 Oct 30.

7. Dungan KM, Povedano ST, Forst T et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014; 384:1349-57. [PubMed 25018121]

9. Glaesner W, Vick AM, Millican R et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010; 26:287-96. [PubMed 20503261]

10. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125469Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. Accessed 2014 Oct 30.

11. Eli Lilly and Company. Trulicity (dulaglutide) injection for subcutaneous use medication guide. Indianapolis, IN; 2014.

12. Eli Lilly and Company. Trulicity (dulaglutide) injection for subcutaneous use instructions for use. Indianapolis, IN; 2014 Sep.

13. US Food and Drug Administration. BLA 125469 Trulicity (Dulaglutide) Glucagon-like peptide-1 (GLP-1) receptor agonist risk evaluation and mitigation strategy (REMS). From FDA website.

14. US Food and Drug Administration. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Silver Spring, MD; 2013 Mar 14. From FDA website.

15. US Food and Drug Administration. Incretin mimetic drugs for type 2 diabetes: Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Rockville, MD; 2013 Mar 14. From FDA website.

16. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013; 173:534-9.

17. Umpierrez GE, Blevins T, Rosenstock J et al. The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: the EGO study. Diabetes Obes Metab. 2011; 13:418-25. [PubMed 21251180]

18. Novo Nordisk. Victoza [liraglutide (rDNA origin) injection] solution for injection prescribing information and patient information. Princeton, NJ; 2015 Mar.

19. Eli Lilly and Company, Indianapolis, IN: Personal communication.

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