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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

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Warning

    Risk of Thyroid C-Cell Tumors
  • Dulaglutide causes dose- and treatment duration-dependent thyroid C-cell tumors (adenomas and carcinomas) in male and female rats after lifetime exposure.

  • Unknown whether dulaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as relevance to humans has not been determined.

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

    Counsel patients regarding potential risk of MTC and inform them about symptoms of thyroid tumors. (See Advice to Patients.)

    Routine monitoring of serum calcitonin or use of thyroid ultrasound of uncertain value for early detection of MTC in patients receiving dulaglutide. (See Risk of Thyroid C-Cell Tumors under Cautions.)

Introduction

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

Uses for Dulaglutide

Type 2 Diabetes Mellitus

Glycemic Control

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

Used alone or as add-on therapy with metformin, the combination of metformin and a sulfonylurea, the combination of metformin and a thiazolidinedione, a sodium-glucose cotransporter 2 (SGLT2) inhibitor with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin.

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A1c; HbA1c], weight, and cardiovascular mortality).

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Experts recommend that patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit. In patients with these comorbidities, consider GLP-1 receptor agonist or SGLT2 inhibitor therapy independently of patient's HbA1c.

In patients with type 2 diabetes mellitus and CKD, consider a GLP-1 receptor agonist or SGLT2 inhibitor shown to reduce the risk of CKD progression, cardiovascular events, or both, in addition to metformin therapy or in those in whom metformin cannot be used.

In patients on metformin monotherapy without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, base decision regarding addition of other antidiabetic agents on avoidance of adverse effects, cost, and individual patient factors.

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

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

Not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Reduction in Risk of Major Adverse Cardiovascular Events

Used to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.

Beneficial Effects on Renal Function

Some experts suggest that use of a GLP-1 receptor agonist (e.g., dulaglutide, liraglutide, semaglutide) may reduce risk of progression of albuminuria, cardiovascular events, or both in patients with type 2 diabetes mellitus and CKD who are at increased risk for cardiovascular events.

Dulaglutide Dosage and Administration

General

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

Administration

Administer by sub-Q injection using a prefilled injection pen; prefilled syringes not currently available in the US.

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. 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.

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

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. If changing the day of weekly administration, allow at least 3 days to elapse between doses.

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

Dosage

Adults

Type 2 Diabetes Mellitus
Sub-Q

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

Special Populations

No special population dosage recommendations.

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

Cautions for Dulaglutide

Contraindications

  • Personal or family history of MTC.

  • MEN 2.

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

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. Dulaglutide causes dose- and treatment duration-dependent thyroid C-cell tumors in male and female rats after lifetime exposure. 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.

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

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions (severe urticaria, systemic rash, facial edema, lip swelling), including anaphylaxis and angioedema, reported. Discontinue dulaglutide and treat promptly according to standard of care if hypersensitivity reaction occurs; monitor patient until signs and symptoms have resolved. Exercise caution if used in patients with history of anaphylaxis or angioedema to other GLP-1 receptor agonists.

Other Warnings and Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis reported during clinical trials. 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). FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report.

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

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

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. A lower dosage of the concomitant insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

Renal Effects

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

GI Effects

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

Data lacking on use of dulaglutide in patients with severe GI disease, including severe gastroparesis; use not recommended in such patients.

Diabetic Retinopathy Complications

In a clinical study, more diabetic retinopathy complications occurred in patients receiving dulaglutide compared with those receiving placebo. Rapid improvement in glycemic control has been associated with a temporary worsening of diabetic retinopathy. Monitor patients with a history of diabetic retinopathy for progression of this condition.

Specific Populations

Pregnancy

Data lacking on use of dulaglutide in pregnant women. Reproduction studies in rats and rabbits using dulaglutide have demonstrated decreased growth and teratogenic effects. Use during pregnancy only if potential benefit justifies possible risk to the fetus.

Lactation

Data lacking on the presence of dulaglutide in milk in humans, effects on breast-fed infant, or effects on milk production.

Consider developmental and health benefits of breast-feeding along with mother's clinical need for dulaglutide and any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in patients <18 years of age; manufacturer states that drug is not recommended for use in such patients.

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

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

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.

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

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

No substantial change in acetaminophen peak plasma concentration or overall AUC

No dosage adjustment necessary

Atorvastatin

Decreased AUC and peak plasma concentration of atorvastatin

Clinical relevance not known; no dosage adjustment necessary

Digoxin

No substantial change in digoxin peak plasma concentration or overall AUC

No dosage adjustment necessary

Lisinopril

No substantial change in lisinopril peak plasma concentration or overall AUC

No dosage adjustment necessary

Metformin

No substantial change in metformin peak plasma concentration or overall AUC

No dosage adjustment necessary

Metoprolol

No substantial change in metoprolol peak plasma concentration or overall AUC

No dosage adjustment necessary

Hormonal contraceptives, oral

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

No dosage adjustment necessary

Sitagliptin

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

No dosage adjustment of either drug necessary

Warfarin

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

No dosage adjustment necessary

Dulaglutide Pharmacokinetics

Absorption

Bioavailability

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

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

Special Populations

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

In patients with mild, moderate, or severe renal impairment or ESRD, AUC increased by 20, 28, 14, or 12%, respectively.

Elimination

Metabolism

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

Half-life

Approximately 5 days.

Stability

Storage

Parenteral

Injection

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

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

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. Each GLP-1 analog is 90% homologous to human GLP-1 (7–37).

  • Increases insulin release in the presence of elevated glucose concentrations.

  • Suppresses glucagon secretion.

  • Delays gastric emptying, reducing postprandial glucose concentrations.

Advice to Patients

  • Importance of patients reading the medication guide before initiating therapy and each time the drug is dispensed.

  • 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. Patients should report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, dyspnea) to their clinician.

  • Importance of informing patients about the possibility of acute pancreatitis with dulaglutide therapy. Importance of patients informing clinicians if they have a history of pancreatitis. 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.

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

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

  • 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. Importance of informing patients of potential risk of worsening renal function, which may require dialysis in some cases.

  • Importance of informing patients to contact their clinician if they experience changes in vision during treatment with dulaglutide.

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

  • Importance of informing patients not to take an extra dose of dulaglutide to make up for a missed dose. 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. 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.

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

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

  • Importance of informing patients of other important precautionary information. (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 2022, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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