AHFS Class:

• Glycogenolytic Agents 68:22.12

Generic Name(s):

• Dasiglucagon

Chemical Name:

• (4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-2-methylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid

Molecular Formula:

• C₁₅₂H₂₂₂N₃₈O₅₀

Dasiglucagon, an antihypoglycemic agent, is a glucagon analog that increases blood glucose concentration by stimulating hepatic glycogenolysis.1,5,6,7,8,9

Hypoglycemia

Dasiglucagon hydrochloride is used for the treatment of severe hypoglycemia in patients with diabetes mellitus.1 Dasiglucagon is only effective in patients with hypoglycemia if liver glycogen is available; the drug may be of little or no value in patients with chronic hypoglycemia or in those with hypoglycemia associated with starvation or adrenal insufficiency.1

Efficacy and safety of dasiglucagon for this indication have been evaluated in 3 randomized, double-blind, placebo-controlled studies in patients with type 1 diabetes mellitus, including 2 studies in a total of 215 adults (NCT03378635, NCT03688711) and one study in 42 pediatric patients (NCT03667053), following controlled insulin-induced hypoglycemia.1,2,3,4 In all 3 studies, the primary efficacy end point was the time from study drug administration to plasma glucose recovery (defined as an increase in plasma glucose concentration of at least 20 mg/dL) without the need for additional intervention (i.e., IV glucose administration) within 45 minutes.1,2,3,4 In all 3 studies, the median time to plasma glucose recovery was shorter with dasiglucagon than with placebo.1,2,3,4

In the 2 studies in adults, patients were randomized to receive a single sub-Q injection of dasiglucagon 0.6 mg, placebo, or glucagon 1 mg (one study only) following induction of hypoglycemia (target baseline plasma glucose concentration of less than 60 mg/dL; mean baseline concentration of 55-58.8 mg/dL).1,2,3 The median time to plasma glucose recovery was shorter with dasiglucagon compared with placebo (10 versus 35-40 minutes) and was numerically similar for dasiglucagon and glucagon (10 versus 12 minutes).1,2,3 A high proportion of dasiglucagon-treated patients achieved plasma glucose recovery within predefined time points.2,3 In one study, 65, 99, and 99% of the 82 patients who received dasiglucagon recovered within 10, 15, and 20 minutes, respectively, following the dose.2 In the other study, 30 of 34 patients who received dasiglucagon recovered within 15 minutes and all but one patient recovered within 30 minutes.3

In the study in pediatric patients, children and adolescents 6-17 years of age who weighed at least 20 kg were randomized to receive a single sub-Q injection of dasiglucagon 0.6 mg, placebo, or glucagon 1 mg following induction of hypoglycemia (target baseline plasma glucose concentration of less than 80 mg/dL; mean baseline concentration of 72 mg/dL).1,4 The median time to plasma glucose recovery was shorter with dasiglucagon compared with placebo (10 versus 30 minutes) and was numerically similar for dasiglucagon and glucagon (10 minutes each).1,4 Among the 20 patients who received dasiglucagon, plasma glucose recovery occurred within 15 minutes in 19 patients and within 20 minutes in all 20 patients.4

General

Patients and their caregivers should be informed of the signs and symptoms of severe hypoglycemia.1 Because effective treatment of severe hypoglycemia requires assistance from other individuals, patients should be advised to inform family members and friends about the availability of dasiglucagon and provide them with instructions for use of the drug.1

Administration

Dasiglucagon is administered by sub-Q injection only.1 Injection sites include the lower abdomen, buttocks, thigh, and outer upper arm.1

Dasiglucagon is supplied in single-use auto-injectors and prefilled syringes.1 Dasiglucagon injection should be inspected visually prior to administration.1 The solution should appear clear, colorless, and free from particles and should be discarded if it is discolored or contains particulate matter.1

Dasiglucagon should be administered as soon as possible after severe hypoglycemia is recognized.1 Immediately following administration, emergency assistance should be summoned.1 If the patient has not responded within 15 minutes after the initial dose, an additional dose may be administered using a new auto-injector or prefilled syringe while awaiting emergency assistance.1 Once the patient has responded to treatment, oral carbohydrates should be administered to restore liver glycogen stores and to prevent recurrence of hypoglycemia.1

Dosage

Dosage of dasiglucagon hydrochloride is expressed in terms of dasiglucagon.1

Hypoglycemia

For the treatment of severe hypoglycemia in adults and pediatric patients 6 years of age and older with diabetes mellitus, the recommended sub-Q dose of dasiglucagon is 0.6 mg; if the patient has not responded to the initial dose after 15 minutes, a second 0.6-mg dose may be administered.1

Special Populations

The manufacturer makes no special population dosage recommendations at this time.1

Contraindications

Dasiglucagon is contraindicated in patients with pheochromocytoma because of the risk of substantial increase in blood pressure and in those with insulinoma because of the risk of hypoglycemia.1

Warnings/Precautions

Pheochromocytoma

In patients with pheochromocytoma, glucagon may stimulate tumor release of catecholamines.1 If a patient's blood pressure increases substantially after dasiglucagon administration and a previously undiagnosed pheochromocytoma is suspected, IV administration of 5-10 mg of phentolamine mesylate may effectively lower blood pressure.1 (See Contraindications under Cautions.)

Insulinoma

In patients with insulinoma, administration of glucagon preparations may produce an initial increase in blood glucose concentration; however, dasiglucagon administration may directly or indirectly (through an initial rise in blood glucose concentration) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia.1 (See Contraindications under Cautions.) If a patient experiences symptoms of hypoglycemia after receiving dasiglucagon, IV or oral glucose should be administered.1

Hypersensitivity Reactions

Allergic reactions, including generalized rash and, occasionally, anaphylactic shock with respiratory distress and hypotension, have been reported in patients receiving glucagon preparations.1

Decreased Hepatic Glycogen Stores

Dasiglucagon is effective in treating hypoglycemia only if hepatic glycogen stores are sufficient.1 Patients in states of starvation and those with adrenal insufficiency or chronic hypoglycemia may not have adequate hepatic glycogen stores and should instead receive glucose for treatment of severe hypoglycemia.1

Immunogenicity

As with all therapeutic peptides, there is potential for immunogenicity with dasiglucagon.1 In clinical trials, less than 1% of patients receiving dasiglucagon developed treatment-emergent antidrug antibodies.1 In 2 patients who received a single dose of dasiglucagon, antibodies to the drug were detectable for at least 14 months after the dose.1 One patient who received multiple doses of dasiglucagon developed antidrug antibodies with transient neutralizing activity and with cross-reactivity to glucagon.1 Although no safety or efficacy concerns were observed in these 3 patients, it is unknown whether antibody development can affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of dasiglucagon.1

Specific Populations

Pregnancy

There are no available data regarding use of dasiglucagon in pregnant women by which to establish a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes.1 Untreated hypoglycemia during pregnancy can cause complications and can be fatal.1

In animal reproduction studies, daily sub-Q administration of dasiglucagon to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at exposure levels of 7 and 709 times, respectively, the recommended human dose of 0.6 mg; in rabbits at dosages of 20 or more times the recommended human dose, dasiglucagon caused fetal skeletal and visceral malformations.1

Lactation

It is not known whether dasiglucagon is distributed into human or animal milk, affects breast-fed infants, or affects milk production.1 Because dasiglucagon is a peptide and would be expected to be broken down to its constituent amino acids in an infant's digestive tract, the drug is unlikely to harm breast-fed infants.1

Pediatric Use

Safety and efficacy of dasiglucagon for the treatment of severe hypoglycemia in pediatric patients 6 years of age and older with diabetes mellitus are supported by evidence from a controlled study in 42 pediatric patients with type 1 diabetes mellitus.1 (See Hypoglycemia under Uses.) Safety and efficacy of the drug have not been established in pediatric patients younger than 6 years of age.1

Geriatric Use

Clinical studies of dasiglucagon did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1

Common Adverse Effects

Adverse effects reported in 2% or more of adults or pediatric patients receiving dasiglucagon include nausea, vomiting, headache, and injection site pain.1 Diarrhea also has been reported in 2% or more of adults receiving the drug.1

Beta-Adrenergic Blocking Agents

Patients receiving β-adrenergic blocking agents may experience a transient increase in heart rate and blood pressure after receiving dasiglucagon.1

Indomethacin

Dasiglucagon may be ineffective for increasing blood glucose concentration or may even produce hypoglycemia in patients receiving indomethacin.1

Warfarin

Dasiglucagon may increase the anticoagulant effect of warfarin.1

Description

Dasiglucagon, an antihypoglycemic agent, is a peptide analog of human glucagon, a hormone synthesized and secreted by the α₂ cells of the pancreatic islets of Langerhans.1,5 Dasiglucagon consists of 29 amino acids with 7 amino acid substitutions relative to glucagon that increase stability of the drug in aqueous solution at physiologic pH.1,5,6,8,9 Dasiglucagon, a glucagon receptor agonist, increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating hepatic glycogenolysis and release of glucose from the liver.1,7 Dasiglucagon and glucagon have similar potency at the human glucagon receptor.7 The availability of dasiglucagon injection and more stable parenteral and intranasal formulations of glucagon provide opportunities to expand the use of this hormone in managing insulin-induced hypoglycemia in nonhospital settings.5,6,8 (See Glucagon 68:22.12.)

Following sub-Q administration of a single 0.6-mg dose dasiglucagon in adults with type 1 diabetes mellitus, the mean peak plasma concentration of the drug was attained in approximately 35 minutes1,9 and the mean increase in glucose concentration from baseline to 90 minutes was 168 mg/dL.1 In pediatric patients with type 1 diabetes mellitus, the mean peak plasma concentration of the drug was attained in approximately 21 minutes and the mean increase in glucose concentration from baseline to 60 minutes was 162 mg/dL.1 Like endogenous glucagon, dasiglucagon is eliminated via proteolytic degradation in the blood, liver, and kidneys.1 The half-life of dasiglucagon is approximately 30 minutes.1,9

Advice to Patients

Importance of advising patients and their family members or caregivers to read the manufacturer's patient information and instructions for use of dasiglucagon.1

Importance of instructing patients and their family members or caregivers on how to recognize severe hypoglycemia, the risks of prolonged hypoglycemia, appropriate use of dasiglucagon, and proper use of the auto-injectors and/or prefilled syringes.1

Risk of allergic reactions.1 Importance of advising patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.1

Inform patients that the inside of the auto-injector cap and the inside of the needle cover of the prefilled syringe contain dry natural rubber, which may cause allergic reactions in patients with latex allergy.1

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

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

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Zealand Pharma US. Zegalogue^® (dasiglucagon) injection prescribing information. Boston, MA: 2021 Mar.

2. Pieber TR, Aronson R, Hövelmann U et al. Dasiglucagon: A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial. Diabetes Care . 2021; 44:1361-7. [PubMedCentral][PubMed 33883196]

3. Bailey TS, Willard J, Klaff LJ et al. Dasiglucagon, a next-generation glucagon analogue, for treatment of severe hypoglycaemia via an autoinjector device: Results of a phase 3, randomized, double-blind trial. Diabetes Obes Metab . 2021; :1-7. [PubMed 34169625]

4. Battelino T, Tehranchi R, Bailey T et al. Dasiglucagon, a next-generation ready-to-use glucagon analog, for treatment of severe hypoglycemia in children and adolescents with type 1 diabetes: Results of a phase 3, randomized controlled trial. Pediatr Diabetes . 2021; 22:734-741. [PubMed 33934456]

5. Hawkes CP, De Leon DD, Rickels MR. Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia. Curr Diab Rep . 2019; 19:97. [PubMedCentral][PubMed 31493043]

6. Li S, Hu Y, Tan X et al. Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes. Expert Opin Pharmacother . 2020; 21:1311-1318. [PubMed 32267182]

7. Blair HA. Dasiglucagon: First Approval. Drugs . 2021; 81:1115-1120. [PubMed 34047955]

8. Xu B, Tang G, Chen Z. Dasiglucagon: an effective medicine for severe hypoglycemia. Eur J Clin Pharmacol . 2021; [PubMed 34223944]

9. Hövelmann U, Bysted BV, Mouritzen U et al. Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog. Diabetes Care . 2018; 41:531-537. [PubMed 29273578]