Nasal Glucagon

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Generic Name: GLUCAGON NASAL POWDER

Proprietary Name: Baqsimi (Eli Lilly)

Approval Rating: 3S

Therapeutic Class: Antidotes, Hypoglycemia

Similar Drugs: Glucagon Injection

Sound-/Look-Alike Names: Glimepiride, Glipizide, GlucaGen, Glucophage, Glucotrol, Glyburide, Glycotrol

Indications

Nasal glucagon is Food and Drug Administration (FDA)-approved for the treatment of severe hypoglycemia in patients 4 years of age and older with diabetes mellitus. ¹

Glucagon injection is approved for the treatment of severe hypoglycemia in patients with diabetes mellitus.^2,3

Glucagon injection is also approved as a diagnostic aid in radiological examination of the stomach, duodenum, small bowel, and colon to temporarily diminish intestinal motility.^2,3

Clinical Pharmacology

Glucagon is a hormone normally synthesized in the alpha cells in the islets of Langerhans in the pancreas. Glucagon primarily influences glycogenolysis in hepatocytes, and sufficient hepatic glycogen stores are required for efficacy. Repeated use of glucagon over a short period of time becomes less efficacious.^1-4

Recombinant glucagon is a polypeptide hormone identical to endogenous human glucagon that raises blood glucose levels by glycogenolysis. For the injectable pharmaceutical product available as a powder for reconstitution, glucagon is synthesized in a nonpathogenic laboratory strain of Escherichia coli that has been genetically altered ³ or is produced by expression of recombinant DNA in a Saccharomyces cerevisiae vector with subsequent purification. ² The glucagon used in the nasal formulation is a synthetic form with the same 29 amino acids as both recombinant injectable and endogenous human glucagon. ⁵

Pharmacokinetics

Glucagon is rapidly absorbed after intranasal administration. Peak plasma levels (C_max) are reached within 15 minutes in adults and 15 to 20 minutes in children. The apparent volume of distribution is approximately 885 L. Median half-life is approximately 35 minutes in adults and 21 to 31 minutes in children. Glucagon is degraded in the liver, kidneys, and plasma. ¹

In a crossover study comparing intranasal glucagon 3 mg and intramuscular (IM) glucagon 1 mg in adults with type 1 diabetes, time to maximum change in blood glucose concentration from baseline was approximately 5 minutes slower with intranasal glucagon; however, pharmacologic levels of glucagon were detected within 5 minutes of administration by both routes. Median time to C_max was 20 minutes after intranasal administration and 15 minutes after IM administration (P < .001). Mean C_max was lower after intranasal administration (3155 pg/mL) than after IM administration (3672 pg/mL; P = .003). In an analysis of administration when nadir glucose was less than 50 mg/dL, the mean time required to achieve blood glucose normalization (at least 70 mg/dL, or at least a 20 mg/dL increase from glucose nadir) was 13 minutes for IM glucagon and 16 minutes for intranasal glucagon (P < .001). ⁶

Similar results were observed in a study comparing intranasal glucagon 2 mg and 3 mg with IM glucagon 1 mg in children and adolescents 4 to 16 years of age with type 1 diabetes. Both routes produced a rise in glucose of at least 25 mg/dL within 20 minutes of dosing. Plasma glucagon levels rose within 5 minutes of administration by either route, reaching peak glucagon concentrations in a mean of 15 to 20 minutes with intranasal administration and 17 minutes with IM administration. Peak glucagon levels ranged from 2952 to 5832 pg/mL following intranasal administration and from 4382 to 6343 pg/mL following IM administration. ⁷

The presence of nasal congestion or concomitant use of a nasal decongestant had no impact on the pharmacokinetics of glucagon following nasal administration.^1,8

Comparative Efficacy

Indication: Hypoglycemia in Type 1 Diabetes Mellitus

Guidelines

• Guideline: American Diabetes Association: standards of medical care in diabetes – 2019

• Reference: American Diabetes Association ⁹

• Comments: Glucagon is used in hypoglycemic emergencies to rapidly raise plasma blood glucose levels in diabetic patients. Glucagon should be prescribed in individuals at increased risk of hypoglycemia (blood glucose less than 54 mg/dL), so it is available if needed. Glucagon is indicated especially for those unable or unwilling to consume carbohydrates by mouth. In addition, supplemental administration of carbohydrates is recommended after administration of glucagon. Caregivers and individuals in close contact with the patient should receive instruction on the use of glucagon and its administration. The intranasal form of glucagon is not specifically mentioned in the guidelines.

Studies

• Drug: Nasal Glucagon

• Reference: Deeb LC, et al, 2018 ⁵

• Study Design: Phase 3, prospective, open-label, multicenter, nonrandomized study

• Study Funding: Eli Lilly & Company

• Patients: 26 children or adolescents (4 to younger than 18 years) with type 1 diabetes mellitus of more than 1 year’s duration and experiencing moderate or severe hypoglycemic events. Patients had to be living with 1 or more caregivers and in good general health. Exclusion criteria were pheochromocytoma or insulinoma; cardiovascular, gastrointestinal (GI), liver, or kidney disease; or use of systemic beta-blockers, indomethacin, warfarin, or anticholinergic medications. Of the 26 patients enrolled, 11 were excluded due to study site noncompliance; of the remaining 15 patients, 14 experienced 1 or more hypoglycemic events and received treatment with nasal glucagon; the 14 patients were included in the efficacy and safety analyses. Mean patient age was 10.2 years; 64.3% were male; 100% were white; mean duration of diabetes was 6.3 years; and 71.4% were using an insulin pump, with a mean total daily insulin dose of 42.3 units.

• Intervention: Patients received nasal glucagon 3 mg administered as a single dose for the treatment of a moderate to severe hypoglycemic event. Blood glucose was measured just before or immediately after treatment and again at 15, 30, and 45 minutes after dosing. If the patient did not respond within 15 minutes after nasal glucagon administration, the caregiver was instructed to seek emergency medical assistance. During the study, administration of nasal glucagon was allowed whenever a patient experienced a moderate or severe hypoglycemic event, for up to a maximum of 4 events.

• Results: During the study, the 14 patients experienced 33 moderate hypoglycemic events. All patients had neuroglycopenic symptoms with a blood glucose level of 70 mg/dL or less (range, 42-70 mg/dL) at the time of nasal glucagon administration.

Primary End Point(s)

• ● Proportion of patients with treatment response (defined as awakening or returning to normal status, as judged by caregiver, within 30 minutes following nasal glucagon administration): All hypoglycemic events (100%) resolved, with patients returning to normal status within 30 minutes after nasal administration of glucagon. More than half (54.5%) of hypoglycemic events resolved and patients returned to normal status within 10 minutes of nasal glucagon administration. Time to return to normal status after nasal administration was less than 5 minutes in 21.2% of patients, 5 to less than 10 minutes in 33.3%, 10 to less than 15 minutes in 12.1%, 15 to less than 20 minutes in 15.2%, 20 to less than 25 minutes in 15.2%, and 25 to less than 30 minutes in 3%.

Secondary End Point(s):

• ● Blood glucose levels improved over time, from a baseline mean of 55 mg/dL to greater than 70 mg/dL at 15 minutes after nasal glucagon administration; levels continued to increase over 45 minutes.

• ● Very few of the caregivers had previous experience with injectable glucagon. Caregivers reported that the nasal form was easy to very easy to administer in 93.9% of hypoglycemic events. Overall, caregivers were relatively satisfied, satisfied, or very satisfied with the nasal formulation. The glucagon dose was administered within 30 seconds of the hypoglycemic episode in 60.6% of events and within 2 minutes in 100% of events.

• Comments: The study was conducted at 2 medical centers in the United States. Hypoglycemia awareness at baseline was evaluated using the Clarke Hypoglycemia Awareness Questionnaire. Caregivers and patients were trained in nasal glucagon use. Caregivers were given the User-Friendliness Assessment Questionnaire to describe nasal glucagon ease of use. Patients were given a Nasal Score Questionnaire post episode. Caregiver reports of ease of use of the nasal glucagon formulation were similar to a smaller study conducted to evaluate the ability of primary caregivers and acquaintances without medical training to administer nasal glucagon versus injectable glucagon during simulated severe hypoglycemic episodes. The study found that instruction time was faster, retention of information was more complete, and time to deliver the medication to the patient and success in delivering the medication were superior in the nasal glucagon groups compared with the IM groups for both laypersons and experienced caregivers. ¹⁰

• Limitations: This was a small study that did not use randomization, concealed allocation, blinding, or controls. The study population was primarily male and all white.

• Reference: Seaquist ER, et al, 2018^11,12

• Study Design: Phase 3, prospective, multicenter, single-arm, nonrandomized, open-label study

• Study Funding: Eli Lilly & Company, Locemia Solutions

• Patients: 129 adults (18-75 years of age) with type 1 diabetes mellitus of more than 1 year’s duration and body mass index (BMI) of 18.5 to 35 kg/m²; patients were otherwise healthy. Exclusion criteria were pheochromocytoma or insulinoma, or use of systemic beta-blockers, indomethacin, warfarin, or anticholinergic medications. Of the 101 patients who completed the study, 69 patients experiencing 1 or more hypoglycemic episode(s) requiring nasal glucagon and with evaluable response data were included in the efficacy analysis. In the main safety analysis population (patients who experienced at least 1 hypoglycemic episode and received at least 1 nasal glucagon dose; n = 74), mean patient age was 46.2 years, and 52.7% were female.

• Intervention: Patients received nasal glucagon 3 mg administered as a single dose following the onset of a hypoglycemic episode.

Results:

Primary End Point(s):

• ● Proportion of patients with treatment response (defined as awakening or returning to normal status within 30 minutes following nasal glucagon administration): Of 69 patients, 66 (95.7%) awakened or achieved normal status within 30 minutes of administration of nasal glucagon in at least 1 evaluable hypoglycemic event; 64 (92.8%) awakened or achieved normal status within 30 minutes in all evaluable events. Of the 157 evaluable hypoglycemic episodes (145 moderate and 12 severe) treated during the study, 151 (96.2%) resolved within 30 minutes, and all (100%) severe hypoglycemic episodes resolved within 15 minutes.

Secondary End Point(s):

• ● Mean blood glucose level improved progressively, from 47.9 mg/dL at the time of nasal glucagon administration to 84.4 mg/dL after 15 minutes; levels continued to increase further. In 4 of the 6 events that did not resolve within 30 minutes of nasal glucagon administration, blood glucose levels were greater than 70 mg/dL within 30 minutes but did not return to normal status because of headache and/or nasal irritation; in the other 2 events, patients eventually returned to normal status within 45 minutes.

• ● Caregivers rated the nasal glucagon drug instructions as easy to understand in 91% of events and rated the drug as easy to administer in 80.5% of events. Overall, caregivers were satisfied with nasal glucagon in 94.4% of events.

• Comments: Patients were selected from 9 centers in the United States and Canada. Hypoglycemia awareness at baseline was evaluated using the Clarke Hypoglycemia Awareness Questionnaire. Caregivers were trained in nasal glucagon use. Caregivers were given the User-Friendliness Assessment Questionnaire to describe nasal glucagon ease of use. Patients were given a Nasal Score Questionnaire post episode. The study demonstrated ease of use and preference for nasal glucagon by caregivers.

• Limitations: This was a small, single-arm study with no comparator group. Participants were predominantly white.

• Drug: Nasal Glucagon vs Glucagon for Injection

• Reference: Rickels MR, et al, 2016^6,13

• Study Design: Phase 3, randomized, open-label, noninferiority, crossover study

• Study Funding: Leona M. and Harry B. Helmsley Charitable Trust, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institutes of Health

• Patients: 77 adults (18-64 years of age) with type 1 diabetes mellitus of at least 2 years’ duration and weighing 50 kg or more, with BMI between 20 and 35 kg/m². Exclusion criteria included severe hypoglycemic episode in the month before enrollment; pheochromocytoma or insulinoma; history of seizure disorder; cardiovascular, GI, liver, or kidney disease; use of systemic beta-blockers; donation of 225 mL or more of blood within 8 weeks of enrollment; or consumption of 3 or more alcoholic beverages daily. The efficacy analysis included 75 patients who successfully completed both dosing visits. Baseline characteristics were similar between the nasal and injection groups.

• Intervention: Patients underwent 2 glucagon dosing visits. Hypoglycemic episodes were induced using an infusion of insulin after an overnight fast of at least 8 hours. The infusion was stopped once glucose concentration was less than 60 mg/dL; blood samples for glucose and glucagon were obtained 5 minutes later and a dose of glucagon was administered (time zero). At one visit, glucagon 1 mg was given IM in the deltoid muscle of the nondominant arm, and at a separate visit, intranasal glucagon 3 mg was administered into the nostril on the same side of the body. Dosing visits were scheduled 1 to 4 weeks apart.

Results:

Primary End Point(s):

• ● Treatment success (defined as an increase in blood glucose to at least 70 mg/dL or an increase of at least 20 mg/dL from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase blood glucose level): Success criteria were met in 74 of 75 (98.7%) administrations of nasal glucagon and in 75 of 75 (100%) administrations of IM glucagon (unadjusted difference, 1.3% [1-sided 97.5% confidence interval (CI), 4%]; adjusted difference, 1.5% [1-sided 97.5% CI, 4.3%]); prespecified criteria for noninferiority were met. One patient who failed to achieve success criteria in the nasal group had a blood glucose nadir of 47 mg/dL, with a rise to 65 mg/dL in 30 minutes and to 72 mg/dL in 40 minutes without any other intervention.

Secondary End Point(s):

• ● Mean time to success was 13 minutes with IM glucagon and 16 minutes with nasal glucagon (P < .001).

• Comments: The study was conducted at 8 clinics within the Type 1 Diabetes Mellitus Exchange Clinic Network. Because of the residual activity of circulating insulin, glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes following, glucagon administration. The rise in blood glucose concentration after nasal administration was about 5 minutes slower than after IM administration.

Contraindications, Warnings, and Precautions

Contraindications

Intranasal glucagon is contraindicated in patients with hypersensitivity to glucagon nasal powder or any of its inactive ingredients (ie, betadex, dodecylphosphocholine), patients with pheochromocytoma, or those with insulinoma. ¹

Warnings and Precautions

Catecholamine release in patients with pheochromocytoma is possible due to interactions between nasal glucagon and the catecholamine-secreting tumor. The resulting elevation in catecholamine release may cause an increase in blood pressure. Patients who experience a sudden increase in blood pressure after the administration of glucagon should be given phentolamine mesylate 5 to 10 mg intravenously (IV). ¹

Use of intranasal glucagon is contraindicated in patients with insulinoma. Administration of glucagon in patients with insulinoma may produce an initial increase in blood glucose levels and then stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops hypoglycemia following nasal glucagon, administer oral or IV glucose. ¹

Allergic reactions and hypersensitivity, including generalized rash, breathing difficulty, hypotension, and anaphylactic shock, have been reported with glucagon. ¹

Lack of efficacy in those with reduced hepatic glycogen (eg, patients in states of starvation, with adrenal insufficiency, or with chronic hypoglycemia) may occur. Nasal glucagon relies on stored hepatic glycogen to increase blood sugar. Patients with these conditions should be treated with oral or IV glucose. ¹

Reports (eg, case studies, a small number of observational studies) of the use of glucagon during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In addition, glucagon may not be able to cross the human placental barrier during early gestation. ¹

No information is available on the presence of glucagon in human or animal milk, or its effects on breastfeeding infants or milk production. Because glucagon is a peptide, it should be broken down in the infant’s digestive tract to constituent amino acids and is unlikely to cause harm to the infant. ¹

The safety and effectiveness of nasal glucagon have not been established in pediatric patients younger than 4 years of age. ¹

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of nasal glucagon cannot be directly compared with rates in clinical trials of other similar drugs and may not reflect the rates observed in practice. ¹ Common adverse reactions in adults and children related to nasal administration of glucagon were nausea, vomiting, and upper respiratory irritation (see Tables 1 and 2). The incidence of other types of adverse reactions is summarized in Tables 3 and 4. ¹ Table 5 is a comparison of the adverse events reported in the prescribing information for nasal glucagon and injectable glucagon dosage forms.^1-3

Table 1.

Pooled Adverse Reactions (≥2%) in Adult Patients With Type 1 and Type 2 Diabetes Receiving Nasal Glucagon in Clinical Trials. ¹

Adverse reaction	Nasal glucagon 3 mg (N = 153)
Nausea	26.1%
Headache	18.3%
Vomiting	15%
Upper respiratory tract irritation a	12.4%

^aRhinorrhea, nasal discomfort, congestion, cough, and epistaxis.

Table 2.

Adverse Reactions (≥2%) in Children With Type 1 Diabetes Receiving Nasal Glucagon in a Clinical Trial. ¹

Adverse reaction	Nasal glucagon 3 mg (N = 36)
Vomiting	30.6%
Headache	25%
Nausea	16.7%
Upper respiratory tract irritation a	16.7%

^aNasal discomfort, nasal congestion, and sneezing.

Table 3.

Pooled Solicited Nasal and Nonnasal Adverse Reactions in Adult Patients With Type 1 and Type 2 Diabetes Receiving Nasal Glucagon in Clinical Trials. ¹

Adverse reaction	Nasal glucagon 3 mg (N = 153)
Watery eyes	58.8%
Nasal congestion	42.5%
Nasal itching	39.2%
Runny nose	34.6%
Redness of the eyes	24.8%
Itching of the eyes	21.6%
Sneezing	19.6%
Itching of the throat	12.4%
Itching of the ears	3.3%

Table 4.

Solicited Nasal and Nonnasal Adverse Reactions in Pediatric Patients With Type 1 Diabetes Receiving Nasal Glucagon in a Clinical Trial. ¹

Adverse reaction	Nasal glucagon 3 mg (N = 36)
Watery eyes	47.2%
Nasal congestion	41.7%
Nasal itching	27.8%
Runny nose	25%
Sneezing	19.4%
Itchy eyes	16.7%
Redness of eyes	13.9%
Itching of throat	2.8%
Itching of ears	2.8%

Table 5.

Comparison of the Adverse Events Reported With Nasal Glucagon and Injectable Glucagon Dosage Forms.^1-3

Adverse reaction	Nasal glucagon	Injectable glucagon
Headache	X	X
Nausea	X	X
Vomiting	X	X
Upper respiratory tract irritation	X
Necrolytic migratory erythema		X
Injection-site reaction		X

The majority of adverse reactions in the published clinical trials were classified as low to moderate in severity and resolved within 1 hour.^5,12 Other observed adverse reactions with nasal glucagon–treated patients across clinical trials were dysgeusia, pruritus, tachycardia, hypertension, and additional upper respiratory tract irritation events (nasal pruritus, throat irritation, and parosmia). ¹

Necrolytic migratory erythema (NME), a skin rash associated with glucagonomas, can be exacerbated by continuous glucagon administration. This adverse event has only been reported postmarketing with use of injectable glucagon following continuous infusion and is characterized by scaly, pruritic erythematous plaques, bullae, or erosions on the face, groin, perineum, and legs. Treatment involves discontinuation of glucagon. The use of corticosteroids may be ineffective. There have been no reports of NME with the nasal glucagon formulation.^1-3

Drug Interactions

Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given glucagon.^1-3

In patients taking indomethacin, nasal glucagon may lose its ability to raise blood glucose or may even produce hypoglycemia.^1-3

Glucagon, including the nasal formulation, may increase in the anticoagulant effect of warfarin.^1-3 Drug interactions reported with nasal and injectable glucagon are compared in Table 6.^1-3

Table 6.

Comparison of Nasal Glucagon and Injectable Glucagon Drug Interactions.^1-3

	Nasal glucagon	Injectable glucagon
Beta-blockers	X	X
Anticholinergics		X
Indomethacin	X	X
Warfarin	X	X

Coadministration with an anticholinergic drug may increase GI adverse effects and is not recommended. ²

Recommended Monitoring

Monitor for improvements in the signs and symptoms of hypoglycemia; blood glucose measurements can be used to monitor response. ¹

Dosing

The recommended dose of nasal glucagon is 3 mg administered as 1 actuation of the intranasal device into 1 nostril; emergency assistance should be called immediately after administering the dose. The tip of the device should be inserted into the nostril and then the plunger pressed in until the green line is no longer showing. No inhaling is required. If the patient responds to treatment, they should be given oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia. If there has been no response after 15 minutes, an additional 3 mg dose of nasal glucagon from a new device may be administered. ¹

Product Availability and Storage

Glucagon nasal powder was approved on July 24, 2019. ¹⁴ It is available as an intranasal device containing one 3 mg dose of glucagon as a preservative-free, white powder. The product is available in cartons that contain 1 or 2 intranasal devices. ¹

Nasal glucagon should be stored at temperatures not exceeding 30°C (86°F) in the shrink-wrapped tube provided. ¹ Removal of the shrink wrapping from the tube prior to use may expose the product to moisture and cause it to not work as expected. The shrink wrap should be kept on the tube until administration of the product is necessary. ¹

Drug Safety/Risk Evaluation and Mitigation Strategy (REMS)

No REMS program has been established for nasal glucagon. ¹⁴

Conclusion

Nasal glucagon is FDA-approved for the treatment of severe hypoglycemia in patients 4 years of age and older with diabetes mellitus. The standard of care for moderate or severe hypoglycemia in patients with diabetes mellitus is IM or subcutaneous administration of glucagon. Glucagon emergency kits are carried by many diabetic patients, especially those treated with insulin. Correct administration of glucagon by a layperson or otherwise inexperienced bystander can be crucial in an emergency, and glucagon for injection kits can be intimidating or difficult to use for the general public. Instructions and pictures can be insufficient to guide in reconstituting and administering the drug. A nasal glucagon dosage form offers an alternative that is easier for laypersons to use and has similar efficacy and pharmacokinetic profiles to its injectable counterpart. The nasal device is associated with fewer steps and only requires insertion into 1 nostril for delivery. Outcomes and safety in diabetic patients, especially children, can be greatly improved by prescription of nasal glucagon rescue kits, particularly in cases when an inexperienced user must intervene on the patient’s behalf.