AHFS Class:

• Glycogenolytic Agents 68:22.12

Generic Name(s):

• Glucagon

• Glucagon Hydrochloride

Glucagon, an antihypoglycemic agent, is a hormone synthesized and secreted by the α₂ cells of the pancreatic islets of Langerhans that increases blood glucose concentration by stimulating hepatic glycogenolysis.

Hypoglycemia

Glucagon is used for the emergency treatment of severe hypoglycemia in patients with diabetes mellitus. Glucagon is only effective in patients with hypoglycemia if liver glycogen is available; the drug is of little or no value in patients with chronic hypoglycemia or in those with hypoglycemia associated with starvation or adrenal insufficiency. Following glucagon administration, supplemental carbohydrate should be administered as soon as possible, especially to pediatric patients. The hyperglycemic response produced by glucagon may be reduced in emaciated or undernourished patients or in those with uremia or hepatic disease. Unlike IV dextrose, parenteral administration of glucagon results in a smooth, gradual termination of insulin coma. Glucagon is convenient for use in emergency situations when dextrose cannot be administered IV. The availability of more stable parenteral and intranasal formulations of glucagon that do not require reconstitution prior to use provide opportunities to expand the use of this hormone in managing insulin-induced hypoglycemia in nonhospital settings.24 The American Diabetes Association states that glucagon should be prescribed for all patients with diabetes mellitus who are at increased risk of level 2 (glucose concentration less than 54 mg/dL) or level 3 hypoglycemia (severe events characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia) so that the drug is available if needed.19

Depending on the stage of coma and the route of administration, patients usually become conscious within 5-20 minutes following parenteral administration of glucagon. After the patient responds, supplemental carbohydrate should be administered to restore liver glycogen and prevent secondary hypoglycemia. In patients in very deep coma, IV dextrose should be administered in addition to glucagon. If an unconscious diabetic patient suspected of being in insulin coma does not awaken following administration of glucagon, an additional dose of glucagon can be administered; emergency assistance should be sought. Other causes of coma should be considered. Failure of glucagon to relieve the coma may be caused by marked depletion of hepatic glycogen stores or irreversible brain damage resulting from prolonged hypoglycemia. In emergency situations in which hypoglycemia is suspected but not established, glucagon should not be substituted for IV dextrose.

Safety and efficacy of parenterally administered glucagon have been established in patients with diabetes mellitus.6 In several studies, almost all patients who received glucagon had a successful increase in plasma glucose concentrations within 30 minutes of administration.6 In 2 crossover studies in adults with type 1 diabetes mellitus, a single subcutaneous dose of glucagon (1 mg) administered following induction of hypoglycemia with insulin (target blood glucose concentration of less than 50 mg/dL; mean baseline concentration of 45-49 mg/dL) increased blood glucose to a concentration exceeding 70 mg/dL or by at least 20 mg/dL within 30 minutes in approximately 97-100% of patients.6,16 The mean time to reversal of hypoglycemia was 10-14 minutes.6 In another study, pediatric patients 2-17 years of age with type 1 diabetes mellitus received a single subcutaneous dose of glucagon (0.5 or 1 mg in those 12 years of age or older; 0.5 mg in those younger than 12 years of age) following insulin-induced reduction of blood glucose concentration to less than 80 mg/dL.6 In all patients, blood glucose concentration increased by at least 25 mg/dL following glucagon administration.6 Glucose response was similar across age groups.6

Safety and efficacy of intranasal glucagon have been established in multiple clinical studies in patients with type 1 or type 2 diabetes mellitus.5,7,8 In 2 open-label, crossover studies in adults with type 1 or type 2 diabetes mellitus, a single 3-mg intranasal dose of glucagon was noninferior to a single 1-mg IM dose of the drug in reversing insulin-induced hypoglycemia.5,7 Following induction of hypoglycemia (target baseline blood glucose concentration of less than 50 or 60 mg/dL; mean baseline concentration of 44-47 or 54-56 mg/dL, respectively), intranasal or IM administration of glucagon increased blood glucose concentration to at least 70 mg/dL or by at least 20 mg/dL within 30 minutes in 99-100 or 100% of patients, respectively.5,7 The mean time to reversal of hypoglycemia was 12-16 minutes following intranasal administration compared with 10-12 minutes following IM administration.5 In another study, pediatric patients 4 years of age or older with type 1 diabetes mellitus were randomized to receive intranasal glucagon (3 mg) or IM glucagon (0.5 or 1 mg depending on body weight) following insulin-induced reduction of blood glucose concentration to less than 80 mg/dL; both formulations of glucagon increased blood glucose concentration in all patients in all age groups by at least 20 mg/dL within 20 minutes following administration (mean time of 11-14 or 11-12 minutes with intranasal or IM administration, respectively).5,8

Radiographic Examination of the GI Tract

Glucagon is used as a diagnostic aid in the radiographic examination of the stomach, duodenum, small intestine, and colon when a hypotonic state would be advantageous. Concomitant administration of glucagon used as a diagnostic aid and anticholinergic agents is not recommended because of the possibility of increased adverse GI effects.1,4,9

-Adrenergic or Calcium-channel Blocking Agent Overdosage

Glucagon has been used with some success as a cardiac stimulant for the management of cardiac manifestations (e.g., bradycardia, hypotension, myocardial depression) associated with β-adrenergic blocking agent overdosage† or calcium-channel blocking agent overdosage†. Resuscitation following cardiac arrest from β-blocker or calcium-channel blocker overdosage should follow standard basic life support (BLS) and advanced cardiac life support (ACLS) algorithms.196 Some data indicate that administration of glucagon may be useful in treating severe cardiovascular instability associated with β-blocker overdosage that is refractory to standard measures, including vasopressors, and some experts state that such use is reasonable.10,20,196 Evidence of efficacy in calcium-channel blocker overdosage is more limited;196 however, some experts state that treatment with glucagon also may be considered in patients with severe, refractory cardiovascular instability associated with calcium-channel blocker overdosage.10,196

Sensitivity Reactions

Glucagon has been used in the treatment of anaphylaxis that is unresponsive to epinephrine in patients receiving β-adrenergic blocking agents†.11,21,22,23 Although evidence of efficacy is limited,22,23 glucagon is thought to exert a beneficial effect by directly activating adenylate cyclase and therefore bypassing the β-adrenergic receptor blockade.22

Reconstitution and Administration

Glucagon and glucagon hydrochloride may be administered by subcutaneous, IM, or IV injection.1,4,6,9,18 Glucagon also is administered intranasally.5 The drug also has been administered by continuous IV infusion for the treatment of β-adrenergic or calcium-channel blocking agent overdosage†.10,15,20

Patients with diabetes mellitus and their caregivers should be informed of the signs and symptoms of severe hypoglycemia.1,4,5,6,9,18 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 glucagon and provide them with instructions for use of the drug.1,4,5,6,9,18 Glucagon should be administered as soon as possible after severe hypoglycemia is recognized.1,4,5,6,9,18 Immediately following administration, emergency assistance should be summoned.1,4,5,6,9,18 If the patient has not responded within 15 minutes after the initial dose, an additional dose may be administered while awaiting emergency assistance.1,4,5,6,9,18 Once the patient has responded to treatment, oral carbohydrates should be administered to restore liver glycogen stores and to prevent recurrence of hypoglycemia.1,4,5,6,9,18

Following radiographic examinations requiring use of glucagon as a diagnostic aid, patients who have been fasting should be given oral carbohydrate if compatible with the procedure.4,9,18

Parenteral Administration

Glucagon or Glucagon Hydrochloride for Injection

Glucagon for injection is reconstituted by adding 1 mL of the sterile diluent provided by the manufacturer to a vial labeled as containing 1 mg of the drug to provide a solution containing 1 mg of glucagon per mL.1 The vial should be swirled gently until the powder is completely dissolved.1 The reconstituted solution should be inspected visually for particulate matter and discoloration; the solution should appear clear with a water-like consistency, and should not be used if it is cloudy or contains particulate matter.1

Glucagon hydrochloride for injection (e.g., GlucaGen^®) is reconstituted by adding 1 mL of sterile water for injection to a vial labeled as containing 1 mg of glucagon to provide a solution containing 1 mg of glucagon per mL.4,9,18 The vial should be shaken gently until the powder is completely dissolved.4,9,18 The reconstituted solution should be inspected visually for particulate matter and discoloration; the solution should appear clear and colorless, and should not be used if it is cloudy or contains particulate matter.4,9,18

Reconstituted solutions of glucagon or glucagon hydrochloride may be administered IV (under medical supervision only) or by IM or subcutaneous injection into the upper arms, thighs, or buttocks.1,4,9,18 The solutions should be used immediately after reconstitution, and any unused portion should be discarded.1,4,9,18

To prepare a continuous IV infusion solution for treatment of β-adrenergic blocking agent overdosage, reconstituted glucagon should be diluted in 5% dextrose injection.15

Glucagon Injection

Glucagon injection in prefilled syringes and auto-injectors (Gvoke^®) is for subcutaneous use only.6 Each syringe or auto-injector contains one 0.5- or 1-mg dose of glucagon and cannot be reused.6 The prefilled syringes and auto-injectors should be kept in the foil pouch until time of administration.6 Glucagon injection should be inspected visually prior to administration.6 The solution should appear clear and colorless to pale yellow and be free of particles; the solution should be discarded if it is discolored or contains particulate matter.6 The appropriate dose should be injected subcutaneously into the lower abdomen, outer thigh, or outer upper arm.6

Intranasal Administration

Each glucagon intranasal device (Baqsimi^®) contains one 3-mg dose of glucagon and cannot be reused.5 The intranasal device should be kept in the shrink-wrapped tube until time of administration and should not be tested prior to administration.5 If the tube has been opened and the device exposed to moisture, the drug may not work as expected.5 The drug should be administered by inserting the tip of the intranasal device into one nostril and pressing the device plunger all the way down until the green line is no longer showing.5 The patient does not need to inhale the dose.5 The manufacturer's prescribing information should be consulted for additional instructions on use of the intranasal device.5

Dosage

Dosage of glucagon or glucagon hydrochloride is expressed in terms of glucagon.1,4,5,6,9,18

Hypoglycemia

Parenteral Dosage

For the treatment of severe hypoglycemia, the recommended subcutaneous, IM, or IV dose of glucagon administered as reconstituted glucagon for injection is 1 mg in adults and children weighing at least 20 kg and 0.5 mg in children weighing less than 20 kg; alternatively, a dose of 20-30 mcg/kg can be administered in children weighing less than 20 kg.1

For the treatment of severe hypoglycemia, the recommended subcutaneous, IM, or IV dose of glucagon administered as reconstituted glucagon hydrochloride for injection (e.g., GlucaGen^®) is 1 mg in adults and children weighing 25 kg or more and 0.5 mg in children weighing less than 25 kg.4,9,18 If the weight of the child is unknown, children younger than 6 years of age should receive a dose of 0.5 mg and those 6 years of age or older should receive 1 mg.4,9,18

When glucagon prefilled syringes or auto-injectors (Gvoke^®) are used for the treatment of severe hypoglycemia, the recommended subcutaneous dose of glucagon in adults and adolescents at least 12 years of age is 1 mg; in children 2 to less than 12 years of age, the recommended subcutaneous dose is 1 mg in those weighing at least 45 kg and 0.5 mg in those weighing less than 45 kg.6

If the patient has not responded to the initial dose of glucagon after 15 minutes, an additional dose of the drug (equivalent to the initial dose) may be administered.1,4,6,9,18

Intranasal Dosage

For the treatment of severe hypoglycemia in adults and children 4 years of age and older, the recommended intranasal dosage of glucagon is 3 mg (one actuation of the Baqsimi^® intranasal device) administered into one nostril.5 If the patient has not responded to the initial dose after 15 minutes, a second 3-mg dose may be administered.5

Radiographic Examination of the GI Tract

When glucagon is used as a diagnostic aid in the radiographic examination of the stomach, duodenum, and small intestine in adults, the dose depends on the onset of action and duration of effect required for the specific examination.1 The onset of action after the injection depends on the organ under examination and the route of administration.4,9 The usual dose is 0.2-0.5 mg IV or 1 mg IM,1,4,9 although IV or IM doses up to 2 mg may be used if required.1 (See Pharmacokinetics: Absorption.)

For relaxation of the stomach, one manufacturer recommends a dose of 0.5 mg IV or 2 mg IM since the stomach is less sensitive to the effects of the drug.1 To facilitate a more satisfactory radiographic examination of the colon, a dose of 2 mg may be given as a single IM injection approximately 10 minutes prior to initiation of the procedure.1 Alternatively, other manufacturers state the usual dose to relax the colon is 0.5-0.75 mg IV or 1-2 mg IM.4,9 Glucagon doses of 2 mg are associated with a higher incidence of nausea and vomiting than lower doses of the drug.1

-Adrenergic or Calcium-channel Blocking Agent Overdosage

For the management of cardiac manifestations of β-blocker overdosage† in adults, glucagon has been administered as a direct IV injection at a dose of 3-10 mg administered slowly over 3-5 minutes, followed by an IV infusion of 2-5 mg/hour.10,15,20 Because of the amount of glucagon required to sustain this therapy, the availability of an adequate supply of glucagon must be considered.15,20

For the management of cardiac manifestations of calcium-channel blocker overdosage† in adults, glucagon has been administered as a direct IV injection at a dose of 3-10 mg over 3-5 minutes, followed by an IV infusion of 3-5 mg/hour.10

Adverse Effects

Injection site reactions (e.g., edema, erythema, pain, discomfort), hypoglycemia or hypoglycemic coma, adverse GI effects (nausea, vomiting, abdominal pain, diarrhea), adverse cardiovascular effects (hypotension, hypertension, tachycardia), pallor, headache, dizziness, asthenia, and somnolence have been reported in patients receiving parenteral glucagon, although causality and frequency of such effects have not been fully established.1,4,6,9 Nausea and vomiting may be more common in patients receiving higher (2 mg) doses of the drug.1 Hypotension has been reported up to 2 hours following parenteral administration of glucagon as a diagnostic aid for upper GI endoscopic procedures.1,4 The risk of hypoglycemia may be increased in patients receiving indomethacin.1,4,6,9 (See Indomethacin under Drug Interactions.)

Hypersensitivity reactions, including generalized rash, urticaria, and anaphylaxis with respiratory distress and hypotension, have been reported in patients receiving glucagon.1,4,5,6,9

In pediatric patients and adults receiving intranasal glucagon, nausea, headache, or vomiting has occurred in 15-31% of patients and upper respiratory tract irritation (rhinorrhea, nasal discomfort, nasal congestion, cough, epistaxis, sneezing) has occurred in 12-17% of patients.5 When symptoms were solicited by questionnaire, watery eyes or nasal congestion was reported in 42-59% of patients; runny nose, ocular redness, ocular or nasal pruritus, or sneezing was reported in 14-39% of patients; and aural or throat pruritus was reported in 3-12% of patients.5 Dysgeusia, pruritus, tachycardia, hypertension, throat irritation, and parosmia also have been reported.5

Necrolytic migratory erythema (NME), a rash commonly associated with glucagonomas and characterized by scaly, pruritic, erythematous plaques, bullae, and erosions, has been reported in patients receiving continuous IV infusions of glucagon.1,4,6,9 NME lesions may affect the face, groin, perineum, and legs or may be more widespread.1,4,6,9 Reported cases of NME have resolved following discontinuance of glucagon therapy; treatment with corticosteroids has not been shown to be effective.1,4,6,9 If NME occurs, the risks and benefits of continued treatment with continuous IV infusions of glucagon should be considered.1,4,6,9

Precautions and Contraindications

Glucagon is contraindicated in patients with insulinoma.1,4,5,6 Although administration of glucagon may produce an initial increase in blood glucose concentration in patients with insulinoma, the drug may cause hypoglycemia by directly or indirectly (through an initial increase in blood glucose concentration) stimulating exaggerated insulin release from an insulinoma.1,4,5,6 If a patient develops symptoms of hypoglycemia after receiving glucagon, oral or IV glucose should be administered.1,4,5,6

Because administration of glucagon may stimulate tumor release of catecholamines in patients with pheochromocytoma, which may cause a marked increase in blood pressure, glucagon is contraindicated in patients with pheochromocytoma.1,4,5,6 If a patient experiences a substantial increase in blood pressure after receiving glucagon and a previously undiagnosed pheochromocytoma is suspected, IV administration of 5-10 mg of phentolamine mesylate has been used effectively to lower blood pressure for the short time that control would be needed.1,4,5,6

Because of the potential for hypoglycemia, use of glucagon as a diagnostic aid is contraindicated in patients with glucagonoma.1,4,9 In patients suspected of having glucagonoma, blood concentrations of glucagon should be determined prior to administration of glucagon and blood glucose concentrations should be monitored during glucagon treatment.1,4,9 If symptoms of hypoglycemia develop, oral or IV glucose should be administered.9

In patients with cardiac disease, glucagon may increase myocardial oxygen demand, blood pressure, and heart rate, which may be life-threatening and may require treatment.1,4,9 When glucagon is used as a diagnostic aid in patients with cardiac disease, cardiac monitoring is recommended.1,4,9

Use of glucagon as a diagnostic aid in patients with diabetes mellitus may result in hyperglycemia; blood glucose concentrations should be monitored and treated if indicated.1,4,9

When glucagon is used for the treatment of hypoglycemia, liver glycogen must be available. Patients in states of starvation, with adrenal insufficiency, or with chronic hypoglycemia may not have adequate stores of hepatic glycogen for glucagon administration to be effective.1,4,5,6 Patients with these conditions should be treated with glucose.1,4,5,6

Patients with diabetes mellitus should be fully and completely advised about the nature of the disease, what they must do to prevent and detect complications, and how to control their condition. Patients should be properly instructed in the early detection and treatment of hypoglycemia, and should be advised to routinely carry sugar, candy, or other readily absorbable carbohydrate so that it may be taken at the first sign of a developing hypoglycemic reaction. Patients (and their families or caregivers and other close contacts) should be properly instructed in the technique of preparing and administering glucagon before an emergency situation occurs. Patients should be instructed to notify their clinician when hypoglycemic reactions occur so that appropriate adjustment of insulin dosage can be made.

Since glucagon is a protein, the possibility of immunogenicity should be considered. Antibodies to glucagon have been detected in some patients receiving intranasal glucagon; however, no neutralizing antibodies have been detected.5

Glucagon is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,4,5,6

Pediatric Precautions

Glucagon has been used safely and effectively for the treatment of hypoglycemia in children.1,4,6 Prefilled syringes and auto-injectors of glucagon have been used safely in children 2 years of age and older.6 Safety and efficacy of intranasal glucagon have been established in children 4 years of age and older.5 Safety and efficacy of glucagon in diagnostic procedures in children have not been established.1,4,9

Geriatric Precautions

There is insufficient experience from clinical trials in patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1,5,6 However, other clinical experience has not identified differences in response between geriatric patients and younger patients.1,5,6

When glucagon is used as a diagnostic aid in geriatric patients, dosage of the drug should be selected with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients.1

Pregnancy and Lactation

Available data from case reports and a limited number of observational studies involving administration of glucagon in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes.4 Multiple small studies have demonstrated that endogenous glucagon is not transferred across the human placenta during early gestation.4 No embryofetal toxicity was observed in reproduction studies in rats and rabbits at glucagon doses up to 100 and 200 times, respectively, the human dose (based on body surface area).4

It is not known whether glucagon is distributed into human milk.4 Effects of the drug on breast-fed infants and on milk production also are unknown.4 However, because glucagon is a peptide and would be expected to be broken down to its constituent amino acids in the infant's digestive tract, the drug is unlikely to harm an exposed infant.4

Anticholinergic Agents

The inhibitory effects of anticholinergic agents and glucagon on GI motility may be additive, potentially increasing the risk of adverse GI effects; concomitant use of the drugs during radiographic examinations is not recommended.4

Beta-Adrenergic Blocking Agents

Patients receiving β-adrenergic blocking agents may experience a transient increase in pulse and blood pressure after receiving glucagon.4,5,6 Treatment of these increases in blood pressure and heart rate may be required in patients with coronary artery disease.4

Decongestants

In patients with the common cold, use of nasal decongestants did not alter the pharmacokinetics or pharmacodynamics of intranasally administered glucagon.5

Indomethacin

Glucagon may be ineffective for increasing blood glucose concentration or may even produce hypoglycemia in patients receiving indomethacin.4,5,6 Blood glucose concentrations should be monitored when glucagon is administered to patients receiving indomethacin.4

Insulin

Because insulin and glucagon have antagonistic effects, blood glucose concentration should be monitored when glucagon is used as a diagnostic aid during radiographic examinations in patients receiving insulin.4

Warfarin

Glucagon may increase the anticoagulant effect of warfarin.4,5,6 Patients should be monitored for unusual bruising or bleeding; adjustment of warfarin dosage may be required.4

Pharmacology

Exogenous glucagon elicits all the pharmacologic responses usually produced by endogenous glucagon.

Glucagon is an antihypoglycemic agent that increases blood glucose concentration by stimulating hepatic glycogenolysis. Some of the metabolic effects produced by glucagon in various tissues (e.g., liver, adipose tissue) are similar to those of epinephrine. Glucagon stimulates the formation of adenylate cyclase, which catalyzes the conversion of ATP to cAMP, particularly in the liver and in adipose tissue. Formation of cAMP initiates a series of intracellular reactions including activation of phosphorylase, which promote the degradation of glycogen to glucose. The increase in blood glucose concentration occurs within minutes. Endogenous secretion of glucagon is stimulated when blood glucose concentration is low or when serum insulin concentration is increased. In general, the actions of glucagon are antagonistic to those of insulin; however, glucagon has been reported to stimulate insulin secretion in healthy individuals and in patients with type 2 diabetes mellitus. Glucagon also has been reported to enhance peripheral utilization of glucose. The intensity of the hyperglycemic effect of glucagon depends on hepatic glycogen reserve and the presence of phosphorylases. The action of glucagon is not blocked by sympatholytic agents such as dihydroergotamine. The hyperglycemic effect of glucagon is increased and prolonged by concomitant administration of epinephrine.

Glucagon produces extrahepatic effects that are independent of its hyperglycemic action. Although the exact mechanism(s) of action has not been conclusively determined, glucagon produces relaxation of smooth muscle of the stomach, duodenum, small intestine, and colon. The drug has also been shown to inhibit gastric and pancreatic secretions.

Glucagon has a positive inotropic and chronotropic effect. Following rapid IV administration in anesthetized animals, glucagon causes a decrease in blood pressure. Glucagon has also been shown to decrease plasma amino nitrogen concentration; enhance renal excretion of electrolytes; decrease synthesis of protein and fat; increase the metabolic rate; and, following prolonged administration, to produce a diabetic effect, which may persist for several days.

Pharmacokinetics

Absorption

Because of its polypeptide nature, glucagon is destroyed in the GI tract, and therefore must be administered parenterally or intranasally.

Following parenteral administration of glucagon, blood glucose concentration increases within 10 minutes and peak blood glucose concentrations occur within 30 minutes; hyperglycemic activity persists for 60-90 minutes following IV or IM injection.1,4 Following intranasal administration of glucagon, glucose concentration increases within 10 minutes and peak glucose concentrations are attained within approximately 60 minutes.5

Following IV administration of a single 0.25- to 0.5-mg or 2-mg dose of the drug, relaxation of GI smooth muscle occurs within 1 minute and persists for 9-17 or 22-25 minutes, respectively.1,4 Following IM administration of a single 1-mg dose of the drug, relaxation of GI smooth muscle occurs within 8-10 minutes and persists for 12-27 minutes; after a single 2-mg IM dose, relaxation of GI smooth muscle occurs within 4-7 minutes and persists for 21-32 minutes.1,4

Peak plasma glucagon concentrations are obtained in about 10-13, 15-20, or 10-50 minutes following IM, intranasal, or subcutaneous administration.1,4,5,6,9

Nasal congestion associated with the common cold does not alter the pharmacokinetics or pharmacodynamics of intranasally administered glucagon.5

Elimination

Glucagon has a plasma half-life of about 8-18, 26-45, or 32-42 minutes following IV, IM, or subcutaneous administration, respectively.1,4,6,9,25 Following intranasal administration, the median half-life is approximately 35 minutes in adults and 21-31 minutes in pediatric patients.5 Glucagon is extensively degraded in the liver, kidney, and plasma.1,4,5,6

Chemistry and Stability

Chemistry

Glucagon is a hormone synthesized and secreted by the α₂ cells of the pancreatic islets of Langerhans. Glucagon is a straight-chain polypeptide with a molecular weight of 3483 and contains 29 amino acids; histidine is the N-terminal acid and threonine is the C-terminal residue of the molecule. Glucagon is not chemically or structurally related to insulin; unlike insulin, glucagon does not contain cysteine and has no disulfide linkages. Although structurally identical to endogenous human glucagon, commercially available glucagon is prepared synthetically (e.g., via solid-phase peptide synthesis)6,9,17 or using recombinant DNA technology and special laboratory strains of nonpathogenic Escherichia coli or Saccharomyces cerevisiae .1,4,18 One mg of glucagon is equivalent to 1 International Unit (IU, unit).1

Glucagon occurs as a fine, white or off-white, crystalline powder; is practically odorless and tasteless; and is practically insoluble in water and soluble in dilute alkali and acid solutions. Commercially available glucagon for injection is a sterile, white to off-white, lyophilized powder for reconstitution for IV, IM, or subcutaneous administration; a sterile diluent containing glycerin, hydrochloric acid, and sterile water for injection is provided by the manufacturer for reconstitution.1 Commercially available glucagon hydrochloride for injection is commercially available as a sterile, white, lyophilized powder for reconstitution for IV, IM, or subcutaneous administration; glucagon hydrochloride for injection is supplied in single-dose vials either alone or in kits that also include sterile water for injection for reconstitution.4,9,18 Glucagon injection is commercially available as a clear, colorless to pale yellow solution in prefilled syringes and auto-injectors for subcutaneous injection.6 Glucagon also is commercially available as a preservative-free white powder in a single-use intranasal device.5

Stability

Glucagon lyophilized powder for injection should be stored at 20-25°C and should not be used past the expiration date.1 Glucagon hydrochloride lyophilized powder for injection is stable for at least 24 months following the date of manufacture when stored at 20-25°C.4,9,18 The lyophilized powders should not be frozen and should be kept in the original packages for protection from light.1,4,9,18 Following reconstitution, solutions of glucagon or glucagon hydrochloride should be used immediately.1,4,9,18

Glucagon injection in prefilled syringes or auto-injectors should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.6 Glucagon injection should not be refrigerated or frozen, and should not be exposed to extreme temperatures.6 The prefilled syringes and auto-injectors should be stored in the original sealed foil pouch until time of use.6

Glucagon nasal powder should be stored at temperatures up to 30°C; the intranasal device should be stored in the shrink-wrapped tube provided by the manufacturer for protection from moisture until time of use.5

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Eli Lilly and Company. Glucagon for injection prescribing information. Indianapolis, IN; 2021 Jan.

4. Boehringer Ingelheim. GlucaGen^® (glucagon hydrochloride) for injection prescribing information. Ridgefield, CT; 2021 Jul.

5. Eli Lilly and Company. Baqsimi^® (glucagon) nasal powder prescribing information. Indianapolis, IN; 2021 Aug.

6. Xeris Pharmaceuticals. Gvoke^® PFS and Hypopen (glucagon) injection prescribing information. Chicago, IL; 2021 Jul.

7. Rickels MR, Ruedy KJ, Foster NC et al. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized crossover noninferiority study. Diabetes Care . 2016; 39:264-70. [PubMed 26681725]

8. Sherr JL, Ruedy KJ, Foster NC et al. Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care . 2016; 39:555-62. [PubMed 26884472]

9. Fresenius Kabi USA, LLC. Glucagon hydrochloride for injection prescribing information. Lake Zurich, IL; 2020 Aug.

10. Kusumoto FM, Schoenfeld MH, Barrett C et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation . 2019; 140:e382-e482. [PubMed 30586772]

11. Lieberman P, Nicklas RA, Randolph C et al. Anaphylaxis--a practice parameter update 2015. Ann Allergy Asthma Immunol . 2015; 115:341-84. [PubMed 26505932]

15. Shepherd G. Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers. Am J Health Syst Pharm . 2006; 63:1828-35. [PubMed 16990629]

16. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212097Orig1s000: Clinical review(s). From FDA website. [Web]

17. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210134Orig1s000: Non-clinical review(s). From FDA website. [Web]

18. Novo Nordisk. GlucaGen^® Hypokit (glucagon hydrochloride) for injection prescribing information. Plainsboro, NJ; 2021 Mar.

19. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021; 44:S73-S84. [PubMed 33298417][Web]

20. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol . 2016; 81:453-61. [PubMed 26344579][PubMedCentral]

21. Van de Voorde P, Turner NM, Djakow J et al. European Resuscitation Council Guidelines 2021: Paediatric Life Support. Resuscitation . 2021; 161:327-387. [PubMed 33773830]

22. Francuzik W, Dölle-Bierke S, Knop M et al. Refractory Anaphylaxis: Data From the European Anaphylaxis Registry. Front Immunol . 2019; 10:2482. [PubMed 31749797][PubMedCentral]

23. Cardona V, Ansotegui IJ, Ebisawa M et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J . 2020; 13:100472. [PubMed 33204386][PubMedCentral]

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

25. Eli Lilly and Company. Glucagon for injection prescribing information. Indianapolis, IN; 2005 Feb.

196. Panchal AR, Bartos JA, Cabañas JG et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2020; 142:S366-S468. [PubMed 33081529]