GlucaGen

Generic Name: Glucagon
Class: Glycogenolytic Agents
ATC Class: H04AA01
VA Class: HS503
CAS Number: 16941-32-5

Introduction

Antihypoglycemic agent; biosynthetic (recombinant DNA-derived) form of human glucagon hormone prepared using special laboratory strains of nonpathogenic Escherichia coli or Saccharomyces cerevisiae.1 2 a b c

Uses for GlucaGen

Hypoglycemia

Emergency treatment of severe hypoglycemia; effective only if liver glycogen available.a b c

Convenient for use in emergency situations when dextrose cannot be administered IV;a however, severe hypoglycemia initially should be treated with IV dextrose, if possible.b

Do not substitute for IV dextrose in emergency situations in which hypoglycemia is suspected but not established.a

Increase in blood glucose concentration produced by glucagon not as great in patients with type 1 diabetes mellitus as in those with type 2 diabetes mellitus; administer supplemental carbohydrate as soon as possible, especially to pediatric patients.a b c

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Little or no value for treatment of chronic hypoglycemia or hypoglycemia associated with starvation or adrenal insufficiency.a

Radiographic Examination of GI Tract

Diagnostic aid in radiographic examination of the stomach, duodenum, small intestine, and colon when a hypotonic state would be advantageous; appears to be as effective as antimuscarinic agents and associated with fewer adverse effects.a b c

β-Adrenergic or Calcium-Channel Blocking Agent Overdosage

Has been used with some success as a cardiac stimulant for management of cardiac manifestations (e.g., bradycardia, hypotension, myocardial depression, impaired conduction, cardiogenic shock, cardiac arrest) associated with severe β-adrenergic blocking agent overdosage or calcium-channel blocking agent overdosage;a d g h i j k l has successfully reversed such manifestations in patients unresponsive to other drugs (e.g., atropine, dobutamine, dopamine, epinephrine).a j l

Administer early in the management of severe β-adrenergic blocking agent overdosage.a i j k

Sensitivity Reactions

Has been used rarely in patients with anaphylaxis unresponsive to epinephrine, particularly in patients receiving β-adrenergic blocking agents, who have an increased incidence and severity of anaphylaxis and may develop a paradoxical response to epinephrine.l m May prevent cardiopulmonary arrest.l

GlucaGen Dosage and Administration

General

  • Monitor blood glucose concentrations in patients with hypoglycemia until patient is asymptomatic.b c

  • After clinical response is achieved or following completion of procedure, administer supplemental carbohydrate to restore liver glycogen and prevent secondary hypoglycemia.1 a b c

Administration

IV, IM, or Sub-Q Administration

Administer by IV, IM, or sub-Q injection.a b c

Reconstitution

Glucagon (Lilly): Reconstitute by adding 1 mL of sterile diluent to vial labeled as containing 1 mg of glucagon to provide a solution containing 1 mg of glucagon per mL.1 b Do not use concentrations >1 mg/mL.1 b Use only diluent provided by manufacturer; do not use diluent to reconstitute other drugs.1 b

Glucagon hydrochloride (GlucaGen): Reconstitute by adding 1 mL of sterile diluent (if supplied by manufacturer) or 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.2 c

Use reconstituted solutions immediately; discard any unused portion.1 2 b c

Dilution

To prepare continuous IV infusion solution for treatment of β-adrenergic or calcium-channel blocking agent overdosage, dilute reconstituted glucagon in 5% dextrose injection.a h

Dosage

Available as glucagon (rDNA origin, Lilly) and glucagon hydrochloride (rDNA origin, GlucaGen); dosage expressed in terms of glucagon.a b c

1 mg of glucagon is equivalent to 1 International Unit (IU, unit).1 b c

Pediatric Patients

Hypoglycemia
Glucagon (Lilly)
IV, IM, or Sub-Q

Children <20 kg: 0.5 mg.1 b d e f Alternatively, 20–30 mcg/kg may be administered.1 b d

Children ≥20 kg: 1 mg.1 b d e f

An additional dose may be administered if patient does not awaken within 15 minutes following administration of drug; however, seek emergency assistance so that IV dextrose may be administered because of potential serious adverse effects associated with prolonged cerebral hypoglycemia.a b c If patient fails to respond to glucagon, IV dextrose must be given.a c

Glucagon Hydrochloride (GlucaGen)
IV, IM, or Sub-Q

Children <25 kg: 0.5 mg.2 c d f

Children ≥25 kg: 1 mg.2 c d f

Alternatively, if weight is not known, usual dose in children <6–8 years of age is 0.5 mg and in children >6–8 years of age is 1 mg.c f

An additional dose may be administered if patient does not awaken within 15 minutes following administration of drug; however, seek emergency assistance so that IV dextrose may be administered because of potential serious adverse effects associated with prolonged cerebral hypoglycemia.a c If patient fails to respond to glucagon, IV dextrose must be given.a c

β-Adrenergic or Calcium-Channel Blocking Agent Overdosage
IV

In children, initially, 50–100 mcg/kg as a loading dose (i.e., bolus), followed by a continuous IV infusion of 100 mcg/kg per hour.d

Alternatively, in adolescents, some experts have suggested a dose of 5–10 mg administered over several minutes, followed by an IV infusion of 1–5 mg/hour for the treatment of β-adrenergic blocking agent overdosage.l

Adults

Hypoglycemia
Glucagon (Lilly) and Glucagon Hydrochloride (GlucaGen)
IV, IM, or Sub-Q

1 mg.1 2 b c

An additional dose may be administered if patient does not awaken within 15 minutes following administration of drug; however, seek emergency assistance so that IV dextrose may be administered because of potential serious adverse effects associated with prolonged cerebral hypoglycemia.a b If patient fails to respond to glucagon, IV dextrose must be given.a c

Radiographic Examination of GI Tract
IV

Stomach, duodenum, or small intestine: 0.25–2 mg, depending on onset of action and duration of effect required for specific examination.1 2 3 b c (See Absorption under Pharmacokinetics.)

For relaxation of the stomach, one manufacturer (Lilly) has recommended a dose of 0.5 mg since the stomach is less sensitive to effect of drug.1 3 b

IM

Stomach, duodenum, or small intestine: 1–2 mg, depending on onset of action and duration of effect required for specific examination.1 2 3 b c (See Absorption under Pharmacokinetics.)

For relaxation of the stomach, one manufacturer (Lilly) has recommended a dose of 2 mg since the stomach is less sensitive to effect of drug.1 3 b

Colon: One manufacturer (Lilly) has recommended a dose of 2 mg approximately 10 minutes prior to initiating examinations of colon; may facilitate a more satisfactory radiographic examination.1 3 b

β-Adrenergic or Calcium-Channel Blocking Agent Overdosage
IV

Initially (as a loading dose), 50–150 mcg/kg (approximately 3–10 mg for a 70-kg patient)j over 1–2 minutes; higher doses may be needed if ineffective.a d h i j k Loading dose has been repeated every 3–10 minutes, if needed; however, continuous IV infusion should follow loading dose administration because of drug’s short duration of action.j k (See Absorption under Pharmacokinetics.)

Continuous IV infusion: 1–5 mg/hour; infusion rate may be reduced according to response.a d h i j k Alternatively, a continuous IV infusion of 50–100 mcg/kg per hour has been administered.i k Also, some experts suggest an IV infusion rate based on effective loading dose per hour (e.g., if initial effective cumulative loading dose is 10 mg, hourly infusion rate should be 10 mg/hour).j k

Sensitivity Reactions
IV or IM

1–2 mg every 5 minutes has been administered in patients with anaphylaxis unresponsive to epinephrine.l

Special Populations

Geriatric Patients

Select dosage with caution, usually initiating therapy at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.b (See Geriatric Use under Cautions.)

Cautions for GlucaGen

Contraindications

  • Known hypersensitivity to glucagon or any ingredient in the formulation.b c

  • Pheochromocytoma.b c (See Pheochromocytoma under Cautions.)

  • Glucagon (rDNA origin, GlucaGen): Insulinoma.c (See Insulinoma under Cautions.)

Warnings/Precautions

Warnings

Insulinoma

IV administration may produce an initial increase in blood glucose concentrations in patients with insulinoma; however, insulinoma may release insulin and secondary hypoglycemia may occur.b Administer glucose orally, IV, or by gavage, whichever is most appropriate, or other adequate carbohydrate if patient develops symptoms of hypoglycemia following administration of drug.b c

Use with caution in patients with suspected insulinoma or history suggesting insulinoma.a b c

Glucagon (rDNA origin, GlucaGen) contraindicated in patients with insulinoma.c

Pheochromocytoma

Exogenous administration of glucagon stimulates release of catecholamines, which may cause a sudden and marked increase in BP in patients with pheochromocytoma.a b c If BP suddenly increases, phentolamine mesylate may be administered IV in an attempt to control BP.b

Use contraindicated in patients with known pheochromocytoma; use with caution in patients with suspected pheochromocytoma or history suggesting pheochromocytoma.a b c

Sensitivity Reactions

Hypersensitivity Reactions

Consider possibility of hypersensitivity reactions since glucagon is a protein.a

Allergic reactions, including rash,2 c urticaria, respiratory distress, and rarely, hypotension and anaphylaxis with respiratory distress reported.1 2 b Anaphylactic reactions generally occurred in association with endoscopic examination during which patients often received other agents (e.g., contrast media, local anesthetics).2 c

If patient develops respiratory difficulties following administration of drug, administer standard therapy for anaphylaxis (e.g., epinephrine).c

Glucagon-specific antibodies not detected during a 3-month study of individuals receiving either animal-source glucagon or biosynthetic glucagon (rDNA origin).1 b

General Precautions

Treatment Considerations

Liver glycogen must be available when glucagon is used for treatment of severe hypoglycemia;a b c otherwise, an inadequate reversal of hypoglycemia may occur.c Use with caution in patients with conditions associated with reduced concentrations of releasable glucose in the liver (e.g., prolonged fasting, starvation, adrenal insufficiency, chronic hypoglycemia);a b c administer glucose in these patients.b

Use with caution in patients with diabetes.c

Cardiovascular Effects

Possible tachycardia and hypertension; may require treatment in patients with CAD.c

Specific Populations

Pregnancy

Category B.b c

Lactation

Not known whether glucagon is distributed into milk; use with caution.b c However, one manufacturer states that drug is not likely to have an effect on infants if ingested;c drug has short half-life and intact drug is not absorbed in GI tract.b c (See Absorption and see Elimination under Pharmacokinetics.)

Pediatric Use

Safety and efficacy established for treatment of hypoglycemia.1 2 b c

Safety and efficacy not established for use as a diagnostic aid.1 2 b c

Geriatric Use

Insufficient experience from clinical trials in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.b However, other clinical experience has not identified differences in response between geriatric patients and younger adults.b

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.b (See Geriatric Patients under Dosage and Administration.)

Use with caution to inhibit GI motility in geriatric patients with known cardiac disease.c

Common Adverse Effects

Dose-related nausea,a b c vomiting.a b c

Interactions for GlucaGen

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Possible increased adverse effectsa b c

β-Adrenergic blocking agents

Possible increased pulse rate and BPc

Epinephrine

Increased and prolonged hyperglycemic effect of glucagona

Sympatholytic agents (e.g., dihydroergotamine)

Do not appear to inhibit actions of glucagona

GlucaGen Pharmacokinetics

Absorption

Bioavailability

Hydrolyzed and destroyed in GI tract because of polypeptide nature;a b c must administer parenterally.a

Prolonged absorption from injection site following IM administration.c

Peak plasma glucagon concentrations attained in about 20 or 13 minutes following sub-Q or IM administration, respectively.b c

Peak blood glucose concentrations attained in about 30–45,b c 26–30,b c or 5–20 minutesc following sub-Q, IM, or IV administration, respectively.b c

Onset

Blood glucose concentrations increase within 10 minutes following IM administration.c

Unconscious patient with severe hypoglycemia usually awakens within 15 minutes following administration.b

Smooth muscle relaxation occurs in 45 seconds to 1 minute following IV administration of 0.25–2 mg, and within 8–10 or 4–7 minutes following IM administration of 1 or 2 mg, respectively.1 2 b c

Duration

Hyperglycemic activity persists for about 60–90 minutes.2 c

Smooth muscle relaxation persists for about 9–17 or 22–25 minutes following IV administration of 0.25–0.5 mg or 2 mg, respectively, and for about 12–27 or 21–32 minutes following IM administration of 1 or 2 mg, respectively.1 2 b c

Elimination

Metabolism

Exact metabolic fate not established; extensively degraded in plasma, liver, and kidneys.a b c

Elimination Route

Urinary excretion of intact drug not established.b

Half-life

8–18 minutes following IV administration.1 b

45 minutes following IM administration.2 c

Stability

Storage

Parenteral

For Injection

Glucagon (rDNA origin, Lilly): 20–25°C.1 b Use reconstituted solution immediately; discard any unused portion.a b

Glucagon hydrochloride (rDNA origin, GlucaGen): 20–25°C for up to 24 months.c Do not freeze; protect from light.c Use reconstituted solution immediately; discard any unused portion.a c

Actions

  • Structurally and pharmacologically identical to endogenous human glucagon, a hormone synthesized and secreted by α2 cells of pancreatic islets of Langerhans.a b c

  • Increases blood glucose concentration by stimulating hepatic glycogenolysis.a b c

  • Produces some metabolic effects in various tissues (e.g., liver, adipose tissue) similar to those of epinephrine.a

  • Stimulates formation of adenylate cyclase, which catalyzes conversion of adenosine triphosphate (ATP) to cyclic adenosine-3’,5’-monophosphate (cAMP), particularly in liver and adipose tissue, resulting in initiation of a series of intracellular reactions (e.g., activation of phosphorylase) promoting degradation of glycogen to glucose.a

  • Actions usually antagonistic to insulin; however, may stimulate insulin secretion in healthy individuals and in patients with type 2 diabetes mellitus.a

  • May enhance peripheral utilization of glucose.a

  • Intensity of hyperglycemic effect depends on hepatic glycogen reserve and presence of phosphorylases.a

  • Produces extrahepatic effects independent of hyperglycemic action, although mechanism not fully elucidated; relaxes smooth muscle of the stomach, duodenum, small intestine, and colon.a b c

  • Inhibits gastric and pancreatic secretions.a

  • Produces positive inotropic and chronotropic effects.a c

  • Decreases plasma amino nitrogen concentrations, enhances renal excretion of electrolytes, decreases synthesis of protein and fat, increases metabolic rate, and produces a diabetic effect, which may persist for several days, following prolonged administration.a

Advice to Patients

  • Importance of advising patients with diabetes about nature of disease, preventing and detecting complications, and managing their condition.a

  • Importance of providing manufacturer’s patient information.a b c

  • Importance of understanding proper storage, preparation, and administration techniques before an emergency situation occurs, including appropriate dosages to administer in adults and children.a b c

  • Importance of properly instructing patients and family members in detection and treatment of mild hypoglycemia in order to prevent severe hypoglycemia.a b c

  • Importance of instructing patients that glucagon should be used only for severe hypoglycemia; provide instruction in detection of severe hypoglycemia.c

  • Provide instructions regarding measures to prevent hypoglycemic reactions due to insulin (e.g., adhering to diet, insulin, and exercise regimens; regular monitoring of blood glucose concentrations; routinely carrying sugar, candy, or other readily absorbable carbohydrate to treat symptoms of hypoglycemia).a b

  • Importance of informing family members to arouse patient as quickly as possible because prolonged hypoglycemia may result in damage to CNS, and to administer supplemental carbohydrates as soon as the patient awakens and is able to swallow (particularly in children and adolescents).b c

  • Importance of informing clinicians if hypoglycemic reactions occur so that appropriate adjustment of treatment regimen may be made.a b c

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.b c

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

  • Importance of advising patients of other important precautionary information.b c (See Cautions.)

Preparations

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

Glucagon (Recombinant DNA origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

1 mg (1 unit)

Glucagon Emergency Kit (with 1 mL diluent available in Hyporet disposable syringe)

Lilly

Glucagon Hydrochloride (Recombinant DNA origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

1 mg (1 unit) (of glucagon)

GlucaGen

Bedford

GlucaGen Diagnostic Kit (with 1 mL sterile water for injection diluent)

Bedford

GlucaGen HypoKit (with 1 mL sterile water for injection diluent available in disposable syringe)

Novo Nordisk

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

GlucaGen HypoKit 1MG Solution (NOVO NORDISK): 1/$152.53 or 3/$442.38

Glucagon Emergency 1MG Kit (LILLY): 1/$140.99 or 3/$384.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Eli Lilly and Company. Glucagon (rDNA origin) for injection prescribing information. Indianapolis, IN; 1999 Feb.

2. Bedford Laboratories. GlucaGen (glucagon [rDNA origin]) for injection prescribing information. Bedford, OH; 1999 Jul.

3. Bedford Laboratories, Bedford, OH: Personal communication.

a. AHFS Drug Information 2007. McEvoy GK, ed. Glucagon. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 3210-1.

b. Eli Lilly and Company. Glucagon (rDNA origin) for injection prescribing information. Indianapolis, IN; 2005 Feb.

c. Novo Nordisk. GlucaGen (glucagon [rDNA origin]) for injection prescribing information. Princeton, NJ; 2004 Dec.

d. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby: 2002:27-8, 49, 705-6.

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

f. Novo Nordisk, Princeton, NJ: Personal communication.

g. Anon. Pharmaceutical drug overdose. Treat Guidel Med Lett. 2006; 4:61-6. [PubMed 16929234]

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

i. Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003; 41:595-602. [PubMed 14514004]

j. Kerns W. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007; 25:309-31; abstract viii. [PubMed 17482022]

k. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev. 2004; 23:223-38. [PubMed 15898828]

l. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

m. Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J. 2005; 22:272-3. [PubMed 15788828]

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