GLUCAGON EMERGENCY KIT

General Administration Information
For storage information, see specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Glucagon is administered by subcutaneous, intramuscular, or intravenous injection. Some products (e.g., Gvoke) are only for subcutaneous use.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Reconstitution of Lyophilized Glucagon injection 1 mg vial:
-Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial of lyophilized injection powder.
-Shake gently until the powder is completely dissolved and no particles remain.
-The reconstituted solution should be clear and of water-like consistency. Discard if there are signs of gel formation or particles.
-The final concentration is approximately 1 mg/mL.
-Use immediately after reconstitution. Discard any unused portion.
Intravenous Administration
IV Push
-Must be administered by a health care professional only.
-After reconstitution, administer the dose IV as a bolus over a time period of 1 minute.
-Single bolus doses above 1 mg IV have caused nausea and vomiting and are not recommended.

Intramuscular Administration
-See the manufacturer's "Instructions for Use" for the specific product prescribed.
-Reconstitute as directed. Withdraw the correct patient dose.
-Inject IM into the upper arm, thigh, or buttocks [Upper arm is usually reserved for older children and adolescents only].
-Discard any unused portion.

Subcutaneous Administration
-Train patients and/or caregivers in the proper injection technique.
-See the manufacturer's "Instructions for Use" for the specific product prescribed.

GlucaGen Subcutaneous Administration (e.g., GlucaGen, GlucaGen Hypokit)
-Reconstitute as directed. Withdraw the correct dose from the vial.
-Inject subcutaneously in the upper arm, thigh, or buttocks.
-If used as an outpatient: Call for emergency assistance immediately after administering the dose.
-Once patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
-Discard any unused portion. Put used syringes in an FDA-cleared sharps disposal container right away after use.

Gvoke Subcutaneous Administration (i.e., auto-injector, pre-filled syringe, and vial and syringe kit)

-For subcutaneous use only.
-For the auto-injector or pre-filled syringe: Do not open foil pouch until it is ready to be used.
-For the vial and syringe kit: Store in original carton until ready to administer. Reconstitute as directed.
-Inspect prior to use. The solution should be clear and colorless to pale yellow and free of particles. Do not use if the solution is discolored or contains particulate matter.
-Withdraw the correct dose (if required).
-Administer in the lower abdomen, outer thigh, or outer upper arm.
-If used as an outpatient: Call for emergency assistance immediately after administering the dose.
-If there has been no response after 15 minutes, administer an additional dose from a new device (or vial and syringe kit).
-Once patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
-Do not reuse injectors or syringes. Each injection or vial contains 1 dose of glucagon and cannot be reused; discard any unused portion. Dispose of used auto-injector or syringes properly in an FDA-cleared sharps disposal container right away after use.



Inhalation Administration
Intranasal Inhalation Administration
Nasal powder (Baqsimi)-For nasal use only.
-Do not remove the shrink wrap or open the tube until it is ready to be used. Opening the tube could expose it to moisture causing it to not work as expected.
-Do not push the plunger or test the device prior to administration.
-When ready to use, remove the shrink wrap by pulling on the red stripe. Open the lid and remove the device from the tube without pressing the plunger.
-Hold device between fingers and thumb and administer the dose by inserting the tip into 1 nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled.
-Call for emergency assistance immediately after administering the dose.
-Once patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
-Do not reuse glucagon device. Each device contains 1 dose of glucagon and cannot be reused.

Nausea (less than 10%) and vomiting (less than 1%) are the most common adverse reactions associated with glucagon administration; they are more likely to occur at doses above 1 mg and with rapid administration. Nausea (45%), headache (7%), vomiting (19%), and abdominal pain (3%) were the most frequently reported systemic adverse reactions associated with glucagon auto-injector administration in pediatric patients. Nausea (16.7%), headache (25%), and vomiting (30.6%) are the most frequently reported systemic adverse reactions associated with intranasal glucagon administration in pediatric patients 4 years of age and older. These reactions also occur with low blood glucose; therefore, the exact incidence attributable to the drug is unclear. Dizziness, asthenia, pallor, diarrhea, and somnolence were reported during postmarketing experience with glucagon.

Allergic reactions to glucagon may occur and include generalized rash and in some cases anaphylactic shock with breathing difficulties and hypotension. The anaphylactoid reactions have generally occurred in association with endoscopic examination during which patients often received other agents, including contrast media and local anesthetics. Should these reactions occur after glucagon administration, administer standard treatment for anaphylaxis, including an injection of epinephrine in the event of respiratory difficulties. Hypotension, as an anaphylactoid-related reaction to glucagon, is rare. However, hypotension has been reported up to 2 hours after administration in patients receiving glucagon as premedication for upper gastrointestinal (GI) endoscopy procedures. Glucagon exerts positive inotropic and chronotropic effect and may, therefore, cause transient sinus tachycardia and hypertension after administration; increases in blood pressure and pulse rate may require therapy in patients with pheochromocytoma or coronary artery disease. Because glucagon is a cardiac stimulant, it can theoretically cause chest pain in patients with angina. The actual incidence of this reaction is not known but appears to be rare. In clinical trials, tachycardia and hypertension were reported after intranasal glucagon administration in adult and pediatric patients.

Hypoglycemia (less than 1%) and hypoglycemic coma (less than 1%) have been reported when glucagon has been used as a diagnostic aid. When used as a diagnostic aid in patients with diabetes, glucagon may cause hyperglycemia and should be used with caution. Hypoglycemia (39%) and hyperglycemia (7%) were reported in clinical trials of glucagon auto-injector administration in pediatric patients.

Severe hyponatremia and thrombocytopenia has been reported in a neonate after continuous infusion of glucagon 1 mg/day over 24 hours to treat hypoglycemia. Serum sodium and platelet values returned to normal values 24 hours after glucagon discontinuation. As a result of the stimulation of insulin release, it is possible that susceptible patients may experience hypokalemia. Monitor serum electrolytes as appropriate.

In patients receiving continuous glucagon infusion, necrolytic migratory erythema (NME), a skin rash commonly associated with glucagonomas (glucagon-producing tumors), and characterized by scaly, erythematous plaques with pruritus, bullae (bullous rash), and erosions, has been reported during postmarketing surveillance. NME lesions may affect the face, groin, perineum, and legs or may be more widespread. Treatment of NME is the discontinuation of glucagon; treatment with corticosteroids is not effective. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. In clinical trials, pruritus was reported after intranasal glucagon administration in adult and pediatric patients.

Nasal and ocular symptoms were reported after intranasal glucagon administration. Upper respiratory tract irritation, defined as nasal discomfort, nasal congestion, and sneezing, was reported in 16.7% of pediatric patients aged 4 and older. Epistaxis and cough were reported in adult patients. During clinical trials, the following adverse reactions were reported in pediatric patients: watery eyes (47.2%), nasal congestion (41.7%), nasal itching (27.8%), rhinorrhea (25%), sneezing (19.4%), itchy eyes (16.7%), redness of eyes (13.9%), itching of throat (2.8%), and itching of ears (2.8%). Dysgeusia and upper respiratory tract irritation events (nasal pruritus, throat irritation, and parosmia) were also reported after intranasal glucagon administration in adult and pediatric patients.

As with all therapeutic proteins, there is a potential for immunogenicity. In 3 clinical trials, 3 out of 124 patients (2%) had treatment-emergent anti-drug antibody formation as detected by an affinity capture elution (ACE) ligand-binding immunogenicity assay after receiving intranasal glucagon treatment. No neutralizing antibodies were detected.

Injection site reaction was reported with the glucagon auto-injector in 3% of pediatric patients during clinical trials. Injection site discomfort and urticaria were both reported in 3% of pediatric patients.

Glucagon is contraindicated in patients with a known hypersensitivity to glucagon or lactose, or any other constituent of the formulations. Immediate hypersensitivity reactions may occur after administration of glucagon, as demonstrated by rare cases of anaphylactic shock, respiratory difficulties, hypotension, and rash.

Glucagon is contraindicated in patients who have been diagnosed with or suspected of having an insulinoma. In patients with insulinoma, glucagon may produce an initial increase in blood glucose; however, glucagon administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from the insulinoma. Any patient developing symptoms of hypoglycemia after a dose of glucagon should be given glucose orally or intravenously, whichever is most appropriate. Glucagon is also contraindicated in patients with glucagonoma when used as a diagnostic aid. Test patients suspected of having glucagonoma for blood levels of glucagon prior to diagnostic use, and monitor for changes in blood glucose levels during treatment. If a patient develops symptoms of hypoglycemia after a diagnostic dosage, administer glucose orally
or intravenously.

Glucagon is contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor. If the patient develops a substantial increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure for the short time that control would be needed.

Glucagon is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation (e.g., anorexia nervosa), malnutrition, adrenal insufficiency, or chronic hypoglycemia may not have adequate levels of hepatic glycogen for glucagon administration to be effective. Patients with these conditions should be treated with glucose. After the end of a diagnostic procedure where glucagon has been administered, oral carbohydrates should be administered to patients who have been fasting, if this is compatible with the diagnostic procedure applied.

Glucagon may increase myocardial oxygen demand, blood pressure, and pulse rate which may be life-threatening in patients with cardiac disease or coronary artery disease. Cardiac monitoring is recommended in patients with cardiac disease during use of glucagon as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy.

Inform patients that hypoglycemia has occurred when glucagon has been used for diagnostic purposes. Inform patients of the symptoms of hypoglycemia and how to treat it. Advise patients to avoid activities requiring coordination and concentration, such as driving or operating machinery, until ingesting a meal. Advise patients to inform their health care provider if hypoglycemia occurs so that treatment may be given if necessary. When used as a diagnostic aid in patients with diabetes mellitus, glucagon may cause hyperglycemia; monitor such patients for changes in blood glucose levels during treatment.

Description: Recombinant glucagon is identical to endogenous glucagon, a hormone synthesized by the alpha-2 cells of the pancreatic islets of Langerhans that acts to increase blood glucose. Exogenous glucagon is most commonly used in the treatment of emergent and/or refractory hypoglycemia after oral carbohydrates and/or intravenous (IV) dextrose infusion. Glucagon is advantageous because it may be given without venous access; it can be given intranasally, intravenously, intramuscularly, or subcutaneously. Glucagon is also approved for use as a diagnostic aid in adults undergoing endoscopic or radiologic examinations of the GI tract; off-label use for this purpose in selected pediatric patients is also described. Glucagon is used off-label as a cardiac stimulant as an adjunctive treatment for refractory bradycardia in beta-adrenergic blocker overdose. Glucagon is FDA-approved in pediatric patients for the treatment of hypoglycemia and has been used in patients as young as neonates.

General dosing information:
-When used to treat low blood glucose, glucagon depletes glycogen stores. To restore liver glycogen and prevent secondary low blood glucose, administer fast-acting and long-acting oral carbohydrates once patient responsive.
-An unconscious hypoglycemic patient usually awakens within 15 minutes of glucagon administration.
-If a hypoglycemic patient fails to respond to glucagon, intravenous glucose must be administered.

For the treatment of severe hypoglycemia:
Intramuscular, Intravenous, or Subcutaneous dosage:
Neonates: 0.2 mg/kg/dose IM, IV, or subcutaneously is commonly used although there is variability in clinical practice; doses of 0.003 to 0.3 mg/kg/dose have been reported in the literature. May repeat every 15 minutes for up to 3 doses. Of note, FDA-approved product labeling does not provide specific recommendations for neonatal dosing, and there is a wide variance between the doses reported in the literature and pediatric doses recommended by the product labeling. In addition, recommendations from product labeling vary by specific product. For glucagon (recombinant by Eli Lilly), 0.02 to 0.03 mg/kg/dose or 0.5 mg/dose for patients weighing less than 20 kg is the recommended dose. For GlucaGen, 0.5 mg/dose for patients weighing less than 25 kg is recommended.
Infants and Children weighing less than 25 kg (guideline dosing): 0.03 mg/kg/dose IM, IV, or subcutaneously once (Max: 0.5 mg/dose); may repeat every 15 minutes for up to 3 doses. Administer in conjunction with glucose/dextrose.
Children and Adolescents weighing 25 kg or more (guideline dosing): 0.03 mg/kg/dose IM, IV, or subcutaneously once (Max: 1 mg/dose); may repeat every 15 minutes for up to 3 doses. Administer in conjunction with glucose/dextrose.
Continuous Intravenous Infusion*:
Neonates: 0.5 to 1 mg/day given as a continuous IV infusion regardless of age or weight (usual dose = 0.01 to 0.02 mg/kg/hour) is recommended by some experts. Administer IV dextrose concurrently. Continue glucagon infusion until blood glucose is stable then wean over 24 to 72 hours.
Intramuscular, Intravenous, or Subcutaneous dosage (GlucaGen):
Infants and Children weighing less than 25 kg and Children younger than 6 years with unknown weight: 0.5 mg IM, IV, or subcutaneously once; if there has been no response after 15 minutes, an additional 0.5 mg dose may be administered using a new kit while waiting for emergency assistance. Administer in conjunction with glucose/dextrose.
Children and Adolescents weighing 25 kg or more and Children 6 years and older with unknown weight: 1 mg IM, IV, or subcutaneously once; if there has been no response after 15 minutes, an additional 1 mg dose may be administered using a new kit while waiting for emergency assistance. Administer in conjunction with glucose/dextrose.
Intramuscular, Intravenous, or Subcutaneous dosage (glucagon, recombinant by Eli Lilly):
Infants and Children weighing less than 20 kg: 0.02 to 0.03 mg/kg/dose or 0.5 mg/dose IM, IV, or subcutaneously once; may repeat a 0.5 mg dose using a new kit if there has been no response after 15 minutes. Administer in conjunction with glucose/dextrose.
Children and Adolescents weighing 20 kg or more: 1 mg IM, IV, or subcutaneously once; if there has been no response after 15 minutes, an additional 1 mg dose may be administered using a new kit while waiting for emergency assistance. Administer in conjunction with glucose/dextrose.
Subcutaneous dosage (Gvoke):
Children 2 to 12 years weighing less than 45 kg: 0.5 mg subcutaneously. Instruct patients to seek medical attention immediately after administration of the first dose. May repeat 0.5 mg dose if there has been no response after 15 minutes; the patient should not administer more than 2 sequential doses unless under direct medical supervision.
Children 2 to 12 years weighing 45 kg or more and Adolescents: 1 mg subcutaneously. Instruct patients to seek medical attention immediately after administration of the first dose. May repeat 1 mg dose if there has been no response after 15 minutes; the patient should not administer more than 2 sequential doses unless under direct medical supervision.
Nasal dosage (Baqsimi):
Children and Adolescents 4 to 17 years: 1 actuation (3 mg/dose) into 1 nostril. Instruct patients to seek medical attention immediately after administration of the first dose. May repeat 3 mg dose if there has been no response after 15 minutes; the patient should not administer more than 2 sequential doses unless under direct medical supervision.

For the treatment of congenital hyperinsulinemia* (e.g., hyperinsulinemic hypoglycemia):
Intravenous or Subcutaneous dosage:
Neonates: 0.001 to 0.02 mg/kg/hour IV or subcutaneously may reduce the infusion rate of glucose needed to maintain normoglycemia. Some experts recommend glucagon infusion with concurrent administration of octreotide; if administered concurrently, the lower initial rate of glucagon 0.001 mg/kg/hour is recommended. Monitor blood glucose closely.

For the adjunctive treatment of beta-blocker toxicity* or calcium channel blocker toxicity* (e.g., verapamil toxicity*):
Intravenous dosage:
Neonates: Safety and efficacy have not been established; very limited data are available. There have been case reports of using glucagon for neonatal beta-blocker toxicity due to maternal receipt prior to delivery; however, doses reported are not consistent. One report describes a dose of 0.25 mg IM in a 35-week gestational age neonate (birth weight 2,250 grams); repeated doses were required for recurrence of hypoglycemia. In another case, a 32-week gestational age neonate (birth weight 1,805 grams) was given an initial dose of glucagon 0.3 mg/kg IV, which resulted in an immediate improvement in heart rate and blood pressure. Five additional doses were required and ranged from 0.3 to 0.6 mg/kg/dose IV.
Infants and Children: Initially, 0.03 to 0.15 mg/kg IV bolus over 1 to 2 minutes. Max: 10 mg/dose. May repeat dose as needed every 3 to 5 minutes. Effect is usually seen within 1 to 3 minutes and peaks at 5 to 7 minutes. Due to short half-life, a continuous IV infusion of 0.05 to 0.1 mg/kg/hour may be required to maintain inotropic and chronotropic effects. Initial Max: 5 mg/hour. Titrate to clinical effect.
Adolescents: Initially, 5 to 10 mg IV bolus over 1 to 2 minutes. May repeat dose as needed every 3 to 5 minutes. Effect is usually seen within 1 to 3 minutes and peaks at 5 to 7 minutes. Due to short half-life, a continuous IV infusion of 1 to 5 mg/hour may be required to maintain inotropic and chronotropic effects. Initial Max: 5 mg/hour. Titrate to clinical effect.

For use as a diagnostic aide in radiographic examination* and magnetic resonance imaging* (MRI) of the GI tract:
Intravenous dosage:
Children and Adolescents: Dosage not established; not FDA-approved for pediatric patients. However, off-label IV use for GI radiologic procedures is widely reported. Doses in literature are similar to those used in adults as listed in diagnostic glucagon package inserts. One publication used a weight-based protocol in their institution for MRI enterography in non-sedated children and adolescents: Patients weighing less than 24.9 kg are administered 0.5 mg IV. Patients weighing 24.9 kg or more receive 1 mg IV. Administered as a slow IV push over 5 minutes while IV saline is simultaneously administered via the same IV tubing. IV glucagon improves visualization of both the small- and large-bowel, but adds time to the diagnostic procedure and many patients experience nausea (48%). Emesis occurs in about 10% of patients. After the procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure applied.

For use in acute allergic reactions* or anaphylaxis* in patients who are receiving beta-adrenergic blocking agents and fail to respond to epinephrine:
Intravenous dosage:
Children and Adolescents: 0.02 to 0.03 mg/kg/dose (Max: 1 mg/dose) IV given over 5 minutes, followed by 5 to 15 mcg/minute IV infusion; titrate to clinical response.

Maximum Dosage Limits:
-Neonates
1 mg/dose IV, IM, or subcutaneously is the maximum dose typically used; however, indication and clinical response determine dosage titration. Safety and efficacy of intranasal administration have not been established.
-Infants
1 mg/dose IV, IM, or subcutaneously is the maximum dose typically used; however, indication and clinical response determine dosage titration. Safety and efficacy of intranasal administration have not been established.
-Children
Children 1 to 3 years: 1 mg/dose IV, IM, or subcutaneously is the maximum dose typically used; however, indication and clinical response determine dosage titration. Safety and efficacy of intranasal administration have not been established.
Children 4 to 12 years: 3 mg/dose for intranasal use and 1 mg/dose IV, IM, or subcutaneously is the maximum dose typically used; however, indication and clinical response determine dosage titration.
-Adolescents
3 mg/dose for intranasal use and 1 mg/dose IV, IM, or subcutaneously is the maximum dose typically used; however, indication and clinical response determine dosage titration.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Glucagon injections produce the same pharmacologic effects as endogenous glucagon. Native human glucagon is a hormone synthesized by the alpha-2 cells of the pancreatic islets of Langerhans and acts to increase blood glucose. Glucagon increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect. As a result, blood glucose levels are increased within minutes of glucagon administration. Blood glucose concentration increase within 10 minutes of injection, with maximal blood glucose levels occurring 30 to 45 minutes after injection, depending on the route of administration. The duration of hyperglycemic action after intravenous or intramuscular injection is 60 to 90 minutes.

Extra hepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. The exact mechanism by which glucagon exerts its effects on GI smooth muscle are unknown.

Pharmacokinetics: Glucagon is administered intranasally, intravenously, intramuscularly, and subcutaneously. Similar to other polypeptides, parenteral administration avoids rapid and complete degradation in the gastrointestinal (GI) tract. Mean Vd is 0.25 L/kg. The metabolism of glucagon has not been clearly defined, but it is extensively degraded by the liver, kidneys, and plasma. The plasma half-life of IV glucagon is approximately 8 to 18 minutes. The half-life of intranasal glucagon is 35 minutes and 45 minutes for intramuscular injection.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Blood glucose concentrations rise within 10 minutes and reach peak concentrations approximately 5 to 20 minutes after IV administration of glucagon. Hyperglycemic effects last for 60 to 90 minutes. Gastrointestinal smooth muscle relaxation occurs in 45 seconds and lasts for 9 to 17 minutes after a 0.25 to 0.5 mg dose and 22 to 25 minutes after a 2 mg dose.

Intramuscular Route
Blood glucose concentrations rise within 10 minutes and reach peak concentrations 30 minutes after IM injection. There is prolonged absorption from the injection site; the mean half-life is 45 minutes after IM injection in adults. In an adult pharmacodynamic study, mean peak glucose concentrations after a 1 mg dose were 138 mg/dL, 26 minutes after IM injection. Hyperglycemic effects last for 60 to 90 minutes. Gastrointestinal smooth muscle relaxation occurs in 8 to 10 minutes and persists for 12 to 27 minutes after a 1 mg dose; relaxation occurs in 4 to 7 minutes and persists for 21 to 32 minutes after a 2 mg dose.

Subcutaneous Route
Blood glucose concentrations reach peak 30 minutes after subcutaneous injection. In an adult pharmacodynamic study, mean peak glucose concentrations after a 1 mg dose were 136 mg/dL, 30 minutes after subcutaneous injection.

Other Route(s)
Intranasal Route
Mean peak plasma concentrations occur approximately 15 minutes after an intranasal dose of glucagon.


-Special Populations
Pediatrics
In pediatric patients (4 to 16 years of age), mean peak plasma concentrations occur between 15 and 20 minutes after an intranasal dose of glucagon. The median half-life is 21 to 31 minutes.

Other
Common cold with nasal congestion did not impact the pharmacokinetics of intranasal glucagon.