Glucagon

Introduction Overview

Generic Name

glucagon

Brand Name

Gvoke HypoPen

Dosage Form

single-dose prefilled autoinjector (0.5 mg/0.1 mL, 1 mg/0.2 mL), single-dose prefilled syringe (1 mg/0.2 mL), single-dose vial and syringe kit (1 mg/0.2 mL), intravenous injection (1 mg/0.2 mL)

Drug Class

Glucose elevating agents

Pharmacokinetics

Absorption: Glucagon administered subcutaneously via Gvoke HypoPen or prefilled syringe demonstrates rapid absorption with onset of action typically within 15 minutes, allowing for quick reversal of hypoglycemia. The subcutaneous route facilitates systemic uptake through the capillary-rich subcutaneous tissue, leading to effective bioavailability suitable for emergency use.

Distribution: Following absorption, glucagon distributes rapidly throughout the extracellular fluid. It exhibits extensive hepatic uptake owing to the liver being its primary site of action. Plasma protein binding is minimal, and the hormone’s volume of distribution approximates that of extracellular fluid, facilitating rapid interaction with hepatic glucagon receptors.

Metabolism: Glucagon is primarily metabolized by liver and kidney enzymes through proteolytic cleavage. It has a short plasma half-life of approximately 3 to 6 minutes due to rapid degradation by hepatic and renal dipeptidyl peptidase enzymes. This rapid metabolism necessitates prompt dosing in hypoglycemic emergencies to achieve therapeutic effect.

Elimination: The elimination of glucagon metabolites occurs mainly via renal excretion. Due to its peptide nature and rapid enzymatic breakdown, intact glucagon is rarely detected in urine. The short half-life and metabolism pathways underscore the need for single-dose administration and careful monitoring post-injection to ensure sustained glycemic correction.

Dosage Forms

Available Dosage Forms:
- Single-dose prefilled autoinjector (HypoPen) containing 0.5 mg/0.1 mL and 1 mg/0.2 mL formulations.
- Single-dose prefilled syringe (PFS) with 1 mg/0.2 mL dosage.
- Single-dose vial and syringe kit containing 1 mg/0.2 mL.
- Intravenous injection formulation (1 mg/0.2 mL) specifically for Gvoke VialDx used as a diagnostic aid.

Dosages for Adults and Adolescents:
- For hypoglycemia treatment in adults and adolescents aged 12 years and older, a single subcutaneous dose of 1 mg (0.2 mL) is administered.
- In the diagnostic setting, intravenous doses range from 0.2 mg to 0.75 mg depending on the gastrointestinal region being targeted for motility inhibition.

Specific Patient Populations:
- Pediatrics aged 2 to 12 years: 0.5 mg subcutaneously once if weight is less than 45 kg, and 1 mg if 45 kg or greater.
- Use in children under 2 years of age is not established for safety or efficacy.
- Gvoke VialDx intravenous use is limited to adults under medical supervision.
- Special consideration for patients with adrenal or pancreatic tumors is critical due to risk of adverse effects.

Clinical Guidelines:
- Repeat dosing is permitted if no response after 15 minutes; however, use of a new device or vial is mandatory.
- Oral carbohydrates should be administered once patient regains consciousness and is able to swallow safely to maintain glycemic control.

Mechanism Of Action

Glucagon, the active ingredient in Gvoke HypoPen, is a peptide hormone that primarily acts by binding to specific G protein-coupled glucagon receptors located on hepatocyte membranes. This binding activates adenylate cyclase via Gs proteins, resulting in elevated intracellular cyclic AMP (cAMP) levels.

The increased cAMP acts as a second messenger that activates protein kinase A (PKA), which in turn phosphorylates key enzymes involved in glycogenolysis. This cascade leads to the activation of glycogen phosphorylase and inhibition of glycogen synthase, promoting the breakdown of glycogen stores into glucose molecules in the liver. The newly generated glucose is then released into the bloodstream, effectively raising systemic blood glucose levels to counteract hypoglycemia.

Furthermore, glucagon exerts a relaxing effect on smooth muscle cells in the gastrointestinal tract, leading to reduced motility and delayed transit. This property is leveraged in Gvoke VialDx as a diagnostic aid during radiologic examinations where temporary inhibition of gastrointestinal movement is desirable for clearer imaging results.

Compared with other glucose-elevating agents, glucagon provides a swift and direct endogenous source of glucose by mobilizing hepatic glycogen, a mechanism that is dependent on adequate glycogen stores. Unlike exogenous glucose administration, glucagon is effective even when oral intake is impossible. Clinical studies affirm the efficacy and safety profile of glucagon for emergency hypoglycemia treatment, with rapid onset of action and predictable pharmacodynamics.

Pharmacological Actions

Rapid elevation of blood glucose levels via hepatic glycogenolysis.
Activation of adenylate cyclase and increased intracellular cAMP in hepatocytes.
Relaxation of smooth muscle in the gastrointestinal tract reducing motility.
Counterregulation to insulin-induced hypoglycemia in diabetic patients.
Enhancement of gluconeogenesis and lipolysis through secondary metabolic pathways.
Transient antagonism of insulin action to restore normoglycemia.
Diagnostic use as a gastrointestinal motility inhibitor in radiologic imaging.
Promotion of catecholamine release from adrenal medulla under stress conditions.
Minimal systemic protein binding facilitating rapid distribution.
Rapid enzymatic degradation providing a favorable safety profile for acute use.

Therapeutic Or Clinical Uses

Emergency treatment of severe hypoglycemia in diabetic patients aged 2 years and older.
Subcutaneous administration to reverse insulin-induced hypoglycemia when oral carbohydrate intake is not feasible.
Intravenous use as a diagnostic aid to inhibit gastrointestinal motility during radiologic examinations.
Management of hypoglycemia unresponsive to oral therapies in outpatient and inpatient settings.
Adjunctive therapy in patients with impaired glucoregulatory mechanisms due to pancreatic or adrenal disorders.
Utilized in pre-hospital or home settings through easy-to-use autoinjector devices.
Treatment of hypoglycemic coma or unresponsiveness in insulin-dependent diabetes mellitus.
Diagnostic facilitation of imaging by reducing bowel peristalsis and motility.
Emergency glucagon kits for caregivers to rapidly administer in diabetic emergencies.
Alternative to intravenous dextrose in selected emergency situations where IV access is delayed or not available.

Side Or Adverse Effects

Nausea and vomiting, common post-glucagon administration reactions.
Injection site reactions including pain, redness, swelling, or itching.
Headache occurring in both adult and pediatric patients.
Transient hyperglycemia as a result of elevated glucose release.
Hypoglycemia potentially induced in patients with pancreatic insulinomas or glucagonomas due to inappropriate insulin secretion.
Serious allergic reactions including urticaria, rash, angioedema, difficulty breathing, and anaphylaxis.
High blood pressure episodes, especially in patients with adrenal gland tumors (pheochromocytoma).
Dizziness and hot flushes noted during intravenous use of Gvoke VialDx.
Taste disturbances, including dysgeusia, following administration as a diagnostic aid.
Rare cardiovascular effects, including rapid or slow heart rate and arrhythmias.
Potential worsening of pre-existing heart conditions when used intravenously.
Abdominal pain and gastrointestinal discomfort especially in children.
Risk of hypokalemia secondary to metabolic shifts induced by glucagon.
Fatigue and malaise reported in some cases post-administration.

Precautions

Avoid use in patients with known hypersensitivity to glucagon or any inactive ingredients including lactose.
Exercise caution in patients with pheochromocytoma due to risk of hypertensive crises.
Contraindicated in patients with insulinoma or glucagonoma tumors to prevent paradoxical hypoglycemia.
Ensure patients have adequate hepatic glycogen reserves prior to administration for efficacy.
Monitor blood glucose closely following administration, as repeated dosing may be necessary.
Use cautiously in patients with cardiovascular disease due to potential for heart rate and blood pressure changes.
Pregnant and breastfeeding women should use glucagon only if potential benefits justify risks.
Prolonged fasting or starvation states may reduce glucagon effectiveness.
Caregivers should be trained in proper administration technique and instructed to seek emergency help immediately.
Avoid concurrent use with beta-blockers or indomethacin unless medically indicated.
Observe for signs of allergic reactions during and after administration.
Do not reuse single-dose autoinjectors, syringes, or vials to prevent dosing errors and contamination.
Educate patients and families on the importance of oral carbohydrate intake post-recovery.
Store medication at recommended temperatures to preserve potency and stability.
Inform healthcare providers of all concomitant medications to evaluate drug interaction risks.

Warnings

May cause serious hypersensitivity reactions including anaphylaxis; discontinue use and seek emergency care if symptoms arise.
Risk of increasing blood pressure dangerously in patients with adrenal gland tumors (pheochromocytomas).
Potential hypoglycemia in patients with pancreatic insulinomas or glucagonomas due to insulin release stimulation.
High blood sugar episodes especially when used as a diagnostic aid in diabetic patients.
Cardiovascular monitoring recommended during intravenous administration in patients with known heart disease.
Do not administer intravenously unless specifically indicated and supervised by healthcare professionals.
Repeated doses should only be given if no response and under guided medical oversight.
Avoid administering glucagon if patient is fasting for prolonged periods or depleted of glycogen stores.
Use with caution in patients with chronic hypoglycemia or impaired counterregulation mechanisms.
Patients should be warned of potential side effects such as nausea and vomiting, which can lead to aspiration.
Emergency medical assistance must be sought immediately after glucagon administration to ensure patient safety.
Not established as safe or effective in children under 2 years of age; use with discretion in pediatric population.
Use in pregnancy and breastfeeding only when benefit outweighs potential risks; limited human data available.
Storage outside recommended temperature range may reduce efficacy and increase risks.
Not a substitute for ongoing diabetes management; comprehensive care and monitoring remain essential.

Contraindication

Known allergy or hypersensitivity to glucagon or any component of Gvoke HypoPen or Gvoke VialDx formulations.
Presence of pancreatic insulinoma tumors due to risk of worsening hypoglycemia.
Adrenal gland tumors such as pheochromocytoma owing to potential hypertensive crises.
Use of Gvoke VialDx contraindicated in patients with pancreatic glucagonomas.
Not recommended for patients with depleted hepatic glycogen stores, e.g., prolonged fasting or starvation.
Severe hypersensitivity reactions to prior glucagon administration preclude repeated use.
Avoid use in uncorrected hypokalemia without appropriate management.
Do not use intravenous Gvoke formulations outside of medical supervision and diagnostic purposes.
Contraindicated in neonates and infants under 2 years of age due to unestablished safety.
Hypersensitivity to lactose-containing formulations precludes use for lactose-intolerant individuals.
Incompatible with certain drug therapies without appropriate adjustments.
Contraindicated in patients with conditions leading to catecholamine sensitivity unless under strict supervision.
Use contraindicated if there is known obstruction or ileus of the gastrointestinal tract requiring motility.
Do not administer if the device or vial is compromised or expired.
Contraindication in patients unwilling or unable to follow emergency care procedures after use.

Drug Interactions

Beta-adrenergic blockers may reduce glucagon’s efficacy in raising blood glucose levels.
Indomethacin can blunt glucagon-induced glycogenolysis and thus decrease effectiveness.
Warfarin effects may be altered due to glucagon’s influence on metabolism pathways, requiring monitoring.
Oral anticoagulants interactions may necessitate dose adjustments following glucagon administration.
Concurrent use with insulin requires careful glucose monitoring to avoid hypoglycemia or hyperglycemia.
Drugs causing hypoglycemic effects may have additive effects if used concomitantly with glucagon.
Phenytoin levels might be affected indirectly through hepatic enzyme modulation.
Potential interference with beta-agonists that could mask cardiac responses during treatment.
Glucagon may alter gastrointestinal motility affecting absorption of orally administered drugs.
Non-steroidal anti-inflammatory drugs (NSAIDs) could interact impacting glucagon’s metabolic effects.
Use with digitalis compounds requires caution due to possible effects on heart rate and rhythm.
Concurrent use with catecholamines may potentiate cardiovascular effects.
Interactions with diuretics could affect electrolyte balance during glucagon therapy.
Alcohol intake can exacerbate hypoglycemia risk and interfere with glucagon response.
Combination with drugs affecting hepatic enzymes may alter glucagon degradation rates.

Preparations Of The Drug

Gvoke HypoPen: single-dose prefilled autoinjector available in 0.5 mg/0.1 mL and 1 mg/0.2 mL strengths for subcutaneous injection.
Gvoke Prefilled Syringes (PFS): single-dose syringes containing 1 mg/0.2 mL glucagon for subcutaneous administration.
Gvoke Vial and Syringe Kit: single-dose vial with 1 mg/0.2 mL glucagon intended for reconstitution and subcutaneous injection.
Gvoke VialDx: aqueous glucagon formulation (1 mg/0.2 mL) for intravenous use as a gastrointestinal motility inhibitor during diagnostic radiological procedures.
All preparations are sterile, preservative-free formulations containing inactive ingredients such as trehalose dihydrate, sulfuric acid, mannitol (in kit only), and dimethyl sulfoxide to maintain stability and isotonicity.
Storage recommendations include room temperature between 20°C to 25°C (68°F to 77°F), avoiding refrigeration or freezing to preserve drug potency.
Each preparation is designed for single use with no permissible re-dosing from the same device to prevent dosing errors.
Comes with detailed Instructions for Use to educate caregivers on proper administration technique.
Packaging includes safety features to prevent needle-stick injuries and ensure ease of use during emergencies.
Manufactured under stringent quality control to guarantee sterility, dosage accuracy, and product reliability.
Distributed by Xeris Pharmaceuticals, Inc. (Gvoke administration forms) and American Regent, Inc. (Gvoke VialDx).