Glucagon is an antihypoglycemic agent and a gastrointestinal motility inhibitor. Glucagon is a single chain containing 29 amino acid residues and has a molecular weight of 3483 and is identical to human glucagon. Glucagon is of synthetic origin produced by solid phase synthesis. Its molecular formula is C 153 H 225 N 43 O 49 S with the following structure: GVOKE HypoPen, GVOKE PFS, and GVOKE Kit GVOKE HypoPen (glucagon) injection, GVOKE PFS (glucagon) injection, and GVOKE Kit (glucagon) injection (these three presentations are also referred to as GVOKE (glucagon) injection in this labeling) are clear, colorless to pale yellow, sterile solutions for subcutaneous injection. GVOKE HypoPen and GVOKE PFS: Each 0.2 mL contains 1 mg of glucagon, 11.1 mg of trehalose dihydrate NF, and 1.2 mg of 1N sulfuric acid in 209 mg dimethyl sulfoxide diluent. GVOKE HypoPen: Each 0.1 mL contains 0.5 mg of glucagon, 5.6 mg of trehalose dihydrate NF, and 0.6 mg of 1N sulfuric acid in 104 mg dimethyl sulfoxide diluent. GVOKE Kit: Each 0.2 mL contains 1 mg of glucagon, 11.1 mg of trehalose dihydrate NF, 5.8 mg of mannitol USP, and 1.32 mg of 1N sulfuric acid in 205 mg dimethyl sulfoxide diluent. GVOKE VialDx GVOKE VialDx (glucagon) injection is a clear, colorless to pale yellow, sterile solution for intravenous injection available in 1 mg per 0.2 mL vial. Each 0.2 mL of GVOKE VialDx contains 1 mg of glucagon, 11.1 mg of trehalose dihydrate NF, 5.8 mg of mannitol USP, and 1.32 mg of 1N sulfuric acid in 205 mg dimethyl sulfoxide diluent prior to dilution with 0.9% Sodium Chloride [for dilution instructions, see Dosage and Administration ( 2.2) ] . The diluted solution contains 0.45 mg per mL glucagon, 5 mg per mL trehalose dihydrate, 93.2 mg per mL dimethyl sulfoxide, 2.6 mg per mL mannitol, and 0.60 mg per mL 1 N sulfuric acid. Its molecular formula is C153H225N43O49S with the following structure:

GVOKE is an antihypoglycemic agent indicated for subcutaneous use for the treatment of severe hypoglycemia in adult and pediatric patients aged two years and older with diabetes GVOKE VialDx is a gastrointestinal motility inhibitor indicated for intravenous use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients 1.1 Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes GVOKE is indicated for subcutaneous use for the treatment of severe hypoglycemia in adult and pediatric patients aged two and older with diabetes

Diagnostic Aid in Adults GVOKE VialDx is indicated for intravenous use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients.

GVOKE HypoPen, GVOKE PFS, GVOKE Kit (these three presentations are also referred to as GVOKE in this labeling) , and GVOKE VialDx are clear, colorless to pale yellow solutions. Subcutaneous Injection Injection: 0.5 mg/0.1 mL single-dose prefilled autoinjector (GVOKE HypoPen) Injection: 1 mg/0.2 mL single-dose prefilled autoinjector (GVOKE HypoPen) Injection: 1 mg/0.2 mL single-dose prefilled syringe (GVOKE PFS) Injection: 1 mg/0.2 mL single-dose vial and syringe kit (GVOKE Kit) Intravenous Injection: Injection: 1 mg/0.2 mL single-dose vial (GVOKE VialDx) Subcutaneous Injection: 0.5 mg/0.1 mL single-dose prefilled autoinjector (GVOKE HypoPen) 1 mg/0.2 mL single-dose prefilled autoinjector (GVOKE HypoPen) 1 mg/0.2 mL single-dose prefilled syringe (GVOKE PFS) 1 mg/0.2 mL single-dose vial and syringe kit (GVOKE Kit)( 3 ) Intravenous Injection 1 mg/0.2 mL single-dose vial (GVOKE VialDx)( 3 )

Dosage and Administration of GVOKE for Subcutaneous Use to Treat Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes Important Administration Instructions Administer GVOKE HypoPen, GVOKE PFS, or GVOKE Kit subcutaneously. These three presentations are referred to as GVOKE in this labeling Administer GVOKE according to the printed instructions on the foil pouch label, carton, or the Instructions for Use. Visually inspect GVOKE prior to administration. The solution should appear clear and colorless to pale yellow. Administer GVOKE subcutaneously in the lower abdomen, outer thigh, or outer upper arm. Call for emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, may administer an additional dose from a new HypoPen, GVOKE PFS, or GVOKE Kit while waiting for emergency assistance. When the patient has responded to GVOKE, give oral carbohydrates. Do not attempt to reuse GVOKE. Each GVOKE device or vial contains a single dose of glucagon. Do not reuse and discard any unused portion. Recommended Dosage Recommended dose for adult and pediatric patients aged 12 years of age and older is 1 mg. Recommended dose for adult and pediatric patients aged 12 years of age and older is 1 mg. The recommended dose for pediatric patients aged 2 to less than 12 years of age who weigh: Less than 45 kg, is 0.5 mg 45 kg or greater, is 1 mg Dosage and Administration of GVOKE VialDx for Intravenous Use as a Diagnostic Aid in Adults GVOKE VialDx is only for intravenous use under medical supervision. The recommended diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bulb is 0.2 mg to 0.5 mg; the recommended dose to relax the colon is 0.5 mg to 0.75 mg. See the Full Prescribing Information for administration instructions for GVOKE VialDx

Dosage and Administration of GVOKE for Subcutaneous Use to Treat Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes Important Administration Instructions To treat severe hypoglycemia in adult and pediatric patients aged 2 years and older with diabetes, administer GVOKE HypoPen, GVOKE PFS, or GVOKE Kit subcutaneously. These three presentations are only for subcutaneous use and are referred to as GVOKE in this labeling. For GVOKE HypoPen or GVOKE PFS: Do not open foil pouch until ready to administer. For GVOKE Kit: Store in original carton until ready to administer. Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires the help of others to recover, instruct the patient to inform those around them about GVOKE and its Instructions for Use. Administer GVOKE subcutaneously as soon as possible when severe hypoglycemia is recognized. Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for GVOKE. Visually inspect GVOKE prior to administration. The solution should be clear, colorless to pale yellow Withdraw the correct dose . Administer subcutaneously in the lower abdomen, outer thigh, or outer upper arm, according to the printed instructions on the foil pouch label, carton, or the Instructions for Use. Call for emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, an additional dose from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance. When the patient has responded to GVOKE, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia. Each GVOKE HypoPen, GVOKE PFS, or GVOKE Kit product contains a single dose of glucagon. Do not reuse and discard any unused portion. Recommended Dosage in Adult and Pediatric Patients Aged 12 Years and Older to Treat Severe Hypoglycemia To treat severe hypoglycemia in patients 12 years of age and older with diabetes, use GVOKE HypoPen, GVOKE PFS, or GVOKE Kit: The recommended dose is 1 mg administered by subcutaneous injection into lower abdomen, outer thigh, or outer upper arm. If there has been no response after 15 minutes, an additional 1 mg dose from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance Recommended Dosage in Pediatric Patients Aged 2 to less than 12 Years of Age to Treat Severe Hypoglycemia To treat severe hypoglycemia in pediatric patients aged 2 to less than 12 years of age with diabetes, use GVOKE HypoPen, GVOKE PFS, or GVOKE Kit. The recommended dose in those who weigh: Less than 45 kg is 0.5 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. 45 kg or greater is 1 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. If there has been no response after 15 minutes, an additional 0.5 mg dose (for those who weigh less than 45 kg) or 1 mg dose (for those who weigh 45 kg or greater) from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance

Dosage and Administration of GVOKE VialDx for Intravenous Use as a Diagnostic Aid in Adults Important Administration Information For use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract, use GVOKE VialDx. GVOKE VialDx is only for intravenous use under medical supervision Must be diluted with 0.9% Sodium Chloride Injection prior to administration. Using a syringe, draw 0.2 mL from the GVOKE VialDx vial and dispense into a separate empty sterile container containing 2 mL of 0.9% Sodium Chloride Injection. Gently swirl the container until the solution is thoroughly mixed. The mixed solution should be clear and colorless to pale yellow. Inspect visually for particulate matter and discoloration. The final concentration of the diluted solution is 0.45 mg/mL of glucagon. Draw the required dose from the container into a syringe for administration . If not used immediately, diluted GVOKE VialDx may be stored for up to 8 hours after initial dilution. Inject the solution intravenously via a 1-minute slow push using consistent pressure. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure. GVOKE VialDx contains a single dose of glucagon. Do not reuse. Discard any unused portion. Recommended Dosage in Adults as a Diagnostic Aid For use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract, use GVOKE VialDx. The recommended intravenous dose for relaxation of the : Stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg Colon is 0.5 mg to 0.75 mg The onset of action after an injection will depend on the organ under examination .

Substantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor. Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, glucagon may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously. Serious Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension.( 5.3 ) Lack of Efficacy with Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen: Patients with insufficient hepatic stores of glycogen may not respond to GVOKE for subcutaneous use for the treatment of severe hypoglycemia. Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia. Necrolytic Migratory Erythema (NME): a skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. GVOKE and GVOKE VialDx are not approved for continuous infusion. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus: GVOKE VialDx in patients with diabetes mellitus may cause hyperglycemia. Monitor patients with diabetes for changes in blood glucose levels during treatment and treat hyperglycemia if indicated. Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease: GVOKE VialDx may increase myocardial oxygen demand, blood pressure, and pulse rate. Cardiac monitoring is recommended in patients with cardiac disease during use of GVOKE VialDx as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy. Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid: GVOKE VialDx administered to patients with glucagonoma may cause secondary hypoglycemia. Test patients suspected of having glucagonoma for blood levels of glucagon prior to treatment and monitor for changes in blood glucose levels during treatment. 5.1 Substantial Increase in Blood Pressure in Patients with Pheochromocytoma GVOKE and GVOKE VialDx are 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, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure

Hypoglycemia in Patients with Insulinoma In patients with insulinoma, administration of 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 an insulinoma and cause hypoglycemia. GVOKE and GVOKE VialDx are contraindicated in patients with insulinoma . If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously

Serious Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. Discontinue GVOKE or GVOKE VialDx if symptoms of serious hypersensitivity reactions occur. Advise patients and/or caregivers to seek immediate medical attention if the patient experiences any symptoms of serious hypersensitivity reactions.GVOKE and GVOKE VialDx are contraindicated in patients with a prior hypersensitivity reaction to glucagon, or any of the excipients in GVOKE and GVOKE VialDx

Lack of Efficacy with Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen Patients with insufficient hepatic stores of glycogen may not respond to GVOKE for the treatment of severe hypoglycemia . Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia

Necrolytic Migratory Erythema Necrolytic migratory erythema (NME), a skin rash commonly associated with glucagonomas (glucagon-producing tumors) and characterized by scaly, pruritic erythematous plaques, bullae, and erosions, has been reported postmarketing following continuous glucagon infusion.GVOKE and GVOKE VialDx are not approved for continuous infusion. NME lesions may affect the face, groin, perineum and legs or be more widespread. In the reported cases NME resolved with discontinuation of the glucagon, and treatment with corticosteroids was not effective. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks

Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus GVOKE VialDx in patients with diabetes mellitus may cause hyperglycemia. Monitor patients with diabetes for changes in blood glucose levels during treatment with GVOKE VialDx and treat hyperglycemia, if indicated

Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease GVOKE VialDx may increase myocardial oxygen demand, blood pressure, and pulse rate which may be life threatening in patients with cardiac disease. Cardiac monitoring is recommended in patients with cardiac disease during use of GVOKE VialDx as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy

Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid Use of GVOKE VialDx in patients with glucagonoma may cause secondary hypoglycemia. GVOKE VialDx is contraindicated in patients with glucagonoma when used as a diagnostic aid . Test patients suspected of having glucagonoma for blood levels of glucagon prior to administration of GVOKE VialDx, and monitor for changes in blood glucose levels during treatment. If a patient develops symptoms of hypoglycemia after administration of GVOKE VialDx, administer glucose orally or intravenously.

Table 4: Clinically Significant Drug Interaction with GVOKE and GVOKE VialDx Beta-Blockers Clincial Impact: Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given GVOKE or GVOKE VialDx. Intervention The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease. Insulin Clincial Impact: Insulin acts antagonistically to glucagon. Intervention Monitor blood glucose when GVOKE VialDx is used as a diagnostic aid in patients receiving insulin. Indomethacin Clincial Impact: In patients taking indomethacin, GVOKE may lose its ability to raise blood glucose or may even produce hypoglycemia. Intervention Monitor blood glucose levels during glucagon treatment of patients taking indomethacin. Anticholinergic Drugs Clincial Impact: The concomitant use of anticholinergic drugs and GVOKE VialDx increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Intervention Concomitant use of anticholinergic drugs with GVOKE VialDx is not recommended. Warfarin Clincial Impact: GVOKE and GVOKE Vial Dx may increase the anticoagulant effect of warfarin. Intervention Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required. Beta-blockers: GVOKE- or GVOKE VialDx-treated patients taking concomitant beta-blockers may have a transient increase in pulse and blood pressure. Indomethacin: In patients taking concomitant indomethacin, GVOKE may lose its ability to raise glucose or may produce hypoglycemia. Anticholinergic drugs: Concomitant use of anticholinergic drugs with GVOKE VialDx for use as a diagnostic aid is not recommended. Warfarin: GVOKE and GVOKE VialDx may increase the anticoagulant effect of warfarin. Insulin: Monitor blood glucose when GVOKE VialDx is used as a diagnostic aid in patients receiving insulin. See 17 for PATIENT COUNSELING INFORMATION and FDA ‑ approved patient labeling for GVOKE.