Glucagon Injection, Solution

1 INDICATIONS AND USAGE • 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 ( 1.1 ) • 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 ( 1.2 ) 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. 1.2 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.

2 DOSAGE AND ADMINISTRATION Dosage and Administration of GVOKE for Subcutaneous Use to Treat Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes ( 2.1 ) • 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: o Less than 45 kg, is 0.5 mg o 45 kg or greater, is 1 mg Dosage and Administration of GVOKE VialDx for Intravenous Use as a Diagnostic Aid in Adults ( 2.2 ) • 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. 2.1 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 (see below for dosage recommendations). 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: o Less than 45 kg is 0.5 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. o 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. 2.2 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 (see below for dosage recommendations). 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 [see Clinical Pharmacology ( 12.2 )]: 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 [see Clinical Pharmacology ( 12.2 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Substantial Increase in Blood Pressure in Patients with Pheochromocytoma [see Warnings and Precautions ( 5.1 )] . Hypoglycemia in Patients with Insulinoma [see Warnings and Precautions ( 5.2 )] . Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Lack of Efficacy With Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen [see Warnings and Precautions ( 5.4 )] Necrolytic Migratory Erythema [see Warnings and Precautions ( 5.5 )] . Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus [see Warnings and Precautions ( 5.6 )] Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease [see Warnings and Precautions ( 5.7 )] Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence 2% or greater) reported for GVOKE were: o Adults—nausea, vomiting, injection site edema raised 1 mm or greater, and headache ( 6.1 ) o Pediatric Patients—nausea, hypoglycemia, vomiting, headache, abdominal pain, hyperglycemia, injection site discomfort and reaction, and urticaria ( 6.1 ) Most common adverse reactions (incidence 5 % or greater) reported for GVOKE VialDx were nausea, dysgeusia, headache, dizziness and hot flush ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at toll-free 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of GVOKE and GVOKE VialDx cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. GVOKE for Subcutaneous Use for the Treatment of Severe Hypoglycemia in Adult and Pediatric Patients 2 Aged Years and Older with Type 1 Diabetes Mellitus Adverse Reactions in Adult Patients The safety of GVOKE for subcutaneous use for the treatment of severe hypoglycemia in adults with diabetes was evaluated in two randomized, blinded, 2-way crossover studies conducted in adults with type 1 diabetes mellitus. In total, 154 patients received a subcutaneous injection of GVOKE [see Clinical Studies ( 14.1 )] . The most common adverse reactions that occurred in 2% or more of adults treated with GVOKE during these two clinical trials are listed in Table 1 . Table 1: Adverse Reactions that occurred ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus Treated with GVOKE a a Adverse Reactions that occurred within 12 hours. GVOKE 1 mg dose (N = 154) Nausea 30% Vomiting 16% Injection site edema raised 1 mm or greater 7% Headache 5% Injection site pain was reported by 1% of GVOKE-treated patients. Hypertension and tachycardia have occurred with glucagon treatment. Adverse Reactions in Pediatric Patients Aged 2 Years and Older The safety of GVOKE for the treatment of severe hypoglycemia in patients with diabetes was evaluated in one single-arm, open-label, study in 31 pediatric patients with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] . The data in Table 2 reflect the exposure of 31 pediatric patients to 0.5 mg or 1 mg of GVOKE given subcutaneously. The most common adverse reactions that occurred in ≥2% of GVOKE-treated pediatric patients aged 2 years and older are listed in Table 2 . Table 2: Adverse Reactions That Occurred ≥ 2% in GVOKE-treated Pediatric Patients Aged 2 Years and Older with Type 1 Diabetes Mellitus a a Adverse Reactions that occurred within 12 hours. 2 to 6 years of age (0.5 mg dose) N =7 6 to 12 years of age (0.5 mg dose) N = 13 12 to 18 years of age (1 mg dose) N = 11 Total N = 31 Nausea 43% 54% 36% 45% Hypoglycemia 29% 54% 27% 39% Vomiting 14% 23% 18% 19% Headache 0% 15% 0% 7% Abdominal pain 0% 8% 0% 3% Hyperglycemia 14% 8% 0% 7% Injection site discomfort 0% 8% 0% 3% Injection site reaction 0% 0% 9% 3% Urticaria 0% 8% 0% 3% GVOKE VialDx for Intravenous Use As a Diagnostic Aid in Adults The safety of GVOKE VialDx for intravenous use as a diagnostic aid in adults was evaluated in an open-label single-dose study in 83 adult healthy volunteers. Table 3 displays the most common adverse reactions that occurred in 5% or greater in healthy volunteers who received 0.75 mg of GVOKE VialDx intravenously. Table 3: Adverse Reactions that Occurred ≥ 5 % in Adult Healthy Volunteers Who Received 0.75 mg of GVOKE VialDx for Intravenous Use as a Diagnostic Aid N=83 Nausea 37.3% Dysgeusia 18.1% Headache 10.8% Hot Flush 9.6% Dizziness 8.4% 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of glucagon. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Necrolytic migratory erythema (NME) cases have been reported postmarketing in patients receiving continuous infusion of glucagon. Hypoglycemia and hypoglycemic coma. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see Drug Interactions ( 7 )] .

12.3 Pharmacokinetics Absorption Subcutaneous injection of 1 mg GVOKE in adult type 1 diabetes mellitus patients resulted in a mean glucagon C max of 2481.3 pg/mL, t max of 50 minutes and AUC 0‑240min of 3454.6 pg*min/mL.See Figure 3 . Figure 3: : Plasma Glucagon Concentration (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of 1 mg of GVOKE in Adults with Type 1 Diabetes Mellitus Distribution The apparent volume of distribution was in the range of 137-2425 L. Elimination The half-life of GVOKE was determined to be 32 minutes. Metabolism Glucagon is extensively degraded in liver, kidney, and plasma. Excretion Urinary excretion of intact glucagon has not been measured. Specific Populations Pediatrics Subcutaneous injection of 0.5 mg GVOKE in patients with type 1 diabetes mellitus ages 2 to under 6 years resulted in a mean glucagon C max of 2300 pg/mL, t max of 41 minutes, and AUC 0‑180min of 138900 pg/mL*min. Subcutaneous injection of 0.5 mg GVOKE in patients with type 1 diabetes ages 6 to under 12 years resulted in a mean C max of 1600 pg/mL, median t max of 34 minutes and AUC 0‑180min of 104700 pg/mL*min. Subcutaneous injection of 1 mg GVOKE in patients with type 1 diabetes ages 12 to less than 18 years resulted in a mean C max of 1900 pg/mL, t max of 51 minutes AUC 0‑180min of 134300 pg/mL*min. Mean plasma glucagon levels were similar across the age groups following age appropriate doses of GVOKE. See Figure 4 . Figure 4: Plasma Glucagon Concentration (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of GVOKE in Pediatric Patients with Type 1 Diabetes Mellitus Figure 3 Figure 4