Gvoke HypoPen 1 mg Auto-Injector

1 INDICATIONS AND USAGE GVOKE is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above. GVOKE is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above. ( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Hypersensitivity and Allergic Reactions [see Warnings and Precautions ( 5.3 )] . • Necrolytic Migratory Erythema [see Warnings and Precautions ( 5.5 )] . • Most common adverse reactions (incidence 2% or greater) reported were: • Adults—nausea, vomiting, injection site edema raised 1 mm or greater, and headache ( 6.1 ) • Pediatric Patients—nausea, hypoglycemia, vomiting, headache, abdominal pain, hyperglycemia, injection site discomfort and reaction, and urticaria ( 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 cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Adverse Reactions in Adult Patients The safety of GVOKE was evaluated in two randomized, blinded, 2-way crossover studies conducted in adults with type 1 diabetes mellitus. In total, 154 patients received an injection of GVOKE [see Clinical Studies ( 14.1 )] . The most common adverse reactions occurring in 2% or more of adult subjects treated with GVOKE during clinical trials are listed in Table 1 . Table 1: Adverse Reactions Occurring ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus Treated with GVOKE a a Adverse Reactions occurring 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 patients with GVOKE. Hypertension and tachycardia have occurred with glucagon treatment. Adverse Reactions in Pediatric Patients Aged 2 Years and Older The safety of GVOKE 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. The most common adverse reactions occurring in 2% or greater of pediatric patients treated with GVOKE are listed in Table 2 . Table 2: Adverse Reactions Occuring ≥ 2% in Pediatric Patients with Type 1 Diabetes Treated with GVOKE a a Adverse Reactions occurring within 12 hours. Ages 2 to under 6 years of age (0.5 mg dose) N =7 Ages 6 to under 12 years of age (0.5 mg dose) N = 13 Ages 12 to under 18 (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% 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 )] .

4 CONTRAINDICATIONS GVOKE is contraindicated in patients with: • Pheochromocytoma because of the risk of substantial increase in blood pressure [see Warnings and Precautions ( 5.1 )] • Insulinoma because of the risk of hypoglycemia [see Warnings and Precautions ( 5.2 )] • Known hypersensitivity to glucagon or to any of the excipients in GVOKE. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension [see Warnings and Precautions ( 5.3 )] . • Pheochromocytoma ( 4 ) • Insulinoma ( 4 ) • Known hypersensitivity to glucagon or to any of the excipients ( 4 )

11 DESCRIPTION GVOKE contains glucagon, an antihypoglycemic agent used to treat severe hypoglycemia. 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 produced by solid phase synthesis with subsequent purification. Its molecular formula is C 153 H 225 N 43 O 49 S with the following structure: GVOKE is a clear, colorless to pale yellow, sterile solution for subcutaneous injection available in 0.5 mg per 0.1 mL (auto-injector) or 1 mg per 0.2 mL (auto-injector, pre-filled syringe, and vial and syringe kit). GVOKE Auto-Injector (HypoPen) and GVOKE Pre-Filled Syringe Each 0.2 mL of GVOKE 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. Each 0.1 mL of GVOKE 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 Vial and Syringe Kit Each 0.2 mL of GVOKE 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. Its molecular formula is C153H225N43O49S with the following structure:

2 DOSAGE AND ADMINISTRATION • GVOKE auto-injector, pre-filled syringe, and vial and syringe kit are for subcutaneous injection only ( 2.1 ) • The recommended dose for adults and pediatric patients aged 12 years and older is 1 mg ( 2.2 ) • The recommended dose for pediatric patients aged 2 to under 12 years of age is weight dependent: ( 2.2 ) • For pediatric patients who weigh less than 45 kg, the recommended dose is 0.5 mg GVOKE • For pediatric patients who weigh 45 kg or greater, the recommended dose is 1 mg GVOKE • Administer GVOKE according to the printed instructions on the foil pouch label, carton, or the Instructions for Use ( 2.1 ) • Visually inspect GVOKE prior to administration. The solution should appear clear and colorless to pale yellow and be free of particles. If the solution is discolored or contains particulate matter, do not use ( 2.1 ) • Administer the injection in the lower abdomen, outer thigh, or outer upper arm ( 2.1 ) • Call for emergency assistance immediately after administering the dose ( 2.1 ) • When the patient has responded to treatment, give oral carbohydrates ( 2.1 ) • Do not attempt to reuse GVOKE. Each GVOKE device or vial contains a single dose of glucagon and cannot be reused. Discard any unused portion. ( 2.1 ) • If there has been no response after 15 minutes, an additional weight appropriate dose of GVOKE from a new device or vial and syringe kit may be administered while waiting for emergency assistance ( 2.1 ) 2.1 Important Administration Instructions GVOKE auto-injector (HypoPen), pre-filled syringe, and vial and syringe kit are for subcutaneous injection only. 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 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. Emphasize the following instructions to the patient or caregiver: • For the HypoPen or pre-filled syringe: Do not open foil pouch until ready to administer. • For the vial and syringe kit: Store in original carton until ready to administer. • 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 and be free of particles. If the solution is discolored or contains particulate matter, do not use. • Administer the injection in the lower abdomen, outer thigh, or outer upper arm. • Withdraw the correct dose. • Call for emergency assistance immediately after administering the dose. • If there has been no response after 15 minutes, an additional dose from a new device or vial and syringe kit may be administered while waiting for emergency assistance. • When the patient has responded to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia. • Do not attempt to reuse GVOKE. Each GVOKE device or vial contains a single dose of glucagon and cannot be reused. Discard any unused portion. 2.2 Dosage in Adults and Pediatric Patients Aged 2 Years and Above Adults and Pediatric Patients Aged 12 and Older • The recommended dose of GVOKE 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 of GVOKE from a new device or vial and syringe kit may be administered while waiting for emergency assistance. Pediatric Patients Aged 2 to Under 12 Years of Age • The recommended dose for pediatric patients who weigh less than 45 kg is 0.5 mg GVOKE administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. • The recommended dose for pediatric patients who weigh 45 kg or greater is 1 mg GVOKE 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 weight appropriate dose of GVOKE from a new device or vial and syringe kit may be administered while waiting for emergency assistance.

10 OVERDOSAGE If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure, and pulse rate. In case of suspected overdosing, serum potassium may decrease and should be monitored and corrected if needed. If the patient develops a dramatic increase in blood pressure, phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.

7 DRUG INTERACTIONS • Beta-blockers: Patients taking beta-blockers may have a transient increase in pulse and blood pressure. ( 7.1 ) • Indomethacin: In patients taking indomethacin GVOKE may lose its ability to raise glucose or may produce hypoglycemia. ( 7.2 ) • Warfarin: GVOKE may increase the anticoagulant effect of warfarin. ( 7.3 ) See 17 for PATIENT COUNSELING INFORMATION and FDA ‑ approved patient labeling. 7.1 Beta-Blockers Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given GVOKE. 7.2 Indomethacin In patients taking indomethacin, GVOKE may lose its ability to raise blood glucose or may even produce hypoglycemia. 7.3 Warfarin GVOKE may increase the anticoagulant effect of warfarin.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics After administration of 1 mg GVOKE in adult patients with diabetes, the mean maximum glucose increase from baseline was 176 mg/dL. Figure 1: Mean ± Standard Error of the Mean (SEM) Plasma Glucose vs. Time from 1 mg GVOKE Injection in Adult Subjects with Type 1 Diabetes Mellitus In pediatric patients with type 1 diabetes (2 to less than 18 years), the mean maximum glucose increase from baseline was 134 mg/dL (2 to less than 6 years), 145 mg/dL (6 to less than 12 years), and 123 mg/dL (12 to less than 18 years). Figure 2: Mean (± SEM) Plasma Glucose vs. Time from GVOKE Injection in Pediatric Subjects with Type 1 Diabetes Mellitus Figure 1 Figure 2 12.3 Pharmacokinetics Absorption Subcutaneous injection of 1 mg GVOKE in adult type 1 diabetes mellitus subjects 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. Figure 3: Mean (± SEM) Plasma Glucagon Concentration vs. Time for 1 mg GVOKE Injection 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 subjects 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 subjects 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 subjects 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. Figure 4: Mean (± SEM) Plasma Glucagon Concentration vs. Time from GVOKE Injection in Pediatric Patients with Type 1 Diabetes Mellitus Figure 3 Figure 4

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics After administration of 1 mg GVOKE in adult patients with diabetes, the mean maximum glucose increase from baseline was 176 mg/dL. Figure 1: Mean ± Standard Error of the Mean (SEM) Plasma Glucose vs. Time from 1 mg GVOKE Injection in Adult Subjects with Type 1 Diabetes Mellitus In pediatric patients with type 1 diabetes (2 to less than 18 years), the mean maximum glucose increase from baseline was 134 mg/dL (2 to less than 6 years), 145 mg/dL (6 to less than 12 years), and 123 mg/dL (12 to less than 18 years). Figure 2: Mean (± SEM) Plasma Glucose vs. Time from GVOKE Injection in Pediatric Subjects with Type 1 Diabetes Mellitus Figure 1 Figure 2

12.3 Pharmacokinetics Absorption Subcutaneous injection of 1 mg GVOKE in adult type 1 diabetes mellitus subjects 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. Figure 3: Mean (± SEM) Plasma Glucagon Concentration vs. Time for 1 mg GVOKE Injection 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 subjects 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 subjects 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 subjects 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. Figure 4: Mean (± SEM) Plasma Glucagon Concentration vs. Time from GVOKE Injection in Pediatric Patients with Type 1 Diabetes Mellitus Figure 3 Figure 4

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3 DOSAGE FORMS AND STRENGTHS GVOKE injection is a clear, colorless to pale yellow solution available as follows: • 0.5 mg/0.1 mL single-dose pre-filled HypoPen auto-injector • 1 mg/0.2 mL single-dose pre-filled HypoPen auto-injector • 1 mg/0.2 mL single-dose pre-filled syringe • 1 mg/0.2 mL single-dose vial and syringe kit Injection: • 0.5 mg/0.1 mL single-dose pre-filled HypoPen auto-injector ( 3 ) • 1 mg/0.2 mL single-dose pre-filled HypoPen auto-injector ( 3 ) • 1 mg/0.2 mL single-dose pre-filled syringe ( 3 ) • 1 mg/0.2 mL single-dose vial and syringe kit ( 3 )

Gvoke Kit Vial glucagon injection, solution GLUCAGON GLUCAGON Gvoke Kit glucagon injection, solution GLUCAGON GLUCAGON Gvoke PFS 0.5 mg Pre-filled Syringe glucagon injection, solution SULFURIC ACID DIMETHYL SULFOXIDE GLUCAGON GLUCAGON Gvoke PFS 1 mg Pre-filled Syringe glucagon injection, solution SULFURIC ACID DIMETHYL SULFOXIDE GLUCAGON GLUCAGON Gvoke HypoPen 1 mg Auto-Injector glucagon injection, solution SULFURIC ACID DIMETHYL SULFOXIDE GLUCAGON GLUCAGON Gvoke HypoPen 0.5 mg Auto-Injector glucagon injection, solution SULFURIC ACID DIMETHYL SULFOXIDE GLUCAGON GLUCAGON

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals to evaluate carcinogenic potential have not been performed. Recombinant glucagon was positive in the bacterial Ames assay. It was determined that an increase in colony counts was related to technical difficulties in running this assay with peptides. Studies in rats have shown that glucagon does not cause impaired fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals to evaluate carcinogenic potential have not been performed. Recombinant glucagon was positive in the bacterial Ames assay. It was determined that an increase in colony counts was related to technical difficulties in running this assay with peptides. Studies in rats have shown that glucagon does not cause impaired fertility.

NDA212097

Gvoke HypoPen 1 mg Auto-Injector

glucagon injection, solution

72065-121

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

1 mg Auto-Injector AI 1mg device label AI 1 mg Pouch label AI 1 mg 1-pack carton label AI 1mg 2-pack carton label

17 PATIENT COUNSELING INFORMATION Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Recognition of Severe Hypoglycemia Inform patient and family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia. Administration Review the Patient Information and Instructions for Use with the patient and family members or caregivers. Serious Hypersensitivity Inform patients that allergic reactions can occur with GVOKE. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [ see Warnings and Precautions ( 5.3 ) ].

INSTRUCTIONS FOR USE GVOKE HypoPen® [GEE-voke hypo-pen] (glucagon injection) Auto-injector for subcutaneous use This “Instructions for Use” contains information on how to inject GVOKE HypoPen® Section headings and other template-related items found in this IFU are for organization of the document only and are not intended for use in corresponding artwork/patient-facing IFU files. Figure numbers in this content document may not correspond to figure numbers in corresponding artwork/patient-facing IFU files. Appropriate trademark symbol (™ or ®) should be used upon first use of a trademarked name on each page; usage may differ from this content file and final artwork based on page layout. 1. GVOKE HYPOPEN® VISUAL Understanding GVOKE HypoPen Adult GVOKE HypoPen contains a 1 mg dose of glucagon and is in a foil pouch. Below is a picture of the pouch. See the GVOKE HypoPen package for a full view of the Quick-Use Guide. Adult GVOKE HypoPen (1 mg dose) Pediatric GVOKE HypoPen contains a 0.5 mg dose of glucagon and is in a foil pouch. Below is a picture of the pouch. See the GVOKE HypoPen package for a full view of the Quick-use guide. Pediatric GVOKE HypoPen (0.5 mg dose) HypoPen Device Note: GVOKE HypoPen should be used one time and then thrown away (discarded) 2. IMPORTANT INFORMATION YOU NEED TO KNOW BEFORE INJECTING GVOKE HYPOPEN® • Become familiar with the following instructions before an emergency happens. • Do not use this auto-injector past the expiration date printed on the device. Replace GVOKE HypoPen before the expiration date on the box. • If you have questions regarding the use of this product, talk to a healthcare provider or pharmacist. Make sure that relatives, close friends, or caregivers know that if you become unconscious, they should call for emergency medical help right away. GVOKE HypoPen may have been prescribed so that relatives, close friends, and caregivers can give the injection if you become hypoglycemic (severe low blood sugar) and are unable to take sugar by mouth. If you are unconscious, GVOKE HypoPen can be given while awaiting medical assistance. Show your relatives, close friends, or caregivers where you store GVOKE HypoPen and how to use it. They need to know how to use GVOKE HypoPen before an emergency situation happens. Indications for Use GVOKE HypoPen is for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above. Symptoms of severe hypoglycemia include, unconsciousness, and seizures or convulsions. Give GVOKE HypoPen if: 1. the patient is unconscious, 2. the patient is unable to eat sugar or a sugar-sweetened product, 3. the patient is having a seizure, or 4. you have tried to give the patient sugar or drinks that are high in sugar such as a regular soft drink (soda) or fruit juice and the patient does not get better. Milder cases of hypoglycemia should be treated promptly by eating sugar or a sugar sweetened product. (See Information on Hypoglycemia for more information on the symptoms of low blood sugar.) GVOKE HypoPen will not work when taken by mouth (orally). Information on Hypoglycemia Early symptoms of hypoglycemia (low blood sugar) include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • light-headedness • abnormal behavior • inability to concentrate • blurred vision • hunger • slurred speech • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • unsteady movement • headache • personality changes If not treated, the patient may progress to severe hypoglycemia which can include: • confusion • seizures • unconsciousness • death The occurrence of early symptoms calls for quick and, if necessary, repeated administration of some form of carbohydrate. Patients should always carry a quick source of sugar, such as candy mints or glucose tablets. The prompt treatment of mild hypoglycemic symptoms can prevent severe hypoglycemic reactions. If the patient does not improve or if administration of carbohydrate is impossible, GVOKE HypoPen® should be given or the patient should be treated with intravenous glucose by a medical professional. Possible Problems with GVOKE HypoPen Treatment Common side effects in adults and pediatric patients are nausea and vomiting. The product may cause serious side effects including serious allergic reactions, fast heart beat and high blood pressure. People may be allergic to glucagon or to one of the inactive ingredients in GVOKE HypoPen or may experience fast heart-beat for a short while. If you experience any other reactions that may have been caused by GVOKE HypoPen, please contact your healthcare provider. Important: • Act quickly. Prolonged unconsciousness may be harmful. • After the injection is complete, turn the unconscious patient on his or her side to prevent them from choking in case they throw up (vomit). • Carefully read and follow these instructions. Have a healthcare provider show you the right way to use GVOKE HypoPen. Important Warnings • Do not open pouch until time of use. • Do not use after the expiration date has passed. • Do not use if the red needle cap has been removed or is damaged. • Do not remove the red cap until you are ready to inject. • Do not put or press thumb, fingers, or hand over the yellow needle guard. • Call a healthcare provider as soon as glucagon has been injected. • If the patient does not wake up within 15 minutes, give another dose of GVOKE HypoPen® and call for emergency medical help right away. • Feed the patient as soon as he or she wakes up and is able to swallow. Read and become familiar with the following instructions before an emergency happens. If you have questions about using GVOKE HypoPen, talk with your healthcare provider or pharmacist. 3. PREPARING TO INJECT GVOKE HYPOPEN Step 1. Remove GVOKE HypoPen from Foil Pouch • Tear open pouch at the dotted line and carefully remove GVOKE HypoPen (see Figure 1 ). Figure 1 Step 2. Check the Expiration Date • Check the expiration date printed on the label of GVOKE HypoPen (see Figure 2 ). • Important: Do not use GVOKE HypoPen if the expiration date has passed. If GVOKE HypoPen is expired, throw it away in an FDA cleared sharps container and use a new GVOKE HypoPen. Figure 2 Step 3. Inspect the Solution • Look at the liquid medicine through the viewing window. It must be clear and colorless, or a pale yellow (see Figure 3 ). • Important: Do not use GVOKE HypoPen ® or inject if the liquid contains lumps, flakes, or particles. Do not inject if solution is not visible in the viewing window. • If you do not have another GVOKE HypoPen to use, call for emergency help right away. Figure 3 4. INJECTING GVOKE HYPOPEN Step 4. Pull Off Red Cap • Pull the red needle cap straight off the device (see Figure 4 ). • Important: Do not put your thumb, fingers, or hand on or near the needle guard or needle opening to help prevent accidental needle sticks. Figure 4 Step 5. Choose Injection Site and Expose Bare Skin • Choose the lower abdomen, outer thigh, or outer upper arm for your injection site (see Figure 5 ). • Remove any clothing covering the injection site (see Figure 6 ). The injection must be performed straight into the skin. • Important: Do not inject through clothing. Figure 5 Figure 6 Step 6. Push and Hold to Start Injection • Push and hold GVOKE HypoPen® straight down against the injection site. Listen for a “Click”. • Continue to hold the device down and count slowly to 5 (see Figure 7 ). • When the injection is complete, the viewing window will be red (see Figure 8 ). • Important: Do not lift up GVOKE HypoPen until the injection is complete. Figure 7 Figure 8 Step 7. Lift Away from Skin Lift the device straight up from the injection site (see Figure 9 ). • The yellow needle guard will lock over the needle. Figure 9 Step 8. Turn Patient onto Side • When an unconscious person wakes up, he or she may throw up (vomit). • Turn the unconscious patient on their side to prevent choking (see Figure 10 ). Figure 10 Step 9. Make Sure Patient Receives Immediate Medical Attention After Use • Call for emergency medical help right after GVOKE HypoPen® has been injected. • Even if GVOKE HypoPen helps the patient to wake up, you should still call for emergency medical help right away. • The patient’s healthcare provider should also be notified whenever a severe drop in blood sugar (hypoglycemic reactions) happens. Hypoglycemia may happen again after receiving an injection from GVOKE HypoPen. The patient’s diabetes medicine may need to be changed. • Feed the patient as soon as he or she wakes up and is able to swallow. Give the patient a fast-acting source of sugar (such as a regular soft drink or fruit juice) and a longacting source of sugar (such as crackers and cheese or a meat sandwich). If the patient does not wake up within 15 minutes, give another dose of glucagon if a second GVOKE HypoPen is available and notify emergency medical services right away. 5. STORING GVOKE HYPOPEN Storage Information • Store in sealed original foil pouch until time of use. • Store at room temperature, 68° to 77°F (20° to 25°C). • Do not refrigerate or freeze. 6. DISPOSING OF GVOKE HYPOPEN® Re-cap and Dispose of GVOKE HypoPen in an FDA Cleared Sharps Disposal Container If a puncture-resistant sharps container is not available, carefully re-cap and store GVOKE HypoPen in a safe place until it can be disposed of into a FDA cleared sharps container (see Figure 11 ). • Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have a FDA cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic • can be closed with a tight-fitting puncture-resistant lid, without sharps being able to come out • upright and stable during use • leak-resistant • properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal . Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Always keep the sharps container out of the reach of children. If needed, make sure to get a refill of GVOKE HypoPen. Figure 11 7. ADDITIONAL INFORMATION This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Xeris Pharmaceuticals, Inc. Chicago, IL 60607 Revised 04/2023 ©2023 by Xeris Pharmaceuticals, Inc. Ai Pouch 1 mg AI Pouch 0.5 mg AI Image IFUA-SideB-F1 IFUA-SideB-F2 IFUA-SideB-F3 IFUA-SideB-F4 IFUA-SideB-F5 IFUA-SideB-F6 IFUA-SideB-F7 IFUA-SideB-F8 IFUA-SideB-F9 IFUA-SideB-F10 IFUA-SideB-F11

Gvoke Kit Patient Package Insert PATIENT INFORMATION GVOKE® (Gee-voke) (glucagon) injection, for subcutaneous use What is GVOKE? • GVOKE is a prescription medicine used to treat very low blood sugar (severe hypoglycemia) in people with diabetes aged 2 years and older. • It is not known if GVOKE is safe and effective in children under 2 years of age. Do not use GVOKE if you : • have a tumor in the gland on top of your kidneys (adrenal gland) called pheochromocytoma. • have a tumor in your pancreas called insulinoma. • are allergic to glucagon or any of the ingredients in GVOKE. See the end of this Patient Information leaflet for a complete list of ingredients in GVOKE. Before using GVOKE, tell your healthcare provider about all of your medical conditions, including if you: • have adrenal gland problems. • have a tumor in your pancreas. • have not had food or water for a long time (prolonged fasting or starvation). • have low blood sugar that does not go away (chronic hypoglycemia). • are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. It is not known if GVOKE passes into your breast milk. You and your healthcare provider should decide if you can use GVOKE while breastfeeding. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. GVOKE may affect the way other medicines work, and other medicines may affect how GVOKE works. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use GVOKE? • Read the detailed Instructions for Use that comes with GVOKE. • Use GVOKE exactly how your healthcare provider tells you to use it. • Make sure your relatives, close friends, and caregivers know where you store GVOKE and how to use it the right way before you need their help. • Act quickly. Having very low blood sugar for a period of time may be harmful. • Your healthcare provider will tell you how and when to use GVOKE. • After giving GVOKE, your caregiver should call for emergency medical help right away. • When you are able to safely swallow food or drink, your caregiver should give you a fast-acting source of sugar (such as a regular soft drink or fruit juice) and a long-acting source of sugar (such as crackers and cheese or a meat sandwich). • If you do not respond to treatment after 15 minutes, your caregiver may give you another dose, if available. Tell your healthcare provider each time you use GVOKE. Low blood sugar may happen again after receiving an injection of GVOKE. Your diabetes medicine may need to be changed. What are the possible side effects of GVOKE? GVOKE may cause serious side effects, including: • High blood pressure. GVOKE can cause high blood pressure in certain people with tumors in their adrenal glands. • Low blood sugar. GVOKE can cause low blood sugar in people with certain tumors in their pancreas called insulinomas by making too much insulin in their bodies. Signs and symptoms of low blood sugar may include: o sweating o drowsiness o dizziness o sleep disturbances o irregular heartbeat o anxiety o tremor o blurred vision o hunger o slurred speech o restlessness o depressed mood o tingling in the hands, feet, lips, or tongue o irritability o abnormal behavior o lightheadedness o unsteady movement o inability to concentrate o personality changes o headache • Serious allergic reaction. Call your healthcare provider or get medical help right away if you have a serious allergic reaction including: o rash o difficulty breathing o low blood pressure The most common side effects of GVOKE in adults include: • nausea • vomiting • swelling at the injection site • headache The most common side effects of GVOKE in children include: o nausea o low blood sugar o high blood sugar o vomiting o abdominal pain o headache o pain or redness at the injection site o itching These are not all the possible side effects of GVOKE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store GVOKE? • Store GVOKE in the original container until time of use. • Store at room temperature between 68°F to 77°F (20° C to 25°C). • Do not refrigerate or freeze. Keep GVOKE and all medicines out of the reach of children. General information about the safe and effective use of GVOKE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GVOKE for a condition for which it was not prescribed. Do not give GVOKE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about GVOKE that is written for health professionals. What are the ingredients in GVOKE? Active ingredient: glucagon. Inactive ingredients: trehalose dihydrate NF, 1N sulfuric acid, mannitol USP (kit only) in 205 mg dimethyl sulfoxide. Distributed by: Xeris Pharmaceuticals, Inc., Chicago, IL For more information go to www.gvokeglucagon.com or call 1-877-937-4737. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 05/2023

14 CLINICAL STUDIES 14.1 Adult Patients with Type 1 Diabetes Mellitus GVOKE was evaluated in adult patients aged 18 to 74 years with type 1 diabetes in two multi-center 2-way crossover studies, Study A was double-blinded with 80 patients, and Study B was single-blinded with 81 patients. Both studies involved 2 clinic visits 7 to 28 days apart, with random assignment to receive GVOKE 1 mg during one session and GEK 1 mg during the other. 154 subjects received an injection of GVOKE and 157 subjects received an injection of GEK. A total of 152 subjects received both GVOKE and GEK. The efficacy of GVOKE was compared to GEK in subjects who were in a state of insulin‑induced hypoglycemia via insulin infusion with target plasma glucose less than 50 mg/dL. In Study A, mean plasma glucose at time of glucagon administration was 44.8 mg/dL and 45.2 mg/dL for GVOKE and GEK, respectively. In Study B, mean plasma glucose at time of glucagon administration was 47.7 mg/dL and 48.7 mg/dL for GVOKE and GEK, respectively. Treatment ‘success’ was defined as plasma glucose increase from mean value at time of glucagon administration to absolute value greater than 70 mg/dL or relative increase of 20 mg/dL or greater, at 30 minutes after glucagon administration. In a pooled analysis of Study A and Study B, the proportion of patients who achieved treatment ‘success’ was 98.7 % in the GVOKE group and 100% in the GEK group and the comparison between groups met the pre-specified non-inferiority margin. A summary of treatment ‘success’ rates is shown in Table 3 . The mean time to treatment ‘success’ was 13.8 minutes in the GVOKE group and 10 minutes in the GEK group. Table 3: Adult Patients Meeting Treatment Success in Studies A and B Combined a Treatment success is defines as blood glucose greater than 70 mg/dL or an increase of blood glucose by 20 mg/dL or greater from baseline. The efficacy analysis population consisted of all patients who received both doses of the study drug. b Percentage based on number of patients from both studies. Study A (n=80) Study B (n=81) Pooled Studies A and B (n=161) b GVOKE GEK GVOKE GEK GVOKE GEK Treatment Success-n (%) a 76 (97%) 79 (100%) 76 (100%) 78 (100%) 152 (99%) 157 (100%) Glucose criteria met- n (%) Greater than 70 mg/dL 74 (95%) 79 (100%) 76 (100%) 78 (100%) 150 (97%) 157 (100%) 20 mg/dL or greater increase from baseline 76 (97%) 79 (100%) 76 (100%) 78 (100%) 152 (99%) 157 (100%) 14.2 Pediatric Patients with Type 1 Diabetes Mellitus GVOKE was evaluated in a study in 31 pediatric patients with type 1 diabetes mellitus. Patients were administered insulin to induce a plasma glucose of less than 80 mg/dL. Patients ages 2 to under 6 years and 6 to under 12 years of age then received a 0.5 mg dose of GVOKE. Patients ages 12 and older received a 0.5 mg or 1 mg dose of GVOKE. All evaluable pediatric patients (30/30) achieved a target glucose increase of at least 25 mg/dL. Following administration, plasma glucose levels over time showed similar glucose responses for patients in each age group. A summary of plasma glucose results are shown in Table 4 . Table 4: Pediatric Patients with Type 1 Diabetes Mellitus Plasma Glucose by Age Group SD=standard deviation Age Group GVOKE Dose Plasma Glucose (mg/dL) Mean (SD) Baseline 30 minutes Change 2 to under 6 years (n=7) 0.5 mg 68.1 (8.3) 149.6 (15.2) 81.4 (18.3) 6 to under 12 years (n=13) 0.5 mg 71.6 (7.6) 155.8 (26.5) 84.2 (25.3) 12 to under 18 years (n=11) 0.5 mg 75.2(2.1) 128.1(20.46) 52.9(19.88) 1 mg 74.5(4.84) 129.5 (29.5) 55 (27.3)

8.5 Geriatric Use Clinical studies of GVOKE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Limited clinical trial experience has not identified differences in responses between the elderly and younger patients.

8.4 Pediatric Use The safety and effectiveness of GVOKE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients ages 2 years and above. Use of GVOKE for this indication is supported by evidence from a study in 31 pediatric patients ages 2 and older with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] . The safety and effectiveness of GVOKE have not been established in pediatric patients younger than 2 years of age.

8.1 Pregnancy Risk Summary Available data from case reports and a small number of observational studies with glucagon use in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated a lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In a rat reproduction study, no embryofetal toxicity was observed with glucagon administered by injection during the period of organogenesis at doses representing up to 40 times the human dose, based on body surface area (mg/m 2 ) (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In pregnant rats given animal sourced glucagon twice-daily by injection at doses up to 2 mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m 2 ) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from case reports and a small number of observational studies with glucagon use in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated a lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In a rat reproduction study, no embryofetal toxicity was observed with glucagon administered by injection during the period of organogenesis at doses representing up to 40 times the human dose, based on body surface area (mg/m 2 ) (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In pregnant rats given animal sourced glucagon twice-daily by injection at doses up to 2 mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m 2 ) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality. 8.2 Lactation Risk Summary There is no information available on the presence of glucagon in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, glucagon is a peptide and would be expected to be broken down to its constituent amino acids in the infant's digestive tract and is therefore, unlikely to cause harm to an exposed infant. 8.4 Pediatric Use The safety and effectiveness of GVOKE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients ages 2 years and above. Use of GVOKE for this indication is supported by evidence from a study in 31 pediatric patients ages 2 and older with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] . The safety and effectiveness of GVOKE have not been established in pediatric patients younger than 2 years of age. 8.5 Geriatric Use Clinical studies of GVOKE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Limited clinical trial experience has not identified differences in responses between the elderly and younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING GVOKE injection is supplied as a clear, colorless to pale yellow solution in the following configurations: Strength Package Size NDC number 0.5 mg per 0.1 mL 1 single-dose auto-injector (HypoPen) 72065-120-11 0.5 mg per 0.1 mL 2 single-dose auto-injectors (HypoPen) 72065-120-12 1 mg per 0.2 mL 1 single-dose auto-injector (HypoPen) 72065-121-11 1 mg per 0.2 mL 2 single-dose auto-injectors (HypoPen) 72065-121-12 1 mg per 0.2 mL 1 single-dose pre-filled syringe 72065-131-11 1 mg per 0.2 mL 2 single-dose pre-filled syringes 72065-131-12 1 mg per 0.2 mL 1 single-dose vial and syringe 72065-140-11 Store GVOKE at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). Do not refrigerate or freeze. Do not expose to extreme temperatures. Store the GVOKE HypoPen and pre-filled syringe in the original sealed foil pouch until time of use. Store the vial and pouched syringe together in original carton until time of use. Discard any unused portion.