DailyMed Label: Gvoke Kit

DailyMed Label: Gvoke Kit

2023

DailyMed Prescription

Gvoke Kit

glucagon injection, solution

Xeris Pharmaceuticals, Inc.

NDC: 72065-141

NDC: 72065-141

NDC: 72065-140

NDC: 72065-140

NDC: 72065-130

NDC: 72065-130

NDC: 72065-131

NDC: 72065-131

NDC: 72065-121

NDC: 72065-121

NDC: 72065-120

NDC: 72065-120

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:

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 )

• 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 ) 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. 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.

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 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 )

• Substantial Increase in Blood Pressure in Patients Pheochromocytoma: Contraindicated in patients with pheochromocytoma because GVOKE may stimulate the release of catecholamines from the tumor. ( 4 , 5.1 ) • Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, GVOKE may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops symptoms of hypoglycemia after a dose of GVOKE, give glucose orally or intravenously. ( 4 , 5.2 ) • Hypersensitivity and Allergic Reactions: Allergic reactions have been reported and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. ( 4 , 5.3 ) • Lack of Efficacy in Patients with Decreased Hepatic Glycogen: GVOKE is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for GVOKE to be effective. Patients with these conditions should be treated with glucose. ( 5.4 ) • Necrolytic Migratory Erythema (NME): a skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. ( 5.5 ) GVOKE is contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor [see Contraindications ( 4 )] . 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. 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 is contraindicated in patients with insulinoma [see Contraindications ( 4 )] . If a patient develops symptoms of hypoglycemia after a dose of GVOKE, give glucose orally or intravenously. Allergic reactions have been reported with glucagon, these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. GVOKE is contraindicated in patients with a prior hypersensitivity reaction [see Contraindications ( 4 )] . GVOKE is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for GVOKE administration to be effective. Patients with these conditions should be treated with glucose. 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. 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.

The following serious adverse reactions are described below and elsewhere in labeling:

• 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. Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given GVOKE. In patients taking indomethacin, GVOKE may lose its ability to raise blood glucose or may even produce hypoglycemia. GVOKE may increase the anticoagulant effect of warfarin.

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. 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. 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. 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.

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.

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. 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 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

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.

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%) 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)

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