information and fda‑approved patient labeling.

oke, give glucose orally or intravenously. 5.3 hypersensitivity and allergic reactions 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 ) ]. 5.4 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 administration to be effective. patients with these conditions should be treated with glucose. 5.5 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. 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. 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 )

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. 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 )

% in adult patients with type 1 diabetes mellitus treated with gvoke 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 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 ) ]. 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 at toll-free 1-877-937-4737 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

information and fda‑approved patient labeling.

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/m2) 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.

absorption subcutaneous injection of 1 mg gvoke in adult type 1 diabetes mellitus subjects resulted in a mean glucagon cmax of 2481.3 pg/ml, tmax of 50 minutes and auc0‑240min 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 cmax of 2300 pg/ml, tmax of 41 minutes, and auc0‑180min of 138900 pg/ml*min. subcutaneous injection of 0.5 mg gvoke in subjects ages 6 to under 12 years resulted in a mean cmax of 1600 pg/ml, median tmax of 34 minutes and auc0‑180min of 104700 pg/ml*min. subcutaneous injection of 1 mg gvoke in subjects ages 12 to less than 18 years resulted in a mean cmax of 1900 pg/ml, tmax of 51 minutes auc0‑180min 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 1 figure 2 figure 3 figure 4

, 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 study a (n=80) study b (n=81) pooled studies a and b (n=161) 2 gvoke gek gvoke gek gvoke gek treatment success-n (%) 1 76 (97%) 79 (100%) 76 (100%) 78 (100%) 152 (99%) 157 (100%) glucose criteria met- n (%) greater than 70 mg/dl 20 mg/dl or greater increase from baseline 74 (95%) 76 (97%) 79 (100%) 79 (100%) 76 (100%) 76 (100%) 78 (100%) 78 (100%) 150 (97%) 152 (99%) 157 (100%) 157 (100%) 1 - 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. 2 - percentage based on number of patients from both studies. 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 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) sd=standard deviation

nge in the original sealed foil pouch until time of use. store the vial and pouched together in original carton until time of use. discard any unused portion.