Gvoke Kit Vial: Package Insert and Label Information

GVOKE KIT VIAL- glucagon injection, solution
GVOKE KIT- glucagon injection, solution
GVOKE PFS 0.5 MG PRE-FILLED SYRINGE- glucagon injection, solution
GVOKE PFS 1 MG PRE-FILLED SYRINGE- glucagon injection, solution
GVOKE HYPOPEN 1 MG AUTO-INJECTOR- glucagon injection, solution
GVOKE HYPOPEN 0.5 MG AUTO-INJECTOR- glucagon injection, solution
Xeris Pharmaceuticals, Inc.

GVOKE is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above.

DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

GVOKE auto-injector, 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.

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) ].

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
  • 0.5 mg/0.1 mL single-dose pre-filled syringe
  • 1 mg/0.2 mL single-dose pre-filled syringe
  • 1 mg/0.2 mL single-dose vial and syringe kit

WARNINGS AND PRECAUTIONS

5.1 Substantial Increase in Blood Pressure in Patients Pheochromocytoma

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.

5.2 Hypoglycemia in Patients with Insulinoma

In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, glucagon administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. GVOKE 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.

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.

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) ].

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

GVOKE 1 mg dose

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)

Ages 6 to under 12 years of age

(0.5 mg dose)

Ages 12 to under 18

(1 mg dose)

Total

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) ].

DRUG INTERACTIONS

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.

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.

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/m2) (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/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.

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.

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:

Its molecular formula is C153H225N43O49S with the following structure:
(click image for full-size original)

GVOKE is a clear, colorless to pale yellow, sterile solution for subcutaneous injection available in 0.5 mg per 0.1 mL or 1 mg per 0.2 mL auto-injector or pre-filled syringe, and in 1 mg per 0.2 mL 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 NF, in 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 NF, in 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 NF, and NF in dimethyl sulfoxide diluent.

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

Figure 1
(click image for full-size original)

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 2
(click image for full-size original)

12.3 Pharmacokinetics

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

Figure 3
(click image for full-size original)

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 4
(click image for full-size original)
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