Gvoke Drug Information

Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older

with Diabetes GVOKE is indicated for subcutaneous use for the treatment of severe hypoglycemia in adult and pediatric patients aged two and older with diabetes.

Diagnostic Aid in Adults

GVOKE VialDx is indicated for intravenous use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients.

Dosage and

Administration of GVOKE for Subcutaneous Use to Treat Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes Important Administration Instructions To treat severe hypoglycemia in adult and pediatric patients aged 2 years and older with diabetes, administer GVOKE HypoPen, GVOKE PFS, or GVOKE Kit subcutaneously. These three presentations are only for subcutaneous use and are referred to as GVOKE in this labeling. For GVOKE HypoPen or GVOKE PFS: Do not open foil pouch until ready to administer.

For GVOKE Kit: Store in original carton until ready to administer. Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires the help of others to recover, instruct the patient to inform those around them about GVOKE and its Instructions for Use.

Administer GVOKE subcutaneously as soon as possible when severe hypoglycemia is recognized. Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for GVOKE. Visually inspect GVOKE prior to administration. The solution should be clear, colorless to pale yellow Withdraw the correct dose (see below for dosage recommendations). Administer subcutaneously in the lower abdomen, outer thigh, or outer upper arm, according to the printed instructions on the foil pouch label, carton, or the Instructions for Use.

Call for emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, an additional dose from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance. When the patient has responded to GVOKE, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.

Each GVOKE HypoPen, GVOKE PFS, or GVOKE Kit product contains a single dose of glucagon. Do not reuse and discard any unused portion. Recommended Dosage in Adult and Pediatric Patients Aged 12 Years and Older to Treat Severe Hypoglycemia To treat severe hypoglycemia in patients 12 years of age and older with diabetes, use GVOKE HypoPen, GVOKE PFS, or GVOKE Kit: The recommended dose is 1 mg administered by subcutaneous injection into lower abdomen, outer thigh, or outer upper arm.

If there has been no response after 15 minutes, an additional 1 mg dose from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance Recommended Dosage in Pediatric Patients Aged 2 to less than 12 Years of Age to Treat Severe Hypoglycemia To treat severe hypoglycemia in pediatric patients aged 2 to less than 12 years of age with diabetes, use GVOKE HypoPen, GVOKE PFS, or GVOKE Kit. The recommended dose in those who weigh: Less than 45 kg is 0.5 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. 45 kg or greater is 1 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm. If there has been no response after 15 minutes, an additional 0.5 mg dose (for those who weigh less than 45 kg) or 1 mg dose (for those who weigh 45 kg or greater) from a new GVOKE HypoPen, GVOKE PFS, or GVOKE Kit may be administered while waiting for emergency assistance.

Dosage and

Administration of GVOKE VialDx for Intravenous Use as a Diagnostic Aid in Adults Important Administration Information For use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract, use GVOKE VialDx. GVOKE VialDx is only for intravenous use under medical supervision Must be diluted with 0.9% Sodium Chloride Injection prior to administration. Using a syringe, draw 0.2 mL from the GVOKE VialDx vial and dispense into a separate empty sterile container containing 2 mL of 0.9% Sodium Chloride Injection.

Gently swirl the container until the solution is thoroughly mixed. The mixed solution should be clear and colorless to pale yellow. Inspect visually for particulate matter and discoloration.

The final concentration of the diluted solution is 0.45 mg/mL of glucagon. Draw the required dose from the container into a syringe for administration (see below for dosage recommendations). If not used immediately, diluted GVOKE VialDx may be stored for up to 8 hours after initial dilution. Inject the solution intravenously via a 1-minute slow push using consistent pressure.

After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure. GVOKE VialDx contains a single dose of glucagon. Do not reuse.

Discard any unused portion. Recommended Dosage in Adults as a Diagnostic Aid For use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract, use GVOKE VialDx. The recommended intravenous dose for relaxation of the : Stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg Colon is 0.5 mg to 0.75 mg The onset of action after an injection will depend on the organ under examination .

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of GVOKE and GVOKE VialDx cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. GVOKE for Subcutaneous Use for the Treatment of Severe Hypoglycemia in Adult and Pediatric Patients 2 Aged Years and Older with Type 1 Diabetes Mellitus Adverse Reactions in Adult Patients The safety of GVOKE for subcutaneous use for the treatment of severe hypoglycemia in adults with diabetes was evaluated in two randomized, blinded, 2-way crossover studies conducted in adults with type 1 diabetes mellitus. In total, 154 patients received a subcutaneous injection of GVOKE . The most common adverse reactions that occurred in 2% or more of adults treated with GVOKE during these two clinical trials are listed in Table 1. Table 1: Adverse Reactions that occurred ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus Treated with GVOKE a a Adverse Reactions that occurred within 12 hours.

GVOKE 1 mg dose (N = 154) Nausea 30% Vomiting 16% Injection site edema raised 1 mm or greater 7% Headache 5% Injection site pain was reported by 1% of GVOKE-treated patients. Hypertension and tachycardia have occurred with glucagon treatment. Adverse Reactions in Pediatric Patients Aged 2 Years and Older The safety of GVOKE for the treatment of severe hypoglycemia in patients with diabetes was evaluated in one single-arm, open-label, study in 31 pediatric patients with type 1 diabetes mellitus . The data in Table 2 reflect the exposure of 31 pediatric patients to 0.5 mg or 1 mg of GVOKE given subcutaneously.

The most common adverse reactions that occurred in ≥2% of GVOKE-treated pediatric patients aged 2 years and older are listed in Table 2. Table 2: Adverse Reactions That Occurred ≥ 2% in GVOKE-treated Pediatric Patients Aged 2 Years and Older with Type 1 Diabetes Mellitus a a Adverse Reactions that occurred within 12 hours. 2 to 6 years of age (0.5 mg dose) N =7 6 to 12 years of age (0.5 mg dose) N = 13 12 to 18 years of age (1 mg dose) N = 11 Total N = 31 Nausea 43% 54% 36% 45% Hypoglycemia 29% 54% 27% 39% Vomiting 14% 23% 18% 19% Headache 0% 15% 0% 7% Abdominal pain 0% 8% 0% 3% Hyperglycemia 14% 8% 0% 7% Injection site discomfort 0% 8% 0% 3% Injection site reaction 0% 0% 9% 3% Urticaria 0% 8% 0% 3% GVOKE VialDx for Intravenous Use As a Diagnostic Aid in Adults The safety of GVOKE VialDx for intravenous use as a diagnostic aid in adults was evaluated in an open-label single-dose study in 83 adult healthy volunteers. Table 3 displays the most common adverse reactions that occurred in 5% or greater in healthy volunteers who received 0.75 mg of GVOKE VialDx intravenously. Table 3: Adverse Reactions that Occurred ≥ 5 % in Adult Healthy Volunteers Who Received 0.75 mg of GVOKE VialDx for Intravenous Use as a Diagnostic Aid N=83 Nausea 37.3% Dysgeusia 18.1% Headache 10.8% Hot Flush 9.6% Dizziness 8.4%

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 .

• Table 4: Clinically Significant Drug Interaction with GVOKE and GVOKE VialDx Beta-Blockers Clincial Impact: Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given GVOKE or GVOKE VialDx. Intervention The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.
• Insulin Clincial Impact: Insulin acts antagonistically to glucagon. Intervention Monitor blood glucose when GVOKE VialDx is used as a diagnostic aid in patients receiving insulin.
• Indomethacin Clincial Impact: In patients taking indomethacin, GVOKE may lose its ability to raise blood glucose or may even produce hypoglycemia. Intervention Monitor blood glucose levels during glucagon treatment of patients taking indomethacin.
• Anticholinergic Drugs Clincial Impact: The concomitant use of anticholinergic drugs and GVOKE VialDx increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Intervention Concomitant use of anticholinergic drugs with GVOKE VialDx is not recommended.
• Warfarin Clincial Impact: GVOKE and GVOKE Vial Dx may increase the anticoagulant effect of warfarin. Intervention Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.
• Beta-blockers: GVOKE- or GVOKE VialDx-treated patients taking concomitant beta-blockers may have a transient increase in pulse and blood pressure.
• Indomethacin: In patients taking concomitant indomethacin, GVOKE may lose its ability to raise glucose or may produce hypoglycemia.
• Anticholinergic drugs: Concomitant use of anticholinergic drugs with GVOKE VialDx for use as a diagnostic aid is not recommended.
• Warfarin: GVOKE and GVOKE VialDx may increase the anticoagulant effect of warfarin.
• Insulin: Monitor blood glucose when GVOKE VialDx is used as a diagnostic aid in patients receiving insulin. See 17 for PATIENT COUNSELING INFORMATION and FDA ‑ approved patient labeling for GVOKE.

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.

Pediatric Use The safety and effectiveness of GVOKE for subcutaneous use for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged 2 years and older. Use of GVOKE for this indication is supported by evidence from two adequate and well-controlled studies in adults with type-1 diabetes mellitus and from a study in 31 pediatric patients ages 2 and older with type 1 diabetes mellitus . The safety and effectiveness of GVOKE for subcutaneous use for the treatment of severe hypoglycemia in patients with diabetes have not been established in pediatric patients younger than 2 years of age. Safety and effectiveness of GVOKE VialDx for intravenous use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in pediatric patients have not been established.

and GVOKE VialDx are contraindicated in patients with: Pheochromocytoma because of the risk of substantial increase in blood pressure Insulinoma because of the risk of hypoglycemia Prior hypersensitivity reaction to glucagon or to any of the excipients in GVOKE or GVOKE VialDx. Serious hypersensitivity reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension . GVOKE VialDx for use as a diagnostic aid is also contraindicated in patients with glucagonoma because of risk of hypoglycemia Pheochromocytoma Insulinoma Prior hypersensitivity reaction to glucagon or to any of the excipients Glucagonoma when used as a diagnostic aid

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.

In the event of an overdose of GVOKE, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendation.