Gvoke Hypopen

1.1 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.

1.2 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.

2.1 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.

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The recommended dose in those who weigh:

o

Less than 45 kg is 0.5 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm.

o

45 kg or greater is 1 mg administered by subcutaneous injection into the lower abdomen, outer thigh, or outer upper arm.

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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 [see Clinical Pharmacology ]:

• 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 [see Clinical Pharmacology ].

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.

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.

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 [see Clinical Studies ] and from a study in 31 pediatric patients ages 2 and older with type 1 diabetes mellitus [see Clinical Studies ].

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.

Geriatric Use

Clinical studies of GVOKE and GVOKE VialDx did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients.

Substantial Increase in Blood Pressure in Patients with Pheochromocytoma

GVOKE and GVOKE VialDx are contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor [see Contraindications ]. 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.

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 and GVOKE VialDx are contraindicated in patients with insulinoma [see Contraindications ]. If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously.

Serious Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. Discontinue GVOKE or GVOKE VialDx if symptoms of serious hypersensitivity reactions occur. Advise patients and/or caregivers to seek immediate medical attention if the patient experiences any symptoms of serious hypersensitivity reactions.GVOKE and GVOKE VialDx are contraindicated in patients with a prior hypersensitivity reaction to glucagon, or any of the excipients in GVOKE and GVOKE VialDx [see Contraindications ].

Lack of Efficacy with Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen

Patients with insufficient hepatic stores of glycogen may not respond to GVOKE for the treatment of severe hypoglycemia [see Clinical Pharmacology ]. Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia.

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.GVOKE and GVOKE VialDx are not approved for continuous 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.

5.6 Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus

GVOKE VialDx in patients with diabetes mellitus may cause hyperglycemia. Monitor patients with diabetes for changes in blood glucose levels during treatment with GVOKE VialDx and treat hyperglycemia, if indicated.

5.7 Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease

GVOKE VialDx may increase myocardial oxygen demand, blood pressure, and pulse rate which may be life threatening in patients with cardiac disease. Cardiac monitoring is recommended in patients with cardiac disease during use of GVOKE VialDx as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy.

5.8 Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid

Use of GVOKE VialDx in patients with glucagonoma may cause secondary hypoglycemia. GVOKE VialDx is contraindicated in patients with glucagonoma when used as a diagnostic aid [see Contraindications ]. Test patients suspected of having glucagonoma for blood levels of glucagon prior to administration of GVOKE VialDx, and monitor for changes in blood glucose levels during treatment. If a patient develops symptoms of hypoglycemia after administration of GVOKE VialDx, administer glucose orally or intravenously.