0.2 ML glucagon 5 MG/ML Prefilled Syringe

INDICATIONS AND USAGE For the treatment of severe hypoglycemia: Glucagon is indicated as a treatment for severe hypoglycemia (low blood sugar) which may occur in patients with diabetes mellitus. Because patients with type 1 diabetes may have less of an increase in blood glucose levels compared with a stable type 2 patient, supplementary carbohydrate should be given as soon as possible, especially to a pediatric patient. For use as a diagnostic aid: Glucagon is indicated as a diagnostic aid in the radiologic examination of the stomach, duodenum, small bowel, and colon when diminished intestinal motility would be advantageous. Glucagon is as effective for this examination as are the anticholinergic drugs. However, as use of glucagon in combination with anticholinergic drugs may result in increased side effects, the use of glucagon in combination with anticholinergic drugs is not recommended. INDICATIONS FOR USE Use glucagon to treat insulin coma or insulin reaction resulting from severe hypoglycemia (very low blood sugar). Symptoms of severe hypoglycemia include disorientation, unconsciousness, and seizures or convulsions. Give glucagon if (1) the patient is unconscious (2) the patient is unable to eat sugar or a sugar-sweetened product (3) the patient is having a seizure, or (4) repeated administration of sugar or a sugar-sweetened product such as a regular soft drink or fruit juice does not improve the patient’s condition. Milder cases of hypoglycemia should be treated promptly by eating sugar or a sugar-sweetened product. (See INFORMATION ON HYPOGLYCEMIA below for more information on the symptoms of hypoglycemia.) Glucagon is not active when taken orally. DIRECTIONS FOR USE TO PREPARE GLUCAGON FOR INJECTION 1.Remove the flip-off seal from the bottle of glucagon. Wipe rubber stopper on bottle with alcohol swab. 2.Remove the needle protector from the syringe, and inject the entire contents of the syringe into the bottle of glucagon. DO NOT REMOVE THE PLASTIC CLIP FROM THE SYRINGE. Remove syringe from the bottle. 3.Swirl bottle gently until glucagon dissolves completely. GLUCAGON SHOULD NOT BE USED UNLESS THE SOLUTION IS CLEAR AND OF A WATER-LIKE CONSISTENCY. TO INJECT GLUCAGON Use Same Technique as for Injecting Insulin 4.Using the same syringe, hold bottle upside down and, making sure the needle tip remains in solution, gently withdraw all of the solution (1 mg mark on syringe) from bottle. The plastic clip on the syringe will prevent the rubber stopper from being pulled out of the syringe; however, if the plastic plunger rod separates from the rubber stopper, simply reinsert the rod by turning it clockwise. The usual adult dose is 1 mg. For children weighing less than 44 lb (20 kg), give 1/2 adult dose (0.5 mg). For children, withdraw 1/2 of the solution from the bottle (0.5 mg mark on syringe). DISCARD UNUSED PORTION. USING THE FOLLOWING DIRECTIONS, INJECT GLUCAGON IMMEDIATELY AFTER MIXING. 5.Cleanse injection site on buttock, arm, or thigh with alcohol swab. 6.Insert the needle into the loose tissue under the cleansed injection site, and inject all (or 1/2 for children weighing less than 44 lb) of the glucagon solution. Apply light pressure at the injection site, and withdraw the needle. Press an alcohol swab against the injection site. 7.Turn the patient on his/her side. When an unconscious person awakens, he/she may vomit. Turning the patient on his/her side will prevent him/her from choking. 8.FEED THE PATIENT AS SOON AS HE/SHE AWAKENS AND IS ABLE TO SWALLOW. Give the patient a fast-acting source of sugar (such as a regular soft drink or fruit juice) and a long-acting source of sugar (such as crackers and cheese or a meat sandwich). If the patient does not awaken within 15 minutes, give another dose of glucagon and INFORM A DOCTOR OR EMERGENCY SERVICES IMMEDIATELY. 9.Even if the glucagon revives the patient, his/her doctor should be promptly notified. A doctor should be notified whenever severe hypoglycemic reactions occur. Instructions 1 Instructions 2 Instructions 3 Instructions 4

DOSAGE AND ADMINISTRATION Dosage and Administration of GVOKE for Subcutaneous Use to Treat Severe Hypoglycemia in Adult and Pediatric Patients Aged 2 Years and Older with Diabetes ( 2.1 ) Important Administration Instructions Administer GVOKE HypoPen, GVOKE PFS, or GVOKE Kit subcutaneously. These three presentations are referred to as GVOKE in this labeling 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. Administer GVOKE subcutaneously in the lower abdomen, outer thigh, or outer upper arm. Call for emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, may administer an additional dose from a new HypoPen, GVOKE PFS, or GVOKE Kit while waiting for emergency assistance. When the patient has responded to GVOKE, give oral carbohydrates. Do not attempt to reuse GVOKE. Each GVOKE device or vial contains a single dose of glucagon. Do not reuse and discard any unused portion. Recommended Dosage Recommended dose for adult and pediatric patients aged 12 years of age and older is 1 mg. Recommended dose for adult and pediatric patients aged 12 years of age and older is 1 mg. The recommended dose for pediatric patients aged 2 to less than 12 years of age who weigh: Less than 45 kg, is 0.5 mg 45 kg or greater, is 1 mg Dosage and Administration of GVOKE VialDx for Intravenous Use as a Diagnostic Aid in Adults ( 2.2 ) GVOKE VialDx is only for intravenous use under medical supervision. The recommended diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bulb is 0.2 mg to 0.5 mg; the recommended dose to relax the colon is 0.5 mg to 0.75 mg. See the Full Prescribing Information for administration instructions for GVOKE VialDx. 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. 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. 2.2 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 ( 12.2 )]: 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 ( 12.2 )] .

WARNINGS AND PRECAUTIONS Substantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor. ( 5.1 ) Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, glucagon may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously. ( 5.2 ) 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.( 5.3 ) 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 subcutaneous use for the treatment of severe hypoglycemia. Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia. ( 5.4 ) Necrolytic Migratory Erythema (NME): a skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. GVOKE and GVOKE VialDx are not approved for continuous infusion. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. ( 5.5 ) 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 and treat hyperglycemia if indicated. ( 5.6 ) 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. 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. ( 5.7 ) Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid: GVOKE VialDx administered to patients with glucagonoma may cause secondary hypoglycemia. Test patients suspected of having glucagonoma for blood levels of glucagon prior to treatment and monitor for changes in blood glucose levels during treatment. ( 5.8 ) 5.1 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 ( 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 and GVOKE VialDx are contraindicated in patients with insulinoma [see Contraindications ( 4 )] . If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously. 5.3 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 ( 4 )] . 5.4 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 (12.2)] . Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia. 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.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 ( 4 )]. 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.

CONTRAINDICATIONS GVOKE and GVOKE VialDx are 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 )] 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 [see Warnings and Precautions ( 5.3 )] . GVOKE VialDx for use as a diagnostic aid is also contraindicated in patients with glucagonoma because of risk of hypoglycemia [see Warnings and Precautions ( 5.8 )] Pheochromocytoma ( 4 ) Insulinoma ( 4 ) Prior hypersensitivity reaction to glucagon or to any of the excipients ( 4 ) Glucagonoma when used as a diagnostic aid ( 4 )

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. Extrahepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. 12.2 Pharmacodynamics GVOKE for Subcutaneous Use for the Treatment of Severe Hypoglycemia in Patients with Type 1 Diabetes Mellitus: After subcutaneous administration of 1 mg GVOKE in adult patients with type 1 diabetes, the mean maximum glucose increase from baseline was 176 mg/dL (see Figure 1). Plasma Glucose (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of 1 mg of GVOKE in Adult Patients with Type 1 Diabetes Mellitus In pediatric patients with type 1 diabetes mellitus (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) (see Figure 2). Figure 2: Plasma Glucose (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of GVOKE in Pediatric Patients with Type 1 Diabetes Mellitus GVOKE VialDx Table 5 presents the pharmacodynamic properties of another glucagon product after intravenous administration Table 5: Pharmacodynamic Properties of Another Glucagon Product After Intravenous Administration a Dose is determined based on the length of the procedure Route of Administration Dose a Time of Maximal Glucose Concentration Time of Onset of Action for GI Smooth Muscle Relaxation Duration of Smooth Muscle Relaxation Intravenous 0.25 to 0.5 mg 5 to 20 minutes 45 seconds 9 to 17 minutes Figure 1 Figure 2 12.3 Pharmacokinetics Absorption Subcutaneous injection of 1 mg GVOKE in adult type 1 diabetes mellitus patients 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.See Figure 3. Figure 3: : Plasma Glucagon Concentration (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of 1 mg of GVOKE 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 patients with type 1 diabetes mellitus 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 patients with type 1 diabetes 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 patients with type 1 diabetes 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. See Figure 4. Figure 4: Plasma Glucagon Concentration (mean ± standard error of the mean) vs. Time After Subcutaneous Administration of GVOKE in Pediatric Patients with Type 1 Diabetes Mellitus Figure 3 Figure 4