Glucagon

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.

1 INDICATIONS AND USAGE Glucagon for Injection is an antihypoglycemic agent and a gastrointestinal motility inhibitor indicated: • for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes. ( 1.1 ) • as a diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients. ( 1.2 ) 1.1 Severe Hypoglycemia Glucagon for Injection is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes mellitus. 1.2 Diagnostic Aid Glucagon for Injection is indicated as a diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients.

2 DOSAGE AND ADMINISTRATION Dosage in adult and pediatric patients to treat severe hypoglycemia ( 2.2 ) • Adults and Pediatric Patients Weighing 20 kg or More: ▪ The recommended dosage is 1 mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. ▪ If there has been no response after 15 minutes, an additional 1 mg dose (1 mL) may be administered while waiting for emergency assistance. • Pediatric Patients Weighing Less Than 20 kg: ▪ The recommended dosage is 0.5 mg (0.5 mL) or dose equivalent to 20 mcg/kg to 30 mcg/kg injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. ▪ If there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) may be administered while waiting for emergency assistance. Important Administration Instructions for Using Glucagon for Injection to Treat Severe Hypoglycemia ( 2.1 ) • Glucagon for Injection is for subcutaneous, intramuscular, or intravenous injection. Administer intravenously ONLY under medical supervision. • See the Full Prescribing Information for administration instructions Dosage in Adults for Using Glucagon for Injection as a Diagnostic Aid ( 2.4 ) • Doses required for relaxation of the stomach, duodenum, and small bowel, depend on the onset and duration of effect required for the examination. • The dose for relaxation of the duodenum and small bowel is 0.25 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. • For the stomach 0.5 mg intravenous or 2 mg intramuscular doses are recommended. • For the colon, it is recommended that a 2 mg dose be administered intramuscularly approximately 10 minutes prior to the procedure. • See the Full Prescribing Information for administration instructions ( 2.3 ) 2.1 Important Administration Instructions for Using Glucagon for Injection to Treat Severe Hypoglycemia Glucagon for Injection is for subcutaneous, intramuscular, or intravenous injection. Administer intravenously ONLY under medical supervision. 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 Glucagon for Injection and its Instructions for Use. Administer Glucagon for Injection 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 Glucagon for Injection. Emphasize the following instructions to the patient or caregiver: • Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing Glucagon for Injection powder and inject all the liquid from the syringe into the vial. • Swirl the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted solution should be clear and of a water-like consistency at time of use. Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use. • The reconstituted solution is 1 mg per mL glucagon. Use immediately after reconstitution. • Immediately after reconstitution, use the same syringe to withdraw the correct dose of Glucagon for Injection. • Inject the solution subcutaneously or intramuscularly in the upper arm, thigh, or buttocks. In addition, healthcare providers may administer intravenously. • Call for emergency assistance immediately after administering the dose. • If there has been no response after 15 minutes, an additional dose of Glucagon for Injection may be administered while waiting for emergency assistance. • When the patient has responded to the treatment and is able to swallow, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia. • Discard any unused portion. 2.2 Dosage for Treatment of Severe Hypoglycemia Adults and Pediatric Patients Weighing 20 kg or More • The recommended dosage is 1 mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks. Alternatively, healthcare providers may administer the dose intravenously. • If there has been no response after 15 minutes, an additional 1 mg dose (1 mL) of Glucagon for Injection may be administered while waiting for emergency assistance. Pediatric Patients Weighing Less Than 20 kg • The recommended dosage is 0.5 mg (0.5 mL) or dose equivalent to 20 mcg/kg to 30 mcg/kg injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks. Alternatively, healthcare providers may administer the dose intravenously. • If there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of Glucagon for Injection may be administered while waiting for emergency assistance. 2.3 Important Administration Instructions for Using Glucagon for Injection as a Diagnostic Aid • Reconstitute Glucagon for Injection with 1 m

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3) ] • Necrolytic Migratory Erythema [see Warnings and Precautions (5.5) ] • Hyperglycemia in Patients with Diabetes Mellitus when Used as a Diagnostic Aid [see Warnings and Precautions (5.6) ] • Blood Pressure and Heart Rate Increase in Patients with Cardiac Disease when used as a Diagnostic Aid [see Warnings and Precautions (5.7) ] The following 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. • Injection site reactions including erythema and swelling • Nausea • Vomiting • Headache • Dizziness • Asthenia • Pallor • Diarrhea • Somnolence • Generalized allergic reactions including anaphylactic shock with breathing difficulties and hypotension • Hypertension and tachycardia • Decreased blood pressure. Hypotension has been reported up to 2 hours after administration in patients receiving glucagon as premedication for upper gastrointestinal endoscopy procedures. • Hypoglycemia and hypoglycemic coma. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see Drug Interactions (7) ] . • Necrolytic Migratory Erythema (NME) cases have been reported post marketing in patients receiving continuous infusion of glucagon. Glucagon adverse reactions include: injection site reactions, nausea, vomiting, headache, dizziness, asthenia, pallor, diarrhea, somnolence, and decreased blood pressure. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Table 1: Clinically Significant Drug Interactions with Glucagon for Injection Beta-Blockers Clinical Impact: Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given Glucagon for Injection. Intervention: The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease. Indomethacin Clinical Impact: In patients taking indomethacin, Glucagon for Injection 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 Clinical Impact: The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Intervention: Concomitant use of anticholinergic drugs with Glucagon for Injection for use as a diagnostic aid is not recommended. Warfarin Clinical Impact: Glucagon for Injection may increase the anticoagulant effect of warfarin. Intervention: Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required. Insulin Clinical Impact: Insulin acts antagonistically to glucagon. Intervention: Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in patients receiving insulin. • Beta-blockers : Patients taking beta-blockers may have a transient increase in pulse and blood pressure. ( 7 ) • Indomethacin : In patients taking indomethacin Glucagon for Injection may lose its ability to raise glucose or may produce hypoglycemia. ( 7 ) • Anticholinergic drugs : Concomitant use of anticholinergic drugs with Glucagon for Injection for use as a diagnostic aid is not recommended. ( 7 ) • Warfarin : Glucagon for Injection may increase the anticoagulant effect of warfarin. ( 7 ) • Insulin : Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in patients receiving insulin. ( 7 )