GLUCAGON

Glucagon is an antihypoglycemic agent and a gastrointestinal motility inhibitor. It is produced by solid phase peptide synthesis. The chemical structure of the glucagon is identical to human glucagon. Glucagon is a single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is: Molecular Formula = C 153 H 225 N 43 O 49 S Molecular Weight = 3483 Glucagon for Injection is a sterile, lyophilized white powder in a 3 mL vial for subcutaneous, intramuscular or intravenous use. The reconstituted solution contains glucagon as hydrochloride 1 mg per mL and lactose monohydrate (107 mg). Glucagon for Injection is supplied at pH 2.5 to 3.5 and is soluble in water. Figure

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. 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.

Dosage in adults and pediatric patients using the glucagon emergency kit for low blood sugar to treat severe hypoglycemia ( 2.2 ) Adults and Pediatric Patients Weighing More Than 25 kg or for Pediatric Patients with Unknown Weight 6 Years and Older: - 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) of Glucagon for Injection may be administered using a new kit while waiting for emergency assistance. Pediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than 6 Years of Age: - The recommended dosage is 0.5 mg (0.5 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 0.5 mg dose (0.5 mL) of Glucagon for Injection may be administered using a new kit while waiting for emergency assistance. Important Administration Instructions for Using the Glucagon Emergency Kit for Low Blood Sugar 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 Diagnostic Kit and Glucagon for Injection Single-Dose Vial as a Diagnostic Aid ( 2.4 ) The recommended diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg administered intravenously or 1 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or 1 mg to 2 mg administered intramuscularly. See the Full Prescribing Information for administration instructions ( 2.3 ) 2.1 Important Administration Instructions for Using the Glucagon Emergency Kit for Low Blood Sugar 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. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted solution should be clear and colorless. 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. Immediately after reconstitution, 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. 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 in Adults and Pediatric Patients for Using the Glucagon Emergency Kit for Low Blood Sugar to Treat Severe Hypoglycemia Adults and Pediatric Patients Weighing More Than 25 kg or for Pediatric Patients with Unknown Weight 6 Years and Older 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) of Glucagon for Injection may be administered using a new kit while waiting for emergency assistance. Pediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than 6 Years of Age The recommended dosage is 0.5 mg (0.5 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 0.5 mg dose (0.5 mL) of Glucagon for Injection may be administered using a new kit while waiting for emergency assistance. 2.3 Important Administration Instruction for Using Glucagon for Injection Diagnostic Kit and Glucagon for Injection Single-Dose Vial as a Diagnostic Aid Reconstitute Glucagon for Injection with 1 mL of Sterile Water for Injection. Using a syringe, withdraw all of the Sterile Water for Injection (if supplied) or 1 mL Sterile Water for Injection and inject into the Glucagon for Injection vial. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and colorless. 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. Immediately after reconstitution, inject the solution intravenously or intramuscularly into upper arm, thigh, or buttocks. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure. 2.4 Dosage in Adults for Using Glucagon for Injection Diagnostic Kit and Glucagon for Injection Single-Dose Vial as a Diagnostic Aid The recommended diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg administered intravenously or 1 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or 1 mg to 2 mg administered intramuscularly [see Clinical Pharmacology ( 12.2 )] . The onset of action after an injection will depend on the organ under examination and route of administration [see Clinical Pharmacology ( 12.2 )] .

Glucagon for Injection is contraindicated in patients with: Pheochromocytoma [see Warnings and Precautions ( 5.1 )] Insulinoma [see Warnings and Precautions ( 5.2 )] because of the risk of hypoglycemia Known hypersensitivity to glucagon or any of the excipients in Glucagon for Injection. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension [see Warnings and Precautions ( 5.3 )] Glucagonoma [see Warnings and Precautions ( 5.8 )] because of risk of hypoglycemia when used as a diagnostic aid Pheochromocytoma ( 4 ) Insulinoma ( 4 ) Known hypersensitivity to glucagon or to any of the excipients ( 4 ) Glucagonoma when used as a diagnostic aid ( 4 )

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 )] Most common adverse reactions ( >5% or greater incidence): Injection site swelling, injection site erythema, vomiting, nausea, decreased blood pressure, asthenia, headache, dizziness, pallor, diarrhea, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in clinical trials of another drug and may not reflect the rates observed in practice. In a randomized single-blind clinical study of Glucagon for Injection, 29 healthy subjects received a single dose of 1 mg Glucagon for Injection intramuscularly. Table 1 shows the most common adverse reactions that were not present at baseline and occurred in at least 5% of patients. Table 1: Adverse Reactions Occurring in ≥ 5% of Healthy Subjects Who Received Glucagon for Injection Intramuscularly Glucagon for Injection (N=29) % of Patients Nausea 17 Vomiting 7 In a randomized, single-blind clinical study of Glucagon for Injection, 31 healthy subjects received a single dose of 1 mg Glucagon for Injection subcutaneously. Table 2 shows the most common adverse reactions that were not present at baseline and occurred in at least 5% of patients. ( 2.1 )]. Table 2: Adverse Reactions Occurring ≥5% in Healthy Subjects Who Received Glucagon for Injection Subcutaneously Glucagon for Injection (N=31) % of Patients Injection site swelling 58 Injection site erythema 55 Vomiting 36 Nausea 32 Decreased blood pressure 23 Asthenia 23 Headache 13 Dizziness 10 Pallor 10 Diarrhea 7 Somnolence 7 Other Adverse Reactions Hypertension and tachycardia have occurred with glucagon treatment. 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. 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 postmarketing in patients receiving continuous infusion of glucagon.

Beta-blockers : Patients taking beta-blockers may have a transient increase in pulse and blood pressure. ( 7.1 ) Indomethacin: In patients taking indomethacin Glucagon for Injection may lose its ability to raise glucose or may produce hypoglycemia. (7.2) Anticholinergic drugs: Concomitant use of anticholinergic drugs with Glucagon for Injection for use as a diagnostic aid is not recommended. (7.3) Warfarin: Glucagon for Injection may increase the anticoagulant effect of warfarin. (7.4) Insulin: Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in patients receiving insulin. (7.5) 7.1 Table 3: 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 increases 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.

16.2 Recommended Storage Before Reconstitution The package containing Glucagon for Injection vials may be stored up to 24 months at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature] prior to reconstitution. Do not freeze. Keep in the original package to protect from light. After Reconstitution Use reconstituted glucagon solution immediately. Discard any unused portion [see Dosage and Administration ( 2.3 )] .