Glucagon

Indications and Usage ( 1 ) 09/2019 Dosage and Administration ( 2 ) 09/2019 Contraindications ( 4 ) 09/2019 Warnings and Precautions ( 5 ) 09/2019

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 o …

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 …

3 DOSAGE FORMS AND STRENGTHS Glucagon for Injection is a white lyophilized powder supplied as follows: Treatment of Severe Hypoglycemia 1 mg single-dose vial of Glucagon for Injection with a 1 mL single-dose syringe of Sterile Water for Injection, USP (Glucagon Emergency Kit for Low Blood Sugar) Use as a Diagnostic Aid 1 mg single-dose vial of Glucagon for Injection 1 mg single-dose vial of Glucagon for Injection with a 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit) For Injection ( 3 ): Treatment of Severe Hypoglycemia: 1 mg single-dose vial of Glucagon for Injection with a 1 mL single-dose syringe of Sterile Water for Injection, USP (Glucagon Emergency Kit for Low Blood Sugar) Use as a Diagnostic Aid: 1 mg single-dose vial of Glucagon for Injection Use as a Diagnostic Aid: 1 mg single-dose vial of Glucagon for Injection with a 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit)

4 CONTRAINDICATIONS Glucagon for Injection is contraindicated in patients with: • Pheochromocytoma because of the risk of substantial increase in blood pressure [see Warning and Precautions (5.1) ] • Insulinoma because of the risk of hypoglycemia [see Warning and Precautions (5.2) ] • 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 Warning and Precautions (5.3) ] • Glucagonoma when used as a diagnostic aid because of the risk of hypoglycemia [see Warnings and Precautions (5.8) ] • Pheochromocytoma ( 4 ) • Insulinoma ( 4 ) • Known hypersensitivity to glucagon or to any of the excipients ( 4 ) • Glucagonoma when used as a diagnostic aid ( 4 )

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 )] 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.

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 )

8 USE IN SPECIFIC POPULATIONS 8.1 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% to 4% and 15% to 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. 8.2 Lactation Risk Summary There is no information available on the presence of glucagon in human or animal milk, the effects of glucagon on the breastfed child or the effects of glucagon 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. 8.4 Pediatric Use The safety and effectiveness of glucagon for injection for the treatment of severe hypoglycemia in pediatric patients with diabetes have been established. Safety and effectiveness for use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of glucagon did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient when used as a diagnostic aid should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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.

11 DESCRIPTION Glucagon is an antihypoglycemic agent and a gastrointestinal motility inhibitor. Glucagon is produced by solid state peptide synthesis. The chemical structure of the glucagon is identical to human glucagon. Glucagon is a single-chain polypeptide that contains 29 amino acid residues and has a molecular weight of 3482.8 Daltons. The empirical formula is C 153 H 225 N 43 O 49 S. The primary sequence of glucagon is shown below. Glucagon (synthetic origin) is a white to off-white powder. It is relatively insoluble in water but is soluble at a pH of less than 3 or more than 9.5. Glucagon for injection, USP is a sterile, white to off white lyophilized powder or plug in a vial and a syringe of sterile diluent for intravenous, intramuscular, or subcutaneous use. The vial contains 1 mg of glucagon USP, 49 mg of lactose monohydrate. Hydrochloric acid may have been added during manufacture to adjust the pH of the glucagon to 2.5 to 3.0. One International Unit of glucagon is equivalent to 1 mg of glucagon. The 1 mL diluent syringe contains 12 mg of glycerin, 1 mg hydrochloric acid, and Water for Injection, at pH 1.8 to 2.2. Glucagon Primary Sequence

OVERDOSAGE Signs and Symptoms - If overdosage occurs, nausea, vomiting, gastric hypotonicity, and diarrhea would be expected without causing consequential toxicity. Intravenous administration of glucagon has been shown to have positive inotropic and chronotropic effects. A transient increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking β-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be transient because of glucagon’s short half-life. The increase in blood pressure and pulse rate may require therapy in patients with pheochromocytoma or coronary artery disease. When glucagon was given in large doses to patients with cardiac disease, investigators reported a positive inotropic effect. These investigators administered glucagon in doses of 0.5 to 16 mg/hour by continuous infusion for periods of 5 to 166 hours. Total doses ranged from 25 to 996 mg, and a 21-month-old infant received approximately 8.25 mg in 165 hours. Side effects included nausea, vomiting, and decreasing serum potassium concentration. Serum potassium concentration could be maintained within normal limits with supplemental potassium. The intravenous median lethal dose for glucagon in mice and rats is approximately 300 mg/kg and 38.6 mg/ kg, respectively. Because glucagon is a polypeptide, it would be rapidly destroyed in the gastrointestinal tract if it were to be accidentally ingested. Treatment ---To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR) . In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. In view of the extremely short half-life of glucagon and its prompt destruction and excretion, the treatment of overdosage is symptomatic, primarily for nausea, vomiting, and possible hypokalemia. If the patient develops a dramatic increase in blood pressure, 5 to 10 mg of phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of glucagon.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Glucagon for Injection is supplied as a sterile, lyophilized white powder in a vial. Presentation/ Product Code Unit of Sale NDC Strength Description/Unit of Use NDC 10 Single dose vials NP509613 63323-596-16 1 mg per vial 1 mL single dose vial of Glucagon for Injection (NDC 63323-596-08) Diagnostic Kit NP509603 63323-594-03 1 mg per vial 1 mL single dose vial of Glucagon for Injection (NDC 63323-596-06) with 1 mL single dose vial of Sterile Water for Injection, USP for reconstitution (NDC 63323-185-03) The container closure is not made with natural rubber latex. 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 The Glucagon for Injection must be reconstituted with Sterile Water for Injection prior to use. Use reconstituted glucagon solution immediately. Discard any unused portion [see Dosage and Administration ( 2.3 )] .

16.1 How Supplied Glucagon for Injection is supplied as a sterile, lyophilized white powder in a vial. Presentation/ Product Code Unit of Sale NDC Strength Description/Unit of Use NDC 10 Single dose vials NP509613 63323-596-16 1 mg per vial 1 mL single dose vial of Glucagon for Injection (NDC 63323-596-08) Diagnostic Kit NP509603 63323-594-03 1 mg per vial 1 mL single dose vial of Glucagon for Injection (NDC 63323-596-06) with 1 mL single dose vial of Sterile Water for Injection, USP for reconstitution (NDC 63323-185-03) The container closure is not made with natural rubber latex.

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 The Glucagon for Injection must be reconstituted with Sterile Water for Injection prior to use. Use reconstituted glucagon solution immediately. Discard any unused portion [see Dosage and Administration ( 2.3 )] .