GLUCAGON

Glucagon for Injection (synthetic origin) is a polypeptide hormone identical to human glucagon that increases blood glucose and relaxes smooth muscle of the gastrointestinal tract. Glucagon is produced by solid state peptide synthesis and is highly purified. Glucagon is a single-chain polypeptide that contains 29 amino acid residues and has a molecular weight of 3483. The empirical formula is C 153 H 225 SN 43 O 49 S. The primary sequence of glucagon is shown below. Crystalline 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 is available for use intravenously, intramuscularly, or subcutaneously in a kit that contains a vial of sterile glucagon and a syringe of sterile diluent. The vial contains 1 mg of glucagon and 49 mg of lactose. Hydrochloric acid may have been added during manufacture to adjust the pH of the glucagon. One International Unit of glucagon is equivalent to 1 mg of glucagon.1 The diluent syringe contains 12 mg/mL of glycerin, Water For Injection, and hydrochloric acid. Sequence

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

General Instructions for Use: The diluent is provided for use only in the preparation of glucagon for parenteral injection and for no other use. Glucagon should not be used at concentrations greater than 1 mg/mL. Reconstituted glucagon should be used immediately. Discard any unused portion. Reconstituted glucagon solutions should be used only if they are clear and of a water-like consistency. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Directions for Treatment of Severe Hypoglycemia: Severe hypoglycemia should be treated initially with intravenous glucose, if possible. If parenteral glucose can not be used, dissolve the lyophilized glucagon using the accompanying diluting solution and use immediately. For adults and for pediatric patients weighing more than 44 lb (20 kg), give 1 mg by subcutaneous, intramuscular, or intravenous injection. For pediatric patients weighing less than 44 lb (20 kg), give 0.5 mg or a dose equivalent to 20 to 30 mcg/kg.2-6 Discard any unused portion. An unconscious patient will usually awaken within 15 minutes following the glucagon injection. If the response is delayed, there is no contraindication to the administration of an additional dose of glucagon; however, in view of the deleterious effects of cerebral hypoglycemia emergency aid should be sought so that parenteral glucose can be given. After the patient responds, supplemental carbohydrate should be given to restore liver glycogen and to prevent secondary hypoglycemia. Directions for Use as a Diagnostic Aid: Dissolve the lyophilized glucagon using the accompanying diluting solution and use immediately. Discard any unused portion. The doses in the following table may be administered for relaxation of the stomach, duodenum, and small bowel, depending on the onset and duration of effect required for the examination. Since the stomach is less sensitive to the effect of glucagon, 0.5 mg intravenous or 2 mg intramuscular are recommended. * Administration of 2 mg (2 units) doses produces a higher incidence of nausea and vomiting than do lower doses. Dose Route of Administration Time of Onset of Action Approximate Duration of Effect 0.25-0.5 mg (0.25-0.5 units) IV 1 minute 9-17 minutes 1-mg (1 unit) IM 8-10 minutes 12-27 minutes 2 mg* (2 units) IV 1 minute 22-25 minutes 2 mg* (2 units) IM 4-7 minutes 21-32 minutes For examination of the colon, it is recommended that a 2 mg (2 units) dose be administered intramuscularly approximately 10 minutes prior to the procedure. Colon relaxation and reduction of patient discomfort may allow the radiologist to perform a more satisfactory examination.

Glucagon is contraindicated in patients with known hypersensitivity to it or in patients with known pheochromocytoma.

Side effects may include nausea and vomiting. These reactions may also occur with hypoglycemia. Generalized allergic reactions have been reported (see WARNINGS ). In a three month controlled study of 75 volunteers comparing animal-sourced glucagon with glucagon manufactured through rDNA technology, no glucagon-specific antibodies were detected in either treatment group. Necrolytic migratory erythema (NME) cases have been reported postmarketing in patients receiving continuous infusions of glucagon (see WARNINGS ).

STORAGE Store the kit at controlled room temperature between 20° to 25°C (68° to 77°F) before mixing glucagon with the diluent. Glucagon that has been mixed with diluent should be used immediately. Discard any unused portion. Solutions should be clear and of a water-like consistency at time of use.