GLUCAGON
FOR INJECTION
(rDNA ORIGIN)

Glucagon for Injection (rDNA origin) is a polypeptide hormone identical to human glucagon that increases blood glucose and relaxes smooth muscle of the gastrointestinal tract. Glucagon is synthesized in a special non-pathogenic laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for glucagon.

Glucagon is a single-chain polypeptide that contains 29 amino acid residues and has a molecular weight of 3483.

The empirical formula is C₁₅₃H₂₂₅N₄₃O₄₉S. The primary sequence of glucagon is shown below.

Crystalline glucagon 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 (1 unit) 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.

Glucagon has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. Administration of the intravenous glucagon showed dose proportionality of the pharmacokinetics between 0.25 and 2.0 mg. Calculations from a 1 mg dose showed a small volume of distribution (mean, 0.25 L/kg) and a moderate clearance (mean, 13.5 mL/min/kg). The half-life was short, ranging from 8 to 18 minutes.

Maximum plasma concentrations of 7.9 ng/mL were achieved approximately 20 minutes after subcutaneous administration (see Figure 1A). With intramuscular dosing, maximum plasma concentrations of 6.9 ng/mL were attained approximately 13 minutes after dosing.

Glucagon is extensively degraded in liver, kidney, and plasma. Urinary excretion of intact glucagon has not been measured.

In a study of 25 volunteers, a subcutaneous dose of 1 mg glucagon resulted in a mean peak glucose concentration of 136 mg/dL 30 minutes after injection (see Figure 1B). Similarly, following intramuscular injection, the mean peak glucose level was 138 mg/dL, which occurred at 26 minutes after injection. No difference in maximum blood glucose concentration between animal-sourced and rDNA glucagon was observed after subcutaneous and intramuscular injection.

Glucagon is indicated as a treatment for severe hypoglycemia.

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.

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, the addition of the anticholinergic agent may result in increased side effects.

Severe adverse reactions are very rare, although nausea and vomiting may occur occasionally. 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.

• 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 (1 unit/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.

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 (1 unit) by subcutaneous, intramuscular, or intravenous injection.
• For pediatric patients weighing less than 44 lb (20 kg), give 0.5 mg (0.5 unit) or a dose equivalent to 20 to 30 μg/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.

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 (0.5 units) IV or 2 mg (2 units) IM are recommended.

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.

• Drug Information for the Health Care Professional. 18th ed. Rockville, Maryland: The United States Pharmacopeial Convention, Inc; 1998; I:1512.
• Gibbs et al: Use of glucagon to terminate insulin reactions in diabetic children. Nebr Med J 1958;43:56-57.
• Cornblath M, et al: Studies of carbohydrate metabolism in the newborn: Effect of glucagon on concentration of sugar in capillary blood of newborn infant. Pediatrics 1958;21:885-892.
• Carson MJ, Koch R: Clinical studies with glucagon in children. J Pediatr 1955;47:161-170.
• Shipp JC, et al: Treatment of insulin hypoglycemia in diabetic campers. Diabetes 1964;13:645-648.
• Aman J, Wranne L: Hypoglycemia in childhood diabetes II: Effect of subcutaneous or intramuscular injection of different doses of glucagon. Acta Pediatr Scand 1988;77:548-553.

Literature revised February 18, 2005

Eli Lilly and Company

Indianapolis, IN 46285, USA

Copyright © 1999, 2005, Eli Lilly and Company. All rights reserved.

GLUCAGON
FOR INJECTION
(rDNA ORIGIN)

BECOME FAMILIAR WITH THE FOLLOWING INSTRUCTIONS BEFORE AN EMERGENCY ARISES. DO NOT USE THIS KIT AFTER DATE STAMPED ON THE BOTTLE LABEL. IF YOU HAVE QUESTIONS CONCERNING THE USE OF THIS PRODUCT, CONSULT A DOCTOR, NURSE OR PHARMACIST.

Make sure that your relatives or close friends know that if you become unconscious, medical assistance must always be sought. Glucagon may have been prescribed so that members of your household can give the injection if you become hypoglycemic and are unable to take sugar by mouth. If you are unconscious, glucagon can be given while awaiting medical assistance.

Show your family members and others where you keep this kit and how to use it. They need to know how to use it before you need it. They can practice giving a shot by giving you your normal insulin shots. It is important that they practice. A person who has never given a shot probably will not be able to do it in an emergency.

IMPORTANT

• Act quickly. Prolonged unconsciousness may be harmful.
• These simple instructions will help you give glucagon successfully.
• Turn patient on his/her side to prevent patient from choking.
• The spans of the syringe are inactive. You must mix the spans of the syringe with the glucagon in the accompanying bottle before giving injection. (See DIRECTIONS FOR USE below.)
• Do not prepare Glucagon for Injection until you are ready to use it.

WARNING: THE PATIENT MAY BE IN A COMA FROM SEVERE HYPERGLYCEMIA (HIGH BLOOD GLUCOSE) RATHER THAN HYPOGLYCEMIA. IN SUCH A CASE, THE PATIENT WILL NOT RESPOND TO GLUCAGON AND REQUIRES IMMEDIATE MEDICAL ATTENTION.

INDICATIONS FOR USE

Use glucagon to treat insulin coma or insulin reaction resulting from severe hypoglycemia (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

• Remove the flip-off seal from the bottle of glucagon. Wipe rubber stopper on bottle with alcohol swab.
• Remove the needle protector from the syringe, and inject the entire spans of the syringe into the bottle of glucagon. DO NOT REMOVE THE PLASTIC CLIP FROM THE SYRINGE. Remove syringe from the bottle.
• 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

• 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 (1 unit). 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.

• Cleanse injection site on buttock, arm, or thigh with alcohol swab.
• 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. THERE IS NO DANGER OF OVERDOSE. Apply light pressure at the injection site, and withdraw the needle. Press an alcohol swab against the injection site.
• 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.
• 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.
• Even if the glucagon revives the patient, his/her doctor should be promptly notified. A doctor should be notified whenever severe hypoglycemic reactions occur.

INFORMATION ON HYPOGLYCEMIA

Early symptoms of hypoglycemia (low blood glucose) include:

If not treated, the patient may progress to severe hypoglycemia that can include:

The occurrence of early symptoms calls for prompt and, if necessary, repeated administration of some form of carbohydrate. Patients should always carry a quick source of sugar, such as candy mints or glucose tablets. The prompt treatment of mild hypoglycemic symptoms can prevent severe hypoglycemic reactions. If the patient does not improve or if administration of carbohydrate is impossible, glucagon should be given or the patient should be treated with intravenous glucose at a medical facility. Glucagon, a naturally occurring substance produced by the pancreas, is helpful because it enables the patient to produce his/her own blood glucose to correct the hypoglycemia.

POSSIBLE PROBLEMS WITH GLUCAGON TREATMENT

Severe side effects are very rare, although nausea and vomiting may occur occasionally.

A few people may be allergic to glucagon or to one of the inactive ingredients in glucagon, or may experience rapid heart beat for a short while.

If you experience any other reactions which are likely to have been caused by glucagon, please contact your doctor.

STORAGE

Before dissolving glucagon with diluting solution — Store the kit at controlled room temperature between 20° to 25°C (68° to 77°F).

After dissolving glucagon with diluting solution — Should be used immediately. Discard any unused portion. Solutions should be clear and of a water-like consistency at time of use.

Literature revised February 18, 2005

Eli Lilly and Company

Indianapolis, IN 46285, USA

Copyright © 1999, 2005, Eli Lilly and Company. All rights reserved.