DESCRIPTION

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 C153H225SN43O49S. 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.

CLINICAL PHARMACOLOGY

Glucagon increases blood glucose concentration and is used in the treatment of severe hypoglycemia. Glucagon acts only on liver glycogen, converting it to glucose.

Glucagon administered through a parenteral route relaxes smooth muscle of the stomach, duodenum, small bowel, and colon.

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.

CONTRAINDICATIONS

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

WARNINGS

Glucagon should be administered cautiously to patients with a history suggestive of insulinoma, pheochromocytoma, or both. In patients with insulinoma, intravenous administration of glucagon may produce an initial increase in blood glucose; however, because of glucagon’s hyperglycemic effect the insulinoma may release insulin and cause subsequent hypoglycemia. A patient developing symptoms of hypoglycemia after a dose of glucagon should be given glucose orally, intravenously, or by gavage, whichever is most appropriate.

Exogenous glucagon also stimulates the release of catecholamines. In the presence of pheochromocytoma, glucagon can cause the tumor to release catecholamines, which may result in a sudden and marked increase in blood pressure. If a patient develops a sudden increase in blood pressure, 5 to 10 mg of phentolamine mesylate may be administered intravenously in an attempt to control the blood pressure.

Generalized allergic reactions, including urticaria, respiratory distress, and hypotension, have been reported in patients who received glucagon by injection.

Necrolytic migratory erythema (NME), a skin rash commonly associated with glucagonomas (glucagon-producing tumors) and characterized by scaly, pruritic erythematous plaques, bullae, and erosions, has been reported postmarketing following continuous glucagon infusion. NME lesions may affect the face, groin, perineum and legs or be more widespread. In the reported cases NME resolved with discontinuation of the glucagon, and treatment with corticosteroids was not effective. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks.

PRECAUTIONS

ADVERSE REACTIONS

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).

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.

DOSAGE AND ADMINISTRATION

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.

1. If parenteral glucose can not be used, dissolve the lyophilized glucagon using the accompanying diluting solution and use immediately.
2. For adults and for pediatric patients weighing more than 44 lb (20 kg), give 1 mg by subcutaneous, intramuscular, or intravenous injection.
3. 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
4. Discard any unused portion.
5. 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.
6. 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.

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.

HOW SUPPLIED

Glucagon Emergency Kit for Low Blood Sugar (Glucagon for Injection) contains:

1 mg glucagon for injection (as a sterile, lyophilized white

to off-white powder) in a single-dose vial and 1 mL of diluent for glucagon in a prefilled syringe.

NDC 0548-5850-00

Stability and Storage:

Before Reconstitution - Vials of glucagon, as well as the diluent for glucagon, may be stored at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature.]

The USP defines controlled room temperature by the following: A temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

After Reconstitution - Glucagon for Injection should be

used immediately. Discard any unused portion.

REFERENCES

1. Drug Information for the Health Care Professional. 18th ed. Rockville, Maryland: The United States Pharmacopeial Convention, Inc; 1998; I: 1512.
2. Gibbs et al: Use of glucagon to terminate insulin reactions in diabetic children. Nebr Med J 1958;43:56-57.
3. 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.
4. Carson MJ, Koch R: Clinical studies with glucagon in children. J Pediatr 1955;47:161-170.
5. Shipp JC, et al: Treatment of insulin hypoglycemia in diabetic campers. Diabetes 1964; 13 :645-648.
6. 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 October 2019

Amphastar Pharmaceuticals, Inc. ©2019

Rancho Cucamonga, CA 91730 U.S.A.

Rev. 10/19

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.

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

Side effects may include nausea and vomiting, a temporary increase in heart rate, and allergic reactions to glucagon or to one of the inactive ingredients in glucagon.

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

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.

Literature revised October 2019

Rx Only

Amphastar Pharmaceuticals, Inc. © 2019

Rancho Cucamonga, CA 91730 U.S.A.

Rev. 10/19

6958506F