GLUCAGON
DESCRIPTION:
Chemically unrelated to insulin, glucagon is a single-chain polypeptide
containing 29 amino acid residues and having a molecular weight of 3,483.
The empirical formula is C153H225N43O49S.
Crystalline glucagon is a white powder containing less than 0.05% zinc. It is
relatively insoluble in water but is soluble at a pH of less than 3 or more than
9.5. Glucagon is stable in lyophilized form at room temperatures.
Glucagon for Injection contains glucagon as the hydrochloride. The 1-mg vials
contain 1 mg (1 unit) of glucagon and 49 mg of lactose. One USP unit of
glucagon is equivalent to 1 International Unit of glucagon and also to about 1
mg of glucagon. (Ref. 1) The diluent contains glycerin, 1.6%, with 0.2% phenol
as a preservative. Sodium hydroxide and/or hydrochloric acid may have been added
during manufacture to adjust the pH.
ACTIONS/CLINICAL PHARMACOLOGY:
Glucagon causes an increase in blood glucose concentration and is used in the
treatment of hypoglycemia. It is effective in small doses, and no evidence of
toxicity has been reported with its use. Glucagon acts only on liver glycogen,
converting it to glucose.
Parenteral administration of glucagon produces relaxation of the smooth muscle
of the stomach, duodenum, small bowel, and colon.
The half-life of glucagon in plasma is approximately 3 to 6 minutes, which is
similar to that of insulin.
INDICATIONS AND USAGE:
For The Treatment Of Hypoglycemia:
Glucagon is useful in counteracting severe hypoglycemic reactions.
The patient with type I diabetes does not have as great a response in blood
glucose levels as does the stable type II diabetes patient. Therefore,
supplementary carbohydrate should be given as soon as possible, especially to
the child or adolescent 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 a hypotonic state would be
advantageous.
Glucagon is as effective for this examination as are the anticholinergic drugs,
but it has fewer side effects. When glucagon is administered concomitantly with
an anticholinergic agent, the response is not significantly greater than when
either drug is used alone. However, the addition of the anticholinergic agent
results in increased side effects.
CONTRAINDICATIONS:
Glucagon is contraindicated in patients with known hypersensitivity to it or in
patients with pheochromocytoma.
WARNINGS:
Glucagon should be administered cautiously to patients with a history suggestive
of insulinoma and/or pheochromocytoma. In patients with insulinoma, intravenous
administration of glucagon will produce an initial increase in blood glucose;
however, because of glucagon's insulin-releasing effect, it may cause the
insulinoma to release its insulin and subsequently cause hypoglycemia. A patient
developing symptoms of hypoglycemia after a dose of glucagon should be given
glucose orally, intravenously, or by gavage, whichever is more appropriate.
Exogenous glucagon also stimulates the release of catecholamines. In the
presence of pheochromocytoma, glucagon can cause the tumor to release
catecholamines, which results in a sudden and marked increase in blood pressure.
If a patient suddenly develops a marked 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.
PRECAUTIONS:
General--Glucagon is helpful in hypoglycemia only if liver glycogen is
available. Because glucagon is of little or no help in states of starvation,
adrenal insufficiency, or chronic hypoglycemia, glucose should be considered for
the treatment of hypoglycemia.
Laboratory Tests--Blood glucose determinations may be obtained to follow the
patient in hypoglycemic shock until he or she is asymptomatic.
Carcinogenesis, Mutagenesis, Impairment Of Fertility--Because glucagon is
usually given in a single dose and has a very short half-life (3 to 6 minutes),
no studies have been done regarding carcinogenesis.
Reproduction studies have been performed in rats at doses up to 2 mg/kg b.i.d.
(up to 120 times the human dose) and have revealed no evidence of impaired
fertility.
Usage In Pregnancy--Pregnancy Category B- -Reproduction studies have been
performed in rats at doses up to 2 mg/kg b.i.d. (up to 120 times the human
dose), and have revealed no evidence of harm to the fetus due to glucagon. There
are, however, no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
Nursing Mothers--It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
glucagon is administered to a nursing woman. If the drug is excreted in human
milk during its short half-life, it will be handled like any other polypeptide,
ie, it will be hydrolyzed and absorbed. Glucagon is not active when taken orally
because it is destroyed in the gastrointestinal tract before it can be absorbed.
ADVERSE REACTIONS:
Glucagon is relatively free of adverse reactions except for occasional nausea
and vomiting, which may also occur with hypoglycemia. Generalized allergic
reactions have been reported (See Warnings).
OVERDOSAGE:
Signs And Symptoms--No cases of human overdosage of glucagon have been reported.
Glucagon is generally well tolerated. If overdosage occurred, it would not be
expected to cause consequential toxicity but would be expected to be associated
with nausea, vomiting, gastric hypotonicity, and diarrhea.
Intravenous administration of glucagon has been shown to have a positive
inotropic and chronotropic effect. A transient increment in both blood pressure
and pulse rate may occur following the administration of glucagon. Patients
taking beta-blockers might be expected to have a greater increment in both pulse
and blood pressure. This increase 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 cardiac patients, 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 996mg, and a 21-month child 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 is approximately 300
mg/kg.
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 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; it is
extremely unlikely that one of these procedures would ever be indicated.
DOSAGE AND ADMINISTRATION:
FOR THE TREATMENT OF HYPOGLYCEMIA:
The diluent is provided for use only in the preparation of glucagon for
Intermittent parenteral injection and for no other use.
If glucagon is to be given at doses higher than 2mg, it should be reconstituted
with Sterile Water for Injection instead of the supplied diluting solution and
used immediately.
Directions For Use Of Glucagon--1. Dissolve the lyophilized glucagon in the
accompanying diluent.
2. Glucagon should not be used at concentrations greater than 1 mg (1 unit/mL).
3. Glucagon solutions should not be used unless they are clear and of a water-
like consistency.
4. For adults and for pediatric patients weighing more than 20 kg, give 1 mg (1
unit) by subcutaneous, intramuscular, or intravenous injection.
5. For pediatric patients weighing less than 20 kg, give 0.5 mg (0.5 unit) or a
dose equivalent to 20-30 mcgm/kg. (REF. 2-6)
6. The patient will usually awaken within 15 minutes. If the response is
delayed, there is no contraindication to the administration of 1 or 2 additional
doses of glucagon; however, in view of the deleterious effects of cerebral
hypoglycemia and depending on the duration and depth of coma, the use of
parenteral glucose Must be considered by the physician.
7. Intravenous glucose Must be given if the patient fails to respond to
glucagon.
8. When the patient responds, give supplemental carbohydrate to restore the
liver glycogen and prevent secondary hypoglycemia.
Family--Instructions describing the method of using this preparation are
included in the literature that accompanies the patient's package. It is
advisable for the patient and family members to become familiar with the
technique of preparing Glucagon for Injection before an emergency arises.
Patients are instructed to use 1 mg (1 unit) for adults and, if recommended by a
doctor, 1/2 the adult dose (0.5 mg) [0.5 unit] for pediatric patients weighing
less than 44 lb (20 kg).
General Management Of Hypoglycemia--The following are helpful measures in the
prevention of hypoglycemic reactions due to insulin:
1. Reasonable uniformity from day to day with regard to diet, insulin, and
exercise.
2. Careful adjustment of the insulin program so that the type (or types) of
insulin, dose, and time (or times) of administration are suited to the
individual patient.
3. Frequent testing of the blood or urine for glucose so that a change in
insulin requirements can be foreseen.
4. Routine carrying of sugar, candy, or other readily absorbable carbohydrate by
the patient so that it may be taken at the first warning of an oncoming
reaction.
If the patient is unaware of the symptoms of hypoglycemia, he/she may lapse into
insulin shock; therefore, the physician should instruct the patient in this
regard when feasible.
It is important that the patient be aroused as quickly as possible, because
prolonged hypoglycemic reactions may result in cortical damage. Glucagon or
intravenous glucose will awaken the patient sufficiently so that oral
carbohydrates may be taken.
CAUTION--Although the patient may use glucagon for the treatment of hypoglycemia
during an emergency, the physician must still be notified when hypoglycemic
reactions occur so that the treatment regimen may be adjusted if necessary.
FOR USE AS A DIAGNOSTIC AID:
Dissolve the lyophilized glucagon in the accompanying diluting solution.
Glucagon should not be used at concentrations greater than 1 mg (1 unit/mL).
The following doses may be administered for relaxation of the stomach, duodenum,
and small bowel, depending on the time of onset of action and the 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.
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Dose Route of Time of Onset Approximate Duration
Administration of Action of Effect
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0.25-0.5 mg IV 1 minute 9-17 minutes
1 mg IM 8-10 minutes 12-27 minutes
2 mg* IV 1 minute 22-25 minutes
2 mg* IM 4-7 minutes 21-32 minutes
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* Administration of 2-mg (2 units) doses produces a higher incidence of
nausea and vomiting than do lower doses.
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For examination of the colon, it is recommended that a 2-mg (2 units) dose be
administered intramuscularly approximately 10 minutes prior to initiation of the
procedure. Relaxation of the colon and reduction of discomfort to the patient
will allow the radiologist to perform a more satisfactory examination. STABILITY
AND STORAGE:
BEFORE RECONSTITUTION--Vials of Glucagon as well as the Diluting Solution for
Glucagon for Injection, USP, may be stored at controlled room temperature, 59
deg to 86 deg F (15 deg to 30 deg C).
AFTER RECONSTITUTION--Glucagon for Injection should be used immediately. DISCARD
ANY UNUSED PORTION.)
REFERENCES:
1. Drug Information For The Health Care Professional. 11th ed. Rockville,
Maryland: The United States Pharmacopeial Convention, Inc; 1991;IA:1380.
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;47:167-170.
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.
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