INFORMATION FOR THE PHYSICIAN
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`PA 2286 AMP
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`GLUCAGON
`FOR INJECTION
`(rDNA ORIGIN)
`DESCRIPTION
`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.
`
`10
`Tyr Ser Lys Tyr Leu
`Asp
`
`15
`Asp Ser Arg Arg Ala
`
`20
`Gln
`
`Asp
`
`Phe
`
`Val
`
`Gln
`
`25
`
`Trp
`Leu
`Met
`
`Asn
`
`Ser
`
`Thr
`
`Phe
`
`5
`
`Thr
`
`Gly
`Gln
`
`Ser
`
`1
`29
`His
`Thr
`COOH
`H2N
`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.
`
`CLINICAL PHARMACOLOGY
`Glucagon increases blood glucose concentration and is used in the treatment of 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.
`Pharmacokinetics
`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.
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`Pharmacodynamics
`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.
`
`Figure 1
`Mean (SE) serum glucagon and blood glucose levels after subcutaneous injection of
`glucagon (1 mg) in 25 normal volunteers
`A
`
`0
`
`3
`
`1
`2
`Time from dosing, hours
`
`
`
`B
`
`
`
`00
`
`
`
`11
`
`
`22
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`Time, hoursTime, hours
`
`
`
`33
`
`
`
`44
`
`
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
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`Glucagon Concentrations, ng/ml
`
`
`
`160160
`
`
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`120120
`
`
`
`8080
`
`
`
`4040
`
`
`
`00
`
`Blood Glucose Concentrations, mg/dL
`Blood Glucose Concentrations, mg/dL
`
`
`
`
`
`INDICATIONS AND USAGE
`For the treatment of hypoglycemia:
`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.
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`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, the
`addition of the anticholinergic agent may result in increased side effects.
`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.
`PRECAUTIONS
`
`General
`Glucagon is effective in treating hypoglycemia only if sufficient liver glycogen is present.
`Because glucagon is of little or no help in states of starvation, adrenal insufficiency, or chronic
`hypoglycemia, hypoglycemia in these conditions should be treated with glucose.
`Information for Patients
`Refer patients and family members to the attached Information for the User for instructions
`describing the method of preparing and injecting glucagon. Advise the patient and family
`members to become familiar with the technique of preparing glucagon before an emergency
`arises. Instruct patients to use 1 mg (1 unit) for adults and 1/2 the adult dose (0.5 mg) [0.5 unit]
`for pediatric patients weighing less than 44 lb (20 kg).
`Patients and family members should be informed of the following measures to prevent
`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.
`To prevent severe hypoglycemia, patients and family members should be informed of the
`symptoms of mild hypoglycemia and how to treat it appropriately.
`Family members should be informed to arouse the patient as quickly as possible because
`prolonged hypoglycemia may result in damage to the central nervous system. Glucagon or
`intravenous glucose should awaken the patient sufficiently so that oral carbohydrates may be
`taken.
`Patients should be advised to inform their physician when hypoglycemic reactions occur so
`that the treatment regimen may be adjusted if necessary.
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`Laboratory Tests
`Blood glucose determinations should be obtained to follow the patient with hypoglycemia until
`patient is asymptomatic.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Because glucagon is usually given in a single dose and has a very short half-life, no studies
`have been done regarding carcinogenesis. In a series of studies examining effects on the bacterial
`mutagenesis (Ames) assay, it was determined that an increase in colony counts was related to
`technical difficulties in running this assay with peptides and was not due to mutagenic activities
`of the glucagon.
`Reproduction studies have been performed in rats at doses up to 2 mg/kg glucagon
`administered two times a day (up to 40 times the human dose based on body surface
`area, mg/m2) and have revealed no evidence of impaired fertility.
`Pregnancy
`Pregnancy Category B — Reproduction studies have not been performed with recombinant
`glucagon. However, studies with animal-sourced glucagon were performed in rats at doses up to
`2 mg/kg glucagon administered two times a day (up to 40 times the human dose based on body
`surface area, mg/m2), and have revealed no evidence of impaired fertility or 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 hydrolyzed and
`absorbed like any other polypeptide. Glucagon is not active when taken orally because it is
`destroyed in the gastrointestinal tract before it can be absorbed.
`Pediatric Use
`For the treatment of hypoglycemia: The use of glucagon in pediatric patients has been reported
`to be safe and effective.2-6
`For use as a diagnostic aid: Effectiveness has not been established in pediatric patients.
`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 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.
`ADVERSE REACTIONS
`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.
`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 -blockers might be expected to have a
`greater increase in both pulse and blood pressure, an increase of which will be transient because
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`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; it is extremely unlikely that one of these
`procedures would ever be indicated.
`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 (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.
`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 (1 unit)
`by subcutaneous, intramuscular, or intravenous injection.
`3. 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
`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.
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`Time of Onset of
`Action
`1 minute
`
`Approximate
`Duration of Effect
`9-17 minutes
`
`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 (0.5 units) IV
`or 2 mg (2 units) IM are recommended.
`Dose
`Route of
`Administration
`IV
`
`0.25-0.5 mg
`(0.25-0.5 units)
`12-27 minutes
`8-10 minutes
`IM
`1-mg (1 unit)
`22-25 minutes
`1 minute
`IV
`2 mg*(2 units)
`21-32 minutes
`4-7 minutes
`IM
`2 mg*(2 units)
`* Administration of 2 mg (2 units) doses produces a higher incidence of nausea and vomiting than do lower doses.
`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 [rDNA origin])
`(MS8031):
`1 mg (1 unit) — (VL7529), with 1 mL of diluting solution (Hyporet®* HY7530) (1s)
`
`NDC 0002-8031-01
`_____________________
`* Hyporet® (disposable syringe, Lilly).
`
`Stability and Storage:
`Before Reconstitution — Vials of Glucagon, as well as the Diluting Solution for Glucagon,
`may be stored at controlled room temperature 20° to 25°C (68° to 77°F)[see USP].
`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 (rDNA origin) 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.
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`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 September 19, 2012
`Marketed by: Lilly USA, LLC
`Indianapolis, IN 46285, USA
`PA 2286 AMP
`Copyright © 1999, 2012, Eli Lilly and Company. All rights reserved.
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