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Glucagon Hydrochloride Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Glucagon is an antihypoglycemic agent, and a gastrointestinal motility inhibitor.

Glucagon [rDNA origin] for injection manufactured by Novo Nordisk A/S is produced by expression of recombinant DNA in a Saccharomyces cerevisiae vector with subsequent purification.

The chemical structure of the glucagonis identical to naturally occurring human glucagon and to glucagon extracted from beef and pork pancreas. Glucagon with the empirical formula of C153H225N43O49S, and a molecular weight of 3483, is a single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is:

Glucagon 1 mg (1 unit) is supplied as a sterile, lyophilized white powder in a 2 ml vial, alone, or accompanied by Sterile Water for Reconstitution (1 ml) also in a 2 ml vial (10 pack or diagnostic kit). It is also supplied as a HypoKit with a disposable prefilled syringe containing 1 ml Sterile Water for Reconstitution. Glucagon, as supplied at pH 2.5-3.5, is soluble in water.

Active Ingredient in each vial: Glucagon as hydrochloride 1 mg (corresponding to 1 unit).

Other Ingredients: Lactose monohydrate (107 mg)

When the glucagon powder is reconstituted with Sterile Water for Reconstitution (if supplied) or with Sterile Water for Injection, USP, it forms a solution of 1 mg (1 unit)/ml glucagon for subcutaneous (sc), intramuscular (im), or intravenous (iv) injection.

2. INDICATIONS AND USAGE

2.1 Treatment of severe hypoglycemia

Glucagon is used to treat severe hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes treated with insulin. Because glucagon depletes glycogen stores, the patient should be given supplemental carbohydrates as soon as he/she awakens and is able to swallow, especially children or adolescents. Medical evaluation is recommended for all patients who experience severe hypoglycemia.

2.2 Use as a diagnostic aid

Glucagon is indicated for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. 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. Because glucagon depletes glycogen stores, the patient should be given oral carbohydrates as soon as the procedure is completed.

3. DOSAGE AND ADMINISTRATION

3.1 Treatment of severe hypoglycemia

1. Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing glucagon powder and inject all the liquid from the syringe into the vial.

2. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.

3. The reconstituted glucagon gives a concentration of approximately 1 mg/mL glucagon.

4. The reconstituted glucagon should be used immediately after reconstitution.

5. Inject 1 mL (adults and children, weighing more than 55 lbs (25 kg)) or 0.5 mL (children weighing less than 55 lbs (25 kg)) subcutaneously, intramuscularly, or intravenously. If the weight is not known: children younger than 6 years should be given a 0.5 mL and children 6 years and older should be given 1 mL.

6. Discard any unused portion.

7. Emergency assistance should be sought immediately after subcutaneous or intramuscular injection of glucagon.

8. The glucagon injection may be repeated using a new kit while waiting for emergency assistance.

9. Intravenous glucose MUST be administered if the patient fails to respond to glucagon.

10. When the patient has responded to the treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.

3.2 Use as a diagnostic aid

1. Glucagon should be reconstituted with 1 mL of Sterile Water for Reconstitution (if supplied) or 1 mL of Sterile Water for Injection, USP. Using a syringe, withdraw all of the Sterile Water for Reconstitution (if supplied) or 1 mL Sterile Water for Injection, USP and inject into the glucagon vial.

2. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.

3. The reconstituted glucagon gives a concentration of approximately 1 mg/mL glucagon.

4. The reconstituted glucagon should be used immediately after reconstitution.

5. Glucagon must be administered by medical personnel.

6. Discard any unused portion.

7. Onset of action after an injection will depend on the organ under examination and route of administration.

8. The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5 mg to 0.75 mg intravenously and 1 mg to 2 mg intramuscularly.

9. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure applied.

4. CONTRAINDICATIONS

Glucagon is contraindicated in patients with known hypersensitivity to glucagon and in patients with pheochromocytoma or with insulinoma.

5. MECHANISM OF ACTION

Antihypoglycemic Action:

Glucagon induces liver glycogen breakdown, releasing glucose from the liver. Blood glucose concentration rises within 10 minutes of injection and maximal concentrations are attained at approximately a half hour after injection (see Figure). Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect.

Recovery from insulin induced hypoglycemia (mean blood glucose) after im injection of 1 mg Glucagon in Type I diabetic men

Gastrointestinal Motility Inhibition: Extra hepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

Reproduction studies were performed in rats and rabbits at glucagon doses of 0.4, 2.0, and 10 mg/kg. These doses represent exposures of up to 100 and 200 times the human dose based on mg/m2 for rats and rabbits, respectively, and revealed no evidence of harm to the fetus. 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.

6.2 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.

No clinical studies have been performed in nursing mothers, however, glucagon is a peptide and intact glucagon is not absorbed from the GI tract. Therefore, even if the infant ingested glucagon it would be unlikely to have any effect on the infant. Additionally, glucagon has a short plasma half-life thus limiting amounts available to the child.

6.3 Pediatric Use

For the treatment of hypoglycemia: The use of glucagon in pediatric patients has been reported to be safe and effective.

For use as a diagnostic aid: Safety and effectiveness in pediatric patients have not been established.

7. WARNINGS AND PRECAUTIONS

7.1 Pheochromocytoma

Glucagon is contraindicated in patients with pheochromocytoma because Glucagon may stimulate the release of catecholamines from the tumor. 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.

7.2 Insulinoma and Glucagonoma

Glucagon should be administered cautiously to patients suspected of having insulinoma or glucagonoma. In patients with insulinoma, intravenous administration of glucagon may produce an initial increase in blood glucose; however, glucagon administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma. A patient developing symptoms of hypoglycemia after a dose of glucagon should be given glucose orally or intravenously, whichever is most appropriate. Caution should also be observed in administering glucagon to patients with glucagonoma.

7.3 Hypersensitivity and Allergic Reactions

Allergic reactions may occur and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. The anaphylactic reactions have generally occurred in association with endoscopic examination during which patients often received other agents including contrast media and local anesthetics. The patients should be given standard treatment for anaphylaxis including an injection of epinephrine if they encounter respiratory difficulties after glucagon injection.

7.4 Glycogen Stores and Hypoglycemia

In order for glucagon treatment to reverse hypoglycemia, adequate amounts of glucose must be stored in the liver (as glycogen). Therefore, glucagon should be used with caution in patients with conditions such as prolonged fasting, starvation, adrenal insufficiency or chronic hypoglycemia because these conditions result in low levels of releasable glucose in the liver and an inadequate reversal of hypoglycemia by glucagon treatment.

7.5 Cardiac Disease

Caution should be observed when glucagon is used as an adjunct in endoscopic or radiographic procedures to inhibit gastrointestinal motility in patients with known cardiac disease.

7.6 Laboratory Tests

Blood glucose measurements may be considered to monitor the patient’s response.

8. ADVERSE REACTIONS

Side effects may include nausea and vomiting at doses above 1 mg or with rapid injection. Hypotension has been reported up to 2 hours after administration in patients receiving glucagon as premedication for upper GI endoscopy procedures. Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause tachycardia and hypertension. Adverse reactions indicating toxicity of glucagon have not been reported. A temporary increase 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 increase in both pulse and blood pressure, an increase of which will be temporary because of glucagon’s short half-life [see Drug Interactions]. The increase in blood pressure and pulse rate may require therapy in patients with pheochromocytoma or coronary artery disease [see Warnings and Precautions]. Anaphylactic reactions may occur in some cases [see Warnings and Precautions ].

The following adverse reactions have been identified during postapproval use of glucagon. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency.

Table 1 Frequency of Adverse Reactions

9. OVERDOSAGE

Signs and Symptoms

No reports of overdosage with glucagon have been reported. It is expected, if overdosage occurred, that the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure and pulse rate. In case of suspected overdosing, the serum potassium may decrease and should be monitored and corrected if needed.

The IV and SC LD50 for glucagon in rats and mice ranges from 100 to greater than 200 mg/kg body weight.

Treatment

Standard symptomatic treatment may be undertaken if overdosage occurs. 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. It is unknown whether glucagon is dialyzable, but such a procedure is unlikely to provide any benefit given the short half-life and nature of the symptoms of overdose.

10. DRUG INTERACTIONS

10.1 Beta-blockers

Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be temporary 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.

10.2 Indomethacin

When used with indomethacin, glucagon may lose its ability to raise blood glucose or may even produce hypoglycemia. Therefore, caution should be exercised for patients taking indomethacin when glucagon will be administered.

10.3 Anticholinergic Drugs

Coadministration with an anticholinergic drug is not recommended due to increased gastrointestinal side effects.

10.4 Warfarin

Glucagon may increase the anticoagulant effect of warfarin. Therefore, caution should be exercised for patients taking warfarin when glucagon will be administered.

10.5 Insulin

Insulin reacts antagonistically towards glucagon. Therefore, caution should be exercised when glucagon is used as a diagnostic aid in diabetes patients.

11. PHARMACOKINETICS

Intramuscular (im) injection of 1 mg glucagon resulted in a mean Cmax (CV%) of 1686 pg/ml (43%) and median Tmax of 12.5 minutes.

The mean apparent half-life of 45 minutes after im injection probably reflects prolonged absorption from the injection site. Glucagon is degraded in the liver, kidney, and plasma.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: GLUCAGEN, by NOVO NORDISK.

b) Generic drugs: NONE.

2) How Supplied:

GlucaGen is supplied as a sterile, lyophilized white powder in a vial, alone, or accompanied by Sterile Water for Reconstitution also in a vial (Diagnostic Kit or 10-pack). It is also supplied as GlucaGen HypoKit with a disposable prefilled syringe containing Sterile Water for Reconstitution.

GlucaGen HypoKit includes:

1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)

1 disposable syringe containing 1 mL Sterile Water for Reconstitution

NDC 0169-7065-15

GlucaGen Diagnostic Kit includes:

1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)

1 vial containing 1mL Sterile Water for Reconstitution

NDC 55390-004-01

The GlucaGen 10-pack includes:

10 vials, each containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)

NDC 55390-004-10

3) Storage:

Before Reconstitution:

The GlucaGen package may be stored up to 24 months at controlled room temperature 20o to 25o C (68o to 77o F) prior to reconstitution. Do not freeze. Keep in the original package to protect from light. GlucaGen should not be used after the expiry date on the vials.

After Reconstitution:

Reconstituted GlucaGen should be used immediately. Discard any unused portion. If the solution shows any sign of gel formation or particles, it should be discarded.

Rx only

Rev 12/11