1.1 Treatment of severe hypoglycemia

GlucaGen is used to treat severe hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes mellitus treated with insulin. Because GlucaGen 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.

1.2 Use as a diagnostic aid

GlucaGen 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. 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.

2.1 Treatment of severe hypoglycemia

1.

Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen 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 GlucaGen gives a concentration of approximately 1 mg/mL glucagon.

4.

The reconstituted GlucaGen 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.

For GlucaGen Diagnostic Kit and the GlucaGen 10-pack:

2.2 Use as a diagnostic aid

1.

GlucaGen 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 GlucaGen 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 GlucaGen gives a concentration of approximately 1 mg/mL glucagon.

4.

The reconstituted GlucaGen should be used immediately after reconstitution.

5.

GlucaGen 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 [see Pharmacodynamics (12.2)].

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 [see Pharmacodynamics (12.2)].

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.

The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are intended only for use by healthcare providers as a diagnostic aid. The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are not intended for use by patients to treat severe hypoglycemia because they are not packaged with a syringe and diluent necessary for rapid preparation and administration during an emergency outside of a healthcare facility.

5.1 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.

5.2 Insulinoma and Glucagonoma

GlucaGen 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 GlucaGen to patients with glucagonoma.

5.3 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 GlucaGen injection.

5.4 Glycogen Stores and Hypoglycemia

In order for GlucaGen treatment to reverse hypoglycemia, adequate amounts of glucose must be stored in the liver (as glycogen). Therefore, GlucaGen 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 GlucaGen treatment.

5.5 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.

5.6 Laboratory Tests

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

7.1 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.

7.2 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.

7.3 Anticholinergic Drugs

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

7.4 Warfarin

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

7.5 Insulin

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

8.1 Pregnancy

Pregnancy Category B. Reproduction studies were performed in rats and rabbits at GlucaGen 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. Glucagon does not cross the human placenta barrier.

8.3 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 GlucaGen is administered to a nursing woman. No clinical studies have been performed in nursing mothers, however, GlucaGen 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, GlucaGen has a short plasma half-life thus limiting amounts available to the child. Glucagon does not cross the human placental barrier.

8.4 Pediatric Use

For the treatment of severe 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.

12.1 Mechanism of Action

Antihypoglycemic Action: Glucagon induces liver glycogen breakdown, releasing glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect.

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

12.2 Pharmacodynamics

For the treatment of severe hypoglycemia:

Blood glucose concentration rises within 10 minutes of injection and maximal concentrations are attained at approximately 30 minutes after injection (see Figure 1). The duration of hyperglycemic action after intravenous or intramuscular injection is 60 – 90 minutes.

Figure 1. Recovery from Insulin Induced Hypoglycemia (mean blood glucose) After Intramuscular Injection of 1 mg GlucaGen in Type I Diabetic Men

For use as a diagnostic aid:

12.3 Pharmacokinetics

Intramuscular injection of 1 mg GlucaGen 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 intramuscular injection probably reflects prolonged absorption from the injection site. Glucagon is degraded in the liver, kidney, and plasma. 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to evaluate carcinogenic potential have not been performed. Several studies have been conducted to evaluate the mutagenic potential of glucagon. The mutagenic potential tested in the Ames and human lymphocyte assays, was borderline positive under certain conditions for both glucagon (pancreatic) and glucagon (rDNA) origin. In vivo, very high doses (100 and 200 mg/kg) of glucagon (both origins) gave a slightly higher incidence of micronucleus formation in male mice but there was no effect in females. The weight of evidence indicates that GlucaGen is not different from glucagon pancreatic origin and does not pose a genotoxic risk to humans. GlucaGen (rDNA origin) was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility. 

16.1 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 (NDC 0597-0260-10) includes:
1 vial containing 1 mg (1 unit) GlucaGen(glucagon [rDNA origin] for injection)
NDC 0597-0053-01
1 vial containing 1 mL Sterile Water for Reconstitution
NDC 0597-0265-94

GlucaGen Diagnostic Kit is also available as (NDC 55390-004-01) and includes:
1 vial containing 1 mg (1 unit) GlucaGen(glucagon [rDNA origin] for injection)
NDC 55390-004-01
1 vial containing 1 mL Sterile Water for Reconstitution

GlucaGen HypoKit (Two-Pack) includes: 2 packs of GlucaGen HypoKit,
Each HypoKit contains:
1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
1 disposable syringe containing 1 mL Sterile Water for Reconstitution
NDC 0169-7065-21

The GlucaGen 10-pack includes:
10 vials, each containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
NDC 55390-004-10
NDC 0597-0053-45

16.2 Recommended 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.

17.1 Physician Instructions

Refer patients and family members to the FDA-approved patient labeling for instructions describing the method of preparing and injecting GlucaGen. 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 for adults or ½ the adult dose (0.5 mg) for children weighing less than 55 lb (25 kg). 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. Patients should be advised to inform their physician when hypoglycemic reactions occur so that the treatment regimen may be adjusted if necessary.

No studies on the effects on the ability to drive and use machines have been performed. After diagnostic procedures, hypoglycemia has been reported infrequently. The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating machinery. Therefore, these activities should be avoided until the patient has had a meal with oral carbohydrates.

Date of issue: December 12, 2014
Version: 6

GlucaGen® and HypoKit® are registered trademarks of Novo Nordisk A/S

© 1998-2014 Novo Nordisk

For information contact:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877
1-800-243-0127

Manufactured for:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877

By:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark