1.1 Severe Hypoglycemia

GlucaGen is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes.

1.2 Diagnostic Aid

GlucaGen is indicated as a diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients.

2.1 Important Administration Instructions for Using the GlucaGen HypoKit to Treat Severe Hypoglycemia

GlucaGen is for subcutaneous, intramuscular, or intravenous injection. Administer intravenously ONLY under medical supervision.

Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires the help of others to recover, instruct the patient to inform those around them about GlucaGen and its Instructions for Use. Administer GlucaGen as soon as possible when severe hypoglycemia is recognized.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for GlucaGen. Emphasize the following instructions to the patient or caregiver:

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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.

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Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted solution should be clear and colorless. Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use.

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The reconstituted solution is 1 mg per mL glucagon.

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Immediately after reconstitution, using the same syringe, withdraw the correct dose of GlucaGen.

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Inject the solution subcutaneously or intramuscularly in the upper arm, thigh, or buttocks. In addition, healthcare providers may administer intravenously.

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Call for emergency assistance immediately after administering the dose.

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If there has been no response after 15 minutes, an additional dose of GlucaGen may be administered while waiting for emergency assistance.

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

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Discard any unused portion.

2.2 Dosage in Adults and Pediatric Patients for Using the GlucaGen HypoKit to Treat Severe Hypoglycemia

Adults and Pediatric Patients Weighing 25 kg or More or for Pediatric Patients with Unknown Weight 6 Years and Older

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The recommended dosage is 1 mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.

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If there has been no response after 15 minutes, an additional 1 mg dose (1 mL) of GlucaGen may be administered using a new kit while waiting for emergency assistance.

Pediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than 6 Years of Age

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The recommended dosage is 0.5 mg (0.5 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.

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If there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of GlucaGen may be administered using a new kit while waiting for emergency assistance.

For GlucaGen Diagnostic Kit and the GlucaGen 10-pack:

2.3 Important Administration Instruction for Using GlucaGen Diagnostic Kit and the GlucaGen 10-pack as a Diagnostic Aid

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Reconstitute GlucaGen with 1 mL of Sterile Water for Injection. Using a syringe, withdraw all of the Sterile Water for Injection (if supplied) or 1 mL Sterile Water for Injection and inject into the GlucaGen vial.

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Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and colorless. Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use.

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The reconstituted solution is 1 mg per mL glucagon.

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Immediately after reconstitution, inject the solution intravenously or intramuscularly into upper arm, thigh, or buttocks.

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Discard any unused portion.

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

2.4 Dosage in Adults for Using GlucaGen Diagnostic Kit and GlucaGen for Injection Single-Dose Vial as a Diagnostic Aid

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The recommended diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg administered intravenously or 1 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or 1 mg to 2 mg administered intramuscularly [see Clinical Pharmacology (12.2)].

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The onset of action after an injection will depend on the organ under examination and route of administration [see Clinical Pharmacology (12.2)].

5.1 Substantial Increase in Blood Pressure in Patients with Pheochromocytoma

GlucaGen is contraindicated in patients with pheochromocytoma because GlucaGen may stimulate the release of catecholamines from the tumor [see Contraindications (4)]. If the patient develops a substantial increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure for the short time that control would be needed.

5.2 Hypoglycemia in Patients with Insulinoma

In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, GlucaGen administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. GlucaGen is contraindicated in patients with insulinoma [see Contraindications (4)]. If a patient develops symptoms of hypoglycemia after a dose of GlucaGen, give glucose orally or intravenously.

5.3 Hypersensitivity and Allergic Reactions

Allergic reactions have been reported with glucagon, these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. GlucaGen is contraindicated in patients with a prior hypersensitivity reaction [see Contraindications (4)].

5.4 Lack of Efficacy in Patients with Decreased Hepatic Glycogen

GlucaGen is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for GlucaGen administration to be effective. Patients with these conditions should be treated with glucose.

5.5 Necrolytic Migratory Erythema

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.

5.6 Hyperglycemia in Patients with Diabetes Mellitus when Used as a Diagnostic Aid

Treatment with GlucaGen in patients with diabetes mellitus may cause hyperglycemia. Monitor diabetic patients for changes in blood glucose levels during treatment and treat if indicated.

5.7 Blood Pressure and Heart Rate Increase in Patients with Cardiac Disease when used as a Diagnostic Aid

GlucaGen may increase myocardial oxygen demand, blood pressure, and pulse rate which may be life-threatening in patients with cardiac disease. Cardiac monitoring is recommended in patients with cardiac disease during use of GlucaGen as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy.

5.8 Hypoglycemia in Patients with Glucagonoma

Glucagon administered to patients with glucagonoma may cause secondary hypoglycemia. Test patients suspected of having glucagonoma for blood levels of glucagon prior to use as a diagnostic aid as GlucaGen is contraindicated in this setting [see Contraindications (4)].

8.1 Pregnancy

Risk Summary

Available data from case reports and a small number of observational studies with glucagon use in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated a lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In rat and rabbit reproduction studies, no embryofetal toxicity was observed with glucagon administered by injection during the period of organogenesis at doses representing up to 100 and 200 times the human dose, respectively, based on body surface area (mg/m2) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

In rats and rabbits given glucagon by injection at doses of 0.4, 2, and 10 mg/kg (up to 100 and 200 times the human dose based on mg/m2 for rats and rabbits, respectively) there was no evidence of increased malformations or embryofetal lethality.

8.2 Lactation

Risk Summary

There is no information available on the presence of glucagon in human or animal milk, the effects of glucagon on the breastfed child or the effects of glucagon on milk production. However, glucagon is a peptide and would be expected to be broken down to its constituent amino acids in the infant's digestive tract and is therefore, unlikely to cause harm to an exposed infant.

8.4 Pediatric Use

The safety and effectiveness of GlucaGen for the treatment of severe hypoglycemia in pediatric patients with diabetes have been established.

Safety and effectiveness for use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in pediatric patients have not been established.

12.1 Mechanism of Action

Glucagon increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect. Extrahepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon.

12.2 Pharmacodynamics

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 1 Diabetic Men

Diagnostic Aid:

Table 2: Pharmacodynamic Properties of Glucagon for Intravenous Route

 

aDose is determined based on the length of the procedure.

Table 3: Pharmacodynamic Properties of GlucaGen for Intramuscular Route

 

aDose is determined based on the length of the procedure.

The time of maximal glucose concentration for GlucaGen administered subcutaneously is 30-45 minutes.

12.3 Pharmacokinetics

Absorption

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

Elimination

The mean apparent half-life of 45 minutes after intramuscular injection probably reflects prolonged absorption from the injection site.

Metabolism

Glucagon is degraded in the liver, kidney, and plasma. 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals to evaluate carcinogenic potential have not been performed.

Mutagenesis

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. Doses of 100 and 200 mg/kg of glucagon of both pancreatic and recombinant origins gave slightly higher incidences of micronucleus formation in male mice but there was no effect in females. The weight of evidence indicates that synthetic and recombinant glucagon are not different and do not pose a genotoxic risk to humans.

Impairment of Fertility

Glucagon 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 for injection is supplied as a lyophilized white powder available as follows:

16.2 Recommended Storage

Before Reconstitution:
The GlucaGen package may be stored up to 24 months at controlled room temperature 20o to 25oC (68o to 77oF) prior to reconstitution. Do not freeze. Keep in the original package to protect from light.

After Reconstitution:

Use the reconstituted GlucaGen solution immediately. Discard any unused portion [see Dosage and Administration (2)].