GlucaGen HypoKit (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

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.

10 OVERDOSAGE

If overdosage occurs, the patient may experience nausea, vomiting, inhibition of gastrointestinal 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. If the patient develops a dramatic increase in blood pressure, phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.

11 DESCRIPTION

Glucagon is an antihypoglycemic agent and a gastrointestinal motility inhibitor. It is produced by expression of recombinant DNA in a Saccharomyces cerevisiae vector with subsequent purification. The chemical structure of the glucagon is identical to human glucagon. Glucagon with the empirical formula of C153 H225 N43 O49 S, and a molecular weight of 3483, is a single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is:

Structural formula of GlucaGen.
(click image for full-size original)

GlucaGen is a sterile, lyophilized white powder for reconstitution for subcutaneous, intramuscular or intravenous use, supplied in a 2 mL vial (appearance of the powder may vary, and occasionally the powder may appear compacted). Each vial for reconstitution contains 1 mg of glucagon, 107 mg of lactose monohydrate, hydrochloric acid and sodium hydroxide. Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH before lyophilization. The reconstituted solution of GlucaGen contains glucagon 1 mg/mL at pH 2.5-3.5, and is soluble in water.

12 CLINICAL PHARMACOLOGY

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

Figure 1: Graph of recovery from insulin induced hypoglycemia
(click image for full-size original)

Diagnostic Aid:

Table 2: Pharmacodynamic Properties of Glucagon for Intravenous Route

Route of Administration

Dosea

Time of Maximal Glucose Concentration

Time of Onset of Action for GI Smooth Muscle Relaxation

Duration of Smooth Muscle Relaxation

Intravenous

0.25 to 0.5 mg

5 to 20 minutes

45 seconds

9 to 17 minutes

a Dose is determined based on the length of the procedure.

Table 3: Pharmacodynamic Properties of GlucaGen for Intramuscular Route

Route of Administration

Dosea

Time of Maximal Glucose Concentration

Time of Onset of Action for GI Smooth Muscle Relaxation

Duration of Smooth Muscle Relaxation

Intramuscular

1 mg

30 minutes

8 to 10 minutes

12 to 27 minutes

2 mg

30 minutes

4 to 7 minutes

21 to 32 minutes

a Dose is determined based on the length of the procedure.

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

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