DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Dosage in adults and pediatric patients using the GlucaGen HypoKit to treat severe hypoglycemia (2.2) oAdults and Pediatric Patients Weighing 25 kg or More or for Pediatric Patients with Unknown Weight Years and Older: -The recommended dosage is mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. -If there has been no response after 15 minutes, an additional mg dose (1 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.oPediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than Years of Age: -The recommended dosage is 0.5 mg (0.5 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. -If there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.Important Administration Instructions for Using the GlucaGen HypoKit to Treat Severe Hypoglycemia (2.1)oGlucaGen is for subcutaneous, intramuscular, or intravenous injection. Administer intravenously ONLY under medical supervision.oSee the Full Prescribing Information for administration instructions.Dosage in Adults for Using GlucaGen Diagnostic Kit and GlucaGen 10-pack as Diagnostic Aid (2.4)oThe 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 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or mg to mg administered intramuscularly. oSee the Full Prescribing Information for administration instructions. (2.3). oAdults and Pediatric Patients Weighing 25 kg or More or for Pediatric Patients with Unknown Weight Years and Older:. -The recommended dosage is mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.. -If there has been no response after 15 minutes, an additional mg dose (1 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.. oPediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than Years of Age:. -The recommended dosage is 0.5 mg (0.5 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.. -If there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.. oGlucaGen is for subcutaneous, intramuscular, or intravenous injection. Administer intravenously ONLY under medical supervision.. oSee the Full Prescribing Information for administration instructions.. oThe 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 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or mg to mg administered intramuscularly. oSee the Full Prescribing Information for administration instructions. (2.3). 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 prescription for GlucaGen. Emphasize the following instructions to the patient or caregiver:oUsing 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. oShake 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.oThe reconstituted solution is mg per mL glucagon. oImmediately after reconstitution, using the same syringe, withdraw the correct dose of GlucaGen.oInject the solution subcutaneously or intramuscularly in the upper arm, thigh, or buttocks. In addition, healthcare providers may administer intravenously. oCall for emergency assistance immediately after administering the dose.oIf there has been no response after 15 minutes, an additional dose of GlucaGen may be administered while waiting for emergency assistance.oWhen 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.oDiscard any unused portion.. oUsing 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. oShake 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.. oThe reconstituted solution is mg per mL glucagon. oImmediately after reconstitution, using the same syringe, withdraw the correct dose of GlucaGen.. oInject the solution subcutaneously or intramuscularly in the upper arm, thigh, or buttocks. In addition, healthcare providers may administer intravenously. oCall for emergency assistance immediately after administering the dose.. oIf there has been no response after 15 minutes, an additional dose of GlucaGen may be administered while waiting for emergency assistance.. oWhen 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.. oDiscard 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 Years and OlderoThe recommended dosage is mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.oIf there has been no response after 15 minutes, an additional mg dose (1 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.Pediatric Patients Weighing Less Than 25 kg or for Pediatric Patients with Unknown Weight Less Than Years of AgeoThe recommended dosage is 0.5 mg (0.5 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. oIf there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.For GlucaGen Diagnostic Kit and the GlucaGen 10-pack:. oThe recommended dosage is mg (1 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously.. oIf there has been no response after 15 minutes, an additional mg dose (1 mL) of GlucaGen may be administered using new kit while waiting for emergency assistance.. oThe recommended dosage is 0.5 mg (0.5 mL) injected subcutaneously or intramuscularly into the upper arm, thigh, or buttocks, or intravenously. oIf there has been no response after 15 minutes, an additional 0.5 mg dose (0.5 mL) of GlucaGen may be administered using 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 Diagnostic Aid. oReconstitute GlucaGen with mL of Sterile Water for Injection. Using syringe, withdraw all of the Sterile Water for Injection (if supplied) or mL Sterile Water for Injection and inject into the GlucaGen vial.oShake 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.oThe reconstituted solution is mg per mL glucagon. oImmediately after reconstitution, inject the solution intravenously or intramuscularly into upper arm, thigh, or buttocks.oDiscard any unused portion.oAfter the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure.. oReconstitute GlucaGen with mL of Sterile Water for Injection. Using syringe, withdraw all of the Sterile Water for Injection (if supplied) or mL Sterile Water for Injection and inject into the GlucaGen vial.. oShake 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.. oThe reconstituted solution is mg per mL glucagon. oImmediately after reconstitution, inject the solution intravenously or intramuscularly into upper arm, thigh, or buttocks.. oDiscard any unused portion.. oAfter 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 Diagnostic Aid. oThe 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 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or mg to mg administered intramuscularly [see Clinical Pharmacology (12.2)].oThe onset of action after an injection will depend on the organ under examination and route of administration [see Clinical Pharmacology (12.2)].. oThe 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 mg administered intramuscularly; the recommended dose to relax the colon is 0.5 mg to 0.75 mg administered intravenously or mg to mg administered intramuscularly [see Clinical Pharmacology (12.2)].. oThe onset of action after an injection will depend on the organ under examination and route of administration [see Clinical Pharmacology (12.2)].

OVERDOSAGE SECTION.


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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL GlucaGen diagnostic kit. NDC 0597-0260-10GlucaGen(R) (glucagon) for injection1 mg per vialFor intramuscular or intravenous injectionGlucaGen(R) should be reconstitutedwith Sterile Water for Reconstitutionimmediately before useSingle dose. Discard unused portion.Protect from Light.See package insert for complete productinformation.FOR DIAGNOSTIC USE ONLY NOT INTENDED FORUSE BY PATIENTS TO TREAT SEVEREHYPOGLYCEMIARx ONLYBoehringerIngelheim. Image of carton 1 vial.

PEDIATRIC USE SECTION.


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 diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in pediatric patients have not been established.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following important adverse reactions are described below and elsewhere in the labeling:oHypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)]oNecrolytic Migratory Erythema [see Warnings and Precautions (5.5)]oHyperglycemia in Patients with Diabetes Mellitus when Used as Diagnostic Aid [see Warnings and Precautions (5.6)]oBlood Pressure and Heart Rate Increase in Patients with Cardiac Disease when Used as Diagnostic Aid [see Warnings and Precautions (5.7)]The following adverse reactions have been identified during post-approval use of glucagon. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.oInjection site reactions oNauseaoVomitingoHeadacheoDizzinessoAstheniaoPalloroDiarrhea oSomnolenceoGeneralized allergic reactions including anaphylactic shock with breathing difficulties and hypotensionoHypertension and tachycardiaoDecreased blood pressure. Hypotension has been reported up to hours after administration in patients receiving GlucaGen as premedication for upper gastrointestinal endoscopy procedures. oHypoglycemia and hypoglycemic coma. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see Drug Interactions (7)].oNecrolytic Migratory Erythema (NME) cases have been reported post marketing in patients receiving continuous infusion of glucagon.. oHypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)]. oNecrolytic Migratory Erythema [see Warnings and Precautions (5.5)]. oHyperglycemia in Patients with Diabetes Mellitus when Used as Diagnostic Aid [see Warnings and Precautions (5.6)]. oBlood Pressure and Heart Rate Increase in Patients with Cardiac Disease when Used as Diagnostic Aid [see Warnings and Precautions (5.7)]. oInjection site reactions oNausea. oVomiting. oHeadache. oDizziness. oAsthenia. oPallor. oDiarrhea oSomnolence. oGeneralized allergic reactions including anaphylactic shock with breathing difficulties and hypotension. oHypertension and tachycardia. oDecreased blood pressure. Hypotension has been reported up to hours after administration in patients receiving GlucaGen as premedication for upper gastrointestinal endoscopy procedures. oHypoglycemia and hypoglycemic coma. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see Drug Interactions (7)].. oNecrolytic Migratory Erythema (NME) cases have been reported post marketing in patients receiving continuous infusion of glucagon.. Glucagon adverse reactions identified during post approval use are: injection site reactions, nausea, vomiting, headache, dizziness, asthenia, pallor, diarrhea, somnolence, and decreased blood pressure. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong term studies in animals to evaluate carcinogenic potential have not been performed.MutagenesisThe 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 genotoxic risk to humans. Impairment of FertilityGlucagon was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility.

CLINICAL PHARMACOLOGY SECTION.


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 of1 mg GlucaGen in Type Diabetic MenDiagnostic Aid:Table 2: Pharmacodynamic Properties of Glucagon for Intravenous RouteRoute of AdministrationDosea Time of Maximal Glucose ConcentrationTime of Onset of Action for GI Smooth Muscle RelaxationDuration of Smooth Muscle RelaxationIntravenous0.25 to 0.5 mg to 20 minutes45 seconds9 to 17 minutes aDose is determined based on the length of the procedure.Table 3: Pharmacodynamic Properties of GlucaGen for Intramuscular RouteRoute of AdministrationDosea Time of Maximal Glucose ConcentrationTime of Onset of Action for GI Smooth Muscle RelaxationDuration of Smooth Muscle RelaxationIntramuscular1 mg30 minutes8 to 10 minutes12 to 27 minutes2 mg30 minutes4 to minutes21 to 32 minutes aDose is determined based on the length of the procedure.The time of maximal glucose concentration for GlucaGen administered subcutaneously is 30-45 minutes.. aDose is determined based on the length of the procedure.. aDose is determined based on the length of the procedure.. Graph: Recovery from Insulin Induced Hypoglycemia. 12.3 Pharmacokinetics. AbsorptionIntramuscular injection of mg GlucaGen resulted in mean Cmax (CV%) of 1686 pg/mL (43%) and median Tmax of 12.5 minutes.EliminationThe mean apparent half-life of 45 minutes after intramuscular injection probably reflects prolonged absorption from the injection site.MetabolismGlucagon is degraded in the liver, kidney, and plasma.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. GlucaGen is contraindicated in patients with:oPheochromocytoma because of the risk of substantial increase in blood pressure [see Warnings and Precautions (5.1)] oInsulinoma because of the risk of hypoglycemia [see Warnings and Precautions (5.2)]oKnown hypersensitivity to glucagon or the excipients in GlucaGen. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension [see Warnings and Precautions (5.3)] oGlucagonoma when used as diagnostic aid because of risk of hypoglycemia [see Warnings and Precautions (5.8)] oPheochromocytoma because of the risk of substantial increase in blood pressure [see Warnings and Precautions (5.1)] oInsulinoma because of the risk of hypoglycemia [see Warnings and Precautions (5.2)]. oKnown hypersensitivity to glucagon or the excipients in GlucaGen. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension [see Warnings and Precautions (5.3)] oGlucagonoma when used as diagnostic aid because of risk of hypoglycemia [see Warnings and Precautions (5.8)] oPheochromocytoma (4)oInsulinoma (4)oKnown hypersensitivity to glucagon or to any of the excipients (4)oGlucagonoma when used as diagnostic aid (4). oPheochromocytoma (4). oInsulinoma (4). oKnown hypersensitivity to glucagon or to any of the excipients (4). oGlucagonoma when used as diagnostic aid (4).

DESCRIPTION SECTION.


11 DESCRIPTION. Glucagon is an antihypoglycemic agent and gastrointestinal motility inhibitor. It is produced by expression of recombinant DNA in Saccharomyces cerevisiae vector with subsequent purification. The chemical structure of the glucagon is identical to human glucagon. Glucagon with the empirical formula of C153H225N43O49S, and molecular weight of 3483, is single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is:GlucaGen is sterile, lyophilized white powder for reconstitution for subcutaneous, intramuscular or intravenous use, supplied in 2 mL vial (appearance of the powder may vary, and occasionally the powder may appear compacted). Each vial for reconstitution contains 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 mg/mL at pH 2.5-3.5, and is soluble in water.. Structural formula of GlucaGen.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. GlucaGen for injection is white lyophilized powder supplied as follows:Treatment of Severe Hypoglycemiao1 mg single-dose vial of GlucaGen with 1 mL single-dose syringe of Sterile Water for Injection, USP (GlucaGen HypoKit(R))Use as Diagnostic Aido1 mg single-dose vial of GlucaGen o1 mg single-dose vial of GlucaGen with 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit) o1 mg single-dose vial of GlucaGen with 1 mL single-dose syringe of Sterile Water for Injection, USP (GlucaGen HypoKit(R)). o1 mg single-dose vial of GlucaGen o1 mg single-dose vial of GlucaGen with 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit) For Injection (3): Treatment of Severe Hypoglycemia: mg single-dose vial of GlucaGen with 1 mL single-dose syringe of Sterile Water for Injection, USP (GlucaGen HypoKit(R)) Use as Diagnostic Aid: mg single-dose vial of GlucaGen mg single-dose vial of GlucaGen with 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit) For Injection (3):. Treatment of Severe Hypoglycemia:. mg single-dose vial of GlucaGen with 1 mL single-dose syringe of Sterile Water for Injection, USP (GlucaGen HypoKit(R)). Use as Diagnostic Aid:. mg single-dose vial of GlucaGen. mg single-dose vial of GlucaGen with 1 mL single-dose vial of Sterile Water for Injection, USP (Diagnostic Kit).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Table 1: Clinically Significant Drug Interactions with GlucaGenBeta-Blockers Clinical Impact:Patients taking beta-blockers may have transient increase in pulse and blood pressure when given GlucaGen.Intervention:The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.IndomethacinClinical Impact:In patients taking indomethacin, GlucaGen may lose its ability to raise blood glucose or may even produce hypoglycemia.Intervention:Monitor blood glucose levels during GlucaGen treatment of patients taking indomethacin.Anticholinergic DrugsClinical Impact:The concomitant use of anticholinergic drugs and GlucaGen increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Intervention:Concomitant use of anticholinergic drugs with GlucaGen for use as diagnostic aid is not recommended.WarfarinClinical Impact:GlucaGen may increase the anticoagulant effect of warfarin. Intervention:Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.InsulinClinical Impact:Insulin acts antagonistically to glucagon. Intervention:Monitor blood glucose when GlucaGen is used as diagnostic aid in patients receiving insulin.. Beta-blockers: Patients taking beta-blockers may have transient increase in pulse and blood pressure. (7.1) Indomethacin: In patients taking indomethacin GlucaGen may lose its ability to raise glucose or may produce hypoglycemia. (7.2) Anticholinergic drugs: Concomitant use of anticholinergic drugs with GlucaGen for use as diagnostic aid is not recommended. (7.3) Warfarin: GlucaGen may increase the anticoagulant effect of warfarin. (7.4) Insulin: Monitor blood glucose when GlucaGen is used as diagnostic aid in patients receiving insulin. (7.5). Beta-blockers: Patients taking beta-blockers may have transient increase in pulse and blood pressure. (7.1). Indomethacin: In patients taking indomethacin GlucaGen may lose its ability to raise glucose or may produce hypoglycemia. (7.2). Anticholinergic drugs: Concomitant use of anticholinergic drugs with GlucaGen for use as diagnostic aid is not recommended. (7.3). Warfarin: GlucaGen may increase the anticoagulant effect of warfarin. (7.4). Insulin: Monitor blood glucose when GlucaGen is used as diagnostic aid in patients receiving insulin. (7.5).

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. GlucaGen for injection is supplied as lyophilized white powder available as follows: PresentationNDCStrengthDescriptionTreatment of Severe HypoglycemiaGlucaGen HypoKit0169-7065-151 mg per vial1 mL single-dose vial of GlucaGen with mL single-dose syringe of Sterile Water for Injection, USP for reconstitutionUse as Diagnostic AidGlucaGen 10-pack: 10 Single-dose vials 0597-0053-451 mg per vial mL single-dose vial of GlucaGenGlucaGen Diagnostic Kit 0597-0260-101 mg per vial1 mL single-dose vial of GlucaGen with mL single-dose vial of Sterile Water for Injection, USP for reconstitution. 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)].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. GlucaGen is an antihypoglycemic agent and gastrointestinal motility inhibitor indicated:ofor the treatment of severe hypoglycemia in pediatric and adult patients with diabetes (1.1)oas diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients (1.2). ofor the treatment of severe hypoglycemia in pediatric and adult patients with diabetes (1.1). oas diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients (1.2). 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 diagnostic aid for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in adult patients.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Recognition of Severe HypoglycemiaInform patient and family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia. Serious HypersensitivityInform patients that allergic reactions can occur with GlucaGen. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.3)].Manufactured for:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877By:Novo Nordisk A/S2880 Bagsvaerd, DenmarkGlucaGen(R) and HypoKit(R) are registered trademarks of Novo Nordisk A/S (C) 1998-2021 Novo NordiskFor information contact:Boehringer Ingleheim Pharmaceuticals, Inc.Ridgefield, CT 068771-800-243-0127.

LACTATION SECTION.


8.2 Lactation Risk SummaryThere 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 peptide and would be expected to be broken down to its constituent amino acids in the infants digestive tract and is therefore, unlikely to cause harm to an exposed infant.

MECHANISM OF ACTION SECTION.


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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong term studies in animals to evaluate carcinogenic potential have not been performed.MutagenesisThe 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 genotoxic risk to humans. Impairment of FertilityGlucagon was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility.

PHARMACODYNAMICS SECTION.


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 of1 mg GlucaGen in Type Diabetic MenDiagnostic Aid:Table 2: Pharmacodynamic Properties of Glucagon for Intravenous RouteRoute of AdministrationDosea Time of Maximal Glucose ConcentrationTime of Onset of Action for GI Smooth Muscle RelaxationDuration of Smooth Muscle RelaxationIntravenous0.25 to 0.5 mg to 20 minutes45 seconds9 to 17 minutes aDose is determined based on the length of the procedure.Table 3: Pharmacodynamic Properties of GlucaGen for Intramuscular RouteRoute of AdministrationDosea Time of Maximal Glucose ConcentrationTime of Onset of Action for GI Smooth Muscle RelaxationDuration of Smooth Muscle RelaxationIntramuscular1 mg30 minutes8 to 10 minutes12 to 27 minutes2 mg30 minutes4 to minutes21 to 32 minutes aDose is determined based on the length of the procedure.The time of maximal glucose concentration for GlucaGen administered subcutaneously is 30-45 minutes.. aDose is determined based on the length of the procedure.. aDose is determined based on the length of the procedure.. Graph: Recovery from Insulin Induced Hypoglycemia.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionIntramuscular injection of mg GlucaGen resulted in mean Cmax (CV%) of 1686 pg/mL (43%) and median Tmax of 12.5 minutes.EliminationThe mean apparent half-life of 45 minutes after intramuscular injection probably reflects prolonged absorption from the injection site.MetabolismGlucagon is degraded in the liver, kidney, and plasma.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryAvailable data from case reports and small number of observational studies with glucagon use in pregnant women over decades of use have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated 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.DataAnimal DataIn 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.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration (2)--------------------------------------------03/2021Contraindications (4)--------------------------------------------------------03/2021Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8)------------03/2021.

SPL UNCLASSIFIED SECTION.


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

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from case reports and small number of observational studies with glucagon use in pregnant women over decades of use have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated 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.DataAnimal DataIn 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 SummaryThere 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 peptide and would be expected to be broken down to its constituent amino acids in the infants 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 diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract in pediatric patients have not been established.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Substantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because GlucaGen may stimulate the release of catecholamines from the tumor. (4, 5.1) Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, GlucaGen may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If patient develops symptoms of hypoglycemia after dose of GlucaGen, give glucose orally or intravenously. (4, 5.2) Hypersensitivity and Allergic Reactions: Allergic reactions have been reported and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. (4, 5.3) 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 to be effective. Patients with these conditions should be treated with glucose. (5.4) Necrolytic Migratory Erythema (NME): skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. (5.5) Hyperglycemia in Patients with Diabetes Mellitus when Used as 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. (5.6) Blood Pressure and Heart Rate Increase in Patients with Cardiac Disease when Used as Diagnostic Aid: GlucaGen may increase myocardial oxygen demand, blood pressure, and pulse rate. Cardiac monitoring is recommended in patients with cardiac disease during use of GlucaGen as diagnostic aid, and an increase in blood pressure and pulse rate may require therapy. (5.7) 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 treatment. (5.8). Substantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because GlucaGen may stimulate the release of catecholamines from the tumor. (4, 5.1) Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, GlucaGen may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If patient develops symptoms of hypoglycemia after dose of GlucaGen, give glucose orally or intravenously. (4, 5.2) Hypersensitivity and Allergic Reactions: Allergic reactions have been reported and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. (4, 5.3) 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 to be effective. Patients with these conditions should be treated with glucose. (5.4) Necrolytic Migratory Erythema (NME): skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. (5.5) Hyperglycemia in Patients with Diabetes Mellitus when Used as 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. (5.6) Blood Pressure and Heart Rate Increase in Patients with Cardiac Disease when Used as Diagnostic Aid: GlucaGen may increase myocardial oxygen demand, blood pressure, and pulse rate. Cardiac monitoring is recommended in patients with cardiac disease during use of GlucaGen as diagnostic aid, and an increase in blood pressure and pulse rate may require therapy. (5.7) 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 treatment. (5.8). 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 substantial increase in blood pressure and previously undiagnosed pheochromocytoma is suspected, 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 patient develops symptoms of hypoglycemia after 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 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), 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 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 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 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 diagnostic aid as GlucaGen is contraindicated in this setting [see Contraindications (4)].