ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are described elsewhere in the labeling:oHypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)]. oHypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)]. Most common adverse reactions (>=2%) associated with ZEGALOGUE are:Adults: nausea, vomiting, headache, diarrhea, and injection site painPediatrics: nausea, vomiting, headache, and injection site pain (6.1)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.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ZEGALOGUE cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In clinical trials, 316 adult patients with type diabetes and 20 pediatric patients with type diabetes were exposed to ZEGALOGUE.The data in Table reflect exposure of 116 adult patients to ZEGALOGUE in placebo-controlled trials (mean age 40 years). Table reflects exposure of 20 pediatric patients exposed to ZEGALOGUE in placebo-controlled trial. Eight patients were to 11 years old, and 12 were 12 to 17 years old [see Clinical Studies (14)]. Table 1. Adverse Reactions Occurring >=2% and More Frequently than with Placebo in ZEGALOGUE-treated Adult Patients within 12 hours of Treatment in Placebo-Controlled Trials Adverse reaction typePlacebo(N=53) Dasiglucagon(N=116) of Patients% of PatientsNausea4%57%Vomiting2%25%Headache4%11%Diarrhea0%5%Injection site pain0%2%Table 2. Adverse Reactions Occurring >=2% and More Frequently than with Placebo in ZEGALOGUE-treated Pediatric Patients within 12 hours of Treatment in Placebo-Controlled TrialAdverse reaction typePlacebo(N=11)DasiglucagonAge 6-11 years(N=8)DasiglucagonAge 12-17 years(N=12)DasiglucagonAll(N=20)% of Patients% of Patients% of Patients% of PatientsNausea0%25%92%65%Vomiting0%25%67%50%Headache0%0%17%10%Injection site pain0%0%8%5%. Other Adverse ReactionsOther adverse reactions in patients treated with dasiglucagon occurring within 12 hours of treatment include: hypertension, hypotension, bradycardia, presyncope, palpitations, and orthostatic intolerance.. 6.2 Immunogenicity. As with all therapeutic peptides, there is potential for immunogenicity with ZEGALOGUE. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZEGALOGUE with the incidence of antibodies to other products may be misleading.In clinical trials, 4/498 (<1%) of ZEGALOGUE-treated patients developed treatment-emergent anti-drug antibodies (ADAs). Two patients receiving single dose of ZEGALOGUE had detectable ADAs to dasiglucagon for at least 14 months after dosing. One ADA-positive patient receiving multiple doses of ZEGALOGUE had ADAs with transient neutralizing activity and with cross-reactivity against native glucagon. Although no safety or efficacy concerns were noted for these ADA-positive subjects, it is unknown whether ADAs may affect pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of the drug [see Clinical Studies (14)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term studies in animals to evaluate carcinogenicity of dasiglucagon have not been performed.. MutagenesisDasiglucagon was not mutagenic or clastogenic in standard battery of genotoxicity tests: bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, and rat bone marrow micronucleus.. Impairment of FertilityIn fertility and early embryofetal development study in rats, dasiglucagon administered by subcutaneous injection (0.5, 2, and mg/kg/day) did not impair fertility in male and female rats at exposures 179 and 269 times the human dose of 0.6 mg (based on AUC), respectively.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 0.6 mg/0.6 mL Prefilled Syringe 1ct Carton. Emergency Use for Very Low Blood SugarZEGALOGUE(R) (dasiglucagon) injection0.6 mg/0.6 mLPrefilled SyringeSingle-DoseInjection, for subcutaneous use. Rx onlyNDC 0169-1913-01List: 191301Carton contents:1 Single-Dose Prefilled Syringe1 Prescribing InformationOPEN HERENovo Nordisk(R) Carton PFS 1ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ZEGALOGUE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged years and above. Use of ZEGALOGUE for this indication is supported by evidence from study in 42 pediatric patients with type diabetes [see Clinical Studies (14.2)].The safety and effectiveness of ZEGALOGUE have not been established in pediatric patients younger than years of age.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dasiglucagon is glucagon receptor agonist, which 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 dasiglucagon to produce an antihypoglycemic effect.. 12.2 Pharmacodynamics. After administration of ZEGALOGUE in adult patients with type diabetes, the mean glucose increase from baseline at 90 minutes was 168 mg/dL (Figure 1).Figure 1. Mean plasma glucose over time in adults with type diabetes administered 0.6 mg dasiglucagonIn pediatric patients (7 to 17 years) with type diabetes, the mean glucose increase at 60 minutes after administration of ZEGALOGUE was 162 mg/dL (Figure 2).Figure 2. Mean plasma glucose over time in pediatric patients with type diabetes administered 0.6 mg dasiglucagon. Cardiac ElectrophysiologyAt dose resulting in more than times the concentration achieved with the recommended therapeutic dose, ZEGALOGUE does not prolong the QT interval to any clinically relevant extent.. Figure 1. Figure 2. 12.3 Pharmacokinetics. AbsorptionZEGALOGUE absorption following subcutaneous injection of 0.6 mg resulted in mean peak plasma concentration of 5110 pg/mL (1510 pmol/L) at around 35 minutes. DistributionThe mean apparent volume of distribution was 47 to 57 following subcutaneous administration. EliminationThe half-life was approximately 30 minutes.. MetabolismMetabolism data indicated that dasiglucagon is cleared like native glucagon through proteolytic degradation pathways in blood, liver, and kidney.. Specific PopulationsAfter administration of ZEGALOGUE in pediatric patients with type diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Three randomized, double-blind, placebo-controlled, multicenter trials were conducted in patients with type diabetes. Two trials (Trial and Trial B) were conducted in adult patients, and one trial (Trial C) was conducted in pediatric patients aged to 17 years. In all trials, patients were randomized to ZEGALOGUE 0.6 mg, placebo, or (in Trials and C) glucagon for injection 1.0 mg. ZEGALOGUE and the comparators were administered as single subcutaneous injections following controlled induction of hypoglycemia using intravenous administration of insulin. During this procedure, plasma glucose concentration of <60 mg/dL was targeted in Trials and B, whereas the target was <80 mg/dL in Trial C.The primary efficacy endpoint for all trials was time to plasma glucose recovery (treatment success), defined as an increase in blood glucose of >=20 mg/dL from time of administration, without additional intervention within 45 minutes. In Trials and B, plasma glucose values were collected and assessed at pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25, 30, 40, 45, 50, 60, 75, 90 minutes after treatment. Trial assessed plasma glucose at the same timepoints as did Trials and B, with the exception of the 25, 40, 50, 75 and 90-minute post-treatment timepoints. The primary hypothesis test was superiority of ZEGALOGUE versus placebo. There was no formal hypothesis test of ZEGALOGUE versus glucagon for injection.. 14.1 Adult Patients. Trial A, NCT03378635: total of 170 patients were randomized 2:1:1 to ZEGALOGUE, placebo, and glucagon for injection, stratified by injection sites (abdominal region, buttocks, thigh). The mean age of the patients was 39.1 years (96% were 65 years), and the mean duration of diabetes was 20.0 years; 63% were male; 92% were White. The mean baseline plasma glucose was 58.8 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for ZEGALOGUE (10 minutes) versus placebo (40 minutes) (Table 4). Figure shows the cumulative proportions of patients achieving plasma glucose recovery over time. The median time to plasma glucose recovery was numerically similar between ZEGALOGUE (10 minutes) and glucagon for injection (12 minutes).Trial B, NCT03688711: total of 45 patients were randomized 3:1 to ZEGALOGUE and placebo stratified by injection sites (buttocks, deltoid). The mean age of the patients was 41.0 years (95% were 65 years), and the mean duration of diabetes was 22.5 years; 57% were male; 93% were White. The mean baseline plasma glucose was 55.0 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for ZEGALOGUE (10 minutes) versus placebo (35 minutes) (Table 4).Table 4. Plasma Glucose Recovery in Adult PatientsTrial ATrial BZEGALOGUEN=82PlaceboN=43ZEGALOGUEN=34PlaceboN=10N is the number of patients who were randomized and treated.Median time to recovery [95% CIlog-log confidence interval]10 min[10; 10]p 0.001 versus placebo (log-rank test stratified by injection sites) 40 min[30; 40]10 min[8; 12] 35 min[20; -) Figure 3Time to plasma glucose recovery in Trial A. Figure 3Time to plasma glucose recovery in Trial A. Figure 3. 14.2 Pediatric Patients. Trial C, NCT03667053: Pediatric patients aged to 17 years and weighing >=20 kg, were randomized 2:1:1 to ZEGALOGUE, placebo, and glucagon for injection, stratified by injection sites (abdominal region, thigh) and age groups (6-11 years and 12-17 years). total of 42 patients were randomized. The mean age was 12.5 years (range to 17 years), and the mean duration of diabetes was 5.9 years; 56% were male; 95% were White. The mean baseline plasma glucose was 72.0 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for ZEGALOGUE (10 minutes) versus placebo (30 minutes) (Table 5). Figure shows the cumulative proportions of pediatric patients achieving plasma glucose recovery over time. The median time to plasma glucose recovery was numerically similar between ZEGALOGUE (10 minutes) and glucagon for injection (10 minutes).Table 5. Plasma Glucose Recovery in Pediatric PatientsTrial CZEGALOGUEN=20PlaceboN=11N is the number of patients who were randomized and treated.Median time to recovery [95% CIlog-log confidence interval]10 min [8; 12]p 0.001 versus placebo (log-rank test stratified by injection site and age group) 30 min [20; -)Figure 4. Time to plasma glucose recovery in Trial C. Figure 4.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. ZEGALOGUE 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)]. 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)]. Pheochromocytoma (4)Insulinoma (4).

DESCRIPTION SECTION.

11 DESCRIPTION. ZEGALOGUE contains dasiglucagon hydrochloride, which is glucagon analog and an antihypoglycemic agent. Dasiglucagon is comprised of 29 amino acids. The molecular formula of dasiglucagon (anhydrous, free-base) is C152H222N38O50, and its molecular mass is 3382 g/mol (anhydrous, free-base). Dasiglucagon hydrochloride has the following chemical structure:ZEGALOGUE injection is preservative free, sterile, aqueous, clear, and colorless solution for subcutaneous use in single-dose prefilled syringe and an autoinjector. Each prefilled syringe and autoinjector contains 0.63 mg of dasiglucagon provided as dasiglucagon hydrochloride, which is salt with - equivalents of hydrochloride, and contains the following inactive ingredients: 3.82 mg tromethamine, 6.44 mg sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 6.5.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oZEGALOGUE autoinjector and prefilled syringe are for subcutaneous injection only. (2.1)oThe dose in adults and pediatric patients aged years and older is 0.6 mg. (2.2) oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use. (2.1)oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use. (2.1)oAdminister the injection into the lower abdomen, buttocks, thigh, or outer upper arm. (2.1)oCall for emergency assistance immediately after administering the dose. (2.1)oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE from new device may be administered while waiting for emergency assistance. (2.1)oWhen the patient has responded to treatment, give oral carbohydrates. (2.1) oDo not attempt to reuse ZEGALOGUE. Each device contains single dose of dasiglucagon and cannot be reused. (2.1). oZEGALOGUE autoinjector and prefilled syringe are for subcutaneous injection only. (2.1). oThe dose in adults and pediatric patients aged years and older is 0.6 mg. (2.2) oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use. (2.1). oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use. (2.1). oAdminister the injection into the lower abdomen, buttocks, thigh, or outer upper arm. (2.1). oCall for emergency assistance immediately after administering the dose. (2.1). oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE from new device may be administered while waiting for emergency assistance. (2.1). oWhen the patient has responded to treatment, give oral carbohydrates. (2.1) oDo not attempt to reuse ZEGALOGUE. Each device contains single dose of dasiglucagon and cannot be reused. (2.1). 2.1 Administration Instructions. ZEGALOGUE autoinjector and prefilled syringe are for subcutaneous injection only.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 ZEGALOGUE and its Instructions For Use. Administer ZEGALOGUE 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 ZEGALOGUE. Emphasize the following instructions to the patient or caregiver:oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use.oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use.oAdminister the injection in the lower abdomen, buttocks, thigh, or outer upper arm.oCall for emergency assistance immediately after administering the dose. oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE may be administered while waiting for emergency assistance. oWhen the patient has responded to treatment, give oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia.oDo not attempt to reuse ZEGALOGUE. Each ZEGALOGUE device contains single dose of dasiglucagon and cannot be reused.. oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use.. oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use.. oAdminister the injection in the lower abdomen, buttocks, thigh, or outer upper arm.. oCall for emergency assistance immediately after administering the dose. oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE may be administered while waiting for emergency assistance. oWhen the patient has responded to treatment, give oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia.. oDo not attempt to reuse ZEGALOGUE. Each ZEGALOGUE device contains single dose of dasiglucagon and cannot be reused.. 2.2 Recommended Dosage. The recommended dose of ZEGALOGUE in adults and pediatric patients aged years and older is 0.6 mg administered by subcutaneous injection into the lower abdomen, buttocks, thigh, or outer upper arm.If there has been no response after 15 minutes, an additional 0.6 mg dose of ZEGALOGUE from new device may be administered.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. ZEGALOGUE injection is clear, colorless solution available as:o0.6 mg/0.6 mL single-dose autoinjectoro0.6 mg/0.6 mL single-dose prefilled syringe. o0.6 mg/0.6 mL single-dose autoinjector. o0.6 mg/0.6 mL single-dose prefilled syringe. Injection:o0.6 mg/0.6 mL single-dose autoinjector (3)o0.6 mg/0.6 mL single-dose prefilled syringe (3). o0.6 mg/0.6 mL single-dose autoinjector (3). o0.6 mg/0.6 mL single-dose prefilled syringe (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 3. Clinically Significant Drug Interactions with ZEGALOGUEBeta-BlockersClinical Impact:Patients taking beta-blockers may have transient increase in pulse and blood pressure when given ZEGALOGUE.IndomethacinClinical Impact:In patients taking indomethacin, ZEGALOGUE may lose its ability to raise blood glucose or may even produce hypoglycemia.WarfarinClinical Impact: ZEGALOGUE may increase the anticoagulant effect of warfarin.. ZEGALOGUE may increase the anticoagulant effect of warfarin.. oBeta-blockers: Patients taking beta-blockers may have transient increase in pulse and blood pressure. (7)oIndomethacin: In patients taking indomethacin, ZEGALOGUE may lose its ability to raise blood glucose or may produce hypoglycemia. (7)oWarfarin: ZEGALOGUE may increase the anticoagulant effect of warfarin. (7). oBeta-blockers: Patients taking beta-blockers may have transient increase in pulse and blood pressure. (7). oIndomethacin: In patients taking indomethacin, ZEGALOGUE may lose its ability to raise blood glucose or may produce hypoglycemia. (7). oWarfarin: ZEGALOGUE may increase the anticoagulant effect of warfarin. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of ZEGALOGUE included too few patients 65 years of age and older to determine whether these patients respond differently from younger adult patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. ZEGALOGUE injection is clear, colorless solution supplied as follows:PresentationStrengthPackage SizeNDCSingle-dose autoinjector0.6 mg/0.6 mL10169-1912-01Single-dose autoinjector0.6 mg/0.6 mL20169-1912-02Single-dose prefilled syringe0.6 mg/0.6 mL10169-1913-01Single-dose prefilled syringe0.6 mg/0.6 mL20169-1913-02. 16.2 Recommended Storage. Store ZEGALOGUE in refrigerator, 2C to 8C (36F to 46F). Keep away from the cooling element. Do not freeze.ZEGALOGUE can be kept at room temperature between 20C to 25C (68F to 77F) for up to 12 months. Record the date when the product was removed from the refrigerator in the space provided on the protective case. Do not return the product to the refrigerator after storing at room temperature. Store in the provided protective case and protect from light.Discard ZEGALOGUE after the end of the 12-month period at room temperature storage, or after the expiration date stated on the product, whichever occurs first.The inside of the gray cap on ZEGALOGUE autoinjector contains dry natural rubber (a derivative of latex).The inside of the gray needle cover on ZEGALOGUE prefilled syringe contains dry natural rubber (a derivative of latex).

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic peptides, there is potential for immunogenicity with ZEGALOGUE. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZEGALOGUE with the incidence of antibodies to other products may be misleading.In clinical trials, 4/498 (<1%) of ZEGALOGUE-treated patients developed treatment-emergent anti-drug antibodies (ADAs). Two patients receiving single dose of ZEGALOGUE had detectable ADAs to dasiglucagon for at least 14 months after dosing. One ADA-positive patient receiving multiple doses of ZEGALOGUE had ADAs with transient neutralizing activity and with cross-reactivity against native glucagon. Although no safety or efficacy concerns were noted for these ADA-positive subjects, it is unknown whether ADAs may affect pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of the drug [see Clinical Studies (14)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ZEGALOGUE(R) is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged years and above.. ZEGALOGUE is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged years and above. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions For Use).. 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.. AdministrationReview the Patient Information and Instructions For Use with the patient and family members or caregivers.. Serious HypersensitivityInform patients that allergic reactions can occur with glucagon products like ZEGALOGUE. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.3)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE. ZEGALOGUE(R) (ze gah log)(dasiglucagon) injection0.6 mg/0.6 mLEmergency Use for Very Low Blood SugarSingle-DosePrefilled SyringeInjection, for subcutaneous useImportant: ZEGALOGUE is used to treat very low blood sugar (severe hypoglycemia) where you need help from others.ZEGALOGUE contains dose of dasiglucagon in prefilled syringe and cannot be reused.Read and understand this Instructions For Use before an emergency happens.Show your family and friends where you keep ZEGALOGUE and explain how to use it by sharing these instructions, so they know how to use ZEGALOGUE before an emergency happens.The inside of the gray needle cover contains dry natural rubber, which may cause allergic reactions in people with latex allergy.Read before Injecting ZEGALOGUEoDo not use ZEGALOGUE if the:oexpiration date has passedogray needle cover is missing orosyringe appears damaged oWhen opening the red protective case make sure to hold it up straight (with the gray cap on top) to avoid dropping ZEGALOGUE.oDo not remove the gray needle cover until you are ready to inject ZEGALOGUE.oFor questions or more information about ZEGALOGUE, call your healthcare provider.Storage informationoStore ZEGALOGUE in the refrigerator between 36F to 46F (2C to 8C).oDo not freeze.oStore ZEGALOGUE in the red protective case it comes in.oZEGALOGUE can also be stored at room temperature between 68F to 77F (20C to 25C) for up to 12 months. See example to the right for how to keep track of this 12-month period.oDo not return to refrigerator after storing at room temperature.oThrow away ZEGALOGUE if it has been stored at room temperature for more than 12 months.oReplace ZEGALOGUE before the expiration date printed on the red protective case.oKeep ZEGALOGUE and all medicines out of the reach of children.Description of partsBefore injectionChoose injection site and expose skinInjection sites include:oOuter upper armsoLower abdomen (at least inches from the belly button)oFront or back of thighsoButtocksRoll back any clothing to expose bare skin. Do not inject through clothes.Hold the red protective case upright and remove gray capoHold the red protective case upright with the gray cap on top.oPull the gray cap up to open.oCarefully remove ZEGALOGUE from the red protective case without dropping it.How to injectStep 1Remove the gray needle coverPull the gray needle cover straight off. Be careful not to bend the needle.Step 2Pinch the skin and insert the needleGently pinch the skin and insert the entire needle into the skin at 45 angle.Step 3Give the injectionAfter inserting the needle, release the pinched skin and slowly press the plunger rod all the way down until the syringe is empty and the plunger rod stops.Step 4Remove the needleAfter the plunger rod stops and the injection is complete, carefully remove the needle from the injection site.After injectionoAfter you have given the injection, roll the unconscious person on to their side to prevent choking.oCall for emergency medical help or healthcare provider right away after you have injected ZEGALOGUE. Even if the ZEGALOGUE injection helps the person to wake up, still call for emergency medical help right away. If the person does not respond after 15 minutes, another dose may be given, if available.oOnce the person is able to safely consume food or drink, give the person fast-acting source of sugar (such as fruit juice) and long-acting source of sugar (such as crackers with cheese or peanut butter).oReplace the used ZEGALOGUE right away so you will have new ZEGALOGUE in case you need it.Hypoglycemia may happen again after receiving ZEGALOGUE treatment.Early symptoms of hypoglycemia may include:osweatingodrowsinessodizzinessosleep disturbancesoirregular heartbeat (palpitation)oanxietyotremoroblurred visionohungeroslurred speechorestlessnessodepressed moodotingling in the hands, feet, lips, or tongueoirritabilityoabnormal behaviorolightheadednessounsteady movementoinability to concentrateopersonality changesoheadacheIf not treated early, hypoglycemia may worsen and the person may have severe hypoglycemia. Signs of severe hypoglycemia include confusion, seizures, unconsciousness, and death.How to throw away (dispose of) ZEGALOGUEDispose of your ZEGALOGUE and the gray needle cover in an FDA-cleared sharps disposal container.Put your expired or used needles and syringes in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.If you do not have an FDA-cleared sharps disposal container, you may use household container that is: omade of heavy-duty plasticocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outoupright and stable during useoleak-resistantoproperly labeled to warn of hazardous waste inside the containerWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the correct way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit it.Do not recycle your used sharps disposal container.This Instructions For Use has been approved by the U.S. Food and Drug Administration.Distributed by:Novo Nordisk Inc., Plainsboro, NJ, USAManufactured by:Rechon Life Science AB, Malmo, SwedenRevised 01/2023. oDo not use ZEGALOGUE if the:oexpiration date has passedogray needle cover is missing orosyringe appears damaged oexpiration date has passed. ogray needle cover is missing or. osyringe appears damaged. oWhen opening the red protective case make sure to hold it up straight (with the gray cap on top) to avoid dropping ZEGALOGUE.. oDo not remove the gray needle cover until you are ready to inject ZEGALOGUE.. oFor questions or more information about ZEGALOGUE, call your healthcare provider.. oStore ZEGALOGUE in the refrigerator between 36F to 46F (2C to 8C).. oDo not freeze.. oStore ZEGALOGUE in the red protective case it comes in.. oZEGALOGUE can also be stored at room temperature between 68F to 77F (20C to 25C) for up to 12 months. See example to the right for how to keep track of this 12-month period.. oDo not return to refrigerator after storing at room temperature.. oThrow away ZEGALOGUE if it has been stored at room temperature for more than 12 months.. oReplace ZEGALOGUE before the expiration date printed on the red protective case.. oKeep ZEGALOGUE and all medicines out of the reach of children.. oOuter upper arms. oLower abdomen (at least inches from the belly button). oFront or back of thighs. oButtocks. oHold the red protective case upright with the gray cap on top.. oPull the gray cap up to open.. oCarefully remove ZEGALOGUE from the red protective case without dropping it.. oAfter you have given the injection, roll the unconscious person on to their side to prevent choking.. oCall for emergency medical help or healthcare provider right away after you have injected ZEGALOGUE. Even if the ZEGALOGUE injection helps the person to wake up, still call for emergency medical help right away. If the person does not respond after 15 minutes, another dose may be given, if available.. oOnce the person is able to safely consume food or drink, give the person fast-acting source of sugar (such as fruit juice) and long-acting source of sugar (such as crackers with cheese or peanut butter).. oReplace the used ZEGALOGUE right away so you will have new ZEGALOGUE in case you need it.. osweating. odrowsiness. odizziness. osleep disturbances. oirregular heartbeat (palpitation). oanxiety. otremor. oblurred vision. ohunger. oslurred speech. orestlessness. odepressed mood. otingling in the hands, feet, lips, or tongue. oirritability. oabnormal behavior. olightheadedness. ounsteady movement. oinability to concentrate. opersonality changes. oheadache. omade of heavy-duty plastic. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out. oupright and stable during use. oleak-resistant. oproperly labeled to warn of hazardous waste inside the container. Figure. PFS-description.jpg. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk Summary There is no information on the presence of dasiglucagon in either human or animal milk, or the effects of the drug on the breastfed infant or milk production. Dasiglucagon 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. Dasiglucagon is glucagon receptor agonist, which 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 dasiglucagon to produce an antihypoglycemic effect.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term studies in animals to evaluate carcinogenicity of dasiglucagon have not been performed.. MutagenesisDasiglucagon was not mutagenic or clastogenic in standard battery of genotoxicity tests: bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, and rat bone marrow micronucleus.. Impairment of FertilityIn fertility and early embryofetal development study in rats, dasiglucagon administered by subcutaneous injection (0.5, 2, and mg/kg/day) did not impair fertility in male and female rats at exposures 179 and 269 times the human dose of 0.6 mg (based on AUC), respectively.

OVERDOSAGE SECTION.

10 OVERDOSAGE. If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, and/or increases in blood pressure and heart rate. In case of suspected overdosing, serum potassium may decrease and should be monitored and corrected if needed. If the patient develops marked 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.Appropriate supportive treatment should be initiated according to the patients clinical signs and symptoms.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. After administration of ZEGALOGUE in adult patients with type diabetes, the mean glucose increase from baseline at 90 minutes was 168 mg/dL (Figure 1).Figure 1. Mean plasma glucose over time in adults with type diabetes administered 0.6 mg dasiglucagonIn pediatric patients (7 to 17 years) with type diabetes, the mean glucose increase at 60 minutes after administration of ZEGALOGUE was 162 mg/dL (Figure 2).Figure 2. Mean plasma glucose over time in pediatric patients with type diabetes administered 0.6 mg dasiglucagon. Cardiac ElectrophysiologyAt dose resulting in more than times the concentration achieved with the recommended therapeutic dose, ZEGALOGUE does not prolong the QT interval to any clinically relevant extent.. Figure 1. Figure 2.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionZEGALOGUE absorption following subcutaneous injection of 0.6 mg resulted in mean peak plasma concentration of 5110 pg/mL (1510 pmol/L) at around 35 minutes. DistributionThe mean apparent volume of distribution was 47 to 57 following subcutaneous administration. EliminationThe half-life was approximately 30 minutes.. MetabolismMetabolism data indicated that dasiglucagon is cleared like native glucagon through proteolytic degradation pathways in blood, liver, and kidney.. Specific PopulationsAfter administration of ZEGALOGUE in pediatric patients with type diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no available data on dasiglucagon use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated hypoglycemia in pregnancy can cause complications and may be fatal. In animal reproduction studies, daily subcutaneous administration of dasiglucagon to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at exposures and 709 times the human dose of 0.6 mg based on AUC, respectively (see Data).. Data. Animal DataIn an embryo-fetal development study, pregnant rats were treated daily with subcutaneous doses of 2, 10, and 24 mg/kg/day during the period of organogenesis (gestation day to 17). Maternal toxicity, in terms of decreased body weight gain, lower fetal body weight, and delayed bone ossification, was observed at >=10 mg/kg/day (>=475 times the human dose, based on AUC). In an embryo-fetal development study, pregnant rabbits were treated daily with subcutaneous doses of 0.1, 0.3, and mg/kg/day during the period of organogenesis (gestation day to 19). Lower fetal body weight and delayed bone ossification were observed at mg/kg/day (100 times the human dose, based on AUC), dose that also induced maternal toxicity in terms of decreased body weight gain. At >=0.3 mg/kg/day (>=20 times the human dose), dasiglucagon caused fetal skeletal and visceral malformations. No adverse fetal developmental effects were observed at 0.1 mg/kg/day, corresponding to exposure times the human dose.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationZEGALOGUE (ze gah log)(dasiglucagon) injection, for subcutaneous useWhat is ZEGALOGUEZEGALOGUE is prescription medicine used to treat very low blood sugar (severe hypoglycemia) in people with diabetes aged years and older.It is not known if ZEGALOGUE is safe and effective in children under years of age.Do not use ZEGALOGUE if you:ohave tumor called pheochromocytoma in the gland on top of your kidneys (adrenal gland).ohave tumor called insulinoma in your pancreas.Before using ZEGALOGUE, tell your healthcare provider about all of your medical conditions, including if you:ohave tumor in your pancreas.oare allergic to dasiglucagon or any other ingredients in ZEGALOGUE. See the end of this Patient Information for complete list of ingredients in ZEGALOGUE.ohave not had food or water for long time (prolonged fasting or starvation).ohave adrenal insufficiency.ohave low blood sugar that does not go away (chronic hypoglycemia).oare pregnant or plan to become pregnant.oare breastfeeding or plan to breastfeed. It is not known if ZEGALOGUE passes into your breast milk. You and your healthcare provider should decide if you can use ZEGALOGUE while breastfeeding.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use ZEGALOGUEoRead the detailed Instructions For Use that come with ZEGALOGUE.oUse ZEGALOGUE exactly how your healthcare provider tells you to use it.oMake sure your caregiver knows where you keep your ZEGALOGUE and how to use ZEGALOGUE the right way before you need it.oYour caregiver must act quickly. Having very low blood sugar for period of time may be harmful.oYour healthcare provider will tell you how and when to use ZEGALOGUE.oAfter giving ZEGALOGUE, your caregiver should call for emergency medical help right away.oOnce you are able to safely consume food or drink, your caregiver should give you fast-acting source of sugar (such as fruit juice) and long-acting source of sugar (such as crackers with cheese or peanut butter).oIf you do not respond to treatment after 15 minutes, your caregiver may give you another dose, if available.oTell your healthcare provider each time you use ZEGALOGUE. Your healthcare provider may need to change the dose of your other diabetes medicines.What are the possible side effects of ZEGALOGUEZEGALOGUE may cause serious side effects, including:ohigh blood pressure. ZEGALOGUE can cause high blood pressure in certain people with tumors in their adrenal glands.olow blood sugar. ZEGALOGUE can cause certain people with tumors in their pancreas called insulinomas to have low blood sugar.oserious allergic reaction. Call your healthcare provider or get medical help right away if you have serious allergic reaction including: rash, difficulty breathing, or low blood pressure (hypotension).The most common side effects of ZEGALOGUE include:1.Adults2.nausea3.vomiting4.headache5.diarrhea6.injection site pain1.Children2.nausea3.vomiting4.headache5.injection site painThese are not all of the possible side effects of ZEGALOGUE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ZEGALOGUEoStore ZEGALOGUE in refrigerator between 36F to 46F (2C to 8C).oDo not freeze ZEGALOGUE.oZEGALOGUE can also be stored at room temperature between 68F to 77F (20C to 25C) for up to 12 months. See example in the Instructions For Use for how to keep track of this 12-month period.oDo not return ZEGALOGUE to the refrigerator after storing at room temperature.oThrow away ZEGALOGUE if it has been stored at room temperature for more than 12 months.oReplace ZEGALOGUE before the expiration date printed on the red protective case.oStore ZEGALOGUE in the red protective case it comes in.Keep ZEGALOGUE and all medicines out of the reach of children.General information about the safe use of ZEGALOGUE.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ZEGALOGUE for condition for which it was not prescribed. Do not give ZEGALOGUE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ZEGALOGUE that is written for healthcare professionals.What are the ingredients in ZEGALOGUEActive ingredient: dasiglucagon, provided as dasiglucagon hydrochlorideInactive ingredients: tromethamine, sodium chloride and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pHDistributed by: Novo Nordisk Inc., Plainsboro, NJ, USAManufactured by: Rechon Life Science AB, Malmo, SwedenFor more information go to www.zegalogue.com or call 1-800-727-6500.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2023. ohave tumor called pheochromocytoma in the gland on top of your kidneys (adrenal gland).. ohave tumor called insulinoma in your pancreas.. ohave tumor in your pancreas.. oare allergic to dasiglucagon or any other ingredients in ZEGALOGUE. See the end of this Patient Information for complete list of ingredients in ZEGALOGUE.. ohave not had food or water for long time (prolonged fasting or starvation).. ohave adrenal insufficiency.. ohave low blood sugar that does not go away (chronic hypoglycemia).. oare pregnant or plan to become pregnant.. oare breastfeeding or plan to breastfeed. It is not known if ZEGALOGUE passes into your breast milk. You and your healthcare provider should decide if you can use ZEGALOGUE while breastfeeding.. oRead the detailed Instructions For Use that come with ZEGALOGUE.. oUse ZEGALOGUE exactly how your healthcare provider tells you to use it.. oMake sure your caregiver knows where you keep your ZEGALOGUE and how to use ZEGALOGUE the right way before you need it.. oYour caregiver must act quickly. Having very low blood sugar for period of time may be harmful.. oYour healthcare provider will tell you how and when to use ZEGALOGUE.. oAfter giving ZEGALOGUE, your caregiver should call for emergency medical help right away.. oOnce you are able to safely consume food or drink, your caregiver should give you fast-acting source of sugar (such as fruit juice) and long-acting source of sugar (such as crackers with cheese or peanut butter).. oIf you do not respond to treatment after 15 minutes, your caregiver may give you another dose, if available.. oTell your healthcare provider each time you use ZEGALOGUE. Your healthcare provider may need to change the dose of your other diabetes medicines.. ohigh blood pressure. ZEGALOGUE can cause high blood pressure in certain people with tumors in their adrenal glands.. olow blood sugar. ZEGALOGUE can cause certain people with tumors in their pancreas called insulinomas to have low blood sugar.. oserious allergic reaction. Call your healthcare provider or get medical help right away if you have serious allergic reaction including: rash, difficulty breathing, or low blood pressure (hypotension).. 1.Adults. 2.nausea. 3.vomiting. 4.headache. 5.diarrhea. 6.injection site pain. 1.Children. 2.nausea. 3.vomiting. 4.headache. 5.injection site pain. oStore ZEGALOGUE in refrigerator between 36F to 46F (2C to 8C).. oDo not freeze ZEGALOGUE.. oZEGALOGUE can also be stored at room temperature between 68F to 77F (20C to 25C) for up to 12 months. See example in the Instructions For Use for how to keep track of this 12-month period.. oDo not return ZEGALOGUE to the refrigerator after storing at room temperature.. oThrow away ZEGALOGUE if it has been stored at room temperature for more than 12 months.. oReplace ZEGALOGUE before the expiration date printed on the red protective case.. oStore ZEGALOGUE in the red protective case it comes in.

SPL UNCLASSIFIED SECTION.

2.1 Administration Instructions. ZEGALOGUE autoinjector and prefilled syringe are for subcutaneous injection only.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 ZEGALOGUE and its Instructions For Use. Administer ZEGALOGUE 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 ZEGALOGUE. Emphasize the following instructions to the patient or caregiver:oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use.oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use.oAdminister the injection in the lower abdomen, buttocks, thigh, or outer upper arm.oCall for emergency assistance immediately after administering the dose. oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE may be administered while waiting for emergency assistance. oWhen the patient has responded to treatment, give oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia.oDo not attempt to reuse ZEGALOGUE. Each ZEGALOGUE device contains single dose of dasiglucagon and cannot be reused.. oAdminister ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use.. oVisually inspect ZEGALOGUE prior to administration. The solution should appear clear, colorless, and free from particles. If the solution is discolored or contains particulate matter, do not use.. oAdminister the injection in the lower abdomen, buttocks, thigh, or outer upper arm.. oCall for emergency assistance immediately after administering the dose. oIf there has been no response after 15 minutes, an additional dose of ZEGALOGUE may be administered while waiting for emergency assistance. oWhen the patient has responded to treatment, give oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia.. oDo not attempt to reuse ZEGALOGUE. Each ZEGALOGUE device contains single dose of dasiglucagon and cannot be reused.

STORAGE AND HANDLING SECTION.

16.2 Recommended Storage. Store ZEGALOGUE in refrigerator, 2C to 8C (36F to 46F). Keep away from the cooling element. Do not freeze.ZEGALOGUE can be kept at room temperature between 20C to 25C (68F to 77F) for up to 12 months. Record the date when the product was removed from the refrigerator in the space provided on the protective case. Do not return the product to the refrigerator after storing at room temperature. Store in the provided protective case and protect from light.Discard ZEGALOGUE after the end of the 12-month period at room temperature storage, or after the expiration date stated on the product, whichever occurs first.The inside of the gray cap on ZEGALOGUE autoinjector contains dry natural rubber (a derivative of latex).The inside of the gray needle cover on ZEGALOGUE prefilled syringe contains dry natural rubber (a derivative of latex).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no available data on dasiglucagon use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated hypoglycemia in pregnancy can cause complications and may be fatal. In animal reproduction studies, daily subcutaneous administration of dasiglucagon to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at exposures and 709 times the human dose of 0.6 mg based on AUC, respectively (see Data).. Data. Animal DataIn an embryo-fetal development study, pregnant rats were treated daily with subcutaneous doses of 2, 10, and 24 mg/kg/day during the period of organogenesis (gestation day to 17). Maternal toxicity, in terms of decreased body weight gain, lower fetal body weight, and delayed bone ossification, was observed at >=10 mg/kg/day (>=475 times the human dose, based on AUC). In an embryo-fetal development study, pregnant rabbits were treated daily with subcutaneous doses of 0.1, 0.3, and mg/kg/day during the period of organogenesis (gestation day to 19). Lower fetal body weight and delayed bone ossification were observed at mg/kg/day (100 times the human dose, based on AUC), dose that also induced maternal toxicity in terms of decreased body weight gain. At >=0.3 mg/kg/day (>=20 times the human dose), dasiglucagon caused fetal skeletal and visceral malformations. No adverse fetal developmental effects were observed at 0.1 mg/kg/day, corresponding to exposure times the human dose. 8.2 Lactation. Risk Summary There is no information on the presence of dasiglucagon in either human or animal milk, or the effects of the drug on the breastfed infant or milk production. Dasiglucagon 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 ZEGALOGUE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged years and above. Use of ZEGALOGUE for this indication is supported by evidence from study in 42 pediatric patients with type diabetes [see Clinical Studies (14.2)].The safety and effectiveness of ZEGALOGUE have not been established in pediatric patients younger than years of age.. 8.5 Geriatric Use. Clinical studies of ZEGALOGUE included too few patients 65 years of age and older to determine whether these patients respond differently from younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSubstantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because ZEGALOGUE may stimulate the release of catecholamines from the tumor. (4, 5.1)oHypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose, but ZEGALOGUE may stimulate exaggerated insulin release from an insulinoma and cause subsequent hypoglycemia. If patient develops symptoms of hypoglycemia after dose of ZEGALOGUE, give glucose orally or intravenously. (4, 5.2)oHypersensitivity and Allergic Reactions: Allergic reactions have been reported with glucagon products and may include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. (5.3)oLack of Efficacy in Patients with Decreased Hepatic Glycogen: ZEGALOGUE 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 ZEGALOGUE to be effective. Patients with these conditions should be treated with glucose. (5.4). oSubstantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because ZEGALOGUE may stimulate the release of catecholamines from the tumor. (4, 5.1). oHypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose, but ZEGALOGUE may stimulate exaggerated insulin release from an insulinoma and cause subsequent hypoglycemia. If patient develops symptoms of hypoglycemia after dose of ZEGALOGUE, give glucose orally or intravenously. (4, 5.2). oHypersensitivity and Allergic Reactions: Allergic reactions have been reported with glucagon products and may include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. (5.3). oLack of Efficacy in Patients with Decreased Hepatic Glycogen: ZEGALOGUE 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 ZEGALOGUE to be effective. Patients with these conditions should be treated with glucose. (5.4). 5.1 Substantial Increase in Blood Pressure in Patients with Pheochromocytoma. ZEGALOGUE is contraindicated in patients with pheochromocytoma because glucagon products 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.. 5.2 Hypoglycemia in Patients with Insulinoma. In patients with insulinoma, administration of glucagon products may produce an initial increase in blood glucose; however, ZEGALOGUE administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. ZEGALOGUE is contraindicated in patients with insulinoma [see Contraindications (4)]. If patient develops symptoms of hypoglycemia after dose of ZEGALOGUE, give glucose orally or intravenously.. 5.3 Hypersensitivity and Allergic Reactions. Allergic reactions have been reported with glucagon products; these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions. 5.4 Lack of Efficacy in Patients with Decreased Hepatic Glycogen. ZEGALOGUE 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 ZEGALOGUE administration to be effective. Patients with these conditions should be treated with glucose.