Zegalogue

1 INDICATIONS AND USAGE ZEGALOGUE ® is indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and above. ZEGALOGUE is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and above. ( 1 )

2 DOSAGE AND ADMINISTRATION • ZEGALOGUE autoinjector and prefilled syringe are for subcutaneous injection only. ( 2.1 ) • The dose in adults and pediatric patients aged 6 years and older is 0.6 mg. ( 2.2 ) • Administer ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use. ( 2.1 ) • Visually 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 ) • Administer the injection into the lower abdomen, buttocks, thigh, or outer upper arm. ( 2.1 ) • Call for emergency assistance immediately after administering the dose. ( 2.1 ) • If there has been no response after 15 minutes, an additional dose of ZEGALOGUE from a new device may be administered while waiting for emergency assistance. ( 2.1 ) • When the patient has responded to treatment, give oral carbohydrates. ( 2.1 ) • Do not attempt to reuse ZEGALOGUE. Each device contains a 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 a prescription for ZEGALOGUE. Emphasize the following instructions to the patient or caregiver: • Administer ZEGALOGUE according to the printed instructions on the protective case label and the Instructions For Use. • Visually 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. • Administer the injection in the lower abdomen, buttocks, thigh, or outer upper arm. • Call for emergency assistance immediately after administering the dose. • If there has been no response after 15 minutes, an additional dose of ZEGALOGUE may be administered while waiting for emergency assistance. • When the patient has responded to treatment, give oral carbohydrates to restore liver glycogen and prevent recurrence of hypoglycemia. • Do not attempt to reuse ZEGALOGUE. Each ZEGALOGUE device contains a single dose of dasiglucagon and cannot be reused. 2.2 Recommended Dosage The recommended dose of ZEGALOGUE in adults and pediatric patients aged 6 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 a new device may be administered.

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

4 CONTRAINDICATIONS ZEGALOGUE is contraindicated in patients with: • Pheochromocytoma because of the risk of substantial increase in blood pressure [see Warnings and Precautions (5.1) ] • Insulinoma because of the risk of hypoglycemia [see Warnings and Precautions (5.2) ] Pheochromocytoma ( 4 ) Insulinoma ( 4 )

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: • Hypersensitivity 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 pain Pediatrics: 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 1 diabetes and 20 pediatric patients with type 1 diabetes were exposed to ZEGALOGUE. The data in Table 1 reflect exposure of 116 adult patients to ZEGALOGUE in 2 placebo-controlled trials (mean age 40 years). Table 2 reflects exposure of 20 pediatric patients exposed to ZEGALOGUE in a placebo-controlled trial. Eight patients were 7 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 2 Placebo-Controlled Trials Adverse reaction type Placebo (N=53) Dasiglucagon (N=116) % of Patients % of Patients Nausea 4% 57% Vomiting 2% 25% Headache 4% 11% Diarrhea 0% 5% Injection site pain 0% 2% Table 2. Adverse Reactions Occurring ≥2% and More Frequently than with Placebo in ZEGALOGUE-treated Pediatric Patients within 12 hours of Treatment in a Placebo-Controlled Trial Adverse reaction type Placebo (N=11) Dasiglucagon Age 6-11 years (N=8) Dasiglucagon Age 12-17 years (N=12) Dasiglucagon All (N=20) % of Patients % of Patients % of Patients % of Patients Nausea 0% 25% 92% 65% Vomiting 0% 25% 67% 50% Headache 0% 0% 17% 10% Injection site pain 0% 0% 8% 5% Other Adverse Reactions Other 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 a 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 a 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) ] .

7 DRUG INTERACTIONS Table 3. Clinically Significant Drug Interactions with ZEGALOGUE Beta-Blockers Clinical Impact: Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given ZEGALOGUE. Indomethacin Clinical Impact: In patients taking indomethacin, ZEGALOGUE may lose its ability to raise blood glucose or may even produce hypoglycemia. Warfarin Clinical Impact: ZEGALOGUE may increase the anticoagulant effect of warfarin. • Beta-blockers: Patients taking beta-blockers may have a transient increase in pulse and blood pressure. ( 7 ) • Indomethacin: In patients taking indomethacin, ZEGALOGUE may lose its ability to raise blood glucose or may produce hypoglycemia. ( 7 ) • Warfarin: ZEGALOGUE may increase the anticoagulant effect of warfarin. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on dasiglucagon use in pregnant women to evaluate for a 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 7 and 709 times the human dose of 0.6 mg based on AUC, respectively (see Data ) . Data Animal Data In 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 6 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 1 mg/kg/day during the period of organogenesis (gestation day 6 to 19). Lower fetal body weight and delayed bone ossification were observed at 1 mg/kg/day (100 times the human dose, based on AUC), a 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 7 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 a peptide and would be expected to be broken down to its constituent amino acids in the infant's digestive tract and is therefore unlikely to cause harm to an exposed infant. 8.4 Pediatric Use The safety and effectiveness of ZEGALOGUE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged 6 years and above. Use of ZEGALOGUE for this indication is supported by evidence from a study in 42 pediatric patients with type 1 diabetes [see Clinical Studies (14.2) ] . The safety and effectiveness of ZEGALOGUE have not been established in pediatric patients younger than 6 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.

12.1 Mechanism of Action Dasiglucagon is a 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.

11 DESCRIPTION ZEGALOGUE contains dasiglucagon hydrochloride, which is a glucagon analog and an antihypoglycemic agent. Dasiglucagon is comprised of 29 amino acids. The molecular formula of dasiglucagon (anhydrous, free-base) is C 152 H 222 N 38 O 50 , and its molecular mass is 3382 g/mol (anhydrous, free-base). Dasiglucagon hydrochloride has the following chemical structure: ZEGALOGUE injection is a preservative free, sterile, aqueous, clear, and colorless solution for subcutaneous use in a single-dose prefilled syringe and an autoinjector. Each prefilled syringe and autoinjector contains 0.63 mg of dasiglucagon provided as dasiglucagon hydrochloride, which is a salt with 3 - 5 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

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 a 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 patient's clinical signs and symptoms.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZEGALOGUE injection is a clear, colorless solution supplied as follows: Presentation Strength Package Size NDC Single-dose autoinjector 0.6 mg/0.6 mL 1 0169-1912-01 Single-dose autoinjector 0.6 mg/0.6 mL 2 0169-1912-02 Single-dose prefilled syringe 0.6 mg/0.6 mL 1 0169-1913-01 Single-dose prefilled syringe 0.6 mg/0.6 mL 2 0169-1913-02 16.2 Recommended Storage Store ZEGALOGUE in a refrigerator, 2°C to 8°C (36°F to 46°F). Keep away from the cooling element. Do not freeze. ZEGALOGUE can be kept at room temperature between 20°C to 25°C (68°F to 77°F) 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).