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.

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 )

5 WARNINGS AND PRECAUTIONS • Substantial 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 ) • Hypoglycemia 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 a patient develops symptoms of hypoglycemia after a dose of ZEGALOGUE, give glucose orally or intravenously. ( 4 , 5.2 ) • Hypersensitivity 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 ) • 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 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 a substantial increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure. 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 a patient develops symptoms of hypoglycemia after a 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.

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 )

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) ] .

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.