nts 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.

tains 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.

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) ] .

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.

udy, 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.

oncentration achieved with the recommended therapeutic dose, zegalogue does not prolong the qt interval to any clinically relevant extent. 12.3 pharmacokinetics absorption zegalogue absorption following subcutaneous injection of 0.6 mg resulted in a mean peak plasma concentration of 5110 pg/ml (1510 pmol/l) at around 35 minutes. distribution the mean apparent volume of distribution was 47 l to 57 l following subcutaneous administration. elimination the half-life was approximately 30 minutes. metabolism metabolism data indicated that dasiglucagon is cleared like native glucagon through proteolytic degradation pathways in blood, liver, and kidney. specific populations after administration of zegalogue in pediatric patients with type 1 diabetes, the mean peak plasma concentration of 3920 pg/ml occurred at around 21 minutes.

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 c assessed plasma glucose at the same timepoints as did trials a 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: a 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 3 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: a 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 patients trial a trial b zegalogue n=82 placebo n=43 zegalogue n=34 placebo n=10 n is the number of patients who were randomized and treated. median time to recovery [95% ci log-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 3 time to plasma glucose recovery in trial a figure 3 14.2 pediatric patients trial c, nct03667053: pediatric patients aged 6 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). a total of 42 patients were randomized. the mean age was 12.5 years (range 7 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 4 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 patients trial c zegalogue n=20 placebo n=11 n is the number of patients who were randomized and treated. median time to recovery [95% ci log-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

r 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).

iciency. have low blood sugar that does not go away (chronic hypoglycemia). are pregnant or plan to become pregnant. are 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 i use zegalogue? read the detailed instructions for use that come with zegalogue. use zegalogue exactly how your healthcare provider tells you to use it. make sure your caregiver knows where you keep your zegalogue and how to use zegalogue the right way before you need it. your caregiver must act quickly. having very low blood sugar for a period of time may be harmful. your healthcare provider will tell you how and when to use zegalogue. after giving zegalogue, your caregiver should call for emergency medical help right away. once you are able to safely consume food or drink, your caregiver should give you a fast-acting source of sugar (such as fruit juice) and a long-acting source of sugar (such as crackers with cheese or peanut butter). if you do not respond to treatment after 15 minutes, your caregiver may give you another dose, if available. tell 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 zegalogue? zegalogue may cause serious side effects, including: high blood pressure . zegalogue can cause high blood pressure in certain people with tumors in their adrenal glands. low blood sugar . zegalogue can cause certain people with tumors in their pancreas called insulinomas to have low blood sugar. serious allergic reaction . call your healthcare provider or get medical help right away if you have a serious allergic reaction including: rash, difficulty breathing, or low blood pressure (hypotension). the most common side effects of zegalogue include: adults nausea vomiting headache diarrhea injection site pain children nausea vomiting headache injection site pain these 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 i store zegalogue? store zegalogue in a refrigerator between 36°f to 46°f (2°c to 8°c). do not freeze zegalogue. zegalogue can also be stored at room temperature between 68°f to 77°f (20°c to 25°c) for up to 12 months. see example in the instructions for use for how to keep track of this 12-month period. do not return zegalogue to the refrigerator after storing at room temperature. throw away zegalogue if it has been stored at room temperature for more than 12 months. replace zegalogue before the expiration date printed on the red protective case. store 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 a patient information leaflet. do not use zegalogue for a 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 zegalogue? active ingredient: dasiglucagon, provided as dasiglucagon hydrochloride inactive ingredients: tromethamine, sodium chloride and water for injection. hydrochloric acid and/or sodium hydroxide may be added to adjust ph manufactured for: zealand pharma a/s, 2860 søborg, denmark by rechon lifescience ab, malmö, sweden for more information go to www.zegalogue.com or call 1-877-501-9342 .