Glucagon

BAQSIMI™ is indicated for the treatment of severe hypoglycemia in adults and pediatric patients aged 1 year and older with diabetes. BAQSIMI ® is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in adults and pediatric patients aged 1 year and older with diabetes. ( 1 )

Nasal Powder: 3 mg glucagon: as a white powder in an intranasal device containing one dose of glucagon Nasal powder: intranasal device containing one dose of glucagon 3 mg ( 3 )

BAQSIMI 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 )] Prior hypersensitivity reaction to glucagon or to any of the excipients in BAQSIMI. Allergic reactions have been reported with glucagon and include anaphylactic shock with breathing difficulties and hypotension [see Warnings and Precautions ( 5.3 )] Pheochromocytoma ( 4 ) Insulinoma ( 4 ) Known hypersensitivity to glucagon or to any of the excipients ( 4 )

Substantial Increase in Blood Pressure in Patients with Pheochromocytoma : Contraindicated in patients with pheochromocytoma because BAQSIMI may stimulate the release of catecholamines from the tumor. ( 5.1 ) Hypoglycemia in Patients with Insulinoma : In patients with insulinoma, administration may produce an initial increase in blood glucose; however, BAQSIMI may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops symptoms of hypoglycemia after a dose of BAQSIMI, give glucose orally or intravenously. ( 5.2 ) Serious Hypersensitivity Reactions : Serious hypersensitivity reactions have been reported and 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 : BAQSIMI 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 BAQSIMI 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 BAQSIMI is contraindicated in patients with pheochromocytoma because glucagon may stimulate 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 may produce an initial increase in blood glucose; however, BAQSIMI administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. BAQSIMI is contraindicated in patients with insulinoma [see Contraindications ( 4 )]. If a patient develops symptoms of hypoglycemia after a dose of BAQSIMI, give glucose orally or intravenously.

5.3 Serious Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. Discontinue BAQSIMI if symptoms of serious hypersensitivity reactions occur. Advise patients and/or caregivers to seek immediate medical attention if the patient experiences any symptoms of serious hypersensitivity reactions. BAQSIMI is contraindicated in patients with a prior hypersensitivity reaction [see Contraindications ( 4 )].

5.4 Lack of Efficacy in Patients with Decreased Hepatic Glycogen Patients with insufficient hepatic stores of glycogen may not respond to BAQSIMI for the treatment of severe hypoglycemia [see Clinical Pharmacology ( 12.2 )]. Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation or in patients with adrenal insufficiency or chronic hypoglycemia.

The following clinically significant adverse reactions are described elsewhere in labeling: Substantial Increase in Blood Pressure in Patients with Pheochromocytoma [see Warnings and Precautions ( 5.1 )] . Hypoglycemia in Patients with Insulinoma [see Warnings and Precautions ( 5.2 )] . Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] . Lack of Efficacy in Patients with Decreased Hepatic Glycogen [see Warnings and Precautions ( 5.4 )] . Most common (≥10%) adverse reactions associated with BAQSIMI are nausea, vomiting, headache, upper respiratory tract irritation (i.e., rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis), watery eyes, redness of eyes, itchy nose, throat and eyes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 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 BAQSIMI cannot be directly compared with rates in clinical trials of other drugs and may not reflect the rates observed in practice. Adverse Reactions in Adult Patients Two similarly designed comparator-controlled trials, Study 1 and Study 2, evaluated the safety of a single intranasal dose of BAQSIMI compared to a 1 mg dose of intra-muscular glucagon (IMG) in adult patients with diabetes [see Clinical Studies ( 14.1 )]. Table 1 presents adverse reactions that occurred with BAQSIMI at an incidence of ≥2% in a pool of Study 1 and Study 2. Table 1: Pooled Adverse Reactions (≥2%) in Adult Patients with Type 1 and Type 2 Diabetes in Study 1and Study 2 a Upper Respiratory Tract Irritation: rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis. Adverse Reaction BAQSIMI 3 mg (N=153) % Nausea 26 Headache 18 Vomiting 15 Upper Respiratory Tract Irritation a 12 Nasal and ocular symptoms with BAQSIMI were solicited through a patient questionnaire in Study 1 and 2 and these adverse reactions are presented in Table 2 . Table 2: Solicited Nasal and Non-Nasal Adverse Reactions in Adult Patients with Type 1 and Type 2 Diabetes Pooled from Study 1 and 2 a Patients were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration. Adverse Reaction a BAQSIMI 3 mg (n=153) % Any increase in symptom severity a Watery eyes 59 Nasal congestion 43 Nasal itching 39 Runny nose 35 Redness of eyes 25 Itchy eyes 22 Sneezing 20 Itching of throat 12 Itching of ears 3 Adverse Reactions in Pediatric Patients Aged 1 Year and Above A single dose of BAQSIMI was compared to weight-based doses of 0.5 mg or 1 mg of IMG in pediatric patients aged 4 to less than 17 years with type 1 diabetes in Study 3 [see Clinical Studies ( 14.2 )]. Table 3 presents adverse reactions that occurred with BAQSIMI in pediatric patients at an incidence of ≥2% in Study 3. Table 3: Adverse Reactions (≥2%) Occurring in Pediatric Patients Aged 4 to less than 17 Years with Type 1 Diabetes in Study 3 a Upper Respiratory Tract Irritation: nasal discomfort, nasal congestion, sneezing. Adverse Reaction BAQSIMI 3 mg (n=36) % Vomiting 31 Headache 25 Nausea 17 Upper Respiratory Tract Irritation a 17 Nasal and ocular symptoms with BAQSIMI were solicited through a patient questionnaire in pediatric patients in Study 3 and these adverse reactions are presented in Table 4 . Table 4: Solicited Nasal and Non-Nasal Adverse Reactions in Pediatric Patients Aged 4 to less than 17 Years with Type 1 Diabetes in Study 3 a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration. Adverse Reaction a BAQSIMI 3 mg (n=36) % Any increase in symptom severity a Watery eyes 47 Nasal congestion 42 Nasal itching 28 Runny nose 25 Sneezing 19 Itchy eyes 17 Redness of eyes 14 Itching of throat 3 Itching of ears 3 The safety of a single 3 mg intranasal dose of BAQSIMI was assessed in an open-label study of 7 pediatric patients aged 1 to less than 4 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] . The safety profile observed in this trial in pediatric patients was comparable to that observed in adults and pediatric patients aged 4 to less than 17 years [see Clinical Pharmacology ( 12.2 , 12.3 )] . Other Adverse Reactions in Adult and Pediatric Patients Other observed adverse reactions with BAQSIMI-treated patients across clinical trials were, dysgeusia, pruritus, tachycardia, hypertension, and additional upper respiratory tract irritation events (nasal pruritus, throat irritation, and parosmia).

Beta-blockers : Patients taking beta-blockers may have a transient increase in pulse and blood pressure. ( 7.1 ) Indomethacin : In patients taking indomethacin BAQSIMI may lose its ability to raise glucose or may produce hypoglycemia. ( 7.2 ) Warfarin : BAQSIMI may increase the anticoagulant effect of warfarin. ( 7.3 )

7.1 Beta-blockers Patients taking beta-blockers may have a transient increase in pulse and blood pressure when given BAQSIMI.

7.2 Indomethacin In patients taking indomethacin, BAQSIMI may lose its ability to raise blood glucose or may even produce hypoglycemia.

7.3 Warfarin BAQSIMI may increase the anticoagulant effect of warfarin.

8.1 Pregnancy Risk Summary Available data from case reports and a small number of observational studies with glucagon use in pregnant women over decades of use have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated a lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In a rat reproduction study, no embryofetal toxicity was observed with glucagon administered by injection during the period of organogenesis at doses representing up to 40 times the human dose, based on body surface area (mg/m 2 ) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In pregnant rats given animal sourced glucagon twice-daily by injection at doses up to 2 mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m 2 ) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality.

8.2 Lactation Risk Summary There is no information available on the presence of glucagon in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, glucagon 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 BAQSIMI for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged 1 year and older. Use of BAQSIMI for this indication is supported by evidence from an adequate and well-controlled study in adults with type 1 diabetes mellitus [see Clinical Studies ( 14.1 )] , a study in 48 pediatric patients aged 4 to less than 17 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] , and additional pharmacokinetic and safety data from a study of seven pediatric patients aged 1 to less than 4 years with type 1 diabetes mellitus [see Adverse Reactions ( 6.1 ),Clinical Pharmacology ( 12.2 , 12.3 ), and Clinical Studies ( 14.2 )] . The safety and effectiveness of BAQSIMI have not been established in pediatric patients younger than 1 year of age.

8.5 Geriatric Use Clinical studies of BAQSIMI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult patients.

Glucagon increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect.