ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below and elsewhere in labeling:Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)].. Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)].. 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 Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Data. 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 PatientsTwo similarly designed comparator-controlled trials, Study and Study 2, evaluated the safety of single dose of BAQSIMI compared to 1 mg dose of intra-muscular glucagon (IMG) in adult patients with diabetes [see Clinical Studies (14)]. Table presents adverse reactions that occurred with BAQSIMI at an incidence of >=2% in pool of Study and Study 2.Table 1: Pooled Adverse Reactions (>=2%) in Adult Patients with Type and Type Diabetes in Study and Study 2a Upper Respiratory Tract Irritation: rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis.Adverse ReactionBAQSIMI mg(N=153)%Nausea26.1Headache18.3Vomiting15.0Upper Respiratory Tract Irritationa 12.4Nasal and ocular symptoms with BAQSIMI were solicited through patient questionnaire in Study and and these adverse reactions are presented in Table 2.Table 2: Solicited Nasal and Non-Nasal Adverse Reactions in Adult Patients with Type and Type Diabetes Pooled from Study and 2a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration.Adverse ReactionaBAQSIMI mg(n=153)%Any increase in symptom severityaWatery eyes58.8Nasal congestion42.5Nasal itching39.2Runny nose34.6Redness of eyes24.8Itchy eyes21.6Sneezing19.6Itching of throat12.4Itching of ears3.3. Adverse Reactions in Pediatric Patients Aged Years and AboveA single dose of BAQSIMI was compared to weight-based doses of 0.5 mg or mg of IMG in pediatric patients with type diabetes in Study [see Clinical Studies (14)]. Table 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 with Type Diabetes in Study 3a Upper Respiratory Tract Irritation: nasal discomfort, nasal congestion, sneezing.Adverse ReactionBAQSIMI mg(n=36)%Vomiting30.6Headache25.0Nausea16.7Upper Respiratory Tract Irritationa 16.7Nasal and ocular symptoms with BAQSIMI were solicited through patient questionnaire in pediatric patients in Study and these adverse reactions are presented in Table 4.Table 4: Solicited Nasal and Non-Nasal Adverse Reactions in Pediatric Patients with Type Diabetes in Study 3a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration.Adverse ReactionaBAQSIMI mg(n=36)%Any increase in symptom severityaWatery eyes47.2Nasal congestion41.7Nasal itching27.8Runny nose25.0Sneezing19.4Itchy eyes16.7Redness of eyes13.9Itching of throat2.8Itching of ears2.8. Other Adverse Reactions in Adult and Pediatric PatientsOther 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).. 6.2 Immunogenicity. As with all therapeutic peptides, there is the potential for immunogenicity. 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 incidence of antibodies to BAQSIMI with the incidences of antibodies to other products may be misleading.In clinical trials, 3/124 (2%) of BAQSIMI-treated patients had treatment-emergent anti-drug antibodies as detected by an affinity capture elution (ACE) ligand-binding immunogenicity assay. No neutralizing antibodies were detected.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long term studies in animals to evaluate carcinogenic potential have not been performed. Recombinant glucagon was positive in the bacterial Ames assay. It was determined that an increase in colony counts was related to technical difficulties in running this assay with peptides. Studies in rats have shown that glucagon does not cause impaired fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. 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.. 12.2 Pharmacodynamics. After administration of BAQSIMI in adult patients with diabetes, the mean maximum glucose increase from baseline was 140 mg/dL (Figure 1).In pediatric patients with type diabetes (4 to <17 years), the mean maximum glucose increase from baseline was 138 mg/dL (4 to <8 years), 133 mg/dL (8 to <12 years), and 102 mg/dL (12 to <17 years) (Figure 2).Sex and body weight had no clinically meaningful effects on the pharmacodynamics of BAQSIMI.Common cold with nasal congestion tested with or without use of decongestant did not impact pharmacodynamics of BAQSIMI.Figure Mean glucose concentration over time after glucagon dose in adult Type Diabetes patients with insulin-induced hypoglycemia.Figure Mean glucose concentration over time in pediatric Type Diabetes patients administered BAQSIMI. Figure. Figure. 12.3 Pharmacokinetics. AbsorptionGlucagon absorption via the intranasal route, achieved mean peak plasma levels of 6130 pg/mL at around 15 minutes.. DistributionThe apparent volume of distribution was approximately 885 L.. EliminationThe median half-life was approximately 35 minutes.. MetabolismGlucagon is known to be degraded in the liver, kidneys, and plasma.. Specific Populations. PediatricsIn pediatric patients (4 to <17 years), glucagon via the intranasal route, achieved mean peak plasma levels between 15 and 20 minutes. The median half-life was 21 to 31 minutes.. Patients with ColdsCommon cold with nasal congestion did not impact the pharmacokinetics of BAQSIMI.. Drug Interaction StudiesCommon cold with use of decongestant did not impact the pharmacokinetics of BAQSIMI.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Patients. Study (NCT03339453) was randomized, multicenter, open-label, 2-period, crossover study in adult patients with type diabetes. The efficacy of single mg dose of BAQSIMI was compared to 1 mg dose of intra-muscular glucagon (IMG). Insulin was used to reduce blood glucose levels to <60 mg/dL. Seventy patients were enrolled, with mean age of 41.7 years and mean diabetes duration of 20.1 years. Twenty-seven (39%) were female.The primary efficacy outcome measure was the proportion of patients achieving treatment success, which was defined as either an increase in blood glucose to >=70 mg/dL or an increase of >=20 mg/dL from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase the blood glucose level. Glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes, following glucagon administration.The mean nadir blood glucose was 54.5 mg/dL for BAQSIMI and 55.8 mg/dL for IMG. BAQSIMI demonstrated non-inferiority to IMG in reversing insulin-induced hypoglycemia with 100% of BAQSIMI-treated patients and 100% of IMG-treated patients achieving treatment success. The mean time to treatment success was 11.6 and 9.9 minutes in the BAQSIMI and IMG mg treatment groups, respectively.Table 5: Adult Patients with Type Diabetes Meeting Treatment Success and Other Glucose Criteria in Study 1a The Efficacy Analysis Population consisted of all patients who received both doses of the Study Drug with evaluable primary outcome.b Difference calculated as (percentage with success in BAQSIMI) (percentage with success in IMG).c 2-sided 95% confidence interval (CI) of paired differences using Wald-Min correction; non-inferiority margin -10%.Type Diabetes(N=66)aBAQSIMI mgIMG1 mgTreatment Success n (%)66 (100%)66 (100%)Treatment Difference (2-sided 95% confidence limit)b, c0% (-2.9%, 2.9%)Glucose criterion met n (%) (i) >=70 mg/dL (ii) Increase by >=20 mg/dL from nadir Both (i) and (ii)66 (100%)66 (100%)66 (100%)66 (100%)66 (100%)66 (100%)Study (NCT01994746) was randomized, multicenter, open-label, 2-period, crossover study in adult patients with type diabetes or type diabetes. The efficacy of single mg dose of BAQSIMI was compared to 1 mg dose of intra-muscular glucagon (IMG). Insulin was used to reduce blood glucose levels to the hypoglycemic range with target blood glucose nadir of <50 mg/dL.Study enrolled 83 patients 18 to <65 years of age. The mean age of patients with type diabetes (N=77) was 32.9 years and mean diabetes duration of 18.1 years, and 45 (58%) patients were female. The mean age of patients with type diabetes (N=6) was 47.8 years, with mean diabetes duration of 18.8 years, and (67%) patients were female.The mean nadir blood glucose was 44.2 mg/dL for BAQSIMI and 47.2 mg/dL for IMG. BAQSIMI demonstrated non-inferiority to IMG in reversing insulin-induced hypoglycemia with 98.8% of BAQSIMI-treated patients and 100% of IMG-treated patients achieving treatment success within 30 minutes.The mean time to treatment success was 15.9 and 12.1 minutes in the BAQSIMI and IMG mg treatment groups, respectively.Table 6: Adult Patients with Type and Type Diabetes Meeting Treatment Success and Other Glucose Criteria in Study 2a The Efficacy Analysis Population consisted of all patients who received both doses of the Study Drug with evaluable primary outcome.b Difference calculated as (percentage with success in BAQSIMI) (percentage with success in IMG).c 2-sided 95% confidence interval (CI) of paired differences using Wald-Min correction; non-inferiority margin -10%.d Percentage based on number of patients.Type and Type Diabetes (N=80)aBAQSIMI3 mgIMG1 mgTreatment Success n (%)79 (98.8%)80 (100%)Treatment Difference (2-sided 95% confidence limit)b,c-1.3% (-4.6%, 2.2%)Glucose criterion met n (%)d (i) >=70 mg/dL77 (96%)79 (99%) (ii) Increase by >=20 mg/dL from nadir79 (99%)80 (100%) Both (i) and (ii)77 (96%)79 (99%). 14.2 Pediatric Patients. Study (NCT01997411) was randomized, multicenter, clinical study that assessed BAQSIMI compared to intra-muscular glucagon (IMG) in pediatric patients aged years and older with type diabetes. Insulin was used to reduce blood glucose levels, and glucagon was administered after glucose reached <80 mg/dL. Efficacy was assessed based on percentage of patients with glucose increase of >=20 mg/dL from glucose nadir within 30 minutes following BAQSIMI administration.Forty-eight patients were enrolled and received at least one dose of study drug. The mean age in the Young Children cohort (4 to <8 years) was 6.5 years. In the Children cohort (8 to <12 years), mean age was 11.1 years and in the Adolescents cohort (12 to <17 years) mean age was 14.6 years. In all age cohorts, the population was predominantly male and white.Across all age groups, all (100%) patients in both treatment arms achieved an increase in glucose >=20 mg/dL from glucose nadir within 20 minutes of glucagon administration. The mean time to reach glucose increase of >=20 mg/dL for BAQSIMI and IMG for all age groups is shown in Table 7.Table 7: Mean Time to Reach Glucose Increase of >=20 mg/dL from Nadir in Pediatric Patients with Type Diabetes in Study 3Increase from NadirMean Time Post-Glucagon Administration (minutes)Young Children(4 to <8 years old)Children(8 to <12 years old)Adolescents(12 to <17 years old)IMGaN=6BAQSIMI3 mgN=12IMGaN=6BAQSIMI3 mgN=12IMGaN=12BAQSIMI3 mgN=12a 0.5 mg or mg of IMG (based upon body weight)>=20 mg/dL10.810.812.511.312.514.2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 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)] Known hypersensitivity 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 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)] Known hypersensitivity 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). Pheochromocytoma (4). Insulinoma (4). Known hypersensitivity to glucagon or to any of the excipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. BAQSIMI contains glucagon, an antihypoglycemic agent used to treat severe hypoglycemia. Glucagon is single-chain polypeptide containing 29 amino acid residues and has molecular weight of 3483, and is identical to human glucagon.Its molecular formula is C153H225N43O49S, with the following molecular structure:BAQSIMI is preservative-free, white powder for intranasal administration in an intranasal device containing one dose of mg glucagon. BAQSIMI contains glucagon as the active ingredient and betadex, and dodecylphosphocholine as the excipients.. Molecular Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. BAQSIMI is for intranasal use only. (2.1)The recommended dose of BAQSIMI is mg administered as one actuation of the intranasal device into one nostril. (2.2)Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use. (2.1)Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled. (2.1)Call for emergency assistance immediately after administering the dose. (2.1)When the patient responds to treatment, give oral carbohydrates. (2.1)Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused. (2.1)If there has been no response after 15 minutes, an additional mg dose may be administered while waiting for emergency assistance. (2.2). BAQSIMI is for intranasal use only. (2.1). The recommended dose of BAQSIMI is mg administered as one actuation of the intranasal device into one nostril. (2.2). Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use. (2.1). Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled. (2.1). Call for emergency assistance immediately after administering the dose. (2.1). When the patient responds to treatment, give oral carbohydrates. (2.1). Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused. (2.1). If there has been no response after 15 minutes, an additional mg dose may be administered while waiting for emergency assistance. (2.2). 2.1 Important Administration Instructions. BAQSIMI is for intranasal use only.Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires help of others to recover, instruct the patient to inform those around them about BAQSIMI and its Instructions for Use. Administer BAQSIMI 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 BAQSIMI. Emphasize the following instructions to the patient or caregiver:Do not push the plunger or test the device prior to administration.Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use.Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled.Call for emergency assistance immediately after administering the dose.When the patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused.. Do not push the plunger or test the device prior to administration.. Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use.. Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled.. Call for emergency assistance immediately after administering the dose.. When the patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.. Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused.. 2.2 Dosage in Adults and Pediatric Patients Aged Years and Above. The recommended dose of BAQSIMI is mg administered as one actuation of the intranasal device into one nostril.If there has been no response after 15 minutes, an additional mg dose of BAQSIMI from new device may be administered while waiting for emergency assistance.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Nasal Powder:3 mg glucagon: as white powder in an intranasal device containing one dose of glucagon. mg glucagon: as white powder in an intranasal device containing one dose of glucagon. Nasal powder: intranasal device containing one dose of glucagon mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Beta-blockers: Patients taking beta-blockers may have 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). Beta-blockers: Patients taking beta-blockers may have 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 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.

GERIATRIC USE SECTION.

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 subjects. Limited clinical trial experience has not identified differences in responses between the elderly and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. BAQSIMI is supplied as an intranasal device containing one mg dose of glucagon as preservative free, white powder.BAQSIMI One Pack(TM) carton contains intranasal device (NDC 0002-6145-11)BAQSIMI Two Pack(TM) carton contains intranasal devices (NDC 0002-6145-27)Store at temperatures up to 86F (30C) in the shrink wrapped tube provided.Keep BAQSIMI in the shrink wrapped tube until ready to use. If the tube has been opened, BAQSIMI may have been exposed to moisture and may not work as expected.Discard BAQSIMI and tube after use.. BAQSIMI One Pack(TM) carton contains intranasal device (NDC 0002-6145-11). BAQSIMI Two Pack(TM) carton contains intranasal devices (NDC 0002-6145-27). Store at temperatures up to 86F (30C) in the shrink wrapped tube provided.. Keep BAQSIMI in the shrink wrapped tube until ready to use. If the tube has been opened, BAQSIMI may have been exposed to moisture and may not work as expected.. Discard BAQSIMI and tube after use.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BAQSIMI(TM) is indicated for the treatment of severe hypoglycemia in adult and pediatric patients with diabetes ages years and above.. BAQSIMI(TM) is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in adult and pediatric patients with diabetes ages 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 Hypoglycemia:Inform patient and family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia.. Administration:Review the Patient Information and Instructions for Use with the patient and family members or caregivers.. Serious Hypersensitivity:Inform patients that allergic reactions can occur with BAQSIMI. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.3)].Literature revised: October 2020Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 2019, 2020, Eli Lilly and Company. All rights reserved.BAQ-0002-USPI-20201027.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEBAQSIMI(TM)(glucagon) nasal powder3 mgRead the Instructions for Use for BAQSIMI before using it. BAQSIMI is used to treat very low blood sugar (severe hypoglycemia) that may cause you to need help from others. You should make sure you show your caregivers, family and friends where you keep BAQSIMI and explain how to use it by sharing these instructions. They need to know how to use BAQSIMI before an emergency happens. Tube and Device PartsImportant Information to KnowDo not remove the Shrink Wrap or open the Tube until you are ready to use it.If the Tube has been opened, BAQSIMI could be exposed to moisture. This could cause BAQSIMI not to work as expected. Do not push the plunger or test BAQSIMI before you are ready to use it.BAQSIMI contains dose of glucagon nasal powder and cannot be reused.BAQSIMI is for nasal (nose) use only.BAQSIMI will work even if you have cold or are taking cold medicine.Preparing the DoseRemove the Shrink Wrap by pulling on red stripe.Open the Lid and remove the Device from the Tube. Caution: Do not press the Plunger until ready to give the dose. Giving the DoseHold Device between fingers and thumb.Do not push Plunger yet.Insert Tip gently into one nostril until finger(s) touch the outside of the nose.Push Plunger firmly all the way in.Dose is complete when the Green Line disappears.After giving BAQSIMICall for emergency medical help right away.If the person is unconscious turn the person on their side.Throw away the used Device and Tube.Encourage the person to eat as soon as possible. When they are able to safely swallow, give the person fast acting source of sugar, such as juice. Then encourage the person to eat snack, such as crackers with cheese or peanut butter.If the person does not respond after 15 minutes, another dose may be given, if available.Storage and HandlingDo not remove the Shrink Wrap or open the Tube until you are ready to use it.Store BAQSIMI in the shrink wrapped Tube at temperatures up to 86o (30oC ).Replace BAQSIMI before the expiration date printed on the Tube or carton.Other InformationCaution: Replace the used BAQSIMI right away so you will have new BAQSIMI in case you need it.Keep BAQSIMI and all medicines out of the reach of children.For Questions or More Information about BAQSIMICall your healthcare providerCall Lilly at 1-800-Lilly-Rx (1-800-545-5979)Visit www.baqsimi.comBAQSIMI is trademark of Eli Lilly and Company.Marketed by: Lilly USA, LLCIndianapolis, IN 46285, USACopyright (C) 2019, Eli Lilly and Company. All rights reserved.BAQSIMI Device meets all applicable requirements defined in ISO 20072This Instructions for Use has been approved by the U.S. Food and Drug AdminstrationIssued: July 2019BAQ-0001-IFU-20190724. Do not remove the Shrink Wrap or open the Tube until you are ready to use it.. If the Tube has been opened, BAQSIMI could be exposed to moisture. This could cause BAQSIMI not to work as expected. Do not push the plunger or test BAQSIMI before you are ready to use it.. BAQSIMI contains dose of glucagon nasal powder and cannot be reused.. BAQSIMI is for nasal (nose) use only.. BAQSIMI will work even if you have cold or are taking cold medicine.. Remove the Shrink Wrap by pulling on red stripe.. Open the Lid and remove the Device from the Tube. Caution: Do not press the Plunger until ready to give the dose. Hold Device between fingers and thumb.. Do not push Plunger yet.. Insert Tip gently into one nostril until finger(s) touch the outside of the nose.. Push Plunger firmly all the way in.. Dose is complete when the Green Line disappears.. Call for emergency medical help right away.. If the person is unconscious turn the person on their side.. Throw away the used Device and Tube.. Encourage the person to eat as soon as possible. When they are able to safely swallow, give the person fast acting source of sugar, such as juice. Then encourage the person to eat snack, such as crackers with cheese or peanut butter.. If the person does not respond after 15 minutes, another dose may be given, if available.. Do not remove the Shrink Wrap or open the Tube until you are ready to use it.. Store BAQSIMI in the shrink wrapped Tube at temperatures up to 86o (30oC ).. Replace BAQSIMI before the expiration date printed on the Tube or carton.. Caution: Replace the used BAQSIMI right away so you will have new BAQSIMI in case you need it.. Keep BAQSIMI and all medicines out of the reach of children.. Call your healthcare provider. Call Lilly at 1-800-Lilly-Rx (1-800-545-5979). Visit www.baqsimi.com. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 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. 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long term studies in animals to evaluate carcinogenic potential have not been performed. Recombinant glucagon was positive in the bacterial Ames assay. It was determined that an increase in colony counts was related to technical difficulties in running this assay with peptides. Studies in rats have shown that glucagon does not cause impaired fertility.

OVERDOSAGE SECTION.

10 OVERDOSAGE. If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure and pulse rate. In case of suspected overdosing, serum potassium levels may decrease and should be monitored and corrected if needed. If the patient develops dramatic 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL Baqsimi mg Nasal Powder Two Pack. NDC 0002-6145-27baqsimiTM (glucagon) nasal powder3 mgFor Treatment of Severe Low Blood SugarFor Nasal Use OnlyContains nasal devices.Keep tubes sealed until ready to use.Rx onlyBAQSIMI Two PackTM www.baqsimi.comLilly. PACKAGE LABEL Baqsimi mg Nasal Powder Two Pack.

PEDIATRIC USE SECTION.

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 ages years and above. Use of BAQSIMI for this indication is supported by evidence from study in 48 pediatric patients from to <17 years of age with type diabetes mellitus. [see Clinical Studies (14.2)].The safety and effectiveness of BAQSIMI have not been established in pediatric patients younger than years of age.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. After administration of BAQSIMI in adult patients with diabetes, the mean maximum glucose increase from baseline was 140 mg/dL (Figure 1).In pediatric patients with type diabetes (4 to <17 years), the mean maximum glucose increase from baseline was 138 mg/dL (4 to <8 years), 133 mg/dL (8 to <12 years), and 102 mg/dL (12 to <17 years) (Figure 2).Sex and body weight had no clinically meaningful effects on the pharmacodynamics of BAQSIMI.Common cold with nasal congestion tested with or without use of decongestant did not impact pharmacodynamics of BAQSIMI.Figure Mean glucose concentration over time after glucagon dose in adult Type Diabetes patients with insulin-induced hypoglycemia.Figure Mean glucose concentration over time in pediatric Type Diabetes patients administered BAQSIMI. Figure. Figure.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionGlucagon absorption via the intranasal route, achieved mean peak plasma levels of 6130 pg/mL at around 15 minutes.. DistributionThe apparent volume of distribution was approximately 885 L.. EliminationThe median half-life was approximately 35 minutes.. MetabolismGlucagon is known to be degraded in the liver, kidneys, and plasma.. Specific Populations. PediatricsIn pediatric patients (4 to <17 years), glucagon via the intranasal route, achieved mean peak plasma levels between 15 and 20 minutes. The median half-life was 21 to 31 minutes.. Patients with ColdsCommon cold with nasal congestion did not impact the pharmacokinetics of BAQSIMI.. Drug Interaction StudiesCommon cold with use of decongestant did not impact the pharmacokinetics of BAQSIMI.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from case reports and small number of observational studies with glucagon use in pregnant women over decades of use have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In 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/m2) (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 DataIn pregnant rats given animal sourced glucagon twice-daily by injection at doses up to mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m2) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: July 2019PATIENT INFORMATIONBAQSIMI(TM) (BAK-see-mee)(glucagon) nasal powderWhat is BAQSIMIBAQSIMI is prescription medicine used to treat very low blood sugar (severe hypoglycemia) in people with diabetes ages years and above.It is not known if BAQSIMI is safe and effective in children under years of age.Do not use BAQSIMI if you:have tumor in the gland on top of your kidneys (adrenal gland) called pheochromocytoma.have tumor in your pancreas called insulinoma.are allergic to glucagon, or any other ingredients in BAQSIMI. See the end of this Patient Information for complete list of ingredients in BAQSIMI.Before using BAQSIMI, tell your healthcare provider about all of your medical conditions, including if you:have tumor in your pancreas.have not had food or water for long time (prolonged fasting or starvation).are pregnant or plan to become pregnant.are breastfeeding or plan to breastfeed. It is not known if BAQSIMI passes into your breast milk. You and your healthcare provider should decide if you can use BAQSIMI 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 BAQSIMIRead the detailed Instructions for Use that comes with BAQSIMI.Use BAQSIMI exactly how your healthcare provider tells you to use it.Make sure your caregiver knows where you keep your BAQSIMI and how to use BAQSIMI the right way before you need their help.Your healthcare provider will tell you how and when to use BAQSIMI.BAQSIMI contains only dose of medicine and cannot be reused.BAQSIMI should be given in one side of your nose (nostril) but does not need to be inhaled.BAQSIMI will work even if you have cold or are taking cold medicine.After giving BAQSIMI, the caregiver should call for emergency medical help right away.If the person does not respond after 15 minutes, another dose may be given, if available.Tell your healthcare provider each time you use BAQSIMI.What are the possible side effects of BAQSIMIBAQSIMI may cause serious side effects, including:High blood pressure. BAQSIMI can cause high blood pressure in certain people with tumors in their adrenal glands.Low blood sugar. BAQSIMI can cause certain people with tumors in their pancreas to have low blood sugar.Serious allergic reaction. Call your healthcare provider or get medical help right away if you have serious allergic reaction including:rashdifficulty breathinglow blood pressureThe most common side effects of BAQSIMI include:nauseavomitingheadacherunny nosediscomfort in your nosestuffy noseredness in your eyesitchy nose, throat and eyeswatery eyesThese are not all the possible side effects of BAQSIMI. For more information, ask your healthcare provider.Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store BAQSIMIStore BAQSIMI at temperatures up to 86oF (30oC).Keep BAQSIMI in the shrink wrapped tube until you are ready to use it.Keep BAQSIMI and all medicines out of the reach of children.General Information about the safe and effective use of BAQSIMI.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BAQSIMI for condition for which it was not prescribed. Do not give BAQSIMI 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 BAQSIMI that is written for healthcare professionals.What are the ingredients in BAQSIMIActive Ingredient: glucagon Inactive Ingredients: betadex and dodecylphosphocholineMarketed by: Lilly USA, LLC, Indianapolis, IN 46285, USAwww.baqsimi.comCopyright (C) 2019, Eli Lilly and Company. All rights reserved. For more information, call 1-800-LillyRx (1-800-545-5979) or go to the following website: www.baqsimi.com.BAQ-0001-PPI-20190724. have tumor in the gland on top of your kidneys (adrenal gland) called pheochromocytoma.. have tumor in your pancreas called insulinoma.. are allergic to glucagon, or any other ingredients in BAQSIMI. See the end of this Patient Information for complete list of ingredients in BAQSIMI.. have tumor in your pancreas.. have not had food or water for long time (prolonged fasting or starvation).. are pregnant or plan to become pregnant.. are breastfeeding or plan to breastfeed. It is not known if BAQSIMI passes into your breast milk. You and your healthcare provider should decide if you can use BAQSIMI while breastfeeding.. Read the detailed Instructions for Use that comes with BAQSIMI.. Use BAQSIMI exactly how your healthcare provider tells you to use it.. Make sure your caregiver knows where you keep your BAQSIMI and how to use BAQSIMI the right way before you need their help.. Your healthcare provider will tell you how and when to use BAQSIMI.. BAQSIMI contains only dose of medicine and cannot be reused.. BAQSIMI should be given in one side of your nose (nostril) but does not need to be inhaled.. BAQSIMI will work even if you have cold or are taking cold medicine.. After giving BAQSIMI, the caregiver should call for emergency medical help right away.. If the person does not respond after 15 minutes, another dose may be given, if available.. Tell your healthcare provider each time you use BAQSIMI.. High blood pressure. BAQSIMI can cause high blood pressure in certain people with tumors in their adrenal glands.. Low blood sugar. BAQSIMI can cause certain people with tumors in their pancreas to have low blood sugar.. Serious allergic reaction. Call your healthcare provider or get medical help right away if you have serious allergic reaction including:. rash. difficulty breathing. low blood pressure. nausea. vomiting. headache. runny nose. discomfort in your nose. stuffy nose. redness in your eyes. itchy nose, throat and eyes. watery eyes. Store BAQSIMI at temperatures up to 86oF (30oC).. Keep BAQSIMI in the shrink wrapped tube until you are ready to use it.

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2.1 Important Administration Instructions. BAQSIMI is for intranasal use only.Instruct patients and their caregivers on the signs and symptoms of severe hypoglycemia. Because severe hypoglycemia requires help of others to recover, instruct the patient to inform those around them about BAQSIMI and its Instructions for Use. Administer BAQSIMI 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 BAQSIMI. Emphasize the following instructions to the patient or caregiver:Do not push the plunger or test the device prior to administration.Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use.Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled.Call for emergency assistance immediately after administering the dose.When the patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused.. Do not push the plunger or test the device prior to administration.. Administer BAQSIMI according to the printed instructions on the shrink-wrapped tube label and the Instructions for Use.. Administer the dose by inserting the tip into one nostril and pressing the device plunger all the way in until the green line is no longer showing. The dose does not need to be inhaled.. Call for emergency assistance immediately after administering the dose.. When the patient responds to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.. Do not attempt to reuse BAQSIMI. Each BAQSIMI device contains one dose of glucagon and cannot be reused.

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8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from case reports and small number of observational studies with glucagon use in pregnant women over decades of use have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Multiple small studies have demonstrated lack of transfer of pancreatic glucagon across the human placental barrier during early gestation. In 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/m2) (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 DataIn pregnant rats given animal sourced glucagon twice-daily by injection at doses up to mg/kg (up to 40 times the human dose based on body surface area extrapolation, mg/m2) during the period of organogenesis, there was no evidence of increased malformations or embryofetal lethality.. 8.2 Lactation. Risk SummaryThere 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 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 BAQSIMI for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients ages years and above. Use of BAQSIMI for this indication is supported by evidence from study in 48 pediatric patients from to <17 years of age with type diabetes mellitus. [see Clinical Studies (14.2)].The safety and effectiveness of BAQSIMI have not been established in pediatric patients younger than years 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 subjects. Limited clinical trial experience has not identified differences in responses between the elderly and younger patients.

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5 WARNINGS AND PRECAUTIONS. Substantial Increase in Blood Pressure in Patients withPheochromocytoma: Contraindicated in patients with pheochromocytoma because BAQSIMI may stimulate the release of catecholamines from the tumor. (4, 5.1)Hypoglycemia in Patients withInsulinoma: 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 patient develops symptoms of hypoglycemia after dose of BAQSIMI, give glucose orally or intravenously. (4, 5.2)Hypersensitivity and Allergic Reactions: Allergic reactions have been reported and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. (4, 5.3)Lack of Efficacy in Patients with Decreased HepaticGlycogen: 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). Substantial Increase in Blood Pressure in Patients withPheochromocytoma: Contraindicated in patients with pheochromocytoma because BAQSIMI may stimulate the release of catecholamines from the tumor. (4, 5.1). Hypoglycemia in Patients withInsulinoma: 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 patient develops symptoms of hypoglycemia after dose of BAQSIMI, give glucose orally or intravenously. (4, 5.2). Hypersensitivity and Allergic Reactions: Allergic reactions have been reported and include generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. (4, 5.3). Lack of Efficacy in Patients with Decreased HepaticGlycogen: 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 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 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 patient develops symptoms of hypoglycemia after dose of BAQSIMI, give glucose orally or intravenously.. 5.3 Hypersensitivity and Allergic Reactions. Allergic reactions have been reported with glucagon, these include generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. BAQSIMI is contraindicated in patients with prior hypersensitivity reaction [see Contraindications (4)]. 5.4 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 administration to be effective. Patients with these conditions should be treated with glucose.