BAQSIMI™ is indicated for the treatment of severe hypoglycemia in adult and pediatric patients with diabetes ages 4 years and above.

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 a 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.

2.2 Dosage in Adults and Pediatric Patients Aged 4 Years and Above

The recommended dose of BAQSIMI is 3 mg administered as one actuation of the intranasal device into one nostril.

If there has been no response after 15 minutes, an additional 3 mg dose of BAQSIMI from a new device may be administered while waiting for emergency assistance.

Nasal Powder:

• 3 mg glucagon: as a white powder in an intranasal device containing one dose of glucagon.

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)]

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 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 a 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.

The following serious adverse reactions are described below and elsewhere in labeling:

• Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.3)].

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 Patients

Two similarly designed comparator-controlled trials, Study 1 and Study 2, evaluated the safety of a single dose of BAQSIMI compared to a 1 mg dose of intra-muscular glucagon (IMG) in adult patients with diabetes [see Clinical Studies (14)].

Table 1 presents adverse reactions that occurred with BAQSIMI at an incidence of ≥2% in a pool of Study 1 and Study 2.

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.

Adverse Reactions in Pediatric Patients Aged 4 Years 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 with type 1 diabetes in Study 3 [see Clinical Studies (14)].

Table 3 presents adverse reactions that occurred with BAQSIMI in pediatric patients at an incidence of ≥2% in Study 3.

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.

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).

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 3 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.

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/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 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/m2) 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 ages 4 years and above. Use of BAQSIMI for this indication is supported by evidence from a study in 48 pediatric patients from 4 to <17 years of age with type 1 diabetes mellitus. [see Clinical Studies (14.2)].

The safety and effectiveness of BAQSIMI have not been established in pediatric patients younger than 4 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.

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 a 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.

BAQSIMI contains glucagon, an antihypoglycemic agent used to treat severe hypoglycemia. Glucagon is a single-chain polypeptide containing 29 amino acid residues and has a molecular weight of 3483, and is identical to human glucagon.

Its molecular formula is C153H225N43O49S, with the following molecular structure:

BAQSIMI is a preservative-free, white powder for intranasal administration in an intranasal device containing one dose of 3 mg glucagon. BAQSIMI contains glucagon as the active ingredient and betadex, and dodecylphosphocholine as the excipients.

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 1 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.

12.3 Pharmacokinetics

Absorption

Glucagon absorption via the intranasal route, achieved mean peak plasma levels of 6130 pg/mL at around 15 minutes.

Distribution

The apparent volume of distribution was approximately 885 L.

Elimination

The median half-life was approximately 35 minutes.

Metabolism

Glucagon is known to be degraded in the liver, kidneys, and plasma.

Specific Populations

Pediatrics

In 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 Colds

Common cold with nasal congestion did not impact the pharmacokinetics of BAQSIMI.

Drug Interaction Studies

Common cold with use of decongestant did not impact the pharmacokinetics of BAQSIMI.

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.

14.1 Adult Patients

Study 1 (NCT03339453) was a randomized, multicenter, open-label, 2-period, crossover study in adult patients with type 1 diabetes. The efficacy of a single 3 mg dose of BAQSIMI was compared to a 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 a mean age of 41.7 years and a 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 1 mg treatment groups, respectively.

Study 2 (NCT01994746) was a randomized, multicenter, open-label, 2-period, crossover study in adult patients with type 1 diabetes or type 2 diabetes. The efficacy of a single 3 mg dose of BAQSIMI was compared to a 1 mg dose of intra-muscular glucagon (IMG). Insulin was used to reduce blood glucose levels to the hypoglycemic range with a target blood glucose nadir of <50 mg/dL.

Study 2 enrolled 83 patients 18 to <65 years of age. The mean age of patients with type 1 diabetes (N=77) was 32.9 years and a mean diabetes duration of 18.1 years, and 45 (58%) patients were female. The mean age of patients with type 2 diabetes (N=6) was 47.8 years, with a mean diabetes duration of 18.8 years, and 4 (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 1 mg treatment groups, respectively.

14.2 Pediatric Patients

Study 3 (NCT01997411) was a randomized, multicenter, clinical study that assessed BAQSIMI compared to intra-muscular glucagon (IMG) in pediatric patients aged 4 years and older with type 1 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 a 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 a glucose increase of ≥20 mg/dL for BAQSIMI and IMG for all age groups is shown in Table 7.

BAQSIMI is supplied as an intranasal device containing one 3 mg dose of glucagon as a preservative free, white powder.

• BAQSIMI One Pack™ carton contains 1 intranasal device (NDC 0548-8351-01)
• BAQSIMI Two Pack™ carton contains 2 intranasal devices (NDC 0548-8352-02)
• Store at temperatures up to 86°F (30°C) 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.

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 2020

BAQ-0002-USPI-20201027