BAQSIMI 3mg single dose nose powder medication leaflet

Baqsimi 3 mg nasal powder in single-dose container

Each single-dose container delivers nasal powder with 3 mg of glucagon.

For the full list of excipients, see section 6.1.

Nasal powder in single-dose container (nasal powder).

White to practically white powder.

Baqsimi is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and childrenaged 4 years and over with diabetes mellitus.

Adults, adolescents and children aged 4 years and over

The recommended dose is 3 mg glucagon administered into one nostril.

No dose adjustment is required based on age.

Efficacy and safety data are very limited in patients aged 65 years and absent in patients aged 75 andabove.

No dose adjustment is required based on renal function.

No dose adjustment is required based on hepatic function.

Paediatric population aged 0 - < 4 years

The safety and efficacy of Baqsimi in infants and children aged 0 to < 4 years have not yet beenestablished. No data are available.

Nasal use only. Glucagon nasal powder is given in a single nostril. Glucagon is passively absorbedthrough the nasal mucosa. It is not necessary to inhale or breathe deeply after dosing.

Patients and their caregivers should be instructed on the signs and symptoms of severe hypoglycaemia.

As severe hypoglycaemia requires the help of others to recover, the patient should be instructed toinform those around them about Baqsimi and its package leaflet. Baqsimi should be administered assoon as possible when severe hypoglycaemia is recognised. The patient or caregiver should beinstructed to read the package leaflet. The following instructions should be emphasised:

Instructions for administering glucagon nasal powder1. Remove the shrink wrap by pulling on the red stripe.2. Remove the single-dose container from the tube. Do not press the plunger until ready to give thedose.3. Hold the single-dose container between fingers and thumb. Do not test before use as it containsonly one dose of glucagon and cannot be reused.4. Insert the tip of the single-dose container gently in one of the nostrils until finger(s) touch theoutside of the nose.5. Push the plunger all the way in. The dose is complete when the green line is no longer showing.6. If the person is unconscious, turn the person on their side to prevent choking.7. After giving the dose, the caregiver should call for medical help right away.8. When the patient has responded to treatment, give oral carbohydrate to restore liver glycogenand prevent relapse of hypoglycaemia.

For special warnings and precautions for use see section 4.4.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Phaeochromocytoma (see section 4.4).

Phaeochromocytoma

In the presence of phaeochromocytoma, glucagon may stimulate the release of catecholamines fromthe tumour. If the patient develops a dramatic increase in blood pressure, use of non-selectiveα-adrenergic blockade has been shown to be effective in lowering blood pressure. Baqsimi iscontraindicated in patients with phaeochromocytoma (see section 4.3).

Insulinoma

In patients with insulinoma, administration of glucagon may produce an initial increase in bloodglucose. However, glucagon administration may directly or indirectly (through an initial rise in bloodglucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycaemia. A patientdeveloping symptoms of hypoglycaemia after a dose of glucagon should be given glucose orally orintravenously.

Hypersensitivity and allergic reactions

Allergic reactions, which have been reported with injectable glucagon, may occur and includegeneralised rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. Ifthe patient experiences difficulty breathing call for immediate medical assistance.

Glycogen stores and hypoglycaemia

Glucagon is effective in treating hypoglycaemia only if sufficient liver glycogen is present. Becauseglucagon is of little or no help in states of starvation, adrenal insufficiency, chronic alcohol abuse orchronic hypoglycaemia, these conditions should be treated with glucose.

To prevent relapse of the hypoglycaemia, oral carbohydrates should be given to restore liver glycogen,when the patient has responded to treatment.

No interaction studies have been performed.

Insulin

Insulin reacts antagonistically towards glucagon.

Indomethacin

When used with indomethacin, glucagon may lose its ability to raise blood glucose or may evenproduce hypoglycaemia.

Beta-blockers

Patients taking beta-blockers might be expected to have a greater increase in both pulse and bloodpressure, an increase of which will be transient because of glucagon's short half-life.

Glucagon treatment results in catecholamine release from the adrenal glands, and concomitant use ofbeta-blockers could result in unopposed alpha-adrenergic stimulation and consequently, a greaterincrease in blood pressure (see section 4.4).

Glucagon may increase the anticoagulant effect of warfarin.

Reproduction and fertility studies with glucagon nasal powder were not conducted in animals.

Baqsimi can be used during pregnancy. Glucagon does not cross the human placenta barrier. The useof glucagon has been reported in pregnant women with diabetes and no harmful effects are knownwith respect to the course of pregnancy and the health of the unborn and the neonate.

Baqsimi can be used during breast-feeding. Glucagon is cleared from the bloodstream very quicklyand thus the amount excreted in the milk of nursing mothers following treatment of severehypoglycaemic reactions is expected to be extremely small. As glucagon is degraded in the digestivetract and cannot be absorbed in its intact form, it will not exert any metabolic effect in the child.

No fertility studies have been conducted with glucagon nasal powder.

Studies in rats have shown that glucagon does not cause impaired fertility.

Baqsimi has negligible influence on the ability to drive and use machines.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia which maypersist for a brief period after receiving treatment. This may present a risk in situations where theseabilities are especially important, such as driving or using machines.

The most frequently reported adverse reactions are lacrimation increased (36%), upper respiratorytract irritation (34%), nausea (27%), headache (21%), and vomiting (16%).

Adverse reactions are listed in table 1 as MedDRA preferred term by system organ class and frequency.

The corresponding frequency category for each adverse reaction is based on the following convention:very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare(≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 1. Frequency of adverse reactions of glucagon nasal powder

System organ class Very common Common Uncommon

Nervous system disorders Headache Dysgeusia

Eye disorders Lacrimation Ocular hyperaemiaincreased Eye pruritus

Respiratory, thoracic and Upper respiratorymediastinal disorders tract irritationa

Gastrointestinal disorders Vomiting

Nausea

Skin and subcutaneous tissue Pruritusdisorders

Investigations Increased systolic Increased heartblood pressureb rateb

Increased diastolicblood pressureba Upper respiratory tract irritation: rhinorrhoea, nasal discomfort, nasal congestion, nasalpruritus, sneezing, throat irritation, cough, epistaxis, and parosmia.b Increases in heart rate and blood pressure: as assessed by vital sign measurements.

Frequencies are based on shifts from pre-treatment to post-treatment values.

Overall, 5.6% of patients developed treatment-emergent anti-glucagon antibodies. These antibodieswere not neutralising and did not lower the efficacy of glucagon nor were they associated with thedevelopment of treatment-emergent adverse reactions.

Based on data from clinical trials, the frequency, type and severity of adverse reactions observed inchildren aged 4 years and above are expected to be the same as in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs, the patient may experience nausea, vomiting, inhibition of gastrointestinal tractmotility, increase in blood pressure and pulse rate. In case of suspected overdosing, serum potassiummay decrease and should be monitored and corrected if needed. If the patient develops a dramaticincrease in blood pressure, use of non-selective α-adrenergic blockade has been shown to be effectivein lowering blood pressure for the short time that control would be needed (see section 4.4).

Pharmacotherapeutic group: Pancreatic hormones, glycogenolytic hormones, ATC code: H04AA01

Glucagon increases blood glucose concentration by activating hepatic glucagon receptors, therebystimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen arenecessary for glucagon to produce an anti-hypoglycaemic effect.

Gender and body weight had no clinically meaningful effect on the pharmacodynamics of glucagonnasal powder.

After administration of 3 mg glucagon nasal powder in adult patients with type 1 diabetes, glucoselevels began to rise as early as 5 minutes (see figure 1). By 10 minutes, the median glucose level wasabove 3.9 mmol/L (70 mg/dL). The mean maximum glucose increase was 7.8 mmol/L (140 mg/dL).

In paediatric patients with type 1 diabetes (aged 4 to < 17 years), after administration of 3 mgglucagon nasal powder, glucose levels began to rise as early as 5 minutes (see figure 2) with a meanmaximum glucose increase of 5.7 mmol/L (102 mg/dL) to 7.7 mmol/L (138 mg/dL).

Common cold with nasal congestion with or without concomitant use of a decongestant did not impactpharmacodynamics of glucagon nasal powder.

Figure 1. Mean glucose concentration over time in adult patients with type 1 diabetes

Figure 2. Mean glucose concentration over time in paediatric patients with type 1 diabetes14 2524 to <8 years 2348 to <12 years12 12 to <17 years 21610 1808 1446 1084 722 360 10 20 30 40 50 60 70 80 90

Time (minutes)

The adult pivotal study was a randomized, multicentre, open-label, 2-period, cross-over study in adultpatients with type 1 diabetes or type 2 diabetes. The primary objective was to compare the efficacy ofa single 3 mg dose of glucagon nasal powder against a 1 mg dose of intramuscular glucagon in adultpatients with type 1 diabetes. Insulin was used to reduce blood glucose levels to the hypoglycaemicrange with a target blood glucose nadir of < 2.8 mmol/L (< 50 mg/dL).

The pivotal study enrolled 83 total patients aged 18 to < 65 years. Seventy-seven patients had type 1diabetes, with a mean age of 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 meandiabetes duration of 18.8 years, and 4 (67%) patients 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 ≥ 3.9 mmol/L (≥ 70 mg/dL) or an increaseof ≥ 1.1 mmol/L (≥ 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 asthe minimum glucose measurement at the time of, or within 10 minutes, following glucagonadministration.

For patients with type 1 diabetes, the mean nadir blood glucose was 2.5 mmol/L (44.2 mg/dL) forglucagon nasal powder and 2.7 mmol/L (48.9 mg/dL) for intramuscular glucagon. Glucagon nasalpowder demonstrated non-inferiority to intramuscular glucagon in reversing insulin-inducedhypoglycaemia with 98.7% of glucagon nasal powder-treated patients and 100 % of intramuscularglucagon-treated patients achieving treatment success within 30 minutes (see table 2). All patients metglucose treatment success criteria within 40 minutes. All patients with type 2 diabetes (100 %)achieved treatment success within 30 minutes.

The mean time to treatment success was 16.2 and 12.2 minutes in the glucagon nasal powder andintramuscular glucagon 1 mg treatment groups, respectively. Time to treatment success represents thetime from glucagon administration to patient achieving treatment success; it does not include the timefor reconstitution and preparation of the intra-muscular injection in the control group.

Mean Glucose (mmol/L)

Mean Glucose (mg/dL)

By 30 minutes post-glucagon administration, patients in both glucagon nasal powder andintramuscular glucagon groups had similar improvement in symptoms of hypoglycaemia, as evaluatedby Edinburgh Hypoglycaemia Symptom Questionnaire.

Table 2. Patients meeting treatment success and other glucose criteria in pivotal study

Type 1 diabetes Type 1 and type 2 diabetes(n=75)a (n=80)aglucagon intramuscular glucagon intramuscularnasal glucagon nasal glucagonpowder 1 mg powder 1 mg3 mg 3 mg

Treatment success - n (%) 74 (98.7%) 75 (100%) 79 (98.8%) 80 (100%)

Treatment difference (2-sided 95%confidence interval)b,c 1.3% (-3.8%, 7.2%) 1.3% (-3.6%, 6.8%)

Glucose criterion met - n (%)d(i) ≥ 3.9 mmol/L (≥ 70 mg/dL) 72 (97%) 74 (99%) 77 (97%) 79 (99%)(ii) Increase by ≥ 1.1 mmol/L(≥ 20 mg/dL) from nadir 74 (100%) 75 (100%) 79 (100%) 80 (100%)

Both (i) and (ii) 72 (97%) 74 (99%) 77 (97%) 79 (99%)a The efficacy analysis population consisted of all patients who received both doses of the study medicinalproduct with evaluable primary outcome.b Difference calculated as (percentage with success in intramuscular glucagon) - (percentage with success inglucagon nasal powder).c 2-sided 95% confidence interval (CI) using the unconditional profile likelihood method based on ‘exact’ tailareas; non-inferiority margin=10%.d Percentage based on number of patients meeting treatment success.

In a similarly designed clinical confirmatory study, 70 patients with type 1 diabetes were enrolled witha mean age of 41.7 years (20-64 years), and a mean diabetes duration of 19.8 years. Twenty-seven(39%) were female. Insulin was used to reduce blood glucose levels to < 3.3 mmol/L (< 60 mg/dL).

The mean nadir blood glucose was 3 mmol/L (54.2 mg/dL) for glucagon nasal powder and3.1 mmol/L (55.7 mg/dL) for intramuscular glucagon. Glucagon nasal powder demonstrated non-inferiority to intramuscular glucagon in reversing insulin-induced hypoglycaemia with 100% ofglucagon nasal powder-treated patients and 100% of intramuscular glucagon-treated patients achievingtreatment success (see table 3). The mean time to treatment success was 11.4 and 9.9 minutes in theglucagon nasal powder and intramuscular glucagon 1 mg treatment groups, respectively.

Table 3. Patients meeting treatment success and other glucose criteria in confirmatory study

Type 1 diabetes(n=66)aglucagon intramuscularnasal powder glucagon3 mg 1 mg

Treatment success - n (%) 66 (100%) 66 (100%)

Treatment difference (2-sided 95 % confidenceinterval)b,c 0% (-5.4%, 5.4%)

Glucose criterion met - n (%)(i) ≥ 3.9 mmol/L (≥ 70 mg/dL) 66 (100%) 66 (100%)(ii) Increase by ≥ 1.1 mmol/L (≥ 20 mg/dL) from nadir 66 (100%) 66 (100%)

Both (i) and (ii) 66 (100%) 66 (100%)a The efficacy analysis population consisted of all patients who received both doses of the study medicinalproduct with evaluable primary outcome.b Difference calculated as (percentage with success in intramuscular glucagon) - (percentage with success inglucagon nasal powder); non-inferiority margin = 10%.c 2-sided 95% confidence interval (CI) using the unconditional profile likelihood method based on ‘exact’ tailareas.

In an adult actual use study of approximately 6 months duration, 129 patients with type 1 diabetes(mean age, 46.6 years; range, 18 to 71 years) and their caregivers were dispensed glucagon nasalpowder to treat moderate or severe hypoglycaemic events in the home or work setting. A total of157 moderate or severe hypoglycaemic events reported by 69 patients were included in the efficacyanalysis. An episode of severe hypoglycaemia was defined as an episode wherein the person withdiabetes is clinically incapacitated (that is, unconscious, convulsions, severe mental disorientation) tothe point where the person requires third-party assistance to treat the hypoglycaemia. An episode ofmoderate hypoglycaemia was defined as an episode wherein the person with diabetes was showingsigns of neuroglycopenia (that is, weakness, difficulty speaking, double vision, drowsiness, inability toconcentrate, blurred vision, anxiety, hunger, tiredness or confusion) and had a glucometer reading ofapproximately 60 mg/dL (3.3 mmol/L) or less. In 151 (96.2%) of these events, patients awoke orreturned to normal status within 30 minutes following glucagon nasal powder administration. In all(100%) 12 severe hypoglycaemic events, patients awoke, stopped convulsions (7 events from4 patients having presented with convulsions before glucagon nasal powder dosing) or returned tonormal status within 5 to 15 minutes following glucagon nasal powder administration.

The paediatric pivotal study was a randomised, multicentre, clinical study that assessed glucagon nasalpowder compared to intramuscular glucagon in children and adolescents with type 1 diabetes.

Glucagon was administered after glucose reached < 4.4 mmol/L (< 80 mg/dL) on the dosing day.

Efficacy was assessed based on percentage of patients with a glucose increase of ≥ 1.1 mmol/L(≥ 20 mg/dL) from glucose nadir within 30 minutes following glucagon administration.

Forty-eight patients were enrolled and received at least one dose of study medicinal product. The meanage 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 agewas 14.6 years. In all age cohorts, the population was predominantly male and white.

Across all age groups, 3 mg glucagon nasal powder and intramuscular glucagon 0.5 mg (childrenbelow 25 kg) or 1 mg (children 25 kg or above), demonstrated similar glycaemic responses. All(100%) patients in both treatment arms across all age groups achieved an increase in glucose≥ 1.1 mmol/L (≥ 20 mg/dL) from glucose nadir within 20 minutes of glucagon administration.

The mean time to reach a glucose increase of ≥ 1.1 mmol/L (≥ 20 mg/dL) was similar betweenglucagon nasal powder and intramuscular glucagon for all age groups (see table 4).

Table 4. Mean time to reach glucose increase of ≥ 1.1 mmol/L (≥ 20 mg/dL) from nadir inpaediatric pivotal study

Mean time post-glucagon administration (minutes)

Young children Children Adolescents(4 to < 8 years old) (8 to < 12 years old) (12 to < 17 years old)

Increase fromnadir intra- glucagon intra- glucagon intra- glucagonmuscular nasal muscular nasal muscular nasalglucagona powder glucagona powder glucagona powdern=6 3 mg n=6 3 mg n=12 3 mgn=12 n=12 n=12≥ 1.1 mmol/L(≥ 20 mg/dL) 10.0 10.8 12.5 11.3 12.5 14.2a 0.5 mg or 1 mg of intramuscular glucagon (based upon body weight).

In a paediatric actual use study of approximately 6 months duration, 26 patients aged 4 to < 18 yearsold with type 1 diabetes (mean age, 11.7 years; range, 5 to 17 years) and their caregivers weredispensed 3 mg glucagon nasal powder to treat moderate including major hypoglycaemic events in thehome or school setting. A total of 33 moderate hypoglycaemic events reported by 14 patients wereincluded in the efficacy analysis. An episode of major hypoglycaemia was defined as an episode withneuroglycopenia symptoms and a glucose level below 50 mg/dL (2.8 mmol/L). An episode ofmoderate hypoglycaemia is defined as an episode wherein the child/adolescent with diabetes hassymptoms and/or signs of neuroglycopenia and has a blood glucose level of ≤ 70 mg/dL (3.9 mmol/L).

In all events, including major hypoglycaemia (8 events from 5 patients), patients returned to normalstatus within 5 to 30 minutes following glucagon nasal powder administration.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Baqsimi in one or more subsets of the paediatric population in the treatment of severe hypoglycaemia(see section 4.2 for information on paediatric use).

Glucagon absorption via the nasal route achieved mean peak plasma levels of 6 130 pg/mL at15 minutes.

The apparent volume of distribution of glucagon was approximately 885 L via the nasal route.

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

The mean half-life of glucagon was approximately 38 minutes via the nasal route.

No formal studies have been performed to evaluate renal impairment.

No formal studies have been performed to evaluate hepatic impairment.

In paediatric patients (aged 4 to < 17 years), glucagon absorption via the nasal route, achieved meanpeak plasma levels between 15 and 20 minutes.

Common cold and use of decongestant

Common cold with nasal congestion with or without concomitant use of a decongestant did not impactpharmacokinetics via the nasal route.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development..

Betadex (E459)

Dodecylphosphocholine

Not applicable.

2 years.

Do not store above 30 °C.

Keep the single-dose container in the shrink-wrapped tube until ready to use in order to protect frommoisture.

The single-dose container consists of polyethylene and polypropylene.

The shrink-wrapped tube is comprised of polyethylene and polypropylene containing a desiccant.

Pack sizes of 1 or 2 single-dose containers.

Not all pack sizes may be marketed.

Handling

This is a ready to use medicinal product and for single-use only.

The single-dose container contains only one dose and therefore it must not be primed or tested prior touse.

The instructions for using the medicinal product in the package leaflet must be followed carefully.

If the tube has been opened, the single-dose container may have been exposed to moisture. This couldcause the medicinal product to not work as expected. Examine the shrink wrapped tube periodically. Ifthe tube has been opened, replace the medicinal product.

Discard nasal glucagon single-dose container and tube after use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amphastar France Pharmaceuticals

Usine Saint Charles

Eragny Sur Epte

France

EU/1/19/1406/001

EU/1/19/1406/002

Date of first authorisation: 16 December 2019

Date of latest renewal: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.