glucagon: prescribing information – dosing, contraindications, interactions, side effects

Baqsimi is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 1 year and over with diabetes mellitus.

Posology

Adults, adolescents and children aged 1 year and over
The recommended dose is 3 mg glucagon administered into one nostril.

Elderly
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 and above.

Renal impairment
No dose adjustment is required based on renal function.

Hepatic impairment
No dose adjustment is required based on hepatic function.

Paediatric population aged 0 - < 1 year
The safety and efficacy of Baqsimi in infants and children aged 0 to < 1 year have not yet been established. No data are available.

Method of administration

Nasal use only. Glucagon nasal powder is given in a single nostril. Glucagon is passively absorbed through 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 to inform those around them about Baqsimi and its package leaflet. Baqsimi should be administered as

soon as possible when severe hypoglycaemia is recognised. The patient or caregiver should be instructed to read the package leaflet. The following instructions should be emphasised:

Instructions for administering glucagon nasal powder
1.
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 the dose.
3.
Hold the single-dose container between fingers and thumb. Do not test before use as it contains only 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 the outside 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 glycogen and 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).

Summary of the safety profile

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

Tabulated list of adverse reactions

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 increased
Ocular hyperaemia
Eye pruritus

Respiratory, thoracic and mediastinal disorders
Upper respiratory tract irritationa

Gastrointestinal disorders
Vomiting
Nausea

Skin and subcutaneous tissue disorders

Pruritus

Investigations

Increased systolic blood pressureb
Increased diastolic blood pressureb
Increased heart rateb a Upper respiratory tract irritation: rhinorrhoea, nasal discomfort, nasal congestion, nasal pruritus, 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.

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

Paediatric population

Based on data from clinical trials, the frequency, type and severity of adverse reactions observed in children aged 1 year and above are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Phaeochromocytoma

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

Insulinoma

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

Hypersensitivity and allergic reactions

Allergic reactions, which have been reported with injectable glucagon, may occur and include generalised rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension. If the 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. Because glucagon is of little or no help in states of starvation, adrenal insufficiency, chronic alcohol abuse or chronic 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 even produce hypoglycaemia.

Beta-blockers

Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure, 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 of beta-blockers could result in unopposed alpha-adrenergic stimulation and consequently, a greater increase in blood pressure (see section 4.4).

Warfarin

Glucagon may increase the anticoagulant effect of warfarin.

Pregnancy

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 use of glucagon has been reported in pregnant women with diabetes and no harmful effects are known with respect to the course of pregnancy and the health of the unborn and the neonate.

Breast-feeding

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

Fertility

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 may persist for a brief period after receiving treatment. This may present a risk in situations where these abilities are especially important, such as driving or using machines.

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

5.
PHARMACOLOGICAL PROPERTIES

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

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 anti-hypoglycaemic effect.

Pharmacodynamic effects

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

After administration of 3 mg glucagon nasal powder in adult patients with type 1 diabetes, glucose levels began to rise as early as 5 minutes (see figure 1). By 10 minutes, the median glucose level was above 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 1 to < 17 years), after administration of 3 mg glucagon nasal powder, glucose levels began to rise as early as 5 minutes, with a mean maximum glucose increase of 5.7 mmol/L (102 mg/dL) to 7.7 mmol/L (138 mg/dL). The mean maximum glucose increase from baseline was 7.33 mmol/L (132 mg/dL) (1 to <4 years), 7.67 mmol/L (138 mg/dL) (4 to <8 years), 7.39 mmol/L (133 mg/dL) (8 to <12 years), and 5.67 mmol/L (102 mg/dL) (12 to <17 years) (Figure 2).

Common cold with nasal congestion with or without concomitant use of a decongestant did not impact pharmacodynamics 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 diabetes

Clinical efficacy

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

Mean Glucose (mg/dL)
Time (minutes)
―◆― 1 to <4 years
―◼― 4 to <8 years
―▲― 8 to <12 years
―⚫― 12 to <17 years

The pivotal study enrolled 83 total patients aged 18 to < 65 years. Seventy-seven patients had type 1 diabetes, 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 mean diabetes duration of 18.8 years, and 4 (67%) patients were female.

Absorption

Glucagon absorption via the nasal route achieved mean peak plasma levels of 6 130 pg/mL at 15 minutes.

Distribution

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

Biotransformation

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

Elimination

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

Renal impairment

No formal studies have been performed to evaluate renal impairment.

Hepatic impairment

No formal studies have been performed to evaluate hepatic impairment.

Paediatric population

In paediatric patients (aged 1 to < 17 years), glucagon absorption via the nasal route, achieved mean peak plasma levels between 10 and 20 minutes.

Common cold and use of decongestant

Based on clinical data in adults and paediatric patients, no significant effect on response is expected in case of inability to clear nasal passages, such as in the case of young children with a runny nose, because glucagon exposure is sufficient to produce a near-maximum glucose response, despite cold and/or nasal congestion.

Ogluo is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 2 years and over with diabetes mellitus.

Posology

Adults and adolescents (≥6 years)
The recommended dose is 1 mg, administrated by subcutaneous injection.

Paediatric population (≥2 to <6 years)

• The recommended dose for paediatric patients who weigh less than 25 kg is 0.5 mg administered by subcutaneous injection.
• The recommended dose for paediatric patients who weigh 25 kg or greater is 1 mg administered by subcutaneous injection.

Time to respond and additional doses
The patient will normally respond within 15 minutes. When the patient has responded to the treatment, give an oral carbohydrate to restore the liver glycogen and prevent relapse of hypoglycaemia. If the patient does not respond within 15 minutes, an additional dose of Ogluo from a new device may be administered while waiting for emergency assistance. It is recommended that patients are prescribed two Ogluo devices.

Special populations

Elderly (≥ 65 years old)
Ogluo can be used in elderly patients. No dose adjustment is required.

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

Renal impairment
Ogluo can be used in patients with renal impairment. No dose adjustment is required.

Hepatic impairment
Ogluo can be used in patients with hepatic impairment. No dose adjustment is required.

Paediatric population (<2 years)
The safety and efficacy of Ogluo in children aged less than 2 years have not been established. No data are available.

Method of administration

Ogluo pre-filled pen and pre-filled syringe are for subcutaneous injection only.

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 to inform those around them about Ogluo and its package leaflet. Ogluo should be administered as soon as possible when severe hypoglycaemia is recognised.

The patient or caregiver should be instructed to read the package leaflet at the time they receive a prescription for Ogluo. The following instructions should be emphasised:

• The foil pouch should not be opened until glucagon needs to be administered.
• The medicinal product should be administered according to the printed instructions on the foil pouch label, carton, or the package leaflet.
• The solution should be visually inspected prior to administration. The solution should appear clear and colourless to pale yellow and be free of particles. If the solution is discoloured or contains particulate matter, the medicinal product should not be used.
• Any clothing covering the injection site should be removed. The injection should be administered in the lower abdomen, outer thigh, or outer upper arm.
• Emergency assistance should be called immediately after administering the dose, even if the patient is not unconsious.
• Each device contains a single dose of glucagon and cannot be reused.

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

Pheochromocytoma.

Summary of the safety profile

The most frequently reported adverse reactions are nausea (30%) and vomiting (16%).

Tabulated list of adverse reactions

Frequencies of adverse reactions considered related to treatment with Ogluo during clinical trials are presented below. The adverse drug reactions are classified according to the System Organ Class.
Frequency groups are defined by 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), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Table 1.
Frequency of adverse reactions of glucagon injection
System organ class
Subject incidence
Adverse drug reaction
Nervous system disorders
Common
Headache
Cardiac disorders
Common
Tachycardia

System organ class
Subject incidence
Adverse drug reaction
Gastrointestinal disorders
Very common
Very common
Common
Uncommon
Vomiting
Nausea
Diarrhoea
Abdominal pain
General disorders and administration site conditions
Common
Common
Uncommon
Uncommon
Injection site pain
Injection site oedema
Injection site bruising
Injection site erythema

Description of selected adverse reactions

The most frequently reported adverse reactions are nausea (43%), vomiting (13%), and headache (5%).
Adverse reactions are mild to moderate in severity and resolved on their own. No serious adverse reactions have been related to glucagon.

Hypersensitivity reactions, including anaphylactic reactions, have been reported as ‘very rare’ (<1/10,000 patients) with injectable glucagon. These are known medicinal product class effects of glucagon.

Paediatric population

The most frequently reported adverse reactions are nausea (48%), vomiting (19%), hyperglycaemia (7%), and headache (7%). Hypoglycaemia (42%) was observed in clinical trials but was not considered related to glucagon. The most frequently reported adverse reactions observed by age group are presented below.

Table 2.
Frequency of most common adverse reactions among paediatric populations

Ages 2 to under 6 years of age
(0.5 mg dose)
N =7
Ages 6 to under
12 years of age
(0.5 mg dose)
N = 13
Ages 12 to under 18
(0.5 mg dose)
N = 11
Ages 12 to under 18
(1 mg dose)
N = 11
Nausea
43%
54%
36%
36%
Vomiting
14%
23%
0%
18%
Hyperglycaemia
14%
8%
0%
0%
Headache
0%
15%
0%
0%

Other special populations

Efficacy and safety data for Ogluo are very limited in patients aged 65 years and absent in patients aged 75 and above, in or pregnant patients, or patients with hepatic or renal impairment. Based upon data from clinical trials and post-marketing experience,the frequency, type, and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment are expected to be the same as in the general population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Glycogen stores and hypoglycaemia

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

Glucagon will not be effective in patients whose liver glycogen is depleted. For that reason, glucagon has little or no effect when the patient has been fasting for a prolonged period, or is suffering from adrenal insufficiency, chronic hypoglycaemia, or alcohol induced hypoglycaemia.

Glucagon, unlike adrenaline, has no effect upon muscle phosphorylase and therefore cannot assist in the transference of carbohydrate from the much larger stores of glycogen that are present in the skeletal muscle.

Insulinoma

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

Caution should also be observed in patients with glucagonoma.

Recovery time

Please take into account that approximately 15% of patients achieved glucose recovery after 20 minutes or more in the pivotal trial.

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 paradoxically, may even produce hypoglycaemia.

Warfarin

Glucagon may increase the anticoagulant effect of warfarin.

Beta-blockers

Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be temporary because of glucagon’s short half-life. The increase in blood pressure and pulse rate may require therapy in patients with coronary artery disease.

Pregnancy

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

Breast-feeding

Glucagon is cleared from the bloodstream very fast (mainly by the liver) (t1/2= 3–6 minutes); thus the amount excreted in the milk of breast-feeding mothers following treatment of severe hypoglycaemic reactions is expected to be extremely small. As glucagon is degraded in the digestive tract and cannot be absorbed in its intact form, it will not exert any metabolic effect in the child. Ogluo can be used during breast-feeding.

Fertility

Animal reproduction studies have not been conducted with Ogluo. Studies in rats have shown that glucagon does not cause impaired fertility.

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

After a severe hypoglycaemic event, the patient’s ability to concentrate and react may be impaired;
therefore the patient should not drive or operate machinery after a severe hypoglycaemic event until the patient has stabilised.

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Pancreatic hormones, glycogenolytic hormones: H04AA01.

Mechanism of action

Glucagon is a hyperglycaemic agent that mobilises hepatic glycogen, which is released into the blood as glucose. Hepatic stores of glycogen are necessary for glucagon to produce an anti-hypoglycaemic effect.

Pharmacodynamic effects

After administration of 1 mg Ogluo in adult patients with diabetes, the mean maximum plasma glucose increase from baseline was 176 mg/dL. After administration, plasma glucose begins to rise as early as 5 minutes. From the time of injection, the mean time to plasma glucose >70 mg/dL or ≥20 mg/dL increase was 14.8 (±5.3) minutes.

Clinical efficacy and safety

Ogluo was evaluated in 132 adult patients aged 18 to 74 years with type 1 diabetes in a multicentre randomised, active-controlled, single-blind, 2-way crossover study. The study involved 2 clinic visits 7 to 28 days apart, with random assignment to receive glucagon 1 mg solution for injection during one session and reconstituted glucagon 1 mg powder and solvent for solution for injection during the other.
A total of 127 subjects received an injection of Ogluo and 123 subjects received a glucagon powder and solvent for solution for injection.

The efficacy of glucagon 1 mg solution for injection was compared to reconstituted glucagon 1 mg powder and solvent for solution for injection in subjects who were in a state of insulin-induced hypoglycaemia with target plasma glucose less than 3.0 mmol/L (<54 mg/dL). Treatment ‘success’ was defined as plasma glucose increase from time of glucagon administration to absolute value greater than 3.89 mmol/L (>70 mg/dL) or relative increase of 1.11 mmol/L (≥20 mg/dL) or greater, within 30 minutes after glucagon administration. The proportion of patients who achieved treatment ‘success’ was 99.2% in the glucagon 1 mg solution for injection group and 100% in the reconstituted glucagon 1 mg powder and solvent for solution for injection group, and the comparison between groups met the prespecified non-inferiority margin.

From the time of administration, which does not include the preparation time for each medicinal product prior to administration the mean time to treatment ‘success’ was 14.8 (±5.3) minutes in the glucagon 1 mg solution for injection group and 10.4 (±1.8) minutes in the reconstituted glucagon 1 mg powder and solvent for solution for injection group.

From the time of decision to dose, which includes the preparation time for each medicinal product prior to administration, the mean time to treatment ‘success’ was 15.6 (±5.2) minutes in the glucagon 1 mg solution for injection group and 12.2 (±2.0) minutes in the reconstituted glucagon 1 mg powder and solvent for solution for injection.

Paediatric population

Absorption

Subcutaneous injection of 1 mg Ogluo in adult type 1 diabetes mellitus subjects resulted in a mean glucagon Cmax of 2481.3 pg/mL, tmax of 50 minutes and AUC0-240min of 3454.6 pg*hr/mL.

Distribution

The apparent volume of distribution was in the range of 137-2425 Liters.

Metabolism

Glucagon is extensively degraded in liver, kidney, and plasma.

Elimination

The mean half-life of Ogluo was determined to be 31.9 ± 9.13 minutes.

Paediatric population

Subcutaneous injection of 0.5 mg Ogluo in subjects with type 1 diabetes mellitus ages 2 to under 6 years resulted in a mean glucagon Cmax of 2 300 pg/mL, tmax of 41 minutes, and AUC0-180min of 138 900 pg/mL*min. Subcutaneous injection of 0.5 mg Ogluo in subjects with type 1 diabetes mellitus ages 6 to under 12 years resulted in a mean Cmax of 1 600 pg/mL, median tmax of 34 minutes and AUC0-180min of 104 700 pg/mL*min. Subcutaneous injection of 1 mg Ogluo in subjects with type 1 diabetes mellitus ages 12 to less than 18 years resulted in a mean Cmax of 1 900 pg/mL, tmax of 51 minutes AUC0-180min of 134 300 pg/mL*min.