GlucaGen HypoKit 1 mg powder and solvent for solution for injection

Section 4 - Possible side effects

Text added:

"Not known: frequency cannot be estimated from the available data

•       injection site reactions."

Section 6

Text added:

"This medicine is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

 Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Portugal, Slovakia, Slovenia, Spain, United Kingdom (Northern Ireland): GlucaGen

 Norway and Sweden: Glucagon Novo Nordisk"

Revision date updated to: 02/2023

Section 4.4

Text added:

"Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded."

Text updated:

"Diagnostic indication

….

GlucaGen may increase myocardial oxygen demand, blood pressure, and pulse rate. Monitor patients with cardiac disease during use of GlucaGen as a diagnostic aid and treat if indicated.

 GlucaGen may cause short term hyperglycaemia in patients with diabetes mellitus when used as a diagnostic aid. Monitor patients with diabetes for changes in blood glucose levels during use and treat if indicated.

 Caution should be observed in patients with glucagonoma when used as diagnostic aid.

Caution should be observed when GlucaGen is used as an adjunct in endoscopic or radiographic procedures in diabetic patients or in elderly patients with known cardiac disease.

Therapeutic and diagnostic indications"

Section 4.8

Under ‘Therapeutic indication’ and ‘Diagnostic indication’, new event added with a frequency of ‘Not known (cannot be estimated from the available data)’:

"Injection site reactions"

Section 10

Revision date updated to: 02/2023

File name updated.

Correction made to file name.

Section 2:

New text added:

GlucaGen contains sodium

GlucaGen contains less than 1 mmol sodium (23 mg) per maximum dose (2 ml), that is to say essentially ‘sodium-free’.

Section 6:

Revision date updated to 05/2021.

Section 4.4

Text added:

Excipients

GlucaGen contains less than 1 mmol sodium (23 mg) per maximum dose (2 ml), that is to say essentially ‘sodium-free’.

Section 10:

Date of revision of text updated to: 05/2021

Section 2: statement regarding latex removed

Section 4: HPRA contact details shortened

Section 4.4: 

Latex warning removed: "The tip cap of the syringe included in the GlucaGen HypoKit contains natural rubber latex which may cause allergic reactions in latex sensitive individuals."

Section 4.8:

HPRA contact details shortened

3.            PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Before reconstitution the compacted powder should be a white or nearly white powder. The solvent should be clear and colourless without particles.

4.            CLINICAL PARTICULARS

4.1          Indications

Therapeutic indication

TreatmentGlucaGen is indicated for treatment of severe hypoglycaemic reactions, which may occur in the management of insulin treated personschildren and adults with diabetes mellitus.

Diagnostic indication

MotilityGlucaGen is indicated for motility inhibition in examinations of the gastrointestinal tract in adults.

4.2          Posology and method of administration

Dissolve the freeze-dried product in the accompanying solvent, as described under item 6.6.

Posology

•          Therapeutic indication (Severe hypoglycaemia)

Dosage for adult patients:

 Administer 1 mg by subcutaneous or intramuscular injection.

Special populations

Paediatric population (<18 years old): GlucaGen can be used for the treatment of severe hypoglycaemia in children and adolescents.

Dosage for paediatric patients:

 Administer 0.51 mg (children abovebelow 25 kg or olderyounger than 6-–8 years) or 0.51 mg (children belowabove 25 kg or youngerolder than 6-–8 years).

Elderly (≥ 65 years old): GlucaGen can be used in elderly patients.

Renal and hepatic impairment: GlucaGen can be used in patients with renal and hepatic impairment.

•          Diagnostic indication (Inhibition of gastrointestinal motility)

Dosage for adult patients: The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum and small bowel is 0.2–0.5 mg given as intravenous injection or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5–0.75 mg intravenously or 1–2 mg intramuscularly.

Special populations

Paediatric population (<18 years old): The safety and efficacy of GlucaGen for inhibition of gastrointestinal motility in children and adolescents have not been established. No data are available.

Elderly (≥ 65 years old): GlucaGen can be used in elderly patients.

Renal and hepatic impairment: GlucaGen can be used in patients with renal and hepatic impairment.

Method of administration

Dissolve the compacted powder in the accompanying solvent, as described in section 6.6.

Therapeutic indication (Severe hypoglycaemia):

Administer by subcutaneous or intramuscular injection. The patient will normally respond within 10 minutes. When the patient has responded to the treatment, give oral carbohydrate to restore the liver glycogen and prevent relapse of hypoglycaemia. If the patient does not respond within 10 minutes, intravenous glucose should be given.

Medical consultation is required for all patients with severe hypoglycaemia.

Diagnostic indication (Inhibition of gastrointestinal motility)):

GlucaGen must be administered by medical personnel. Onset of action after an intravenous injection of 0.202–0.5 mg occurs within one minute and the duration of effect is between 5 and 20 minutes depending on the organ under examination. The onset of action after an intramuscular injection of 121–2 mg occurs after 5155–15 minutes and lasts approximately 104010–40 minutes depending on the organ.

After end of the diagnostic procedure oral carbohydrate should be given, if this is compatible with the diagnostic procedure applied.

Dose range from 0.2-2 mg depending on the diagnostic technique used and the route of administration. The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum and small bowel is 0.2-0.5 mg given intravenously or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5-0.75 mg intravenously or 1-2 mg intramuscularly.

4.3          Contraindications

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

Phaeocromocytoma.

4.4          Special warnings and precautions for use

Due to the instability of GlucaGen in solution, the product should be given immediately after reconstitution and must not be given as an intravenous infusion.

The tip cap of the syringe included in the GlucaGen HypoKit contains natural rubber latex which may cause allergic reactions in latex sensitive individuals.

Therapeutic indication

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.

The tip cap of the syringe included in the GlucaGen HypoKit contains natural rubber latex which may cause allergic reactions in latex sensitive individuals.

Diagnostic indication

Persons who have been given glucagon in connection with diagnostic procedures may experience discomfort, in particular if they have been fasting. Nausea, hypoglycaemia, and blood pressure changes have been reported in these situations. After the end of a diagnostic procedure, oral carbohydrates should be given to patients, who have been fasting, if this is compatible with the diagnostic procedure applied. If fasting is needed post-examination or in case of severe hypoglycaemia, glucose given intravenously given glucose may be required.

Glucagon reacts antagonistically towards insulin and caution should be observed if GlucaGen is used in patients with insulinoma. Caution should also be observed in patients with glucagonoma.

Caution should also be observed when GlucaGen is used as an adjunct in endoscopic or radiographic procedures in diabetic patients or in elderly patients with known cardiac disease.

Glucagon stimulates the release of catecholamines. In the presence of phaeocromocytoma, glucagon can cause the tumour to release large amounts of catecholamines, which will cause an acute hypertensive reaction. Glucagon is contraindicated in patients with phaeochromocytoma (see section 4.3).

GlucaGen should not be given via intravenous infusion.

4.5          Interaction with other medicinal products and other forms of interaction

Insulin: Reacts antagonistically towards glucagon.

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.

Interactions between GlucaGen and other drugs are not known when GlucaGen is used in the approved indications.

4.6          Fertility, pregnancy Pregnancy and lactation

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. GlucaGen can be used during pregnancy.

Breast-feeding

Glucagon is cleared from the bloodstream very fast (mainly by the liver) (t_1/2= 363–6 min.); thus the amount excreted in the milk of nursing mothers following treatment of severe hypoglycaemic reactions willis 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. GlucaGen can be used during breast-feeding.

Fertility

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

4.7          Effects on ability to drive and use machines

No studies onAfter a severe hypoglycaemic event, the effects on thepatient’s ability to concentrate and react may be impaired. Therefore the patient should not drive and use machines have been performed.or operate machinery after a severe hypoglycaemic event until the patient has stabilised.

.

After diagnostic procedures hypoglycaemia has been reported infrequently. Therefore driving a carvehicle and operating machinery  should be avoided until the patient has had a meal with oral carbohydrates.

4.8          Undesirable effects

Summary of the safety profile

Severe

adverse reactions are very rare, although nausea, vomiting and abdominal pain may occur occasionally. Hypersensitivity reactions, including anaphylactic reactions, have been reported as ‘very rare’ (less than 1 case per 10,000 patients). When used in the diagnostic indication, hypoglycaemia/hypoglycaemic coma have been reported, especially in patients who have fasted. Cardiovascular adverse events, such as tachycardia and blood pressure changes have only been reported when GlucaGen is used as an adjunct in endoscopic or radiographic procedures.

Tabulated summary of adverse reactions

Frequencies of undesirable effects considered related to GlucaGen treatment with GlucaGen during clinical trials and/or post -marketing surveillance isare presented below. Undesirable effects which have not been observed in clinical trials, but have been reported spontaneously, are presented as "‘very rare".rare’. During marketed use reporting of adverse drug reactions is very rare (<  1/10,000). However, post-marketing experience is subject to under-reporting and this reporting rate should be interpreted in that light. The estimated number of treatment episodes is 46.9 millions over a 16 year period.

Therapeutic indication

Paediatric population

Based on data from clinical trials and post-marketing experience, the frequency, type and severity of adverse reactions observed in children are expected to be the same as in adults.

Other special populations

Based on 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.

Diagnostic indication

*¹ After a diagnostic procedure it canthis could be more pronounced in patients havingthat have fasted, (see section 4.4 Special warnings and precautions for use).

*² Cardio-vascularCardiovascular adverse events have only been reported, when GlucaGen is used as an adjunct in endoscopic or radiographic procedures.

Paediatric population

1.  Name of the Medicinal Product

by subcutaneous or intramuscular injection. Post treatment: as described below.
a       Administration by medical personnel
b.      Administration to the patient by a relative

Section 1. Name of the medicinal product

The second presentation of GlucaGen is now included: GlucaGen 1 mg Powder and solvent for injection.

Section 2. Qualitative and Quantitative composition

The non-proprietary name has been changed from 'Glucagon, biosynthetic (rys)' to 'Glucagon rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae)'.

Section 3. Pharmaceutical form

A description of the product before and after reconstitution has been added.

Section 4.1. Indications

In the therapeutic indication 'diabetic patients receiving insulin' has been changed to 'insulin treated persons with diabetes'.

Under diagnostic indications the division into examinations with radiography/endoscopy and CT/NMR/DSA has been deleted. The indication is not general 'Motility inhibitor in examinations of the gastrointestinal tract', with no mention of type of procedure.

Section 4.2. Posology and method of administration

An important change here is that intravenous injection is no longer recommended for the therapeutic indication, treatment of severe hypoglycaemia. The section dealing with dosage and administration for severe hypoglycaemia is no longer divided into administration by medical personnel or by relatives since it is now equally applicable to both. The dosage for children has not been changed, but the wording has been clarified as the previous wording was ambiguous.

For the diagnostic indication it is now stated that administration should only be by medical personnel. A new statement has been added that oral carbohydrate should be given at the end of the diagnostic procedure if compatible with the diagnostic procedure applied. To be consistent with the more general diagnostic indication (Section 4.1) mention of dosages specific procedures (CT/NMR/DSA) has been deleted.

Section 4.3 Contraindications

Hypersensitivity to 'any of the excipients' has been changed to specifically mention lactose. This is the only excipient in GlucaGen which has the potential for causing hypersensitivity reactions.

 Section 4.4 Special warnings and precautions for use

The warnings have been divided into those relevant for the therapeutic indication and those relevant for the diagnostic indication.

 A new paragraph has been included under the diagnostic indication. This concerns patients experiencing discomfort especially if they have been fasting, and the need for oral carbohydrate at the end of the procedure. The possibility of patients needing intravenous glucose under certain circumstances is also mentioned.

 A new warning that GlucaGen should not be given via intravenous infusion has been included.

 Section 4.7 Effect on ability to drive and use machines

This has been amended to state that no studies have been performed and to include a warning concerning the possibility of hypoglycaemia following use of GlucaGen in diagnostic procedures.

 Section 4.8 Undesirable effects

This section has been amended so that adverse events are separated into those occurring with the therapeutic indication and those occurring with the diagnostic indication.

 Section 6.5 Nature and contents of container

This section now includes details of the second type of container for the diluent (glass vial).

Section 1. Name of the medicinal product

The second presentation of GlucaGen is now included: GlucaGen 1 mg Powder and solvent for injection.

Section 2. Qualitative and Quantitative composition

The non-proprietary name has been changed from 'Glucagon, biosynthetic (rys)' to 'Glucagon rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae)'.

Section 3. Pharmaceutical form

A description of the product before and after reconstitution has been added.

Section 4.1. Indications

In the therapeutic indication 'diabetic patients receiving insulin' has been changed to 'insulin treated persons with diabetes'.

Under diagnostic indications the division into examinations with radiography/endoscopy and CT/NMR/DSA has been deleted. The indication is not general 'Motility inhibitor in examinations of the gastrointestinal tract', with no mention of type of procedure.

Section 4.2. Posology and method of administration

An important change here is that intravenous injection is no longer recommended for the therapeutic indication, treatment of severe hypoglycaemia. The section dealing with dosage and administration for severe hypoglycaemia is no longer divided into administration by medical personnel or by relatives since it is now equally applicable to both. The dosage for children has not been changed, but the wording has been clarified as the previous wording was ambiguous.

For the diagnostic indication it is now stated that administration should only be by medical personnel. A new statement has been added that oral carbohydrate should be given at the end of the diagnostic procedure if compatible with the diagnostic procedure applied. To be consistent with the more general diagnostic indication (Section 4.1) mention of dosages specific procedures (CT/NMR/DSA) has been deleted.

Section 4.3 Contraindications

Hypersensitivity to 'any of the excipients' has been changed to specifically mention lactose. This is the only excipient in GlucaGen which has the potential for causing hypersensitivity reactions.

Section 4.4 Special warnings and precautions for use

The warnings have been divided into those relevant for the therapeutic indication and those relevant for the diagnostic indication.

A new paragraph has been included under the diagnostic indication. This concerns patients experiencing discomfort especially if they have been fasting, and the need for oral carbohydrate at the end of the procedure. The possibility of patients needing intravenous glucose under certain circumstances is also mentioned.

A new warning that GlucaGen should not be given via intravenous infusion has been included.

Section 4.7 Effect on ability to drive and use machines

This has been amended to state that no studies have been performed and to include a warning concerning the possibility of hypoglycaemia following use of GlucaGen in diagnostic procedures.

Section 4.8 Undesirable effects

This section has been amended so that adverse events are separated into those occurring with the therapeutic indication and those occurring with the diagnostic indication.

Section 6.5 Nature and contents of container

This section now includes details of the second type of container for the diluent (glass vial); this is not available in the UK and a comment has been added as such.

Section 6.6. Special precautions for disposal

Instructions of ruse of the presentation containing tow vials is included (not relevant for UK)

The principal changes are as follows:

1. Name of the medicinal product

The name of the product has been harmonised throughout the EU. In Ireland this has meant a minor name change from 'GlucaGen 1 mg HypoKit' to 'GlucaGen HypoKit 1 mg'.

2. Qualitative and quantitative composition

Reference included to glucagon being produced in Saccharomyces cerivisiae cells by recombinant DNA technology.

3. Pharmaceutical form

A description of the glucagon powder and the solvent has been included.

4.2. Posology and method of administration

The general statement that reconstituted GlucaGen is given by subcutaneous, intramuscular or intravenous injection which was given at the beginning of this section has been deleted. Instead the recommended routes of administration are given as appropriate for each indication. It should be noted that intravenous administration is no longer recommended for treatment of severe hypoglycaemia, even when administered by medical personnel.  

For treatment of severe hypoglycaemia the recommended dosage for children has been reworded and separated from the dosage for adults as the previous wording was considered ambiguous.

For the diagnostic indications two additional statements have been included:

'GlucaGen must be administered by medical personnel'

and

'After end of the diagnostic procedure oral carbohydrate can be given, if this is compatible with the diagnostic procedure applied.'

4.3. Contraindications

Hypersensitivity to lactose has been included.

4.4. Special warnings and special precautions for use

The statement concerning the need for caution if glucagon is used in patients with insulinoma has been expanded to state that caution is required with regard to relapse of hypoglycaemia.

A new paragraph has been added concerning possible effects of use of glucagon in diagnostic procedures and precautions to take after the procedure:

'Persons who have been given glucagon in connection with diagnostic procedures amy experience discomfort, in particular if they have been fasting. Nausea, hypoglycaemia and blood pressure changes have been reported in these situations. After the end of a diagnostic procedure oral carbohydrate can be given to patients who have been fasting, if this is compatible with the diagnostic procedure applied. In case of severe hypoglycaemia, intravenously given glucose may be required.'

A warning that 'GlucaGen should not be given by intravenous infusion' has been included.

4.7 Effect on ability to drive and use machines

A new statement has been included:

'No studies on the effects on the ability to drive and use machines have been performed. After diagnostic procedures hypoglycaemia has been reported infrequently. Therefore driving a car should be avoided until the patient has had a meal with carbohydrate.'

4.8 Undesirable effects

The whole section has been revised according to new requirements for describing adverse reactions; this includes tabulation of adverse reactions to include frequency, and separation of adverse reactions which may occur in connection with treatment of hypoglycaemia from adverse reactions which may occur in connection with diagnostic use.

Hypertension is a new adverse reaction listing. It is noted that cardiovascular adverse events have only been reported when GlucaGen is used as an adjunct in endoscopic or radiographic procedures.

A note that nausea and vomiting sometimes seen on injection of glucagon may also be seen 2-3 hours after injection.  

6. Pharmaceutical particulars

There have been a number of editorial changes to sections 6.1, 6.3, 6.4, 6.5 and 6.6. No additional information has been included other than statements in section 6.6 describing the appearance of the reconstituted solution and that unused product should be disposed of in accordance with local requirements.