Novo Nordisk Limited

GlucaGen HypoKit 1 mg powder and solvent for solution for injection.

Active substance: Glucagon, rDNA (produced by recombinant DNA technology in Saccharomyces Cerevisiae).

Glucagon rDNA, is structurally identical to human glucagon.

- Glucagon 1 mg (1 IU) as hydrochloride

One vial contains 1 mg glucagon corresponding to 1 mg glucagon/ml after reconstitution.

For excipients, see section 6.1

Powder and solvent for solution for injection.

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

Therapeutic indications

Treatment of severe hypoglycaemic reactions, which may occur in the management of insulin treated persons with diabetes mellitus.

Diagnostic indications

Motility inhibition in examinations of the gastrointestinal tract

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

Therapeutic indication (Severe hypoglycaemia)

Dosage for adult patients

Administer 1 mg.

Dosage for paediatric patients

Administer 1 mg (children above 25 kg or older than 6-8 years) or 0.5 mg (children below 25 kg or younger than 6-8 years).

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 motility)

GlucaGen must be administered by medical personnel. Onset of action after an intravenous injection of 0.2 - 0.5mg 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 1 - 2mg occurs after 5-15 minutes and lasts approximately 10-40 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 - 2mg 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 - 0.5mg given intravenously or 1mg given intramuscularly; the usual dose to relax the colon is 0.5 - 0.75mg intravenously or 1 - 2mg intramuscularly.

Hypersensitivity to glucagon or lactose.

Phaeocromocytoma.

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.

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, 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.

GlucaGen should not be given by intravenous infusion.

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.

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

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.

Glucagon is cleared from the bloodstream very fast (mainly by the liver) (t ½ = 3-6 min.); thus the amount excreted in the milk of nursing mothers following treatment of severe hypoglycaemic reactions will 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.

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 oral carbohydrate.

Frequencies of undesirable effects related to GlucaGen treatment during clinical trials and/or post marketing surveillance are presented below. Undesirable effects which have not been observed in clinical trials but have been reported spontaneously are presented as "very rare". During marketed use reporting of adverse 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

Diagnostic indication

*¹ After a diagnostic procedure it can be more pronounced in patients having fasted (see section 4.4 Special warnings and precautions for use).

*² Cardiovascular adverse events have only been reported when GlucaGen is used an adjunct in endoscopic or radiographic procedures.

Adverse effects of overdose have not been reported. See section 4.8.

In case of dosages substantially above the approved range, the serum potassium may decrease and should be monitored and corrected if needed.

Pharmacotherapeutic group : H 04 AA 01.

Glucagon is a hyperglycaemic agent that mobilises hepatic glycogen, which is released into the blood as glucose. 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.

Glucagon stimulates the release of catecholamines. In the presence of phaeo-chromocytoma, glucagon can cause the tumour to release large amounts of catecholamines which will cause an acute hypertensive reaction.

Glucagon inhibits the tone and motility of the smooth muscle in the gastrointestinal tract.

Metabolic clearance rate of glucagon in humans is approximately 10ml/kg/min. It is degraded enzymatically in the blood plasma and in the organs to which it is distributed. The liver and kidney are major sites of glucagon clearance, each organ contributing about 30% to the overall metabolic clearance rate.

Glucagon has a short half-life in the blood of about 3-6 minutes.

Onset of effect occurs within 1 min. after an intravenous injection. Duration of action is in the range of 5-20 min. depending upon dose and the organ under examination. The onset of effect occurs within 5-15 minutes after an intramuscular injection, with a duration of 10-40 min. depending upon dose and organ.

When used in treatment of severe hypoglycaemia, an effect on blood glucose is usually seen within 10 minutes.

No relevant preclinical data exist that provide information useful to the prescriber.

Lactose monohydrate

Hydrochloric acid for pH adjustment

Sodium hydroxide for pH adjustment

Water for injections

The reconstituted solution contains glucagon 1mg/ml and lactose monohydrate 107 mg/ml.

There are no known incompatibilities with GlucaGen.

Prior to reconstitution, the shelf life of the product is 3 years.

The reconstituted GlucaGen should be used immediately after preparation.

The sealed container should be protected from light and stored in a refrigerator (+2^oC to 8^oC).

The user can store GlycaGen HypoKit at room temperature (up to 25^oC) for 18 months within the shelf life period.

Freezing should be avoided.

If in rare cases the reconstituted product shows any signs of fibril formation (viscous appearance) or insoluble matter it should be discarded.

Container for GlucaGen:

Vial made of glass type 1, Ph.Eur., closed with a bromobutyl stopper and covered with an aluminium cap.

Container for solvent:

Vial made of glass type I, Ph. Eur., closed with a bromobutyl disc with teflon and covered with an aluminium cap.

Pre-filled syringe of glass type 1, Ph. Eur., with plunger (bromobutyl rubber) and needle.

The vial is provided with a tamper-proof plastic cap which must be removed before use.

Not all presentations of GlucaGen are necessarily marketed.

Reconstitution

GlucaGen 1 mg

Draw up the water for injections (1.1 ml) in a disposable syringe. Inject the water for injections into the vial containing the freeze-dried glucagon.

Shake the vial gently until the glucagon is completely dissolved and the solution is clear. Withdraw the solution back into the syringe.

GlucaGen HypoKit 1 mg:

Inject the water for injections (1.1ml) into the vial containing the freeze-dried glucagon. Shake the vial gently until the glucagon is completely dissolved and the solution is clear. Withdraw the solution back into the syringe.

Note that a syringe with a thinner needle and a finer graduation may be more suitable for use in diagnostic procedures.

The reconstituted solution appears clear and colourless and forms an injection of 1mg (1 IU) per ml to be administered subcutaneously, intramuscularly or intravenously.

Any unused product or waste material should be disposed of in accordance with local requirements.

Novo Nordisk A/S

Novo Allē

DK-2880 Bagsvaerd

Denmark

PA 0218/031/002

Date of first authorisation: 17 December 1991

Date of last renewal: 15 October 2006

September 2009