Dasiglucagon

Dasiglucagon is a glucagon receptor agonist, an analogue of the natural hormone glucagon. It raises blood glucose by activating glucagon receptors on liver cells, which stimulates the breakdown of glycogen and the release of glucose from the liver.

Mechanism of Action

• Receptor activation: dasiglucagon binds hepatic glucagon receptors, which are G-protein-coupled receptors. DrugBank describes activation of adenylate cyclase and a rise in intracellular cyclic AMP, which stimulates glycogen breakdown and glucose production in the liver.
• Glycogen dependence: glucose is released mainly from liver glycogen, so hepatic glycogen stores are necessary for an antihypoglycaemic effect.
• Effect on glucose: in adults with type 1 diabetes, mean plasma glucose rose by 9.3 mmol/L (168 mg/dL) from baseline to 90 minutes after a dose. In paediatric patients aged 7 to 17 years the mean rise at 60 minutes was 9.0 mmol/L (162 mg/dL). Gender and injection site had no clinically meaningful effect.
• Clinical studies: three randomised, double-blind, placebo-controlled trials were done in type 1 diabetes, two in adults and one in paediatric patients aged 6 to 17 years. Dasiglucagon 0.6 mg was compared with placebo and, in two of the trials, with glucagon for injection 1.0 mg.
• Immunogenicity: anti-drug antibodies were uncommonly detected, with no evidence of an effect on pharmacokinetics, efficacy or safety, although data are limited.

Pharmacokinetics

• Absorption: after a 0.6 mg subcutaneous injection in adults, the mean peak plasma concentration was about 1,510 pmol/L at around 35 minutes.
• Distribution: the mean apparent volume of distribution was 47 to 57 L after subcutaneous administration.
• Metabolism: like native glucagon, it is cleared by proteolytic degradation in blood, liver and kidney. In vitro it does not inhibit CYP enzymes or drug transporters at clinically relevant concentrations.
• Elimination: half-life of about 30 minutes.
• Special populations: in paediatric patients aged 7 to 17 years with type 1 diabetes, the mean peak concentration was about 1,160 pmol/L at around 21 minutes. No formal studies have been done in hepatic impairment, yet no dose adjustment is required in renal or hepatic impairment or in the elderly.

• Severe hypoglycaemia: treatment of severe hypoglycaemia in adults, adolescents and children aged 6 years and over with diabetes mellitus.

• Hypersensitivity to dasiglucagon or to any of the excipients.
• Phaeochromocytoma: glucagon products can make this tumour release large amounts of catecholamines, causing an acute hypertensive reaction.

The most frequently reported adverse reactions are nausea (62.2%), vomiting (31.6%) and headache (9.6%). The reactions below come from clinical studies.

Very common (≥1/10): nausea, vomiting.

Common (≥1/100 to <1/10): headache, dizziness, diarrhoea, injection site erythema.

Uncommon (≥1/1,000 to <1/100): presyncope, palpitations, bradycardia, hypotension, hypertension, hot flush, upper abdominal pain, hyperhidrosis, injection site pruritus, injection site pain, injection site oedema, fatigue.

Hypersensitivity reactions, including anaphylactic reactions, have been seen with injectable glucagon and reported as very rare (fewer than 1 case per 10,000 patients); they are a known class effect of glucagon. In a placebo-controlled trial of 20 paediatric patients aged 7 to 17 years, the safety results were consistent with adults, except that nausea (65%) and vomiting (50%) were more frequent than in adults.

Dasiglucagon does not inhibit CYP enzymes or drug transporters in vitro at clinically relevant concentrations.

• Insulin: acts antagonistically to dasiglucagon.
• Indometacin: with indometacin, dasiglucagon may lose its ability to raise blood glucose, or may even produce hypoglycaemia.
• Warfarin: dasiglucagon may increase the anticoagulant effect of warfarin.
• Beta-blockers: a greater rise in pulse and blood pressure may be expected. It is transient because of the short half-life of dasiglucagon, but may need treatment in patients with coronary artery disease.

Dasiglucagon is given as a single subcutaneous injection as soon as severe hypoglycaemia is recognised. Severe hypoglycaemia requires the help of others, so patients and their carers should be taught its signs and symptoms and how to use the syringe, and patients should tell those around them about Zegalogue and its package leaflet.

Recommended Dose

• 0.6 mg as a subcutaneous injection, for adults, adolescents and children aged 6 years and over.
• No response after 15 minutes: an additional dose from a new pre-filled syringe may be given.
• Injection site: lower abdomen, buttocks, thigh or outer upper arm.

Instructions for Use

1. Insert the needle into the skin and press the plunger fully down until the syringe is empty.
2. If the person is unconscious, turn them on their side to prevent choking.
3. The carer should call for medical help right away.
4. If there is no response after 15 minutes, an additional dose from a new pre-filled syringe may be given while waiting for emergency help.
5. Once the patient has responded, give oral carbohydrate to restore liver glycogen and prevent relapse of hypoglycaemia.

Each pre-filled syringe contains a single dose and cannot be reused.

Special Populations

• Elderly: can be used, with no dose adjustment. Efficacy and safety data are very limited at 65 years of age and absent from 75 years upwards.
• Renal impairment: can be used, with no dose adjustment.
• Hepatic impairment: can be used, with no dose adjustment.
• Children: the adult dose applies from 6 years of age. Safety and efficacy below 6 years have not been established and no data are available.

Glycogen Stores and Relapse

Dasiglucagon works only if the liver holds enough glycogen. Once the patient has responded, oral carbohydrates are given to restore liver glycogen and prevent a relapse. Patients who are starving, or who have adrenal insufficiency, chronic alcohol abuse or chronic hypoglycaemia, may not have enough hepatic glycogen for dasiglucagon to work and should be treated with glucose.

Phaeochromocytoma

Glucagon stimulates catecholamine release. In the presence of a phaeochromocytoma, glucagon products can make the tumour release large amounts of catecholamines and cause an acute hypertensive reaction, so dasiglucagon is contraindicated.

Insulinoma

In patients with an insulinoma, glucagon products may first raise blood glucose, but dasiglucagon may directly or indirectly stimulate exaggerated insulin release from the tumour and cause hypoglycaemia. A patient who develops symptoms of hypoglycaemia after a dose should be given glucose orally or intravenously.

Latex and Sodium

In latex-sensitive individuals the medicinal product may cause severe allergic reactions. Each dose (0.6 mL) contains less than 1 mmol sodium (23 mg), that is to say it is essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data on dasiglucagon in pregnant women. Glucagon has been used in pregnant women with diabetes without known harm to the pregnancy, the unborn child or the newborn. Animal studies with dasiglucagon showed reproductive toxicity, but untreated hypoglycaemia in pregnancy can cause complications and may be fatal. Use should be considered only if the expected benefit justifies the potential risk to the foetus.
• Breastfeeding: dasiglucagon is cleared from the blood very quickly, so only extremely small amounts are expected in milk, and it is degraded in the child’s digestive tract and cannot be absorbed intact. It can be used during breastfeeding.
• Fertility: animal data show no effect on male or female fertility.

Effect on Driving

Dasiglucagon has no or negligible influence on the ability to drive and use machines. However, concentration and reaction may be impaired by the hypoglycaemia itself, which can persist briefly after treatment. This may be a risk in situations such as driving or using machines.

Store in a refrigerator (2–8 °C) and do not freeze. Keep the syringe in its original protective case to protect it from light, and keep it cold during transport and delivery.

During the shelf life, the product may be kept below 25 °C for a single period of no longer than 1 year, without passing the original expiry date. Once it has been out of the refrigerator it must not be returned. The new expiry date is written on the protective case label, the original date is crossed out, and the product is used or discarded by the new date. Keep out of the sight and reach of children.

The product is supplied as a glass (type I) pre-filled syringe with a staked stainless steel needle, containing 0.6 mL, in packs of 1 or 2 single-dose syringes; not all pack sizes may be marketed.

3 years when stored in a refrigerator (2–8 °C). Within this period it may be kept below 25 °C once, for no longer than 1 year, as described under Storage Conditions.

Prescription only (Rx): a medicinal product subject to medical prescription. Zegalogue is a rescue injection that a carer or another person gives to a patient with diabetes during severe hypoglycaemia, so it is supplied to the patient, the carer or the treating clinic on prescription, with cold-chain delivery because it is stored in a refrigerator. Patients and carers should be shown how to use the syringe and given the package leaflet.