Insulin Degludec

Registered South African indications:

• Diabetes mellitus

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Severe renal impairment or ESRD
• Severe hepatic impairment
• Elderly
• Severe hyperglycaemia
• Hypoglycaemia
• Long-standing diabetes mellitus
• Concomitant infections (e.g. fever and infections)
• Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland
• Transferring patient to another type, brand or manufacturer of insulin
• Changes to meal plan (e.g. skipping a meal)
• Unplanned strenuous physical exercise
• Greatly improved blood glucose control (e.g. intensified insulin therapy)
• Visual impairment
• Diabetic retinopathy
• Driving and the ability to operate heavy machinery

Forms avail. in SA and covered in this monograph: inj

Insulin-dependent diabetes mellitus 

The dose of insulin should be individually adjusted

• SC (inj): Initial: 0.4-0.5 units/kg/day; Maintenance: 0.4-1.0 units/kg/day
• See link: General prescribing points on the principles of insulin dosing

For patients at higher risk of hypoglycaemia (on oral hypoglycaemic agents, malnutrition, elderly, and low cognitive status), conservative initial doses of 0.2-0.4 units/kg/day may be considered to avoid the potential for hypoglycaemia

Higher initial doses may be required in patients who are obese, sedentary, or presenting with ketoacidosis

Type 2 diabetes mellitus: can be combined with oral antidiabetic products, used alone or in combination with bolus insulin

Type 1 diabetes mellitus: must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements

Insulin degludec is intended for subcutaneous administration only

Patients who forget a dose are advised to take it upon discovery and then resume their once daily dosage schedule. Ensure a minimum of 8 hours between injections

See Additional Prescriber Points

Not registered for use in South Africa for children and adolescents

Pregnancy

• Caution
• There is no clinical experience with the use of insulin degludec in pregnant women
• Insulin is the preferred treatment of type 1and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus when pharmacologic therapy is needed. Insulin products other than insulin degludec are currently recommended to treat diabetes mellitus in pregnancy
• Animal reproduction studies have not revealed any difference between insulin degludec and human insulin regarding embryotoxicity and teratogenicity
• As with all insulins, the primary concern is severe maternal hypoglycaemia
• In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy
• Insulin requirements usually decrease in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements usually return rapidly to pre-pregnancy values

Breastfeeding

• Compatible 
• There is no clinical experience with insulin degludec during breastfeeding
• In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma
• It is unknown whether insulin degludec is excreted in human milk
• No metabolic effects are anticipated in the breastfed newborn/infant

Fertility

• Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility

Renal impairment

• eGFR >30-89 ml/min/1.73m²: No dose adjustment recommended
• eGFR <29 ml/min/1.73m² or ESRD: Caution; dose adjustment recommended
  Reduce recommended dose by up to 20%. Monitor glucose target and renal function

Hepatic impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; dose adjustment recommended
  Adjust insulin dose according to blood glucose target

Elderly

• Caution; dose adjustment recommended
  Conservative initial dose is required to avoid risk for hypoglycaemia. Reduce the initial recommended dose by 10-20%. Avoid intensive glucose control (risk for hypoglycaemia and CVS-related mortality)
  Control of geriatric patient's blood glucose needs to be individualised. In cases of severe hypoglycaemia, dosage reductions of 20-40% have been recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Prohibited - At all times

Endocrine and Metabolic Disorders

• Hypoglycaemia
  - Thirst
  - Increased frequency of urination
  - Nausea and/or vomiting
  - Drowsiness
  - Flushed dry skin
  - Dry mouth
  - Loss of appetite
  - Acetone odour of breath

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Lipodystrophy
• Injection site reactions
  - Haematoma
  - Pain
  - Haemorrhage
  - Erythema
  - Nodules
  - Swelling
  - Discolouration
  - Warmth
  - Injection site mass

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Swelling of the tongue and lips
  - Diarrhoea
  - Nausea
  - Tiredness
  - Itching

Sensory Disorders

• Diabetic retinopathy

Others

• Peripheral oedema

• Pioglitazone
• Beta-blockers
• Octreotide/lanreotide
• Alcohol
• Oral antidiabetic medicinal products
• GLP-1 receptor agonists
• Monoamine oxidase inhibitors
• Angiotensin converting enzyme (ACE) inhibitors
• Salicylates
• Anabolic steroids
• Sulfonamides
• Oral contraceptives
• Thiazides
• Glucocorticoids
• Thyroid hormones
• Sympathomimetics
• Growth hormone
• Danazol

Diabetes mellitus

• Blood glucose
• HbA1c
• Renal function
• Hepatic function

Gestational diabetes mellitus

• Blood glucose 4 times daily (1 fasting and 3 after meals)

Method of administration

• Insulin degludec MUST NOT be administered through the following routes:
  - Intravenous administration
  - Intramuscular administration
  - Use with insulin infusion pumps
• Insulin degludec should be avoided in patients with acute severe hyperglycaemic attacks and/or DKA
• Insulin degludec is administered subcutaneously by injection in the thigh, the upper arm or the abdominal wall
• Injection sites are always to be rotated within the same region in order to reduce the risk of lipodystrophy
• Insulin degludec must not be drawn from the cartridge of the pre-filled pen into a syringe
• Patients should be instructed to always use a new needle. The re-use of insulin pen needles increases the risk of blocked needles, which may cause under- or overdosing

Hyperglycaemia

• Insulin degludec should not be used to treat severe hyperglycaemia; administration of rapid-acting insulin is recommended instead
• Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead to hyperglycaemia and potentially to diabetic ketoacidosis
• Concomitant illness, especially infections may lead to hyperglycaemia thereyby causing an increased insulin requirement
• Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include symptoms listed above in Adverse Reactions
• In type 1 diabetes, untreated hyperglycaemic events usually lead to diabetic ketoacidosis, which is potentially lethal

Incompatibilities

• Substances added to insulin degludec may cause degradation of insulin degludec
• Insulin degludec must not be added to infusion fluids
• Insulin degludec must not be mixed with other medicinal products

Transfer from other insulin medicinal products

• Close glucose monitoring is recommended during the transfer and in the following weeks. Doses and timing of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetic treatment may need to be adjusted
• For type 2 diabetes mellitus patients taking once-daily basal, basal-bolus, premix or self-mixed insulin therapy, changing the basal insulin to insulin degludec can be done unit-to-unit based on the previous insulin dose followed by individual dose adjustments
• For type 2 diabetes mellitus patients, a dose reduction of 20% based on the previous basal insulin dose followed by individual dosage adjustments should be considered when
  - transferring to insulin degludec from twice-daily basal insulin
  - transferring to insulin degludec from insulin glargine (300 units/ml)
• For type 1 diabetes mellitus patients, a dose reduction of 20% based on the previous basal insulin dose or basal component of a continuous subcutaneous insulin infusion regimen should be considered with subsequent individual dosage adjustments based on the glycaemic response

Use in combination with GLP-1 receptor agonists in type 2 diabetes mellitus

• The recommended daily starting dose is 10 units followed by individual dosage adjustments
• When adding GLP-1 receptor agonists to insulin degludec, it is recommended to reduce the dose of insulin degludec by 20% to minimise the risk of hypoglycaemia. Subsequently, dosage should be adjusted individually

Special precautions for storage before first use

• Store in a refrigerator (2^oC - 8^oC). Do not freeze
• Keep away from the freezing element
• Keep the cap on the pen in order to protect it from light

Special precautions for disposal and other handling

• This medicinal product is intended for use by one person only. It must not be refilled
• Insulin degludec must not be used if the solution does not appear clear and colourless
• Insulin degludec that has been frozen must not be used
• Any waste material should be disposed of in accordance with local requirements

Insulin degludec is an ultra-long-acting basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect. Insulin degludec differs from human insulin by the omission of the amino acid threonine in position B-30 of the B-chain, and the subsequent addition of a side chain composed of glutamic acid and a C16 fatty acid. Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin. The blood-glucose-lowering effect of insulin degludec is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

Injection (per ml) 100u

• Tresiba (Novo Nordisk) originator