Drugs List

Therapeutic Indications

Uses

Diabetes mellitus Type 2 where oral therapy inadequate
Insulin-dependent diabetes mellitus

Insulin degludec is a long acting insulin for treatment of Type 1 diabetes mellitus. It must be used in combination with a short acting insulin to cover mealtime insulin requirements.

In patients with type 2 diabetes mellitus, insulin degludec can be administered alone, in combination with oral anti-diabetic medicinal products as well as in combination with GLP-1 receptor agonists and bolus insulin.

Administration

Insulin degludec is for subcutaneous administration only.

Administer in the thigh, the upper arm or the abdominal wall.

Contraindications

Children under 1 year

Precautions and Warnings

Elderly
Breastfeeding
Hepatic impairment
Pregnancy
Renal impairment

Advise patient to take precautions to avoid hypoglycaemia whilst driving
Contains metacresol
Change in injection site area may necessitate dose adjustment
Consider cutaneous amyloidosis if injection site subcutaneous lumps occur
Do not use if contents have been frozen
Not for use in infusion pumps or external or implanted insulin pumps
Rotate injection sites within a given area to avoid lipodystrophy
Solution must not be drawn from cartridge or pre-filled pen into a syringe
Use designated delivery device only
Use only if the solution is clear and colourless
Monitor dosage closely in presence of renal or hepatic impairment
Advise patient to report cutaneous amyloidosis symptoms
Antibodies to ingredient may develop
Compensatory response to hypoglycaemia may be impaired
Consider dose reduction to prevent hypoglycaemia if dietary intake reduced
Increased risk of early morning hypoglycaemia
Risk of hypoglycaemia may be increased by exercise or ingestion of alcohol
Consider dosage modification if diet or exercise levels are changed
Dose steps may not be equivalent between strengths/brands-see product info
Insulin requirements may increase during illness,puberty or emotional upset
Removal of stress factors may necessitate dose adjustment
Transfer from other brands of insulin may involve dosage adjustment
Pregnancy & breastfeeding: Insulin requirements may vary
Advise patient they have to inform the DVLA of antidiabetic medication
Advise patient to contact doctor if travel between time zones is planned
Advise patients of the warning signs of hypoglycaemia
Advise patients to have glucose available in the event of hypoglycaemia

As with other insulin analogues, patients with high insulin doses because of antibodies to human insulin may experience an improved insulin response with insulin degludec. With improved metabolic control and resulting increase in insulin sensitivity, a further adjustment in dosage regimen may become necessary.

Close glucose monitoring is recommended during transfer from other insulin products and in the following weeks. Doses and timing of concurrent rapid acting or short acting insulin products or other concomitant anti-diabetic treatment may need to be adjusted.

For patients with type 2 diabetes taking 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 basal insulin dose followed by individual dosage adjustments.

In children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake and physical activities in order to minimise the risk of hypoglycaemia.

For most patients with type 1 diabetes, changing the basal insulin to insulin degludec can be done unit-to-unit based on the previous basal insulin dose followed by individual dosage adjustments.
For patients with type 1 diabetes transferring from twice-daily basal insulin or if HbA1c is less than 8%, doses should be determined individually.

Cases of cardiac failure have been reported when pioglitazone and insulin are used in combination, especially in patients with a high risk of development of cardiac failure. If this combination is used, patients should be observed for symptoms of heart failure, weight gain and oedema. If deterioration in cardiac symptoms occurs, pioglitazone should be discontinued.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (rapid acting insulin, intermediate acting insulin, long acting insulin etc) species (human insulin analogue, animal), and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change of dose.

In order to avoid dosing errors and potential overdose, a syringe must never be used to draw the solution from the cartridge in the pre-filled pen.

Pregnancy and Lactation

Pregnancy

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/ng3 .

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

There is insufficient experience regarding the use of long-acting insulin analogues during pregnancy. Schaefer (2007) concludes that long-acting insulin analogues should be avoided during pregnancy. Current national guidelines state that if long-acting insulin analogues are required, then isophane insulin (sometimes referred to as NPH insulin) is the long-acting insulin of choice.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Insulin is a natural component of breast milk and insulin treatment of breastfeeding mothers should represent no risk to the infant. Insulin in breast milk is digested by the infant's gut (Briggs, 2011) and is thought to contribute to intestinal maturation and decrease the risk of contracting type 1 diabetes in breastfed infants (Lactmed, via Toxnet).

Proper insulin levels are required for lactation. Good glycaemic control decreases the delay in establishment of lactation that is observed in diabetic mothers as well as enhancing maternal serum and milk prolactin concentrations.

No adverse effects have been reported relating the use of insulin to breastfeeding, therefore it is considered safe to for diabetic mothers receiving insulin to continue breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal hunger
Allergic reaction
Anxiety
Cognitive impairment
Cold sweat
Concentration difficulties
Confusion
Convulsions
Cool pale skin
Cutaneous amyloidosis
Death
Drowsiness
Fatigue
Headache
Hypoglycaemia
Inflammation (injection site)
Insulin antibodies
Lipoatrophy
Lipodystrophy (injection site)
Lipohypertrophy
Local pain (injection site)
Local reaction at injection site
Nausea
Nervousness
Oral oedema
Palpitations
Peripheral oedema
Stinging, redness and swelling at injection site
Tiredness
Tremor
Unconsciousness
Urticaria
Visual disturbances
Weakness
Worsening of diabetic retinopathy (temporary)

Presentation

Solution for injection containing insulin degludec

Patients and professionals should be aware that the 200 units/ml strength is higher than that of other existing insulin products available in the UK.

Drugs List

Therapeutic Indications

Uses

Diabetes mellitus Type 2 where oral therapy inadequate
Insulin-dependent diabetes mellitus

Insulin degludec is a long acting insulin for treatment of Type 1 diabetes mellitus. It must be used in combination with a short acting insulin to cover mealtime insulin requirements.

In patients with type 2 diabetes mellitus, insulin degludec can be administered alone, in combination with oral anti-diabetic medicinal products as well as in combination with GLP-1 receptor agonists and bolus insulin.

Dosage

The desired blood glucose levels, the insulin preparations to be used and the insulin dosage (doses and timings) must be determined individually and adjusted to suit the patient's diet, physical activity and life-style.

Insulin degludec is an insulin analogue with a prolonged duration of action. It should be given once daily, at any time, but at the same time each day.

A minimum of 8 hours between injections should always be ensured.

Patients who forget a dose are advised to take it upon discovery and then resume their usual-once daily dosing schedule.

There is no clinical experience with flexibility in dosing time in children and adolescents.

Type 2 diabetes
When administering insulin degludec alone or to an existing regimen with or without GLP-1 receptor agonists, the recommended daily starting dose is 10 units followed by individual dosage adjustments.

When adding GLP-1 receptor agonists to an existing insulin degludec regimen, the dosage of insulin degludec should be reduced by 20%. Subsequent individual dosage adjustments are required.

Type 1 diabetes
Insulin degludec is administered once daily and used in combination with short acting meal-time insulin. Subsequent individual dosage adjustments are required.

Additional Dosage Information

Administration

Insulin degludec is for subcutaneous administration only.

Administer in the thigh, the upper arm or the abdominal wall.

Contraindications

Children under 1 year

Precautions and Warnings

Elderly
Breastfeeding
Hepatic impairment
Pregnancy
Renal impairment

Advise patient to take precautions to avoid hypoglycaemia whilst driving
Contains metacresol
Change in injection site area may necessitate dose adjustment
Consider cutaneous amyloidosis if injection site subcutaneous lumps occur
Do not use if contents have been frozen
Not for use in infusion pumps or external or implanted insulin pumps
Rotate injection sites within a given area to avoid lipodystrophy
Solution must not be drawn from cartridge or pre-filled pen into a syringe
Use designated delivery device only
Use only if the solution is clear and colourless
Monitor dosage closely in presence of renal or hepatic impairment
Advise patient to report cutaneous amyloidosis symptoms
Antibodies to ingredient may develop
Compensatory response to hypoglycaemia may be impaired
Consider dose reduction to prevent hypoglycaemia if dietary intake reduced
Increased risk of early morning hypoglycaemia
Risk of hypoglycaemia may be increased by exercise or ingestion of alcohol
Consider dosage modification if diet or exercise levels are changed
Dose steps may not be equivalent between strengths/brands-see product info
Insulin requirements may increase during illness,puberty or emotional upset
Removal of stress factors may necessitate dose adjustment
Transfer from other brands of insulin may involve dosage adjustment
Pregnancy & breastfeeding: Insulin requirements may vary
Advise patient they have to inform the DVLA of antidiabetic medication
Advise patient to contact doctor if travel between time zones is planned
Advise patients of the warning signs of hypoglycaemia
Advise patients to have glucose available in the event of hypoglycaemia

As with other insulin analogues, patients with high insulin doses because of antibodies to human insulin may experience an improved insulin response with insulin degludec. With improved metabolic control and resulting increase in insulin sensitivity, a further adjustment in dosage regimen may become necessary.

Close glucose monitoring is recommended during transfer from other insulin products and in the following weeks. Doses and timing of concurrent rapid acting or short acting insulin products or other concomitant anti-diabetic treatment may need to be adjusted.

For patients with type 2 diabetes taking 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 basal insulin dose followed by individual dosage adjustments.

In children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake and physical activities in order to minimise the risk of hypoglycaemia.

For most patients with type 1 diabetes, changing the basal insulin to insulin degludec can be done unit-to-unit based on the previous basal insulin dose followed by individual dosage adjustments.
For patients with type 1 diabetes transferring from twice-daily basal insulin or if HbA1c is less than 8%, doses should be determined individually.

Cases of cardiac failure have been reported when pioglitazone and insulin are used in combination, especially in patients with a high risk of development of cardiac failure. If this combination is used, patients should be observed for symptoms of heart failure, weight gain and oedema. If deterioration in cardiac symptoms occurs, pioglitazone should be discontinued.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (rapid acting insulin, intermediate acting insulin, long acting insulin etc) species (human insulin analogue, animal), and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change of dose.

In order to avoid dosing errors and potential overdose, a syringe must never be used to draw the solution from the cartridge in the pre-filled pen.

Pregnancy and Lactation

Pregnancy

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/ng3 .

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

There is insufficient experience regarding the use of long-acting insulin analogues during pregnancy. Schaefer (2007) concludes that long-acting insulin analogues should be avoided during pregnancy. Current national guidelines state that if long-acting insulin analogues are required, then isophane insulin (sometimes referred to as NPH insulin) is the long-acting insulin of choice.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Insulin is a natural component of breast milk and insulin treatment of breastfeeding mothers should represent no risk to the infant. Insulin in breast milk is digested by the infant's gut (Briggs, 2011) and is thought to contribute to intestinal maturation and decrease the risk of contracting type 1 diabetes in breastfed infants (Lactmed, via Toxnet).

Proper insulin levels are required for lactation. Good glycaemic control decreases the delay in establishment of lactation that is observed in diabetic mothers as well as enhancing maternal serum and milk prolactin concentrations.

No adverse effects have been reported relating the use of insulin to breastfeeding, therefore it is considered safe to for diabetic mothers receiving insulin to continue breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise patients a minimum of 8 hours between injections should always be ensured.

Patients should be shown the container to confirm the version of insulin is the one they are expecting.

Advise patient to always use a new needle. The re-use of insulin pen needles increases the risk blocked needles which can cause over or underdosing.

Patient should be advised that injection sites should be rotated within the same area to minimise the risk of developing lipodystrophy.

Advise patient to seek medical advice regarding dosage if they are intending to travel between different time zones.

Advise female patients to consult their GP if pregnancy is suspected or planned.

Advise patient of the warning signs of hypoglycaemia.

Diabetic patients should be advised to carry a source of sugar, for example some sugar lumps or a few biscuits in case of hypoglycaemia.

Patients should be aware that emotional upset or concurrent illness, especially infection and fever, will usually increase insulin requirements.

Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly.

Advise patients to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent hypoglycaemic episodes.

Advise patient to report cutaneous amyloidosis symptoms.

Inform the patient that he/she needs to inform the Driving and Vehicle Licensing Agency (DVLA) about the medication they are receiving. The Drivers Medical Group at the DVLA will be able to advise the patient on the legal issues surrounding the treatment of diabetes mellitus and driving.

The DVLA can be contacted by post at the following address:

Drivers' medical enquiries, DVLA, Swansea, SA99 1TU

By phone on 0300 790 6806; or by fax on 0845 850 0095

Detailed guidance on eligibility to drive, and precautions required, is available from the DVLA.

https://www.gov.uk/government/publications/at-a-glance

Further information concerning diabetes and driving may be obtained from the DVLA website at:

https://www.gov.uk/government/organisations/driver-and-vehicle-licensing-agency

Side Effects

Abnormal hunger
Allergic reaction
Anxiety
Cognitive impairment
Cold sweat
Concentration difficulties
Confusion
Convulsions
Cool pale skin
Cutaneous amyloidosis
Death
Drowsiness
Fatigue
Headache
Hypoglycaemia
Inflammation (injection site)
Insulin antibodies
Lipoatrophy
Lipodystrophy (injection site)
Lipohypertrophy
Local pain (injection site)
Local reaction at injection site
Nausea
Nervousness
Oral oedema
Palpitations
Peripheral oedema
Stinging, redness and swelling at injection site
Tiredness
Tremor
Unconsciousness
Urticaria
Visual disturbances
Weakness
Worsening of diabetic retinopathy (temporary)

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: August 2015

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Tresiba 100 units/mL, 200 units/mL Pre filled (FlexTouch), 100 units/mL Cartridge (Penfill). Novo Nordisk. Revised October 2017.

MHRA Drug Safety Update September 2020
Available at: https://www.mhra.gov.uk
Last accessed: 16 December 2020