Drugs List

Therapeutic Indications

Uses

Diabetes mellitus

Treatment of diabetes mellitus in adults, adolescents and children over the age of 10 years.

Administration

For subcutaneous injection only.

To be injected subcutaneously in the thigh or abdominal wall. If convenient the gluteal or deltoid regions may be used. Injection sites should be rotated within the same region.

This product is not to be used in insulin infusion pumps.

Contraindications

Children under 6 years
Hypoglycaemia

Precautions and Warnings

Children aged 6 to 10 years
Elderly
Infection
Breastfeeding
Delayed food absorption
Hepatic impairment
Pregnancy
Renal impairment

Insulin requirements may be diminished by renal or hepatic impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Evaluate patient's ability to drive/operate machinery regularly
Change in injection site area may necessitate dose adjustment
Consider cutaneous amyloidosis if injection site subcutaneous lumps occur
Discard if suspension is not uniformly white and cloudy
Rotate injection sites within a given area to avoid lipodystrophy
Use designated delivery device only
Hypoglycaemic symptoms may be masked or altered in long duration diabetes
Hypoglycaemic symptoms may be masked/altered in intensified insulin therapy
Advise patient to report cutaneous amyloidosis symptoms
Antibodies to ingredient may develop
Consider dose reduction to prevent hypoglycaemia if dietary intake reduced
Exercise immediately after a meal may increase risk of hypoglycaemia
Increased activity: insulin requirements may occasionally be increased
Risk of hypoglycaemia may be increased by exercise or ingestion of alcohol
Consider dosage modification if diet or exercise levels are changed
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

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may cause diabetic ketoacidosis and hyperglycaemia. The first symptoms of hyperglycaemia usually develop gradually over a period of hours or days. Symptoms include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events may lead to diabetic ketoacidosis, which is potentially lethal.

If the insulin dose is too high in relation to the insulin requirement, hypoglycaemia may occur. In case of hypoglycaemia (or if hypoglycaemia is suspected) insulin biphasic aspart should not be injected. After stabilising the patient's blood glucose, adjustment of the dose should be considered.

Glucose monitoring should be intensified in elderly patients. Compared with biphasic human insulin, insulin biphasic aspart may have a more pronounced glucose lowering effect up to 6 hours after injection. This will need to be compensated for in the individual patient through dose adjustment and/or food intake.

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for cardiac failure. If this combination is prescribed, patients should be observed for symptoms of heart failure, including weight gain and oedema. Pioglitazone should be discontinued if there is any deterioration in cardiac symptoms.

Insulin resistance frequently occurs in patients with lipid disorders, hypertension and ischaemic heart disease. More than 200 units of insulin daily are usually required in patients with insulin resistance. Greatly increased insulin requirements may be due to factors including antibody formation, infections, endocrine hyperfunctional states (e.g. acromegaly, Cushing's syndrome, thyrotoxicosis) or stress.

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.

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.

Rapid acting insulin analogues aspart and lispro are structurally very similar to human insulin and present a low risk factor when used in pregnancy and they are recommended in current national guidelines. There is inadequate human data to support such statements for insulin glulisine. However, Briggs (2015) concludes that there is no reason to believe that insulin glulisine would pose a risk to the embryo or foetus different from that of other insulins.

There is insufficient experience regarding the use of long-acting insulin analogues during pregnancy. Schaefer (2015) 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.

The use of insulin of animal origin is not recommended during pregnancy, as it is believed to cross the human placenta via an insulin-antibody complex. Studies have also shown an association between levels of animal insulin in the cord blood and development of foetal macrosomia, though further study into this area is required.

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, 2015) 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

Anaphylactic reaction
Angioneurotic oedema
Anxiety
Breathing difficulties
Cognitive impairment
Cold sweat
Concentration difficulties
Confusion
Convulsions
Coolness of skin
Cutaneous amyloidosis
Decrease in blood pressure
Drowsiness
Fatigue
Gastro-intestinal disturbances
Headache
Hunger
Hypersensitivity reactions
Hypoglycaemia
Injection site reactions
Itching
Lipodystrophy (injection site)
Localised and generalised rash
Nausea
Nervousness
Oedema
Palpitations
Peripheral neuropathy
Refraction anomalies
Skin eruption
Sweating
Tiredness
Tremor
Unconsciousness
Urticaria
Visual disturbances
Weakness
Worsening of diabetic retinopathy (temporary)

Presentation

Injection containing soluble insulin aspart and protamine-crystallised insulin aspart

Drugs List

Therapeutic Indications

Uses

Diabetes mellitus

Treatment of diabetes mellitus in adults, adolescents and children over the age of 10 years.

Dosage

Dosing should be individualised to the needs of the patient. Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

Duration of action will vary according to injection site, dose, blood flow, temperature and physical activity or lifestyle factors.

Insulin biphasic aspart has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal, or if necessary, shortly after a meal.

Adults

Elderly

Children

Administration

For subcutaneous injection only.

To be injected subcutaneously in the thigh or abdominal wall. If convenient the gluteal or deltoid regions may be used. Injection sites should be rotated within the same region.

This product is not to be used in insulin infusion pumps.

Contraindications

Children under 6 years
Hypoglycaemia

Precautions and Warnings

Children aged 6 to 10 years
Elderly
Infection
Breastfeeding
Delayed food absorption
Hepatic impairment
Pregnancy
Renal impairment

Insulin requirements may be diminished by renal or hepatic impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Evaluate patient's ability to drive/operate machinery regularly
Change in injection site area may necessitate dose adjustment
Consider cutaneous amyloidosis if injection site subcutaneous lumps occur
Discard if suspension is not uniformly white and cloudy
Rotate injection sites within a given area to avoid lipodystrophy
Use designated delivery device only
Hypoglycaemic symptoms may be masked or altered in long duration diabetes
Hypoglycaemic symptoms may be masked/altered in intensified insulin therapy
Advise patient to report cutaneous amyloidosis symptoms
Antibodies to ingredient may develop
Consider dose reduction to prevent hypoglycaemia if dietary intake reduced
Exercise immediately after a meal may increase risk of hypoglycaemia
Increased activity: insulin requirements may occasionally be increased
Risk of hypoglycaemia may be increased by exercise or ingestion of alcohol
Consider dosage modification if diet or exercise levels are changed
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

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may cause diabetic ketoacidosis and hyperglycaemia. The first symptoms of hyperglycaemia usually develop gradually over a period of hours or days. Symptoms include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events may lead to diabetic ketoacidosis, which is potentially lethal.

If the insulin dose is too high in relation to the insulin requirement, hypoglycaemia may occur. In case of hypoglycaemia (or if hypoglycaemia is suspected) insulin biphasic aspart should not be injected. After stabilising the patient's blood glucose, adjustment of the dose should be considered.

Glucose monitoring should be intensified in elderly patients. Compared with biphasic human insulin, insulin biphasic aspart may have a more pronounced glucose lowering effect up to 6 hours after injection. This will need to be compensated for in the individual patient through dose adjustment and/or food intake.

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for cardiac failure. If this combination is prescribed, patients should be observed for symptoms of heart failure, including weight gain and oedema. Pioglitazone should be discontinued if there is any deterioration in cardiac symptoms.

Insulin resistance frequently occurs in patients with lipid disorders, hypertension and ischaemic heart disease. More than 200 units of insulin daily are usually required in patients with insulin resistance. Greatly increased insulin requirements may be due to factors including antibody formation, infections, endocrine hyperfunctional states (e.g. acromegaly, Cushing's syndrome, thyrotoxicosis) or stress.

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.

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.

Rapid acting insulin analogues aspart and lispro are structurally very similar to human insulin and present a low risk factor when used in pregnancy and they are recommended in current national guidelines. There is inadequate human data to support such statements for insulin glulisine. However, Briggs (2015) concludes that there is no reason to believe that insulin glulisine would pose a risk to the embryo or foetus different from that of other insulins.

There is insufficient experience regarding the use of long-acting insulin analogues during pregnancy. Schaefer (2015) 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.

The use of insulin of animal origin is not recommended during pregnancy, as it is believed to cross the human placenta via an insulin-antibody complex. Studies have also shown an association between levels of animal insulin in the cord blood and development of foetal macrosomia, though further study into this area is required.

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, 2015) 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

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

Advise patients of the warning signs 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 female patients to consult their GP if pregnancy is suspected or planned.

Patients should carry glucose tablets or other suitable form of sugar with them to take in the event of hypoglycaemia and should be advised of the warning signs that they may experience.

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 patients that their ability to drive or operate machinery may be impaired.

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

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

Anaphylactic reaction
Angioneurotic oedema
Anxiety
Breathing difficulties
Cognitive impairment
Cold sweat
Concentration difficulties
Confusion
Convulsions
Coolness of skin
Cutaneous amyloidosis
Decrease in blood pressure
Drowsiness
Fatigue
Gastro-intestinal disturbances
Headache
Hunger
Hypersensitivity reactions
Hypoglycaemia
Injection site reactions
Itching
Lipodystrophy (injection site)
Localised and generalised rash
Nausea
Nervousness
Oedema
Palpitations
Peripheral neuropathy
Refraction anomalies
Skin eruption
Sweating
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: March 2017

Reference Sources

Joint Formulary Committee. British National Formulary. 72nd ed. London: BMJ Group and Pharmaceutical Press; 2016.

Paediatric Formulary Committee. BNF for Children 2016-2017. London: BMJ Group, Pharmaceutical Press, and RCPCH Publications; 2016.

Summary of Product Characteristics: NovoMix 30 Penfill 100 units/ml, NovoMix 30 FlexPen 100 units/ml. Novo Nordisk Limited. Revised December 2016.

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