Drugs List

Therapeutic Indications

Uses

Intermediate acting insulin for the treatment of diabetes mellitus.

Administration

The preparation is administered subcutaneously, in the upper arm, thigh or abdominal wall. If convenient the gluteal region or the deltoid region may be used.

Some brands may also be administered by intramuscular administration. Refer to patient information leaflet.

A subcutaneous injection into the thigh results in a slower and less variable absorption compared to other injection sites.

Injection into a lifted skin fold minimises the risk of intramuscular injection. The injection site should not be massaged after administration.

Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.

Do not use if solution has been frozen.

Incompatibilities

Not to be added to infusion liquids.

Contraindications

Hypoglycaemia

Precautions and Warnings

Be aware that hyperglycaemia and diabetic acidosis may occur as a result of inadequate dosing or discontinuation of treatment, especially in type 1 diabetes patients. If the insulin dose is high in relation to the insulin requirement hypoglycaemia may occur.

Symptoms of hyperglycaemia develop over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite and acetone odour of breath. In type 1 diabetes, untreated hyperglycaemia leads to diabetic ketoacidosis, which may be fatal.

If normal or reduced levels of glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) hypoglycaemia should be considered.

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:
in whom glycaemic control is markedly improved
in whom hypoglycaemia develops gradually
who are elderly
in whom an autonomic neuropathy is present
with a long history of diabetes
suffering from a psychiatric illness
receiving concurrent treatment with certain other medicinal products such as beta blockers
after transfer from animal insulin to human insulin

Adherence of the patient to the dosage and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dosage adjustment. These include:
change of the injection area
improved insulin sensitivity (e.g. by removal of stress factors)
unaccustomed, increased or prolonged physical activity
intercurrent illness (e.g. vomiting, diarrhoea)
inadequate food intake
missed meals
alcohol consumption
certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency)
concurrent treatment with certain other medicinal products

Pregnancy (see 'Pregnancy' section).
Breast feeding (see 'Lactation' section).

Intercurrent illness necessitates intensive metabolic monitoring. Urine tests for ketones and dose adjustment may be required. Insulin requirements are often increased. Type 1 diabetics must consume at least a small amount of carbohydrates regularly even if they feel unable to eat due to illness.

Patients planning travel between time zones should be advised to contact their doctor as injections and meals may have to be taken at different times.

Antibodies may form with treatment of human insulin but the titres are lower than those formed in response to animal insulins.

Do not use insulin isophane with infusion pumps.

Contains metacresol, which may cause allergic reactions.

Do not use if solution has been frozen.

For single patient use only.

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/CG63/NiceGuidance/pdf/English .

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.

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

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 14-17 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, 2008) 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

Drug excreted in breast milk? - Insulin is a natural component of breast milk

UK Drugs in Lactation Advisory Service Classification - This drug may be administered to breastfeeding mothers.

Side Effects

Hypoglycaemia

Severe hypoglycaemia may lead to unconsciousness, and may result in temporary or permanent impairment of brain function or even death.

Symptoms of hypoglycaemia include:
Cold sweat
Cool, pale skin
Tremor
Anxiety
Unusual tiredness
Weakness
Confusion
Difficulty in concentration
Excessive hunger
Visual disturbances (temporary)
Headache
Nausea
Palpitations
Loss of consciousness
Coma
Paraesthesia
Slurred speech

Other adverse reactions attributable to insulin therapy include:
Sodium retention
Oedema
Refraction abnormalities (transitory)
Temporary worsening of diabetic retinopathy leading to blindness.
Hypersensitivity reactions at the injection site (redness, swelling, pain, hives and itching)
Syncope
Weight gain
Peripheral neuropathy

Generalised hypersensitivity reactions including:
Anaphylactic reaction
Skin rash
Urticaria
Sweating
Angioneurotic oedema
Breathing difficulties inc. bronchospasm
Palpitations
Hypotension
Shock
Fainting/loss of consciousness

Lipodystrophy at the injection site due to failure to rotate injection site within an area.

Formation of insulin antibodies
Insulin resistance

Presentation

Suspension for injection containing 100 units/ml isophane (NPH) insulin in a 10ml vial
Suspension for injection containing 100 units/ml isophane (NPH) insulin in a 5ml vial
Suspension for injection containing 100 units/ml isophane (NPH) insulin in a 3ml cartridge
Suspension for injection containing 100 units/ml isophane (NPH) insulin in a 3ml disposable multidose pen

Drugs List

Therapeutic Indications

Uses

Intermediate acting insulin for the treatment of diabetes mellitus.

Dosage

Insulin isophane human may be given alone or mixed with a fast acting insulin. In intensive insulin therapy it may be used as a basal insulin (evening and/or morning), in combination with a short or rapid acting insulin given at meal times.

All doses must be adjusted individually according to the patient's physical activity, lifestyle and diet.

In patients with diabetes mellitus, optimised metabolic control delays the onset and slows the progression of late diabetic complications. Optimised metabolic control, including glucose monitoring, is therefore recommended.

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

The preparation is administered subcutaneously, in the upper arm, thigh or abdominal wall. If convenient the gluteal region or the deltoid region may be used.

Some brands may also be administered by intramuscular administration. Refer to patient information leaflet.

A subcutaneous injection into the thigh results in a slower and less variable absorption compared to other injection sites.

Injection into a lifted skin fold minimises the risk of intramuscular injection. The injection site should not be massaged after administration.

Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.

Do not use if solution has been frozen.

Incompatibilities

Not to be added to infusion liquids.

Contraindications

Hypoglycaemia

Precautions and Warnings

Be aware that hyperglycaemia and diabetic acidosis may occur as a result of inadequate dosing or discontinuation of treatment, especially in type 1 diabetes patients. If the insulin dose is high in relation to the insulin requirement hypoglycaemia may occur.

Symptoms of hyperglycaemia develop over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite and acetone odour of breath. In type 1 diabetes, untreated hyperglycaemia leads to diabetic ketoacidosis, which may be fatal.

If normal or reduced levels of glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) hypoglycaemia should be considered.

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:
in whom glycaemic control is markedly improved
in whom hypoglycaemia develops gradually
who are elderly
in whom an autonomic neuropathy is present
with a long history of diabetes
suffering from a psychiatric illness
receiving concurrent treatment with certain other medicinal products such as beta blockers
after transfer from animal insulin to human insulin

Adherence of the patient to the dosage and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dosage adjustment. These include:
change of the injection area
improved insulin sensitivity (e.g. by removal of stress factors)
unaccustomed, increased or prolonged physical activity
intercurrent illness (e.g. vomiting, diarrhoea)
inadequate food intake
missed meals
alcohol consumption
certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency)
concurrent treatment with certain other medicinal products

Pregnancy (see 'Pregnancy' section).
Breast feeding (see 'Lactation' section).

Intercurrent illness necessitates intensive metabolic monitoring. Urine tests for ketones and dose adjustment may be required. Insulin requirements are often increased. Type 1 diabetics must consume at least a small amount of carbohydrates regularly even if they feel unable to eat due to illness.

Patients planning travel between time zones should be advised to contact their doctor as injections and meals may have to be taken at different times.

Antibodies may form with treatment of human insulin but the titres are lower than those formed in response to animal insulins.

Do not use insulin isophane with infusion pumps.

Contains metacresol, which may cause allergic reactions.

Do not use if solution has been frozen.

For single patient use only.

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/CG63/NiceGuidance/pdf/English .

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.

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

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 14-17 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, 2008) 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

Drug excreted in breast milk? - Insulin is a natural component of breast milk

UK Drugs in Lactation Advisory Service Classification - This drug may be administered to breastfeeding mothers.

Effects on Ability to Drive and Operate Machinery

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance. Patients should be advised to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

In general patients should check their blood glucose concentration before driving and on long journeys, at 2 hour intervals, and they should ensure that a supply of sugar is always available in the car. If hypoglycaemia occurs a car driver should switch off the ignition until recovery is complete, which may take up to 15 minutes or longer.

Counselling

Each cartridge/pre-filled pen must be used by one patient only, even if the needle is changed, to prevent the possible transmission of disease.

The patient should be advised to read and follow the instructions which accompany the product.

Advise patients of the warning signs of hypoglycaemia.

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 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 Group, DVLA, Swansea, SA99 1TU

By phone on 0870 600 0301; 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

Hypoglycaemia

Severe hypoglycaemia may lead to unconsciousness, and may result in temporary or permanent impairment of brain function or even death.

Symptoms of hypoglycaemia include:
Cold sweat
Cool, pale skin
Tremor
Anxiety
Unusual tiredness
Weakness
Confusion
Difficulty in concentration
Excessive hunger
Visual disturbances (temporary)
Headache
Nausea
Palpitations
Loss of consciousness
Coma
Paraesthesia
Slurred speech

Other adverse reactions attributable to insulin therapy include:
Sodium retention
Oedema
Refraction abnormalities (transitory)
Temporary worsening of diabetic retinopathy leading to blindness.
Hypersensitivity reactions at the injection site (redness, swelling, pain, hives and itching)
Syncope
Weight gain
Peripheral neuropathy

Generalised hypersensitivity reactions including:
Anaphylactic reaction
Skin rash
Urticaria
Sweating
Angioneurotic oedema
Breathing difficulties inc. bronchospasm
Palpitations
Hypotension
Shock
Fainting/loss of consciousness

Lipodystrophy at the injection site due to failure to rotate injection site within an area.

Formation of insulin antibodies
Insulin resistance

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 ).

Shelf Life and Storage

Store at 2-8 degrees C in outer container
Do not freeze. Insulin preparations which have been frozen must not be used.
Protect from excessive heat and direct sunlight.

Once in use:
Preparations may be used for up to 28 days. Discard after this period.
Do not store above 30 degrees C
Store in outer container to protect from light.

Further Information

Last Full Review Date: April 2011

Reference Sources

British National Formulary, 60th Edition (2010) Pharmaceutical Press, London.

BNF for Children (2010-2011) Pharmaceutical Press, London

Summary of Product Characteristics: Insulatard 100 IU/ml, Insulatard penfill 100 IU/ml, Insulatard InnoLet 100 IU/ml. Novo Nordisk Ltd. Revised February 2011

Summary of Product Characteristics: Humulin I (Isophane) 100IU/ml suspension for injection in cartridge. Eli Lilly and Company Limited. Revised July 2018.
Summary of Product Characteristics: Humulin I (Isophane) 100IU/ml suspension for injection in vial. Eli Lilly and Company Limited. Revised March 2018.
Summary of Product Characteristics: Humulin I Kwikpen 100IU/ml suspension for injection. Eli Lilly and Company Limited. Revised June 2018.

Summary of Product Characteristics: Insuman Basal cartridge, vials and solostar pre-filled pens. Sanofi Aventis GmbH. Revised August 2020.

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, 8th edition (2008) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

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

UK Drugs in Lactation Advisory Service.
Available at: https://www.ukmicentral.nhs.uk/drugpreg/qrg_p1.asp
Last accessed: April 21, 2011

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Insulin Last revised: July 7, 2010
Last accessed: April 21, 2011