Drugs List

Therapeutic Indications

Uses

Diabetes mellitus

For the treatment of diabetes mellitus when an intermediate acting insulin is indicated.

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.

The average range of total daily insulin requirement for maintenance therapy is often 0.5 to 1.0 units per kg bodyweight per day. The basal metabolic requirement is 40% to 60% of the total daily requirement. The dose should be injected subcutaneously 20 to 30 minutes (50:50 preparations) or 30 to 45 minutes (all other preparations) before a meal.

Administration

The preparation is administered subcutaneously in the upper arm, thigh, gluteal region or abdominal wall. Injection sites must be rotated within a given injection area from one injection to the next.

Some brands may be injected intramuscularly, although this is not recommended.

Contraindications

Hypoglycaemia

Precautions and Warnings

Elderly
Breastfeeding
Hepatic impairment
Pregnancy
Renal impairment

Insulin requirements may be diminished by renal or hepatic impairment
Advise impaired alertness may affect ability to drive or operate machinery
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Not all available brands are licensed for all routes of administration
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
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
Consider monitoring metabolic parameters in patients with co-morbidities
Hypoglycaemic symptoms may be masked or altered in long duration diabetes
Hypoglycaemic symptoms may be masked/altered in diabetic nerve disease
Hypoglycaemic symptoms may be masked/altered in intensified insulin therapy
Monitor dosage closely in presence of renal or hepatic impairment
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
Hypoglycaemic symptoms may be masked/altered with beta blockers
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 be reduced in the elderly
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 on adequate dietary control
Advise patients to have glucose available in the event of hypoglycaemia
Transfer from animal insulin may alter usual hypoglycaemia warning symptoms

Intradermal skin testing is recommended in patients with an allergy to animal insulin. This should be done prior to a transfer to human insulin biphasic isophane, since the patient may experience immunological cross-reactions.

In patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia), particular caution should be exercised. Intensified blood glucose monitoring is advisable. This is also recommended in patients with proliferative retinopathy, particularly if not treated with photocoagulation (due to the risk of transient amaurosis following hypoglycaemia). Factors which are essential to reducing the risk of hypoglycaemia include adherence of the patient to the dose regimen and dietary regimen, correct insulin administration and patient awareness of hypoglycaemia symptoms.

The warning symptoms of hypoglycaemia may be altered/absent in certain risk groups. Such situations may result in severe hypoglycaemia prior to the patient's awareness of hypoglycaemia. Example patient groups include:
Patients in whom hypoglycaemia develops gradually,
Patients in whom glycaemic control is markedly improved,
Patients who are suffering from a psychiatric illness.

In disease of the adrenal, pituitary or thyroid glands, and in the presence of renal or hepatic impairment, insulin requirements may be significantly altered.

In many cases of intercurrent illness, urine tests for ketones are indicated. It is often necessary to adjust the insulin dose. During an intercurrent illness, type 1 diabetics should continue to consume at least a small amount of carbohydrates on a regular basis. These patients must never omit insulin entirely.

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

Insulin biphasic isophane human is considered safe for use in pregnancy.

Good metabolic control throughout pregnancy is essential for patients with pre-existing or gestational diabetes. Insulin requirements may decrease during the first trimester of pregnancy and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly and thus careful monitoring of glucose control is essential.

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.

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 biphasic isophane human is considered safe for use in breastfeeding.

The manufacturer suggests that patients receiving insulin, who are breastfeeding, may require a dose amendment.

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

Allergic reaction
Angioneurotic oedema
Breathing difficulties
Bronchospasm
Cutaneous amyloidosis
Erythema at injection site
Heat and redness (injection site)
Hypoglycaemia
Hypotension
Increased pulse rate
Inflammation (injection site)
Injection site reactions
Insulin antibodies
Itching (injection site)
Lipodystrophy (injection site)
Local pain (injection site)
Oedema
Rash
Refraction anomalies
Retinopathy
Shock
Shortness of breath
Skin reactions
Sodium retention
Sweating
Swelling (injection site)
Urticaria
Visual disturbances
Wheezing
Worsening of diabetic retinopathy (temporary)

Presentation

Preparations containing highly purified human insulin as soluble insulin and isophane insulin

These products have been produced by recombinant technology using E.coli.

Drugs List

Therapeutic Indications

Uses

Diabetes mellitus

For the treatment of diabetes mellitus when an intermediate acting insulin is indicated.

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.

The average range of total daily insulin requirement for maintenance therapy is often 0.5 to 1.0 units per kg bodyweight per day. The basal metabolic requirement is 40% to 60% of the total daily requirement. The dose should be injected subcutaneously 20 to 30 minutes (50:50 preparations) or 30 to 45 minutes (all other preparations) before a meal.

Administration

The preparation is administered subcutaneously in the upper arm, thigh, gluteal region or abdominal wall. Injection sites must be rotated within a given injection area from one injection to the next.

Some brands may be injected intramuscularly, although this is not recommended.

Contraindications

Hypoglycaemia

Precautions and Warnings

Elderly
Breastfeeding
Hepatic impairment
Pregnancy
Renal impairment

Insulin requirements may be diminished by renal or hepatic impairment
Advise impaired alertness may affect ability to drive or operate machinery
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Not all available brands are licensed for all routes of administration
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
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
Consider monitoring metabolic parameters in patients with co-morbidities
Hypoglycaemic symptoms may be masked or altered in long duration diabetes
Hypoglycaemic symptoms may be masked/altered in diabetic nerve disease
Hypoglycaemic symptoms may be masked/altered in intensified insulin therapy
Monitor dosage closely in presence of renal or hepatic impairment
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
Hypoglycaemic symptoms may be masked/altered with beta blockers
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 be reduced in the elderly
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 on adequate dietary control
Advise patients to have glucose available in the event of hypoglycaemia
Transfer from animal insulin may alter usual hypoglycaemia warning symptoms

Intradermal skin testing is recommended in patients with an allergy to animal insulin. This should be done prior to a transfer to human insulin biphasic isophane, since the patient may experience immunological cross-reactions.

In patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia), particular caution should be exercised. Intensified blood glucose monitoring is advisable. This is also recommended in patients with proliferative retinopathy, particularly if not treated with photocoagulation (due to the risk of transient amaurosis following hypoglycaemia). Factors which are essential to reducing the risk of hypoglycaemia include adherence of the patient to the dose regimen and dietary regimen, correct insulin administration and patient awareness of hypoglycaemia symptoms.

The warning symptoms of hypoglycaemia may be altered/absent in certain risk groups. Such situations may result in severe hypoglycaemia prior to the patient's awareness of hypoglycaemia. Example patient groups include:
Patients in whom hypoglycaemia develops gradually,
Patients in whom glycaemic control is markedly improved,
Patients who are suffering from a psychiatric illness.

In disease of the adrenal, pituitary or thyroid glands, and in the presence of renal or hepatic impairment, insulin requirements may be significantly altered.

In many cases of intercurrent illness, urine tests for ketones are indicated. It is often necessary to adjust the insulin dose. During an intercurrent illness, type 1 diabetics should continue to consume at least a small amount of carbohydrates on a regular basis. These patients must never omit insulin entirely.

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

Insulin biphasic isophane human is considered safe for use in pregnancy.

Good metabolic control throughout pregnancy is essential for patients with pre-existing or gestational diabetes. Insulin requirements may decrease during the first trimester of pregnancy and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly and thus careful monitoring of glucose control is essential.

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.

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 biphasic isophane human is considered safe for use in breastfeeding.

The manufacturer suggests that patients receiving insulin, who are breastfeeding, may require a dose amendment.

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

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.

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.

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.

Advise patient on adequate dietary control.

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

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 take precautions to avoid hypoglycaemia whilst driving.

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

Allergic reaction
Angioneurotic oedema
Breathing difficulties
Bronchospasm
Cutaneous amyloidosis
Erythema at injection site
Heat and redness (injection site)
Hypoglycaemia
Hypotension
Increased pulse rate
Inflammation (injection site)
Injection site reactions
Insulin antibodies
Itching (injection site)
Lipodystrophy (injection site)
Local pain (injection site)
Oedema
Rash
Refraction anomalies
Retinopathy
Shock
Shortness of breath
Skin reactions
Sodium retention
Sweating
Swelling (injection site)
Urticaria
Visual disturbances
Wheezing
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: April 2017

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

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

Summary of Product Characteristics: Insuman Comb 15 100 IU/ml suspension for injection in a cartridge. SANOFI. Revised August 2020.
Summary of Product Characteristics: Insuman Comb 25 100 IU/ml suspension for injection in a vial and cartridge. SANOFI. Revised August 2020.
Summary of Product Characteristics: Insuman Comb 25 SoloStar 100 IU/ml suspension for injection in a pre filled pen. SANOFI. Revised August 2020.
Summary of Product Characteristics: Insuman Comb 50 100 IU/ml suspension for injection in a cartridge. SANOFI. Revised August 2020.
Summary of Product Characteristics: Humulin M3 (Mixture 3) 100IU/ml suspension for injection in vial. Eli Lilly and Company Limited. Revised March 2018.
Summary of Product Characteristics: Humulin M3 (Mixture 3) 100IU/ml suspension for injection in cartridge. Eli Lilly and Company Limited. Revised July 2018.
Summary of Product Characteristics: Humulin M3 Kwikpen (Mixture 3) 100IU/ml suspension for injection. Eli Lilly and Company Limited. Revised June 2018.

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

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: 27 January 2017
Last accessed: 22 March 2017