2. 418 BNF 61
6 Endocrine system
6.1 Drugs used in diabetes 418 6.7.3 Metyrapone and trilostane 482
6.1.1 Insulins 419 6.7.4 Somatomedins 483
6.1.1.1 Short-acting insulins 422
This chapter also includes advice on the drug man-
6.1.1.2 Intermediate- and long-acting agement of the following:
insulins 423 Adrenal suppression during illness, trauma or
6.1.1.3Hypodermic equipment 426 surgery, p. 444
Serious infections in patients taking corticoster-
6.1.2Antidiabetic drugs 427 oids, p. 444
6.1.2.1Sulfonylureas 427 Osteoporosis, p. 469
Breast pain (mastalgia), p. 482
6.1.2.2Biguanides 429
6.1.2.3Other antidiabetic drugs 430
6.1.3Diabetic ketoacidosis 435 For hormonal contraception, see section 7.3.
6.1.4Treatment of hypoglycaemia 435
6.1.5Treatment of diabetic nephropa-
6 Endocrine system
thy and neuropathy 436
6.1.6 Diagnostic and monitoring
6.1 Drugs used in diabetes
devices for diabetes mellitus 437 6.1.1 Insulins
6.2 Thyroid and antithyroid drugs 439 6.1.2 Antidiabetic drugs
6.2.1 Thyroid hormones 439 6.1.3 Diabetic ketoacidosis
6.2.2 Antithyroid drugs 440 6.1.4 Treatment of hypoglycaemia
6.1.5 Treatment of diabetic nephropathy
6.3 Corticosteroids 442 and neuropathy
6.3.1 Replacement therapy 442 6.1.6 Diagnostic and monitoring devices for
6.3.2 Glucocorticoid therapy 442 diabetes mellitus
6.4 Sex hormones 449 Diabetes mellitus occurs because of a lack of insulin or
6.4.1 Female sex hormones 449 resistance to its action. It is diagnosed by measuring
6.4.1.1 Oestrogens and HRT 449 fasting or random blood-glucose concentration (and
occasionally by oral glucose tolerance test). Although
6.4.1.2 Progestogens 456 there are many subtypes, the two principal classes of
6.4.2 Male sex hormones and antago- diabetes are type 1 diabetes and type 2 diabetes.
nists 458 Type 1 diabetes, (formerly referred to as insulin-depen-
6.4.3 Anabolic steroids 461 dent diabetes mellitus (IDDM)), occurs as a result of a
deficiency of insulin following autoimmune destruction
6.5 Hypothalamic and pituitary hor- of pancreatic beta cells. Patients with type 1 diabetes
mones and anti-oestrogens 461 require administration of insulin.
6.5.1 Hypothalamic and anterior pitui- Type 2 diabetes, (formerly referred to as non-insulin-
tary hormones and anti-oestro- dependent diabetes (NIDDM)), is due to reduced secre-
gens 461 tion of insulin or to peripheral resistance to the action of
insulin or to a combination of both. Although patients
6.5.2 Posterior pituitary hormones and may be controlled on diet alone, many also require oral
antagonists 466 antidiabetic drugs or insulin (or both) to maintain satis-
6.6 Drugs affecting bone metab- factory control. In overweight individuals, type 2 dia-
betes may be prevented by losing weight and increasing
olism 469 physical activity; use of the anti-obesity drug orlistat
6.6.1 Calcitonin and parathyroid (section 4.5.1) may be considered in obese patients.
hormone 470
6.6.2 Bisphosphonates and other Treatment of diabetes Treatment of all forms of
diabetes should be aimed at alleviating symptoms and
drugs affecting bone metabolism 471
minimising the risk of long-term complications (see
6.7 Other endocrine drugs 477 below); tight control of diabetes is essential.
6.7.1 Bromocriptine and other Diabetes is a strong risk factor for cardiovascular dis-
dopaminergic drugs 477 ease (section 2.12). Other risk factors for cardiovascular
disease such as smoking (section 4.10.2), hypertension
6.7.2 Drugs affecting gonadotrophins 479 (section 2.5), obesity (section 4.5), and hyperlipidaemia
3. BNF 61 6.1.1 Insulins 419
(section 2.12) should be addressed. Cardiovascular risk Driving Drivers with diabetes are required to notify the
in patients with diabetes can be further reduced by the Driver and Vehicle Licensing Agency (DVLA) of their
use of an ACE inhibitor (section 2.5.5.1), low-dose condition if they are treated with insulin or if they are
aspirin (section 2.9) and a lipid-regulating drug (section treated with oral antidiabetic drugs and also have com-
2.12). plications. Detailed guidance on eligibility to drive is
available from the DVLA (www.dvla.gov.uk/
Prevention of diabetic complications Optimal medical.aspx). Driving is not permitted when hypogly-
glycaemic control in both type 1 diabetes and type 2 caemic awareness is impaired or frequent hypoglycae-
diabetes reduces, in the long term, the risk of micro- mic episodes occur.
vascular complications including retinopathy, develop- Drivers need to be particularly careful to avoid hypo-
ment of proteinuria and to some extent neuropathy. glycaemia (see also above) and should be warned of the
However, a temporary deterioration in established dia- problems. Drivers treated with insulin should normally
betic retinopathy may occur when normalising blood- check their blood-glucose concentration before driving
glucose concentration. For reference to the use of an and, on long journeys, at 2-hour intervals; these pre-
ACE inhibitor or an angiotensin-II receptor antagonist in cautions may also be necessary for drivers taking oral
the management of diabetic nephropathy, see section antidiabetic drugs who are at particular risk of hypo-
6.1.5. glycaemia. Drivers treated with insulin should ensure
A measure of the total glycosylated (or glycated) hae- that a supply of sugar is always available in the vehicle
moglobin (HbA1 ) or a specific fraction (HbA1c ) provides and they should avoid driving if their meal is delayed. If
a good indication of glycaemic control over the previous hypoglycaemia occurs, or warning signs develop, the
2–3 months. Overall it is ideal to aim for an HbA1c driver should:
(glycosylated haemoglobin) concentration of 48– . stop the vehicle in a safe place;
59 mmol/mol (6.5–7.5%) or less (reference range 20–
. switch off the ignition;
42 mmol/mol or 4–6%) but this cannot always be
achieved and for those using insulin there is a signifi- . eat or drink a suitable source of sugar;
cantly increased risk of disabling hypoglycaemia; in . wait until recovery is complete before continuing
those at risk of arterial disease, the aim should be to journey; recovery may take 15 minutes or longer
maintain the HbA1c concentration at 48 mmol/mol and should preferably be confirmed by checking
(6.5%) or less. HbA1c should be measured every 3–6 blood-glucose concentration.
months.
Measurement of HbA1c
HbA1c values currently expressed as a percentage,
are aligned to the assay used in the Diabetes Con-
6 Endocrine system
trol and Complications Trial (DCCT). A new stan-
dard, specific for HbA1c , has been created by the 6.1.1 Insulins
International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC), which expresses 6.1.1.1 Short-acting insulins
HbA1c values in mmol of glycosylated haemoglobin 6.1.1.2 Intermediate- and long-acting insulins
per mol of haemoglobin. UK laboratories now
6.1.1.3 Hypodermic equipment
express results in both IFCC-standardised units
(mmol/mol) and DCCT-aligned units (%). From 1
June 2011, results will only be reported in IFCC- Insulin plays a key role in the regulation of carbohy-
standardised units. drate, fat, and protein metabolism. It is a polypeptide
hormone of complex structure. There are differences in
the amino-acid sequence of animal insulins, human
Equivalent values
insulins and the human insulin analogues. Insulin may
IFCC-HbA1c (mmol/mol) DCCT-HbA1c (%) be extracted from pork pancreas and purified by crystal-
lisation; it may also be extracted from beef pancreas, but
42 6.0
beef insulins are now rarely used. Human sequence
48 6.5 insulin may be produced semisynthetically by enzy-
matic modification of porcine insulin (emp) or bio-
53 7.0
synthetically by recombinant DNA technology using
59 7.5 bacteria (crb, prb) or yeast (pyr).
64 8.0 All insulin preparations are to a greater or lesser extent
immunogenic in man but immunological resistance to
75 9.0 insulin action is uncommon. Preparations of human
sequence insulin should theoretically be less immuno-
Laboratory measurement of serum-fructosamine con- genic, but no real advantage has been shown in trials.
centration is technically simpler and cheaper than the Insulin is inactivated by gastro-intestinal enzymes, and
measurement of HbA1c and can be used to assess must therefore be given by injection; the subcutaneous
control over short periods of time, particularly when route is ideal in most circumstances. Insulin is usually
HbA1c monitoring is invalid (e.g. disturbed erythrocyte injected into the upper arms, thighs, buttocks, or abdo-
turnover or abnormal haemoglobin type). men; absorption from a limb site may be increased if the
Tight control of blood pressure in hypertensive patients limb is used in strenuous exercise after the injection.
with type 2 diabetes reduces mortality and protects Generally subcutaneous insulin injections cause few
visual acuity (by reducing considerably the risks of problems; lipodystrophy may occur but can be mini-
maculopathy and retinal photocoagulation) (see also mised by using different injection sites in rotation. Local
section 2.5). allergic reactions are rare.
4. 420 6.1.1 Insulins BNF 61
Insulin is needed by all patients with ketoacidosis, and it with certain endocrine disorders (e.g. Addison’s disease,
is likely to be needed by most patients with: hypopituitarism), or in coeliac disease.
. rapid onset of symptoms;
. substantial loss of weight; Examples of recommended insulin regimens
. weakness; . Multiple injection regimen: short-acting insulin or
. ketonuria; rapid-acting insulin analogue, before meals
. a first-degree relative who has type 1 diabetes. With intermediate-acting or long-acting insulin,
once or twice daily;
Insulin is required by almost all children with diabetes. It
is also needed for type 2 diabetes when other methods . Short-acting insulin or rapid-acting insulin analogue
have failed to achieve good control, and temporarily in mixed with intermediate-acting or long-acting insu-
the presence of intercurrent illness or peri-operatively. lin, once or twice daily (before meals);
Pregnant women with type 2 diabetes may be treated . Intermediate-acting or long-acting insulin, once or
with insulin when diet alone fails. For advice on use of twice daily
oral antidiabetic drugs in the management of diabetes in With or without short-acting insulin or rapid-acting
pregnancy, see section 6.1.2. insulin before meals;
. Continuous subcutaneous insulin infusion (see
NHS Diabetes guidance below).
Safe and Effective Use of Insulin in
Hospitalised Patients (March 2010)
Available at www.diabetes.nhs.uk Hepatic impairment Insulin requirements may be
decreased in patients with hepatic impairment.
Management of diabetes with insulin The aim of
6 Endocrine system
treatment is to achieve the best possible control of Renal impairment Insulin requirements may fall in
blood-glucose concentration without making the patient patients with renal impairment and therefore dose
obsessional and to avoid disabling hypoglycaemia; close reduction may be necessary. The compensatory
co-operation is needed between the patient and the response to hypoglycaemia is impaired in renal impair-
medical team because good control reduces the risk of ment.
complications.
Insulin preparations can be divided into 3 types:
Pregnancy and breast-feeding During pregnancy
. those of short duration which have a relatively and breast-feeding, insulin requirements may alter and
rapid onset of action, namely soluble insulin and doses should be assessed frequently by an experienced
the rapid-acting insulin analogues, insulin aspart, diabetes physician. The dose of insulin generally needs
insulin glulisine, and insulin lispro (section 6.1.1.1); to be increased in the second and third trimesters of
. those with an intermediate action, e.g. isophane pregnancy. The short-acting insulin analogues, insulin
insulin (section 6.1.1.2); and aspart and insulin lispro, are not known to be harmful,
and may be used during pregnancy and lactation. The
. those whose action is slower in onset and lasts for
safety of long-acting insulin analogues in pregnancy has
long periods, e.g. protamine zinc insulin, insulin
not been established, therefore isophane insulin is
detemir, and insulin glargine (section 6.1.1.2).
recommended where longer-acting insulins are needed.
The duration of action of a particular type of insulin
varies considerably from one patient to another, and
needs to be assessed individually. Insulin administration Insulin is generally given by
Mixtures of insulin preparations may be required and subcutaneous injection; the injection site should be
appropriate combinations have to be determined for the rotated to prevent lipodystrophy. Injection devices
individual patient. Treatment should be started with a (‘pens’) (section 6.1.1.3), which hold the insulin in a
short-acting insulin (e.g. soluble insulin) or a rapid-act- cartridge and meter the required dose, are convenient
ing insulin analogue (e.g. insulin aspart) given before to use. Insulin syringes (for use with needles) are
meals with intermediate-acting or long-acting insulin required for insulins not available in cartridge form.
once or twice daily. Alternatively, for those who have For intensive insulin regimens multiple subcutaneous
difficulty with, or prefer not to use, multiple injection injections (3 or more times daily) are usually recom-
regimens, a mixture of premixed short-acting insulin or mended.
rapid acting insulin analogue with an intermediate-act- Short-acting injectable insulins (soluble insulin, insulin
ing or long-acting insulin (most commonly in a propor- aspart, insulin glulisine, and insulin lispro) can also be
tion of 30% soluble insulin and 70% isophane insulin) given by continuous subcutaneous infusion using a
can be given once or twice daily. The dose of short- portable infusion pump. This device delivers a contin-
acting or rapid-acting insulin (or the proportion of the uous basal insulin infusion and patient-activated bolus
short-acting soluble insulin component in premixed doses at meal times. This technique can be useful for
insulin) can be increased in those with excessive post- patients who suffer recurrent hypoglycaemia or marked
prandial hyperglycaemia. The dose of insulin is morning rise in blood-glucose concentration despite
increased gradually according to the patient’s individual optimised multiple-injection regimens (see also NICE
requirements, taking care to avoid troublesome hypo- guidance, below). Patients on subcutaneous insulin infu-
glycaemic reactions. sion must be highly motivated, able to monitor their
Insulin requirements may be increased by infection, blood-glucose concentration, and have expert training,
stress, accidental or surgical trauma, and during advice and supervision from an experienced healthcare
puberty. Requirements may be decreased in those team.
5. BNF 61 6.1.1 Insulins 421
ment of insulin type, dose and frequency together with
NICE guidance suitable timing and quantity of meals and snacks.
Continuous subcutaneous insulin infusion
Some patients have reported loss of hypoglycaemia
for the treatment of diabetes mellitus (type warning after transfer to human insulin. Clinical studies
1) (July 2008) do not confirm that human insulin decreases hypoglyc-
Continuous subcutaneous insulin infusion is recom- aemia awareness. If a patient believes that human insu-
mended as an option in adults and children over 12 lin is responsible for the loss of warning it is reasonable
years with type 1 diabetes: to revert to animal insulin and essential to educate the
. who suffer repeated or unpredictable hypoglyc- patient about avoiding hypoglycaemia. Great care
aemia, whilst attempting to achieve optimal should be taken to specify whether a human or an
glycaemic control with multiple-injection regi- animal preparation is required.
mens, or
. whose glycaemic control remains inadequate Few patients are now treated with beef insulins; when
(HbA1c over 8.5%) despite optimised multiple- undertaking conversion from beef to human insulin, the
injection regimens (including the use of long- total dose should be reduced by about 10% with careful
acting insulin analogues where appropriate). monitoring for the first few days. When changing
between pork and human-sequence insulins, a dose
Continuous subcutaneous insulin infusion is also
change is not usually needed, but careful monitoring is
recommended as an option for children under 12
still advised.
years with type 1 diabetes for whom multiple-injec-
tion regimens are considered impractical or inap-
propriate. Children on insulin pumps should undergo Diabetes and surgery Perioperative control of blood-
a trial of multiple-injection therapy between the ages glucose concentrations in patients with type 1 diabetes
of 12 and 18 years. is achieved via an adjustable, continuous, intravenous
infusion of insulin. Detailed local protocols should be
Soluble insulin by the intravenous route is reserved for available to all healthcare professionals involved in the
urgent treatment, e.g. in diabetic ketoacidosis, and for treatment of these patients; in general, the following
fine control in serious illness and in the peri-operative steps should be followed:
period (see under Diabetes and Surgery, below). . Give an injection of the patient’s usual insulin on the
night before the operation;
Units The word ‘unit’ should not be abbreviated.
. Early on the day of the operation, start an intra-
venous infusion of glucose containing potassium
Monitoring Many patients now monitor their own chloride (provided that the patient is not hyperka-
blood-glucose concentrations (section 6.1.6). Since laemic) and infuse at a constant rate appropriate to
blood-glucose concentration varies substantially the patient’s fluid requirements (usually 125 mL per
6 Endocrine system
throughout the day, ‘normoglycaemia’ cannot always hour); make up a solution of soluble insulin in sod-
be achieved throughout a 24-hour period without caus- ium chloride 0.9% and infuse intravenously using a
ing damaging hypoglycaemia. It is therefore best to syringe pump piggy-backed to the intravenous infu-
recommend that patients should maintain a blood-glu- sion. Glucose and potassium infusions, and insulin
cose concentration of between 4 and 9 mmol/litre for infusions should be made up according to locally
most of the time (4–7 mmol/litre before meals and less agreed protocols;
than 9 mmol/litre after meals), while accepting that on
occasions, for brief periods, it will be above these values; . The rate of the insulin infusion should be adjusted
strenuous efforts should be made to prevent the blood- according to blood-glucose concentration (frequent
glucose concentration from falling below 4 mmol/litre. monitoring necessary) in line with locally agreed
Patients using multiple injection regimens should under- protocols. Other factors affecting the rate of infu-
stand how to adjust their insulin dose according to their sion include the patient’s volume depletion, cardiac
carbohydrate intake. With fixed-dose insulin regimens, function, and age.
the carbohydrate intake needs to be regulated, and Protocols should include specific instructions on how to
should be distributed throughout the day to match the manage resistant cases (such as patients who are in
insulin regimen. The intake of energy and of simple and shock or severely ill or those receiving corticosteroids or
complex carbohydrates should be adequate to allow sympathomimetics) and those with hypoglycaemia.
normal growth and development but obesity must be
If a syringe pump is not available, soluble insulin should
avoided.
be added to the intravenous infusion of glucose and
potassium chloride (provided the patient is not hyper-
Hypoglycaemia Hypoglycaemia is a potential pro- kalaemic), and the infusion run at the rate appropriate to
blem with insulin therapy. All patients must be carefully the patient’s fluid requirements (usually 125 mL per
instructed on how to avoid it. hour) with the insulin dose adjusted according to
Loss of warning of hypoglycaemia among insulin-trea- blood-glucose concentration in line with locally agreed
ted patients can be a serious hazard, especially for protocols.
drivers and those in dangerous occupations. Very tight Once the patient starts to eat and drink, give subcuta-
control of diabetes lowers the blood-glucose concentra- neous insulin before breakfast and stop intravenous
tion needed to trigger hypoglycaemic symptoms; an insulin 30 minutes later; the dose may need to be 10–
increase in the frequency of hypoglycaemic episodes 20% more than usual if the patient is still in bed or
may reduce the warning symptoms experienced by the unwell. If the patient was not previously receiving insu-
patient. Beta-blockers can also blunt hypoglycaemic lin, an appropriate initial dose is 30–40 units daily in four
awareness (and also delay recovery). divided doses using soluble insulin before meals and
To restore the warning signs, episodes of hypoglycaemia intermediate-acting insulin at bedtime and the dose
must be minimised; this involves appropriate adjust- adjusted from day to day. Patients with hyperglycaemia
6. 422 6.1.1 Insulins BNF 61
often relapse after conversion back to subcutaneous Dose
insulin calling for one of the following approaches: . By subcutaneous, intramuscular or intravenous
. additional doses of soluble insulin at any of the four injection or intravenous infusion, according to
injection times (before meals or bedtime) or requirements
. temporary addition of intravenous insulin infusion
Highly purified animal
(while continuing the subcutaneous regimen) until
Counselling Show container to patient and confirm that
blood-glucose concentration is satisfactory or patient is expecting the version dispensed
. complete reversion to the intravenous regimen
Hypurin c Bovine Neutral (Wockhardt) A
(especially if the patient is unwell).
Injection, soluble insulin (bovine, highly purified)
100 units/mL. Net price 10-mL vial = £18.48; car-
tridges (for Autopen c Classic) 5 Â 3 mL = £27.72
6.1.1.1 Short-acting insulins Hypurin c Porcine Neutral (Wockhardt) A
Injection, soluble insulin (porcine, highly purified)
Soluble insulin is a short-acting form of insulin. For 100 units/mL. Net price 10-mL vial = £16.80; car-
maintenance regimens it is usual to inject it 15 to 30 tridges (for Autopen c Classic) 5 Â 3 mL = £25.20
minutes before meals.
Soluble insulin is the most appropriate form of insulin Human sequence
for use in diabetic emergencies e.g. diabetic ketoacid- Counselling Show container to patient and confirm that
patient is expecting the version dispensed
osis (section 6.1.3) and at the time of surgery. It can be
given intravenously and intramuscularly, as well as sub- Actrapid c (Novo Nordisk) A
cutaneously. Injection, soluble insulin (human, pyr) 100 units/mL.
When injected subcutaneously, soluble insulin has a Net price 10-mL vial = £7.48
rapid onset of action (30 to 60 minutes), a peak action Note Not recommended for use in subcutaneous insulin infusion
6 Endocrine system
pumps—may precipitate in catheter or needle
between 2 and 4 hours, and a duration of action of up to
8 hours. Humulin S c (Lilly) A
When injected intravenously, soluble insulin has a very Injection, soluble insulin (human, prb) 100 units/mL.
short half-life of only about 5 minutes and its effect Net price 10-mL vial = £15.68; 5 Â 3-mL cartridge (for
disappears within 30 minutes. most Autopen c Classic or HumaPen c ) = £19.08
The rapid-acting human insulin analogues, insulin Insuman c Rapid (Sanofi-Aventis) A
aspart, insulin glulisine, and insulin lispro have a Injection, soluble insulin (human, crb) 100 units/mL,
faster onset and shorter duration of action than soluble net price 5 Â 3-mL cartridge (for ClikSTAR c and
insulin; as a result, compared to soluble insulin, fasting OptiPen c Pro 1) = £17.50; 5 Â 3-mL Insuman c
and preprandial blood-glucose concentrations are a Rapid OptiSet c prefilled disposable injection devices
little higher, postprandial blood-glucose concentration (range 2–40 units, allowing 2-unit dosage adjustment)
is a little lower, and hypoglycaemia occurs slightly less = £17.50
frequently. Subcutaneous injection of insulin analogues Note Not recommended for use in subcutaneous insulin infusion
pumps
may be convenient for those who wish to inject shortly
before or, when necessary, shortly after a meal. They
can also help those susceptible to hypoglycaemia before Mixed preparations
lunch and those who eat late in the evening and are See Biphasic Isophane Insulin (section 6.1.1.2)
prone to nocturnal hypoglycaemia. They can also be
administered by subcutaneous infusion (see Insulin
Administration, above). Insulin aspart and insulin lispro INSULIN ASPART
can be administered intravenously and can be used as (Recombinant human insulin analogue)
alternatives to soluble insulin for diabetic emergencies Indications diabetes mellitus
and at the time of surgery. Cautions section 6.1.1; interactions: Appendix 1
(antidiabetics)
INSULIN Hepatic impairment section 6.1.1
(Insulin Injection; Neutral Insulin; Soluble Renal impairment section 6.1.1
Insulin) Pregnancy section 6.1.1
A sterile solution of insulin (i.e. bovine or porcine) or Breast-feeding section 6.1.1
of human insulin; pH 6.6–8.0 Side-effects see under Insulin
Indications diabetes mellitus; diabetic ketoacidosis Dose
(section 6.1.3) . By subcutaneous injection, ADULT and CHILD over 2
Cautions section 6.1.1; interactions: Appendix 1 years, immediately before meals or when necessary
(antidiabetics) shortly after meals, according to requirements
Hepatic impairment section 6.1.1 . By subcutaneous infusion, intravenous injection or
Renal impairment section 6.1.1 intravenous infusion, ADULT and CHILD over 2 years,
Pregnancy section 6.1.1 according to requirements
Breast-feeding section 6.1.1 NovoRapid c (Novo Nordisk) A
Side-effects see notes above; transient oedema; local Injection, insulin aspart (recombinant human insulin
reactions and fat hypertrophy at injection site; rarely analogue) 100 units/mL, net price 10-mL vial =
hypersensitivity reactions including urticaria, rash; £16.28; Penfill c cartridge (for NovoPen c devices) 5 Â
overdose causes hypoglycaemia 3-mL = £28.84; 5 Â 3-mL FlexPen c prefilled
7. BNF 61 6.1.1 Insulins 423
disposable injection devices (range 1–60 units, allow- 5 Â 3-mL Humalog c KwikPen prefilled disposable
ing 1-unit dosage adjustment) = £32.00 injection devices (range 1–60 units, allowing 1-unit
Counselling Show container to patient and confirm that dosage adjustment) = £29.46
patient is expecting the version dispensed Counselling Show container to patient and confirm that
patient is expecting the version dispensed
INSULIN GLULISINE
(Recombinant human insulin analogue)
6.1.1.2 Intermediate- and long-acting
Indications diabetes mellitus
insulins
Cautions section 6.1.1; interactions: Appendix 1
(antidiabetics)
When given by subcutaneous injection, intermediate-
Hepatic impairment section 6.1.1 and long-acting insulins have an onset of action of
Renal impairment section 6.1.1 approximately 1–2 hours, a maximal effect at 4–12
Pregnancy section 6.1.1 hours, and a duration of 16–35 hours. Some are given
Breast-feeding section 6.1.1 twice daily in conjunction with short-acting (soluble)
Side-effects see under Insulin insulin, and others are given once daily, particularly in
Dose elderly patients. Soluble insulin can be mixed with
. By subcutaneous injection, ADULT and CHILD over 6 intermediate and long-acting insulins (except insulin
years, immediately before meals or when necessary detemir and insulin glargine) in the syringe, essentially
shortly after meals, according to requirements retaining the properties of the two components,
although there may be some blunting of the initial effect
. By subcutaneous infusion, or intravenous infusion
of the soluble insulin component (especially on mixing
ADULT and CHILD over 6 years, according to require-
with protamine zinc insulin, see below).
ments
Isophane insulin is a suspension of insulin with prot-
Apidra c (Sanofi-Aventis) A amine; it is of particular value for initiation of twice-daily
Injection, insulin glulisine (recombinant human insu- insulin regimens. Patients usually mix isophane with
lin analogue) 100 units/mL, net price 10-mL vial = soluble insulin but ready-mixed preparations may be
£16.60; 5Â 3-mL cartridge (for ClikSTAR c , OptiPen c appropriate (biphasic isophane insulin, biphasic insu-
Pro 1, and Autopen c 24) = £28.30; 5 Â 3-mL lin aspart, or biphasic insulin lispro).
OptiClik c cartridge (for OptiClik c Pen) = £30.27; 5 Â
3-mL Apidra c Optiset c prefilled disposable injection Insulin zinc suspension (30% amorphous, 70% cryst-
devices (range 2–40 units, allowing 2-unit dosage alline) has a more prolonged duration of action.
adjustment) = £28.30; 5 Â 3-mL Apidra c SoloStar c Protamine zinc insulin is usually given once daily with
prefilled disposable injection devices (range 1– short-acting (soluble) insulin. It has the drawback of
6 Endocrine system
80 units, allowing 1-unit dosage adjustment) = £25.00 binding with the soluble insulin when mixed in the
Counselling Show container to patient and confirm that same syringe and is now rarely used.
patient is expecting the version dispensed
Note The Scottish Medicines Consortium (p. 4) has advised Insulin glargine and insulin detemir are both long-
(October 2008) that Apidra c is accepted for restricted use acting human insulin analogues with a prolonged dura-
within NHS Scotland for the treatment of adults and children tion of action; insulin glargine is given once daily and
over 6 years with diabetes mellitus in whom the use of a short- insulin detemir is given once or twice daily. NICE
acting insulin analogue is appropriate
(December 2002) has recommended that insulin glar-
gine should be available as an option for patients with
INSULIN LISPRO type 1 diabetes.
(Recombinant human insulin analogue) NICE (May 2009) has recommended that, if insulin is
Indications diabetes mellitus required in patients with type 2 diabetes, insulin detemir
Cautions section 6.1.1; children (use only if benefit or insulin glargine may be considered for those:
likely compared to soluble insulin); interactions: . who require assistance with injecting insulin or
Appendix 1 (antidiabetics) . whose lifestyle is significantly restricted by recur-
Hepatic impairment section 6.1.1 rent symptomatic hypoglycaemia or
Renal impairment section 6.1.1 . who would otherwise need twice-daily basal insulin
Pregnancy section 6.1.1 injections in combination with oral antidiabetic
Breast-feeding section 6.1.1 drugs or
Side-effects see under Insulin . who cannot use the device needed to inject iso-
Dose phane insulin.
. By subcutaneous injection shortly before meals or
when necessary shortly after meals, according to
requirements
. By subcutaneous infusion, or intravenous injection,
INSULIN DETEMIR
(Recombinant human insulin analogue—long
or intravenous infusion, according to requirements
acting)
Humalog (Lilly) A
c
Indications diabetes mellitus
Injection, insulin lispro (recombinant human insulin
analogue) 100 units/mL, net price 10-mL vial = Cautions section 6.1.1.1; interactions: Appendix 1
£16.61; 5 Â 3-mL cartridge (for Autopen c Classic or (antidiabetics)
HumaPen c ) = £28.31; 5 Â 3-mL Humalog c -Pen Hepatic impairment section 6.1.1
prefilled disposable injection devices (range 1– Renal impairment section 6.1.1
60 units, allowing 1-unit dosage adjustment) = £29.46; Pregnancy section 6.1.1
8. 424 6.1.1 Insulins BNF 61
Breast-feeding section 6.1.1 Hepatic impairment section 6.1.1
Side-effects see under Insulin (section 6.1.1.1) Renal impairment section 6.1.1
Dose Pregnancy section 6.1.1
. By subcutaneous injection, ADULT and CHILD over 6 Breast-feeding section 6.1.1
years, according to requirements Side-effects see under Insulin (section 6.1.1.1)
Levemir c (Novo Nordisk) A Dose
Injection, insulin detemir (recombinant human insulin . By subcutaneous injection, according to require-
analogue) 100 units/mL, net price 5 Â 3-mL cartridge ments
(for NovoPen c devices) = £42.00; 5 Â 3-mL FlexPen c
prefilled disposable injection device (range 1–60 units, Highly purified animal
allowing 1-unit dosage adjustment) = £42.00; 5 Â 3- Hypurin c Bovine Lente (Wockhardt) A
mL Levemir InnoLet c prefilled disposable injection Injection, insulin zinc suspension (bovine, highly
devices (range 1–50 units, allowing 1-unit dosage purified) 100 units/mL. Net price 10-mL vial = £27.72
adjustment) = £44.85 Counselling Show container to patient and confirm that
patient is expecting the version dispensed
Counselling Show container to patient and confirm that
patient is expecting the version dispensed
ISOPHANE INSULIN
INSULIN GLARGINE (Isophane Insulin Injection; Isophane Prot-
(Recombinant human insulin analogue—long amine Insulin Injection; Isophane Insulin
acting) (NPH)—intermediate acting)
A sterile suspension of bovine or porcine insulin or of human
Indications diabetes mellitus insulin in the form of a complex obtained by the addition of
Cautions section 6.1.1.1; interactions: Appendix 1 protamine sulphate or another suitable protamine
(antidiabetics) Indications diabetes mellitus
Hepatic impairment section 6.1.1
6 Endocrine system
Cautions section 6.1.1.1; interactions: Appendix 1
Renal impairment section 6.1.1 (antidiabetics)
Pregnancy section 6.1.1 Hepatic impairment section 6.1.1
Breast-feeding section 6.1.1 Renal impairment section 6.1.1
Side-effects see under Insulin (section 6.1.1.1) Pregnancy section 6.1.1
Dose Breast-feeding section 6.1.1
. By subcutaneous injection, ADULT and CHILD over 6 Side-effects see under Insulin (section 6.1.1.1); prot-
years, according to requirements amine may cause allergic reactions
Lantus c (Sanofi-Aventis) A Dose
Injection, insulin glargine (recombinant human insu- . By subcutaneous injection, according to require-
lin analogue) 100 units/mL, net price 10-mL vial = ments
£26.00; 5 Â 3-mL cartridge (for ClikSTAR c ,
OptiPen c Pro 1, and Autopen c 24) = £39.00; 5 Â 3- Highly purified animal
mL OptiClik c cartridge (for OptiClik c Pen) = £40.36; Counselling Show container to patient and confirm that
patient is expecting the version dispensed
5 Â 3-mL Lantus c OptiSet c prefilled disposable
injection devices (range 2–40 units, allowing 2-unit Hypurin c Bovine Isophane (Wockhardt) A
dosage adjustment) = £39.00; 5 Â 3-mL Lantus c Injection, isophane insulin (bovine, highly purified)
SoloStar c prefilled disposable injection devices 100 units/mL. Net price 10-mL vial = £27.72; car-
(range 1–80 units, allowing 1-unit dosage adjustment) tridges (for Autopen c Classic) 5 Â 3 mL = £41.58
= £40.36
Note The Scottish Medicines Consortium (p. 4) has advised Hypurin c Porcine Isophane (Wockhardt) A
(October 2002) that insulin glargine is accepted for restricted Injection, isophane insulin (porcine, highly purified)
use within NHS Scotland for the treatment of type 1 diabetes: 100 units/mL. Net price 10-mL vial = £25.20; car-
. in those who are at risk of or experience unacceptable tridges (for Autopen c Classic) 5 Â 3 mL = £37.80
frequency or severity of nocturnal hypoglycaemia on
attempting to achieve better hypoglycaemic control Human sequence
during treatment with other insulins Counselling Show container to patient and confirm that
. as a once daily insulin therapy for patients who require a patient is expecting the version dispensed
carer to administer their insulin.
It is not recommended for routine use in patients with type 2 Insulatardc (Novo Nordisk) A
diabetes unless they suffer from recurrent episodes of Injection, isophane insulin (human, pyr) 100 units/
hypoglycaemia or require assistance with their insulin mL. Net price 10-mL vial = £7.48; Insulatard Penfill c
injections. cartridge (for Novopen c devices) 5 Â 3 mL = £22.90;
Counselling Show container to patient and confirm that
patient is expecting the version dispensed
5 Â 3-mL Insulatard InnoLet c prefilled disposable
injection devices (range 1–50 units, allowing 1-unit
dosage adjustment) = £20.40
INSULIN ZINC SUSPENSION
(Insulin Zinc Suspension (Mixed)—long acting) Humulin I c (Lilly) A
A sterile neutral suspension of bovine and/or porcine insulin or Injection, isophane insulin (human, prb) 100 units/
of human insulin in the form of a complex obtained by the mL. Net price 10-mL vial = £15.68; 5 Â 3-mL cartridge
addition of a suitable zinc salt; consists of rhombohedral (for Autopen c Classic or HumaPen c ) = £19.08; 5 Â
crystals (10–40 microns) and of particles of no uniform shape 3-mL Humulin I-Pen c prefilled disposable injection
(not exceeding 2 microns)
devices (range 1–60 units, allowing 1-unit dosage
Indications diabetes mellitus adjustment) = £28.44; 5 Â 3-mL Humulin I KwikPen c
Cautions section 6.1.1.1; interactions: Appendix 1 prefilled disposable injection devices (range 1–
(antidiabetics) 60 units, allowing 1-unit dosage adjustment) = £21.70
9. BNF 61 6.1.1 Insulins 425
Insuman c Basal (Sanofi-Aventis) A BIPHASIC INSULIN LISPRO
Injection, isophane insulin (human, crb) 100 units/ (Intermediate-acting insulin)
mL, net price 5-mL vial = £5.61; 5 Â 3-mL cartridge
(for ClikSTAR c and OptiPen c Pro 1) = £17.50; 5 Â 3- Indications diabetes mellitus
mL Insuman c Basal OptiSet c prefilled disposable Cautions see section 6.1.1.1 and Insulin Lispro;
injection devices (range 2–40 units, allowing 2-unit interactions: Appendix 1 (antidiabetics)
dosage adjustment) = £17.50 Hepatic impairment section 6.1.1
Renal impairment section 6.1.1
Mixed preparations Pregnancy section 6.1.1
See Biphasic Isophane Insulin (below) Breast-feeding section 6.1.1
Side-effects see under Insulin (section 6.1.1.1); prot-
PROTAMINE ZINC INSULIN amine may cause allergic reactions
(Protamine Zinc Insulin Injection—long acting) Dose
A sterile suspension of insulin in the form of a complex . By subcutaneous injection, up to 15 minutes before or
obtained by the addition of a suitable protamine and zinc
chloride; this preparation was included in BP 1980 but is not
soon after a meal, according to requirements
included in BP 1988
Humalog c Mix25 (Lilly) A
Indications diabetes mellitus Injection, biphasic insulin lispro (recombinant human
Cautions section 6.1.1.1; see also notes above; inter- insulin analogue), 25% insulin lispro, 75% insulin
actions: Appendix 1 (antidiabetics) lispro protamine, 100 units/mL, net price 10-mL vial
Hepatic impairment section 6.1.1 = £16.61; 5 Â 3-mL cartridge (for Autopen c Classic or
Renal impairment section 6.1.1 HumaPen c ) = £29.46; 5 Â 3-mL prefilled disposable
injection devices (range 1–60 units, allowing 1-unit
Pregnancy section 6.1.1
dosage adjustment) = £30.98; 5 Â 3-mL Humalog c
Breast-feeding section 6.1.1 Mix25 KwikPen prefilled disposable injection devices
Side-effects see under Insulin (section 6.1.1.1); prot- (range 1–60 units, allowing 1-unit dosage adjustment)
amine may cause allergic reactions = £30.98
Dose Counselling Show container to patient and confirm that
. By subcutaneous injection, according to require- patient is expecting the version dispensed; the proportions of
the two components should be checked carefully (the order
ments in which the proportions are stated may not be the same in
Hypurin c Bovine Protamine Zinc (Wockhardt) A other countries)
Injection, protamine zinc insulin (bovine, highly pur- Humalog c Mix50 (Lilly) A
ified) 100 units/mL. Net price 10-mL vial = £27.72 Injection, biphasic insulin lispro (recombinant human
6 Endocrine system
Counselling Show container to patient and confirm that
patient is expecting the version dispensed insulin analogue), 50% insulin lispro, 50% insulin
lispro protamine, 100 units/mL, net price 5 Â 3-mL
cartridge (for Autopen c Classic or HumaPen c ) =
£29.46; 5 Â 3-mL prefilled disposable injection
Biphasic insulins devices (range 1–60 units, allowing 1-unit dosage
adjustment) = £29.46; 5 Â 3-mL Humalog c Mix50
KwikPen prefilled disposable injection devices (range
BIPHASIC INSULIN ASPART 1–60 units, allowing 1-unit dosage adjustment) =
(Intermediate-acting insulin) £30.98
Indications diabetes mellitus Counselling Show container to patient and confirm that
patient is expecting the version dispensed; the proportions of
Cautions see section 6.1.1.1; interactions: Appendix 1 the two components should be checked carefully (the order
(antidiabetics) in which the proportions are stated may not be the same in
Hepatic impairment section 6.1.1 other countries)
Renal impairment section 6.1.1
Pregnancy section 6.1.1
Breast-feeding section 6.1.1 BIPHASIC ISOPHANE INSULIN
Side-effects see under Insulin (section 6.1.1.1); prot- (Biphasic Isophane Insulin Injection—inter-
amine may cause allergic reactions mediate acting)
Dose A sterile buffered suspension of either porcine or human insulin
complexed with protamine sulphate (or another suitable prot-
. By subcutaneous injection, up to 10 minutes before or amine) in a solution of insulin of the same species
soon after a meal, according to requirements
Indications diabetes mellitus
NovoMix c 30 (Novo Nordisk) A Cautions section 6.1.1.1; interactions: Appendix 1
Injection, biphasic insulin aspart (recombinant (antidiabetics)
human insulin analogue), 30% insulin aspart, 70% Hepatic impairment section 6.1.1
insulin aspart protamine, 100 units/mL, net price 5 Â
Renal impairment section 6.1.1
3-mL Penfill c cartridges (for NovoPen c devices) =
£28.84; 5 Â 3-mL FlexPen c prefilled disposable Pregnancy section 6.1.1
injection devices (range 1–60 units, allowing 1-unit Breast-feeding section 6.1.1
dosage adjustment) = £32.00 Side-effects see under Insulin (section 6.1.1.1); prot-
Counselling Show container to patient and confirm that amine may cause allergic reactions
patient is expecting the version dispensed; the proportions of Dose
the two components should be checked carefully (the order
in which the proportions are stated may not be the same in . By subcutaneous injection, according to require-
other countries) ments
10. 426 6.1.1 Insulins BNF 61
Highly purified animal Injection devices
Counselling Show container to patient and confirm that Autopen c (Owen Mumford)
patient is expecting the version dispensed; the proportions of Injection device, Autopen c 24 (for use with Sanofi-Aventis
the two components should be checked carefully (the order 3-mL insulin cartridges), allowing 1-unit dosage adjustment,
in which the proportions are stated may not be the same in max. 21 units (single-unit version) or 2-unit dosage adjust-
other countries) ment, max. 42 units (2-unit version), net price (both) =
£15.73; Autopen c Classic (for use with Lilly and Wockhardt
3-mL insulin cartridges), allowing 1-unit dosage adjustment,
Hypurin c Porcine 30/70 Mix (Wockhardt) A max. 21 units (single-unit version) or 2-unit dosage adjust-
Injection, biphasic isophane insulin (porcine, highly ment, max. 42 units (2-unit version), net price (all) = £15.97
purified), 30% soluble, 70% isophane, 100 units/mL.
ClikSTAR c (Sanofi-Aventis)
Net price 10-mL vial = £16.80; cartridges (for Autop-
Injection device, for use with Lantus c , Apidra c , and
en c Classic) 5 Â 3 mL = £25.20
Insuman c 3-mL insulin cartridges; allowing 1-unit
dose adjustment, max. 80 units, net price = £25.00
Human sequence HumaPen c Luxura (Lilly)
Counselling Show container to patient and confirm that Injection device, for use with Humulin c and Humalog c 3-
patient is expecting the version dispensed; the proportions of mL cartridges; allowing 1-unit dosage adjustment, max.
the two components should be checked carefully (the order 60 units, net price = £26.36
in which the proportions are stated may not be the same in HumaPen c Luxura HD (Lilly)
other countries)
Injection device, for use with Humulin c and Humalog c 3-
mL cartridges; allowing 0.5-unit dosage adjustment, max.
Humulin M3 (Lilly) A
c 30 units, net price = £26.36
Injection, biphasic isophane insulin (human, prb), NovoPenc (Novo Nordisk)
30% soluble, 70% isophane, 100 units/mL. Net price Injection device; for use with Penfill c insulin cartridges;
10-mL vial = £15.68; 5 Â 3-mL cartridge (for most NovoPen c Junior (for 3-mL cartridges), allowing 0.5-unit
dosage adjustment, max. 35 units, net price = £24.79;
6 Endocrine system
Autopen c Classic or HumaPen c ) = £19.08; 5 Â 3-mL
Humulin M3 KwikPen c prefilled disposable injection NovoPen c 3 Demi (for 3-mL cartridges), allowing 0.5-unit
dosage adjustment, max. 35 units, net price = £25.21;
devices (range 1–60 units, allowing 1-unit dosage NovoPen c 4 (for 3-mL cartridges), allowing 1-unit dosage
adjustment) = £21.70 adjustment, max. 60 units, net price = £26.56
OptiClikc (Sanofi-Aventis)
Insuman c Comb 15 (Sanofi-Aventis) A Injection device, for use with Lantus OptiClik c or Apidra
Injection, biphasic isophane insulin (human, crb), Opticlik c insulin cartridges, allowing 1-unit dosage adjust-
15% soluble, 85% isophane, 100 units/mL, net price 5 ment, max. 80 units, net price = £20.13
 3-mL Insuman c Comb 15 OptiSet c prefilled OptiPen c Pro 1 (Sanofi-Aventis)
disposable injection devices (range 2–40 units, allow- Injection device, for use with Insuman c insulin cartridges;
ing 2-unit dosage adjustment) = £17.50 allowing 1-unit dosage adjustment, max. 60 units, net price =
£22.00
Insuman c Comb 25 (Sanofi-Aventis) A Lancets
Injection, biphasic isophane insulin (human, crb), Lancets—sterile, single use (Drug Tariff)
25% soluble, 75% isophane, 100 units/mL, net price 1
Ascensia Microlet c 100 = £3.76, 200 = £7.17; BD Micro-
5-mL vial = £5.61; 5 Â 3-mL cartridge (for ClikSTAR c Fine c + 100 = £3.16, 200 = £6.13; CareSens c 100 = £2.95;
and OptiPen c Pro 1) = £17.50; 5 Â 3-mL Insuman c Cleanlet Fine c 100 = £3.19, 200 = £6.13; Fastclix c 204 =
Comb 25 OptiSet c prefilled disposable injection £9.20; 1 Finepoint c 100 = £3.54; 1 FreeStyle c 200 = £7.02;
1
Milward Steri-Let c , 23 gauge, 100 = £3.00, 200 = £5.70, 28
devices (range 2–40 units, allowing 2-unit dosage gauge, 100 = £3.00, 200 = £5.70; 1 Monolet c 100 = £3.28, 200
adjustment) = £17.50; 5 Â 3-mL Insuman c Comb 25 = £6.24; Monolet Extra c 100 = £3.28; MPD Ultra Thin c 100
SoloStar c prefilled disposable injection devices = £3.30, 200 = £6.50; Multiclix c 204 = £9.27; One Touch
(range 1–80 units, allowing 1-unit dosage adjustment) Comfort c 200 = £7.22; 1 One Touch UltraSoft c 100 = £3.61;
2
Softclix c 200 = £7.40; 2 Softclix XL c 50 = £1.85; Thin
= £19.80 Lancets (formerly MediSense Thin c ), 200 = £7.16; 1 Unilet
ComforTouch c 100 = £3.60, 200 = £6.83; Unilet Eco c 100 =
£2.94, 200 = £5.49; 1 Unilet General Purpose Superlite c 100
Insuman c Comb 50 (Sanofi-Aventis) A = £3.67, 200 = £6.96; Unistik 3 Comfort c , 28-gauge, 100 =
Injection, biphasic isophane insulin (human, crb), £6.24, 200 = £12.20; Unistik 3 Extra c , 21-gauge, 100 = £6.24,
50% soluble, 50% isophane, 100 units/mL, net price 5 200 = £12.20; Unistik 3 Normal c , 23-gauge, 100 = £6.24,
 3-mL cartridge (for ClikSTAR c and OptiPen c Pro 200 = £12.20; Universal c (formerly VitalCare c ), 200 =
1) = £17.50; 5 Â 3-mL Insuman c Comb 50 OptiSet c £6.37; Vitrex Soft c , 23-gauge, 100 = £3.00, 200 = £5.70;
Vitrex Gentle c 28-gauge, 100 = £3.19, 200 = £6.13;
prefilled disposable injection devices (range 2– WaveSense Ultra-Thin c , 28-gauge, 200 = £6.90, 33-gauge,
40 units, allowing 2-unit dosage adjustment) = £17.50 200 = £6.90
Compatible finger-pricking devices (unless indicated otherwise,
see footnotes), all D: B-D Optimus c , Glucolet c , Monojector c ,
Penlet II c , Soft Touch c
1. D Autolet c and D Autolet Impression c are also
6.1.1.3 Hypodermic equipment compatible finger-pricking devices
2. Use D Softclix c finger-pricking device
Patients should be advised on the safe disposal of
Needles
lancets, single-use syringes, and needles. Suitable
Hypodermic Needle, Sterile single use (Drug Tariff)
arrangements for the safe disposal of contaminated
For use with reusable glass syringe, sizes 0.5 mm (25G),
waste must be made before these products are pre- 0.45 mm (26G), 0.4 mm (27G). Net price 100-needle pack =
scribed for patients who are carriers of infectious dis- £2.74
eases. Brands include Microlance c , Monoject c
11. BNF 61 6.1.2 Antidiabetic drugs 427
Needles for Prefilled and Reusable Pen Injectors (Drug Exenatide and liraglutide, both given by subcutaneous
Tariff) injection, are also available for the treatment of type 2
Screw on, needle length 6.1 mm or less, net price 100-needle diabetes, see section 6.1.2.3.
pack = £12.53; 6.2–9.9 mm, 100-needle pack = £8.89; 10 mm
or more, 100-needle pack = £8.89
Brands include BD Micro-Fine c +, NovoFine c , NovoTwist c , Pregnancy and breast-feeding During pregnancy,
Unifine c Pentips women with pre-existing diabetes can be treated with
Snap on, needle length 6.1 mm or less, net price 100-needle metformin [unlicensed use], either alone or in combina-
pack = £12.02; 6.2–9.9 mm, 100-needle pack = £8.52; 10 mm tion with insulin (section 6.1.1). Metformin can be
or more, 100-needle pack = £8.52 continued, or glibenclamide resumed, during breast-
Brands include Penfine c feeding for those with pre-existing diabetes. Women
with gestational diabetes may be treated, with or with-
Syringes out concomitant insulin (section 6.1.1), with gliben-
Hypodermic Syringe (Drug Tariff) clamide from 11 weeks gestation (after organogenesis)
Calibrated glass with Luer taper conical fitting, for use with [unlicensed use] or with metformin [unlicensed use].
U100 insulin. Net price 0.5 mL and 1 mL = £9.22 Women with gestational diabetes should discontinue
Brands include Abcare c
hypoglycaemic treatment after giving birth.
Pre-Set U100 Insulin Syringe (Drug Tariff) Other oral hypoglycaemic drugs, exenatide, and liraglu-
Calibrated glass with Luer taper conical fitting, supplied with tide are contra-indicated in pregnancy.
dosage chart and strong box, for blind patients. Net price
1 mL = £21.99
6.1.2.1 Sulfonylureas
U100 Insulin Syringe with Needle (Drug Tariff)
Disposable with fixed or separate needle for single use or
single patient-use, colour coded orange. Needle length 8 mm, The sulfonylureas act mainly by augmenting insulin
diameters 0.33 mm (29G), 0.3 mm (30G), net price 10 (with secretion and consequently are effective only when
needle), 0.3 mL = £1.38, 0.5 mL = £1.33, 1 mL = £1.32; needle some residual pancreatic beta-cell activity is present;
length 12 mm, diameters 0.45 mm (26G), 0.4 mm (27G), during long-term administration they also have an
0.36 mm (28G), 0.33 mm (29G), net price 10 (with needle),
0.3 mL = £1.45; 0.5 mL = £1.43; 1 mL = £1.44 extrapancreatic action. All may cause hypoglycaemia
Brands include BD Micro-Fine c +, Clinipak c , Insupak c , Mono- but this is uncommon and usually indicates excessive
ject c Ultra, Omnikan c , Plastipak c dosage. Sulfonylurea-induced hypoglycaemia may per-
sist for many hours and must always be treated in
Accessories hospital.
Needle Clipping (Chopping) Device (Drug Tariff) Sulfonylureas are considered for patients who are not
Consisting of a clipper to remove needle from its hub and overweight, or in whom metformin is contra-indicated
6 Endocrine system
container from which cut-off needles cannot be retrieved;
designed to hold 1500 needles, not suitable for use with
or not tolerated. Several sulfonylureas are available and
lancets. Net price = £1.35 choice is determined by side-effects and the duration of
Brands include BD Safe-Clip c action as well as the patient’s age and renal function.
Glibenclamide, a long-acting sulfonylurea, is associated
Sharpsguard (Drug Tariff) with a greater risk of hypoglycaemia; for this reason it
Net price 1-litre sharpsbin = 85p should be avoided in the elderly, and shorter-acting
alternatives, such as gliclazide or tolbutamide, should
be used instead.
When the combination of strict diet and sulfonylurea
6.1.2 Antidiabetic drugs treatment fails, other options include:
6.1.2.1 Sulfonylureas . combining with metformin (section 6.1.2.2) (reports
6.1.2.2 Biguanides of increased hazard with this combination remain
unconfirmed);
6.1.2.3 Other antidiabetic drugs
. combining with pioglitazone, but see section
6.1.2.3;
Oral antidiabetic drugs are used for the treatment of
type 2 diabetes mellitus. They should be prescribed only . combining with saxagliptin, sitagliptin, or vildaglip-
if the patient fails to respond adequately to at least 3 tin (section 6.1.2.3);
months’ restriction of energy and carbohydrate intake . combining with exenatide or liraglutide (section
and an increase in physical activity. They should be used 6.1.2.3);
to augment the effect of diet and exercise, and not to . combining with acarbose (section 6.1.2.3), which
replace them. may have a small beneficial effect, but flatulence
For patients not adequately controlled by diet and oral can be a problem;
hypoglycaemic drugs, insulin may be added to the . combining with bedtime isophane insulin (section
treatment regimen or substituted for oral therapy. 6.1.1) but weight gain and hypoglycaemia can
When insulin is added to oral therapy, it is generally occur.
given at bedtime as isophane or long-acting insulin, and
when insulin replaces an oral regimen it may be given as The risk of hypoglycaemia associated with sulfonylureas
twice-daily injections of a biphasic insulin (or isophane (see notes above) should be discussed with the patient,
insulin mixed with soluble insulin), or a multiple injec- especially when concomitant glucose-lowering drugs
tion regimen. Weight gain and hypoglycaemia may be are prescribed.
complications of insulin therapy but weight gain may be Insulin therapy should be instituted temporarily during
reduced if the insulin is given in combination with met- intercurrent illness (such as myocardial infarction,
formin. coma, infection, and trauma). Sulfonylureas should be
12. 428 6.1.2 Antidiabetic drugs BNF 61
omitted on the morning of surgery; insulin is required Renal impairment see notes above
because of the ensuing hyperglycaemia in these circum- Pregnancy see notes above
stances. Breast-feeding see notes above
Side-effects see notes above
Cautions Sulfonylureas can encourage weight gain
and should be prescribed only if poor control and Dose
symptoms persist despite adequate attempts at dieting; . Initially 5 mg daily with or immediately after break-
metformin (section 6.1.2.2) is considered the drug of fast, dose adjusted according to response (ELDERLY
choice in obese patients. Caution is needed in the avoid, see notes above); max. 15 mg daily
elderly.
Glibenclamide (Non-proprietary) A
Contra-indications Sulfonylureas should be avoided Tablets, glibenclamide 2.5 mg, net price 28-tab pack
where possible in acute porphyria (section 9.8.2). Sulfo- = 95p; 5 mg, 28-tab pack = £1.07
nylureas are contra-indicated in the presence of keto-
acidosis.
GLICLAZIDE
Hepatic impairment Sulfonylureas should be avoided
or a reduced dose should be used in severe hepatic Indications type 2 diabetes mellitus
impairment, because there is an increased risk of hypo- Cautions see notes above; interactions: Appendix 1
glycaemia. Jaundice may occur. (antidiabetics)
Contra-indications see notes above
Renal impairment Sulfonylureas should be used with Hepatic impairment see notes above
care in those with mild to moderate renal impairment, Renal impairment see notes above
because of the hazard of hypoglycaemia; they should be Pregnancy see notes above
avoided where possible in severe renal impairment.
Breast-feeding see notes above
Glipizide should also be avoided if the patient has
6 Endocrine system
both renal and hepatic impairment. If necessary, the Side-effects see notes above
short-acting drug tolbutamide can be used in renal Dose
impairment, as can gliclazide which is principally meta- . Initially, 40–80 mg daily, adjusted according to
bolised in the liver, but careful monitoring of blood- response; up to 160 mg as a single dose, with break-
glucose concentration is essential; care is required to fast; higher doses divided; max. 320 mg daily
use the lowest dose that adequately controls blood
Gliclazide (Non-proprietary) A
glucose.
Tablets, scored, gliclazide 80 mg, net price 28-tab
Pregnancy The use of sulfonylureas in pregnancy pack = £1.10, 60-tab pack = £1.52
Brands include DIAGLYK c
should generally be avoided because of the risk of neo-
natal hypoglycaemia; however, glibenclamide can be Diamicron c (Servier) A
used during the second and third trimesters of Tablets, scored, gliclazide 80 mg, net price 60-tab
pregnancy in women with gestational diabetes, see pack = £4.38
section 6.1.2.
Modified release
Breast-feeding The use of sulfonylureas (except
glibenclamide [unlicensed use], see section 6.1.2) in Diamicron c MR (Servier) A
breast-feeding should be avoided because there is a Tablets, m/r, gliclazide 30 mg, net price 28-tab pack =
theoretical possibility of hypoglycaemia in the infant. £2.81, 56-tab pack = £5.62. Label: 25
Dose initially 30 mg daily with breakfast, adjusted according to
response every 4 weeks (after 2 weeks if no decrease in blood
Side-effects Side-effects of sulfonylureas are gener- glucose); max. 120 mg daily
ally mild and infrequent and include gastro-intestinal Note Diamicron c MR 30 mg may be considered to be
disturbances such as nausea, vomiting, diarrhoea, and approximately equivalent in therapeutic effect to standard
constipation. Hyponatraemia has been reported with formulation Diamicron c 80 mg
glimepiride and glipizide.
Sulfonylureas can occasionally cause a disturbance in
liver function, which may rarely lead to cholestatic GLIMEPIRIDE
jaundice, hepatitis, and hepatic failure. Hypersensitivity Indications type 2 diabetes mellitus
reactions can occur, usually in the first 6–8 weeks of
Cautions see notes above; manufacturer recommends
therapy. They consist mainly of allergic skin reactions
regular hepatic and haematological monitoring but
which progress rarely to erythema multiforme and
limited evidence of clinical value; interactions:
exfoliative dermatitis, fever, and jaundice; photosensit-
Appendix 1 (antidiabetics)
ivity has rarely been reported with glipizide. Blood
disorders are also rare but may include leucopenia, Contra-indications see notes above
thrombocytopenia, agranulocytosis, pancytopenia, Hepatic impairment see notes above
haemolytic anaemia, and aplastic anaemia. Renal impairment see notes above
Pregnancy see notes above
Breast-feeding see notes above
GLIBENCLAMIDE Side-effects see notes above
Indications type 2 diabetes mellitus Dose
Cautions see notes above; interactions: Appendix 1 . Initially 1 mg daily, adjusted according to response in
(antidiabetics) 1-mg steps at 1–2 week intervals; usual max. 4 mg
Contra-indications see notes above daily (exceptionally, up to 6 mg daily may be used);
Hepatic impairment see notes above taken shortly before or with first main meal
13. BNF 61 6.1.2 Antidiabetic drugs 429
Glimepiride (Non-proprietary) A there are some residual functioning pancreatic islet
Tablets, glimepiride 1 mg, net price 30-tab pack = cells.
£1.40; 2 mg, 30-tab pack = £1.38; 3 mg, 30-tab pack = Metformin is the drug of first choice in overweight
£4.57; 4 mg, 30-tab pack = £1.75 patients in whom strict dieting has failed to control
Amaryl c (Sanofi-Aventis) A diabetes, if appropriate it may also be considered as
Tablets, all scored, glimepiride 1 mg (pink), net price an option in patients who are not overweight. It is also
30-tab pack = £4.33; 2 mg (green), 30-tab pack = used when diabetes is inadequately controlled with
£7.13; 3 mg (yellow), 30-tab pack = £10.75; 4 mg sulfonylurea treatment. When the combination of strict
(blue), 30-tab pack = £14.24 diet and metformin treatment fails, other options
include:
. combining with a sulfonylurea (section 6.1.2.1)
GLIPIZIDE (reports of increased hazard with this combination
remain unconfirmed);
Indications type 2 diabetes mellitus
. combining with pioglitazone (section 6.1.2.3);
Cautions see notes above; interactions: Appendix 1
(antidiabetics) . combining with repaglinide or nateglinide (section
6.1.2.3);
Contra-indications see notes above
Hepatic impairment see notes above . combining with saxagliptin, sitagliptin, or vildaglip-
tin (section 6.1.2.3);
Renal impairment see notes above
Pregnancy see notes above . combining with exenatide or liraglutide (section
Breast-feeding see notes above 6.1.2.3);
Side-effects see notes above; also dizziness, drowsi- . combining with acarbose (section 6.1.2.3), which
ness may have a small beneficial effect, but flatulence
Dose can be a problem;
. Initially 2.5–5 mg daily shortly before breakfast or . combining with insulin (section 6.1.1) but weight
lunch, adjusted according to response; max. 20 mg gain and hypoglycaemia can be problems (weight
daily; up to 15 mg may be given as a single dose; gain minimised if insulin given at night).
higher doses divided Insulin treatment is almost always required in medical
Glipizide (Non-proprietary) A and surgical emergencies; insulin should also be sub-
Tablets, glipizide 5 mg, net price 56-tab pack = £4.23 stituted before elective surgery (omit metformin on the
morning of surgery and give insulin if required).
Minodiab c (Pharmacia) A
Tablets, scored, glipizide 5 mg, net price 28-tab pack Hypoglycaemia does not usually occur with metformin;
6 Endocrine system
= £1.26 other advantages are the lower incidence of weight gain
and lower plasma-insulin concentration. It does not
exert a hypoglycaemic action in non-diabetic subjects
unless given in overdose.
TOLBUTAMIDE Gastro-intestinal side-effects are initially common with
Indications type 2 diabetes mellitus metformin, and may persist in some patients, particu-
Cautions see notes above; interactions: Appendix 1 larly when very high doses such as 3 g daily are given.
(antidiabetics) Very rarely, metformin can provoke lactic acidosis. It is
Contra-indications see notes above most likely to occur in patients with renal impairment,
Hepatic impairment see notes above see Lactic Acidosis below.
Renal impairment see notes above Metformin is used for the symptomatic management of
Pregnancy see notes above polycystic ovary syndrome [unlicensed indication];
Breast-feeding see notes above however, treatment should be initiated by a specialist.
Side-effects see notes above; also headache, tinnitus Metformin improves insulin sensitivity, may aid weight
Dose reduction, helps to normalise menstrual cycle (increas-
ing the rate of spontaneous ovulation), and may
. 0.5–1.5 g (max. 2 g) daily in divided doses with or
improve hirsutism.
immediately after meals or as a single dose with or
immediately after breakfast
Tolbutamide (Non-proprietary) A METFORMIN HYDROCHLORIDE
Tablets, tolbutamide 500 mg, net price 28-tab pack =
£1.74 Indications diabetes mellitus (see notes above); poly-
cystic ovary syndrome [unlicensed indication]
Cautions see notes above; determine renal function
before treatment and at least annually (at least twice a
year in patients with additional risk factors for renal
6.1.2.2 Biguanides impairment, or if deterioration suspected); interac-
tions: Appendix 1 (antidiabetics)
Metformin, the only available biguanide, has a different Lactic acidosis Use with caution in renal impairment—
mode of action from the sulfonylureas, and is not inter- increased risk of lactic acidosis; avoid in significant renal
impairment. NICE1 recommends that the dose should be
changeable with them. It exerts its effect mainly by reviewed if eGFR less than 45 mL/minute/1.73 m2 and to
decreasing gluconeogenesis and by increasing periph-
eral utilisation of glucose; since it acts only in the 1. NICE clinical guideline 87 (May 2009): Type 2 diabetes:
presence of endogenous insulin it is effective only if The management of type 2 diabetes
