l CONCEPTION AND CONTRACEPTION Effective
contraception must be used in women of child-bearing
l PREGNANCY Manufacturer advises avoid—teratogenic in
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises avoid.
▶ Monitor ECG before and one week after initiation, and
then as clinically indicated thereafter.
▶ Adrenal insufficiency Monitor adrenal function within one
week of initiation, then regularly thereafter. When cortisol
levels are normalised or close to target and effective dose
established, monitor every 3–6 months as there is a risk of
autoimmune disease development or exacerbation after
normalisation of cortisol levels. If symptoms suggestive of
adrenal insufficiency such as fatigue, anorexia, nausea,
vomiting, hypotension, hyponatraemia, hyperkalaemia,
and/or hypoglycaemia occur, measure cortisol levels and
discontinue treatment temporarily (can be resumed
thereafter at lower dose) or reduce dose and if necessary,
initiate corticosteroid substitution.
▶ Hepatotoxicity Monitor liver function before initiation of
treatment, then weekly for 1 month after initiation, then
monthly for 6 months—more frequently if dose adjusted or
abnormal liver function detected. Reduce dose if liver
enzymes increase less than 3 times the normal upper
limit—consult product literature; if liver enzymes are
raised to 3 times or greater the normal upper limit,
discontinue treatment permanently.
l PATIENT AND CARER ADVICE Patients or their carers should
be told how to recognise signs of liver disorder, and
advised to discontinue treatment and seek prompt medical
attention if symptoms such as anorexia, nausea, vomiting,
fatigue, jaundice, abdominal pain, or dark urine develop.
Patients or their carers should also be told how to
recognise signs of adrenal insufficiency.
Driving and skilled tasks Dizziness and somnolence may
affect the performance of skilled tasks (e.g. driving).
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug. Forms available
from special-order manufacturers include: oral suspension
CAUTIONARY AND ADVISORY LABELS 2, 5, 21
▶ Ketoconazole (non-proprietary) A
Ketoconazole 200 mg Ketoconazole 200mg tablets | 60 tablet P £480.00 DT = £480.00
l DRUG ACTION Metyrapone is a competitive inhibitor of
11b-hydroxylation in the adrenal cortex; the resulting
inhibition of cortisol (and to a lesser extent aldosterone)
production leads to an increase in ACTH production
which, in turn, leads to increased synthesis and release of
cortisol precursors. Metyrapone may be used as a test of
Differential diagnosis of ACTH-dependent Cushing’s
syndrome (specialist supervision in hospital)
▶ Adult: 750 mg every 4 hours for 6 doses
Management of Cushing’s syndrome (specialist
▶ Adult: Usual dose 0.25–6 g daily, dose to be tailored to
cortisol production, dose is either low, and tailored to
cortisol production, or high, in which case
corticosteroid replacement therapy is also needed
Resistant oedema due to increased aldosterone secretion
in cirrhosis, nephrotic syndrome, and congestive heart
failure (with glucocorticoid replacement therapy)
(specialist supervision in hospital)
▶ Adult: 3 g daily in divided doses
l CONTRA-INDICATIONS Adrenocortical insufficiency
l CAUTIONS Avoid in Acute porphyrias p. 1058 . gross
hypopituitarism (risk of precipitating acute adrenal failure)
. hypertension on long-term administration . hypothyroidism (delayed response)
l INTERACTIONS → Appendix 1: metyrapone
▶ Common or very common Dizziness . headache . hypotension . nausea . sedation . vomiting
▶ Rare or very rare Abdominal pain . adrenal insufficiency . allergic dermatitis . hirsutism
▶ Frequency not known Alopecia . bone marrow failure . hypertension
l PREGNANCY Avoid (may impair biosynthesis of fetalplacental steroids).
l BREAST FEEDING Avoid—no information available.
l HEPATIC IMPAIRMENT Manufacturer advises caution (risk
Driving and skilled tasks Drowsiness may affect the
performance of skilled tasks (e.g. driving).
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 21
▶ Metopirone (HRA Pharma UK Ltd)
Metyrapone 250 mg Metopirone 250mg capsules | 100 capsule P £363.66 DT = £363.66
Diabetes mellitus is a group of metabolic disorders in which
persistent hyperglycaemia is caused by deficient insulin
secretion or by resistance to the action of insulin. This leads
to the abnormalities of carbohydrate, fat and protein
metabolism that are characteristic of diabetes mellitus.
Type 1 diabetes mellitus p. 684 and Type 2 diabetes
mellitus p. 686 are the two most common classifications of
diabetes. Other common types of diabetes are gestational
diabetes (develops during pregnancy and resolves after
delivery) and secondary diabetes (may be caused by
pancreatic damage, hepatic cirrhosis, or endocrine disease).
Treatment with endocrine, antiviral, or antipsychotic drugs
may also cause secondary diabetes.
Drivers with diabetes may be required to notify the Driver
and Vehicle Licensing Agency (DVLA) of their condition
depending on their treatment, the type of licence they hold,
and whether they have diabetic complications (including
episodes of hypoglycaemia). All drivers who are treated with
insulin must inform the DVLA, with some exceptions for
682 Diabetes mellitus and hypoglycaemia BNF 78
temporary treatment. Detailed guidance on notification
requirements, eligibility to drive, and precautions required,
is available from the DVLA at www.gov.uk/guidance/diabetesmellitus-assessing-fitness-to-drive.
The DVLA recommends (2018) that drivers with diabetes
need to be particularly careful to avoid hypoglycaemia and
should be informed of the warning signs and actions to take.
Drivers treated with insulin should always carry a glucose
meter and blood-glucose strips when driving, and check
their blood-glucose concentration no more than 2 hours
before driving and every 2 hours while driving. More
frequent self-monitoring may be required if, for any reason,
there is a greater risk of hypoglycaemia, such as after
physical activity or altered meal routine.
Blood-glucose should always be above 5 mmol/litre while
driving. If blood-glucose falls to 5 mmol/litre or below, a
snack should be taken. Drivers treated with insulin should
ensure that a supply of fast-acting carbohydrate is always
available in the vehicle. If blood-glucose is less than
4 mmol/litre, or warning signs of hypoglycaemia develop, the
driver should not drive. If already driving, the driver should:
. stop the vehicle in a safe place;
. switch off the engine, remove keys from the ignition, and
. eat or drink a suitable source of sugar;
. wait until 45 minutes after blood-glucose has returned to
normal, before continuing journey.
Drivers must not drive if hypoglycaemia awareness has
been lost and the DVLA must be notified; driving may
resume if a medical report confirms that awareness has been
Depending on the type of licence, notification and
monitoring may also be necessary for drivers taking oral
antidiabetic drugs, particularly those which carry a risk of
hypoglycaemia (e.g. sulfonylureas, nateglinide p. 701,
Note: additional criteria apply for drivers of large goods or
passenger carrying vehicles—consult DVLA guidance.
Alcohol can make the signs of hypoglycaemia less clear, and
can cause delayed hypoglycaemia; specialist sources
recommend that patients with diabetes should drink alcohol
only in moderation, and when accompanied by food.
The oral glucose tolerance test is used mainly for diagnosis
of impaired glucose tolerance; it is not recommended or
necessary for routine diagnostic use when severe symptoms
of hyperglycaemia are present. In patients who have less
severe symptoms and a blood-glucose concentration that
does not establish or exclude diabetes (e.g. impaired fasting
glycaemia), an oral glucose tolerance test may be required. It
is also used to establish the presence of gestational diabetes.
An oral glucose tolerance test involves measuring the
blood-glucose concentration after fasting, and then 2 hours
after drinking a standard anhydrous glucose drink.
Anhydrous glucose may alternatively be given as the
appropriate amount of Polycal ® or as Rapilose ® OGTT oral
Glycated haemoglobin (HbA1c) forms when red blood cells
are exposed to glucose in the plasma. The HbA1c test reflects
average plasma glucose over the previous 2 to 3 months and
provides a good indicator of glycaemic control. Unlike the
oral glucose tolerance test, an HbA1c test can be performed
at any time of the day and does not require any special
HbA1c values are expressed in mmol of glycated
haemoglobin per mol of haemoglobin (mmol/mol), a
standardised unit specific for HbA1c created by the
International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC). HbA1c values were previously
aligned to the assay used in the Diabetes Control and
Complications Trial (DCCT) and expressed as a percentage.
IFCC-HbA1c (mmol/mol) DCCT-HbA1c (%)
The HbA1c test is used for monitoring glycaemic control in
both Type 1 diabetes p. 684 and Type 2 diabetes p. 686 and is
now also used for diagnosis of type 2 diabetes.g HbA1c
should not be used for diagnosis in those with suspected
type 1 diabetes, in children, during pregnancy, or in women
who are up to two months postpartum. It should also not be
. had symptoms of diabetes for less than 2 months;
. a high diabetes risk and are acutely ill;
. treatment with medication that may cause
. end-stage chronic kidney disease;
HbA1c used for diagnosis of diabetes should be interpreted
with caution in patients with abnormal haemoglobin,
anaemia, altered red cell lifespan, or who have had a recent
g HbA1c is also a reliable predictor of microvascular and
macrovascular complications and mortality. Lower HbA1c is
associated with a lower risk of long term vascular
complications and patients should be supported to aim for
an individualised HbA1c target (see Type 1 diabetes p. 684
HbA1c should usually be measured in patients with type 1
with type 2 diabetes should be monitored every 3 to
6 months until HbA1c and medication are stable when
monitoring can be reduced to every 6 months. h
HbA1c monitoring is invalid for patients with disturbed
erythrocyte turnover or for patients with a lack of, or
abnormal haemoglobin. In these cases, quality-controlled
plasma glucose profiles, total glycated haemoglobin
estimation (if there is abnormal haemoglobin), or
fructosamine estimation can be used.
Laboratory measurement of fructosamine concentration
measures the glycated fraction of all plasma proteins over
the previous 14 to 21 days but is a less accurate measure of
Patients with diabetes may be eligible for the New Medicines
Service / Medicines Use Review service provided by a
community pharmacist. For further information, see
Advanced Pharmacy Services in Guidance on prescribing p. 1.
Type 1 diabetes describes an absolute insulin deficiency in
which there is little or no endogenous insulin secretory
capacity due to destruction of insulin-producing beta-cells
in the pancreatic islets of Langerhans. This form of the
disease has an auto-immune basis in most cases, and it can
occur at any age, but most commonly before adulthood.
Loss of insulin secretion results in hyperglycaemia and
other metabolic abnormalities. If poorly managed, the
resulting tissue damage has both short-term and long-term
adverse effects on health; this can result in retinopathy,
nephropathy, neuropathy, premature cardiovascular disease,
and peripheral arterial disease.
Typical features in adult patients presenting with type 1
diabetes are hyperglycaemia (random plasma-glucose
concentration above 11 mmol/litre), ketosis, rapid weight
loss, a body mass index below 25 kg/m2
50 years, and a personal/family history of autoimmune
disease (though not all features may be present).
Treatment is aimed at using insulin regimens to achieve as
optimal a level of blood-glucose control as is feasible, while
avoiding or reducing the frequency of hypoglycaemic
episodes, in order to minimise the risk of long-term
microvascular and macrovascular complications.
Disability from complications can often be prevented by
early detection and active management of the disease (see
Diabetic complications p. 688).g The target for glycaemic
control should be individualised for each patient,
considering factors such as daily activities, aspirations,
likelihood of complications, adherence to treatment,
comorbidities, occupation and history of hypoglycaemia.
A target HbA1c concentration of 48 mmol/mol (6.5%) or
lower is recommended in patients with type 1 diabetes.
Blood-glucose concentration should be monitored at least
four times a day, including before each meal and before bed.
. a fasting blood-glucose concentration of 5–7 mmol/litre
. a blood-glucose concentration of 4–7 mmol/litre before
meals at other times of the day;
. a blood-glucose concentration of 5–9 mmol/litre at least
. a blood-glucose concentration of at least 5 mmol/litre
g Type 1 diabetes requires insulin replacement,
supported by active management of other cardiovascular risk
factors, such as hypertension and high circulating lipids (see
Diabetic complications p. 688). hInsulin replacement
therapy aims to recreate normal fluctuations in circulating
insulin concentrations while supporting a flexible lifestyle
with minimal restrictions. Flexible insulin therapy usually
involves self-injecting multiple daily doses of insulin, with
doses adjusted according to planned exercise, intended food
intake and other factors, including current blood-glucose,
which the patient needs to test on a regular basis.
g Patients who have a BMI of 25 kg/m2 or above
(23 kg/m2 or above for patients of South Asian or related
ethnicity) who wish to improve their blood-glucose control
while minimising their effective insulin dose, may benefit
from metformin hydrochloride p. 692 [unlicensed indication]
as an addition to insulin therapy.
Dietary control is important in both type 1 and type 2
diabetes and patients should receive advice from a dietitian.
Dietary advice should include information on weight control,
cardiovascular risk, hyperglycaemic effects of different foods
and appropriate changes in insulin doses according to food
intake. Healthy eating can reduce cardiovascular risk and
dietary modifications may be recommended to account for
various associated features of diabetes such as excess weight
and obesity, low body-weight, eating disorders,
hypertension and renal failure. Patients with type 1 diabetes
should be offered carbohydrate-counting training as part of a
structured education programme. h
Insulin therapy in type 1 diabetes
g All patients with type 1 diabetes require insulin therapy
(see also Insulin p. 685). Treatment should be initiated and
managed by clinicians with relevant expertise; there are
several different types of regimens. h
Multiple daily injection basal-bolus insulin regimens
One or more separate daily injections of intermediate-acting
insulin or long-acting insulin analogue as the basal insulin;
alongside multiple bolus injections of short-acting insulin
before meals. This regimen offers flexibility to tailor insulin
therapy with the carbohydrate load of each meal.
One, two, or three insulin injections per day of short-acting
insulin mixed with intermediate-acting insulin. The insulin
preparations may be mixed by the patient at the time of
injection, or a premixed product can be used.
Continuous subcutaneous insulin infusion (insulin pump)
A regular or continuous amount of insulin (usually in the
form of a rapid-acting insulin analogue or soluble insulin),
delivered by a programmable pump and insulin storage
reservoir via a subcutaneous needle or cannula.
g Patients with type 1 diabetes should be offered multiple
daily injection basal-bolus insulin regimens as the first-line
choice. Twice-daily insulin detemir p. 717 should be offered
as the long-acting basal insulin therapy. Once-daily insulin
glargine p. 718 may be prescribed if insulin detemir is not
tolerated, or if a twice-daily regimen is not acceptable to the
patient. Insulin detemir may also be offered as an alternative
Patients who are using alternative basal regimens may
continue if agreed targets are being achieved; other basal
insulin regimens should be considered only if the
[biphasic], basal-only, or bolus-only regimens) are not
recommended for adults with newly diagnosed type 1
A rapid-acting insulin analogue is recommended as the
bolus or mealtime insulin replacement, rather than soluble
routine use after meals should be discouraged. Patients who
have a strong preference for an alternative mealtime insulin
should be offered their preferred insulin.
Alternatively, if a multiple daily injection basal–bolus
regimen is not possible, a twice-daily mixed insulin regimen
should be considered if it is preferred.
In patients who are using a twice-daily human insulin
mixed regimen and have hypoglycaemia that affects their
quality of life, a trial of a twice-daily analogue mixed insulin
Continuous subcutaneous insulin infusion (insulin pump)
therapy, should only be offered to adults who suffer
disabling hypoglycaemia, or, who have high HbA1c
concentrations (69 mmol/mol [8.5%] or above) with multiple
daily injection therapy (including, if appropriate, the use of
long-acting insulin analogues) despite a high level of care.
Insulin pump therapy should be initiated by a specialist
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