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 483 126.96.36.199 Short-acting insulins 422 This chapter also includes advice on the drug man- 188.8.131.52 Intermediate- and long-acting agement of the following: insulins 423 Adrenal suppression during illness, trauma or 184.108.40.206Hypodermic equipment 426 surgery, p. 444 Serious infections in patients taking corticoster- 6.1.2Antidiabetic drugs 427 oids, p. 444 220.127.116.11Sulfonylureas 427 Osteoporosis, p. 469 Breast pain (mastalgia), p. 482 18.104.22.168Biguanides 429 22.214.171.124Other 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 126.96.36.199 Oestrogens and HRT 449 fasting or random blood-glucose concentration (and occasionally by oral glucose tolerance test). Although 188.8.131.52 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
BNF 61 6.1.1 Insulins 419(section 2.12) should be addressed. Cardiovascular risk Driving Drivers with diabetes are required to notify thein patients with diabetes can be further reduced by the Driver and Vehicle Licensing Agency (DVLA) of theiruse of an ACE inhibitor (section 184.108.40.206), low-dose condition if they are treated with insulin or if they areaspirin (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 theHowever, a temporary deterioration in established dia- problems. Drivers treated with insulin should normallybetic retinopathy may occur when normalising blood- check their blood-glucose concentration before drivingglucose 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 oralthe management of diabetic nephropathy, see section antidiabetic drugs who are at particular risk of hypo-6.1.5. glycaemia. Drivers treated with insulin should ensureA measure of the total glycosylated (or glycated) hae- that a supply of sugar is always available in the vehiclemoglobin (HbA1 ) or a speciﬁc fraction (HbA1c ) provides and they should avoid driving if their meal is delayed. Ifa good indication of glycaemic control over the previous hypoglycaemia occurs, or warning signs develop, the2–3 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 beachieved 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 continuingthose at risk of arterial disease, the aim should be to journey; recovery may take 15 minutes or longermaintain 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 220.127.116.11 Short-acting insulins HbA1c values in mmol of glycosylated haemoglobin 18.104.22.168 Intermediate- and long-acting insulins per mol of haemoglobin. UK laboratories now 22.214.171.124 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, andmeasurement of HbA1c and can be used to assess must therefore be given by injection; the subcutaneouscontrol over short periods of time, particularly when route is ideal in most circumstances. Insulin is usuallyHbA1c 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 theTight 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 fewvisual 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. Localsection 2.5). allergic reactions are rare.
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 of6 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 126.96.36.199); 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 188.8.131.52); 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 184.108.40.206). 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 220.127.116.11), 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.
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 beSoluble insulin by the intravenous route is reserved for available to all healthcare professionals involved in theurgent treatment, e.g. in diabetic ketoacidosis, and for treatment of these patients; in general, the followingﬁne 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 potassiumMonitoring 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 toblood-glucose concentration varies substantially the patient’s ﬂuid requirements (usually 125 mL per 6 Endocrine systemthroughout 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 aing 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 insulincose concentration of between 4 and 9 mmol/litre for infusions should be made up according to locallymost of the time (4–7 mmol/litre before meals and less agreed protocols;than 9 mmol/litre after meals), while accepting that onoccasions, for brief periods, it will be above these values; . The rate of the insulin infusion should be adjustedstrenuous efforts should be made to prevent the blood- according to blood-glucose concentration (frequentglucose concentration from falling below 4 mmol/litre. monitoring necessary) in line with locally agreedPatients 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, cardiaccarbohydrate intake. With ﬁxed-dose insulin regimens, function, and age.the carbohydrate intake needs to be regulated, and Protocols should include speciﬁc instructions on how toshould be distributed throughout the day to match the manage resistant cases (such as patients who are ininsulin regimen. The intake of energy and of simple and shock or severely ill or those receiving corticosteroids orcomplex 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 shouldavoided. 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 toblem with insulin therapy. All patients must be carefully the patient’s ﬂuid requirements (usually 125 mL perinstructed on how to avoid it. hour) with the insulin dose adjusted according toLoss of warning of hypoglycaemia among insulin-trea- blood-glucose concentration in line with locally agreedted 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 intravenoustion 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 ormay 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 fourawareness (and also delay recovery). divided doses using soluble insulin before meals andTo restore the warning signs, episodes of hypoglycaemia intermediate-acting insulin at bedtime and the dosemust be minimised; this involves appropriate adjust- adjusted from day to day. Patients with hyperglycaemia
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 18.104.22.168 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 infusion6 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 22.214.171.124) 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
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) 126.96.36.199 Intermediate- and long-actingIndications diabetes mellitus insulinsCautions 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 ofRenal impairment section 6.1.1 approximately 1–2 hours, a maximal effect at 4–12Pregnancy section 6.1.1 hours, and a duration of 16–35 hours. Some are givenBreast-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 inDose 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 theCounselling Show container to patient and conﬁrm that same syringe and is now rarely used.patient is expecting the version dispensedNote 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 andover 6 years with diabetes mellitus in whom the use of a short- insulin detemir is given once or twice daily. NICEacting 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 isIndications diabetes mellitus required in patients with type 2 diabetes, insulin detemirCautions 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 orRenal impairment section 6.1.1 . who would otherwise need twice-daily basal insulinPregnancy section 6.1.1 injections in combination with oral antidiabeticBreast-feeding section 6.1.1 drugs orSide-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 188.8.131.52; 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
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 184.108.40.206) 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 220.127.116.11) 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 18.104.22.168; interactions: Appendix 1 protamine sulphate or another suitable protamine (antidiabetics) Indications diabetes mellitus Hepatic impairment section 6.1.16 Endocrine system Cautions section 22.214.171.124; 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 126.96.36.199) 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 188.8.131.52); 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 184.108.40.206; interactions: Appendix 1 preﬁlled disposable injection devices (range 1– (antidiabetics) 60 units, allowing 1-unit dosage adjustment) = £21.70
BNF 61 6.1.1 Insulins 425Insuman 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 220.127.116.11 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 18.104.22.168); prot- PROTAMINE ZINC INSULIN amine may cause allergic reactions (Protamine Zinc Insulin Injection—long acting) DoseA sterile suspension of insulin in the form of a complex . By subcutaneous injection, up to 15 minutes before orobtained by the addition of a suitable protamine and zincchloride; this preparation was included in BP 1980 but is not soon after a meal, according to requirementsincluded in BP 1988 Humalog c Mix25 (Lilly) AIndications diabetes mellitus Injection, biphasic insulin lispro (recombinant humanCautions section 22.214.171.124; 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 vialHepatic impairment section 6.1.1 = £16.61; 5 Â 3-mL cartridge (for Autopen c Classic orRenal impairment section 6.1.1 HumaPen c ) = £29.46; 5 Â 3-mL preﬁlled disposable injection devices (range 1–60 units, allowing 1-unitPregnancy section 6.1.1 dosage adjustment) = £30.98; 5 Â 3-mL Humalog cBreast-feeding section 6.1.1 Mix25 KwikPen preﬁlled disposable injection devicesSide-effects see under Insulin (section 126.96.36.199); prot- (range 1–60 units, allowing 1-unit dosage adjustment) amine may cause allergic reactions = £30.98Dose 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 inHypurin 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 injectionBiphasic 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) £30.98Indications diabetes mellitus Counselling Show container to patient and conﬁrm that patient is expecting the version dispensed; the proportions ofCautions see section 188.8.131.52; interactions: Appendix 1 the two components should be checked carefully (the order (antidiabetics) in which the proportions are stated may not be the same inHepatic impairment section 6.1.1 other countries)Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1 BIPHASIC ISOPHANE INSULINSide-effects see under Insulin (section 184.108.40.206); 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 mellitusNovoMix c 30 (Novo Nordisk) A Cautions section 220.127.116.11; 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 18.104.22.168); 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
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 Â 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, Â 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 22.214.171.124 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
BNF 61 6.1.2 Antidiabetic drugs 427Needles for Preﬁlled and Reusable Pen Injectors (Drug Exenatide and liraglutide, both given by subcutaneousTariff) 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 126.96.36.199. 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 = £21.99 188.8.131.52 SulfonylureasU100 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 associatedSharpsguard (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: 184.108.40.206 Sulfonylureas . combining with metformin (section 220.127.116.11) (reports 18.104.22.168 Biguanides of increased hazard with this combination remain unconﬁrmed); 22.214.171.124 Other antidiabetic drugs . combining with pioglitazone, but see section 126.96.36.199;Oral antidiabetic drugs are used for the treatment oftype 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 188.8.131.52);months’ restriction of energy and carbohydrate intake . combining with exenatide or liraglutide (sectionand an increase in physical activity. They should be used 184.108.40.206);to augment the effect of diet and exercise, and not to . combining with acarbose (section 220.127.116.11), whichreplace them. may have a small beneﬁcial effect, but ﬂatulenceFor 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 (sectiontreatment regimen or substituted for oral therapy. 6.1.1) but weight gain and hypoglycaemia canWhen insulin is added to oral therapy, it is generally occur.given at bedtime as isophane or long-acting insulin, andwhen insulin replaces an oral regimen it may be given as The risk of hypoglycaemia associated with sulfonylureastwice-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 drugstion regimen. Weight gain and hypoglycaemia may be are prescribed.complications of insulin therapy but weight gain may be Insulin therapy should be instituted temporarily duringreduced if the insulin is given in combination with met- intercurrent illness (such as myocardial infarction,formin. coma, infection, and trauma). Sulfonylureas should be
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 18.104.22.168) 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 has6 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
BNF 61 6.1.2 Antidiabetic drugs 429Glimepiride (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 controlAmaryl 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 22.214.171.124) GLIPIZIDE (reports of increased hazard with this combination remain unconﬁrmed);Indications type 2 diabetes mellitus . combining with pioglitazone (section 126.96.36.199);Cautions see notes above; interactions: Appendix 1 (antidiabetics) . combining with repaglinide or nateglinide (section 188.8.131.52);Contra-indications see notes aboveHepatic impairment see notes above . combining with saxagliptin, sitagliptin, or vildaglip- tin (section 184.108.40.206);Renal impairment see notes abovePregnancy see notes above . combining with exenatide or liraglutide (sectionBreast-feeding see notes above 220.127.116.11);Side-effects see notes above; also dizziness, drowsi- . combining with acarbose (section 18.104.22.168), which ness may have a small beneﬁcial effect, but ﬂatulenceDose 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 medicalGlipizide (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 withIndications 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 isContra-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 ofPregnancy 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 weightDose 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 breakfastTolbutamide (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 22.214.171.124 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 bechangeable with them. It exerts its effect mainly by reviewed if eGFR less than 45 mL/minute/1.73 m2 and todecreasing 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