(US Adopted Name, rINN)

Drug Nomenclature

Profile

Buformin is a biguanide antidiabetic. It has been given orally in the treatment of type 2 diabetes mellitus in doses of up to 300 mg daily. Buformin is also used as the hydrochloride.

Proprietary Preparations

Czech Republic: Adebit † Silubin- †

Hungary: Adebit

Spain: Silubin †

Switzerland: Silubin †

Carbutamide

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, Spanish):

Profile

Carbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in single daily doses of 0.5 to 1 g, but is more toxic than chlorpropamide.

Proprietary Preparations

France: Glucidoral

Epalrestat

(rINN)

Drug Nomenclature

Profile

Epalrestat inhibits the enzyme aldose reductase which catalyses the conversion of glucose to sorbitol. It has been suggested that accumulation of sorbitol in certain cells, occurring only in conditions of hyperglycaemia and resulting in a hyperosmotic effect, may be involved in the pathogenesis of some diabetic complications. Aldose reductase inhibitors have no influence on blood-glucose concentrations. Epalrestat is given orally for the treatment of diabetic complications including neuropathy, in a usual dose of 50 mg three times daily before meals.

Proprietary Preparations

Japan: Kinedak

Glibornuride

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Note. The name glibornuride has frequently but erroneously been applied to glibenclamide.

Profile

Glibornuride is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 12.5 to 75 mg daily. Daily doses of 50 mg or more are given in 2 divided doses.

Proprietary Preparations

Austria: Glutril

France: Glutril

Germany: Gluborid Glutril

Switzerland: Gluborid Glutril

Turkey: Glutril

Glisentide

Drug Nomenclature

Profile

Glisentide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 2.5 to 20 mg daily.

Proprietary Preparations

Spain: Staticum

Glisolamide

Drug Nomenclature

Profile

Glisolamide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.

Proprietary Preparations

Italy: Diabenor

Glisoxepide

Drug Nomenclature

Profile

Glisoxepide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.

Proprietary Preparations

Austria: Pro-Diaban

Glybuzole

Drug Nomenclature

Profile

Glybuzole is an oral antidiabetic with a structure distinct from that of the sulfonylureas, biguanides, or sulfonamidopyrimidines.

Proprietary Preparations

Japan: Gludiase

Glycyclamide

Drug Nomenclature

Profile

Glycyclamide is a sulfonylurea antidiabetic. It is given by mouth in the treatment of type 2 diabetes mellitus.

Preparations

Proprietary Preparations

Italy: Diaborale

Mitiglinide

Profile

Mitiglinide is a meglitinide antidiabetic that is under investiga tion in the treatment of type 2 diabetes mellitus.

Muraglitazar

Profile

Muraglitazar is a dual alfa/gamma peroxisome proliferator-activated receptor (PPAR) activator. It has been investigated in the treatment of type 2 diabetes mellitus.

Adverse effects. A review of data from 5 studies suggested that muraglitazar may be associated with an increased risk of adverse cardiovascular events and heart failure.

Phenformin Hydrochloride

Pharmacopoeias. In China

Profile

Phenformin hydrochloride is a biguanide antidiabetic. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries for the treatment of type 2 diabetes mellitus.

Phenformin was implicated in the controversial reports of excess cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).

Proprietary Preparations

Greece: Informin

India: DBI

Portugal: Debeina

Multi-ingredient

Greece: Daopar †

India: Chlorformin †

Italy: Bi-Euglucon Bidiabe Gliben  † Gliformin Suguan

Pimagedine

Pimagedine Hydrochloride

Drug Approvals

(US Adopted Name, rINNM)

INNs in main languages (French, Latin, and Spanish):

Profile

Pimagedine reportedly inhibits the formation of glycosylated proteins (advanced glycosylation end-products) and has other actions including inhibition of aldose reductase. It has been investigated for the prevention of diabetic complications.

Ruboxistaurin

Profile

Ruboxistaurin is an oral inhibitor of the p-isoform of the enzyme protein kinase C, which is thought to play a role in the development of diabetic microvascular complications. It is under investigation as an adjunct in the treatment of diabetic retinopathy.

Voglibose

Pharmacopoeias. In Japan.

Profile

Voglibose is an alpha-glue osidase inhibitor with general properties similar to those of acarbose. It is used in the treatment of diabetes mellitus in oral doses of 200 to 300 micrograms three times daily before meals.

Hepatic encephalopathy. Vbglibose has been investigated in the management of hepatic encephalopathy.

Proprietary Preparations

Japan: Basen

Philippines: Basen

Thailand: Basen.

Adverse Effects

Gastrointestinal adverse effects including anorexia, nausea, vomiting, and diarrhoea may occur with bigua-nides patients may experience taste disturbance and there may be weight loss. Absorption of various substances including vitamin B₁₂ may be impaired. Skin reactions have been reported rarely. Hypoglycaemia is rare with a biguanide given alone, although it may occur if other contributing factors or drugs are present.

Lactic acidosis, sometimes fatal, has occurred with biguanides, primarily with phenformin. When it has occurred with metformin most cases have been in patients whose condition contra-indicated the use of the drug, particularly those with renal impairment. Phenformin has been implicated in the controversial reports of excessive cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).

Effects on the blood. Megaloblastic anaemia has occurred with biguanide therapy (see Malabsorption, under Effects on the Gastrointestinal Tract, below). A few cases of metformin-induced haemolysis resulting in hyperbilirubinaemia and jaundice have also been described.

Effects on the gastrointestinal tract. DIARRHOEA. In a retrospective survey, 30 of 265 diabetic patients reported diarrhoea or alternating diarrhoea and constipation, comprising: 11 of 54 taking metformin 9 of 45 taking metformin with a sulfonylurea 3 of 53 taking a sulfonylurea only 5 of 78 on insulin therapy 2 of 35 on diet alone. Among 150 nondiabetic controls 12 reported diarrhoea. Chronic diarrhoea described as watery, often explosive, and frequently causing faecal incontinence, has been reported as an adverse effect of late onset in patients receiving metformin. Some patients had been on stable metformin therapy for several years before the onset of diarrhoea. Symptoms ceased upon withdrawal of metformin, and recurred in cases of rechallenge.

MALABSORPTION. Megaloblastic anaemia due to vitamin B₁₂ malabsorption in a 58-year-old woman was associated with long-term treatment with metformin.

In a survey of diabetic patients receiving biguanide therapy,malabsorption of vitamin B₁₂ was observed in 14 of 46 diabetics taking metformin or phenformin metformin was more commonly to blame. Withdrawal of the drug resulted in normal absorption in only 7 of the 14. In a series of 10 patients with vitamin B₁₂ deficiency associated with metformin, vitamin B₁₂ concentrations and blood count abnormalities were reported to have been corrected within 3 months of starting treatment with intramuscular or oral cyanocobalamin 2 patients were transferred to treatment with other antidiabetic agents.

Effects on the liver. Severe cholestatic hepatitis attributed to metformin has been reported.

Effects on the pancreas. Acute pancreatitis is more commonly associated with phenformin. However, there have also been a few cases of pancreatitis associated with metformin, in which renal failure may have precipitated metformin toxicity.

Hypersensitivity. Vasculitis and pneumonitis in a 59-year-old woman was associated with use of metformin. Symptoms improved on withdrawal of metformin, but reappeared on its re-introduction. Cutaneous vasculitis in a 33-year-old woman also resolved on withdrawal of metformin and recurred with its re-introduction.

Hypoglycaemia. UK licensed product information for metformin states that hypoglycaemia does not occur with metformin alone, even in overdosage, although it may occur if given with alcohol or other hypoglycaemics. Interim results from the UK Prospective Diabetes Study, however, indicate that metformin therapy was associated with fewer hypoglycaemic episodes than sulfonylurea or insulin treatment, but more than with diet alone. One or more hypoglycaemic episodes were reported in 6% of the patients receiving the biguanide in this study, although only 1 patient had a severe episode.

Lactic acidosis. There is a small but definite risk of lactic acidosis associated with use of biguanide antidiabetics. Most early reports involved phenformin, which was consequently removed from the market in many countries although cases of phenformin-associated lactic acidosis still occur. There has therefore been concern about the risks of lactic acidosis with metformin, which is still in wide use. However, lactic acidosis with metformin appears to be much less common: a review suggested that the incidence was of the order of 3 cases per 100 000 patient years, which was 20 times less frequent than with phenformin. This concurs with the findings of the FDA after the introduction of metformin to the US market: in the year after the marketing of metformin in the USA, the FDA had received reports of metformin-associated lactic acidosis in 66 patients, the diagnosis being confirmed in 47. This represented a rate of about 5 cases per 100 000. Most patients who do develop lactic acidosis with metformin have one or more precipitating risk factors such as renal impairment, congestive heart failure, or other conditions predisposing to hypoxaemia or acute renal failure, including septicaemia, acute hepatic decompensation, alcohol abuse, acute myocardial infarction, and shock. A systematic review, which considered results comprising nearly 48 000 patient years of treatment with metformin, concluded that provided metformin was prescribed taking into account the proper contra-indications, there was no evidence of an increased risk of lactic acidosis. Nonetheless, there have been a few reports of lactic acidosis developing in metformin-treated patients without apparent risk factors.

Treatment of Adverse Effects

Acute poisoning with biguanides may lead to the development of lactic acidosis (see Metabolic Acidosis) and calls for intensive supportive therapy. Glucose or glucagon may be required for hypoglycaemia, the general management of which is outlined in Insulin.

Precautions

Biguanides are inappropriate for patients with diabetic coma and ketoacidosis, or for those with severe infection, trauma, or other severe conditions where the biguanide is unlikely to control the hyperglycaemia insulin should be used in such situations. Biguanides should not be given to patients with even mild renal impairment, as it may predispose patients to lactic acidosis, and renal function should be monitored throughout therapy. Dehydration may contribute to renal impairment. Conditions associated with hypoxia, such as acute heart failure, recent myocardial infarction, or shock, may increase the risk of lactic acidosis. Other conditions that may also predispose to lactic acidosis in a patient taking a biguanide include excessive alcohol intake and hepatic impairment. Biguanides should be temporarily stopped for examinations using contrast media (see under Interactions, below).

Insulin is preferred for the treatment of diabetes in pregnancy.

Owing to the possibility of decreased vitamin B₁₂ absorption, annual monitoring of vitamin B₁₂ concentrations is advisable during long-term treatment.

Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses.

Interactions

Use of a biguanide with other drugs that lower blood-glucose concentrations increases the risk of hypoglycaemia, while drugs that increase blood glucose may reduce the effect of biguanide therapy.

In general fewer drug interactions have been reported with biguanides than with sulfonylureas. Alcohol may increase the risk of lactic acidosis as well as of hypoglycaemia. Care should be taken if biguanides are given with drugs that may impair renal function.

Anticoagulants. For the effect of metformin on phenprocoumon activity, see Antidiabetics.

Antivirals. Fatal lactic acidosis has been reported in a patient given metformin with didanosine, stavuc&ne, and tenofovir.

Cimetidine. Cimetidine increased plasma-metformin concentrations in 7 healthy subjects. The renal clearance of metformin was reduced competition for proximal tubular secretion was considered responsible. A reduction in metformin dosage may be required in patients taking metformin and cimetidine, in order to reduce the risk of lactic acidosis.

Contrast media. Biguanides should be temporarily stopped for examinations using iodinated contrast media and withheld after the examination until normal renal function is confirmed, because of the risk of contrast media-induced renal impairment leading to biguanide toxicity and associated lactic acidosis. Licensed product information for some contrast media preparations warns that biguanides should be temporarily stopped 48 hours before the examination, and withheld for at least 48 hours after and until normal renal function is confirmed.

A number of guidelines on the use of iodinated contrast media give advice for the management of patients taking metformin. Some suggest that, in general, metformin can be stopped at the time of the examination. Others are more detailed, suggesting that if serum-creatinine is normal metformin may be stopped at the time of the examination, but that if it is raised metformin should be stopped 48 hours before giving the contrast medium.’They all agree that metformin should be withheld for 48 hours after the examination and until normal renal function is confirmed, although one suggests that no special precaution is needed for patients with normal serum-creatinine who are to be given a low volume of iodinated contrast medium (up to 100 mL).

Ketotifen. Platelet counts in 10 diabetic patients receiving biguanides fell (markedly in 3 patients) when they were also given ketotifen. Counts returned to normal a few days after the end of ketotifen therapy. However, the investigators did not consider the effect clinically significant.

Sulfonylureas. For reference to an apparent increase in mortality with an intensive regimen of metformin plus a sulfonylurea.

Uses and Administration

The biguanide antidiabetics are a class of oral antidiabetic drugs used in the treatment of type 2 diabetes mellitus. They are given to supplement treatment by diet modification when such modification has not proved effective on its own. In addition, because biguanides are not associated with weight gain they are preferred in obese patients. Although sulfonylureas may be preferred in non-obese patients, a biguanide is often added or given instead to patients who are not responding to a sulfonylurea. The mode of action of biguanides is not clear. They do not stimulate insulin release but require that some insulin be present in order to exert their antidiabetic effect. Possible mechanisms of action include delay in the absorption of glucose from the gastrointestinal tract, an increase in insulin sensitivity and glucose uptake into cells, and inhibition of hepatic gluconeogenesis. Biguanides do not usually lower blood-glucose concentrations in non-diabetic subjects.

Hyperlipidaemias. The effect of biguanides on lipid metabolism is unclear, although some studies have shown a beneficial effect on serum-lipid profiles in both obese and lean patients with type 2 diabetes, hypertension, and/or hyperlipidaemia. Reductions in concentrations of total cholesterol, low-density and very low-density-lipoprotein cholesterol have been reported, as well as modest increases in high-density-lipoprotein cholesterol. Some studies have also reported a reduction in serum-triglyceride levels. Such effects may be beneficial in the long-term treatment of type 2 diabetes mellitus with concomitant lipid disorders.

Polycystic ovary syndrome. For discussion of the potential of metformin in polycystic ovary syndrome.

The most frequent complication of insulin therapy is hypoglycaemia and patients taking insulin need to be educated about its cause, symptoms, and treatment. Most patients can recognise the early warning signs of hypoglycaemia and by taking sugar immediately can prevent more serious symptoms developing. Comatose patients need to be given intravenous glucose or, if this is not practicable, subcutaneous, intramuscular, or intravenous glucagon (although glucose is still required if mere is no response within 10 minutes). Hypoglycaemia can also develop in patients taking oral antidiabetics, notably the sulfonylureas.

Some patients report loss of the warning signs of hypoglycaemia after transferring from animal to human insulin and these patients, if appropriate, may need to be transferred back to animal insulin. However, the most significant factor in loss of hypoglycaemic warning signs may be exposure to hypoglycaemia itself a study found mat total avoidance of hypoglycaemic episodes for 3 weeks while maintaining glycaemic control restored awareness. Loss of hypoglycaemic awareness, which appears to be due to an adaptive conservation of glucose uptake in the brain, is liable to be a particular problem in patients receiving intensive therapy. There is limited data to suggest that caffeine can improve awareness of hypoglycaemia.

Diabetic ketoacidosis

Diabetic ketoacidosis is caused by an absolute or relative lack of insulin and commonly occurs after noncompliance or failure to adjust insulin dosage in the presence of factors such as infection that increase insulin requirements (see Precautions for Insulin). Failure of an insulin pump can be a cause. Also pregnant diabetic women are more prone to development of diabetic ketoacidosis.

Diabetic ketoacidosis is characterised by hyperglycaemia, hyperketonaemia, and acidaemia, with subsequent dehydration and electrolyte abnormalities. Onset may be rapid, or insidious over many days. Initial presenting symptoms such as thirst, polyuria, fatigue, and weight loss are those of any newly presenting type 1 diabetic they then progress to nausea, vomiting, abdominal pain, and impaired consciousness or coma, and, if untreated, death.

Diabetic ketoacidosis is a medical emergency and should be treated immediately with fluid replacement and insulin. Fluid requirements depend on the needs of the individual overvigorous fluid replacement without severe dehydration carries the risk of precipitating cerebral oedema.

Soluble insulin should also be given immediately. Large doses were formerly thought necessary, but lower dose regimens accompanied by adequate hydration have since been shown to be preferable. Insulin resistance in diabetic ketoacidosis is generally exacerbated by hyperosmolarity and other confounding factors, and insulin therapy is therefore most effective when preceded or accompanied by adequate fluid and electrolyte replacement. In the UK, the BNF considers that insulin should preferably be given by intravenous infusion, with the intramuscular route used if facilities for intravenous infusion are not available. However, in the USA some consider that an intravenous bolus followed by subcutaneous injection may be appropriate in certain patients. Intramuscular or subcutaneous injection are not appropriate in patients with hypovolaemic shock, due to poor tissue perfusion. Where the response to insulin is inadequate the intravenous route is generally required and the rate of infusion may be doubled on an hourly basis until an appropriate response is seen. A case report has suggested mat mecasermin may be useful if there is insulin resistance.

When the blood-glucose concentration has fallen to about 12.5 mmol/litre the dose of insulin may be reduced by about half and glucose given intravenously, usually in a strength of 5% with saline although in rare cases a glucose strength of 10% may be necessary. The use of glucose enables insulin to be continued in order to clear ketone bodies without inducing hypoglycaemia. Once glucose concentrations have been controlled and acidosis has completely cleared, subcutaneous injections of insulin can begin but intravenous insulin should not be stopped until subcutaneous dosage has begun.

Total body stores of potassium are depleted in patients with diabetic ketoacidosis. Insulin deficiency appears to be the main initiating factor for hyperkalaemia in diabetic ketoacidosis. Although patients may present with raised, normal, or decreased serum-potassium concentrations, the concentrations will start to fall with the correction of acidosis. Potassium is added to the infusion fluid after initial fluid expansion and once insulin therapy has begun. In hyperkalaemic patients, potassium is given once serum concentrations have fallen to within normal limits. In the rare patient presenting with hypokalaemia potassium replacement should be begun before insulin therapy and the latter withheld until potassium concentrations have risen to normal values.

Intravenous bicarbonate is now generally reserved for patients with severe acidaemia a common practice is to give isotonic bicarbonate to those with a pH of less man 7.0 with the aim of raising the pH to 7.1.

Phosphate concentrations are affected in a similar manner to potassium concentrations in the ketoacidotic state, but there is less agreement on the need for routine doses of phosphate. Phosphate concentrations should be monitored and phosphate given if clinically significant hypophospha-taemia occurs.

The precipitating cause of diabetic ketoacidosis should also be identified and managed appropriately.

Hyperosmolar hyperglycaemic state

Hyperosmolar hyperglycaemic state or hyperosmolar hyperglycaemic nonketotic coma (HONK) occurs mainly in elderly patients with type 2 diabetes and though much

less common man diabetic ketoacidosis it carries a higher mortality. Patients may present in coma with severe hyperglycaemia but with minimal ketosis dehydration and renal impairment are common. Treatment is similar to mat of diabetic ketoacidosis, although potassium requirements are lower and large amounts of fluid and less insulin may be required some suggest the use of hypotonic fluid if necessary. There is an increased likelihood of thrombotic events, so prophylactic anticoagulation should be considered.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In British and China

British Pharmacopoeia 2008 (Gliquidone). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol and in methyl alcohol soluble in acetone freely soluble in dimethylforma-mide.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Gliquidone is readily absorbed from the gastrointestinal tract. It is extensively bound to plasma proteins and has a half-life of about 1.5 hours. It is extensively metabolised in the liver, the metabolites having no significant hypoglycaemic effect, and is eliminated chiefly in the faeces via the bile only about 5% of a dose is excreted in the urine.

Uses and Administration

Gliquidone is a sulfonylurea antidiabetic. It has been given orally in the treatment of type 2 diabetes mellitus in a usual initial dosage of 15 mg daily given as a single dose up to 30 minutes before breakfast. Dosage may be adjusted by increments of 15 mg to a usual dose of 45 to 60 mg daily in 2 or 3 unequally divided doses, the largest dose being taken in the morning with breakfast. Single doses above 60 mg and daily doses above 180 mg are not recommended.

Preparations

British Pharmacopoeia 2008: Gliquidone Tablets.

Proprietary Preparations

Austria: Glurenorm

Belgium: Glurenorm

Czech Republic: Glurenorm

Germany: Glurenorm

Greece: Devotan

Hungary: Glurenorm

Indonesia: Glurenorm

Italy: Glurenor

Poland: Glurenorm

Portugal: Glurenor †

Russia: Glurenorm

Spain: Glurenor

Thailand: Glurenor

Turkey: Glurenorm

UK: Glurenorm

Pharmacopoeias. In Europe. Also in USNF.

European Pharmacopoeia, 6th ed. (Guar). Guar is obtained by grinding the endosperms of the seeds of Cyamopsis tetragonolobus. It consists mainly of guar galactomannan. Guar is a white or almost white powder, yielding a mucilage of variable viscosity when dissolved in water. Practically insoluble in alcohol.

European Pharmacopoeia, 6th ed. (Guar Galactomannan). A yellowish-white powder. It is soluble in cold and hot water practically insoluble in organic solvents. Its main components are polysaccharides composed of D-galactose and D-mannose at molecular ratios of 1:1.4 to 1:2. The molecules consist of a linear main chain of β-(1 —>4)-glycosidically linked mannopyranoses and single α-(1 —>6)-glycosidically linked galactopyranoses.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Guar Gum). A gum obtained from the ground endosperms of Cyamopsis tetragonolobus (Leguminosae). It consists chiefly of a high-molecular-weight hydrocolloidal polysaccharide, a galactomannan, composed of galactan and mannan units combined through glycosidic linkages. It is a white to yellowish-white, practically odourless, powder. Dispersible in hot or cold water forming a colloidal solution.

Adverse Effects and Precautions

Guar gum can cause gastrointestinal disturbance with flatulence, diarrhoea, or nausea, particularly at the start of treatment.

Because guar gum swells on contact with liquid it should always be washed down carefully with water and should not be taken immediately before going to bed. It should not be used in patients with dysphagia, oesophageal disease, or intestinal obstruction.

Interactions

Guar gum may retard the absorption of other drugs where this is likely to pose a problem the other drug should be taken at least an hour before guar gum.

Uses and Administration

Guar gum is used in diabetes mellitus as an adjunct to treatment with diet, insulin, or oral antidiabetics since it results in some reduction in both postprandial and fasting blood-glucose concentrations. It is given with or immediately before meals in doses of 5 g usually 3 times daily. Adverse gastrointestinal effects may be reduced by using a lower initial dose of 5 g once daily before breakfast for 1 week, then increasing to 5 g twice daily, then 3 times daily, as required. Each dose of guar gum granules should be taken stirred in about 200 mL of a cold drink. Alternatively it can be sprinkled over or mixed with food which must be taken with about 200 mL of fluid.

Guar gum is also used to slow gastric emptying in some patients with the dumping syndrome. It is also used as an adjunct in the treatment of hyperlipidaemias.

Guar gum is also used as a thickening and suspending agent, and as a tablet binder. It has been incorporated into processed foods.

Guar gum is an example of a soluble fibre. On contact with water it forms a highly viscous gel, the viscosity of which varies with such factors as its plant source or the form in which it is given.

Fibres such as guar gum reduce postprandial and fasting blood-glucose concentrations as well as plasma-insulin concentrations in healthy subjects and diabetic patients. Such reductions in blood-glucose concentrations and in glycosylated haemoglobin have been demonstrated in both type 1 and type 2 diabetes, but they have generally been small. Possible mechanisms for these effects of guar gum include a delay in gastric emptying, decreased small-bowel motility, decreased glucose absorption resulting from increased viscosity of the contents of the gastrointestinal tract, or inhibition of gastrointestinal hormones.

Guar gum also lowers serum total cholesterol and low-density -lipoprotein (LDL) cholesterol concentrations high-density-lipoprotein (HDL) cholesterol and triglyceride concentrations appear to be unaffected. The most likely mechanism is binding of bile acids, reducing their enterohepatic circulation in a similar way to bile-acid sequestrants. When used alone in patients with hype rcholesterolaemia guar gum has generally produced a modest reduction in plasma-cholesterol and LDL-cholesterol concentrations although some studies have been unable to demonstrate an effect. A few studies have suggested that the cholesterol-lowering effect is attenuated after 8 to 12 weeks of treatment but a long-term study observed a 17% decrease in total serum cholesterol that was maintained for 24 months. Some studies have shown further reductions in cholesterol and LDL-cholesterol concentrations on addition of guar gum to therapy with other li-pid regulating drugs. The usual treatment of hyper lip idaemias is discussed.

There have been suggestions that guar gum reduces appetite by promoting a feeling of fullness, but a meta-analysis has indicated that it is not effective for reducing body-weight. Products containing guar gum have, however, been promoted as slimming aids. Their use cannot be advocated because of the risk of tablets swelling before reaching the stomach and causing oesophageal obstruction.

Preparations

Proprietary Preparations

Argentina: Regudigl

Australia: Benefiber †

Brazil: Benefiber † Biofiber †

Finland: Guarem

Germany: Figur-Verlan Guar Verlan

Hong Kong: Guarem

Ireland: Guarem †

Italy: Novafibra

New Zealand: Guarcol

Spain: Fibraguar Plantaguar

Switzerland: Leiguar

UK: Resource Benefiber

USA: Benefiber

Multi-ingredient

France: Carres Parapsyllium Moxydar Mucipulgite Mulkine Seroxydar

Italy: Cruscasohn Resource Gelificata

Switzerland: Mucipulgite

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Glipizide). A white or almost white crystalline powder. Practically insoluble in water and in alcohol very slightly soluble in acetone and in dichloromethane. It dissolves in dilute solutions of alkali hydroxides.

The United States Pharmacopeia 31, 2008 (Glipizide). Store in airtight containers. Protect from light.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

Porphyria. Glipizide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for sulfonylureas in general.

Antacids. Magnesium hydroxide and sodium bicarbonate have been reported to increase the rate of absorption, although not the total amount absorbed, of a dose of glipizide in healthy subjects. No such effect was seen with aluminium hydroxide

Pharmacokinetics

Glipizide is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring 1 to 3 hours after a single dose. It is extensively bound to plasma proteins and has a half-life of about 2 to 4 hours. It is metabolised mainly in the liver and excreted chiefly in the urine, largely as inactive metabolites.

Uses and Administration

Glipizide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of up to 24 hours. The usual initial dose is 2.5 to 5 mg daily given as a single dose about 30 minutes before breakfast. Dosage may be adjusted at intervals of several days by amounts of 2.5 to 5 mg daily, to a maximum of 20 mg daily. Doses up to 40 mg daily have been used, but see below. Doses larger than 15 mg daily are given in two divided doses before meals. Modified-release formulations of glipizide are available in some countries one such preparation (Glucotrol XL Pfizer, USA) is given in doses of 5 to 10 mg daily as a single dose with breakfast.

Administration. Although glipizide may be given in doses up to a maximum of 40 mg daily, evidence for the benefits of high doses is scanty. A small study in patients with type 2 diabetes mellitus found that not only did increases in glipizide doses to more than 10 mg daily produce little or no benefit, but that the higher doses were associated with reduced rises in plasma-insulin concentrations and a lesser reduction in plasma-glucose concentrations. There is, however, some evidence that glycae-mic control and insulin sensitivity can be improved by the use of a modified-release rather than a conventional formulation of glipizide.

Preparations

British Pharmacopoeia 2008: Glipizide Tablets

The United States Pharmacopeia 31, 2008: Glipizide and Metformin Hydrochloride Tablets Glipizide Tablets.

Proprietary Preparations

Argentina: Minodiab

Australia: Melizide Minidiab

Austria: Glibenese Minidiab

Belgium: Glibenese Minidiab

Brazil: Minidiab

Chile: Minidiab Xiprine

Czech Republic: Antidiabf Glucotrol † Mediab Minidiab

Denmark: Glibenese Minidiab

Finland: Apamid † Glibenese Melizid Minidiab

France: Glibenese Minidiab Ozidia

Greece: Glibenese Minodiab

Hong Kong: Diase Glucotrol Minidiab Sunglucon

Hungary: Minidiab

India: Diaglip Glez Glide Glucolip Glynase Glyzip

Indonesia: Aldiab Glucotrol Glyzid

Ireland: Glibenese

Israel: Gluco-Rite

Italy: Minidiab

Malaysia: Dibizicle † Dipazide Glix Melizide Minidiab

Mexico: Glupitel Luditec Minodiab Pigloss Singloben

The Netherlands: Glibenesej

Norway: Apamid Minidiab

New Zealand: Glipid Minidiab

Philippines: Glix Minidiab

Poland: Antidiab Glibenese

Portugal: Minidiab

Russia: Glibenese Minidiab †

South Africa: Minidiab

Singapore Beapizide Diactin Diasef Melizide Minidiab

Spain: Glibenese Minodiab

Sweden: Apamid † Glipiscandl Minidiab

Switzerland: Glibenese

Thailand: Apamid † Depizide Diase Dipazide Gipzide Glipimed Glizide Glucodiab Glygen GP-Zide Melizide Minibit Minidiab Namedia Pezide

Turkey: Glucotrol Minidiab

UK: Glibenese Minodiab

USA: Glucotrol

Venezuela: Minidiab.

Multi-ingredient

India: Diaglip M Metaglez

USA: Metaglip.

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Glimepiride). A white to almost white powder. It exhibits polymorphism. Practically insoluble in water slightly soluble in dichloromethane soluble in dimethylformamide very slightly soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Glimepiride). A white to almost white powder. Practically insoluble in water sparingly soluble in dichloromethane soluble in dimethylformamide slightly soluble in methyl alcohol. It dissolves in dilute alkali hydroxides and in dilute acids. Store at a temperature not exceeding 25°.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general. In some countries hepatic and haematological monitoring is recommended in patients receiving glimepiride in the UK the BNF considers the practical value of such monitoring unproven.

Fasting. Glimepiride, given in unchanged doses but with the time of the single daily dose switched from morning to just before breaking fast after sunset, was used in Muslim patients during Ramadan without causing an increased incidence of hypoglycaemic episodes.

For further advice on the management of diabetes mellitus in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Glimepiride is completely absorbed from the gastrointestinal tract. Peak plasma concentrations occur in 2 to 3 hours, and it is highly protein bound. The drug is extensively metabolised to two main metabolites, a hydroxy derivative and a carboxy derivative. The half-life after multiple doses is about 9 hours. About 60% of a dose is eliminated in the urine and 40% in the faeces.

Uses and Administration

Glimepiride is a sulfonylurea antidiabetic. It is given orally for the treatment of type 2 diabetes mellitus. Initial doses of 1 to 2 mg daily may be increased if necessary to 4 mg daily for maintenance. The maximum recommended dose is 6 mg in the UK and 8 mg in the USA.

Preparations

The United States Pharmacopeia 31, 2008: Glimepiride Tablets.

Proprietary Preparations

Argentina: Adiuvan Amaryl Endial Glemaz Gluceride Glucopirida Islopir Lomet Next Step

Australia: Amaryl Aylide Diapride Dimirel

Austria: Amaryl

Belgium: Amarylle

Brazil: Amaryl Azulix Bioglic Diamellitis Glimepibal Glimepil Glimeprid † Glimeran Glimesec † Hipomeril

Canada: Amaryl

Chile: Amaryl Glemaz Glucomet

Czech Republic: Amarwin Amaryl Amyx Apo-Glimep Eglymad Glemid GlimTek Glymexan Melyd Metis Oltar

Denmark: Amaryl

Finland: Amaryl

France: Amarel

Germany: Amaryl Glimegamma Glimerid

Greece: Dialosa Glimepiron Glimespes Glimexin Gliperin Mepirid Penoza Pharlecon Saccharofar Solosa Sucryl Tipo II Toremol

Hong Kong: Amaryl Diapride

Hungary: Amaryl Dialosa Glempid GlimeWin Gl

India Gliprex Limeral Meglimid Melyd Sintecal

India: Amaryl Betaglim Diaglim Euglim Glimcip Glimiprex Glimitab Glimulin Glyree Glyree M Karmelitos

Indonesia: Amadiab Amaryl Anpiride Glamarol Glimexal Gluvas Mapryl Metrix Relide

Ireland: Amaryl

Israel: Amaryl

Italy: Amaryl Solosa

Malaysia: Amaryl Diapride Glimaryl Glimin Glimulin Miaryl

Mexico: Amaryl Glupropan Zukedib

The Netherlands: Amaryl

Norway: Amaryl

New Zealand: Amaryl

Philippines: Imerid Norizec Solosa

Poland: Amaryl Amyx Avaron Betaglid Diaril Glemid Glibetic Glibezid Glidiamid Glimehexal Glimesan Glipid Limeral Melyd Oltar Pemidal Symglic

Portugal: Amaryl Diapiride Glimial Gludon

Russia: Amaryl Glemaz

South Africa: Amaryl Glamaryl

Singapore: Amaryl Diapride

Spain: Amaryl Roname

Sweden: Amaryl

Switzerland: Amaryl

Thailand: Amaryl

Turkey: Amaryl Diameprid Glimax

UK: Amaryl Niddaryl

USA: Amaryl

Venezuela: Amaryl Dimavyl Glimerid.

Multi-ingredient

Czech Republic: Avaglim Tandemact

France: Avaglim Tandemact

Greece: Avaglim

Hungary: Avaglim

India: Betaglim Mf Exermet GM Glimiprex M † Glimulin-MF †

Indonesia: Avandaryl

Portugal: Avaglim Tandemact

USA: Avandaryl Duetact.

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In China, and Europe.

European Pharmacopoeia, 6th ed. (Gliclazide). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol sparingly soluble in acetone freely soluble in dichloromethane.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general. The BNF suggests that gliclazide may be suitable for use in patients with renal impairment, but that careful monitoring of blood-glucose concentration is essential. UK licensed product information recommends that it should not be used in patients with severe renal impairment.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Gliclazide is readily absorbed from the gastrointestinal tract. It is extensively bound to plasma proteins. The half-life is about 10 to 12 hours. Gliclazide is extensively metabolised in the liver to metabolites that have no significant hypoglycaemic activity. Metabolites and a small amount of unchanged drug are excreted in the urine.

Uses and Administration

Gliclazide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of 12 to 24 hours. Because its effects are less prolonged than those of chlorpropamide or glibenclamide it may be more suitable for elderly patients, who are prone to hypoglycaemia with longer-acting sulfonylureas. The usual initial dose is 40 to 80 mg daily, gradually increased, if necessary, up to 320 mg daily. Doses of more than 160 mg daily are given in 2 divided doses. A modified-release tablet is also available: the usual initial dose is 30 mg once daily, increased if necessary up to a maximum of 120 mg daily.

Preparations

British Pharmacopoeia 2008: Gliclazide Tablets.

Proprietary Preparations

Argentina: Aglucide Diamicron Unava

Australia: Diamicron Glyade Nidem Oziclide

Austria: Diamicron

Belgium: Diamicron Uni Diamicron

Brazil: Azukon Diamicron Glicaron

Canada: Diamicron

Chile: Dianormax

Czech Republic: Diabrezide Diaprel

Denmark: Diamicron

France: Diamicron

Germany: Diamicron

Greece: Diamicron

Hong Kong: CP-Gliz Diamicron Diamitex Dianorm Glimicron Glucozide Glupozide Glyzyl Licla Marclazide Nidem Qualizide Suclear Sun-Glizide

Hungary: Diaprel Gluctam

India: Diamicron Gliza Glizid Glycigon Glycinorm Glygard Lycazid Semi-Glycigon

Indonesia: Diamicron Fredam Glicab Glidabet Glucodex Glucored Glukolos Glycafor Linodiab Meltika Nufamicron Pedab Tiaglib Xepabet Zumadiac

Ireland: Diabrezide Diaclide Diamicron

Italy: Cronemet Diabrezide Diamicron Dramion Galtes Glucobloc

Malaysia: Diacron † Diamicron Dianid Glimicron Glucozide Glyade Medoclazide Melicron † Opglucon Reclide Sun-Glizide

Mexico: Diamicron

The Netherlands: Diamicron

New Zealand: Diamicron Glizon

Philippines: Clibite Glizid Diaclid Diamicron Dianorm Glubitor Gluconil Glucoprime

Poland: Diabezidum Diabrezide Diaprel Diazidan Glazide Glinormax Norsulin

Portugal: Diamicron

South Africa: Diaglucide Diamicron Glucomed Glycron Glygard Ziclin

Singapore: Diamicron Dianorm Glimicron Glizide Glucozide Medoclazide Melicron †

Spain: Diamicron Uni Diamicron

Switzerland: Diamicron

Thailand: Cadicon Diabeside Diaclaron † Diamaze † Diamexon Diamicron Dianid Glicron Glucocron Glucozide Glycon Medoclazide Serviclazide

Turkey: Betanorm Diamicron Glazid Glumikron Oramikron

United Arab Emirates: Glyzide

UK: Diaglyk Diamicron

Venezuela: Diamicron Glidan Reclide †

Multi-ingredient:

India: Exermet GZ Gliclamet Glizid-M Glycigon-M Glycinorm M Glygard M Glyroz.

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. InJapan and US.

The United States Pharmacopeia 31, 2008 (Acetohexamide). A white, practically odourless, crystalline powder. Practically insoluble in water and in ether soluble 1 in 230 of alcohol and 1 in 210 of chloroform soluble in py-ridine and in dilute solutions of alkali hydroxides.

Profile

Acetohexamide is a sulfonylurea antidiabetic. Its duration of action is 12 hours or more. It has been given orally in the treatment of type 2 diabetes mellitus in a usual initial dose of 250 mg daily before breakfast. The daily dose may then be increased by 250 to 500 mg at intervals of 5 to 7 days, to a maintenance dose of up to 1.5 g daily increasing the dose above 1.5 g does not usually lead to further benefit. Doses in excess of 1 g daily may be taken in 2 divided doses, before the morning and evening meals.

Preparations

The United States Pharmacopeia 31, 2008: Acetohexamide Tablets.

Proprietary Preparations

Canada: Dimelor;

Hong Kong: Dimelor;

Italy: Dimelor;

South Africa: Dimelor;

Spain: Gamadiabet;

United Kingdom: Dimelor;

United States: Dymelor

Insulin is a hormone that plays a key role in regulating carbohydrate, protein, and fat metabolism. The main stimulus for its secretion is glucose, although many other factors including amino acids, catecholamines, glucagon, and somatostatin, are involved in its regulation. The secretion of insulin is not constant and peaks occur in response to the intake of food.

The major effects of insulin on carbohydrate homoeostasis follow its binding to specific cell-surface receptors on insulin-sensitive tissues, notably the liver, muscles, and adipose tissue. It inhibits hepatic glucose production and enhances peripheral glucose disposal thereby reducing blood-glucose concentration. It also inhibits lipolysis thereby preventing the formation of ketone bodies.

Therapy with insulin is essential for the long-term survival of all patients with type 1 diabetes mellitus. It may also be necessary in some patients with type 2 disease. The management of diabetes mellitus and the role of insulin in type 1 and type 2 disease is discussed. Insulin is generally the treatment chosen for all types of diabetes mellitus during pregnancy.

Choice of insulin. The different types of insulin and their formulations are described under Definitions, above. In some countries including the UK the commercially available preparations have been standardised to a single strength containing 100 units/mL a strength of 40 units/mL is still available in some other countries, and in others concentrated injections (500 units/mL) are available to enable high doses to be given subcutaneously in a small volume. All formulations can be given by subcutaneous injection, most by intramuscular injection, but only soluble insulins can be given by the intravenous route. The long-term management of diabetic patients usually involves the subcutaneous route. Syringes and needles for subcutaneous injection are preferably disposable. Pen-injector devices which hold the insulin in cartridge form and meter the required dose are becoming increasingly popular. Soluble insulin is often given by the intraperi-toneal route to patients on continuous ambulatory peritoneal dialysis. More recently, products supplying short-acting insulin by inhalation have been developed.

The various formulations of insulin are classified, according to their duration of action after subcutaneous injection, as short-, intermediate-, or long-acting. The exact duration of action for any particular preparation, however, is variable and may depend upon factors such as interindividual variation, the patient’s antibody status, whether the insulin is of human or animal origin, the dose, and the site of injection. Short-acting insulins are the soluble insulins, which have an onset after about 30 minutes to 1 hour, a peak activity at about 2 to 5 hours, and a duration of about 6 to 8 hours. Some analogues, such as insulins lispro and aspart, are also short-acting, with a faster onset and shorter duration of action than soluble insulin and are sometimes known as rapid-acting insulins. Intermediate-acting insulins include biphasic insulins, isophane insulins, and amorphous insulin zinc suspensions. In general these have an onset within about 2 hours, peak activity after about 4 to 12 hours, and a duration of up to 24 hours. Commercially available mixtures of soluble insulins and isophane insulins have activities which would normally place them within the intermediate-acting category. Mixed insulin zinc suspensions may be classified as either intermediate- or long-acting as the duration of action may be up to 30 hours the onset of action is generally 2 to 3 hours and the time to peak activity 6 to 15 hours. Long-acting insulins include crystalline insulin zinc suspensions and protamine zinc insulins. These generally have an onset after about 4 hours, a peak activity at about 10 to 20 hours, and a duration of up to 36 hours. The insulin analogues insulin glargine and insulin detemir are also long-acting. After intramuscular injection, the onset of action of all insulins is generally more rapid and the duration of action shorter.

The type of formulation, its dose, and the frequency of administration are chosen to suit the needs of the individual patient. Whatever the formulation, human insulin is generally used for all newly diagnosed diabetics.

Control. The dosage of insulin must be determined for each patient and although a precise dose range cannot be given a total dose in excess of about 80 units daily would be unusual and may indicate the presence of a form of insulin resistance. The dose should be adjusted as necessary according to the results of regular monitoring of blood concentrations (or occasionally urine concentrations) of glucose by the patient.

The WHO has recommended that the glucose concentration of venous whole blood under fasting conditions should be kept within the range of 3.3 to 5.6 mmol/litre (60 to 100 mg per 100 mL) and after meals should not be allowed to exceed 10 mmol/litre (180 mg per 100 mL) blood-glucose concentrations should not be allowed to fall below 3 mmol/litre (55 mg per 100 mL). In practice it seems to be generally acceptable for patients to aim for blood-glucose concentrations between 4 and 10 mmol/litre, with the understanding that occasional variations outside this range may occur. It should be remembered that the glucose concentrations in venous plasma, venous whole blood, and capillary whole blood may be slightly different. Control may also be determined by monitoring of glycosylated haemoglobin concentrations ideally the aim is an HbA_1c level of less than 7% or an HbA₁ of less than 8.8%, compared with normal ranges of 4 to 6% and 5 to 7.5% respectively. Insulin requirements may be altered by various factors (see Precautions, above). The aim of any regimen should be to achieve the best possible control of blood glucose by attempting to mimic as closely as possible the pattern of optimum endogenous insulin secretion. Many regimens involve the use of a short-acting soluble insulin with an intermediate-acting insulin, such as isophane insulin or mixed insulin zinc suspension, often given twice daily. It may sometimes be necessary, though, to give 3 or 4 injections daily to achieve good control and this typically involves giving a soluble insulin before meals and an intermediate- or long-acting insulin in the evening. A once-daily injection of an intermediate- or long-acting insulin is now generally considered to be acceptable only for those patients with type 2 diabetes mellitus who still retain some endogenous insulin secretion but nevertheless require insulin therapy, or for those patients with type 1 disease unable to cope satisfactorily with more intensive regimens. If a more intensive regimen is desired, continuous subcutaneous infusion may be employed using soluble insulin in an infusion pump. This delivers a constantbasal infusion of insulin supplying about half of the total daily requirements, the remainder being provided by patient-activated bolus doses before each meal. The technique has a limited place in the management of diabetes patients using it need to be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert advice at all times. Formulations in which the insulin is in suspension are not suitable for continuous subcutaneous infusion and some brands of soluble insulin are unsuitable for this purpose because of the risk of precipitation in the pump catheter.

Ketoacidosis. Insulin is also an essential part of the emergency management of diabetic ketoacidosis. Only short-acting soluble insulins should be used. Treatment includes adequate fluid replacement, usually by infusing sodium chloride 0.9% initially, and the use of potassium salts to prevent or correct hypokalaemia. Insulin should be given by continuous intravenous infusion if possible, although other routes have also been used — for details of regimens see Diabetic Emergencies, under Diabetes Mellitus, below. Since insulin normally corrects hyperglycaemia before ketosis it is usually necessary to continue giving insulin once normoglycaemia has been achieved but to change the rehydration fluid to glucose-saline so that the additional glucose prevents the development of hypoglycaemia.

Administration. ADMINISTRATION ROUTES. The long-term management of diabetic patients usually involves injection by the subcutaneous route. The advice to diabetics has been to inject their insulin using a full-depth perpendicular injection.In many non-obese patients, however, such a technique can result in inadvertent intramuscular injection. Since insulin is absorbed more rapidly after intramuscular than subcutaneous injection, this may lead to greater day-to-day variability in blood-glucose control. In particular, overnight control may be inadequate if intermediate-acting preparations such as isophane insulin are used. Some therefore consider that extended-action insulins should be injected at an angle into a raised skin fold. Although injection of soluble insulin into muscle may produce a more physiological action profile, until more data are available a technique that ensures subcutaneous injection may be prudent with soluble insulins as well.The anatomic site of subcutaneous insulin injection is usually rotated in an attempt to decrease local adverse effects (see Adverse Effects, above). However, the rate of absorption varies between sites and such a practice may also contribute to day-to-day variability in blood-glucose concentrations. For example, large variations in blood-glucose concentrations have been reported on subcutaneous injection into the thigh. Some have suggested rotation of injection sites within an anatomic region, or possibly use of the same anatomic region for injections given at a specific time of day.

Jet injectors deliver insulin at high pressure across the skin into the subcutaneous tissue without use of a needle. The greater dispersion obtained gives more rapid absorption of short- and intermediate-acting insulins and consequently reduces the total duration of action. Mild pain, bruising, and bleeding may be a problem. Despite having been available for some years, there is little information about their benefits and risks and they are not widely used. However, results in a small study in women with gestational diabetes have suggested that jet injection may be associated with less variation in postprandial blood-glucose concentration and a lower incidence of insulin antibodies.Insulin preparations may also be given by intramuscular injection. Absorption is more rapid than from a subcutaneous injection. However, exercise may produce considerable variations in insulin absorption after intramuscular injection. Soluble insulins may be given intravenously this route is used in diabetic ketoacidosis, and also in surgery and labour. Intermittent pulsed intravenous insulin therapy added to a conventional subcutaneous regimen has been reported to improve symptoms of orthos-tatic hypotension and hypertension.

The subcutaneous and intravenous routes, and, rarely, the intramuscular route have all been used for the continuous administration of insulin (see Intensive Administration Regimens, below). Formulations of insulin for intranasal use are under investigation. They have been tried in both type 1 and type 2 diabetes, but bioavailability is low and variable. Absorption enhancers have been used to facilitate uptake of insulin from the nasal mucosa and local adverse effects are dependent, in part, on their irritancy. Similarly, buccal formulations are under investigation,and have become available in some countries. Devices for delivering insulin to the lungs via oral inhalation have been developed. Inhaled insulin is effective in maintaining glycaemic control in both type 1 and type 2 diabetes,although there is some evidence from longer-term studies that it is slightly less effective than subcutaneous injection however, patient acceptability is higher. It is given before meals as a short-acting insulin in patients also receiving intermediate or long-acting subcutaneous insulins or oral antidiabetics in type 2 diabetes it has also been used alone. UK recommendations from NICE are that it should be reserved for patients who are unable to start or intensify subcutaneous insulin therapy because of a marked, persistent fear of injections or severe difficulties with injection sites (for example, due to lipoatrophy). Data regarding the long-term safety of inhaled insulin also need to be collected, given reports of pulmonary effects and higher levels of insulin antibodies in people with type 1 diabetes. A few cases of primary lung malignancies have occurred in clinical trials of inhaled insulin, at a higher incidence than in comparator-treated patients. However, the number of cases was too small to determine whether these events were related to inhaled insulin, and all affected patients had a history of cigarette smoking. Endogenous insulin is delivered into the portal venous system, and then passes immediately to the liver where a large fraction of the insulin is extracted. The above routes of administration all deliver insulin into the peripheral circulation, with the risk of peripheral hyperinsulinaemia which has been considered a risk factor for atherosclerotic complications. Giving insulin via the intraperitoneal or oral routes may overcome this problem to some extent. Peritoneal insulin is used routinely in diabetics undergoing chronic ambulatory peritoneal dialysis, but has also been used for continuous administration (see Intensive Administration Regimens, below). Various formulations of insulin for oral delivery are also under investigation. Rectal or transdermal insulin has also been tried.

INSULIN ANALOGUES AND PROINSULIN. Recombinant-DNA technology has enabled the production of insulin analogues with altered pharmacokinetic profiles. Most of the insulin in pharmaceutical preparations is in the form of hexamers, which require time to dissociate before absorption from a subcutaneous site. Substitution of amino-acid residues at the monomer-monomer interface has produced monomeric insulin analogues that retain the biological activity of insulin. Good results have been reported with an analogue, insulin lispro, in which the B28 and B29 residues are replaced with lysine and proline. This analogue is commercially available and has been widely reviewed. In comparative studies of insulin lispro versus soluble insulin given before meals to patients also receiving a long-acting insulin, insulin lispro was reported to result in good glycaemic control, and could be given immediately before meals (5 to 15 minutes) rather than 20 to 40 minutes before as with soluble insulin. There is a suggestion that it may result in fewer severe hypoglycaemic episodes in such regimens. However, an analysis of 10 clinical trials did not find any difference between insulin lispro and neutral insulin (Humulin R) with respect to overall adverse effects or development of long-term diabetic complications. (See also insulin aspart, below.) A few cases of response to insulin lispro in patients with severe insulin resistance have been reported. Insulin lispro has been complexed with protamine to produce an intermediate-acting form, which is available as a biphasic preparation.

Insulin aspart is another short-acting insulin analogue, with aspartic acid substituted for proline at position B28. It is also used immediately before meals and controls postprandial blood glucose concentrations at least as well as regular human insulin, and may cause fewer hypoglycaemic episodes. A meta-analysis involving 42 studies of insulin lispro or insulin aspart versus regular insulin found that there was evidence of a minor benefit of the analogues in improving HbA_1c values in adult patients with type 1 diabetes no superiority could be shown in patients with type 2 diabetes.

Insulin glulisine is another insulin analogue, with asparagine at position B3 replaced by lysine, and lysine at B29 replaced by glutamic acid. It also has a rapid onset and short duration of action.

Recombinant-DNA technology has also been used to produce a long-acting basal insulin analogue, insulin glargine, suitable for once-daily use. It is available as a solution at pH 4 on subcutaneous injection and neutralisation by tissue buffering processes, microprecipitates are formed that slowly release insulin glargine over 24 hours with no pronounced peak in concentration or in metabolic activity. Controlled studies have reported insulin glargine to be more effective than human isophane insulin in producing glycaemic control as part of a basal-bolus regimen, and to be associated with fewer hypoglycaemic episodes. Insulin detemir is another long-acting insulin analogue that may have some benefit over isophane insulin. It is a neutral soluble human insulin analogue in which the terminal amino acid at B30 has been replaced by a 14-carbon fatty acid chain. This allows insulin detemir to bind reversibly to albumin, producing slow absorption and a prolonged and consistent metabolic effect for up to 24 hours. It appears to be at least as effective as isophane insulin in maintaining overall glycaemic control but with less intra-patient variability, a similar or lower risk of hypoglycaemia, and less body-weight gain.

Proinsulin (the natural precursor of insulin) appears to be more active than insulin in suppressing the hepatic production rather than the peripheral uptake of glucose. It has therefore been studied particularly in patients with type 2 diabetes mellitus. However, development by some manufacturers has been suspended because of a higher rate of adverse cardiac effects in patients treated with proinsulin than in controls.

INTENSIVE ADMINISTRATION REGIMENS. Intensive insulin regimens aim to mimic more closely the physiological insulin pattern in which a basal insulin concentration is supplemented by a preprandial boost of insulin. Such intensive regimens are used to provide tight control in an attempt to avoid long-term complications.

Intensified insulin regimens have the advantage of improving the patient’s lifestyle and allowing flexibility in timing of meals. However, careful dietary control must still be maintained and regular monitoring of blood-glucose concentrations is an important component of such regimens. Therefore patients must be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert 24-hour help. Although there are reports of success with intensive regimens in brittle (labile) diabetics, these patients are generally unlikely to benefit from such regimens.

In multiple-injection regimens, the basal insulin is provided by an injection of intermediate- or long-acting insulin given usually at night, and soluble insulin is given before each main meal. Systems for continuous administration may be designed on an open-loop or closed-loop delivery system. Open-loop systems comprise an infusion pump with the infusion rate programmed or controlled manually according to manual blood-glucose monitoring. Closed-loop systems (the ‘artificial pancreas’) consist of an insulin pump, a glucose sensor, and a computer for analysis of blood-glucose data. Systems for continuous administration have most commonly used the subcutaneous route, but intraperitoneal, intravenous, or intramuscular infusion have also been used. The most extensively used open-loop system is continuous subcutaneous insulin infusion (CSII) using an external pump. A battery-powered pump infuses soluble insulin via a subcutaneous catheter which is resited every 2 to 3 days. A background infusion is given at a predetermined rate, and preprandial bolus doses given using an override switch or manual drive. CSII provides better glycaemic control than conventional injection therapy, but may be only slightly more effective than optimised multiple daily injection therapy. Complications include erythema, abscess, or cellulitis at the injection site and, rarely, contact dermatitis to components of the giving set, pump malfunction, or precipitation of insulin and catheter obstruction. Pump therapy increases the risk of ketoacidosis and intensive regimens are associated with decreased hypoglycaemic awareness and more severe hypoglycaemic episodes compared with conventional therapy, although there is some suggestion that CSII might reduce the risk of severe hypoglycaemia compared with multiple daily injection therapy. If the pump fails or there is an acute increase in insulin requirements, the onset of ketoacidosis may be more rapid and more likely to be associated with dangerous hyperkalaemia than with conventional regimens because there is no depot of insulin.

Further development of open-loop delivery systems has been in the design of implantable insulin pumps. The first pumps delivered insulin at a constant basal rate, but variable rate models are now available. Studies’ have shown that intravenous or intra-peritoneal delivery of insulin from an implantable pump can produce excellent glycaemic control, and fewer episodes of severe hypoglycaemia than are associated with intensive subcutaneous multiple-injection regimens. The main problems associated with such therapy are pump slow-down or catheter obstruction due to aggregation of insulin within the device these can normally be corrected by procedures to flush the pump and catheter, although alternative insulin formulations (e.g. with poloxamer) have been investigated. Other problems may include fibrinous obstruction of the catheter or local intolerance of the pump.

Closed-loop continuous infusion systems are generally confined to research and experimental work because glucose sensors suitable for implantation are still being developed. However, results in animals have suggested that an alternative to such systems may be a vascularised artificial pancreas containing islet cells.

MIXING OF INSULINS. Mixtures of insulin with differing durations of action may be used in order to produce a more normal pattern of blood glucose variation than can be achieved with a single insulin. However, physicochemical changes in the mixture may occur, either immediately on mixing or over time, and the physiological response to the mixture may therefore be different than if the components were given separately. An early review suggested that insulins from different manufacturers should not be mixed, since formulation differences might render them incompatible. It is important that a consistent routine is followed in preparing and using such mixtures, and manufacturers advise that the shorter-acting insulin should be drawn into the syringe first, to avoid contamination of the vial with the longer-acting component. Pre-prepared mixtures are available from many manufacturers and may be preferable provided that the proportions are suited to the patient’s needs.

The American Diabetes Association has issued guidelines for mixing of insulins, including:

• patients well controlled on a particular mixed regimen should maintain their standard procedure for preparing doses

• no other medication or diluent should be mixed with insulin unless approved by the prescriber

• insulin glargine should not be mixed with other forms of insulin because of the low pH of its diluent

• currently available isophane and short-acting insulin formulations when mixed may be used immediately or stored for future use

• rapid-acting insulins (insulin aspart, insulin lispro) can be mixed with isophane, lente, and ultralente insulins. Ultralente insulins do not affect the onset of action of the rapid-acting component a slight decrease in absorption rate but not bioavailability is seen if rapid-acting insulins are mixed with isophane insulin but postprandial blood-glucose response is similar to that seen with mixtures of rapid-acting and ultralente insulin

• mixtures of rapid-acting insulin with an intermediate- or long-acting insulin should be injected within 15 minutes before a meal

• mixing of short-acting (soluble) and lente or ultralente insulin is not recommended, as zinc ions present in the lente insulin may bind with the short-acting insulin and delay its effects. The degree and rate of binding vary with the insulins used, and may not reach equilibrium for 24 hours if such mixtures are used the patient should standardise the interval between mixing and injection

• phosphate-buffered insulins (e.g. isophane insulin) should not be mixed with zinc-containing (lente or ultralente) insulins, as zinc phosphate may be precipitated, and the longer acting insulin may be partially and unpredictably converted to a short-acting form

Insulin formulations may change and the manufacturers should be consulted if their recommendations differ from those in the guidelines.

Diabetes mellitus. Insulin is the mainstay of the treatment of type 1 diabetes mellitus. For a discussion of the treatment of diabetes mellitus, including the contexts in which insulin is used. The possible role of tight glycaemic control with insulin to prevent the development of microvascular and macrovascular complications in patients with type 1 diabetes is discussed, while further discussion of specific regimens and approaches to insulin therapy is given under Administration, above.

DIABETIC EMERGENCIES. As discussed, diabetic ketoacidosis and hyperosmolar hyperglycaemic state are medical emergencies and should be treated immediately with fluid replacement and insulin. Potassium, and possibly phosphate, replacement may also be required, but bicarbonate should not be given unless acidaemia is very severe. In the UK the BNF recommends that insulin be given by intravenous infusion for diabetic ketoacidosis, as a solution of soluble insulin 1 unit/mL via an infusion pump. An infusion rate of 6 units/hour in adults and 0.1 units/kg per hour in children is recommended initially, with the rate doubled or quadrupled if the blood glucose concentration fails to decrease by about 5 mmol/litre per hour. When blood glucose concentrations have fallen to 10 mmol/litre the infusion rate can be reduced to 3 units/hour in adults or about 0.05 units/kg per hour in children, and continued, with glucose 5% to prevent hypoglycaemia, until the patient is ready to take food by mouth. The insulin infusion should not be stopped before subcutaneous insulin has been started. Potassium chloride is included in the infusion as appropriate to prevent insulin-induced hypokalaemia. If facilities for intravenous infusion are not available the insulin is given by intramuscular injection: in adults an initial loading dose of 20 units intramuscularly is followed by 6 units intramuscularly every hour until the blood glucose concentration falls to 10 mmol/litre, when the dose is given every 2 hours. Late hypoglycaemia due to insulin accumulation should be watched for and managed appropriately. In the USA the intramuscular or the subcutaneous route have been used as alternatives to intravenous insulin, with other appropriate management. One successful set of protocols for insulin dosage in diabetic ketoacidosis is as follows: an initial intravenous bolus of 0.15 units/kg is followed by infusion of 0.1 units/kg per hour if blood glucose does not fall by about 2.5 to 3.5 mmol/litre in the first hour the infusion rate is doubled every hour until this rate of decline is achieved. (A similar insulin regimen has proved effective in patients with hyperosmolar hyperglycaemic state.) When given by the intramuscular or subcutaneous routes an initial bolus of 0.4 units/kg is divided and given half by the intravenous route and half either intramuscularly or subcutaneously as appropriate. This is followed by 0.1 units/kg every hour intramuscularly or subcutaneously if response is inadequate it is replaced by an intravenous bolus of 10 units until blood glucose falls by 2.5 to 3.5 mmol/litre. In children intravenous infusion of 0.1 units/kg per hour is recommended, or if intravenous infusion is impractical an initial intramuscular bolus of 0.1 units/kg followed by 0.1 units/kg per hour either intramuscularly or subcutaneously. Treatment is continued at this rate until a serum-glucose concentration of about 12.5 mmol/litre is reached (or about 15 mmol/litre for hyperosmolar hyperglycaemic state), when the rate is decreased to 0.05 to 0.1 units/kg per hour until acidosis is controlled and subcutaneous insulin replacement treatment can be started.

TYPE 2 DIABETES MELLITUS. Traditionally the use of insulin in patients with type 2 diabetes has tended to be reserved for those who cannot be controlled by diet and oral antidiabetics alone. Given the possible association between circulating insulin and atherosclerotic cardiovascular symptoms there has been some concern about the use of exogenous insulin in insulin-resistant patients who are already hyperinsulinaemic. Furthermore, patients switched to insulin tend to gain weightwhich is undesirable in a frequently obese patient group. Insulin is nonetheless being used more frequently in type 2 patients. This is largely because of a trend toward more intensive regimens designed to produce tighter glycaemic control, on the hypothesis that, as in patients with type 1 disease, this will reduce the development and progression of diabetic complications. Results from the UK Prospective Diabetes Study, show that insulin is an effective option in type 2 diabetes, and confirm both the value of intensive therapy in retarding microvascular complications, and that oral therapy should be used before insulin in patients with primary diet failure.

In order to minimise the dose of insulin required, and any risks it may entail, it has been suggested that insulin therapy in type 2 diabetes should be combined with other measures including oral hypoglycaemic drugs. There has long been debate about the value of combined therapy, but a meta-analysis indicated that glycaemic control was better, and insulin requirements lower, in type 2 diabetics who received insulin with a sulfonylurea. For evidence that the insulin analogues insulin lispro and insulin as-part have no advantage over regular insulin in type 2 patients see Insulin Analogues, above.

Diagnosis and testing. PITUITARY FUNCTION. Insulin-induced hypoglycaemia has been used to provide a stressful stimulus in order to assess hypothalamic-pituitary function. The insulin stress or insulin-tolerance test has been used as a standard test for assessment of growth hormone or corticotropin deficiency. However, it is unpleasant, expensive, and not without risk, and is contra-indicated in patients with angina, heart failure, cerebrovascular disease, or epilepsy some recommend its use only when results of alternative tests are equivocal, and it should only be performed in specialist units under strict surveillance.

Hyperkalaemia. Insulin promotes the intracellular uptake of potassium. It is therefore used in the management of moderate to severe hyperkalaemia, when it is given with glucose.

Liver disorders. There have been reports of benefit from the use of insulin and glucagon in the treatment of liver disorders, based on their reported hepatotrophic effect. However, randomised studies have found no benefit from insulin and glucagon infusions in fulminant hepatic failure and acute alcoholic hepatitis.

Myocardial infarction. Discussions on the effects of insulin with glucose and potassium in the ischaemic heart, including its effect in reducing blood free fatty acids, have emphasised its potential benefits in left ventricular failure and cardiogenic shock. A meta-analysis of randomised controlled studies performed before the widespread use of thrombolytics found a reduction in mortality in recipients of glucose-insulin-potassium solutions. However, although a pilot study that included patients undergoing reperfusion (thrombolysis or percutaneous coronary intervention) reported benefit, this was not confirmed in larger randomised studies using standard glucose-insulin-potassium infusions. A further study found that routine use of such infusions in patients undergoing reperfusion had no effect on myocardial salvage, although some improvement was reported in diabetics.

Intensive glucose control, with insulin-glucose infusion followed by multiple daily subcutaneous insulin injections has been reported to reduce mortality in diabetics who suffered a myocardial infarction. A similar study of treatment after myocardial infarction included only patients with type 2 diabetes mellitus who were treated with routine care, or insulin-glucose infusion followed by either long-term subcutaneous insulin or standard glucose control. The study was stopped early due to slow patient recruitment, but results did suggest that although glucose concentration was a strong independent predictor of long-term mortality, the use of long-term insulin treatment did not improve survival compared with conventional treatment at similar levels of glucose control. An observational study in non-diabetics with hyperglycaemia suggested that intensive glucose control also improved outcomes in this population, but another study found no benefit. However, the glucose control achieved in this study was similar in both the intensive and the conventional treatment groups and an analysis based on blood glucose concentrations suggested that strict glucose control was beneficial.For the conventional management of myocardial infarction.

Neonatal hyperglycaemia. Hyperglycaemia is common in very immature neonates because of delayed or reduced insulin production. It can be treated by glucose restriction until glucose tolerance improves. However, this may not provide enough glucose to meet basal metabolic needs, and the use of an insulin infusion can allow sufficient glucose to be given. It has been suggested that insulin is best given intravenously in a separate, easily titratable solution because of the frequent fluctuations of requirement in these infants.

Overdosage with calcium-channel blockers. High-dose insulin, with glucose and potassium as required to maintain normal plasma concentrations of these, has been reported to be of value in the treatment of overdosage with calcium-channel blockers that has not been adequately managed with conventional therapy (which is described under Treatment of Adverse Effects under Nifedipine). A review of 13 reported cases found that various dosage regimens had been tried. These included bolus doses of insulin 10 to 20 units, and continuous infusions of 0.1 to 1 unit/kg per hour. The authors of one report have proposed a regimen that includes an initial intravenous bolus dose of insulin 1 unit/kg, followed by a continuous infusion of 0.5 units/kg per hour this may be increased to 1 unit/kg per hour if necessary.

Preparations

British Pharmacopoeia 2008: Insulin Aspart Injection; Insulin Lispro Injection; Protamine Zinc Insulin Injection

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1and 6.2: Biphasic Insulin Injection; Biphasic Isophane Insulin Injection; Insulin Zinc Injectable Suspension; Insulin Zinc Injectable Suspension (Amorphous); Insulin Zinc Injectable Suspension (Crystalline); Isophane Insulin Injection; Soluble Insulin Injection

The United States Pharmacopeia 31, 2008: Extended Insulin Human Zinc Suspension; Extended Insulin Zinc Suspension; Human Insulin Isophane Suspension and Human Insulin Injection; Insulin Human Injection; Insulin Human Zinc Suspension; Insulin Injection; Insulin Lispro Injection; Insulin Zinc Suspension; Isophane Insulin Human Suspension; Isophane Insulin Suspension; Prompt Insulin Zinc Suspension

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Actrapid HM; Actrapid MC¤; Biohulin C; Biohulin N; Humalog; Humulin 70/30; Humulin L; Humulin NPH; Humulin R; Humulin U; Insulatard HM; Insulatard MC¤; Insuman N; Insuman R; Mixtard 30 HM; Monotard HM¤; Monotard MC¤

Australia: Actraphane HM¤; Actraphane MC¤; Actrapid MC¤; Actrapid; Humalog Mix 25; Humalog; Humulin 20/80, 30/70 and 50/50; Humulin L; Humulin NPH; Humulin R; Humulin UL; Hypurin Isophane; Hypurin Neutral; Initard Human¤; Initard¤; Insulatard Human¤; Insulatard¤; Insulin 2¤; Isotard MC¤; Lantus; Lente MC¤; Mixtard 20/80, 30/70, 50/50; Mixtard¤; Monotard MC¤; Monotard; NovoMix 30; NovoRapid; Protamine Zinc Insulin MC¤; Protaphane MC¤; Protaphane; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard; Velosulin¤

Austria: Actrapid HM; Depot-Insulin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong; Insulatard HM; Insulatard¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman komb Typ 15, Typ 25, and Typ 50¤; Insuman Rapid; Komb-Insulin¤; Lente MC¤; Mixtard 30/70 and 50/50¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard HM; Rapitard MC¤; Ultratard HM; Velosulin HM¤; Velosulin¤

Belgium: Actrapid HM; Humaject 30/70; Humaject NPH; Humaject Regular; Humalog; Humuline 20/80, 30/70, 50/50; Humuline Long; Humuline NPH; Humuline Regular; Humuline Ultralong; Initard Humanum¤; Insulatard HM; Insulatard-X Humanum¤; Lantus; Lente MC¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, 50/50; Mixtard-X Humanum¤; Monotard HM; NovoMix 30; NovoRapid; Ultralente MC¤; Ultratard HM; Velosuline HM

Brazil: Actrapid MC; Biohulin 70/30, 80/20, and 90/10; Biohulin Lenta; Biohulin NPH; Biohulin Regular; Biohulin Ultralenta; Humalog Mix 25; Humalog; Humulin 70/30; Humulin Lenta; Humulin NPH; Humulin Regular; Insuman Comb 85N/15R and 75N/25R; Insuman N; Insuman R; Iolin NPH¤; Iolin Regular¤; Lantus; Monolin NPH¤; Monolin Regular¤; Monotard MC; Neosulin Lenta¤; Neosulin NPH¤; Neosulin Regular¤; Novolin 90/10, 80/20, and 70/30; Novolin L; Novolin N; Novolin R; Novolin U; NovoRapid; Protaphane MC

Canada: Humalog Mix 25; Humalog; Humulin 20/80, 30/70; Humulin L; Humulin N; Humulin R; Humulin U; Iletin II Pork Lente; Iletin II Pork NPH; Iletin II Pork Regular; Iletin Lente¤; Iletin NPH¤; Iletin Regular¤; Iletin Semilente¤; Iletin Ultralente¤; Initard 50/50¤; Insulatard NPH Human¤; Insulatard NPH¤; Insulin-Toronto (Regular)¤; Lente Insulin¤; Mixtard 15/85, 30/70, 50/50¤; Mixtard 30/70¤; Novolin 10/90, 20/80, 30/70, 40/60, 50/50; Novolin Lente; Novolin NPH; Novolin Toronto; Novolin Ultralente; NovoRapid; PZI Iletin¤; Semilente Insulin¤; Ultralente¤; Velosulin (Regular)¤; Velosulin Human¤

Chile: Actrapid HM; Actrapid¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard HM; Insulatard¤; Insuman N; Insuman R; Lantus; Lenta¤; Mixtard HM¤; Monotard HM

Czech Republic: Actrapid HM; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humulin L; Humulin M3; Humulin N; Humulin R; Humulin U; Hypurin Bovine Isophane; Hypurin Bovine Protamin Zink Sulfat; Hypurin Porcin Neutral; Insulatard HM; Insuman Basal; Insuman Komb Typ 15, Typ 25, and Typ 50; Insuman Rapid; Lantus; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM; Velosulin HM

Denmark: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard Ultra¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Rapid; Mixtard 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard; NovoMix 30; NovoRapid; Velosulin

Finland: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular; Humutard Ultra¤; Humutard; Insulin Lente MC¤; Insulin Lyhyt¤; Insulin Pitka¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10, 20, 30, and 50; Monotard; NovoMix 30; NovoRapid; Protaphane; Ultratard; Velosulin¤

France: Actraphane HM¤; Actrapid HM; Apidra; Durasuline¤; Endopancrine 100¤; Endopancrine 40¤; Endopancrine Protamine¤; Endopancrine Zinc Protamine¤; Humalog Mix 25 and 50; Humalog; Insulatard Nordisk¤; Insulatard; Insuline NPH¤; Insuline Semi Tardum¤; Insuline Tardum MX¤; Insuline Ultra Tardum¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Intermediaire 100%¤; Insuman Intermediaire 25/75¤; Insuman Rapid; Lantus; Lente MC¤; Levemir; Lillypen Profil 10, 20, 30, and 40¤; Lillypen Protamine Isophane¤; Lillypen Rapide; Mixtard 10, 20, 30, 40, and 50 HM; Mixtard¤; Monotard¤; NovoMix 30; NovoRapid; Orgasuline 30/70¤; Orgasuline NPH¤; Orgasuline Rapide¤; Protaphane HM¤; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard¤; Umuline Profil 30; Umuline Protamine Isophane (NPH); Umuline Rapide; Umuline Zinc Compose¤; Umuline Zinc¤; Velosulin; Velosuline¤

Germany: Actraphane 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid; B-Insulin; Basal-H-Insulin¤; Berlinsulin H 20/80, 30/70; Berlinsulin H Basal; Berlinsulin H Normal; Depot-H-Insulin¤; Depot-H15-Insulin¤; Depot-Insulin Horm¤; Depot-Insulin S¤; Depot-Insulin¤; H-Insulin¤; H-Tronin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long¤; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong¤; Insulatard Human; Insulatard MC¤; Insulin Basal; Insulin Comb 30/70; Insulin Monotard HM; Insulin Novo Semilente MC; Insulin Rapid; Insulin S; Insulin SNC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Komb-H-Insulin¤; Komb-Insulin S¤; Komb-Insulin¤; L-Insulin SNC¤; L-Insulin¤; Lantus; Lente¤; Mixtard 30/70; Mixtard¤; Monotard; NovoMix 30; NovoRapid; Protaphane; Rapitard¤; Semilente; Ultralente¤; Ultratard HM; Velasulin Human¤; Velasulin MC¤; Velasulin¤; Velosulin

Greece: Actraphane HM¤; Actrapid HM; Humalog Mix 25; Humalog; Humulin Lente; Humulin M2, M3; Humulin NPH; Humulin Regular; Humulin Utralente; Lantus; Mixtard 10, 20, 30, 40, and 50; Monotard HM; NovoMix 30; NovoRapid; PenMix 10, 20, 30, 40, or 50¤; Protaphane HM; Ultratard

Hong Kong: Actrapid HM; Actrapid MC¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard MC¤; Lantus; Mixtard 20 and 30 HM; Monotard HM; Monotard MC¤; NovoRapid; Protaphane HM; Protaphane MC¤; Ultratard HM

Hungary: Humalog M25 and M50; Humalog; Humulin L; Humulin M1, M2, M3, M4; Humulin N; Humulin R; Humulin U; Insulin Actrapid; Insulin Insulatard; Insulin Mixtard 10, 20, 30, 40, 50; Insulin Monotard; Insulin Semilente; Insulin Ultratard; Monotard MC; NovoRapid

India: Actrapid; Human Actrapid; Human Insultard; Human Mixtard 30 and 50; Human Monotard; Lantus; Lentard; Mixulin; Rapidica; Rapimix; Wosulin Biphasic 30/70 and 50/50; Wosulin-N; Wosulin-R; Zinulin

Ireland: Actrapid; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Human Protaphane¤; Human Velosulin¤; Humulin I; Humulin Lente; Humulin M3; Humulin S; Humulin Zn; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard; Neulente¤; Neuphane¤; NovoMix 30; NovoRapid; Ultratard; Velosulin¤

Israel: Humalog Mix 25; Humalog; Humulin 70/30, 80/20; Humulin N; Humulin R; Humulin U¤; Lantus; NovoMix 30; NovoRapid

Italy: Actraphane HM 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid HM; Bio-Insulin 30/70 and 50/50¤; Bio-Insulin I¤; Bio-Insulin L¤; Bio-Insulin R¤; Bio-Insulin U¤; Humalog Mix 25; Humalog; Humulin 30/70 and 50/50; Humulin I; Humulin L; Humulin R; Humulin U; Lantus; Lenta MC¤; Monotard HM; NovoRapid; Protaphane HM; Rapitard MC¤; Ultratard HM

Japan: Humacart 3/7; InnoLet 10R, 20R, 30R, 40R, and 50R; InnoLet N; InnoLet R; Monotard; NovoLet 10R,20R, 30R, 40R, 50R¤; NovoLet N¤; NovoLet R¤; Novolin 10R, 20R, 30R, 40R, and 50R; Novolin N; Novolin R; Novolin U; NovoRapid; Penfill N; Penfill R; Penfill 10R, 20R, 30R, 40R, 50R; Velosulin

Malaysia: Actrapid; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard; Lantus; Mixtard 30 HM; Monotard HM¤; NovoRapid; Ultratard HM¤

Mexico: Anilusin¤; Humalog Mix 25; Humalog; Humanilusin¤; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Insulex¤; Insuman 100N; Insuman 15R/85N, 25R/75N, and 50R/50N; Insuman R; Lantus; Novolin 30/70; Novolin L; Novolin N; Novolin R; Prodiabin-N

Netherlands: Actrapid; Humaject 10/90, 20/80, 30/70, 40/60, 50/50¤; Humaject NPH¤; Humaject Regular¤; Humalog Mix 25; Humalog; Humuline NPH; Humuline Zink¤; Humuline 20/80, 30/70; Humuline; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 15, Comb 25, Comb 50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Mixtard 10, 20, 30, 40, and 50; Monotard; NovoRapid; Ultratard; Velosulin

Norway: Actrapid; Humalog Mix 25; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular¤; Insulatard; Insulin Basal¤; Insulin Infusat¤; Insulin Komb 25/75¤; Insulin Rapid¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin¤

New Zealand: Actrapid; Humalog Mix 25¤; Humalog; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Humulin U¤; Insulatard MC; Lantus; Mixtard 30 or 50; Monotard; NovoRapid; PenMix 10, 20, 30, 40, or 50; Protaphane; Ultratard; Velosulin HM; Velosulin MC

Portugal: Actrapid; Humalog; Humulin Lenta; Humulin M1, M2, M3, M4, M5; Humulin NPH; Humulin Regular; Humulin Ultralenta; Insulatard; Isuhuman Basal; Isuhuman Comb 25; Isuhuman Rapid; Mixtard 10, 20, 30, 40, and 50 HM; Monotard; Ultratard

Russia: Actrapid HM (Актрапид НМ); Actrapid MC (Актрапид MC); Biosulin N (Биосулин Н); Biosulin R (Биосулин Р); Humalog (Хумалог); Humulin M3 (Хумулин М3); Humulin NPH (Хумулин НПХ); Humulin Regular (Хумулин Регуляр); Insulidd L (Инсулидд Л); Insulidd N (Инсулидд Н); Insulidd R (Инсулидд Р); Insulin Lt (Инсулин Лт); Insulin Maxirapid (Инсулин Максирапид); Insuman Basal (Инсуман Базал); Insuman Comb 25 (Инсуман Комб 25); Insuman Rapid (Инсуман Рапид); Lantus (Лантус); Levulin L (Левулин Л); Levulin N (Левулин Н); Levulin R (Левулин Р); Mixtard 30 HM (Микстард 30 НМ); Monotard MC (Монотард Нм); NovoRapid (Новорапид); Protaphane HM (Протафан НМ)

South Africa: Actraphane HM; Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Humulin U¤; Lantus; Mixtard 20/80; Monotard HM; NovoMix 30; NovoRapid; Protaphane HM; Ultratard HM

Singapore: Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard HM; Lantus; Mixtard 20, 30, 50 HM; Monotard HM¤; NovoMix 30; NovoRapid; Ultratard HM¤

Spain: Actrafan HM¤; Actrap MC¤; Actrapid; Combitard Humana 15/85¤; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humaplus 30/70; Humaplus NPH; Humaplus Regular; Humulina 10:90, 20:80, 30:70, 50:50; Humulina Lenta¤; Humulina NPH; Humulina Regular; Humulina Ultralenta¤; Insulatard NPH¤; Insulatard; Lantus; Lente MC¤; Meztardia Humana 50/50¤; Meztardia Nordi¤; Mixtard 10, 20, 30, 40, and 50; Mixtard 30/70¤; Monotard¤; Monotard; NovoMix 30; NovoRapid; Protafan HM¤; Rapitar MC¤; Semilen MC¤; Ultrale MC¤; Ultratard; Velosulin Humana¤; Velosulin¤

Sweden: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 25/75, 50/50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin

Switzerland: Actraphane HM¤; Actrapid HM; Actrapid MC; Humalog; Huminsulin Basal (NPH); Huminsulin Long; Huminsulin Normal; Huminsulin Profil III; Huminsulin Ultralong; Hypurin 30/70 Mix; Hypurin Isophane; Hypurin Neutral; Initard Humaine¤; Initard¤; Insulatard HM; Insulatard MC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Lantus; Lente MC¤; Levemir; Mixtard 30 MC; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Rapitard MC¤; Semilente MC; Ultralente MC¤; Ultratard HM; Velosulin HM; Velosulin MC¤

Thailand: Actrapid HM; Humalog Mix 25¤; Humalog¤; Humulin 70/30¤; Humulin N¤; Humulin R¤; Insulatard; Lantus; Mixtard 20, 30, 50 HM; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM¤

United Arab Emirates: Jusline 70/30; Jusline N; Jusline R

United Kingdom: Actrapid; Apidra; Humaject I¤; Humaject M1, M2, M3, M4, M5¤; Humaject S¤; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Humulin I; Humulin Lente¤; Humulin M3; Humulin S; Humulin Zn¤; Hypurin 30/70; Hypurin Isophane; Hypurin Lente; Hypurin Neutral; Hypurin Protamine Zinc; Hypurin Soluble¤; Initard 50/50¤; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Lentard MC¤; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard¤; NovoMix 30; NovoRapid; PenMix 10/90, 20/80, 30/70, 40/60, 50/50¤; Pork Actrapid; Pork Insulatard; Pork Mixtard 30; Pur-in Isophane¤; Pur-in Mix 15/85, 25/75, 50/50¤; Pur-in Neutral¤; Rapitard MC¤; Semitard MC¤; Ultratard¤; Velosulin¤; Velosulin

United States: Apidra; Exubera; Humalog Mix 75/25 and 50/50; Humalog; Humulin 70/30, 50/50; Humulin BR¤; Humulin L; Humulin N; Humulin R; Humulin U Ultralente; Insulatard NPH Human¤; Insulatard NPH¤; Lantus; Lente Iletin I¤; Lente Iletin II; Lente L¤; Lente; Levemir; Mixtard Human 70/30¤; Mixtard¤; Novolin 70/30; Novolin L¤; Novolin N; Novolin R; NovoLog Mix 70/30; NovoLog; NPH Iletin I¤; NPH Iletin II; Protamine, Zinc & Iletin I¤; Regular Iletin I¤; Regular Iletin II; Semilente Iletin I¤; Semilente¤; Ultralente Iletin I¤; Ultralente U¤; Ultralente; Velosulin Human BR¤; Velosulin¤

Venezuela: Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insuman N; Insuman R; Novolin 70/30; Novolin L; Novolin N; Novolin R