Antidiabetic Drugs

Archive for the ‘Diabetes drugs’ Category

Buformin

(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.

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

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

Adverse Effects and Precautions

As for alpha-glucosidase inhibitors in general (see Acarbose). Skin rash may occur. Miglitol should be used with caution in patients with renal impairment.

Interactions

As for alpha-glucosidase inhibitors in general (see Acarbose). Miglitol may reduce the bioavailability of propranolol and ranitidine.

Pharmacokinetics

Miglitol is completely absorbed at a dose of 25 mg, but only 50 to 70% is absorbed at a dose of 100 mg. It is not metabolised, and is excreted unchanged in the urine with a plasma elimination half-life of about 2 hours.

Uses and Administration

Miglitol is an alpha-glucosidase inhibitor similar in action to acarbose. It is given orally in the management of type 2 diabetes mellitus, alone or with a sulfonylurea. Usual initial doses are 25 mg three times daily with meals, increased if necessary to a maximum of 100 mg three times daily.

Proprietary Preparations

Austria: Diastabol

Czech Republic: Diastabol

France: Diastabol

Germany: Diastabol

Hungary: Diastabol

India: Diamig Mignar †

Mexico: Diastabol

Poland: Diastabol

Portugal: Diastabol Limarcan

Spain: Diastabol Plumarol

Sweden: Diastabol

Switzerland: Diastabol

USA: Glyset

Synonyms: Antidiabéticos sulfonilureas; Sulfonylurea Antidiabetics; Sulphonylurea Antidiabetics

Adverse Effects

Gastrointestinal disturbances such as nausea, vomiting, heartburn, anorexia, diarrhoea, and a metallic taste may occur with sulfonylureas and are usually mild and dose-dependent increased appetite and weight gain may occur. Skin rashes and pruritus may occur and photosensitivity has been reported. Rashes are usually hyper sensitivity reactions and may progress to more serious disorders (see below). Facial flushing may develop in patients receiving sulfonylureas, particularly chlorpropamide, when alcohol is consumed (see under Interactions, below).

Mild hypoglycaemia may occur severe hypoglycaemia is usually an indication of overdosage and is relatively uncommon. Hypoglycaemia is more likely with long-acting sulfonylureas such as chlorpropamide and glibenclamide, which have been associated with severe, prolonged, and sometimes fatal hypoglycaemia. Other severe effects may be manifestations of a hypersensitivity reaction. They include altered liver enzyme values, hepatitis and cholestatic jaundice, leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis, haemolytic anaemia, erythema multiforme or the Stevens-Johnson syndrome, exfoliative dermatitis, and erythema nodosum.

The sulfonylureas, particularly chlorpropamide, occasionally induce a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) characterised by water retention, hyponatraemia, and CNS effects. However, some sulfonylureas, such as glibenclamide, glipizide, and tolazamide are also stated to have mild diuretic actions.

Work on tolbutamide has suggested that the sulfonylureas might be associated with an increase in cardiovascular mortality this has been the subject of considerable debate (see Effects on the Cardiovascular System, below).

Effects on the cardiovascular system. A multicentre study carried out under the University Group Diabetes Program (UGDP) reported an increased incidence in mortality from cardiovascular complications in diabetic patients given tolbutamide as compared with those treated with diet alone or insulin a similar increase was also noted in patients given phenformin. The reports from the UGDP aroused prolonged controversy which was not entirely settled by detailed reassessment of relevant studies. Eventually in 1984 the FDA made it a requirement that sulfonylurea oral antidiabetics be labelled with a specific warning about the possibility of increased cardiovascular mortality associated with the use of these drugs Subsequently the cardiovascular effects of the sulfonylureas were reviewed. It has been hypothesised that the action of the sulfonylureas in preventing the opening of ATP-sensitive potassium channels in the myocardium may abolish adaptive changes (ischaemic preconditioning) that protect the heart against ischaemic insult. A recent retrospective cohort study has also found that, among patients newly treated for type 2 diabetes, sulfonylurea monotherapy was associated with an increased mortality compared with metformin therapy. However, results from the UK Prospective Diabetes Study did not demonstrate any adverse cardiovascular effects associated with sulfonylurea therapy.

Effects on the eyes. When a diabetic patient who had experienced bilateral visual loss for several months and who had been taking chlorpropamide for one year stopped treatment, visual acuity improved and colour vision rapidly returned. A 5-day challenge with chlorpropamide resulted in a mild decrease in acuity followed by return to baseline values when treatment was again stopped. Drug-induced optic neuropathy was considered to have occurred. There is also a report of a patient with type 2 diabetes mellitus who developed myopia two days after starting treatment with glibenclamide 10 mg daily. Visual difficulties resolved a few days after stopping glibenclamide.

Effects on the kidneys. The nephrotic syndrome has been reported in a patient treated with chlorpropamide. Serological testing and renal biopsy showed that the glomerular lesions were of an immune-complex nature. Both the nephrotic syndrome and the glomerulonephritis resolved after treatment was stopped. The patient also developed a skin eruption, hepatitis, and eosino-philia.

Effects on the liver. Chlorpropamide was implicated in 8 of 53 cases of drug-induced acute liver disease admitted to a hospital in Jamaica over the years 1973 to 1988. Hepatocanalicular cholestasis occurred in 5 cases and diffuse necrosis in 3. One patient with massive hepatic necrosis died. Intrahepatic cholestasis, an acute hepatitis-like syndrome, and a combination of both have been described in patients receiving glibenclamide.

Effects on the thyroid. See under Precautions, below.

Hypoglycaemia. Severe hypoglycaemia may occur in any patient treated with any sulfonylurea this potentially life-threatening complication requires prolonged and energetic treatment.Sulfonylureas with a prolonged duration of action such as chlorpropamide and glibenclamide appear to cause severe hypoglycaemia more often than shorteracting drugs such as tolbutamide. Experience with newer drugs is limited.

A review of 1418 cases of drug-induced hypoglycaemia reported since 1940 showed that sulfonylureas (especially chlorpropamide and glibenclamide), either alone or with a second antidiabetic or potentiating agent, accounted for 63% of all cases. A study of sulfonylurea use in nearly 14,000 patients aged 65 years or older confirmed that chlorpropamide and glibenclamide were associated with hypoglycaemia. However, glipizide caused significantly fewer cases than glibenclamide.

An analysis, of 185 children reported to 10 regional poison centres in the USA after ingesting sulfonylureas found that hypoglycaemia developed only in 56. A lack of hypoglycaemia during the first 8 hours after ingestion was predictive of a benign outcome, and it was recommended that suspected cases be observed for 8 hours with frequent blood glucose monitoring. Children who developed signs of hypoglycaemia, or in whom blood glucose fell below 3.3 mmol/litre could be given intravenous glucose if necessary.

Treatment of Adverse Effects

In acute poisoning with sulfonylureas, if the patient is conscious and presents within 1 hour of ingestion, the stomach should be emptied and/or activated charcoal given. Hypoglycaemia should be treated with urgency the general management of hypoglycaemia is described under insulin. The patient should be observed over several days in case hypoglycaemia recurs. Octreotide has been used in the treatment of severe refractory cases of sulfonylurea-induced hypoglycaemia.

Precautions

Sulfonylureas should not be used in type 1 diabetes mellitus. Use in type 2 diabetes mellitus is contra-indicated in patients with ketoacidosis and in those with severe infection, trauma, or other severe conditions where the sulfonylurea is unlikely to control the hyperglycaemia insulin should be used in such situations.

Insulin is also preferred for therapy during pregnancy.

Sulfonylureas with a long half-life such as chlorpropamide or glibenclamide are associated with an increased risk of hypoglycaemia. They should therefore be avoided in patients with impairment of renal or hepatic function, and a similar precaution would tend to apply in other groups with an increased susceptibility to this effect, such as the elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency. Irregular mealtimes, missed meals, changes in diet, or prolonged exercise may also provoke hypoglycaemia. Where a sulfonylurea needs to be used in patients at increased risk of hypoglycaemia, a short-acting drug such as tolbutamide or gliclazide may be preferred these 2 sulfonylureas, being principally inactivated in the liver, are perhaps particularly suitable in renal impairment, although careful monitoring of blood-glucose concentration is essential.

Abuse. Severe hypoglycaemia, at first thought to be due to insulinoma but later found to be due to nesidioblastosis [proliferation of the islet cells], was reported in a woman covertly taking chlorpropamide.

Administration. It has been suggested that continuously high plasma concentrations of sulfonylureas may lead to the development of tolerance, and that therefore the maximum recommended doses should be reduced.

Breast feeding. Some sulfonylureas are distributed into breast milk and the class of drugs should be avoided during breast feeding.

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. References.

Fasting. For the suggestion that sulfonylureas should be used with caution in fasting Muslim patients during Ramadan, and that chlorpropamide is contra-indicated in this group, see under Precautions of Insulin.

Porphyria. Sulfonylureas have been associated with acute attacks of porphyria and are considered unsafe in porphyric patients.

Thyroid disorders. There are conflicting reports concerning the effects of sulfonylureas on thyroid function, with some studies suggesting an increased incidence of thyroid dysfunction in patients treated with tolbutamide or chlorpropamide, while other suggest no antithyroid action. Some licensed product information consequently recommends that chlorpropamide should be avoided in patients with impaired thyroid function. Changes in thyroid function may conversely affect glycaemic control — for mention of the possible effects of thyroid hormones on anti-diabetic drug requirements see under Interactions, below.

Interactions

Many interactions have been reported with the sulfonylureas, largely representing either pharmacokinetic interactions (due to the displacement of the antidiabetic from plasma proteins or alteration in its metabolism or excretion) or pharmacological interactions with drugs having an independent effect on blood glucose. In the former class most reports concern older sulfonylureas such as chlorpropamide and tolbutamide, although the possibility of such reactions with newer drugs should be borne in mind.

A diminished hypoglycaemic effect, possibly requiring an increased dose of sulfonylurea, has been seen or might be expected on theoretical grounds with adrenaline, aminoglutethimide, chlorpromazine, corticosteroids, diazoxide, oral contraceptives, rifamycins, thiazide diuretics, and thyroid hormones.

An increased hypoglycaemic effect has occurred or might be expected with ACE inhibitors, alcohol, allopurinol, some analgesics (notably azapropazone, phenylbutazone, and the salicylates), azole antifungals (fluconazole, ketoconazole, and miconazole), chloramphenicol, cimetidine, clofibrate and related compounds, coumarin anticoagulants, fluoroquinolones, heparin, MAOIs, octreotide (although this may also produce hyperglycaemia), ranitidine, sulfinpyrazone, sulfonamides (including cotrimoxazole), tetracyclines, and tricyclic antidepressants.

Beta blockers have been reported both to increase hypoglycaemia and to mask the typical sympathetic warning signs. There are sporadic and conflicting reports of a possible interaction with calcium-channel blockers, but overall any effect seems to be of little clinical significance.

In addition to producing hypoglycaemia alcohol can interact with chlorpropamide to produce an unpleasant flushing reaction. Such an effect is rare with other sulfonylureas and alcohol.

ACE inhibitors. There are sporadic reports of marked hypoglycaemia developing in patients taking a sulfonylurea who are given an ACE inhibitor (mainly captopril or enalapril) and 2 case-control studies have indicated that the combination is associated with an increased risk of developing severe hypoglycaemia. However, other studies have failed to find much evidence of a problem.

Alcohol. Sulfonylurea-induced alcohol intolerance is seen mainly but not exclusively with chlorpropamide this is similar to the disulfiram-alcohol interaction, although it is not clear whether the mechanism is the same. Since the main symptom of the reaction (facial flushing) appears to occur more commonly in diabetic than non-diabetic subj ects, it has been proposed that this symptom could be used as a diagnostic test for a certain subset of patients with type 2 diabetes mellitus. However, some have not considered the test to be sufficiently specific and despite a great deal having been published on the chlorpropamide-alcohol flushing test (CPAF), its value remains poorly defined. Alcohol, as well as provoking a flushing reaction with chlorpropamide, has been reported both to increase and to decrease the half-life of tolbutamide depending on whether the alcohol administration was acute or chronic. Alcohol may also have a variable effect of its own on blood-glucose concentrations there is a general tendency to increased hypoglycaemia when alcohol and sulfonylureas are taken concurrently.

Analgesics. Phenylbutazone and related drugs such as azapropazone have been associated with acute hypoglycaemic episodes when given to patients receiving sulfonylureas (in most reports, tolbutamide). Other analgesics may enhance the hypoglycaemic effect of sulfonylureas, including indobufen fenclofenac and the salicylates. Although a study in healthy subjects found no interaction, there has been a report of hypoglycaemia with ibuprofen in a diabetic patient who had been stabilised on glibenclamide.

Antibacterials. Chloramphenicol markedly inhibits the metabolism of tolbutamide and increases its half-life, which can result in hypoglycaemia. Sulfonamides, including cotrimoxazole may also enhance the hypoglycaemic effects of the sulfonylureas. There have been rare reports of elevated glibenclamide concentrations and hypoglycaemia when ciprofloxacin was given to patients who were on stable glibenclamide therapy. For reports of hypoglycaemia when gatifloxacin was given to patients already receiving a sulfonylurea (glimepiride in one case, and glibenclamide plus pioglitazone in another). There have also been a few cases of severe hypoglycaemia when clarithromycin was added to glibenclamide or glipizide renal impairment may have played a role in these cases. Rifampicin (and probably other rifamycins) can enhance the metabolism and decrease the effect of tolbutamide, chlorpropamide, and glibenclamide and dosage of the hypoglycaemic drug may need to be increased. The effects on glipizide and glimepirideappear to be less pronounced.

Anticoagulants. Dicoumarol increases serum concentrations and therefore the hypoglycaemic effects of tolbutamide, and possibly chlorpropamide. In addition, sulfonylureas may affect anticoagulant function.

Antiepileptics. For references to phenytoin toxicity when tolbutamide or tolazamide was given, see under Phenytoin.

Antifungals. Increased plasma concentrations of tolbutamide have been reported when fluconazole was given, but there was no evidence of hypoglycaemia, and no hypoglycaemic symptoms were seen in 29 women receiving gliclazide or glibenclamide who were given fluconazole or clotrimazole for vulvovaginitis. A study in healthy subjects found that fluconazole increased plasma concentrations of glimepiride, but again there was no significant effect on glucose concentrations. However, there are reports of hypoglycaemia in a patient who took fluconazole with glipizide, and another who took fluconazole and cotrimoxazole with gliclazide. Similar interactions have been reported for ketoconazole (with tolbutamide, in healthy subjects)and miconazole (with tolbutamide, in a diabetic), suggesting that such combinations should be regarded with caution.

Ciclosporin. For the effect of glibenclamide on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Metformin. Results apparently suggesting increased mortality in patients who received intensive drug therapy with metformin and a sulfonylurea were reported by the UK Prospective Diabetes Study. This was considered to be artefactual, since it was not confirmed by epidemiological analysis, and such combinations are widely used in practice, but some concern remains and further study is needed.

Thyroid hormones. It has been suggested that starting thyroid replacement therapy may increase the requirement for insulin or oral antidiabetic drugs in diabetic patients, which would not seem unreasonable given the stimulant effects of thyroid hormones on metabolic function. For a discussion of the mooted effects of sulfonylureas on thyroid function, see under Precautions, above.

Uses and Administration

The sulfonylurea 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, although metformin is preferred in patients who are obese. Sulfonylureas appear to have several modes of action, apparently mediated by inhibition of ATP-sensitive potassium channels. Initially, secretion of insulin by functioning islet beta cells is increased. However, insulin secretion subsequently falls again but the hypoglycaemic effect persists and may be due to inhibition of hepatic glucose production and increased sensitivity to any available insulin this may explain the observed clinical improvement in glycaemic control. The duration of action of sulfonylureas is variable drugs such as tolbutamide are relatively short-acting (about 6 to 12 hours) while chlorpropamide has a prolonged action (over 24 hours).

Sulfonylurea therapy may be combined with metformin or other oral hypoglycaemics in patients who fail to respond to a single type of drug such combination therapy is usually tried (in the absence of contraindications) before considering the addition of, or transfer to, insulin therapy.

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In British, Japan, and US.

BP 2008 (Tolazamide). A white or almost white, odourless or almost odourless, crystalline powder. Very slightly soluble in water slightly soluble in alcohol soluble in acetone freely soluble in chloroform.

The United States Pharmacopeia 31, 2008 (Tolazamide). A white or off-white crystalline powder, odourless or having a slight odour. Very slightly soluble in water slightly soluble in alcohol soluble in acetone freely soluble in chloroform.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

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

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Tolazamide is slowly absorbed from the gastrointestinal tract, peak plasma concentrations occurring 4 to 8 hours after a dose by mouth, and is extensively bound to plasma proteins. It has a half-life of about 7 hours. It is metabolised in the liver to metabolites with some hypoglycaemic activity. About 85% of an oral dose is excreted in the urine, chiefly as metabolites.

Uses and Administration

Tolazamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of at least 10 hours and sometimes up to 20 hours. The usual initial dose is 100 to 250 mg daily given as a single dose with breakfast. Dosage may be increased if necessary at weekly intervals by 100 to 250 mg, usually to a maximum of 1 g daily no further benefit is likely to be gained with higher doses. Doses of more than 500 mg daily may be given in divided doses.

Preparations

British Pharmacopoeia 2008: Tolazamide Tablets

The United States Pharmacopeia 31, 2008: Tolazamide Tablets

Proprietary Preparations

USA: Tolinase

Drug Nomenclature

Profile

Vildagliptin is an inhibitor of the enzyme dipeptidylpeptidase-4, an enzyme responsible, among other roles, for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1 insulinotropin), which plays a role in regulating insulin secretion. Vildagliptin is used in the treatment of type 2 diabetes mellitus it may be added to metformin, a sulfonylurea, or a thiazolidinedione, when monotherapy with these is insufficient. It is given orally in a dose of 50 mg twice daily when given with metformin or a thiazolidinedione, and in a dose of 50 mg once daily in the morning when given with a sulfonylurea. A total daily dose of more than 100 mg of vildagliptin is not recommended, and in patients taking a combination of vildagliptin with a sulfonylurea, a dose of vildagliptin 100 mg daily is no more effective than vildagliptin 50 mg daily. Vildagliptin may be given with or without food.

Adverse effects of vildagliptin may include dizziness, headache, peripheral oedema, constipation, nasopharyngitis, upper respiratory-tract infection, and arthralgia. Rare cases of hepatic dysfunction, including hepatitis, have been reported. Vildagliptin should not be used in patients with hepatic impairment liver function should be tested before starting the drug, and monitored during therapy (every 3 months in the first year and periodically thereafter). Vildagliptin should be stopped if there is a persistent increase of 3 or more times the upper limit of normal in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or if the patient develops jaundice or other signs of liver dysfunction in such cases, it should not be restarted.

Preparations

Proprietary Preparations

Czech Republic: Galvus

France: Galvus

Portugal: Galvus

United Kingdom: Galvus

Multi-ingredient

Czech Republic: Eucreas

France: Eucreas

United Kingdom: Eucreas

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Adverse Effects and Precautions

Troglitazone has been associated with severe hepatic reactions, sometimes fatal, which has led to its withdrawal in most countries. Regular monitoring of liver function during therapy, and withdrawal of the drug in any patient who develops j aundice or signs of liver dysfunction, is required. It should not be given to patients with pre-existing moderate or severe elevations of liver enzyme values, or active liver disease. Increased plasma volume has been reported in healthy subjects given troglitazone: it should be used with caution in patients with heart failure. Other adverse effects reported in patients receiving troglitazone include dizziness, headache, fatigue, musculoskeletal pain, and nausea and vomiting. There is no evidence of hypoglycaemia associated with the use of troglitazone alone.

Effects on the liver. The UK CSM was aware of over 130 cases of hepatic reactions to troglitazone worldwide as of December 1997, although only 1 had been in the UK. There had been 6 deaths. The average time to the onset of the reaction was 3 months, but the frequency of these reactions, and the existence of risk factors predisposing to them, were unclear. The manufacturers had voluntarily withdrawn the drug in the UK. The US manufacturer and the FDA recommended a schedule for routine monitoring of liver function in November 1997 and revised this again in December 1997. It was estimated that 2% of patients treated with troglitazone would have elevated liver enzyme values necessitating discontinuation of the drug. The FDAhad received 560 reports of troglitazone-associated hepatotoxic-ity by June 1998. There were 24 cases of hepatic failure which were likely to have been caused by the drug 21 patients died and 3 patients received transplants. More intensive liver function monitoring recommendations were made by the US manufacturer again in July 1998 and in June 1999. Subsequently the manufacturer withdrew the drug in Australiaia, Japan, and the USA in March 2000. The clinical details of 94 cases of liver failure associated with troglitazone, which were reported to the FDA, have been reviewed.

Interactions

Troglitazone may enhance the hypoglycaemic effects of sulfonylureas dosage adjustment may be necessary. There is a possibility that troglitazone may enhance the metabolism of drugs metabolised by cytochrome P450 isoenzyme CYP3A4, including some oral contraceptives and terfenadine.

Ciclosporin. For the effect of troglitazone on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Colestyramine. Colestyramine markedly impaired the absorption of troglitazone.

Pharmacokinetics

Troglitazone is rapidly absorbed after oral doses, with peak plasma concentrations 1 to 3 hours after a dose. Bioavailability is about 53% absorption is markedly increased in the presence of food. In the body, troglitazone is more than 99% bound to plasma albumin. It is extensively metabolised in the liver and excreted largely in faeces as metabolites small amounts of metabolites are excreted in urine. Plasma elimination half-life ranges from 10 to 39 hours.

Uses and Administration

Troglitazone is a thiazolidinedione oral antidiabetic (see Rosiglitazone Maleate). It has been given orally for the treatment of type 2 diabetes mellitus although as mentioned above it has been withdrawn in most countries owing to hepato-toxicity.

Preparations

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

Australia: Rezulin¤; Japan: Noscal¤; Mexico: Rezulin; United Kingdom: Romozin¤; United States: Rezulin¤

1

Drug Approvals

(British Approved Name, rINN)

Pharmacopoeias. In China, Europe, International, Japan, and US.

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

The United States Pharmacopeia 31, 2008 (Tolbutamide). A white or practically white, practically odourless, crystalline powder. Practically insoluble in water soluble in alcohol and in chloroform.

Adverse Effects, Treatment, and Precautions

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

Thrombophlebitis with thrombosis has occurred after the intravenous injection of tolbutamide sodium, but this is usually painless and the vein gradually recovers. Rapid injection may cause a transient mild pain or sensation of heat in the vein.

The BNFhas suggested that tolbutamide 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.

Breast feeding. Tolbutamide is distributed into breast milk in relatively low quantities. The American Academy of Pediatricsstates that, although usually compatible with breast feeding, use of tolbutamide by breast-feeding mothers may possibly result in jaundice in the infant.

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

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Tolbutamide is readily absorbed from the gastrointestinal tract and is extensively bound to plasma proteins the half-life is generally within the range of 4 to 7 hours but may be considerably longer. Tolbutamide is metabolised in the liver by liydroxylation mediated by the cytochrome P450 isoenzyme CYP2C9. It is excreted in the urine chiefly as metabolites with little hypoglycaemic activity. Tolbutamide has been detected in breast milk.

Uses and Administration

Tolbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of about 10 hours.

The usual initial dose in type 2 diabetes mellitus may range from 1 to 2 g daily, given either as a single dose with breakfast or, more usually, in divided doses. Maintenance doses usually range from 0.25 to 2 g daily. Although it is unlikely that the response will be improved by increasing the dose further, daily doses of 3 g have been given.

Tolbutamide sodium (C₁₂H₁₇N₂Na0₃S = 292.3) has sometimes been used in the diagnosis of insulinoma as well as other pancreatic disorders including diabetes mellitus. The equivalent of 1 g of tolbutamide is given by intravenous injection as a 5% solution usually over 2 to 3 minutes. Tolbutamide sodium 1.08 g is equivalent to about 1 g of tolbutamide.

Preparations

British Pharmacopoeia 2008: Tolbutamide Tablets

The United States Pharmacopeia 31, 2008: Tolbutamide for Injection Tolbutamide Tablets.

Proprietary Preparations

Australia: Rastinon

Czech Republic: Dirastan

Denmark: Arcosal

Germany: Orabet Hong Kong Diatol

Israel: Orsinon

Mexico: Artosin Bioglusil Dabetil Diatelan Diaval Flusan Ifumelus Rastinon

New Zealand: Diatol

Poland: Diabetol

South Africa: Tydadex

Singapore: Tolmide

USA: Orinase; Orinase Diagnostic

Drug Approvals

(US Adopted Name, rINNM)

Profile

Like vildagliptin, sitagliptin is an inhibitor of the enzyme dipeptidylpeptidase-4, an enzyme responsible, among other roles, for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1 insulinotropin), which plays a role in regulating insulin secretion. It is used in the treatment of type 2 diabetes mellitus, as monotherapy or as dual therapy with metformin, a sulfonylurea, or a thiazolidinedione. Triple therapy using sitagliptin with metformin and a sulfonylurea may be given if dual therapy is inadequate. Sitagliptin is given as the phosphate, but doses are in terms of the base 128.5 mg of sitagliptin phosphate is equivalent to about 100 mg of sitagliptin. The usual oral dose is the equivalent of 100 mg of sitagliptin once daily, as monotherapy or in combination. When given with metformin in a combination preparation, sitagliptin may be given in 2 divided doses. The dose of sulfonylurea may need to be lowered when used with sitagliptin. Sitagliptin may be taken with or without food. Dosage should be adjusted in patients with renal impairment.

Adverse effects reported with sitagliptin include upper respiratory-tract infections, headache, and nasopharyngitis. Hypersensi-tivity reactions including anaphylaxis, angioedema, urticaria, rash, and Stevens-Johnson syndrome have also been reported.

Administration in renal impairment. US licensed product information suggests the following oral doses of sitagliptin in patients with renal impairment, based on creatinine clearance (CC):

• mild impairment (CC 50 mL/minute or more): no adjustment necessary, 100 mg daily

• moderate impairment (CC 30 to less than 50 mL/minute): 50 mg daily

• severe impairment (CC less than 30 mL/minute): 25 mg daily. It may be given without regard to the timing of haemodialysis

Preparations

Proprietary Preparations

Australia: Januvia

Brazil: Januvia

Czech Republic: Januvia Tesavel Xelevia

France: Januvia

Greece: Januvia Xelevia

Malaysia: Januvia

Mexico: Januvia

Portugal: Januvia Tesavel Xelevia

UK: Januvia

USA: Januvia

Multi-ingredient

USA: Janumet

Drug Approvals

(British Approved Name Modified, US Adopted Name, rINN)

Adverse Effects and Precautions

Rosiglitazone may cause hypoglycaemia, headache, weight gain, and anaemia. It may also cause dizziness, gastrointestinal disturbances, muscle cramps and myalgia, dyspnoea, paraesthesia, pruritus, and hypercho-1 esterolaemia. Very rarely angioedema and urticaria have been reported. Rosiglitazone can also increase the risk of bone fracture in women. Rosiglitazone can cause oedema, which may worsen or precipitate heart failure. It should therefore be used with caution in patients with oedema, and should not be used in those with a history of heart failure (see also below). Renal impairment may increase the risk of fluid retention and heart failure. There have been very rare reports of new onset and worsening diabetic macular oedema with decreased visual acuity (see Effects on the Eyes, below). There is some evidence to suggest that rosiglitazone might increase the risk of myocardial ischaemia until further data become available, UK licensed product information advises that rosiglitazone is not recommended in patients with ischaemic heart disease or peripheral arterial disease (see also below). Liver function should be monitored periodically as there have been isolated reports of liver dysfunction, and the drug should be used with caution in patients with hepatic impairment (see Effects on the Liver, below).

In women who are anovulatory because of insulin resistance, rosiglitazone therapy may result in a resumption of ovulation.

Effects on the bones. Use of thiazolidinediones such as pioglitazone or rosiglitazone has been associated with decreases in bone mineral density and increased risk of fractures in female patients. Analysis of data from a comparative study of glycaemic control with rosiglitazone, metformin, or glibenclamide involving 4360 randomised patients found that the risk of fracture in female patients in these 3 groups was 9.3%, 5.1%, and 3.5% respectively the risk in male patients was not significantly different in the 3 groups at around 3.4 to 3.95%. Analysis of data from another large ongoing study was also consistent with an increased fracture risk with rosiglitazone, and data from the manufacturer of pioglitazone involving over 8100 treated patients also revealed an increased risk of fracture in women given the drug the excess risk was calculated to be 0.8 per 100 patient years of use. The pattern of fractures seems to differ from that associated with postmenopausal osteoporosis, being mainly in the upper arm, hand, or foot, rather than hip or spine, but an observational study has suggested that thiazolidinedione use is associated with ongoing loss of whole-body bone mineral density.

Effects on the cardiovascular system. It has been suggested that, in addition to their hypoglycaemic effect, thiazolidinediones may have beneficial effects in the prevention of macrovascular diabetic complications, and there is some evidence that pioglitazone may improve some cardiovascular outcomes (see Diabetic Complications). However, a meta-analysis of 42 studies found that, compared with either placebo or other antidiabetic drugs, rosiglitazone was associated with a significant increase in the risk of myocardial infarction, and an increase of borderline significance in death from cardiovascular causes. There were limitations to this analysis as the studies were not primarily intended to examine cardiovascular outcomes, and many were small and short-term. Another meta-analysis that was restricted to 4 long-term studies (at least 12 months of treatment) that had specified an intention to evaluate cardiovascular adverse effects also found an increased risk of myocardial infarction with rosiglitazone use, without a significant increase in the risk of cardiovascular mortality.

Studies with no recorded cardiovascular events were excluded from the larger meta-analysis, and this has been questioned. An alternative analysis that incorporated these excluded studies, with appropriate analysis adjustment, found odds ratios for myocardial infarction and cardiovascular death that were not statistically significant, and concluded that neither increased nor decreased risk could be established.

In response to concerns raised by the initial meta-analysis, an unplanned interim analysis of an ongoing open-label study designed to assess cardiovascular outcomes has been published (rosiglitazone added to either metformin or a sulfonylurea compared with metformin plus a sulfonylurea) The data, however, were insufficient to determine whether there was an increased risk of myocardial infarction, and the findings were inconclusive regarding any effect on overall risks of hospitalisation or death from cardiovascular causes.

For the risks of heart failure associated with thiazolidinediones, see Effects on the Heart, below.

Effects on the eyes. The manufacturers in the USA and Canada (GSK) have received postmarketing reports of the development or worsening of diabetic macular oedema in patients treated with rosiglitazone-containing products in most cases the patients also reported peripheral oedema or fluid retention. In some cases visual impairment improved or resolved after stopping the drug. Rosiglitazone should be used with caution in patients with pre-existing diabetic retinopathy or macular oedema, and should be stopped, and ophthalmological consultation sought, if visual impairment develops while using the drug.

Effects on the heart. Both pioglitazone and rosiglitazone can cause peripheral and pulmonary oedema, which can worsen or precipitate heart failure a number of cases have been described. A large retrospective cohort study also found that the use of thiazolidinediones increased the risk of heart failure. The incidence of peripheral oedema with monotherapy has been reported to range from 3 to 5%, and this increases slightly when a thiazolidinedione is used with another oral antidiabetic. The incidence is about 15% when a thiazolidinedione is used with insulin. The incidence of heart failure is generally lower, but has been reported to be 2 to 3% when a thiazolidinedione is used with insulin however, a large prospective study, which was intended to examine the cardiovascular benefits of pioglitazone in preventing secondary macrovascular events in diabetic patients with pre-existing macrovascular disease, reported a 6% incidence of heart failure, compared with 4% in the placebo group. Mortality rates from heart failure did not differ between groups. These figures were confirmed on re-analysis.The American Heart Association and American Diabetes Association have recommended that patients with risk factors for heart disease or a depressed ejection fraction but without symptoms, and patients with NYHA class I or II heart failure, should start with a low dose of a thiazolidinedione that is only increased gradually as necessary and with careful monitoring. Patients with more severe heart failure (class III and IV) should not receive these drugs. These recommendations are reflected in US licensed product information. UK licensed product information contraindicates the use of pioglitazone or rosiglitazone in patients with heart failure or any history of heart failure, even of class I or II. For restrictions on combination therapy see Administration, below.

Effects on lipids. Rosiglitazone and pioglitazone have different effects on serum lipids.

Effects on the liver. Several cases of hepatotoxicity have been described in patients receiving rosiglitazone. Most of these occurred within a few weeks or months of starting rosiglitazone therapy. However, the causality of some of these cases has been debated’ because of coexisting disease and concomitant medication.

Licensed product information recommends that liver enzymes should be checked before starting therapy with rosiglitazone patients with aminotransferase (ALT) concentrations more than 2.5 times the upper limit of normal should not be given rosiglitazone. ALT concentrations should then be monitored periodically. If aminotransferase concentrations rise to more than 3 times the upper limit of normal and remain so after retesting then treatment with rosiglitazone should be stopped treatment should also be stopped if jaundice develops.

Fasting. For mention that glitazones can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Interactions

Gemfibrozil, ketoconazole, and trimethoprim, can increase plasma concentrations of rosiglitazone. Conversely, rifampicin can reduce rosiglitazone concentrations. These drugs should be given with caution to patients taking rosiglitazone, and glycaemic control should be monitored.

Use of NSAIDs or insulin with rosiglitazone may increase the risk of oedema and heart failure (see also Effects on the Heart, above, and Administration, below).

Antibacterials. Rifampicin significantly reduced the plasma concentration and elimination half-life of rosiglitazone in studies’ of healthy subjects, probably by induction of the cytochrome P450 isoenzyme CYP2C8. Conversely, trimethoprim can inhibit CYP2C8, and was found to increase the concentration and half-life of rosiglitazone modestly.’

Antifungals. In a study of healthy subjects, ketoconazole increased the plasma concentration and elimination half-life of rosiglitazone, probably by inhibition of the cytochrome P450 isoenzyme CYP2C8 and to a lesser extent CYP2C9

Lipid regulating drugs. Gemfibrozil increased the plasma concentration and about doubled the half-life of rosiglitazone in a study of healthy subjects, probably by inhibiting its metabolism. The authors suggested that these drugs should not be used together, or that the dose of rosiglitazone should be at least halved if gemfibrozil treatment is started.

Pharmacokinetics

Rosiglitazone is well absorbed from the gastrointestinal tract after oral dosing. Peak plasma concentrations occur within 1 hour and the bioavailability is 99%. It is 99.8% bound to plasma proteins. Rosiglitazone is extensively metabolised, almost exclusively by the cytochrome P450 isoenzyme CYP2C8. It is excreted in the urine and faeces, and has a half-life of 3 to 4 hours.

Uses and Administration

Rosiglitazone is a thiazolidinedione oral antidiabetic that improves insulin sensitivity and is used for the treatment of type 2 diabetes mellitus. It is usually given as rosiglitazone maleate but doses are expressed in terms of the base rosiglitazone maleate 1.32 mg is equivalent to about 1 mg of rosiglitazone. The potassium salt is used in some countries. Rosiglitazone is given orally as monotherapy, particularly in patients who are overweight and for whom metformin is contra-indicated or not tolerated. It may also be added to metformin, a sulfonylurea (or a combination of the two), or to insulin, when such therapy is inadequate (but see Administration, below). The usual initial dose is 4 mg daily, given in a single dose or two divided doses. The dose may be increased to a maximum of 8 mg daily if necessary after 8 to 12 weeks in patients receiving monotherapy or combination oral therapy. Rosiglitazone may be taken with or without food.

Administration. Although rosiglitazone is licensed for use with other antidiabetic drugs the specifics of licensing and use may vary from country to country. In both the UK and USA, rosiglitazone (Avandia GSK) is licensed for use with metformin or a sulfonylurea, or both if necessary, in patients in whom single or dual agent therapy is inadequate. In the UK, however, NICE recommends dual therapy only in patients who cannot be given combination therapy with metformin plus a sulfonylurea.The combination of rosiglitazone with insulin is now generally avoided because of an increased risk of heart failure and other cardiac adverse events (see also Effects on the Heart, above), although licensed product information may not necessarily contra-indicate the combination. In the UK, licensed product information for rosiglitazone warns that insulin should only be added to established rosiglitazone therapy in exceptional cases and under close supervision. In the USA, the combination of rosiglitazone and insulin is not recommended.

Inflammatory bowel disease. There is some evidence to suggest that drugs such as rosiglitazone that act as ligands to peroxisome proliferator-activated receptor y (PPARy) may offer a novel therapeutic approach to management of inflammatory bowel disease.

Polycystic ovary syndrome. Insulin resistance is a feature of polycystic ovary syndrome and the use of rosiglitazone is under investigation.

Preparations

Proprietary Preparations

Argentina: Avandia Diaben Gaudil Glimide Gliximina Gludex Rosiglit

Australia: Avandia

Belgium: Avandia

Brazil: Avandia

Canada: Avandia

Chile: Avandia

Czech Republic: Avandia

Denmark: Avandia

Finland: Avandia

France: Avandia

Germany: Avandia

Greece: Avandia

Hong Kong: Avandia

Hungary: Avandia

India: Rezult † Roglin Rosicon

Indonesia: Avandia

Ireland: Avandia

Israel: Avandia

Italy: Avandia

Malaysia: Avandia

Mexico: Avandia

The Netherlands: Avandia

Norway: Avandia

New Zealand: Avandia

Philippines: Avandia

Poland: Avandia

Portugal: Avandia

Russia: Avandia Roglit

South Africa: Avandia

Singapore Avandia

Spain: Avandia

Sweden: Avandia

Switzerland: Avandia

Thailand: Avandia

Turkey: Avandia

UK: Avandia

USA: Avandia

Venezuela: Avandia

Multi-ingredient

Argentina: Avandamet Gludex Plus Rosiglit-Met

Australia: Avandamet

Belgium: Avandamet

Canada: Avandamet

Chile: Avandamet

Czech Republic: Avaglim Avandamet

Denmark: Avandamet

Finland: Avandamet

France: Avaglim Avandamet

Germany: Avandamet

Greece: Avaglim Avandamet

Hong Kong: Avandamet

Hungary: Avaglim Avandamet

India: Glyroz Roglin-M Rosicon M †

Indonesia: Avandamet Avandaryl

Ireland: Avandamet

Israel: Avandamet

Italy: Avandamet

Malaysia: Avandamet

Mexico: Avandamet

The Netherlands: Avandamet

Norway: Avandamet

Philippines: Avandamet

Poland: Avandamet

Portugal: Avaglim Avandamet

Singapore: Avandamet

Spain: Avandamet

Sweden: Avandamet

Switzerland: Avandamet

Thailand: Avandamet

UK: Avandamet

USA: Avandamet Avandaryl

Venezuela: Avandamet

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Repaglinide). A white or almost white powder. It exhibits polymorphism. Practically insoluble in water freely soluble in dichloromethane and in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Repaglinide). A white to off-white solid. Solubleinme-thyl alcohol. Store in airtight containers.

Adverse Effects and Precautions

Repaglinide may cause gastrointestinal adverse effects including abdominal pain, diarrhoea, constipation, nausea, and vomiting. Hypoglycaemia (usually mild), back and joint pain, hypersensitivity reactions including pruritus, rashes and urticaria, and elevated liver enzyme values may occur. There have been rare cases of transient visual disturbances attributed to changes in blood glucose concentrations associated with starting repaglinide treatment. There have also been rare reports of myocardial infarction in patients who were treated with repaglinide and isophane insulin the combination is not recommended.

Precautions are similar to those which apply with the shorter-acting sulfonylurea hypoglycaemics. Repaglinide should be given with caution to patients with hepatic impairment (consideration should be given to extending the interval between doses), and possibly avoided in severe impairment.

Effects on the liver. Hepatotoxic reactions have been reported for repaglinide’ including cholestatic hepatitis and jaundice with pruritus.

Fasting. For mention that nateglinide or repaglinide can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Hypoglycaemia. Mild hypoglycaemia has been reported in patients receiving repaglinide, although in a study comparing flexible repaglinide dosing with frxed glibenclamide dosing, all hypoglycaemic events recorded were in the glibenclamide group.Other studies have found rates of hypoglycaemia in patients receiving repaglinide to be less than, or similar to, sulfonylureas.The risk of hypoglycaemia may be reduced as patients can omit a dose of repaglinide if a meal is missed.

Pregnancy. Insulin is generally preferred to oral antidiabetics in the treatment of diabetes mellitus during pregnancy. Repaglinide has been used in 3 women during the first 6 to 7 weeks of gestation treatment was then changed to insulin for the rest of the pregnancy. Their babies were delivered at term, with adequate weight for birth age and no congenital malformations.

Interactions

As with other oral antidiabetics, the efficacy of repaglinide may be affected by drugs independently increasing or decreasing blood glucose concentrations (see Sulfonylureas).

Drugs that affect the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 may alter the metabolism of repaglinide. Use of repaglinide with the CYP2C8 inhibitor gemfibrozil has resulted in marked reduction in repaglinide clearance, and severe hypoglycaemia UK licensed product information contra-indicates concomitant use.

Antibacterials. A study in healthy subjects found that the plasma concentration of a single dose of repaglinide was reduced, and its half-life shortened, when it was given 12.5 hours after the last dose of a 5-day course ofrifampicin. This effect was attributed to the induction of the cytochrome P450 isoenzyme C YP3A4 by rifampicin. In another study repaglinide was given either with the last dose of a 7-day course of rifampicin or 24 hours later, and the effects on repaglinide were found to be greater on day 8 than day 7. The authors suggested that rifampicin acted as both an inducer and an inhibitor of C YP3 A4 and possibly C YP2C8, and that after rifampicin was stopped its inductive effect lasted longer, thereby having a greater effect 24 hours later. A study in healthy subjects reported that clarithromycin can increase the plasma concentrations and prolong the elimination half-life of repaglinide, probably by inhibition of CYP3A4. Telithromycin, another inhibitor of CYP3A4, also increased plasma concentrations of repaglinide in a study of healthy subjects, although the elimination half-life of repaglinide was not significantly affected. Trimethoprim can have a similar effect by the inhibition of CYP2C8.

For a report of hypoglycaemia when gatifloxacin was given to a patient already receiving repaglinide.

Ciclosporin. Ciclosporin markedly increased plasma concentrations of repaglinide in healthy subjects there is a possibly increased risk of hypoglycaemia if these 2 drugs are taken together.

Grapefruit juice. Grapefruit juice increased the bioavailability of repaglinide in a study of healthy subjects. The half-life of repaglinide was not affected, suggesting that grapefruit juice inhibited its presystemic metabolism by the cytochrome P450 isoenzyme CYP3A4 in the gut wall. Blood-glucose concentrations were not affected.

Lipid regulating drugs. A study in healthy subjects found that gemfibrozil significantly increased the plasma concentrations of repaglinide and enhanced and prolonged its glucose-lowering effect. Use of this combination should be avoided. Another study in healthy subjects found, however, that repaglinide was not affected by bezafibrate or fenofibrate.

Pharmacokinetics

Repaglinide is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 hour. The mean bioavailability is about 60%. Repaglinide is highly bound to plasma proteins, and has a plasma elimination half-life of about 1 hour. It undergoes almost complete hepatic metabolism involving the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. The metabolites, which are inactive, are excreted in the bile. Higher plasma concentrations and prolonged half-life of repaglinide may occur in patients with renal impairment (creatinine clearance less than 40 mL/minute) or chronic liver disease.

Uses and Administration

Repaglinide is a meglitinide antidiabetic used for the treatment of type 2 diabetes mellitus. It has a chemical structure different from that of the sulfonylureas, but appears to have a similar mode of action. Repaglinide is given up to 30 minutes before meals, in usual initial oral doses of 0.5 mg initial doses of 1 or 2 mg are usually given to patients who have had previous hypoglycaemic treatment. The dose maybe adjusted, at intervals of 1 to 2 weeks, up to a maximum of 4 mg before meals a total of 16 mg daily should not be exceeded. Repaglinide is also given with metformin or a thiazolidinedione in type 2 diabetes not adequately controlled by monotherapy.

Administration in renal impairment. Although repaglinide is cleared mainly by hepatic metabolism, small pharmacokinetic studies have reported that exposure to repaglinide may be increased in patients with renal impairment. A larger open-label study that included 151 patients with normal renal function and 130 patients with varying degrees of renal impairment found that the incidence of adverse effects was not influenced by renal function. However, at the end of the 3-month maintenance treatment period, there was a trend towards lower effective doses of repaglinide with increasing degree of renal impairment.

Preparations

The United States Pharmacopeia 31, 2008: Repaglinide Tablets.

Proprietary Preparations

Argentina: Glukenil NovoNorm Sestrine

Australia: NovoNorm

Austria: NovoNorm

Belgium: NovoNorm

Brazil: Gluconorm NovoNorm Prandin

Canada: Gluconorm

Chile: Hipover NovoNorm

Czech Republic: NovoNorm Prandin

Denmark: NovoNorm

Finland: NovoNorm

France: NovoNorm

Germany: NovoNorm

Greece: NovoNorm

Hong Kong: NovoNorm

Hungary: NovoNorm

India: Rapilin

Ireland: NovoNorm

Israel: NovoNorm

Italy: NovoNorm

Malaysia: NovoNorm

Mexico: NovoNorm

The Netherlands: NovoNorm Prandin

Norway: NovoNorm

New Zealand: NovoNorm

Philippines: NovoNorm

Poland: NovoNorm

Portugal: NovoNorm Prandin

Russia: NovoNorm

South Africa: NovoNorm

Singapore: NovoNorm

Spain: NovoNorm Prandin

Sweden: NovoNorm

Switzerland: NovoNorm

Thailand: NovoNorm

Turkey: NovoNorm

UK: Prandin

USA: Prandin