Antidiabetic Drugs

Archive for the ‘Drugs’ Category

Antidiabeticos biguanfdicos

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.

(British Approved Name, rINN)

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

(British Approved Name, US Adopted Name, rINN)

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.

Drug Approvals

(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.

Drug Approvals

(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.

Drug Approvals

(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.

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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

Drug Approvals

(US Adopted Name, rINN)

INNs in other languages:

Adverse Effects and Precautions

As for Repaglinide.

Overdosage. A blood-glucose concentration of 2.0 mmol/litre was measured 1 hour after ingestion of nateglinide 3.42 g in a 30-year-old woman. She was able to walk unaided, but seemed drowsy. The hypoglycaemic effect of nateglinide lasted for 6 hours and was treated with intravenous glucose (total dose 100 g).

Renal impairment. A single-dose pharmacokinetic studyfound that moderate to severe renal impairment (creatinine clearance 15 to 50 mL/minute per 1.73 m) and haemodialysis did not significantly affect the pharmacokinetics of nateglinide. However, the metabolite Ml has been found to accumulate in patients with renal impairment requiring haemodialysis after repeated doses of nateglinide, but it may be removed by haemodialysis. M1 is a maj or metabolite that has modest hypoglycaemic activity compared with nateglinide. An analysis of pooled study data found that efficacy and tolerability of nateglinide in elderly diabetic patients were not significantly affected by renal impairment (mean creatinine clearance 50.9 mL/minute per 1.73 m). Nevertheless, a 56-year-old diabetic woman whose renal failure was managed with haemodialysis experienced severe hypoglycaemia with nateglinide the reaction was attributed to the accumulation of M1 Licensed product information in the UK and USA suggest that no dosage adjustment is necessary in renal impairment, although UK information suggests that dose adjustment might be required in patients on haemodialysis.

Interactions

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

Antibacterials. In a study of healthy subjects, rifampicin reduced the plasma concentrations and half-life of nateglinide, probably by induction of its metabolism by the cytochrome P450 isoenzyme CYP2C9. The glucose-lowering effect of nateglinide was not affected, but there was a marked interindividual variation in the pharmacokinetic changes, and the authors suggested that some diabetic patients could be affected.

Antifungals. In a study of healthy subjects, fluconazole raised the plasma concentrations and prolonged the half-life of nateglinide, probably by inhibition of its metabolism by the cytochrome P450 isoenzyme CYP2C9. The glucose-lowering effect of nateglinide was not affected, but a low dose of nateglinide had been used and the authors suggested that in diabetic patients fluconazole may enhance and prolong the effects of nateglinide.

Lipid regulating drugs. A study investigating the effects of the gemfibrozil and itraconazole combination on the pharmacokinetics of nateglinide showed only a limited interaction. Nateglinide plasma concentrations were raised moderately and the blood glucose response to nateglinide was not significantly changed. This is in contrast to the substantial interaction of gemfibrozil with repaglinide.

Pharmacokinetics

Nateglinide is rapidly absorbed after oral doses, with peak plasma concentrations occurring within one hour and an absolute bioavailability of 73%. Nateglinide is 98% bound to plasma proteins. It is mainly metabolised by cytochrome P450 isoenzyme CYP2C9, and to a lesser extent by CYP3A4. Major metabolites include Ml which is less potent than nateglinide. The parent drug and metabolites are mainly excreted in the urine but about 10% is eliminated in the faeces. The elimination half-life is about 1.5 hours.

Uses and Administration

Nateglinide, like repaglinide, is a meglitinide antidiabetic used in the treatment of type 2 diabetes mellitus. It is given within the 30 minutes before meals in oral doses of 60 or 120 mg three times daily. This may be increased to 180 mg three times daily if necessary. Nateglinide is also given in similar doses with metformin or a thiazolidinedione in type 2 diabetes not adequately controlled by these drugs alone. Although dose adjustment is not generally required in renal impairment, hypoglycaemia has been attributed to accumulation of the metabolite M1 (see above).

Preparations

Proprietary Preparations

Argentina: Nateglin Starlix

Brazil: Starlix

Canada: Starlix

Chile: Gluconol Starlix

Czech Republic: Starlix Trazec

Denmark: Starlix †

Finland: Starlix

Germany: Starlix

Greece: Starlix

Hong Kong: Starlix!

Hungary: Starlix

India: Glinate

Indonesia: Starlix

Ireland: Starlix

Japan: Starsis

Malaysia: Starlix

Mexico: Starlix

The Netherlands: Starlix Trazec

Norway: Starlix

New Zealand: Starlix †

Philippines: Starlix

Portugal: Starlix Trazec

Russia: Starlix

South Africa: Starlix

Singapore: Starlix

Spain: Starlix

Sweden: Starlix

Switzerland: Starlix

Turkey: Starlix

UK: Starlix

USA: Starlix

Multi-ingredient

Brazil: Starform

Venezuela: Starform

Repaglinide

Brand Name Drug: Prandin in the U.S., GlucoNorm in Canada, NovoNorm elsewhere

Benzoic acid derivatives are the most recent addition to the list of treatment options for type 2 diabetes. In 1998, the FDA approved the first agent in this class, repaglinide. Benzoic acid derivatives are similar to sulfonylureas in that they are insulin secretagogues. However, they differ in that they bind to a different receptor on the beta cell membrane. Also, in contrast to sulfonylureas, benzoic acid derivatives do not cause direct exocytic insulin release in the absence of glucose stimulation.

The true benefit of these agents stems from the fact that they have a short duration of action. Repaglinide is administered just before the start of the meal and stimulates insulin secretion. However, the duration of action is much shorter than the sulfonylureas, and the main effect is to reduce postprandial hyperglycemia. Due to the short half-life, repaglinide is useful in patients who have erratic meal schedules.

The main advantage of repaglinide is the potential for decreased incidence of hypoglycemia, making it an effective agent in elderly patients and those with renal insufficiency or other predisposition to hypoglycemia. It is given only at the meal time in 1-mg and 2-mg tablets. Most patients are started on 0.5 mg prior to meals. It often is useful to initially monitor pre- and one-hour postprandial fingerstick glucoses to assess the effects of this agent.

Conclusion

Much of the benefit from tight control in patients with type 1 diabetes has now been extrapolated to the much larger group of patients with type 2 diabetes. Recent data have shown that tight control of type 2 diabetes is strongly associated with a decreased incidence and rate of progression of microvascular complications. Multiple new oral agents recendy have been developed for the treatment of this disorder. Effective use of these agents by physicians is imperative in controlling this disease and preventing or delaying acute and chronic complications in African Americans. It is important to remember that these new agents are relatively ineffective without proper dietary counseling and increased physical activity. In addition to glycemic control, treatment of hypertension and hyperlipidemia will also result in significant decreases in micro- and macrovascular disease in individuals with type 2 diabetes.

Comprehensive screening also is essential as it is estimated that 50% of Americans with the disease are unaware of their illness. The ADA now recommends testing of fasting glucose every three years for all adults >45 years. For higher risk groups, such as African Americans and those with a history of gestational diabetes, screening is recommended on a yearly basis. Those patients with a fasting glucose >126 mg/dL must receive proper dietary and exercise instruction as well as diabetic teaching about the importance of foot care and home glucose monitoring. These measures combined with the effective use of pharmacologic agents in those who fail conservative therapy will improve the control of the type 2 diabetes epidemic in the black community.

Thiazolidinediones were developed in Japan and have been available in the United States since March 1997. Today, more than 600,000 people in the United States are being treated with troglitazone. Until recently, troglitazone was the only available member of this group.

Troglitazone

Brand Name Drug: Rezulin, Resulin or Romozin

Troglitazone has been shown to improve peripheral insulin sensitivity (ie, increase peripheral glucose disposal) by an as yet undetermined mechanism. We do know that the drug binds to an intranuclear receptor (PPARgamma), and this complex has been found to function as a transcriptional activator. How PPARgamma activation by troglitazone results in improved insulin sensitivity is not clear.

Troglitazone comes in 200-mg and 400-mg tablets, and patients are started at 200 mg in the morning with food to aid in rapid absorption. Thereafter, the dose can be increased to 400 mg/day and eventually to the maximum of 600 mg/day. The tablets should be given once in the morning, as there is no advantage to dividing the dose.

Troglitazone was initially proven effective in type 2 diabetic patients who already were being treated with insulin. In 1998, troglitazone was approved by the FDA for use as monotherapy in the treatment of type 2 diabetes. Studies in patients already receiving insulin therapy have shown a significant improvement in HgbA₁C and a reduction in insulin requirements. A 1.5% reduction in HgbA₁C has been reported when troglitazone is added to conventional insulin therapy. Monotherapy has been less effective, with an average decrease in HgbA₁C of .9%. Whether used as single or combination therapy, there is a lag time of several weeks for troglitazone to have a glucose-lowering effect and a delay of several months for maximum glucose lowering effect. The drug is not effective in those patients with relative insulinopenia. It is important to use clinical judgment in determining which patients with type 2 diabetes have significant insulin resistance with hyperinsulinemia and therefore are better candidates for troglitazone therapy. Significant reduction in HgbA₁C recently has been shown when troglitazone is used in combination therapy with glyburide or metformin.

Adverse effects range from mild peripheral edema and weight gain to recendy reported cases of florid hepatic failure. Weight gain can be seen in many patients, likely secondary to increased insulin sensitivity and improved glycemic control. The cases of hepatotoxicity are more concerning and recendy were detailed in Annals of Internal Medicine. In the initial clinical studies, troglitazone was associated with mild increases in liver function tests (1.9% compared with .6% for placebo) and reversible jaundice. However, there have been at least five cases of troglitazone-induced hepatotoxicity and death in the United States since the drug’s release in 1997.

Despite these events, the incidence of liver disease is rare, and troglitazone remains a useful weapon against type 2 diabetes, particularly in those with significant insulin resistance. The FDA now recommends that patients undergo monitoring of their liver function tests (LFTs) on a monthly basis for the first eight months of use. Over the next four months, LFTs can be monitored every other month and then periodically thereafter. Troglitazone should be stopped with any evidence of significant hepatic impairment or a threefold rise in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.

Recendy, two additional thiazolidinediones have become available. It is hoped that rosiglitazone and pioglitazone will have many of the same insulin-sensitizing effects as troglitazone without the risk of hepatic injury.