Extract from the South African Medicines Formulary

Transcription

1 Extract from the South African Medicines Formulary Understanding the Relevance of monograph entries and Interpreting their Applications to drug therapy As Applied to the Learning Example of Patient Case Xolile Mguni When you work through Xolile Mguni s case please make sure that you refer to this earlier monograph extract as your source reference. The reason for this is because this case study was compiled based on the clinical content of the monograph on Drugs in Diabetes in the 9 th edition of the SAMF. As with any medicines formulary, the content of this monograph has been updated in subsequent editions (10 th and 11 th ) of the SAMF. Therefore, for the sake of consistency it is more practical for all practitioners to use the same reference source to complete this learning exercise. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 1

2 A10 DRUGS USED IN DIABETES A10A InsuIins and analogues A10B Blood glucose lowering drugs, excluding insulins A10BA Biguanides A10BB Sulphonamides, urea derivatives A10BD Combinations of oral blood glucose lowering drugs A10BF Alpha glucosidase inhibitors A10BG Thiazolidinediones A10BH Dipeptidyl peptidase IV inhibitors A10BX Other blood glucose lowering drugs excluding insulins Clinical notes: Diabetes mellitus Management of diabetic ketoacidosis Insulin therapy Table: Approximate expected time-actions of the insulin preparations available. Diabetes mellitus Diabetes mellitus is a chronic metabolic disorder. It is characterized by an absolute or relative deficiency of insulin, often associated with peripheral insulin resistance. This results in impaired transport of carbohydrates into the cells in the presence of hyperglycaemia. Catabolism of other energy sources results, so that free fatty acids and amino acids are derived from fats and proteins, gluconeogenesis is increased and, if insulin deficiency is severe, ketogenesis prevails. There are two chief types: Type 1 classically an autoimmune disease characterised by beta-ceil destruction and consequent insulinopenia. If not treated, ketoacidosis occurs. Incidence is mostly in juveniles, but may occur in adults. Lifelong insulin therapy is required. Type 2 a heterogeneous disorder characterised by insulin resistance and a relative deficiency of insulin. It occurs predominantly in obese adults and is becoming more frequent in obese juveniles, with a strong family history. Many patients can be controlled by careful attention to diet, exercise and lifestyle. However, recent guidelines suggest that all patients unless there are contraindications, should receive metformin at diagnosis, combined with strict diet, exercise and lifestyle modification. The addition of other oral antidiabetic agents will depend on whether successful control of blood glucose is achieved. Patients ultimately may require insulin to maintain glycaemic control. In type 2 diabetes insuiin is indicated: * in presence of trauma or severe infection; * in event of ketoacidosis; * usually during pregnancy; * in patients with severely impaired renal or hepatic, function; * when hyperglycaemia does not respond to diet; exercise and oral antidiabetic agents alone, and should be considered earlier rather than later, once HbA1c > 7.5%. This often occurs within a few years after the initial diagnosis, due to progressive insulin deficiency. In adults marked unexpected weight loss in suspected type 2 diabetes suggests that the patient has type 1 and not type 2 diabetes. In selected cases auto-immune markers of type 1 diabetes i.e. insulin autoantibodies (laa), polyclonal autoantibodies (lca) and glutamic acid decarboxylase autoantibodies (anti-gad) may be required to effect a specific diagnosis. Treatment in these cases should be insulin. Latent Autoimmune Diabetes of Adulthood (LADA), or type 1.5 diabetes, occurs in 5-10% of adults who present with diabetes. Conversely, rare monogenic forms of type 2 diabetes may present in young adults as non-insulin-dependant diabetes in the young (NIDDY) or maturity onset diabetes of the young (MODY). Aims of therapy: * The aims of therapy need to be individualised. * The short-term aims are to relieve symptoms, overcome ketoacidosis and catabolism, and restore nutrient reserves and natural resistance to infection. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 2

3 * Long-term aims include attempts to improve life expectancy, to avoid vascular complications affecting quality of life, e.g. blindness, gangrene, renal failure, and to prevent infection, including the reactivation of tuberculosis. * There is clear evidence that improved glycaemic control reduces the risk of microvascular complications (retinopathy, neuropathy, and nephropathy) in both type 1 and type 2- diabetes. * There is also evidence of a 'legacy effect' of improved glycaemic control on macrovascular complications and mortality. * When tight glycaemic control is coupled with the management of other-components of the metabolic syndrome, including obesity, dyslipidaemia and hypertension, there is also good evidence that the macrovascular complications can be reduced. * Hypoglycaemia due to over-treatment with antidiabetic agents is a frequent and serious problem in the older patient - for this reason, the aim in this group may be to keep random blood glucose levels slightly above the normally desired range. Special Prescribers Points * In all diabetics, dietary modification and exercise is the cornerstone of diabetic management. * Drugs for co-morbid illnesses should be carefully selected - the disadvantageous effects of agents such as thiazide or loop diuretics and * glucocorticosteroids should be considered as they all lead to glucose intolerance. * Beta blockers may mask the symptoms of hypoglycaemia, and new evidence suggests that they may cause glucose intolerance especially in combination with thiazide diuretics. * The atypical neuroleptics e.g. olanzapine, may increase the risk of glucose intolerance and should be used with caution in patients with diabetes mellitus and metabolic syndrome. * Pregnant diabetic patients should be managed by specialists or specialist centres if possible. Patient advice: * An 'alert' disc is a sensible precaution and should be worn at all times. * Patients should be encouraged to participate actively in the management of their diabetes; it is essential that they be given a clear understanding of the disease and its management. * Instructions on the correct use of insulin (or oral antidiabetic agents), syringes, and urinary and blood glucose monitoring equipment, must be clear. * Patients (and their families or friends) should be advised of the symptoms and treatment of hypoglycaemia and the importance of prompt action should be emphasised. (See section H04, page 268.) * The importance of individual diet and exercise and their roles in overall diabetic control should be emphasised. * Advice should be given on personal hygiene; especially foot care, the risk of smoking and, the danger of alcohol abuse. * Ophthalmological and oral/dental examinations are indicated at yearly intervals, * The importance of snacks to prevent hypoglycaemia should be emphasised. Management of diabetic ketoacidosis Treatment should always be carried out in a hospital setting as the mortality is 5-10%. It involves the administration of intravenous fluids and insulin, and the correction of accompanying electrolyte disturbances. Treat precipitating causes like infection or myocardial infarction. * Gastric dilatation often occurs and the placement of a nasogastric tube is always required in patients with a suppressed level of consciousness to prevent aspiration. * A urinary catheter should be inserted to measure urine output if the patient is in a coma: Intravenous fluids: Begin with 0.9% sodium chloride solution to rapidly restore intravascular volume and replace with 0.45% sodium chloride solution if the plasma sodium concentration exceeds 145 mmol/l. Adults: 1.5 L during the-first hour, 1 L during the second hour, and then 0.5 L/hour. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 3

4 Children: 15 ml/kg during the first and second hours and 5-8 ml/kg/hour thereafter. When hydration is normal, maintenance administration should be adjusted. Insulin: The IV route is preferred; absorption from IM injection sites may be slow and/or erratic if the patient is shocked. Adults: A short-acting Insulin, 6-10 units, is given immediately as an intravenous bolus and then 5-6 units/hour by continuous IV infusion (or 1M when facilities for infusion are not available). Children: Initially, 0.2 units/kg followed by 0.1 unit/kg/hour. * Blood glucose should be tested hourly and the infusion adjusted accordingly. Also, blood ketones should be measured. Aim to reduce blood glucose by 0.5 mmol/l/hour. * The insulin infusion should be continued until ketones have been cleared. Dextrose should be added to the hydration fluid (i.e. 5% dextrose in 0.45% sodium chloride solution) when blood glucose falls below 15 mmol/l. This allows continued insulin administration until ketonemia is controlled and should only be stopped once the first injection of SC insulin has been administered and metabolic control is achieved. * Acid-base balance and electrolytes should be determined. The serum potassium concentration should be maintained between 4 and 5 mmol/l. Add potassium chloride (20 mmol potassium) to the first litre of fluid, unless the patient is anuric. Then add potassium according to the plasma potassium level: < 3.5 mmol/l - add 40 mmol/l mmol/l add 20 mmol/l > 5.0 mmol/l - no addition of potassium INSULINS AND ANALOGUES In South Africa, all varieties of insulin are biosynthetic (produced by using recombinant DNA technology), and consist of the human molecular structure. Only a single strength, 100 units/ml is available. Insulins differ in their duration of action; preservative content, and buffering and retarding additives. The table below indicates approximate expected time-actions of the different preparations available Ultra fast-acting Insulin analogues:..description of properties and uses.. Fast-acting insuiins:..description of properties and uses.. Intermediate- to long-acting Insulins..Description of properties and uses.. Biphasic Insulins:..Description of properties and uses.. Long-acting Insulin analogues..description of properties and uses.. * A particular insulin preparation, no matter how it is classified, can show wide variation of activity in a population of patients, as well as in a single patient, especially patients with labile diabetes. * The onset and duration of action are also affected by the volume administered and the site and depth of injection. Longer needles are indicated for obese patients. * Avoid injecting in same site i.e. sites must be rotated regularly. * Massaging the site can increase absorption by 10-20%. * The time of injection prior to food intake is critical when conventional short-acting insulins are employed. * Patients already controlled on a specific insulin should not be changed to alternative preparations unless for good medical reason, e.g. if improved metabolic control is sought (there may be obscure differences in individual responses to some of the preparations. Insulin Therapy The majority of patients with type I diabetes present classically with polyuria, polydipsia and Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 4

5 weight loss. Investigation shows hyperglycemia, glycosuria and ketonuria. If not diagnosed early, they may present with ketoacidotic coma. Once over the initial period of ketoacidosis, an insulin regimen has to be chosen. This regimen should mimic normal blood insulin levels as tar as possible, should preferably provide adaptability, and must fit the needs of the individual and suit the patient's circumstances. The initial requirements may be calculated on a unit/kg basis ( units/kg/day), and adjusted according to the patient's response. Insulin regimens 1. Twice-daily injections of a mixture of a shortacting and an intermediate-acting insulin is the most commonly used regimen. Patients who are unable to mix their own insulins because of poor eyesight or a lack of understanding may be given premixed, fixed combination short- and intermediate-acting insulii1g (biphasic insulins). Two-thirds of the daily dose of insulin is given approximately 30 minutes before breakfast and one-third before supper. Where the above regimen leads to lateevening and midnight hyperinsulinaemia with resultant hypoglycaemia between midnight and 03h00, the intermediate-acting insulin dosage before supper may be reduced to counteract this phenomenon if patients are self-mixing. Early morning hyperglycaemia may occur, indicating early morning insulin deficiency. Patients may thus be better controlled by dividing the evening dose, injecting the short-acting insulin before supper and the intermediate insulin at bedtime (about 22h30), together with a snack. 2. A once-daily injection of an intermediateacting insulin may be sufficient in elderly type 2 diabetics inadequately controlled on oral agents alone. A dose before bed may be combined with oral hypoglycaemic agents, if use of the latter alone is inadequate to provide adequate glycaemic control. 3. The following flexible regimen, the 'basalbolus regimen', provides good control in wellmotivated patients with a proper understanding of the disease. Approximately 50% of the daily dose is given as 3 preprandial short-acting insulin injections, and 50% as long/intermediate-acting insulin at bedtime. If the ultrafast, shorter-acting insulin analogues are used for the bolus component, the basal insulin may need to be divided into two doses of intermediate-acting insulin, or one dose of a long-acting analogue. 4. Continuous subcutaneous infusions may be indicated in specialised situations. Insulin (SA EDL: Primary) Indications: Treatment of type I diabetes mellitus; supplement in type 2 diabetes mellitus. Pharmacokinetics: See table on page 71. With soluble insulin, plasma T ½ = minutes whereas biological T ½ = a few hours. Metabolism is mainly in the liver, but also in the kidneys and in muscle. Contraindications: Hypoglycaemia. Cautions: Pregnancy: Category B. Insulin is the agent of choice for the control of diabetes during pregnancy in both type 1 and type 2 diabetics; doses may require adjustment. Lactation: Insulin is not excreted in breast milk. Drug interactions: Oral-contraceptives, diuretics (thiazide and loop) and corticosteroids: Glucose tolerance may be decreased and insulin requirements thus possibly increased. Alcohol, salicylates and MAOIs: The hypoglycaemic effect of insulin is potentiated. Beta-blocking agents: The interference of propranolol (and possibly others) with carbohydrate metabolism poses risks of hypoor hyperglycaemia; monitor insulin requirements closely. All beta blockers have the potential to mask signs and symptoms of hypoglycaemia. Adverse effects: Lipohypertrophy may result from repeated injection in the same site; it may be prevented by frequently changing the injection site. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 5

6 Rare allergic localised skin reactions as well as generalised allergic reactions; atrophy of subcutaneous fat tissue. 'Insulin oedema' has been described in some patients after initiation of therapy. This is usually self-limiting, subsides spontaneously and does not require diuretic therapy. * Insulin requirements may be increased in the presence of infection and at the time of surgery or trauma. * Insulin requirements are generally decreased in severe liver disease or renal impairment. * Where the active ingredient is in suspension, the vial must be gently mixed before use. * Freezing of preparations should be avoided. Adult dose: Daily doses are determined by individual requirements. Diabetic ketoacidosis: See text on page 70. Paediatric dose: Dosage determined according to patient size and requirements. Available in 10 ml vials, disposable pens (penset), or cartridges (for use in pens). Ultra fast-acting Insulin analogues S3..List of Branded Products Fast-acting insuiins:..list of Branded Products Intermediate- to long-acting Insulins:..List of Branded Products Biphasic Insulins:..List of Branded Products Long-acting Insulin analogues..list of Branded Products BLOOD GLUCOSE LOWERING DRUGS, EXCLUDING INSULINS Lifestyle modification underpins the management of type 2 diabetes. Metformin should be commenced simultaneously with strict lifestyle intervention. The prescriber should not encourage a false sense of reliance on medication only; patients are often inclined to believe that the drug will allow them much latitude in their lifestyle (including dietary) approaches to the management of their disorder. It should be borne in mind that the type 2 diabetic, poorly controlled despite lifestyle and oral agents, is likely to be best treated with insulin, either alone or in combination with oral agents, titrated against regular testing. BIGUANIDES The mechanism of action of the biguanides is to reduce hepatic gluconeogenesis and promote the uptake and utilisation of glucose, e.g. in muscle, although for this to occur the presence of some endogenous insulin is required. The biguanides are agents of first choice in the management of type 2 diabetics, but the small risk of lactic acidosis demands that they be used with caution. Risk factors for lactic acidosis include: impaired renal or hepatic function, cardiopulmonary insufficiency, presence of infections, excessive alcohol intake, certain ARVs and certain systemic illnesses, e.g. leukaemia. Metformin is useful in management of obese diabetics because it induces a mild anorexia and so helps to control weight gain. It is frequently used in combination with an insulin secretagogue to provide better control. Thus, when monotherapy with metformin fails to achieve the individualized glycaemic targets, an insulin secretagogue, initially in small doses, is added. Metformin has been shown to improve insulin sensitivity in patients with polycystic ovarian syndrome (unregistered indication). This may lead to resumption of ovulation and improvement in ability to conceive. Recent data suggest that it has a mortality benefit in patients with CCF. Metformin (SA EDL Primary drug) Indications: See notes above. Pharmacokinetics: Partially absorbed orally, bioavailability, about 50%. T ½ = hours; prolonged in renal impairment. Elimination is mainly in urine as unchanged drug. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 6

7 Contraindications: Renal impairment (GFR < 10 ml/min or creatinine > 130 mcmol/l), hepatic dysfunction, recent myocardial infarction or cardiac failure, cardiopulmonary insufficiency, alcoholism, pancreatitis; during surgery and the postoperative period; patients predisposed to lactic acidois; brittle or unstable diabetes, diabetes complicated by ketosis, acidosis and coma. Cautions: Geriatrics: May be used with caution in obese elderly diabetics provided hepatic, renal and cardiac function is not deranged. Paediatrics: Contraindicated. Pregnancy: Category B Relative contraindication. A number of trials have shown safety during pregnancy in either preexisting or gestational diabetes, however insulin remains the treatment of choice. Lactation: Little data available on distribution in breast milk; the risk-benefit should be considered. Drug interactions: Alcohol: Increased risk of lactic acidosis. Agents that impair glucose tolerance, e.g. thiazide diuretics, furosemide, glucocorticosteroids, and oral contraceptives: A diminished glycaemic improvement may result. Sulphonylureas: Increased risk of serious and prolonged hypoglycaemia; care should be taken to avoid hypoglycaemia. Adverse effects: Gastrointestinal disturbances such as anorexia, diarrhoea and a metallic taste in the mouth are common but usually transient; they respond well to temporary lowering of dosage. Lactic acidosis usually occurs only if there are predisposing factors; it is thus important that patients should be selected carefully, with proper dietary attention. Symptoms of lactic acidosis include nausea, vomiting, hyperventilation, malaise and abdominal pain * Treatment should be changed to insulin for control of diabetes in patients under stress, e.g. undergoing surgery, those with infections or suffering from trauma. * Evaluate patient response weekly by determining blood glucose concentrations during, the first month of therapy, and at regular intervals thereafter. * Recent data suggests that metformin improves morbidity and mortality in patients with heart failure. * Long-term treatment has been associated with reduced vitamin B12 absorption. * Metformin does not induce hypoglycaemia on its own. Adult dose: Oral, initially 500 mg once or twice daily or 850 mg once daily; increased gradually if required. Maximum 3 g/day, but should probably not exceed 2550 mg/day. Renal impairment: GFR ml/min 25% of dose; GFR <10 ml/min or a creatinine of 132 mcmol/l, avoid. Metformin [INN] [A10BA02] S3 Glucophage Merck tablets, metformin hydrochloride 500 mg, 850 mg, 1000 mg Arrow Metformin Arrow tablets 500 mg, 850 mg Austell-Metfonnin Austell tablets 500 mg, 850 mg Bigsens Zydus tablets 500 mg, 850mg, 1000 mg Diabetmin GulfDrug tablets 850 mg Forminal CipIa Medpro tablets 500 mg, 850 mg Mylan-Metformin Mylan tablets 500 mg, 850 mg Metforal AI Pharm tablets 5QO mg, 850 mg Metored Pharmaplan tablets 500 mg, 850 mg Metphage Aspen Pharmacare tablets 500 mg, 850 mg Sandoz Metformin Sandoz tablets 500 mg, 850 mg; film-coated tablets 500 mg, 850 mg SULPHONAMIDES, UREA DERIVATIVES Sulphonylureas act mainly by stimulating the release of endogenous insulin. Some pancreatic beta-cell responsiveness should remain intact for these agents to be effective. They may provide good control of blood glucose and have been shown to reduce the microvascular complications of diabetes. They are used in the management of type 2 diabetes not controlled by diet Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 7

8 alone, and may be given together with a biguanide if necessary to achieve control. The sulphonylureas in common use include glibenclamide, gliclazide, glimepiride and glipizide. (Chlorpropamide has no place in therapy as it has been associated with serious and prolonged hypoglycaemia) * Hypoglycaemia is always a potential problem; in most type 2 diabetics it can be prevented by careful titration of dosage. * Low doses are indicated, at least initially and until the response is assessed. * The longer-acting agents such as Chlorpropamide and glibenclamide are most prone to produce hypoglycaemic problems, and finer control is often possible with the shorter-acting agents, provided correct doses are prescribed. * All the sulphonylureas lack data regarding safety in pregnancy; insulin is the agent of choice. * Insulin therapy should be instituted temporarily in patients with severe infections, trauma or undergoing major surgery Glibenclamide (SA EDL Primary drug) Indications: Diabetes mellitus (type 2). Pharmacokinetics: T max = 4 hours. Protein binding; about 90%. T ½ = 10 hours. Duration of action is about 24 hours allowing once-daily dosage. It is metabolised in the liver to weakly active metabolites and eliminated equally via biliary and renal routes. Contraindications: Brittle or unstable diabetes, or diabetes complicated by ketosis, acidosis and coma; severe renal impairment; allergy to sulphonamides or sulphur. Cautions: Porphyria (page 19). In patients with severe infections, trauma or undergoing major surgery, treatment should be changed to insulin. Geriatrics More susceptible to the hypoglycaemic effects of the sulphonylureas; lower initial doses recommended, with cautious adjustment. Long-acting sulphonylureas are contraindicated. Glibenclamide is best avoided since the low doses that would be advisable (initially 1.25 mg daily) cannot be administered with the preparations currently available. In addition, prolonged hypoglycaemia may occur in the elderly due to erratic food intake and the concomitant use of glibenclamide. Paediatrics: Contraindicated. Pregnancy: Category C. Contraindicated; insulin remains the agent of choice for management of diabetes during pregnancy. If used near term, severe prolonged neonatal hypoglycaemia may result. However recent data suggests that it may be safe in the management of gestational diabetes Lactation: Use with caution and only if essential; effects on the infant of the small amount excreted in breast milk have not been determined, but may cause hypoglycaemia. Drug interactions: Aspirin (and possibly other NSAID s) sulphonamides, clofibrate, chloramphenicol, cimetidine, fluconazole, ketoconazole, miconazole: An enhanced hypoglycaemic response to the sulphonylureas may occur. Warfarin: Increased plasma concentrations of both agents initially; dosage adjustment of both agents may be required. Alcohol: An increased risk of hypoglycaemia, and potential for alcohol intolerance leading to flushing, headache, nausea- and vomiting (a disulfiram like reaction). Beta blocking agents: May mask warning symptoms of hypoglycaemia and produce hypoglycaemia in certain diabetics, e.g. during exercise. MAOIs: The interaction is unpredictable; severe and protracted hypoglycaemia has occurred. Hepatic enzyme inducers, e.g. meprobamate, phenytoin, rifampicin: A diminished hypoglycaemic effect may occur. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 8

9 Thiazide diuretics, glucocorticosteroids, furosemide, oral contraceptives and other drugs associated with impaired glucose tolerance: A diminished hypoglycaemic effect may occur. Adverse effects: Common - headache, dizziness, weakness and paraesthesia; also gastrointestinal disturbances with nausea, epigastric fullness and heartburn. Allergic skin reactions (rashes, pruritus, and erythema) are usually transient and subside with continued administration. Rare hepatic dysfunction and jaundice, photosensitivity, blood dyscrasias including thrombocytopenia, agranulocytosis and aplastic anaemia. * Injudicious prescription of high doses has led to fatalities, due to hypoglycaemia, particularly in the elderly. * Evaluate patient response by determining blood glucose concentrations, weekly during the first month of therapy and at least monthly thereafter. * Regular blood testing for glucose and monitoring for ketones in the presence of severe hyperglycaemia is advised throughout treatment. * Glibenclamide (and all sulphonylureas) are contraindicated if adult diabetes is thought to have an autoimmune basis (slowly evolving type 1 diabetes mellitus). * If hypoglycaemia occurs, re-evaluation of treatment (including dietary measures) and adjustment of dosage are required. * Patients should be well informed of the signs and symptoms of hypoglycaemia (palpitations, headache, hunger, nervousness or confusion) and hyperglycaemia (polyuria, polydipsia, numbing and/or tingling of the feet). * It should be emphasised to patients that oral antidiabetic agents are adjuncts to the overall management of diabetes and not substitutes for proper dietary regulation. * Gastrointestinal disturbance may respond to decreasing or dividing the dosage.) * Tablets may be given with, or 30 minutes before, a meal. Adult dose: Oral, initially 2.5 mg in the morning, increased gradually with increments of no more than 2.5 mg at weekly intervals. Maximum 15 mg/day. Divided doses appear to improve the control of hyperglycaemia in patients requiring > 10 mg daily. Renal impairment: GFR < 50 ml/min, avoid. Glibenclamide [INN] [A10BB01] S3 Daonil Aventis tablets, 5 mg Bio-Glibenclamide Biotech tablets 5 mg Diacare Be-Tabs tablets 5 mg Glycomin Aspen Pharmacare tablets 5 mg Norton-Glibenclamide Aspen Pharmacare tablets 5 mg Sandoz Glibenclamide Sandoz tablets 5 mg Gliclazide (SA EDL Primary drug) Indications: Diabetes mellitus (type 2). Pharmacokinetics: Highly bound to plasma proteins. T½ = hours. It is metabolised extensively in the liver to inactive metabolites which, with a small amount of unchanged drug, are excreted mainly in the urine. Contraindications, Cautions, Drug interactions, Adverse effects and of glibenclamide (page 74) apply to all sulphonylureas. In addition: * Gliclazide should be avoided in patients with liver disease, and can be used with caution (in low doses initially) in patients with mild to moderate renal impairment. Adult dose: Oral, initially mg daily with breakfast, adjusted gradually according to response to a maximum of 320 mg/day. Doses exceeding 80 mg daily should be divided into morning and evening doses. The elderly: Initially 40 mg daily and increase cautiously. Modified release formulation: Initially 30 mg once daily with breakfast, increased at monthly intervals, according to response, up to a maximum of 120 mg, taken as a single daily dose. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 9

10 Gliclazide [INN] [A10BB09] S3 Diamicron Servier tablets, 80 mg modified-release tablet, MR 30 mg Alembic Gliclazide GulfDrug tablets 80 mg Arrow Gliclazide Arrow tablets 80 mg Austell-Gliclazide Austell tablets, 40 mg, 80 mg Diaglucide Biogaran tablets 80 mg Adco-Glucomed AI Pharm tablets 80 mg Glycron Aspen Pharmacare tablets 80 mg Glygard Cipla Medpro tablets 80 mg Mylan-Gliclazide Mylan tablets 80 mg Sandoz Gliclazide Sandoz tablets 80 mg Glipizide Indications: Diabetes mellitus (type 2). Pharmacokinetics: Tmax = 1-3 hours. Protein binding, 98-99%. T½ = 2-4 hours. Duration of action is hours. It is metabolised in the liver to inactive metabolites and excreted in the urine. Contraindications, Cautions, Drug interactions, Adverse effects and of glibenclamide (page 74) apply to all sulphonylureas. In addition: * Disulfiram-type reaction with alcohol is less problematic than with other sulphonylureas. Adult dose: Oral, initially mg daily, 1530 minutes before breakfast (2.5 mg in the elderly and in liver impairment), gradually increased, if necessary, to a maximum of 40 mg/day. Amounts exceeding 15 mg/day should be given in divided doses. Glipizide [INN] [A10BB07] S3 Minidiab Pfizer tablets, 5 mg Glimepiride Indications: Diabetes mellitus (type 2). Pharmacokinetics: Tmax = 2.5 hours. Protein binding, 99%. T½ = 5-8 hours. Duration of action is 24 hours. It is metabolised in the liver, 58% excreted in the urine and 35% in the faeces. No unchanged drug found in urine. Contraindications, Cautions, Drug interactions, Adverse effects and of glibenclamide (page 74) apply to all sulphonylureas. In addition: * Contraindicated in liver disease and moderate to severe renal impairment. Adult dose: Oral, initially 1 mg once daily, before breakfast. If necessary, the dose may be increased by 1 mg at weekly intervals up to 6 mg daily, according to blood glucose levels; maximum 8 mg daily. Glimepiride [INN] [Al0BB12] S3 Amaryl Sanofi-Aventis tablets, 1 mg, 2 mg, 3 mg, 4 mg Diaglim Cipla Medpro tablets 1 mg, 2 mg, 4 mg Euglim Simayla tablets 1 mg, 2 mg, 4 mg Glamaryl Sanofi-Aventis tablets 1 mg, 2mg, 4 mg GlimeHexal Simayla tablets 1 mg, 2 mg, 4 mg Mylan-Glimepiride Mylan. tablets 1 mg, 2 mg, 4 mg Sandoz Glimepiride Sandoz tablets 1 mg, 2 mg, 4 mg Sulphonur Specpharm tablets 1 mg, 2 mg, 4 mg Other sulphonylureas inclulde: Chlorpropamide [INN] [A10BB02] S3 * Chlorpropamide has been associated with serious and prolonged hypoglycaemia, and has no place in therapy. Hypomide Aspen Pharmacare, tablets, 250 mg COMBINATIONS OF ORAL BLOOD GLUCOSE LOWERING DRUGS Metformin + sulphonylurea [A10BD02] S3 Glucovance Merck tablets, metformin 250 mg, glibenclamide 1.25 mg; metformin 500mg, glibenclamide 2.5 mg; metformin 500 mg, glibenclamide 5 mg Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 10

11 Adult dose: Diet and exercise alone inadequate: 250 mg/1.25 mg daily. Monotherapy inadequate: 500 mg/2.5 mg daily. Changing from dual therapy with metformin and insulin secretagogue: 500 mg/2.5 mg or 500 mg/5 mg once or twice daily, according to previous dose of individual agents. Adjust at 1-2 weekly intervals, depending on control. Maximum/day metformin 2 g, glibenclamide 20 mg (4 tablets 500 mg/5 mg). Elderly: Initially 250 mg/1.25 mg daily. * Tablets should be taken just before a meal. * Contraindications, cautions, etc. see profiles of metformin and glibenclamide, pages ALPHA GLUCOSIDASE INHIBITORS These agents are potent inhibitors of glucoamylase and sucrase. They act by delaying the digestion of carbohydrates, so that they are digested throughout the small intestine rather than the upper third of the jejunum. This leads to a decrease in the postprandial rise in plasma glucose and postprandial plasma glucose peaks. Acarbose Indications: Type 2 diabetes inadequately controlled by diet alone or diet and oral hypoglycaemic agents, especially in the older patient or where there is intolerance to other hypoglycaemic agents. Pharmacokinetics: Oral absorption is < 2%. Contraindications: Inflammatory bowel disease; gastrointestinal obstruction; hepatic impairment; paediatric use. Cautions: Pregnancy & lactation: Safety and efficacy not established; therefore use not advised. Pregnancy: Category B. Drug interactions: Hypoglycaemic agents and insulin: Acarbose may potentiate the hypoglycaemic effects. Gastrointestinal absorbents: Concomitant use may decrease the effect of acarbose. Adverse effects: Common - flatulence, diarrhoea, gastrointestinal and abdominal pains. Uncommon nausea, vomiting, dyspepsia; transient increase in liver enzymes. Rare oedema, jaundice, thrombocytopenia, rash, erythema, exanthema, urticaria, sub ileus, ileus, hepatitis. * It is of particular value in patients with postprandial hyperglycaemia. * At higher doses, acarbose may give rise to transient idiosyncratic elevations of serum hepatic transarninases. Patients titrated to the maximum recommended dose should be closely monitored, preferably at monthly intervals for the first 6 months. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be warranted, particularly if the elevations persist. Adult dose: Careful initiation of therapy is required in order to reduce the side-effects. Initially 25 mg with the evening meal for 1 week, increasing to 25 mg before breakfast and supper for 2 weeks, then to 3 times daily. The dosage may be increased to mg 3 times daily if response is inadequate. Acarbose [INN] [A10BF01] S3 Glucobay Bayer Schering tablets, 50 mg, 100 mg THIAZOLIDINEDIONES The thiazolidinediones, such as pioglitazone and rosiglitazone, improve glycaemic control by reducing cellular insulin resistance. Recent evidence suggests that they are associated with adverse cardiovascular outcomes i.e. mortality and morbidity, and should probably not be used in patients with known coronary vascular disease and are contraindicated in class III/IV heart failure. There is also a suggestion of bone mass density reduction and skeletal fractures. Thiazolidinediones Indications: Type 2 diabetes inadequately controlled by diet and exercise. For use as monotherapy or in combination with metformin, a sulphonylurea or insulin. Contraindications: Type 1 diabetes, impaired liver function, cardiac failure; pregnancy and Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 11

12 lactation; patients < 18 years of age (safety not established); porphyria (page 19). Adverse effects: Common - angina, CCF, oedema, anaemia, skeletal fractures, headache, upper respiratory infection. Rare: diabetic macular oedema. * Serum ALT/AST should be evaluated prior to the initiation of therapy, every 2 months for the first year and periodically thereafter. * Patients should be advised to seek medical attention immediately if symptoms of hepatotoxicity develop (nausea, vomiting, abdominal pain, dark urine, jaundice). * Anaemia may result from increased plasma volume. * Patients at risk of cardiac failure should be monitored for change in cardiac status. * Macular oedema associated with rosiglitazone resolved or improved in some cases following discontinuation of therapy or dose reduction. * As a result of improving insulin sensitivity, rosiglitazone treatment in premenopausal anovulatory patients with insulin resistance (e.g. patients with polycystic ovary syndrome) may result in resumption of ovulation. * Patients undergoing rapid or excessive weight gain should be evaluated for fluid accumulation and volume-related events, such as oedema and CCF. * Omit during surgery and convert to insulin on the day of surgery. Pioglitazone [INN] [A10BG03] S3 Actos Eli Lilly tablets. 15 mg, 30 mg Cipla Pioglitazone Cipla Medpro tablets 15 mg, 30 mg Adult dose: Oral, mg once daily. If response is inadequate in patients on monotherapy, the dose may be increased up to 45 mg daily or combination therapy considered. Rosiglitazone [INN] [A10BG02] S3 Avandia GlaxoSmithKline tablets, 2 mg, 4 mg Adult dose: Oral, 4 mg daily in a single dose or 2 divided doses. If response is inadequate after 6-8 weeks, the dose may be increased up to 8 mg/day. DIPEPTIDYL PEPTIDASE IV (DPPIV) INHIBITORS Sitagliptin and vildagliptin (not yet registered in South Africa), are incretin enhancers. They inhibit DDP-IV, an enzyme that breaks down glucagon-like peptide-1 (GLP-1). By delaying the degradation of GLP-1 they extend the action of insulin while also suppressing the release of glucagon. They are used to improve glycaemic control in adults with type 2 diabetes alone or in combination with metformin or sulfonylurea. They can be used early in onset of type 2 diabetes. Side effects include gastrointestinal discomfort, peripheral oedema, upper respiratory tract infection, nasopharangitis, and liver dysfunction. These agents must be used with caution in patients with renal impairment. Dosage adjustment is recommended in moderate or severe renal impairment. Liver function tests should be monitored during treatment. OTHER BLOOD GLUCOSE LOWERING DRUGS, EXCLUDING INSULINS Nateglinide and repaglinide are members of a new chemical class of antidiabetic agents, the meglitinides, which act by stimulating insulin release from the pancreas. They are structurally different from the sulphonylureas, but have a similar mode of action. Exenatide is an incretin mimetic that exhibits several antihyperglycaemic actions of glucagonlike peptide-1 (GLP-1). It increases, on a glucose-dependent basis, the synthesis and secretion of insulin from the pancreas. It suppresses glucagon secretion leading to decreased hepatic glucose output. Exenatide is administered subcutaneously and has the advantage of limitation of weight gain; may promote weight loss. Meglitinides Indications: Type 2 diabetes as monotherapy or in combination with metformin. Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 12

13 Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal or liver impairment; should not be used in children. Combination with sulphonylureas should be avoided. Cautions: Porphyria (page 19). Adverse effects: Hypoglycaemia, abdominal pain, diarrhoea, nausea and vomiting; skin hypersensitivity reactions may occur. * Doses should be taken up to 30 minutes before main meals. * Patients should omit a dose if they miss a meal. Nateglinide [INN] [A10BX03] S3 Startix Novartis tablets, 120 mg Adult dose: Oral, usually 120 mg before meals, 3 times daily. Adjunct to metformin: 60 mg before meals may be sufficient inpatients who are close to their therapeutic target. Repaglinide [INN] [A10BX02] S3 NovoNorm Novo Nordisk, tablets, 0.5 mg, 1 mg, 2 mg Adult dose: Oral, initially 0.5 mg before meals, titrated according to response at intervals of 1-2 weeks, up to a maximum single dose of 4 mg. Total daily dose should not exceed 16 mg/day. Exenatide Indications: Combination therapy with metformin and/or a sulphonylurea for patients with type 2 diabetes inadequately controlled by lifestyle modification and other oral antidiabetic therapy. Pharmacokinetics: Time to median peak plasma concentration = 2.1 hours. Mean T½ = 2.4 hours. Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal impairment (creatinine clearance < 30mL/min), gastrointestinal disease such as gastroparesis, dysmotility, and/or/anatomical obstruction; should not be used/in children or in pregnancy and lactation. Combination with insulin, thiazolidinediones, D-phenylalanine derivatives, meglitinides, or alpha glucosidase inhibitors has not been studied. Drug interactions: Other orally administered drugs: May reduce the extent and rate of absorption. Take at least 1 hour before exenatide injection. Adverse effects: Common - hypoglycaemia, decreased appetite, nausea, vomiting, diarrhoea, constipation, GORD, rash. Uncommon - acute pancreatitis, pruritis, angioedema, hypersensitivity. * There is a rare incidence of acute pancreatitis and patients should be informed of the characteristic symptom of pancreatitis i.e. persistent, severe abdominal pain. Adult dose: SC, initially 5 mcg twice daily before main meals for at least one month. Thereafter, increase to 10 mcg twice daily if necessary. Preparations include : Exenatide [INN] [A10BX04] S3 Byetta Eli Lilly inject, 5 mcg, 10 mcg (disposable pen) Pharmacy Education International: Enhancing Patient Lives Through Training Excellence 13