COMMON SENSE PATHOLOGY

UNIT 1, APRIL 2002

Diabetes Diagnosis and Monitoring

Contents
Who to screen Unusual cases Monitoring for complications

Common Sense Pathology is a joint initiative of

The Royal College of Pathologists of Australasia

Look out for future issues of

COMMON SENSE PATHOLOGY

Topics that will be covered include: ALLERGY CARDIAC MARKERS FATIGUE THROMBOPHILIA METABOLIC SYNDROME

Dear Reader It is with great pleasure that the Royal College of Pathologists of Australasia and Australian Doctor present a new series of Common Sense Pathology. The first series was very well received and lauded as providing clear concise information that is useful and necessary for general practitioners, indeed back copies are still eagerly sought. Common Sense Pathology has been sorely missed since its demise in 1999 due to the cessation of a Federal Government funding initiative. The College and Australian Doctor are delighted to have reached an agreement to produce a new series. Suitable topics to present on the appropriate use of pathology in the clinical setting abound, and we look forward to a productive association. We thank Dr Peter Clyne for reviewing each article. The 2002 series will consist of six articles, each of which will be published as a separate booklet and delivered with your Australian Doctor. In addition the articles will be posted on the College website at www.rcpa.edu.au. It is hoped you will find this first article on diagnosis and monitoring of diabetes to be a valuable education and reference tool. Both the College and Australian Doctor are pleased to be able to provide this resource to the medical fraternity.

Yours sincerely

Dr Matthew Meerkin Editor Common Sense Pathology

Dr Kerri Parnell Medical Editor Australian Doctor

Commonsense Pathology is a joint initiative of Australian Doctor and The Royal College of Pathologists of Australasia. It is published by Reed Business Information Tower 2, 475 Victoria Ave, Locked Bag 2999 Chatswood DC NCW 2067. Ph: (02) 94222999 Fax: (02) 94222800 E-mail: mail@australiandoctor.com.au Web site www.australiandoctor.com.au (Inc in NSW) ACN 000 146 921 ABN 47 000 146 921 ISSN 1039-7116
2002 by The Royal College of Pathologists of Australasia website www.rcpa.edu.au

CEO Dr Debra Graves E-mail: debrag@rcpa.edu.au Commonsense Pathology Editor Dr Matthew Meerkin E-mail: mmeerkin@ozemail.com.au Australian Doctor Medical Editor Dr Kerri Parnell E-mail: kerri.parnell@rbi.com.au Managing Editor, Healthcare Kellie Bisset E-mail: kellie.bisset@rbi.com.au Sales Director, Healthcare Neil Covey E-mail: neil.covey@rbi.com.au Production Manager Kirsty Milenkovic E-mail: kirsty.milenkovic@rbi.com.au

Diabetes Diagnosis and Monitoring

Associate Professor Peter Colman Director, Department of Diabetes and Endocrinology Royal Melbourne Hospital
Diabetes diagnostic criteria and determining the cause The Australian Diabetes, Obesity and Lifestyle Study (AusDiab), the first accurate national diabetes prevalence study in this country, has recently reported its frightening findings (1). The prevalence of diabetes in the Australian population aged 25 years and older is 7.5% (8% for males and 7% for females). The prevalence rises from 2.5% in people 35 to 44 years to 23.6% in those 75 years and over. For each known case there is one undiagnosed case. Furthermore, the prevalence of impaired glucose metabolism (either impaired glucose tolerance or impaired fasting glycemia) in the population is 16.3% (17.3% for males and 15.3% for females). In the light of these dramatic figures this issue of Commonsense Pathology will address the diagnostic criteria for diabetes and impaired glucose metabolism, the current approaches taken to case finding for diabetes and extra diagnostic tests that might be indicated to determine the cause of diabetes in unusual cases. It will also look at investigations used routinely in managing patients with diabetes.

CASE 1
A 56-year-old woman presents to her GP with a three-month history of thirst, polyuria and nocturia up to four times. Recently she has also noticed blurring of vision. Her weight is 94kg and height 1.71m with a body mass index (BMI) of 32. She has had hypertension for several years. Her mother had diabetes later in life and ultimately needed treatment with insulin. Her capillary glucose on the surgery glucometer is 15mmol/L. Question 1. What further tests are needed to confirm the diagnosis of diabetes? She should have blood taken for a laboratory plasma glucose, either fasting or random. Use of office glucometers is not recommended for diagnosis on the basis of several studies which examined the sensitivity and specificity compared to an oral glucose tolerance test (oGTT). In one study using a cutoff of 5.8mmol/L the glucometer achieved a sensitivity of 79% in men but only 40% in women, while specificity was 86% and 84% respectively for men and women (2). The criteria for diagnosis of diabetes in the setting of classical symptoms would be a fasting plasma (3) (3). greater7mmol/L or equal or to 7mmol/L or random plasma glucose greater or equal to situation 11.1mmol/L glucose of above random plasma glucose of over 11.1mmol/L . In this an oGTT is In this situation an oGTT is unnecessary. unnecessary. In contrast, the diagnosis of diabetes in an asymptomatic individual should never be made on the basis of a single abnormal plasma glucose value. For the asymptomatic person, at least one additional plasma glucose test result with a value in the diabetic range (either fasting or random) is essential. It is also important to remember that severe hyperglycemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not be regarded as diagnostic for diabetes. The situation should be reviewed when the acute stress has passed. Question 2. Why cant the HbA1c be used for diagnosis? HbA1c has been suggested and evaluated as a potential test for screening and diagnosing type 2 diabetes in keeping with a desire to have a simple and single test which could replace the oGTT. However the WHO recommends that HbA1c should not be used for diagnosis of diabetes due to low sensitivity and lack of standardisation. One study examined HbA1c measurement in cohorts from the NHANES III study (4). Using the current WHO criteria for diagnosis 60% of people with diabetes diagnosed on the basis of a fasting plasma glucose of 7.0 to 7.7mmol/L had normal HbA1c. Measurement of HbA1c is not yet

standardised around the world and therefore it is not currently possible to produce diagnostic thresholds that would be valid in all laboratories. Current regulations in Australia on the clinical use of HbA1c measurement which attract a Medicare benefit preclude its use for this purpose. Question 3. What other investigations should be performed at the time of diagnosis of diabetes? As type 2 diabetes can be undiagnosed for many years it is important to look for evidence of retinopathy and nephropathy at diagnosis. She should have a retinal examination through dilated pupils and once her diabetes is controlled, her urine should be checked for a subclinical increase in albumin excretion (microalbuminuria). There are several methods of testing for microalbuminuria, which differ in the type of urine collection and the method of measurement. Initial screening can be performed on early morning urine samples using either an albumin:creatinine ratio or a semi-quantitative dipstick technique such as Micral-II. Subsequent testing is best performed on a timed overnight or a 24-hour urine specimen. She should also have a fasting lipid profile (cholesterol, triglyceride, HDL-cholesterol and LDL cholesterol) and treatment according to guidelines as diabetes is associated with a higher absolute risk of coronary heart disease (5).

CASE 2
A 58-year-old woman, whose mother had type 2 diabetes, presents asking whether she should be tested for diabetes. She has a BMI of 29 and is on enalapril for hypertension. Her fasting cholesterol is 5.8mmol/l, triglyceride 2.6mmol/L and HDL cholesterol 0.9mmol/L. She has no symptoms of diabetes. A fasting glucose is 6.5mmol/L. Question 1. Should she be tested for diabetes? Yes. The draft Australian National Evidence Based Guidelines (6) suggest tests for undiagnosed diabetes in the following: People with previous history of impaired glucose tolerance or impaired fasting glycemia Women with previous gestational diabetes People aged 55 or over Aboriginal and Torres Strait Islanders aged 35 and over High risk non-English-speaking background groups (Indian subcontinent, Pacific Islands, Chinese origin) aged 35 and over All people with a clinical history of a cardiovascular event (myocardial infarction, angina or stroke) Women with polycystic ovary syndrome who are obese People aged 45 or over who have one or more of the following risk factors: Obesity (BMI > 30) First degree relative with type 2 diabetes Hypertension Question 2. With a fasting glucose of 6.5mmol/L, how would you proceed to diagnose this patients carbohydrate status? For patients with a fasting glucose between 5.5 and 7.0mmol/L or a random glucose between 7.8 and 11.0mmol/L an oGTT should be performed. The diagnostic results for the oGTT are interpreted as follows: Fasting glucose (mmol/L) <5.5 6.1-6.9 <7.0 7.0 >7.0 2 hour post glucose load (mmol/L) <7.8 <7.8 7.8-11.0 11.1 >11.1 Diagnosis Diabetes unlikely Impaired fasting glycemia (IFG) Impaired glucose tolerance (IGT) Diabetes Diabetes

Question 3. What management should be offered to patients with impaired glucose tolerance (IGT)? There are now several trials showing interventions with diet and exercise can decrease the progression to diabetes in those with IGT. The most recent of these, the US Diabetes Prevention Program, a major clinical trial comparing diet and exercise to treatment with metformin in 3234 people with impaired glucose tolerance, showed a reduction in progression to diabetes of 71% by lifestyle intervention and 31% by metformin treatment (7). Two other studies, the Da Qing and the Finnish Diabetes Prevention Study, also show that type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects (8,9). Studies evaluating other pharmacological interventions in impaired glucose tolerance are in progress.

Question 4. How often should people, identified as being at risk through risk factor assessment, be retested? The draft Australian Evidence Based Guidelines suggest periodic testing for undiagnosed diabetes by measuring fasting plasma glucose according to the following schedule: Each year for people with impaired glucose tolerance or impaired fasting glucose Every three years for at-risk people with a plasma glucose within the normal range Each year for people with an initial plasma glucose consistent with a diagnosis of diabetes or IGT/IFG which is not confirmed on subsequent testing

CASE 3
A 65-year-old woman with a past history of Menieres disease, reflux oesophagitis and osteoarthritis presents to her GP with mild fatigue and slight weight loss. Her body weight is 57kg and height 1.62m (BMI 21.7). She is normotensive and has no evidence of vascular disease. There is a history of diabetes in her mother and brother both developed diabetes in middle age and were treated with oral hypoglycemic agents. Fasting glucose is 6.5mmol/L and an oGTT test iss performed. Diabetes is diagnosed with fasting glucose 8.2mmol/L and two-hour 19.3mmol/L. Her HbA1c at diagnosis is 10.1%. With diet, the HbA1c falls to 7.5% but after six months again rises to 8.7% so a sulphonylurea is instituted. HbA1c falls promptly to 6.1%. Two years later, her HbA1c rises to 10% despite increase in the sulphonylurea and the addition of metformin. Question 1. What further testing might assist her management? The clinical scenario of rapid failure of control of diabetes with oral hypoglycemic agents and the low BMI in this patient suggests she may have slowly progressive type 1 diabetes. An assay for glutamic acid decarboxylase antibodies (GADAb) or a measurement of insulin production (fasting insulin or C-peptide with a simultaneous plasma glucose measurement) will assist in making this diagnosis. GADAb are elevated at 56 U (normal <5 U) and the C-peptide is 0.4 nmol/L (normal fasting 0.26-1.40) with a glucose of 14mmol/L This patient has adult onset autoimmune diabetes or latent autoimmune diabetes in adults (LADA). Any patient presenting with apparent type 2 diabetes who does not have an elevated BMI should raise the suspicion of latent autoimmune diabetes of adults. However, LADA has also been described in people with marked obesity. The diagnosis is confirmed by the finding of autoantibodies GADAb or Islet cell antibodies. Patients also have a C-peptide which is in the lower normal fasting range despite high blood glucose. This contrasts with the elevated C-peptide seen in many patients with type 2 diabetes. Clinical trials suggest that up to 10% of patients presenting with apparent type 2 diabetes may have this syndrome. Probably the best evidence comes from the United Kingdom Prospective Diabetes Trial (UKPDS) trial in which 10% of patients with apparent type 2 diabetes entering the trial were found to have positive GADAb (10). Patients with positive GADAb generally display an early requirement for insulin treatment because they are primarily insulin deficient rather than insulin resistant and, for the same reason, dont respond well to diet and oral hypoglycemic treatment (11). There is strong evidence that the presence of GADAb in patients with adult onset diabetes is a sensitive marker for future insulin dependence. In the UKPDS, after a sixyear follow-up, 84% of patients with GADAb required insulin compared with 14% of the antibodynegative patients. The positive predictive value of GADAb for long-term insulin requirement is between 84-95% (12). Question 2. Is there value in making the diagnosis of LADA rather than type 2 diabetes in these patients? This is still not definitively established. Certainly, these patients require insulin treatment early in the course of their disease and may benefit from early insulin treatment. In patients with typical type 1 diabetes presenting at a younger age there is evidence that close glycemic control with intensive insulin leads to continued endogenous insulin production for longer (13). Continued endogenous insulin secretion may be associated with reduced development of complications. There has been only one clinical trial of insulin administration in patients with LADA. In this study low doses of subcutaneous insulin led to increased insulin production as evidenced by improved C-peptide response to an oGTT and decreased HbA1c compared to patients treated with sulphonylureas alone (14).

CASE 4
A 19-year-old female student with a three-month history of skin infections and a recent Bartholins abscess feels generally unwell for several weeks with cramps, nausea and dizziness, but no polyuria or thirst. She has lost approximately 3 kg in weight. There is a family history of diabetes. Urinalysis shows + ketones and +++ glucose. A random blood glucose is 18.7mmol/L. Her BMI is 23 (height 170cm, weight 66.8kg). A blood sample is sent for GADAb and insulin. Due to her low BMI, weight loss, rapid onset of symptoms and ketonuria, a presumptive diagnosis of type 1 diabetes is made and she is commenced on short acting insulin before meals and intermediate acting insulin before bed. Her antibody result is negative. Re-evaluation of the family history reveals that diabetes has been inherited in an autosomal dominant fashion through several generations. Her insulin is stopped and she has perfect glycemic control on a low dose of a sulphonylurea. Question 1. Does she have type 1 diabetes? No, it is more likely that she has maturity onset diabetes of the young (MODY). The clinical syndrome of MODY has been recognised for some years, but over the past 10 years a number of single gene defects in beta cell dysfunction have been described. These patients are frequently characterised by onset of mild hyperglycemia at an early age (generally before age 25). These gene defects are generally inherited in an autosomal dominant pattern. Patients with these forms of diabetes, formerly all referred to as MODY, have impaired insulin secretion with minimal or no defect in insulin action. Abnormalities at a number of different genetic loci on different chromosomes have been described. The most common form is associated with mutations on chromosome 12. At least three different forms of MODY have been described involving three different chromosomal abnormalities. Point mutations in mitochondrial DNA have also been found to be associated with diabetes mellitus and deafness. Sensorineural deafness starts rather early in life and often precedes diabetes mellitus, which emerges at 20-40 years. This form of diabetes has strict maternal inheritance but male and female children are affected at the same rate. Only a daughter can transfer the disease to her progeny. Question 2. Why is it important to recognise these genetically determined forms of diabetes? These are the first of the genetically characterised forms of diabetes. With time it is likely that many more genetic types will be determined. Within the different types there are quite marked differences in the diabetic syndrome. While currently these forms can only be diagnosed in very specialised centres, it is likely that the technology to assist diagnosis will be increasingly available in the relatively near future and it is possible that more targeted therapies will become available for these monogenic types of diabetes.

CASE 5
A 66-year-old man presents for his annual review for diabetes complications screening. He has had type 2 diabetes for 17 years and was initially controlled on diet and oral hypoglycemic agents but three years ago was converted to insulin. Currently he is on Biphasic 30/70 insulin mix 50 units before breakfast and 30 units before his evening meal. His HbA1c is 7.3%. His blood pressure is 130/75. He had a dilated fundus examination six months ago, which revealed stable background diabetic retinopathy. Examination of the feet reveals strong pedal pulses; he has reduced sensation to 10 gram monofilament consistent with a peripheral neuropathy. A urine dipstick examination reveals + glucose, negative urinary protein and negative ketones. Question 1. Should he have any further testing for nephropathy? Yes, he should have a test for microalbuminuria, despite the negative test for protein. This should be performed annually with a measurement of albumin excretion rate (AER). This can be done either in a 24 hour urine sample, timed overnight urine collections or by measuring albumin:creatinine ratio (ACR) in an early morning urine sample. Results are interpreted as below: Albuminuria AER (ug/min) ACR M F Normal <20 <2.5 <3.5 Microalb 20-200 2.5-25 3.5-35 Macroalb >200 >25 >35

Correction to table on previous page

An error appeared in the table on testing for nephropathy. The table below is the corrected version .

Testing for nephropathy

Albuminuria Normal Micro Macro AER (pg/min) <20 20-200 >200 M <2.5 2 .5-25 >25 ACR F <3.5 3 .5-35 >35

It should also be noted that in Case 1, Question 1, a fasting glucose of greater than or equal to 7mmol/L or a two-hour post-glucose level of 11 .1 mmol/L or greater is diagnostic of diabetes

Because of the marked biological variation of the albumin excretion rate, the diagnosis of persistent microalbuminuria requires serial measurements with at least two out three samples abnormal, as well as the exclusion of non-specific factors that elevate the rate, such as exercise, poorly controlled hyperglycemia, urinary tract infection and cardiac failure. Question 2. Why is it important to identify patients with microalbuminuria and how should these patients be managed? Microalbuminuria is an independent risk factor in patients with type 2 diabetes, increasing the risk of cardiovascular death 3-4 times. Microalbuminuria has an 80% positive predictive value for development of overt nephropathy in patients with type 1 diabetes. Patients with microalbuminuria are much more likely to be hypertensive, have hyperlipidemia and an increased risk of ischemic heart disease. These patients should be specifically targeted for intensive blood glucose, hypertension and lipid control. There are a number of studies in patients with type 1 diabetes and microalbuminuria demonstrating that ACE inhibitors reduce the rate of decline in GFR and reduce the albumin excretion rate. The outcomes in type 2 diabetes have been more varied. A recent study, in which 590 hypertensive patients with type 2 diabetes and microalbuminuria were treated with the angiotensin receptor blocker, irbesartan 150mg, 300mg daily or placebo, demonstrated reductions of level of urinary albumin by 24%, 38% with 150mg or 300mg irbesartan compared to 2% with placebo (15). The choice between an ACE inhibitor or an angiotensin receptor blocker in patients with microalbuminuria is uncertain. Both appear to be renoprotective with the largest study being done with irbesartan. However, it is uncertain if the survival benefit seen with ramipril in the HOPE study also occurs with angiotensin receptor blockers (16).
References: (1) Dunstan D, Zimmet P, Welborn T, et al on behalf of the AusDiab Steering Committee. Diabesity and associated disorders in Australia 2000. The accelerating epidemic. Australian diabetes, obesity and lifestyle report, Melbourne: International Diabetes Institute, 2000 (2) Aiao Q, Keinanen-Kiukaanniemi S, Rajala U, Uusimaki A, Kivela SL. Random capillary whole blood glucose test as a screening test for diabetes mellitus in a middle-aged population. Scan J Clin Lab Invest 1995;55:3-8. (3) Colman PG, Thomas DW, Zimmet PZ, Welbourn TA, Garcia-Webb P, Moore PM. New classification and criteria for diagnosis of diabetes mellitus. Med J Aust 1999; 170: 375-378. (4) Davidson MB, Schriger DL, Peters AL, Lorber B. Relationship between fasting plasma glucose and glycosylated hemoglobin. Potential for false-positive diagnoses of type 2 diabetes using new diagnostic criteria. JAMA 1999; 281:1203-11. (5) Lipid Management Guidelines 2001. Med J Aust 2001; 175 (supplement):S57-S88 (6) Australian Centre for Diabetes Strategies. National evidence based guidelines for the management of type 2 diabetes. Part 3. Evidence based guideline for case detection and diagnosis of type 2 diabetes. Available at www.diabetesaustralia.com.au/docs/ Part3-Detection-and-Diagnosis.PDF Last sighted Dec 18,2001 (7) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl J Med 2002;346:393-403. (8) Pan Xiao-Ren, Li GW, Hu YH et al. Effects of diet and exercise in preventing diabetes in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20:537-44. (9) Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344:1343-1350. (10) Turner R et al. (1997). UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 350: 1288-1293. (11) Humphrey ARG, McCarty DJ, MacKay IR, Rowley MJ, Dwyer T, Zimmet P (1998). Autoantibodies to glutamic acid decarboxylase and phenotypic features associated with early insulin treatment in individuals with adult onset diabetes mellitus. Diab. Medicine 15:112-119. (12) Littorin B et. al (1999) Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. Diabetes Care 22:409-412. (13) The Diabetes Control and Complications Research Group. Effect of intensive insulin therapy on residual cell function in patients with type 1 diabetes in the diabetes control and complications trial. Ann Intern Med 1998; 113:49-51. (14) Kobayashi T, Nakanishi K, Murase T, Kosaka K (1996). Small doses of subcutaneous insulin as a strategy for preventing slowly progressive b-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45:622-626. (15) Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870-878. (16) Heart Outcomes Prevention Evaluation Study Investigators. The Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253-259.

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