Adverse Drug Reaction

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Falsely elevated blood glucose readings with Extraneal peritoneal dialysis solution
ISSN: 0219 2152 July 2005 Vol.7 No.2

Extraneal (Baxter) is a brand of peritoneal dialysis solution that contains icodextrin. Icodextrin is a glucose polymer that is broken down into maltose in the body. The accumulation of blood maltose can interact with glucose monitoring systems that are not glucosespecific (e.g. those using the GDH-PQQ method) and give rise to falsely elevated glucose readings. As a result, the patient may receive an excessive dose of insulin leading to a hypoglycaemic episode. On the other hand, cases of hypoglycaemia might not be treated if their hypoglycaemic states are masked by glucose readings that are falsely elevated into the normal range.

Overestimation of blood glucose may result in inappropriate administration of insulin or mask hypoglycaemia
There have been recent overseas adverse reports of patient injuries caused by falsely elevated blood glucose readings in diabetic patients who were using peritoneal dialysis solution that contains icodextr in and blood glucose monitor ing systems that are based on the glucose dehydrogenasepyrroloquinolinequinone (GDHPQQ) method. Some of the cases were fatal. Such drug-device interaction may falsely elevate the capillary blood glucose level readings by 3.6 1.4 mmol/l (1) compared to laboratory venous blood glucose measurements when the GDP-PQQ based glucometers are used (normal fasting glucose: 6.1 8.0 mmol/l). Preventive measures To reduce the risk of the above drug-device interaction, the following preventive measures are recommended: Diabetic patients who require dialysis and are prescribed Extraneal should be issued with a Safety Alert Card provided by Baxter (the manufacturer of Extraneal). Patients should be advised to present this card to any attending medical personnel should

he/she require any medical attention e.g. at the A&E departments in hospitals. Patients on Extraneal should use only glucose-specific glucometers that are not affected by icodextrin metabolites. Patients should be given specific instructions on the appropriate type of home blood glucometer that they should use and they should verify the suitability of the glucometers with the company distributing it. The existing brands of GDH-PQQ based glucometers that should not be used by patients on Extraneal include FreeStyle Papillon and Accu-Chek Active/ Advantage/ Compact/ Complete/ Go. Patients should be advised to read the product information leaflet of the glucose monitoring system before using them.

news

contents
Elevated blood glucose meter readings with Extraneal Case reports of serious ADRs associated with adulterated complementary medicines Labelling changes Safety update Visual disorders & erectile dysfunction drugs Highlights on COX-2 selective & non-selective NSAIDs 01

Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee

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Reference: 1. Peritoneal dialysis International 1998; 18(6): 603-9.

Reporting Made Easy: Online adverse drug reaction reporting is available at http://www.hsa.gov.sg/ADR_online

Serious adverse reactions arising from adulterated complementary medicinal products

Healthcare professionals are encouraged to find out whether their patients are consuming complementary medicine when taking medical history

The Pharmacovigilance Unit, HSA has been receiving adverse reaction reports from our healthcare professionals that are suspected to be associated with the use of complementary medicines. Further investigations revealed that a number of these products had been adulterated with western drugs. Many of these products were obtained by consumers from overseas sources or local peddlers who had brought the products from overseas. Although many of these products are not sold in local retail outlets, HSA has recently issued a press release

on five adulterated products to alert members of the public (see http://www.hsa.gov.sg/html/corporate/pressreleases.html for press release). Healthcare professionals play an important role in helping HSA detect potential adulterated complementary medicinal products as evidenced by the case reports summarised below. Healthcare professionals are encouraged to enquire about complementary medicine use in their patients especially products that have been consumed in the recent three months when they suspected an adverse drug reaction.

Product name / Labelled indication(s)

Jamu Kenis Pil, product of Borobudur from Semarang Indonesia - For symptoms such as frequent feeling of thirst, weight loss despite good appetite, weakness, slow recovery when ill, tiredness, blurred vision and frequent urination.

Summary of ADR (adulterants found)

M a l ay, fe m a l e w i t h d i a b e t i c ketoacidosis arising from uncontrolled diabetes. Adulterant found (per pill): Glibenclamide 0.03 mg (Recommended dose: 30 pills/day).

Jamu Pegal Linu, product of PJ. Guna Sehat Suryo Sudarmo from Cilacap Indonesia - For body ache, rheumatism, blurred vision, disability, stroke and lethargy.

Malay, male with severe neutropenia and consequent necrotising fasciitis. Adulterants found (per packet): Dipyrone 25.7 mg and phenylbutazone 6.1 mg. [Recommended dose: 2 packets/day.]

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Product name / Labelled indication(s)

Summary of ADR (adulterants found)

Ramuan Tradisional Madura, product of CV. Wahyu Ilahi, formulated by K Saum/H Murais, Indonesia - Asthma, rheumatism, high blood pressure, diabetes, kidney stone, tumour, migraine, liver, allergy, gastric, weak heart/heart failure, eczema, lack of appetite, low blood volume, sexual impotency, gout.

Malay, male with with hepatitis B flare-up. Adulterant found: Dexamethasone 0.032 mg/g or 0.166 mg/day (based on daily recommended dose).

Kapsul Asam Urat (TCU), product of Prananda Jaya Sukses from Indonesia - For ner ve pain, waist pain, rheumatism, stiff muscle, leg swelling, listlessness and insomnia.

Adulterants found (per capsule): Pa ra c e t a m o l 1 7 3 . 3 2 m g a n d phenylbutazone 89.73 mg. [Recommended dose: 4 capsules/day.]

Snake Powder Capsule, , Taiwan - For joint pain

Adulterants found (per capsule): Chlor pheniramine 1.73 mg, chloramphenicol 105.74 mg, ibuprofen 274.97 mg and tetracycline 53.37 mg. [Recommended dose: 2 capsules/day.]

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Package insert amendments reflecting safety issues

HSA has approved the following package insert changes due to safety updates from March to May 2005. They are also listed at http://www.hsa.gov.sg/cda/labelchanges. Please note that there might be some lag time in the availability of the package insert which reflects the latest change(s).
1. Ergotamine and caffeine (Cafergot, Novartis) Indicated for acute migraine attacks and no longer for treatment of migraine attacks and related types of vascular headaches. A new restriction: If supplementary antimigraine medication is required, the use of any ergotaminecontaining preparations, dihydroergotamine or sumatriptan or 5HT1- receptor agonists must be avoided. Some new contraindications added include shock, temporal arteritis, hemiplegic or basilar migraine; concomitant treatment with macrolide antibiotics, HIV protease or reverse transcriptase inhibitors, azole antifungals and vasoconstrictor agents. New precautions include: i) avoidance of continued daily use of Cafergot at excessive doses ii) mild to moderate hepatic impairment and cholestasis iii) ergotamine or caffeine dependence may occur on regular use and cause withdrawal symptoms subsequently. New ADR terms added include rare reports of fibrotic changes of the cardiac valves, myocardial ischaemia or rarely, and infarction in patients with no history of CHD. 2. F l u v o x a m i n e ( F a v e r i n , S o l v a y Pharmaceuticals) Glycaemic control may be disturbed in the early stages of treatment requiring adjustment in anti-diabetic drugs. Faverin should be avoided in patients with unstable epilepsy and closely monitored in controlled epilepsy. Rarely, development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported, particularly when given in combination with serotonergic or neuroleptic drugs. Psychomotor restlessness has also been associated with the use of fluvoxamine in the first weeks of treatment. Due to lack of clinical data, fluvoxamine should not be used in children and adolescents under 18 years old for the treatment of major depressive episode. New drug interactions include: Tacrine, methadone, mexiletine, thioridazine, caffeine, ropinirol, terfenadine, astemizole, cisapride, ciclosporin, triazolam, midazolam, alprazolam, diazepam, triptans, tramadol, other SSRIs and St. John's Wort preparations. New data show that pharmacokinetics of Faverin in elderly patients and renal patients are similar to the healthy adult; metabolism is impaired in hepatic insufficiency; steady-state plasma concentrations in children are twice as high as in adolescents. Adolescents achieve same plasma concentrations as adults. 3. Gadopentetic acid, dimeglumine salt (Magnevist, Schering) Contraindicated in patients with impaired renal function. Under warnings, Magnevist use in patients with sickle cell anaemia and other haemoglobinopathies has not been studied and may cause vaso-occlusive complications in vivo; possibility of causing increased haemolysis in patients with haemolytic anaemia; hypotension and anaphylactoid reactions may occur and patients should be observed for several hours post-injection. Precautions added include history of bronchial asthma or other allergic disorders; patients with cardiovascular disease. Patients taking betablockers may be resistant to effects of beta agonists. Patients with seizure disorders or intracranial lesions may be at increased risk of seizure activity when given Magnevist. 4. Ipratropium (Atrovent, Diethelm) Under adverse effects, gastrointestinal motility disorders (e.g. constipation, diarrhoea and vomiting) is added. Inhalation induced bronchospasm (instead of inhalation induced bronchoconstriction) has been observed. 5. Methotrexate (Methotrexate, DBL) A warning that the optimal time interval between the cessation of methotrexate treatment of either partner, and pregnancy, has not been clearly established even though it is suggested that pregnancy should be avoided during and for a minimum of 3 months after therapy for either partner has ceased. 6. Methotrexate (Methotrexate, Wyeth) Additional warnings include new statements on the use of high dose regimens, "tumour lysis syndrome", Stevens-Johnson Syndrome, toxic epidermal necrolysis, Pneumocystis carinii pneumonia (potentially fatal), methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis unrelated to dose, methotrexate given together with radiotherapy, methotrexate's poor elimination from third-space. Some new contraindications include breast-feeding, intrathecal/high-dose therapy, psoriatic and rheumatoid arthritic patients who have alcoholism, alcoholic liver disease, chronic liver disease and immunodeficiency syndrome. Some new special warnings include the fact that folate deficiency may increase methotrexate toxicity; immunisation may be ineffective during methotrexate therapy; chronic leukoencephalopathy and transient acute neurologic syndrome has been repor ted in patients treated with high dosage methotrexate. 7. Moxifloxacin (Avelox, Bayer) A new list of contraindications has been included: (i) patients with a history of tendon disease/disorder related to quinolone treatment; (ii) moxifloxacin has been reported to have caused QT prolongation thus it is contraindicated in patients with: congenital or documented acquired QT prolongation; electrolyte disturbances, par ticularly in uncorrected hypokalaemia; clinical relevant bradycardia; clinical relevant heart failure with reduced left-ventricular ejection fraction; previous history of symptomatic arrhythmias; (iii) Avelox should not be used concurrently with other drugs that prolong the QT interval. New ADR terms added: Decrease in INR, angioedema, psychotic reactions and ventricular tachyarrhythmias including torsade de pointes. 8. Oxandrolone (Oxandrin, Scigen) There are new precautions in the use of Oxandrin in warfarinised patients; an unexpectedly large increase in INR or PT may occur. There was a reported mean increase of S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng.h/ml; a mean 5.5-fold reduction of mean warfarin dose (80-85% reduction) was required to maintain the INR target. 9. Pancuronium (Pavulon, Organon) Hypothermia may increase the neuromuscular blocking effect and duration of Parvulon. Patients with burns may develop a resistance to nondepolarising agents, and their doses have to be titrated to response. 10. Propofol (Diprivan, AstraZeneca) There are new contraindications for children under 3 years and for sedation in intensive care of patients of 16 years or younger. Under additional precautions, Diprivan is not recommended for use in neonates for the induction and maintenance of anaesthesia (may cause cardio-respiratory depression); there is insufficient data on the use of Diprivan for sedation of premature neonates receiving intensive care and for the sedation of children with croup or epiglottis receiving intensive care. There are very rare reports of metabolic acidosis, rhabdomyolysis, hyperkalaemia, and/or cardiac failure (some with fatal outcome) concerning seriously ill patients receiving Diprivan for ICU sedation, demonstrating a possible failure of oxygen delivery to the tissues. 11. Simvastatin (Zocor, MSD) In patients taking danazol, the dose of Zocor should not exceed 10 mg/day. The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, particularly with higher doses of simvastatin. Concomitant use of telithromycin (a potent CYP3A4 inhibitor) should be avoided. 12. Zafirlukast (Accolate, Astrazeneca) The maximum dose has been reduced from 40 mg twice daily to 20 mg twice daily. Higher doses may be associated with elevations of one or more liver enzymes consistent with hepatotoxicity. The use of zafirlukast in children (under 12 years) is contraindicated. Zafirlukast should be used with caution in the elderly (over 65 years), patients with moderate to severe renal impairment and fulminant hepatitis. A new warning also states that zafirlukast does not allow a reduction in existing steroid treatment. 13. Zolmitriptan (Zomig, Astrazeneca) Zomig is contraindicated in patients taking other ergotamine der ivatives or other 5HT 1 receptor agonists. It is warned that excessive use of an acute antimigraine medicinal product may lead to an increased frequency of headache, potentially requiring withdrawal of treatment.

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Vision disorders and erectile dysfunction drugs

Physicians are encouraged to ask patients with NAION about the use of sildenafil or related drugs and to report any suspected cases of vision loss to the Pharmacovigilance Unit

Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra, Pfizer), vardenafil (Levitra, Bayer) and tadalafil (Cialis, Eli Lilly), are known to cause reversible and transitory visual disorders such as blurred vision and increased sensitivity to light in some patients. These visual abnormalities are related to the inhibition of PDE6 enzyme that is involved in the phototransduction pathway of the retina.

Post-marketing reports and regulatory follow up

More recently, concerns have been raised about the occurrence of small numbers of post-marketing reports of sudden loss of vision, attributed to NAION (non-arteritic ischaemic optic neuropathy) occurring in association with PDE5 inhibitors. Post-marketing cases of vision loss in patients taking Viagra have been reported sporadically since its launch in 1998, although earlier clinical trials did not demonstrate this adverse effect. The US Food and Drug Administration (FDA) has received 43 cases of ischaemic optic neuropathy (ION) among patients using the PDE5 inhibitors. Of these, 38 cases have been identified in association with sildenafil, 4 cases with tadalafil and 1 case with vardenafil. Twenty-five of the 43 cases appeared to be the NAION subtype. Most of the cases involved patients with underlying anatomic or vascular risk factors associated with the development of NAION. These include (although not necessarily limited to): low cup-to-disc ratio (crowded disc), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. To-date, the Pharmacovigilance Unit has not received any local case of vision loss associated with sildenafil or related drugs. The true incidence of NAION in Singapore is not known. The US FDA announced recently that it had approved new labelling for all three erectile dysfunction drugs to include information about possible risk of vision loss and the category of patients who may be predisposed to such risk. HSA is working with the pharmaceutical companies on the appropriate actions.

both eyes affected. All affected patients had at least one arteriosclerotic risk factors including hypertension, diabetes, elevated cholesterol or hyperlipidaemia. The dose of sildenafil was either 25 mg, 50 mg or 100 mg. Some had been taking the drug intermittently for months or years for the treatment of erectile dysfunction while others had only used one or a few doses before the occurrence of visual loss. Visual field loss was present in all patients, as was optic disc oedema in the affected eye, often with associated nerve fiber layer haemorrhages. In a previous report by the same author, another five patients (aged between 42 and 69 years old) developed NAION subsequent to ingestion of Viagra and the reported time of occurrence of visual disorder was similar to the above study. (2) All the 12 patients in both reports had optic discs with small cup-to-disk ratios in the unaffected eye. Isolated cases of NAION have been reported with the use of tadalafil. The patients experienced visual field defect within hours to days of tadalafil 20 mg ingestion (3,4).

Comments
The mechanism for NAION is not established. It is not possible at this point to determine whether these events are related directly to the use of PDE5 inhibitors, to the patients underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. Physicians prescribing sildenafil or related drugs to patients with ischaemic risk factors of hypertension, diabetes mellitus, increased serum cholesterol or lipids may wish to alert patients on the potential risk of visual loss with this medication until further clinical experience is obtained. Patients should be advised to stop the use of any PDE5 inhibitors and seek medical attention in the event of a sudden loss of vision in one or both eyes. Physicians are also encouraged to ask patients with NAION about the use of sildenafil or related drugs and to report any suspected serious ADRs to the Pharmacovigilance Unit of HSA.

Case series and studies reported in the literature

Pomeranz and Bhavsar (1) reported seven cases of NAION in patients, aged between 50 and 69 years old, within 36 hours of their last dose of sildenafil. All patients presented with blurred vision and loss of visual field; one patient had

References: 1. Journal of Neuro-Ophthalmology 2005; 25:9-13. 2. Ophthalmology 2002; 109:584-7 3. Archives of Ophthalmology 2005; 123(3): 399-401. 4. Eye 2005; 19(6): 715-7.

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The contents are not to be reproduced in part or in whole, without prior written approval from the editor. Whilst every effort is made in compiling the content of this publication, the publishers, editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements. The mention of any product by the authors does not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2005 Health Sciences Authority of Singapore. All Rights Reserved.

HSAs recommendations on cycloxygenase-2 (COX-2) selective and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs)
HSA convened an expert advisory committee meeting in April 2005 to review the risk-benefit balance of COX-2 selective and non-selective NSAIDs following recent concerns on the cardiovascular safety of these drugs. The exper t recommendations (which exclude aspirin) were issued to our healthcare professionals on 28 April 2005. Below are the highlights: All COX-2 selective and non-selective NSAIDs should be prescribed at the lowest effective dose and the duration of treatment should be periodically reviewed and kept as short as possible; All COX-2 selective and non-selective NSAIDs should not be prescribed in patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures; The benefits and risks of celecoxib and etoricoxib should be carefully assessed before they are prescribed to any individual patient, taking into consideration other available therapeutic options. Celecoxib or etoricoxib may be useful for patients who cannot tolerate or do not respond to other NSAIDs; Celecoxib or etoricoxib should not be prescribed in patients with established ischaemic heart disease, stroke or congestive heart failure; Caution should be exercised when prescribing celecoxib or etoricoxib to patients with risk factors for heart disease such as hypertension, hyperlipidaemia, diabetes and smoking or patients with peripheral arterial disease; Etoricoxib should not be prescribed in patients with hypertension whose blood pressure has not been adequately controlled. Careful monitoring of blood pressure is advised for patients taking etoricoxib as some data suggests that it may be associated with more frequent and severe effects on blood pressure than some other COX-2 selective and non-selective NSAIDs, particularly at high doses; All COX-2 selective and non-selective NSAIDs should be prescribed with care in elderly patients because of the possible risk of renal toxicity; Physicians are also advised to consider the use of gastroprotective agents for patients who are at a high risk of developing gastrointestinal complications whilst on COX-2 selective and non-selective NSAIDs. Patients at high risk would include those who are above 65 years old, those with previous history of peptic ulcer disease or peptic ulcer disease with complications, those who are on aspirin, high dose steroids or anticoagulants, and those who need multiple or high dose NSAIDs.

For more details, please refer to http://www.hsa.gov.sg/html/corporate/pressreleases.html

Enquiries, comments and suggestions to:

Pharmacovigilance Unit Centre for Drug Administration Health Sciences Authority 11 Biopolis Way, #11-03, Helios, Singapore 138667 Tel: (65) 6866 3538 Fax: (65) 6478 9069 Website: http://www.hsa.gov.sg Email: HSA_drugsafety@hsa.gov.sg
Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee, HSA Editor-in-Chief Ms Chan Cheng Leng BSc (Pharm) Hons Executive Editor Ms Ang Pei San BSc (Pharm) Staff Editors Ms Tan Bee Him BSc (Pharm), Dr Ting Kang Nee BPharm (Hons), PhD, Ms Adena Lim BSc (Pharm) Hons Editorial Board Clinical Prof. Goh Chee Leok, Prof. Edmund Lee Joo Deoon, Clinical A/Prof. Chng Hiok Hee, Clinical A/Prof. Gilbert Lau Kwang Fatt, Dr Lee Kheng Hock