Adverse Drug Reaction

n e w s
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee

Update on non-selective NSAIDs and cardiovascular risk

HSAs position on the older NSAIDs
ollowing the worldwide voluntary withdrawal of rofecoxib (Vioxx, Merck Sharp & Dohme) in October 2004 due to an increased cardiovascular (CV) risk, HSA and its Expert Advisory Committee reviewed the CV risks of the entire class of nonsteroidal anti-inflammatory drugs (NSAIDs). Based on the available data at that time, in April 2005, HSA concluded that the coxibs or the newer COX-2-selective inhibitors, namely rofecoxib, celecoxib and etoricoxib were associated with an increased risk of CV events and that the risk increased with increased dose and duration of use. HSA also strengthened the local package inserts products to contraindicate the perioperative use of these drugs in patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures. At that time, due to the lack of information on the CV risks for the older NSAIDs, HSA concluded that the possibility of similar CV risk could not be ruled out although there was insufficient data to show that the older NSAIDs posed similar CV risks as the coxibs. Recently, the availability of several well conducted meta-analyses of randomised trials, case-control and cohort studies involving the older NSAIDs have provided regulators with a better means of assessing the safety profile of these drugs. HSA and its Pharmacovigilance Advisory Committee (PVAC) have reviewed these data and taking into account international regulatory developments, arrived at the following recommendations on the CV risks and the use of this class of drugs : Non-selective NSAIDs are important treatments for arthritis and other anti-inflammatory and painful conditions. Non-selective NSAIDs may be associated with a small increase in the absolute risk of cardiovascular events (e.g. myocardial infarction and stroke), especially when used at high doses for long-term treatment. All NSAIDs should be prescribed at the lowest effective dose and the duration of treatment should be periodically reviewed and kept as short as possible. 1 2
ISSN: 0219 2152 August 2007 Vol.9 No.2

All NSAIDs should not be used perioperatively in patients who h ave rec ently und erg on e C ABG su rge ry a nd revascularisation procedures.

Review of the new CV data on the older NSAIDs Unlike the placebo-controlled, randomised clinical trials which have provided strong evidence of an increased CV risks for the newer coxibs, the new data on CV risks of the older NSAIDs were derived largely from pooled analysis of randomised trials, cohort studies and case control studies.1-5 As it is unlikely that large prospective clinical trials will be conducted on the older NSAIDs, and given the potentially serious nature of the adverse events being considered, HSA and its PVAC have assessed that there was sufficient information from the pooled analyses to allow general conclusions to be made on the CV profile of the non-selective NSAIDs. Overall, the data suggest that older NSAIDs may be associated with a small but increased CV risks (e.g. myocardial infarction, stroke). With the exception of naproxen, other commonly used NSAIDs such as diclofenac, indomethacin, ibuprofen have consistently showed an unfavourable ratio in terms of CV thrombotic events when compared to placebo or when compared to the remote or non-use of anti-inflammatory drugs (see table 1 on page 2). Two of the studies have individually concluded that the extent of NSAID use appears to be the critical determinant in the relation of most NSAIDs to myocardial infarction 4 and that there was close association of the proximity 5 of NSAID use to myocardial infarction the longer the time from NSAIDs discontinuation, the weaker the association. Whilst it was previously hypothesized that the mechanism of COX-2 selectivity is related to higher CV risk, the recent data did not demonstrate this.
continued on Page 2
Update on NSAIDs & cardiovascular risk Reports of abnormal sleep-related events with zolpidem Nimesulide: Suspension of sales following signals of liver toxicities Risk of heart valve damage with pergolide & cabergoline

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Rosiglitazone: Update on cardiovascular safety profile Cardiovascular risks with the use of ADHD drugs Package insert amendments reflecting safety issues Reports of adverse reactions to traditional medicines (Santi Bovine Penis Erecting Capsule, Urat Madu, Asam Urat Flu Tulang)

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CONTENTS

Nimesulide: Suspension of sales following signals of liver toxicities

Doctors are advised to switch patients to alternative treatment options
imesulide, a non-steroidal anti-inflammatory drug (NSAID) was registered by HSA in 1999 for the treatment of acute pain, symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea. It is marketed under five different brands in Singapore: Nidol Tablet, Nidol Satchet, Nimotas-CD Tablet, Nise Tablet and Qnim MD Tablet. HSA has suspended the sales of all oral products of nimesulide The Health Sciences Authority (HSA) has been closely monitoring the liver toxicity profile of this product since 2004, following concerns arising from isolated local ADR reports of liver injury suspected to be associated with the product. Recently, the Irish Medicines Board suspended the sales of all oral nimesulide-containing products in Ireland following signals of an increased risk of liver toxicity. In light of the development in Ireland, a risk versus benefit assessment of nimesulide was conducted by HSA with the conclusions highlighted in the table below. effective 8 June 2007. Physicians are advised not to prescribe the drug to new patients and to consider switching patients currently on nimesulide to alternative treatment options. HSA has issued a Dear Healthcare Professional Letter on 11 June 2007 to all registered doctors, pharmacists and dentists to alert them to the above findings and HSAs decision to suspend the sales of all oral nimesulide products in Singapore. For details of the DHCPL, please log onto the Health Professionals Portal at http://www.hpp.moh.gov.sg Summary of review outcome by HSA The risk-benefit balance of nimesulide is deemed unfavourable because of the potential of an increased risk of serious hepatic reactions which are unpredictable when compared to other NSAIDs and the availability of alternative treatment options.

continued from Page 1 ( Updates on non-selective NSAIDs and cardiovascular risk )

Table 1*: Summary of results for diclofenac, indomethacin, ibuprofen & naproxen Statistical endpoint Diclofenac Ibuprofen for CV risk
Kearney et al (2006)1 McGettigan and Henry(2006)2 Hernandez-Diaz et al (2006)3 Rate ratio (95%CI) Combined risk estimates (95% CI) Relative Risk (95% CI) 1.63 (1.12-2.37) 1.40 (1.16-1.70) 1.44 (1.32-1.56) 1.51 (0.96-2.37) 1.07 (0.97-1.18) 1.07 (1.02-1.12)

Indomethacin
1.30 (1.07-1.60) -

Naproxen
0.92 (0.67-1.26) 0.97 (0.87-1.07) 0.98 (0.92-1.05)

* This is a summary table. Please refer to the respective journal articles for the studies included, detailed results, statistical methods employed & results on other antiinflammatory drugs not listed above.

HSAs follow up actions HSA will be working with the relevant drug companies to strengthen the labelling information in the package inserts of the older NSAIDs to reflect the CV safety concerns.
References 1) BMJ 2006 Jun; 332:1302-08. 2) JAMA 2006 Oct; 296:E1-E12. 3) Basic Clinic Pharmacol Toxicol. 2006 Mar; 98(3):266-74. 4) Pharmacotherapy 2006 Oct; 26:137987. 5) Eur Heart J 2006 Jul; 27:1657-63.

Adverse Drug Reaction News August 2007 Vol.9 No.2

Reports of a b n o r m a l s l e e p - r e l a t e d e v e n t s w i t h zolpidem
Actions by US FDA The US Food and Drugs Administration (FDA) has after reviewing the available post-marketing adverse event information, requested for all sedative-hypnotics (13 in total) in the US to strengthen their product labelling to warn of risks of complex sleep-related behaviours, which may include sleep-driving, making phone calls, and preparing and eating food while asleep. Local reports Recently, HSA has received four reports - two of abnormal sleep-related events, one of amnesia with a dream-like state and one of sleep-walking associated with the use of zolpidem. The ADRs were reported in three Chinese females and a Eurasian female with an age olpidem (Stilnox, Sanofi-Aventis) has been licensed for use in Singapore since 1993 for the treatment of severe sleep disorders in occasional insomnia and transient insomnia. It is structurally unrelated to the benzodiazepines, but has similar sedative-hypnotic actions. range of 40 to 76 years old and who have been taking zolpidem for 22 to 68 days before the onset of the ADR. Although the presence of confounding factors such as the use of concomitant drugs have made causality assessment difficult, the association between the events and zolpidem cannot be ruled out. In addition, the use of higher than recommended The situation in Australia Recently, the Australian Therapeutic Goods Administration (TGA) highlighted numerous domestic reports of abnormal and bizarre sleep-related behaviours associated with zolpidem. In 2002, the TGA noted that an approximate 75% of the reports received for zolpidem described one or more neurological or psychiatric reactions (visual hallucinations, confusion, depression and amnesia). There were also numerous reports describing sleeping or falling asleep and 16 reports of sleep-walking describing inappropriate or automatic behaviour while as leep , inc lu ding b in ge ea tin g and h ou se pa intin g. TGA subsequently strengthened the product labelling to warn of abnormal sleep-related behaviour associated with zolpidem and that zolpidem is not to be taken with alcohol. The TGA has recommended that prescribers be alert to this fact and to warn their patients (especially first-time users) of these effects. TGA will also be updating the package insert of another similar non-benzodiazepine, zopiclone to warn of these unusual adverse effects. The local package insert of Stilnox will be updated to warn of the possible occurrence of abnormal sleep-related events in patients taking zolpidem. Healthcare professionals are encouraged to report any such suspected ADRs to the sedative-hypnotic class of drugs.
References 1) FDA News. March 14, 2007. http: //www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html 2) Australian Adverse Drug Reactions Bulletin, Vol. 26, No.1. Feb 2007 3) Report of TGA regulatory actions related to zolpidem (Stilnox) http://www.tga.gov.au/alerts/stilnox.htm

dosages could be contributory to the occurrence of the event.

HSAs actions and advisory In view of the local and international reports of bizarre sleep related disorders, HSA advises all healthcare professionals to be alert to possible abnormal sleep-related events such as sleep-walking, sleep-binging and sleep-driving in patients who are taking zolpidem.

Adverse Drug Reaction News August 2007 Vol.9 No.2

Risk of heart valve damage with pergolide and cabergoline

An update on the risk of heart valvulopathy and registration status of these products in Singapore
wo recent case-control studies published in the New England Journal of Medicine 1,2 reported that pe rg olid e and c abe rg oline, wh ich are ergot-derived dopamine agonists, commonly used in Parkinson's disease may be associated with a higher than expected increased risk of heart valvulopathy. The study by Rene Schade et al 1 demonstrated that the association between the use of pergolide or cabergoline and heart valvulopathy. They identified 31 cases of clinically or echocardiographically diagnosed, new-onset heart valve regurgitation among 11,417 patients in the UK General P ra c tic e Re s ea rc h Da tab a s e w ho w ere p re sc rib ed anti-Parkinson's disease agents from 1988 to 2005. Of the 31 cases, 6 were exposed to pergolide, 6 to cabergoline and 19 had not been exposed to any dopamine agonist in the previous 12 months. The incidence rates of newly diagnosed cardiac-valve regurgitation were 30 per 10,000 per year for pergolide, 33 per 10,000 per year for cabergoline, and 5.5 per 10,000 per year for no exposure to any dopamine agonist. The rate of heart valve regurgitation was increased in those on pergolide (incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not in the group on other dopamine agonists. The study also concluded that the risk was particularly high among patients who had taken daily doses of pergolide or cabergoline > 3mg; the risk was increased only among those who had taken either drug for 6 months or more. The risk was not increased among patients treated with other dopamine agonists i.e. bromocriptine, lisuride, pramipexole and ropinirole. In another article, Renzo Zanettini et al2 studied 155 patients

Proposed mechanism of heart valve damage It has been proposed that the valvular damage induced by the ergot-derived dopamine agonists may be mediated by the serotoninergic system. Drugs like pergolide and cabergoline have shown to be potent agonists of the serotonin (also known as 5-hydroxytryptamine) receptor subtype 5HT2B, which is expressed in heart valves to mediate mitogenesis. Proliferation of fibroblasts (which could lead to inducing valvular fibroplasias) may therefore occur within valve tissue when the 5HT2B receptors are stimulated.1,2 Appetite suppressants such as fenfluramine and dexfenfluramine are also known to interact with the 5HT2B receptor; and both drugs were withdrawn worldwide in 1997 due to increased risk for serious damage to the heart valves. Pergolide Pergolide is used with levodopa and carbidopa for the treatment of Parkinsons disease. Valvular heart disease was first described in association with pergolide in 2002. However, the recent studies suggest that the condition might occur more frequently than what earlier post-market reports suggested. In light of the additional safety information and the availability of alternative treatments for Parkinsons disease that do not have comparable safety problems, pergolide was voluntarily withdrawn from the US market on 29 March 2007. It is still available and marketed in other countries including Australia, Canada, and the United Kingdom. Pergolide (Celance 0.05mg and 0.25mg) has been registered by HSA since 1992. However, the product has not been marketed in Singapore since July 2005 due to low demand . HSA has received four local reports of heart valvular abnormalities associated with pergolide. Patients were Chinese men, age between 55 and 71 years. They had been taking pergolide for 1.7 to 5.2 years before they were found to have aortic, mitral and/or tricuspid regurgitation after screening. Cabergoline Cabergoline (Dostinex 0.5mg, Pfizer) has been registered in Singapore since 1997. It is indicated for the inhibition of physiologic lactation soon after parturition and suppression of established lactation. It is also licensed for the treatment of hyperprolactinaemic disorders. Cabergoline is not marketed for the treatment of Parkinsons disease in some countries including Singapore, US and Canada. The dose of cabergoline for the treatment of Parkinsons disease (26mg per day) is higher than the dose recommended for hyperprolactinaemic disorders (0.252mg per week). Although the risk of heat valvulopathy is reported in the two studies to be associated with the use of higher doses of cabergoline, prescribers should nevertheless be aware of the potential risk of valvulopathy, especially when the drug is used long-term.
References 1) N Engl J Med 2007 Jan 4; 356(1):29-38. 2) N Engl J Med 2007 Jan 4; 356(1):39-46.

taking dopamine agonists and 90 healthy control subjects. The frequency of clinically important valve regurgitation (moderate to severe, grade 3 to 4) was significantly higher in 23.4% of those on pergolide (n=15) and 28.6% of those on cabergoline (n=14) as compared to the group on non-ergot derived dopamine agonists (0%) and control subjects (5.6%). It was observed that patients with grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than those with lower grades.
Adverse Drug Reaction July 2007 Vol.9 No.2

Rosiglitazone: Update on cardiovascular safety profile

ongoing randomised, multicentre, open-label non-inferiority trial involving 4,447 patients in the NEJM on 5 Jun 2007. The RECORD study compares 2,200 patients on rosiglitazone dual therapy (plus metformin or sulfonylurea) with 2,227 patients on a combination of metformin plus sulfonylurea (control group). After a mean follow-up of 3.75 years, 217 patients in the rosiglitazone group and 202 patients in the control group experienced a statistically non-significant difference for the primary end point of hospitalisation or death from CV causes (hazard ratio 1.08; 95% CI 0.891.31; p=0.43). A statistically significant difference between the rosiglitazone and control group was seen only in the secondary outcome of congestive heart failure (hazard ratio 2.15; 95% CI 1.303.57). One of the limitations of the study was the lack of statistical power due in part to withdrawal of patients from the trial, higherthan-expected numbers of patients who were lost to follow-up, and unexpectedly low rates of the primary end point in both groups. The trial targets to be completed in late 2008. C) Other studies Two other large studies, namely A Diabetes Outcome and Progression Trial (ADOPT) 3 , and the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM)4 do not show an increased in the risk of cardiac ischaemic events with rosiglitazone. However, a recent pooled analysis of 42 clinical trials submitted by GSK to the US Food and Drug Administration (FDA) which included 8,604 patients on rosiglitazone and 5,633 patients randomised to a variety of alternative therapeutic regimens, including placebo suggest that the overall incidence of myocardial ischaemia in rosiglitazone-treated subjects relative to the comparators were 1.99% versus 1.51% with a hazard ratio of 1.3 (95% CI 1.011.70). This data is still being analysed by the US FDA due to the complexity of the data sets. HSAs advisory The various studies provide contradictory findings on the ischaemic CV risk of rosiglitazone. HSA will continue to keep rosiglitazone under close surveillance for CV effects (i.e. cardiac failure, myocardial infarction) and monitor the international developments in this area. Healthcare professionals will be updated on new developments in this area when the data becomes clearer. In the interim, prescribers should continue to carefully make individualised treatment decisions for patients with diabetes mellitus. It is advised that patients on Avandia should be closely monitored for signs and symptoms of heart failure, fluid retention, oedema and rapid increases in weight. Healthcare professionals are encouraged to report all serious adverse effects suspected to be associated with thiazolidinediones (i.e. rosiglitazone, pioglitazone) to the Pharmacovigilance Unit.
References 1) N Engl J Med 2007 Jun 14; 356(24):2457-71 (Epub May 21). 2) N Engl J Med 2007 (Epub Jun 5). 3) N Engl J Med 2006 Dec 7; 355(23):2427-43. 4) Lancet 2006 Sept 23; 368:1096-105. Adverse Drug Reaction News August 2007 Vol.9 No.2

osiglitazone (Avandia, GlaxoSmithKline) is an oral agent for the treatment of type 2 diabetes mellitus belonging to thiazolidinediones (also called glitazones class of drugs). It has been registered by HSA since 2000 for use as an adjunct to diet and exercise; as monotherapy or in combination with metformin or a sulfonylurea to reduce insulin resistance and lower elevated blood glucose in patients with type 2 diabetes mellitus. Avandamet is another registered product containing a combination of two active ingredients, rosiglitazone and metformin. The risk of cardiac adverse events (i.e. heart failure, fluid retention, oedema) is known to be associated with the thiazolidinediones class of drugs. Recently, concerns have been raised about the possible elevation of ischaemic cardiovascular (CV) risk with rosiglitazone therapy. Literature reports A) Meta-analyses of effect of rosiglitazone on the risk of myocardial infarction and death from CV causes An article published by Nissen and Wolski1 in the New England Journal of Medicine (NEJM) on 21 May 2007 raised concern about the possibility of a small increased risk of myocardial infarction and CV death in about 15,500 patients treated with rosiglitazone compared with 12,282 who were assigned to comparator groups with regimens that did not include rosiglitazone. The study which was a meta-analysis of 42 clinical studies noted a statistically significant increased risk of myocardial infarction (OR 1.43; 95% CI 1.031.98, p=0.03) and a statistically non-significant increase in the risk of CV death (OR 1.64; 95% CI 0.982.74, p=0.06) associated with the use of rosiglitazone in comparison to the use of a placebo or other anti-diabetic therapies e.g. metformin, insulin and sulfonylureas. In absolute numbers, the pooled analyses revealed a combined total of 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. There were 39 deaths from CV causes in the rosiglitazone group and 22 in the control group. The findings of this study have caused considerable debate, largely due to several methodologic limitations. These include pooled data from trials that were not originally intended to explore CV outcomes, short duration of trial periods (24 52 weeks), information based on publicly available sources and not on original source data of trials. B) Interim findings of the rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes (RECORD) study In response to recent CV concerns with rosiglitazone, Home et al2 published an unscheduled interim analysis of an

Cardiovascular risks with the use of ADHD drugs

B) UK Medicines and Health products Regulatory Agency (MHRA) The UK MHRA was concerned with the 25 cumulative serious cases of QTc prolongation reported in Eli Lillys overview report (covering 26 November 2002 - 26 May 2005) on spontaneous adverse event reports, studies and literature reports. The review of this data led the UK MHRA to strengthen the label of atomoxetine to include precautions on use in patients with a history of CV problems including QTc prolongation. C) Australian Therapeutic Goods Administration (TGA) The Australian Drug Evaluation Committee (ADEC) of the h e H ea l th S ci e nc e s A u th o rity (H S A ) a n d its Pharmacovigilance Advisory Committee (PVAC) will be strengthening the cardiovascular (CV) labelling of Attention Deficit Hyperactivity Disorder (ADHD) drugs following a review of the data of the reports of sudden death and CV risks from the US Food and Drug Administration (FDA)1,2 and the UK Medicines a nd H e alth p rod u c ts Re gu la to ry A g en c y (MH RA ). 3 The labelling changes will caution on using ADHD drugs in patients with structural cardiac abnormalities or other serious heart problems and recommend assessment by a cardiologist for these patients before initiating treatment. The ADHD drugs that are available locally are methylphenidate (a CNS stimulant) and atomoxetine (a norepinephrine re-uptake inhibitor). There are three licensed products carrying methylphenidate namely, Ritalin (Novartis), Concerta (Johnson & Johnson) and Rubifen (Zyfas Medical) and one product containing atomoxetine, Strattera (Eli Lilly). Assessment by HSAs PVAC and follow up actions by HSA To date, HSA has not received any ADR reports associated with atomoxetine or reports of sudden death associated with methylphenidate. Nevertheless, based on the PVACs assessment of the pharmacology of the drugs and the plausibility of the ADR occurrences, HSA advises healthcare professionals to exercise caution when using ADHD drugs in patients (including children) with structural cardiac abnormalities or other serious heart problems. An assessment by a cardiologist is recommended in patients with existing structural cardiac abnormalities or other serious heart problems before initiating treatment with ADHD drugs, followed by supervision of cardiac function throughout A) US Food and Drug Administration (FDA) From the US FDA Adverse Event Reporting System (AERS) safety database, there were 14 paediatric and four adult sudden death cases reported with methylphenidate for the period January 1992 to February 2005. Of these 14 paediatric cases, six had a documented structural CV abnormality that may have increased the risk of death. As a result of these findings, the US FDA strengthened the labels for methylphenidatecontaining products to include warnings of sudden death in patients with structural cardiac abnormalities. For atomoxetine, a total of seven cases of sudden death were reported in three children and four adults taking atomoxetine at therapeutic doses. The US labelling for atomoxetine has also been strengthened to include the above warnings.
Adverse Drug Reaction News August 2007 Vol.9 No.2

Therapeutic Goods Administration (TGA) has also separately reviewed the safety of ADHD drugs, examining the sudden death, CV disease and psychiatric adverse events associated with these medicines.4 The ADEC recommended the inclusion of warnings relating to the use of these drugs in patients with CV disease including cardiac structural abnormalities. It also included the recommendation that these patients require the assessment by a cardiologist before the initiation of treatment.

Findings and actions taken by international regulatory agencies

treatment. Caution in using ADHD drugs should also be exercised in CV conditions such as severe hypertension, heart failure, recent myocardial infarction and atherosclerosis. In addition, atomoxetine should also be used with caution in patients with congenital or acquired QT prolongation and those with a family history of QT prolongation. The local package inserts of the affected ADHD drugs will be updated to include the above CV safety information.
References 1) US FDA safety review. 27 Apr 2004. 2) US FDA safety review. 28 Feb 2006. 3) MHRA: Strattera (Atomoxetine) Preliminary assessment report December 2005. 4) ADEC 247th Meeting minutes, 4 Aug 2006.

Package insert amendments reflecting safety issues

HSA has approved the following package insert changes due to safety updates from February to May 2007. Details of the updates are listed at http://www.h sa.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. Adalimumab (Humira, Abbott) Limited safety experience of surgical procedures & arthroplasty in patients treated with Humira. Long half-life of adalimumab should be taken into consideration if a surgical procedure is planned; monitor surgical patients for infections. New ADRs: interstitial lung disease including pulmonary fibrosis, reactivation of hepatitis B & demyelinating disorders e.g. optic neuritis. 2. Alendronate (Fosamax, MSD) Caution : localised osteonecrosis of the j aw has occurred in patients with postmenopausal osteoporosis. 3. Allopurinol (Zyloric, GSK) Require dose reductions of didanosine when used concomitantly as plasma didanosine Cmax & AUC may be doubled. 4. Bevacizumab (Avastin, Roche) Warnings: i) Caution in metastatic carcinoma of colon or rectum due to increased risk for gastrointestinal perforations; ii) Discontinue in patients who develop hypertensive encephalopathy; iii) Not to use in patients with CNS metastases; iv) Reversible Posterior Leukoencephalopa thy S yndrome (RPLS) has been rarely reported & treatment includes control of hypertension with discontinuation of Avastin. 5. Bromazepam (Lexotan, Roche) Benzodiazepines may induce anterograde amnesia at higher dosages (e.g. 6 mg), risk increases at higher dosages. Co-administration of cimetidine may prolong the elimination half-life of bromazepam. An increased risk for falls & fractures has been recorded in elderly benzodiazepine users. 6. Calcitonin (Miacalcic Nasal spray & injection, Novartis) Concomitan t use with lithium may lead to a reduction in plasma lithium concentrations. May cause fatigue & visual disturbances hence patients must be warned not to drive or use machines. New ADRs: dysgeusia & visual disturbance. 7. Carbamazepine (Tegretol, Novartis) Contraindicated in patients with history of hepatic porphyrias e.g. variegate porphyria, porphyria cutanea tarda. 8. Clomipramine (Anafranil SR, Novartis) Dose increase should be made with caution especially if drugs that prolong QT interval are co-administered. Observe for suicidality & other psychiatric symptoms in children & adolescents, & to discontinue if needed. Families & caregivers of patients should monitor for psychiatric symptoms. Caution in those with history of increased intraocular pressure, narrow-angle glaucoma & urinary retention e.g. diseases of the prostate. 9. Diphtheria, tetanus, pertussis toxoids (Infanrix & Infanrix-IPV, GSK) Warnings: children with progressive neurological disorders like infantile spasms, uncontrolled epilepsy or progressive encephalopathy, it is better to defer pertussis immunization until the condition i s corrected or stable. New ADRs: Diffuse swelling of injected limb, sometimes involving adjacent joint (uncommon). Swelling more likely when children primed with acell ular pertussis vaccines vs whole cell vaccine; swelling may be more frequent when booster dose is given between 4 & 6 years resolving over an average of 4 days. Swelling of entire injected limb has been reported. 10. Fludarabine (Fludara, Zuellig) Individual dosing should be carefully adjusted according to the observed haematological toxicity. (Please refer to PI for details on dosing regimen). Contraindicated in decompensated haemolytic anaemia. 11. Heparin Sodium (Heparin Injection, Mayne Pharma) Cautions: when neuraxial (epidural/spinal) anaesthesia or spinal puncture is employed, patients on or scheduled to be on heparin are at risk of developing an epidural or spinal haematoma which can result in long term or permanent paralysis. Risk of haematoma is increased by use of indwelling e pidural catheters for administration of analgesia or by concomitant use of drugs affecting haemostasis e.g. NSAIDs, platelet inhibitors, anticoagulants. 12. Human chorionic gonadotrophin (hCG) (Pregnyl, Organon) Warnings: i) Early confirmation of intrauterine pregnancy is important for women undergoing assisted reproduction particularly IVF as they oft en have tubal a bnormalities & i ncidence of ectopic pregnancies might be increased; ii) Rates of pregnancy loss in women undergoing ART are higher than in normal population; iii) Presence of uncontrolled non-gonadal endocrinopathies e.g. thyroid, adrenal or pituitary disorders, should be ruled out; iv) Women prone to thrombosis m ay have increased risk of venous or arterial thromboembolic events during or following treatment; v) Not to use for body weight reduction as hCG ha s no effect on fat metabolism & distribution or appetite. 13. Human Papillomavirus (Gardasil, MSD) New ADRs: dizziness, syncope, nausea, vomiting, anaphylactic/ anaphylactoid reactions, bronchospasm & urticaria. 14. Isosorbide-5-mononitrate (Imdur, AstraZeneca) Phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil & vardenafil) is contraindicated with Imdur durules. Concomitant administration can result in syncope or myocardial infarction. 15. Lamotrigine (Lamictal, GSK) Caution in patients with a history of allergy or rash to other antiepileptic drugs as the frequency of non-serious rash after treatment with Lamictal was ~3 times higher than those without such history. 16. Lignocaine (Xylocaine Injection & Spray, AstraZeneca) Precautions: i) Central nerve blocks may cause cardiovascular depression in the presence of hypovolaemia. Epidural anaesthesia may lead to hypotension & bradycardia; use with caution when cardiovascular function is impaired; ii) Fet al tachycardia frequently follows paracervical block & may be associated with fetal acidosis & hypoxia; iii) Patients on anti-arrhythmic drugs class III e.g. amiodarone, should be under close surveillance & ECG monitoring since cardiac effects may be additive. New ADRs: hyperacusis, paraesthesia circumoral, numbness of tongue, cardiac arrhythmias, hypertension, shock, peripheral nerve injury & arachnoiditis. 17. Mirtazepine (Remeron, Organon) Bone marrow depression (granulocytopenia or agranulocytosis) has been reported. Rarely, agranulocytosis can be fatal which is seen in patients > 65 year s. Careful do sing, regular & close monitori ng is needed in patients with epilepsy & organic brain syndrome, hepatic or renal insufficiency, cardiac diseases like conduction disturbances, angina pectoris, recent MI, & low blood pressure. Caution in those with micturition disturbances like prostate hypertrophy, acute narrow-angle glaucoma & increased intra-ocular pressure, diabetes mellitus, & schizophrenia. Worsening of psychotic symptoms can occur. Depressive phase of manic-depressive psychosis can transform into manic phase. Should not use in children & adolescents < 18 years old as suicide-related behaviours & hostility were more frequently observed in clinical trials. Serotonin syndrome occurs very rarely in patients treated with mirtazepine alone or in combination with SSRIs or venlafaxine. 18. Nadroparin (Fraxiparine, GSK) New ADRs: thrombocytosis, anaphylactoid reaction, calcinosis at injection site. Caution in impaired renal function due to increased risk of bleeding. 19. Pemetrexed (Alimta, Eli Lilly) Warning: Possible suppression of bone marrow function i.e. pancytopenia. New ADR: colitis (rare). 20. Piroxicam (Fel dene, Pfizer) Contraindicated in the treatment of peri-operative pain in the setting of coronary artery bypass graft surgery, severe heart failure, severe renal & hepatic failure. Warnings: i) Avoid concomitant use with NSAIDs including COX-2 inhibitors; risk of serious cardiovascular thrombotic events, myocardial infarction & stroke; ii) Caution in compromised cardiac function & other conditions worsened by fluid retention; iii) Consider lower doses in severe dehydration & kidney disease; iv) Stevens Johnson syndrome & toxic epidermal necrolysis are rarely reported; highest risk for serious skin reactions is during 1st month of treatment. Drug interactions: diuretics, cardiac glycosides, cholestyramine, corticosteroids, cyclosporin, methotrexate & tacrolimus. New ADRs: anorexia, aseptic meningitis, dermatitis exf oliative, erythema multiforme. 21. Pregabalin (Lyrica, Pfizer) Congestive heart failure has been observed postmarket; use with caution in CHF patients. Lyrica should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels or symptoms of myopathy occur. 22. Salmeterol/ Fluticasone (Seretide Accuhaler, GSK) Warning: increased reporting of pneumonia in studies of patients with COPD receiving Seretide. Hypersensitivity reactions e.g. anaphylactic shock have been reported very rarely. 23. Sevoflurane (Sevorane, Abbott) Warnings: serum potassium levels may be increased & result in cardiac arrhythmias & death in paediatric patients during postoperative period, especially in patients with latent & overt neuromuscular disease, particularly in Duchenne muscular dystrophy & concomitant use of succinylcholine has been associated with most of these cases. Early & aggressive intervention to treat hyperkalaemia & resistant arrhythmias & subsequent evaluation for latent neuromuscular disease is recommended. New ADRs: transient elevations or changes in glucose & white blood cell count, hepatic function tests, post-operative hepatitis (rare), hepatic failure (rare) & necrosis (rare); dystonic movement with spontaneous resolution in children, seizure-like activity of short duration, malignant hyperthermia, bronchospasm, anaphylactic or anaphylactoid reactions. 24. Telmisartan/ Hydrochlorothiazide (Micardis Plus, Boehringer Ingelheim) New ADRs: hyperkalaemia, syncope/faint, orthostatic hypotension, abn ormal hepatic function/ liver disorder, increase in blood creatine kinase. The potential for acute renal insufficiency in patients who are dehydrated may be enhanced, hence patients receiving both NSAIDs (i.e. ASA
3g/day & COX-2 inhibitors) & Micardis Plus should be adequately hydrated & be monitored for renal function at the beginning of combined treatment. 25. Terazosin (Hytrin, Abbott) Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients on/or previously treated with alpha-1 blockers. 26. Terbutaline (Bricanyl, AstraZene ca) New ADRs: nausea & tachycardia. As for all beta 2-agonists, cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia & extrasystoles have been rarely reported. Other products with labelling changes include Atenolol/Chlorthialidone, Bicalutamide, Doxazosin, Epoprostenol, Everolimus, Methylprednisolone, Mycobacterium bovis (BCG), & Oxybutynin.

Adverse Drug Reaction July 2007 Vol.9 No.2

Reports of adverse reactions to traditional medicines

he ADR reports received by HSA are not limited to that of western medicines. During the past two years, we found 15 reports related to the consumption of adulterated illegal traditional medicines. As some patients may not consider traditional medicines such as herbal remedies as medicines, healthcare professionals are reminded to ask patients about use of traditional medicines, when investigating suspected adverse reactions. In recent months, the HSA has issued three media advisories alerting the public against taking the following three products which have been found to be adulterated with potent western medicinal ingredients. Santi Bovine Penis Erecting Capsule The product was sent for analytical testing and found to be adulterated with about 32mg of sildenafil per capsule. A 76-year old male patient was reported to have experienced loss of vision in both eyes after Santi Bovine Penis Erecting Capsules bought from a roadside peddler. He had been taking the capsules for a few months but stopped for 20 days before he took another dose of three capsules two days before presentation of the adverse drug reaction. Clinical examination suggested bilateral posterior ischaemic optic neuropathy (PION) as the cause of vision loss. The patient has a medical history of hypertension, hyperlipidaemia and stroke, and was on atenolol, diltiazem and simvastatin. There have been rare worldwide reports of ischaemic optic n e uro p a th y (I ON ) a mo n g p a tie n ts u s in g ma rk e ted phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil, tadalafil and vardenafil. The majority of sildenafil cases appear to be cases of non-arteritic anterior ischaemic optic neuropathy (NAION) unlike the local case. However, it is not Urat Madu Urat Madu, a Jamu medicine was tested to contain sildenafil. Each capsule was found to contain about 48 mg of sildenafil. A 55-year old male patient who had been taking the product had blurring of vision in his right eye for two months before consulting a doctor. The product bought in Batam was labelled to have aphrodisiac properties for persons with impotency. The patient was reported to be taking 12 capsules as and when required before sexual activities. Asam Urat Flu Tulang, PJ. Dewandaru A 22-year old female patient was rep o rte d to d e ve lop dru g hype rsensitivity s yndro me, characterised by erythematous ra s h , ur tic ar ia l v as c u liti s, periorbital swelling, elevated white cell count, esinophilia and transaminitis. She was taking Asam Urat Flu Tulang, two capsules daily for four weeks and was not on other medications. The product labelled to contain mainly herbal ingredients was indicated to treat joint pain, rheumatism and arthritis. The label advised to increase the dose to two capsules three times daily if needed. Upon laboratory testing, it was found to be adulterated with 22mg of diclofenac, 0.25mg of dexamethasone and 205mg of paracetamol per capsule. These amounts of active ingredients are within the therapeutic daily doses of each component. certain whether these events are related directly to the use of PDE-5 inhibitors, to the patients underlying vascular risk factors or anatomical defects, to a combination of these factors, or other factors.

Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Staff Editors Dr Yvonne Koh, BSc (Pharm) Hons, PhD Ms Adena Lim, BSc (Pharm) Hons, MPharm (Clin Pharm) Ms Tan Bee Him, BSc (Pharm) Ms Belinda Tan, BSc (Pharm) 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

Enquiries, comments and suggestions to: Pharmacovigilance Unit Centre for Drug Administration Health Products Regulation Group 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

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 accep t no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or stateme nts. The mention of any product by the authors does not imply any official endorseme nt of the product by the Health Sciences Authority.

Copyright 2007 Health Sciences Authority of Singapore. All Rights Reserved.

Adverse Drug Reaction News August 2007 Vol.9 No.2