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

Safety update on gatifloxacin

Contraindicated in patients with diabetes mellitus and use with caution in patients at risk of dysglycaemia

SA would like to draw the at tention of healthcare professionals to the known adverse effects of hypoglycaemia and hyperglycaemia associated with gatifloxacin (Tequin, Bristol-Myers Squibb) , a fluoroquinolone Very rare cases of antibiotic, and the recent serious blood glucose contraindication disturbances have on the use of the drug in patients been reported with with diabetes mellitus. gatifloxacin.

receiving concomitant medications that may have contributed to the glucose abnormality. A few of these cases resulted in fatalites. The patients particularly at risk include diabetics and the elderly (>75 years of age) who may have unrecognised diabetes, age-related decrease in renal function, underlying medical problems, and/or are taking concomitant medications associated with dysglycaemia. However, dysglycaemia has been reported to occur in patients without a history of diabetes. In a phase IV surveillance trial, Tequin Clinical Experience Study (TeqCES) which included over 15,000 patients, it was found that 0.007% of nondiabetic patients and 1.3% of diabetic patients experienced hyperglycaemia events, while 0.03% of nondiabetic patients and 0.64% of diabetic patients had hypoglycaemic events. (1) In total, serious cases of glucose disturbances were reported in 0.03% of the total study population. These events were reversible with management, which included discontinuation of the drug.

Post-marketing data Serious cases of both hypoglycaemia and hyperglycaemia have been reported with gatifloxacin during post-marketing surveillance.
From the overseas spontaneous postmarketing reports, it was noted that cases of blood glucose disturbances usually occurred in diabetic patients. There were very rare events of hypoglycaemia and hyperglycaemia which were life-threatening. In the majority of cases, the patients had other underlying medical problems and were

Effect on controlled type II diabetes mellitus Studies on the effect of gatifloxacin have been conducted in patients with type II diabetes mellitus controlled on oral hypoglycemic agents. Gatifloxacin has been demonstrated to be associated with transient disturbances in glucose homeostasis, including an increase in serum insulin and decrease in serum glucose following administration of initial doses (i.e. first two days of treatment). This is sometimes associated with symptomatic hypoglycaemia. In addition, increases in fasting serum glucose were observed, usually after the third day of gatifloxacin administration and continuing throughout the duration of treatment. The levels return
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ISSN: 0219 - 2152 March 2006 Vol.8 No.1

1 2 3 4

Safety update on gatifloxacin Letrozole & adverse outcome in babies following maternal exposure Bosentan & serious liver injury Package insert amendments reflecting safety issues

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Analysis of ADR reports for year 2005 Summary of advisories issued by HSA and companies Rosiglitazone & macular oedema

CONTENT

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continued from Page 1 Safety update on gatifloxacin

to pre-dose values by 14 days after the completion of treatment.

Local situation Locally, HSA has received an adverse drug reaction (ADR) report of an 84 - year-old male patient who experienced hypoglycaemia after two days of therapy with gatifloxacin. The patient was on other concomittant medications such as nifedipine, candesartan and clopidogrel. He subsequently recovered from the ADR. Recommendations In light of the post-marketing experience, to ensure the safe and effective use of Tequin, the company, Bristol-Myers Squibb is recommending a contraindication on the use of Tequin in patients with diabetes mellitus. The local package insert of Tequin will be updated to reflect this new safety information.
Physicians are advised to closely monitor the blood glucose of nondiabetic patients who are at risk of dysglycaemic events for signs and symptoms of blood glucose disturbances. Risk factors include older age, renal insuf ficiency, drug interactions with glucose -altering medications (such as anti-diabetic agents like glibenclamide). If signs and symptoms of either hypoglycaemia or hyperglycaemia occur in any patient treated with gatifloxacin, appropriate therapy should be initiated immediately and gatifloxacin should be discontinued. Physicians are reminded to report any suspected ADRs to gatifloxacin to the Pharmacovigilance Unit of the HSA
Reference: 1. BMS letter to doctors in Canada: Important Safety Information on Tequin (gatifloxacin), 19 Dec 2005.

Concern on off-label use of letrozole in treating infertility

Letrozole and adverse outcome in babies following maternal exposure

has warned about potential embryo- and fetotoxicity with or without teratogenicity, including contraindications for use in women with premenopausal endocrine status as well as pregnancy and lactation.

ovartis has issued a Dear Healthcare Professional Letter to alert our healthcare professionals about its concern on the off-label use of letrozole (Femara, Novartis) in treating infertility, even though the package insert

B ac kgr ound ack ground Letrozole, an aromatase inhibitor, is used

in postmenopausal women with breast cancer. It is licensed for: Extended adjuvant treatment of early breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy.

First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer.

Treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status, who have previously been treated with anti-oestrogens.

Post-marketing data Adverse reports in babies following maternal exposure to letrozole has been observed
in a retrospective study and the companys adverse drug reactions database. A retrospective analysis (1) of the outcome of 150 babies following the treatment with letrozole alone or letrozole and gonadotropins at the Montreal Fertility Centre showed that the incidence of locomotor malformations (p=0.0005 95% CI=2.64-27.0) and cardiac anomalies (p=0.0006 95% CI=3.30-58.1) was higher than in the control groups. The company safety database contains 13 case reports of women exposed to Femara during pregnancy. Of the 13 reports, 4 reported adverse outcomes for the foetus (2 miscarriages and 2 birth defects), 3 of which involved the off-label use for infertility. Of the remaining 9 cases, 4 women had normal foetal ultrasounds and delivery while the outcome of the remaining 5 cases were unknown. To date, HSA has not received any ADR reports associated with maternal exposure of the drug. Novartis, in its letter recommends the use of letrozole within the labelled indications

Reference: 1. Fertility and Sterility 2005;84(S1):S95

Adverse Drug Reaction News March 2006 Vol.8 No.1 Page 2

Bosentan and serious liver injury

Patients on bosentan therapy should be closely monitored for elevations in serum aminotransferases

endothelin receptor antagonist indicated for the treatment of pulmonary arterial

osentan (Tracleer, Actelion Pharmaceuticals), licensed for use in Singapore in May 2004, is an

In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with bosentan in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of bosentan in these cases could not be excluded. In at least one case, the initial presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly overtime after discontinuation of bosentan. The combination of hepatocellular injur y (increases in aminotransferases of >3X ULN) and increases in total bilirubin (3X ULN) is a marker for potential serious liver injury. Serum aminotransferase levels must be measured before treatment initiation and monthly thereafter. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injur y (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin 2X ULN, treatment should be stopped. There is no experience with the reintroduction of bosentan in these circumstances. Bosentan should generally be avoided in patients with elevated

The combination of hepatocellular injury (increases in aminotransferases of >3X ULN) and increases in total bilirubin (3X ULN) is a marker for potential serious liver injury.

hyp er t en s io n

in

patients with World Health Organisation class III or IV symptoms, to improve exercise ability and d e crease t h e rat e of clinical worsening. It is k n own to

be associated with hepatotoxicity.

Amendments to the US package insert The US package insert (PI) of Tracleer was recently updated to include additional safet y i n forma t io n rela te d to t h e hepatotoxicity of the drug. The relevant section under Warning in the PI is extracted below (text highlighted in the

coloured box is the new amendment):

Elevations in ALT or AST by more than three times the upper limit of normal (ULN) were observed in 11% of bosentan-treated patients (N=658) compared to 2% of placebo-treated patients (N=280), along with elevated bilirubin to 3X ULN in 0.3% of patients treated with bosentan. Follow up action by HSA The local package insert of Tracleer would be updated to reflect the post-marketing experiences of liver toxicities associated with Tracleer aminotransferase levels (>3X ULN) at baseline because monitoring liver injury may be more difficult.

Adverse Drug Reaction News March 2006 Vol.8 No.1 Page 3

Package insert amendments reflecting safety issues

SA has approved the following package insert changes due to safety updates from September to December 2005. They are also listed at h t t p : / / w w w. h s a . g o v. s g / c d a / labelchanges. Please note that there might be some lag time in the availability of the package insert which reflects the latest change(s).
Ciprofloxacin (Ciprobay infusion, Bayer) Under special warnings and precautions, it is stated that the additional sodium in the infusion should be taken into account for patients with sodium restriction Clarithromycin (Klacid oral suspension, Abbott) New contraindications include use of clarithromycin with ergotamine and dihydroergotamine. Ergot toxicity (vasospasm, ischaemia of extremities, etc.) has been reported with concurrent use of clarithromycin with ergotamine or dihydroergotamine. There are postmarketing reports of torsades de pointes with concurrent use of clarithromycin with quinidine or disopyramide. Serum levels of these drugs should be monitored during treatment. Clarithromycin use with colchicine has been reported to cause colchicine toxicity especially in the elderly and renal-impaired Dothiepin (Prothiaden, Abbott) Under dosage, the dose for elderly is 50-75mg daily initially and increased with caution under close supervision. Half the normal adult dose may be sufficient for the elderly. New contraindications include recent myocardial infarction, any degree of heart block or other cardiac arrhythmias, mania and severe liver disease. It is warned that the elderly are particularly liable to agitation, confusion, delirium and postural hypotension. Avoid use in prostatic hypertrophy. Anaesthetics given concurrently may increase risk of arrhythmias and hypotension. Withdrawal of dothiepin should be gradual. New precautions added include possibility of suicide in depressed patients. Hence, patients should be monitored closely during the first 2-4 wks. Tricyclic antidepressants potentiate the CNS depressant activity of alcohol. New drug interactions include SSRIs and drugs that may affect cardiac conduction (e.g. sotalol, terfenadine, barbiturates) Erythromycin (E.E.S., Eryped, Erythrocin IV, Abbott) Under precautions: i) there have been reports of infantile hypertrophic pyloric stenosis occurring in infants following erythromycin therapy. Benefit of therapy should be weighed against risk and parents should contact their physician if vomiting or irritability with feeding occurs. ii) Erythromycin interferes with fluorometric determination of urinary catecholamines. Erythromycin is contraindicated in patients taking pimozide. Erythromycin given concurrently with theophylline may result in decreased erythromycin serum concentrations; there are rare reports of rhabdomyolysis with concurrent administration of erythromycin and HMG-CoA reductase inhibitors; the clearance of zopiclone has been reported to be decreased by erythromycin Galantamine (Reminyl, Janssen-Cilag) Under method of administration for film-coated tablets and oral solution of galantamine, there are some updates on dosing frequency in patients with moderately

impaired hepatic function. These patients should take 4mg once daily for at least 1 wk followed by 4mg twice daily for at least 4 wks. Daily doses should not exceed 8mg twice daily. For prolonged release capsules, patients with moderately impaired hepatic function should begin with 8mg every other morning for at least 1 wk, followed by 8mg once daily, not exceeding 16mg/day. Some new ADR terms include atrial arrhythmias, palpitations, depression (very rarely with suicidality), leg cramps, paraesthesia, seizures, tinnitus, transient ischaemic attack or cerebrovascular accident Isoflurane (Forane, Abbott) New warnings include markedly increase cerebral blood flow at deeper levels of anaesthesia; transient rise in cerebral spinal fluid pressure reversible with hyperventilation; increase blood loss comparable to that seen with halothane in patients undergoing uterine curettage; isolated cases of carboxyhaemoglobin with use of halogenated inhalational agents. New ADR terms include ileus, potentiation of muscle relaxants, hepatic injury (from liver enzyme elevations to fatal hepatic necrosis) malignant hyperthermia and irritation of airway Leuprolide (Lucrin, Abbott) Leuprolide should not be used in patients with undiagnosed vaginal bleeding. Spontaneous abortion may occur if leuprolide is given during pregnancy. It is not known whether leuprolide is excreted in human milk, hence it should be administered with caution to a nursing mother. It is contraindicated in use in women who may become pregnant or are pregnant. New warnings include possible worsening of preexisting signs and symptoms during the first wk of treatment, contributing to paralysis with possible fatal complications and that safety has not been established in pregnancy. New precautions include reversible bone mineral density changes during treatment and allergies to benzyl alcohol Lidocaine (Xylocaine Jelly 2%, AstraZeneca) Under precautions, patients treated with Class III antiarrhythmic drugs (e.g. amiodarone) should be closely supervised, and ECG monitoring considered as the effects on the heart may be additive Meloxicam (Mobic, Diethelm) Under special warnings, it has been added that meloxicam, as with other cyclooxygenase/prostaglandin inhibitors, may impair fertility and is not recommended in women attempting to conceive. Mobic is contraindicated in pregnancy. Under drug interactions, concomitant use of high doses (>15mg/wk) of methotrexate and NSAIDs including meloxicam is not recommended. Caution should be exercised in renally impaired patient and when both NSAID and methotrexate are given within 3 days. While both drugs are concurrently given, blood cell count and renal function should be monitored. Must not exceed 7.5mg/day in patients with hepatic/renal insufficiency Pramipexole (Sifrol, Boehringer Ingelheim) Under adverse effects, Sifrol may be associated with disorders of libido (decreased or increased). As with other dopamine agonists used for Parkinsons, reversible pathological gambling have been reported at high doses of Sifrol Ribavirin (Rebetol, Schering Plough) Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased

risk of developing lactic acidosis; caution should be exercised when adding Rebetol combination therapy to HAART. Erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome were reported with Rebetol in combination with peginterferon alfa-2b Rosuvastatin (Crestor, Astrazeneca) The starting dose is now reduced to 5mg or 10mg once daily in both statin naive patients or patients switched from another HMG CoA reductase inhibitor. It is advised that 5mg once daily should be considered for Asian patients. Pharmacokinetics data in Asians showed an approximate 2-fold elevation in median AUC compared with Caucasians

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Sevoflurane (Sevorane, Abbott) Seizure-like activity may occur on extremely rare occasions following sevoflurane administration. They were of short duration with no evidence of abnormality during emergence from anaesthesia or postoperatively Sildenafil (Viagra, Pfizer) A new warning that coadministration of sildenafil with alpha-blocker may lead to symptomatic hypotension in susceptible individuals

Terazosin (Hytrin, Abbott) Under precautions, small but significant decrease in haematocrit, haemoglobin, white blood cells, total protein and albumin were observed in controlled trials, suggesting haemodilution. Caution should be observed when terazosin is administered concomitantly with other antihypertensives to avoid possible hypotension. Dose reduction and titration may be necessary when adding a diuretic or other antihypertensives. Hypotension was reported when terazosin has been used with phosphodiesterase-5 (PDE-5) inhibitors. New ADR terms include urinary incontinence (mainly in postmenopausal women), thrombocytopenia, atrial fibrillation, priapism and anaphylaxis Zolpidem (Stilnox, Sanofi Synthelabo) Stilnox is no longer indicated for chronic insomnia. Due to lactose content, Stilnox is contraindicated in congenital galactosaemia, glucose or galactose malabsorption syndrome or lactase deficiency. Dependence may appear at therapeutic dose levels and/or in patients not presenting with individual risk factors, but is reported very rarely for therapeutic doses of zolpidem. Withdrawal symptoms may occur during days following treatment discontinuation. Combination of several benzodiazepines regardless of indication may increase the risk of dependence. Cases of drug abuse were reported. Factors that favour onset of dependence include treatment duration, dosage, history of dependence to other drugs and alcohol. New warnings include impaired psychomotor function, behavioural disorders including unusual patient behaviour patterns, aggressiveness, automatic behaviour with post-event amnesia. New precautions for use include informing patient of treatment duration and treatment discontinuation modalities, gradual discontinuation and possible rebound symptoms. Stilnox should not be given to children. Some drug interactions include other CNS depressants, buprenorphine, ketoconazole and rifampicin. New ADRs include behaviour disorders, impaired consciousness, irritability, aggressiveness, agitation, physical and psychic dependence even at therapeutic doses

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Adverse Drug Reaction News March 2006 Vol.8 No.1 Page 4

Analysis of ADR reports for year 2005

n the year 2005, the Pharmacovigilance Unit of HSA received a total of 1,171 local spontaneous ADR reports. The reports were mainly from healthcare professionals from the public hospitals (63.6%), followed by national specialty centres/ government clinics (16.8%), private clinics/specialist clinics (7.7%), private hospitals (6.5%), pharmaceutical companies (4.7%) and community retail pharmacies (0.6%). Based on a breakdown of the reports according to ethnic groups, Chinese patients constitute the highest proportion (69.5%), followed by Malay (12.6%) and Indian (6.8%) patients. This observed trend was similar to Singapores demographic statistics. Patients between 20 and 69 years of age made up the majority of patients reported to suffer ADRs and there were more reports of ADRs occurring in females than males. The female-to-male ratio is 1.5 : 1 (696 vs 454 reports). Most of the reports received were associated with pharmaceutical products. NSAIDs, antibiotics, contrast media and anti-epileptic drugs were among the top commonly reported drugs causing ADRs. Most of the ADRs reported were skin-related disorders (45.2%). Commonly reported ADRs include angioedema, erythema, exanthema, itching, periorbital oedema, maculopapular rash, rash, shortness of breath and urticaria. Of the total no. of reports, about 24% were considered serious and 18% of the patients were hospitalised due to the adverse reaction
Chart 1: Breakdown of the no. of patients who experienced ADRs by ethnic group (n = 1,171)

Chart 3: Breakdown of the no. of reports by product types

- Complementary medicines include Chinese proprietary medicines, traditional Chinese medicines and Jamu products. - More than one suspected drug may be implicated in an ADR report.

Table 1: Top 15 drugs (by active ingredients) suspected of causing ADRs

NB: More than one suspected drug may be implicated in an ADR report. * % of total no. of suspected active ingredients (=1,516)

Top 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Active ingredient Diclofenac Naproxen Iohexol Coamoxiclav Ceftriaxone Amoxicillin Mefenamic acid Cotrimoxazole Cloxacillin Aspirin Ciprofloxacin Phenytoin Carbamazepine Tramadol Omeprazole

No. of reports (% *) 75 (4.9) 50 (3.3) 42 (2.8) 41 (2.7) 40 (2.6) 30 (2.0) 30 (2.0) 28 (1.8) 26 (1.7) 22 (1.5) 22 (1.5) 22 (1.5) 18 (1.2) 18 (1.2) 17 (1.1)

Chart 2: Breakdown of the no. of patients who experienced ADRs by age group (n = 1,171)

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Table 2: Top 10 ADRs by system-organ classes*

* The system-organ class refers to the adverse reaction terminology developed by the WHO. (NB: More than one ADR term may be described in an ADR report) ** % of total no. of ADR terms (=1,925) reported

Top 1 2 3 4 5 6 7 8 9 10
Page 5 Adverse Drug Reaction News March 2006 Vol.8 No.1

System organ class Skin & appendages disorders Body as a whole - general disorders Gastrointestinal system disorders Respiratory system disorders Liver & biliary system disorders Central & peripheral nervous system disorders White cell & reticuloendothelial disorders Urinary system disorders Vascular (extracardiac) disorders Musculoskeletal system disorders

No. of reports (% **) 871 (45.2) 323 (16.8) 123 (6.4) 100 (5.2) 73 (3.8) 71 (3.7) 70 (3.6) 58 (3.0) 31 (1.6) 30 (1.6)

Table 3: Examples of some serious suspected ADRs received in year 2005

Description Blood disorders WHO ADR preferred term Agranulocytosis Suspected drug (no. of reports) Carbimazole (2) Clozapine (2) Lamotrigine or valproate (1) Dapsone plus pyrimethamine or mefloquine (1) Cloxacillin (1) Phenytoin (1) Valproate (1) Carbimazole (1) Ceftriaxone (1) Pegal Linu Suryo Sudarmo (1) Meropenem (1) Methotrexate (1) Piperacillin plus tazobactam (1) Ticlopidine (3) Vancomycin (1) Carbamazepine (1) Hydroxyurea (1) Methotrexate (2) Ticlopidine (1) Aztreonam (1) Ceftriaxone (2) Hydroxyurea (1) Linezolid (2) Phenytoin (1) Risperidone or valproate (1) Ticlopidine or valproate (1) Valproate (1) Vancomycin (1) Azathioprine (1) Cefazolin (1) Ceftazidime (1) Ceftriaxone (1) Coamoxiclav (1) Diclofenac (1) Enalapril (1) Indomethacin (1) Lidocaine or triaminolone (1) Moxifloxacin (2) Ciclosporin (1) Haloperidol (1) Hyoscine (1) Prochlorperazine (1) Fentanyl or propofol (1) Rabeprazole (1) Fluphenazine or haloperidol (1) Haloperidol (1) Metronidazole (1) Moxifloxacin (1) Ziprasidone (1) Snake powder capsule (1) Tunglin capsule (1) Aprepitant (1) Mycophenolate (1) Carbamazepine (1) Etoricoxib (1) Streptokinase (1) Ezetimibe (1) Clozapine (1) Lingzhi - brand unknown (1) Imatinib (1) Allopurinol (2) Amoxicillin or itraconazole (1) Chlorpromazine (1) Complementary Chinese medicine - brand unknown (3) Kapsul Super Tenaga or Obat Masuk Angin Antangin (1) Shuanghuanlian Koufuye (1) Ginseng + lingzhi - brand unknown (1) Malpighia coccigera (1) Nimesulide (1) Phenytoin (1) Sulpiride (1) Ticlopidine (1) TCU Kapsul Asam Urat Parananda Jaya (1)

Haemolysis Leucopenia

Neutropenia / Neutropenic sepsis

Pancytopenia

Thrombocytopenia

Body as a whole

Anaphylactic reactions

Central & peripheral nervous system disorders

Encephalopathy hypertensive Extrapyramidal disorder

Myoclonic jerks / Myoclonus Neuroleptic malignant syndrome Peripheral neuropathy Seizures cerebral Tardive dyskinesia Cushing's syndrome Syndrome of inappropriate secretion of antidiuretic hormone Blood in stool Erosion gingival Gastrointestinal tract bleeding Pancreatitis Pseudomembranous colits Cholestatic hepatitis and hepatic failure Fulminant hepatitis Hepatitis

Endocrine disorders

Gastrointestinal system disorders

Liver and biliary system disorders

Page 6 Adverse Drug Reaction News March 2006 Vol.8 No.1

Jaundice / Cholestatic jaundice

Musculoskeletal system disorders

Fasciitis necrotising Osteomyelitis / Osteonecrosis

Rhabdomyolysis

Respiratory system disorders

Synovitis / Tenosynovitis Breathing difficulty / Shortness of breath

Bronchospasm

Laryngeal oedema Respiratory failure Stevens Johnson syndrome

Skin reactions

Stevens Johnson syndrome and toxic epidermal necrolysis Toxic epidermal necrolysis

Urinary system disorders

Diabetes insipidus nephrogenic Haematuria Interstitial nephritis Pyelonephritis Renal failure

Vascular (extracardiac) disorders Vision disorders

Leukocytoclastic vasculitis Retinopathy

Azathioprine (1) Complementary Chinese medicine - brand unknown (1) Bromazepam (1) Complementary Chinese medicine - brand unknown (2) Dapsone plus pyrimethamine or mefloquine (1) Fluoxetine or fusidic acid (1) Imatinib (1) Ticlopidine (1) Kuku Bima TL Sidomuncil (1) Alendronate (1) Pamidronate (1) Zoledronate (2) Chlorpromazine or fluphenazine (1) Fenofibrate or vancomycin (1) Lovastatin (1) Adalimumab (1) Amiodarone or oxaliplatin (1) Amoxicillin (1) Aspirin (1) Ceftriaxone (1) Cefuroxime or tramadol (1) Complementary Chinese medicine - brand unknown (1) Diclofenac (1) Drospirenone plus ethinyloestradiol (1) Imipenem plus cilastatin (1) Influenza (1) Metoclopramide (1) Oxaliplatin (1) Propranolol (1) Vancomycin (1) Cefazolin (1) Naproxen (1) Oxaliplatin (1) Bai Jia Hei or Pi Pa Gao (1) Iopamidol (1) Diclofenac (1) Allopurinol (1) Carbamazepine (4) Ceftazidime or omeprazole (1) Celecoxib (1) Cloxacillin or mefenamic acid or piroxicam (1) Codeine or promethazine (1) Cotrimoxazole (1) Cotrimoxazole or ketoconazole (1) Nutrilite Milk Thistle and Dandelion (1) Enalapril (1) Etoricoxib (1) Extrim (1) Imipenem plus cilastatin (1) Isoniazid (1) Letrozole (1) Phenytoin (3) Piperacillin plus tazobactam (1) Valproate (1) Cotrimoxazole (1) Coamoxiclav or mefenamic acid (1) Letrozole (1) Alfuzosin or omeprazole (1) Carbamazepine (1) Cefepime or phenytoin (1) Ciprofloxacin (1) Coamoxiclav (1) Complementary Chinese medicine - brand unknown (1) Hydroxychloroquine (1) Omeprazole (1) Phenytoin (1) Lithium (1) Clopidogrel (1) Ciprofloxacin (1) Rosuvastatin (1) Allopurinol (1) Complementary Chinese medicine - brand unknown (1) Enalapril (1) Malpighia coccigera (1) Rofecoxib or tramadol (1) Clarithromycin or imipenem plus cilastatin (1) Hydroxychloroquine (1)

Page 7 Adverse Drug Reaction News March 2006 Vol.8 No.1

Summary of Dear Healthcare Professional Letters issued by HSA and pharmaceutical companies from January to December 2005
7 Mar Changes to Seroxat (paroxetine) labelling to include warnings on adverse events related to suicidality and hostility in paediatrics [by GlaxoSmithKline] Safety concerns associated with use of erythropoietins (EPOs) in cancer patients Deregistration of thioridazine products with effect from 31 March 2006 Pfizers voluntary suspension of sales of valdecoxib (Bextra) HSAs expert advisory committees recommendations on cyclooxygenase-2 (COX-2) selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) Potential problem of falsely elevated blood glucose readings with Extraneal (icodextrin) peritoneal dialysis solution Advisory on the regulatory control of medicinal products in Singapore Caution regarding use of Seroxat (paroxetine) in pregnancy [by GlaxoSmithKline] Important new safety data on suicidality risk associated with the use of Strattera (atomoxetine) [by Eli Lilly] Letrozole (Femara) and adverse outcome in babies following maternal exposure [by Novartis] Strengthening of labelling of promethazinecontaining preparations for children under two years and new restriction of use in children less than six months old.

Macular oedema associated with rosiglitazone

14 Mar 30 Mar 8 Apr 28 Apr

laxoSmithKline (GSK) has recently issued a Dear Healthcare Professional letter to notify healthcare professionals of new safety information regarding products containing rosiglitazone. Rosiglitazone is a thiazolidinedione antidiabetic agent used as an adjunct to diet and exercise in the management of type II diabetes mellitus . It is available as Avandia (rosiglitazone) and Avandamet (rosiglitazone and metformin). Post -m ar ketin gr epo r ts o fm acul ar oede ma -mar ark ting re por of ma ular oedem GSK has received very rare post-marketing reports in other countries of new onset and worsening macular oedema in patients receiving rosiglitazone. In the majority of these cases, the patients also reported concurrent peripheral oedema. In some cases, the macular oedema resolved or improved following discontinuation of therapy and in one case, macular oedema resolved after dose reduction. According to the Dear Healthcare Professional Letter issued by GSK, macular oedema is known to occur in association with diabetic retinopathy, especially when this condition progresses. Risk factors for macular oedema include duration of diabetes, presence of retinopathy, hypertension, and poor glycaemic control. Patients with macular oedema may complain of blurred or distorted vision, decreased colour sensitivity, and decreased dark adaptation. HSA has not received any local reports of macular oedema associated with rosiglitazone. Physicians are encouraged to report any suspected adverse drug reactions to the Pharmacovigilance Unit of the HSA
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5 Dec 14 Dec

Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Staff Editors Ms Adena Lim, BSc (Pharm) Hons Ms Tan Bee Him, 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 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