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

Reports of fractures with alendronate

Monitoring of patients bone mineral density recommended before and during drug therapy

We are currently following up with these reports to determine the causality and the date of occurrence of these events as many of them lacked details such as onset of the adverse event, dose and duration of alendronate given, use of concomitant medicines and whether bone mineral density (BMD) was measured. Analysis of reports Based on an interim analysis of the available data, the adverse events were observed in female patients who were on alendronate for 110 years (duration reported in 22 patients), with median age of 66.5 years (range: 3782 years). Only 12 reports included patients BMD T-scores for hip which ranged from 1.29 to 2.8. Seven patients were reported to have pain in the fractured limb up to four months prior to sustaining the fracture. Six out of the 26 patients did not encounter any trauma prior to experiencing the fracture. Ten patients had minimal trauma, mainly spontaneous falls, and one patient had delayed bone healing. In nine patients, the events leading to the sustaining of the fractures were not stated. The types of fractures experienced by these patients were mainly sub-trochanteric in nature. Most of these fractures were either simple transverse fractures or short oblique fractures and reporting physicians described them as distinctly different from typical osteoporotic fractures. Background information Alendronate (Fosamax, Merck Sharp & Dohme) has been registered by HSA since 1996 for the treatment and prevention of osteoporosis in post-menopausal women. The recommended dosage for treatment of osteoporosis in post-menopausal women is one 70mg tablet once weekly or one 10mg tablet once daily. For the prevention of osteoporosis in post-menopausal women, the recommended dosage is one 5mg tablet once daily (the 5mg tablet is not marketed locally).
ISSN: 0219 - 2152 March 2007 Vol.9 No.1

ecently, the Pharmacovigilance Unit, HSA has received 25 reports of fractures and one of delayed bone healing with long-term use of alendronate in our local patients.

Other similar drugs that are registered include risedronate (Actonel, Sanofi-aventis) in 2001 and ibandronate (Bonviva, Roche) in 2005. These drugs belong to the bisphosphonate class of drugs which acts as specific inhibitors of osteoclastmediated bone resorption. Bisphosphonates have demonstrated to have fracture reduction benefits for post-menopausal women with prior vertebral fracture or T-scores of 2.5 or lower. There are however anecdotal reports in recent years that suggest bisphosphonates may be associated with the risk of fractures in certain susceptible individuals. Literature review A review of the published medical literature indicates that there are about ten cases of spontaneous nonspinal fractures in patients on alendronate therapy. For the nine patients who were reported to continue taking alendronate after the fractures, six displayed either delayed or absent fracture healing for 3 months to 2 years.1,2 The description of these cases appears similar to some of our local cases in that these were mainly post-menopausal female patients who developed atraumatic nonspinal fractures after 3-8 years of alendronate treatment. Local practice guidelines The MOH Clinical Practice Guidelines for Osteoporosis 3 recommends that for treatment with bisphosphonates, alendronate or risedronate therapy is recommended when patients T-score is less than or equal to 2.5, whether or not patient has a fracture. For such cases, it is recommended to consider monitoring BMD after one year.
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1 Reports of fractures with alendronate 2 Linezolid: safety findings from a clinical

trial in catheter-related infections

5 Evra & risk of thromboembolism 6 Package insert amendments reflecting

safety issues

CONTENTS

3 New safety issues associated with rituximab 8 Bevacizumab: association with hypertensive encephalopathy & reversible 4 Analysis of ADR reports for 2006 posterior leukoencephalopathy syndrome

Linezolid: safety findings from a clinical trial in catheter-related infections

No clinical activity against gram-negative pathogens. Specific gram-negative therapy required if a concomitant gram-negative pathogen is documented or suspected
patients in whom either gram-negative pathogens, mixed gramnegative and gram-positive pathogens, or no pathogen were identified at baseline. Patients randomised to linezolid who had only a grampositive infection at baseline, including the subgroup of patients with gram-positive bacteraemia experienced a survival rate similar to the comparator group. From the companys analysis of the mortality data, a major finding was a lower than predicted mortality incidence in the comparator group and a greater overall incidence of gram-negative bloodstream infections in the linezolid group with a higher mortality in the linezolid patients who had gram-negative infections. The company also noted that the antibiotic treatment for patients with gram-negative infection who died was assessed as inadequate in both arms of the study and may have been a contributing factor to the overall number of deaths in the study. Local situation Arising from this study, HSA is working with the company to update the safety information in the local package insert of Zyvox to include the findings of this study to remind healthcare professionals that linezolid has no clinical activity against gram-negative pathogens and is not approved for the treatment of gram-negative infections or for the treatment of patients with catheter-related bloodstream infections. Specific gram-negative therapy is required if a concomitant gram-negative pathogen is documented or suspected

inezolid (Zyvox, Pfizer) is a synthetic antibacterial agent belonging to the oxazolidinones class of antimicrobial agents. It is licensed for the treatment of nosocomial- and community-acquired pneumonia and for complicated or uncomplicated skin and skin structure infections caused by methicillin or vancomycin resistant grampositive bacteria.

Study in catheter-related gram-positive bloodstream infections shows higher mortality rate in linezolid group A clinical trial in adult patients with catheter-related grampositive bloodstream infections showed a higher mortality rate in the linezolid arm [78/363 (21.5%)] versus the comparator drugs [58/363 (16.0%)] at 84 days poststudy admission with an estimated odds ratio of 1.426 [95% CI 0.9702.098] based on results from logistic regression. The study was an open-label, randomised, comparator-controlled phase 3 study of intravenous/oral linezolid (600mg q12h) versus comparator [intravenous vancomycin (1g q12h) or intravenous oxacillin (2g q6h) followed by oral dicloxacillin (500mg q6h)] with a treatment duration of 7 to 28 days. While causality has not been established, the observed mortality imbalance occurred primarily in linezolid-treated
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Reports of fractures with alendronate

For patients with T-score between 1 to 2.5 (with respect to bisphosphonate use in prevention of osteoporosis), it recommends that it might be a reasonable option to defer intervention in those at low risk for fracture prevention as bisphosphonates have not demonstrated to reduce fractures when used in prevention, despite reducing bone loss. Conclusion HSA will be following up with the case reports to investigate whether there is a causal link Radiograph of a subtrochanteric fracture between the reported
Page 2 Adverse Drug Reaction News March 2007 Vol.9 No.1

adverse events and the drug, and whether there could be other factors that may have predisposed to the fracture. Although the reports received were for alendronate, it may be premature to form the direct causal link between alendronate and these fractures. At the same time, the possible association of such adverse events with other bisphosphonates cannot be excluded. Healthcare professionals are encouraged to report all serious adverse effects especially fractures suspected to be associated with bisphosphonates to the Pharmacovigilance Unit of HSA
References 1. J Clin Endocrinol Metab 2005; 90:1294-301. 2. Geriatrics 2006; 61:31-3. 3. MOH Clinical Practice Guidelines. Osteoporosis. Singapore. February 2002.

New safety issues associated with rituximab

Reports of possible hepatic failure, bowel obstruction and perforation, and progressive multifocal leukoencephalopathy
ituximab (Mabthera, Roche) is a recombinant chimeric anti-CD20 monoclonal antibody licensed in Singapore for: i) treatment of patients with relapsed or chemo-resistant indolent B-cell non-Hodgkins lymphomas (NHL), ii) treatment of patients with CD20 positive diffuse large B-cell non-Hodgkins lymphomas (DLCL) in combination with CHOP* therapy, iii) treatment of previously untreated patients with stage IIIIV follicular lymphoma in combination with CVP** chemotherapy. In the past few months, there have been reports of hepatic failure, bowel obstruction and perforation, and progressive multifocal leukoencephalopathy (PML) suspected to be associated with its use. The causality of some of these adverse events has not been established although its immunosuppressant effects may account for PML. a) Reports of bowel obstruction and gastrointestinal perforations1 In November 2006, Health Canada together with HoffmannLa Roche in Canada issued an advisory to healthcare professionals about the observation of bowel obstruction and gastrointestinal perforations in patients treated with rituximab. The advisory included data from the analysis of the companys worldwide pharmacovigilance database for rituximab which indicated that 47 cases of bowel obstruction (nine deaths) and 37 cases of gastrointestinal perforation (four deaths) have been reported in rituximab patients for an estimated 730,000 cumulative patient exposure. These reports originated from both spontaneous sources and clinical studies, and the majority of these cases were reported for the NHL indication. Of these, two reports of bowel obstruction (one death) and two reports of gastrointestinal perforation originated from Canada. The advisory also mentioned that the presence of risk factors such as underlying medical history (e.g. gastrointestinal lymphoma) and intake of concomitant medications (e.g. chemotherapy and steroids) in the cases of bowel obstruction and gastrointestinal perforation made interpretation of data difficult. However, these confounding factors, a contributory role of rituximab in causing gastrointestinal perforation in patients diagnosed with NHL has not been excluded. In addition, a pooled analysis of clinical trials in patients with NHL has indicated a higher incidence of gastrointestinal perforation in the arms treated with rituximab/chemotherapy compared to the arms treated with chemotherapy alone (0.38% verus 0.15%). In post-marketing reports of patients with NHL, the mean time to onset of symptoms was six days from the start of therapy (range 1 to 77 days) for documented gastrointestinal

perforation. The site of gastrointestinal perforation in the cases of NHL included both the upper and lower gastrointestinal tracts. b) New reports of fulminant hepatitis in hepatitis B virus carriers In Japan, there were 18 new reports of exacerbation of HBV infection over the last two years. Of these, nine were of fulminant hepatitis and eight of death in patients with NHL. The Ministry of Health, Labour and Welfare of Japan has in December 2006, requested the product licence holder to disseminate a dear healthcare professional letter and to strengthen the package insert of rituximab to warn of cases of fatal liver failure caused by fulminant hepatitis or exacerbation of hepatitis in hepatitis B virus carrier treated with rituximab (marketed as Mabthera in Japan). c) Reports of Progressive Multifocal Leukoencephalopathy (PML)2,3 The US Food and Drug Administration has in December 2006 alerted healthcare professionals of two fatal cases of progressive PML in patients treated with rituximab (marketed as Rituxan in US) for systemic lupus erythematosus (SLE) which was not an approved indication of the drug. PML is a demyelinating disease caused by reactivated JC virus which is a latent virus present in 80% of adults. Reactivation or exacerbation of viral infections including JC virus leading to PML may occur when patients receive Rituxan for any reason. To date, there are 23 confirmed reports of PML in patients with lymphoid malignancies treated with rituximab although PML has also been reported in SLE patients not treated with rituximab. Local situation HSA has not received any reports on the above-mentioned adverse events. Nonetheless, physicians are advised to closely monitor patients treated with rituximab for these adverse effects and to report these events to the Pharmacovigilance Unit of HSA should they be encountered
* CHOP cyclophosphamide, doxorubicin, vincristine, prednisolone ** CVP vincristine, cyclophosphamide, prednisolone References 1. Health Canada Advisory for Healthcare Professionals (10/11/06) http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/ 2006/rituxan_3_hpc-cps_e.html 2. US FDA information for Healthcare Professionals (18/12/06) http:// www.fda.gov/cder/drug/infopage/rituximab/default.htm 3. US FDA Public Health Advisory (18/12/06) http://www.fda.gov/ cder/drug/advisory/rituximab.htm
Adverse Drug Reaction News March 2007 Vol.9 No.1 Page 3

Analysis of ADR reports for year 2006

he Pharmacovigilance (PV) Unit of HSA administers the national adverse drug reaction (ADR) monitoring program by collating and reviewing ADR reports received from healthcare professionals and pharmaceutical companies.

complementary medicines (1.2%), health supplements and cosmetics. Based on a breakdown of the reports according to ethnic groups, Chinese patients constituted 60.9% of the reports, followed by Malay (12.5%), and Indian (8.7%) patients. There were more reports received in females than males (768 vs 661 reports). Patients between 5059 years of age made up 19.2% of the reports, followed by those aged 4049 (15.5%), and aged 6069 (14.3%). Conclusion Active participation of ADR reporting by our healthcare professionals is important in maintaining surveillance on the safety profile of marketed drugs. In addition to the quantity of reporting, the quality of reporting is also important to enable better signal detection. Healthcare professionals are reminded that details of the cases such as the date of occurrence of ADR, start and end dates of ingestion of suspected drug, concomitant medications and existing medical conditions are useful to the PV Unit in the assessment of the causal relationship between the suspected drug and observed ADRs. Whenever possible, healthcare professionals are encouraged to provide these data.
* CMIS (Critical Medical Information Store) of the EMRX serves as a shared electronic repository of patients medical alerts, adverse drug reaction and drug allergy data. The CMIS online ADR reporting form is also available at the Health Professional Portal (HPP) to allow healthcare professionals from the private sector to enter an ADR report. The HPP is a one-stop portal for the healthcare professional community to access multiple e-services relating to professional practice and information repository using single-sign-on through a common interface.

In addition to the conventional mode of ADR reporting through email, fax or mail, ADR reports can now be routed electronically to the PV Unit via the ADR/drug allergy reporting module in the Critical Medical Information Store (CMIS)* component of the Electronic Medical Record Exchange (EMRX)** . This platform of e-reporting is being implemented nation wide in phases, starting with National Healthcare Group (NHG) in January 2006. Overview of ADR reports received via conventional and CMIS sources In the year 2006, the PV Unit received 984 ADR reports via the conventional route (i.e. mail, fax and email) and 11,000 reports from CMIS. This issues analysis of ADR reports have incorporated those that came through CMIS in addition to the conventional route of reporting. Although 11,000 reports were received through CMIS, not all were included in the analysis as many of the reports lacked details such as specific ADR terms, suspected drug or had erroneous date of onset of ADR. This could partly be due to the transfer of data from the old patient medical records system and other inherent teething problems. In addition, non-serious reports such as rash and periorbital oedema were not included in the data analysis. A total of 1,523 reports were analysed. These reports were mainly from public hospitals (56.8%), followed by government clinics (20.4%), national specialty centres (12.7%), pharmaceutical companies (5.3%), private clinics/specialist clinics (3.2%) and private hospitals (1.6%). The majority of the reports received were associated with pharmaceutical products (96.6%), followed by biologics/vaccines (1.4%), Chart 1: Breakdown of the no. of patients who experienced ADRs by age group (n=1,523)

** EMRX (Electronic Medical Record Exchange), launched in April 2004, is an electronic platform which enables hospitals and government clinics across the two public healthcare clusters, namely, National Healthcare Group (NHG) and Singapore Health Services (Singhealth) to share vital patient medical information such as inpatient discharge summaries, medical history and laboratory results.

Table 1: Top system-organ classes affected in serious ADRs

System-organ class Respiratory Body as a whole Skin & appendages Haematological Musculoskeletal Liver & biliary Psychiatric Nervous Ocular Renal No. of serious ADR reports 148 141 83 80 50 49 27 15 13 12

More than one ADR term may be described in a single ADR report.
Page 4 Adverse Drug Reaction News March 2007 Vol.9 No.1

Table 2: Top 15 drugs (by active ingredients) suspected of causing serious ADRs
Top 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Active ingredient Diclofenac Atenolol Cotrimoxazole Phenytoin Carbamazepine Aspirin Allopurinol Amoxicillin Ceftriaxone Paracetamol Simvastatin Coamoxiclav Warfarin Cloxacillin Ticlopidine No. of serious ADR reports 28 28 28 25 21 21 21 20 20 20 18 18 17 13 13 Examples of serious ADRs Agranulocytosis; anaphylaxis; laryngeal oedema, wheeze; hepatitis; interstitial nephritis, nephropathy; Stevens Johnson syndrome Anaphylaxis; bradycardia (marked); bronchospasm; erectile dysfunction; exfoliative dermatitis Anaphylaxis; tongue oedema, wheezes; hepatitis, jaundice; conjunctivitis; leucopenia, neutropenia; Stevens Johnson syndrome, toxic epidermal necrolysis Anaphylaxis; conjunctivitis; fatty liver, hepatitis; leucopenia, neutropenia, pancytopenia; exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis Hepatitis; leucopenia, neutropenia, pancytopenia, thrombocytopenia; exfoliative dermatitits, Stevens Johnson syndrome Anaphylaxis; asthma aggravated, bronchospasm; erosive gastritis, gastric ulcer; exfoliative dermatitis, toxic epidermal necrolysis Allopurinol hypersensitivity syndrome; anaphylaxis; hepatitis; acute renal failure, glomerulonephritis, interstitial nephritis; mucositis; pancytopenia; Stevens Johnson syndrome, toxic epidermal necrolysis Anaphylaxis; dyspnoea; exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis Anaphylaxis; leucopenia; Stevens Johnson syndrome, toxic epidermal necrolysis Anaphylaxis; bronchospasm; confusion, hallucination; exfoliative dermatitis Cholestatic hepatitis, hepatitis; exfoliative dermatitis; rhabdomyolysis Anaphylaxis; agranulocytosis; leukocytoclastic vasculitis; rhabdomyolysis; exfoliative dermatitis, Stevens Johnson syndrome Cerebral haemorrhage, intraventricular haemorrhage, subdural haematoma Anaphylaxis; pancytopenia; exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis Agranulocytosis, leucopenia; cholestatic hepatitis, jaundice; pemphigus

Table 3: Drugs suspected of causing serious blood, hepatic and skin adverse reactions
Description Blood disorders WHO preferred term Agranulocytosis/ neutropenia Anaemia, aplastic Anaemia, haemolytic Leucopenia Pancytopenia Pure red cell aplasia Thrombocytopenia Hepatic disorders Autoimmune hepatitis Cholestatic hepatitis Fatty liver Fulminant hepatitis Hepatic failure Hepatic neoplasm Hepatitis Suspected active ingredient (the number in the bracket represents the number of times the drug has been implicated *) (6) Ticlopidine; (4) Carbimazole; (2) Valproic acid; (1) Carbamazepine, Chlorpromazine, Esomeprazole, Coamoxiclav, Cotrimoxazole, Diazepam, Diclofenac, Imipenem/cilastatin, Methotrexate, Mirtazapine, Nalidixic acid, Phenytoin, Propylthiouracil, Topiramate, Trifluoperazine, Trihexyphenidyl, Vancomycin (1) Ethosuximide, Naproxen (1) Dapsone, Methyldopa (3) Ticlopidine; (1) Azathioprine, Carbamazepine, Carbimazole, Ceftriaxone, Hydrocortisone, Phenytoin, Sirolimus, Sulfasalazine, Piperacillin/tazobactam, Quetiapine, Trifluoperazine, Valproic acid, Vancomycin (2) Allopurinol; (1) Azathioprine, Carbamazepine, Chlorpromazine, Ciprofloxacin, Cloxacillin, Esomeprazole, Phenytoin (1) Epoetin alfa (2) Valproic acid; (1) Carbamazepine, Carbimazole, Chlorpromazine, Heparin, Hydrochlorothiazide, Omeprazole (1) Pil Setelan (adulterated with paracetamol, chlorpheniramine and phenylbutazone) (2) Ticlopidine; (1) Chlorpromazine, Cyclophosphamide, Glipizide, Leflunomide, Sodium aurothiomalate, Simvastatin (1) Phenytoin (1) Propylthiouracil (1) Methyldopa, Dapsone/pyrimethamine (1) Ciclosporin (3) Allopurinol, Simvastatin; (2) Complementary medicine, Cotrimoxazole, Isoniazid, Lovastatin; (1) Atorvastatin, Carbamazepine, Cotrimoxazole, Diclofenac, Dr Xeniji, Fluconazole, Gabapentin, Pyrazinamide, Rifampicin, Isotretinoin, Losartan, Memantine, Phenytoin, Thalidomide, Valproic acid (3) Complementary medicine; (1) Isoniazid, Ketoconazole, Moxifloxacin, Naturland Slimexcell Phytotherapy, Nitrofurantoin, Penicillin V, Shou Wu Plus, Ticlopidine (11) Carbamazepine; (9) Cotrimoxazole; (8) Phenytoin; (6) Amoxicillin; (5) Allopurinol; (4) Omeprazole; (2) Cefalexin, Ceftazidime, Ceftriaxone, Celecoxib, Ciprofloxacin, Cloxacillin, Enalapril, Lamotrigine, Naproxen, Spironolactone; (1) Ampicillin, Aspirin, Clopidogrel, Coamoxiclav, Diclofenac, Esomeprazole, Ethambutol, Etoricoxib, Frusemide, Griseofulvin, Imipenem/cilastatin, Isoniazid, Meloxicam, Methotrexate, Pyrazinamide, Rifampicin, Sotalol, Sulfasalazine

Hepatitis with jaundice Skin disorders Stevens Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN)/SJS-TEN

* More than one suspected drug may be implicated in a single ADR report.
Adverse Drug Reaction News March 2007 Vol.9 No.1 Page 5

Evra and risk of thromboembolism

vra (Johnson & Johnson) is a combination transdermal contraceptive patch containing 6mg norelgestromin (NGMN) and 0.6mg ethinylestradiol (EE) and is designed to release these hormones over a 7-day period. It has been registered in Singapore since 2003. Hormonal contraceptives are known to be associated with an increased risk of venous thromboembolism (VTE), particularly during the first year of use of oral contraceptives (OC). In all cases, the risk of VTE increases with age and in the presence of other risk factors for VTE (e.g. obesity). The incidence of VTE in healthy, non-pregnant women who are not taking an OC is about 5 cases per 100,000 women per year. For those taking combined OC containing second generation progestogens, this incidence is about 15 per 100,000 women per year of use. Some studies have reported a greater risk of VTE in women using preparations containing third generation progestogens; the incidence is about 25 per 100,000 women year of use. The risk of VTE with transdermal patches is yet to be established although it remains very small and less than the risk of VTE associated with pregnancy, which is estimated as 60 per 100,000 pregnant women years. In the last two years, there has been a higher number of spontaneous case reports of VTE associated with patients on this transdermal hormonal contraceptive compared to combined OC which raised the concern as to whether transdermal patch could be associated with a higher VTE risk.

Ortho Evra compared to those taking conventional OC. The peak blood levels of oestrogen (Cmax) however were about 25% lower in women using Ortho Evra. While the oestrogen level with the patch remained constant for one week until the patch was removed, the peak blood levels with a daily birth control pill rapidly declined to levels that were lower than on the Ortho Evra. As a result of this finding, the US Food and Drug Administration has amended the US package insert of Ortho Evra to include this new information and a statement that although this increased oestrogen exposure may carry a theoretical risk of increased VTE, the clinical significance is not known. ii) Evra versus OCs A PK study comparing Evra and OC (containing NGM 250mcg and EE 35mcg) showed that Cmax values were found to be two-fold higher for NGMN and EE in subjects administered with the OC compared to Evra, while overall exposure (AUC and Css) was comparable in subjects treated with Evra. Inter-subject variability (%CV) for the PK parameters following delivery from Evra was higher relative to the variability determined from the OC. The clinical relevance of this finding is yet to be determined; and caution should be exercised when making a direct comparison of these PK parameters. b) Epidemiology studies The results of two separate epidemiological studies sponsored by Johnson & Johnson that were designed to evaluate the risk of VTE in Ortho Evra and OC (containing NGM 250mcg and EE 35mcg) were recently completed. These two studies with a nested case-control design were conducted in the US in women aged 15 to 44 years using electronic health claims data. The study by Cole et al1 found a two-fold increase in the risk of VTE in current users of Ortho Evra compared to current OC users (OR 2.4, 95% CI 1.15.5). However, the study by Jick et al2 did not find an increase in risk of VTE for current users of Ortho Evra compared to current OC users (OR 0.9, 95% CI 0.51.6). The epidemiology studies, comparing the risk of VTE in women using the transdermal hormonal contraceptive patch to the risk in women using conventional OC, are being extended as new electronic health claims data becomes available. Conclusion HSA will continue to monitor the safety profile of these drugs and update our healthcare professionals when more information becomes available. Although HSA has not received any reports of serious adverse reactions associated with Evra, the local package insert of Evra will be amended to include the findings of the studies on Ortho Evra and Evra as both products are bioequivalent
References 1. Obstet Gynecol. 2007 Feb; 109(2 pt 1): 339-46. 2. Contraception. 2006 Mar; 73(3): 223-8.

Studies Recent studies have been conducted to attempt to shed some light to the post-marketing observation. Most of the studies were on Ortho Evra, the product marketed in the United States, comprising 6mg NGMN and a higher content of EE at 0.75mg. Although the dosage and the manufacturing process for Evra is different from that for Ortho Evra, the patches were designed to deliver similar systemic amounts of EE and NGMN, and have been demonstrated to be bioequivalent. Hence the post-marketing data and studies on Ortho Evra are considered to apply equally to Evra. a) Pharmacokinetic studies The Pharmacokinetic (PK) profile for the transdermal patches appears to be different from the PK profile for OCs as demonstrated in the studies below: i) Ortho Evra versus OCs A PK study designed to analyse the difference in delivery of EE using Ortho Evra and a conventional OC (containing norgestimate (NGM) 250mcg and EE 35mcg) over a 7-day period found that Ortho Evra has higher steady state concentrations and lower peak concentrations compared to OCs. Under steady state conditions, there was an increased exposure of oestrogen (AUC0168 and Css for EE were 55% and 60% higher, respectively) in women using
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SA has approved the following package insert changes due to safety updates from October 2006 to January 2007. Details of the updates are 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).

Package insert amendments reflecting safety issues

during treatment in the elderly & patients with renal, hepatic, or cardiac dysfunction. Arcoxia may reduce the antihypertensive effect of ACE inhibitors & angiotensin II antagonists. Coadministration with an ACE inhibitor or angiotensin II antagonist may result in possible acute renal failure in renal patients & should be given with caution in the elderly. Rates for serious thrombotic cardiovascular events were higher in patients on etoricoxib vs naproxen 500mg 2 times/day. New ADRs: fluid retention, pancreatitis, confusions & hallucinations. eletriptan, fentanyl & tolterodine. Caution in pregnancy. New ADRs: angioneurotic oedema, adrenocortical insufficiency, photophobia & cirrhosis.

17. Lignocaine (Lignocaine, Pfizer)

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as a benzodiazepine or barbiturate. Rarely, cardiac arrest has occurred without prodromal CNS effects. In children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia.

1. Alendronate (Fosamax, MSD) Under Precautions, it is stated that localised osteonecrosis of the jaw (ONJ) has occurred in patients with postmenopausal osteoporosis.
hereditary fructose intolerance due to sorbitol content of Mucosolvan. Severe skin lesions were reported with Mucosolvan which requires discontinuation. New ADRs: vomiting & heartburn. Use in first trimester of pregnancy is not recommended.

2. Ambroxol (Mucosolvan, Boehringer Ingelheim) Cautionary use in those with rare

9. Fentanyl (Durogesic Transdermal System, J&J) Appropriate initiating dose

should be based on the patients current opioid use. Preferably use in patients who have demonstrated opioid tolerance. Other additional factors include body size, age & extent of debilitation.

reactions associated with extravasation, malaise, dehydration & stomatitis were reported. Studies involving therapy with carboplatin & cyclophosphamide have shown that elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. Increased risk of allergic reactions including anaphylaxis was reported in patients previously exposed to platinum therapy.

3. Carboplatin (Paraplatin, BristolMyers Squibb) Post-market injection site

10. Fluticasone (Flixonase, GSK) Height

monitoring is recommended in children on prolonged treatment (nasal corticosteroid used at high dose & long duration may affect growth).

11. Fondaparinux (Arixta, GSK) In

known congenital long QT syndrome & rare hereditary conditions (e.g. fructose intolerance due to sorbitol content). Clobutinol may lengthen QT interval in patients with congenital long QT syndrome. New ADRs: somnolence & hallucinations (primarily seen in children & geriatrics), torsade de pointes (very rare).

4. Clobutinol (Silomat, Boehringer Ingelheim) Contraindicated in patients with

patients undergoing surgery, the timing of the first dose of Arixtra requires strict adherence.Under Warnings, it is added that Arixtra does not bind to platelet factor 4 and doesn't cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT)-type II. New ADRs: postoperative wound infections, thrombocythaemia, abnormal platelets, coagulation disorder, hypokalaemia, anxiety, bilirubinaemia, syncope, & leg pain.

should be exercised in co-administration of Kaletra with anti-arrhythmics. Systemic corticosteroid effects e.g. Cushing's syndrome & adrenal suppression has been reported in patients receiving ritonavir & inhaled or intranasally administered fluticasone thus co-administration is not recommended. New precautions: (1) post-marketing reports of hepatic dysfunction, including fatalities & consideration for increased AST/ALT monitoring in patients at risk, especially during first few months of treatment, (2) reports of immune reconstitution syndrome in patients treated with combination antiretroviral therapy. Postmarketing reports include bradyarrhythmia, Stevens Johnson syndrome & redistribution/accumulation of body fat. ADRs in paediatrics include taste aversion, vomiting, diarrhoea & rash.

18. Lopinavir & ritonavir (Kaletra, Abbott) Therapeutic concentration monitoring

12. Glyceryl trinitrate (Angised, GSK)

19. Metoprolol (Betaloc ZOK, AstraZeneca) Adjust dosage to avoid

Contraindicated in patients taking sildenafil. May cause dizziness & syncope. Caution in driving or operating machinery. A local burning or tingling sensation may occur in the tongue or mouth.

5. Codergocrine (Hydergine, Novartis)

Use a lower starting dose & maintenance dose for patients with moderate-severe hepatic impairment, with appropriate monitoring. It is cautioned that Hydergine containing lactose, is not recommended in patients with galactose intolerance, lactase deficiency or glucose-galactose malabsorption. Interactions (possibly causing increased dopaminergic effects) may occur between codergocrine & macrolides, HIV protease or reverse transcriptase inhibitors, & azole antifungals. Do not use during pregnancy & lactation. May cause dizziness; caution in driving or operating machinery. New ADRs: bradycardia, headache, dizziness, hypotension (after IV administration), vomiting, diarrhoea, retroperioneal fibrosis & rash.

13. Iloprost trometamol (Ventavis, Zuellig) Caution in patients with Child-Pugh

class B or more severe hepatic impairment & those with mild-moderate hepatic impairment.

images in association with red eyes from corneal oedema, in addition to conjunctival congestion, may be signs of acute narrow-angle glaucoma.

14. Ipratropium (Atrovent, Boehringer Ingelheim) It is cautioned that coloured

6. Diclofenac (Voltaren EC, Novartis)

Contraindicated in treatment of peri-operative pain in coronary artery bypass graft surgery. Caution in the use of aspirin & other NSAIDs in aspirin-sensitive asthmatic patients due to potentially fatal bronchospasm.

tenofovir results in a 40-60% increase in systemic exposure to didanosine. Thus concomitant use is not recommended, especially in patients with high viral load & low CD4 cell count as it may result in virological failure & emergence of early resistance. If combination is used, efficacy & adverse events related to didanosine should be monitored. Rarely, pancreatitis & lactic acidosis.

7. Didanosine (Videx EC, Bristol-Myers Squibb) Co-administration of didanosine &

15. Itraconazole (Sporanox, J&J) Caution in patients with renal & hepatic impairment. Concomitant use with bepridil or nisoldipine is contraindicated. Not to be used in patients with evidence of ventricular dysfunction such as CHF or a history of CHF except for treatment of lifethreatening or other serious infection. Risk of heart failure might increase with total daily dose of itraconazole. New ADRs: leukopenia, neutropenia, thrombocytopenia, serum sickness, angioneurotic oedema, hypertriglyceridaemia, paraesthesia, visual disturbances, tinnitus, dysgeusia, toxic epidermal necrolysis, erythema multiforme, & exfoliative dermatitis. 16. Ketoconazole (Nizoral, J&J) Liver
function should be assessed prior to treatment & monitored regularly during treatment & at the first signs of hepatotoxicity. Stop treatment immediately if hepatotoxicity is suspected. Cumulative dose of treatment is a risk factor for serious hepatotoxicity. Should not co-administer with CYP3A4 substrates e.g. bepridil, disopyramide, halofantrine, levacetylmethadol, sertinidole (can lead to QT prolongation), ergometrine, methylergometrine, nisoldipine & eplerenone. Combination with potent enzyme inducers e.g. nevirapine significantly reduces the bioavailability of ketoconazole. Caution when co-administering with glucocorticoids (e.g. budesonide, dexamethasone & methylprednisolone), HMG-CoA reductase inhibitors, cilostazol,

bradycardia. Contraindicated in unstable decompensated cardiac heart failure (pulmonary oedema, hypoperfusion or hypotension), & in those with continuous or intermittent inotropic therapy acting through beta-receptor agonism. Give lower doses or gradually withdraw treatment if patient developed increasing bradycardia. Sudden withdrawal of beta-blockade in high-risk patients may aggravate chronic heart failure, & increase the risk of myocardial infarction & sudden death. Plasma levels of metoprolol may be raised by co-administration of antiarrhythmics, antihistamines, histamine-2-receptor antagonists, antidepressants, antipsychotics, & COX-2 inhibitors. New ADR: hepatitis & arthralgia.

20. Miconazole (Daktarin oral gel, J&J)

Contraindicated in infants < 6 months old or in those whose swallowing reflex is not yet sufficiently developed. Hypoglycemia may occur in patients using oral hypoglycemics e.g. sulfonylureas & miconazole concomitantly. Miconazole interacts with bepridil, halofantrine, sertindole, ergot alkaloids & isopyramide. New ADRs: angioneurotic oedema, anaphylactic reactions, choking, Lyell syndrome (toxic epidermal necrolysis), Stevens Johnson syndrome, urticaria, & rash.

21. Pramipexole (Sifrol, Boehringer Ingelheim) Patients & caregivers should be

aware of behavioural changes e.g. pathological gambling, increased libido, binge eating & may require dose reduction or discontinuation. New ADRs: abnormal behaviour & dreams, delusion, fatigue, hyperkinesia, increased eating, paranoia, pathological gambling, & weight increase.

8.

Contraindicated in peripheral arterial disease. A maximum duration of treatment for acute pain is 8 days, including that related to primary dysmenorrhoea & minor dental procedures. Discontinue therapy if the condition deteriorated

Etoricoxib

(Arcoxia,

MSD)

in HIV-infected patients receiving stavudine together with didanosine & hydroxyurea. Increased risk of hepatotoxicity & possibly death may occur in patients treated with Zerit in combination with didanosine & hydroxyurea vs Zerit alone. New ADRs: abdominal pain, chills/fever, redistribution/ accumulation of body fat, anorexia, pancreatitis, myalgia, anaemia, leucopenia, symptomatic hyperlactatemia, & insomnia

22. Stavudine (Zerit, Bristol-Myers Squibb) Peripheral neuropathy was reported

Adverse Drug Reaction News March 2007 Vol.9 No.1 Page 7

Bevacizumab association with hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome
Rare but serious adverse reactions

evacizumab (Avastin) is a recombinant humanised monoclonal antibody that is directed against the vascular endothelial growth factor (VEGF). It has been licensed since March 2005 by HSA for use in combination with intravenous 5-fluorouracil/folinic acid or intravenous 5-fluorouracil/folinic acid/irinotecan for the first-line treatment of patients with metastatic carcinoma of the colon or rectum.

New safety information Based on reviews of post-market and clinical trial reports, rare cases of hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome (RPLS) have been seen in patients on Avastin. A total of three confirmed cases of hypertensive encephalopathy have been reported in Avastin clinical studies and in post-marketing experience worldwide, based on an estimated patients exposure of 67,000. Hypertensive encephalopathy is manifested as severe hypertension associated with headache, nausea, vomiting, convulsions or confusion. In all the cases reported, the patients had a medical history of hypertension and experienced markedly increased blood pressure of 200mmHg systolic. One of these three cases resulted in a fatal outcome.1 RPLS, a neurologic disorder, typically presents as headache, seizures and visual loss, and often occurs in the setting of accelerated hypertension.2 It may develop in patients who have kidney failure, high blood pressure or who have a compromised immune system. This condition encompasses a spectrum of disorders, including hypertensive encephalopathy, eclampsia, thrombotic thrombocytopenic
Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Staff Editors Ms Yvonne Koh, BSc (Pharm) Hons Ms Adena Lim, MPharm (Clin Pharm) 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

purpura/haemolytic uraemic syndrome, and is also associated with the use of other medicines like immunosuppressants. Brain imaging, particularly MRI, confirms the diagnosis of RPLS. Reports of patients with RPLS have been confirmed in four and suspected in ten patients receiving Avastin. Two of these reports were recently published in the literature.3 The onset of symptoms was reported to occur from 16 hours to 1 year after starting Avastin. None of these cases had resulted in death. A direct cause and effect between Avastin and these events has not been established but it cannot be ruled out. The majority of the reports stated above were for the treatment of conditions other than the licensed indications metastatic carcinoma of the colon or rectum. Both hypertensive encephalopathy and RPLS are reversible if recognised and treated promptly. Local situation HSA has not received any local reports pertaining to hypertensive encephalopathy and RPLS associated with the use of Avastin. In-line with regulatory actions taken by regulatory agencies such as the Therapeutics Goods Administration of Australia, Health Canada and the US Food and Drug Administration, the local package insert of Avastin will be updated to reflect this new safety information
References

1. Health Canada advisory, warnings and recalls for health professionals, October 2006. http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/prof/2006/ avastin_hpc-cps_e.html 2. Intern Med J 2005; 35:83-90. 3. N Engl J Med 2006; 354:980-2.
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