July 2003 Vol 5 No.

ISSN : 0219-2152

ADVERSE DRUG REACTION NEWS

WOMENS HEALTH INITIATIVE MEMORY STUDY (WHIMS)
Oestrogen plus progestin therapy increases the risk for probable dementia in postmenopausal women aged 65 years or older
Introduction
he WHIMS is an ancillary study to the 2 larger Womens Health Initiative (WHI) hormone therapy trial. It sought to examine whether postmenopausal oestrogen replacement (both oestrogen alone and oestrogen plus progestin) reduces the risk of all-cause dementia and subclinical cognitive impairment in healthy women aged 65 years or older. The planned 8.5 years WHI trial for oestrogen plus progestin was discontinued after 5.6 years because women in the intervention group were found to be at an increased risk for heart disease, stroke, pulmonary embolism and breast cancer compared to women receiving placebo. The WHI oestrogenonly hormone therapy trial, which enrolled women with a prior hysterectomy continues, as does the WHIMS component of this trial.
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Published by the Centre for Pharmaceutical Administration, HSA and the Pharmacovigilance Advisory Committee

SAFETY CONCERNS ON THE USE OF PAROXETINE IN CHILDREN WITH MAJOR DEPRESSION

aroxetine (Seroxat , GlaxoSmithKline) is a selective serotonin re-uptake inhibitor and is approved for use in adults for the treatment of depressive and anxiety disorders. It is not licensed for use in children but is known to be used in this age group outside the licensed indications in many countries.

Regulatory decisions
Recently, the UK Committee on Safety of Medicines (CSM) has contraindicated the use of paroxetine to treat depressive illness in children and adolescents under 18 years of age. This recommendation was based on new data from 3 well-controlled clinical trials in children and adolescents. The data did not demonstrate efficacy of paroxetine in depressive illness in this age group and showed an increase in the risk of harmful outcomes including episodes of self-harm and potentially suicidal behaviour in the Seroxat group compared to placebo. Various analyses suggest that the risk of these outcomes is between 1.5 and 3.2 times greater with Seroxat compared to placebo. The CSM also advised that paediatric patients who are currently on paroxetine should not have their medication discontinued abruptly because of the risk of withdrawal reactions. Their doctors should be consulted to discuss the best course of action.

HSAs review
HSA is currently reviewing the data submitted by the company. Relevant updates reflecting the new data on safety in children and adolescents will be reflected in the local package insert. In the meantime, the HSA advises that paroxetine should not be used in children and adolescents under 18 years of age for the treatment of depression. Paroxetine has been demonstrated to be effective in adults with depressive illnesses. Current evidence does not reveal an increase in the rate of suicidal ideation in adults treated with paroxetine compared to placebo

CONTENTS
Findings of the WHIMS Use of paroxetine in children Use of repaglinide with gemfibrozil Recall of Pan Pharmaceuticals products Oxaliplatin and infusion related ADRs Tamoxifen and uterine sarcoma 1 1 2 2 3 4

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

RECALL OF PAN PHARMACEUTICALS PRODUCTS

he Therapeutics Goods Administration (TGA), Australia has ordered the urgent recall of pharmaceutical products manufactured by Pan Pharmaceuticals Limited (Australia) and suspended its licence following a series of safety and quality breaches on 28 April 2003. The breaches included substitution of ingredients, manipulation of test results and substandard manufacturing processes. Pan Pharmaceuticals represents 70% of the Australian complementary pharmaceutical market. It also does contract manufacturing for many other brands, some of which are available locally.

by Pan Pharmaceuticals (this product is not available in Singapore). Subsequent inspections of Pan Pharmaceuticals manufacturing premises have since found evidence of widespread and serious deficiencies in the companys manufacturing and quality control procedures. The Pan Pharmaceuticals products subjected to recall affect those manufactured since 1 May 2002 as this was the latest date that the TGA could ensure that the company complied with the requirements of good manufacturing practices.

Actions taken by HSA

Due to the serious and widespread nature of the manufacturing problems identified by the TGA, HSA issued a press release on 28 April 2003 to advise the public to refrain from taking nonessential health products manufactured by Pan Pharmaceuticals. To-date, 244 products marketed under 26 different brands in Singapore have been confirmed to be manufactured by Pan Pharmaceuticals and all have been recalled from the market. For a complete listing of the affected products, please refer to the HSA website at http://www.hsa.gov.sg.

Public advisory
The products manufactured by Pan Pharmaceuticals for the Singapore market are non-prescription products and meant only for health supplementation. In addition, the TGA has informed HSA that there was no evidence of intentional adulteration of Pan Pharmaceuticals products with potent western drugs. To-date, no serious adverse drug reactions to these products have been reported locally. Healthcare professionals are encouraged to report any suspected serious adverse drug reactions to vitamins and complementary medicines to the Pharmacovigilance (PV) Unit

Other relevant information

The TGA was alerted to problems at Pan Pharmaceuticals in mid January 2003 when it started to receive serious ADR reports to Travelcalm, an anti-motion sickness medicine manufactured

CONTRAINDICATION OF CONCOMITANT USE OF REPAGLINIDE WITH GEMFIBROZIL

Repaglinide with gemfibrozil: Risk of hypoglycaemia

epaglinide (Novonorm, Novo Nordisk) is a relatively new oral short-acting antidiabetic agent approved for marketing in Singapore in January 1999. It stimulates insulin release and is indicated for the treatment of non insulindependent diabetes mellitus where hyperglycaemia is not controlled satisfactorily by diet, weight reduction and exercise. Drug interactions A recent paper (Niemi et al 2003) reported an interaction between repaglinide and gemfibrozil, a lipid lowering agent used for the treatment of dyslipidaemia. When administered concomitantly, the blood glucose lowering effect of repaglinide was markedly enhanced and prolonged. In this randomised crossover study, 12 healthy volunteers received twice daily for 3 days of a) either 600 mg gemfibrozil or 100 mg itraconazole b) both gemfibrozil and itraconazole, or c) placebo. On day 3, they ingested 0.25 mg of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 hours and serum insulin and C-peptide concentrations for 3 hour post-dose. It was found that gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1 fold (range 5.5 to 15.0 fold; p<0.001) and prolonged its half-life from 1.3 to 3.7 hours (p<0.001). Although itraconazole alone raised repaglinides AUC by only 1.4 fold (1.1 to 1.9 fold;
2

p<0.001), the gemfibrozil-itraconazole combination raised it by 19.4 fold (12.9 to 24.7 fold) and prolonged the half-life of repaglinide to 6.1 hours (p<0.001). Plasma repaglinde concentration at 7 hours was increased 28.6 fold by gemfibrozil and 70.4 fold by the gemfibrozil-itraconazole combination (p<0.001). The alterations in the pharmacokinetics of repaglinide were due to inhibition of CYP2C8 by gemfibrozil as this enzyme plays a major role in the metabolism of repaglinide. In addition, Novo Nordisk has received 5 spontaneous reports of serious hypoglycaemic episodes in patients treated concomitantly with repaglinide and gemfibrozil. Contraindication Based on the information above, the concomitant use of repaglinide and gemfibrozil is contraindicated. The local package insert of repaglinide will be amended to reflect this new information
Reference: Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: Potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia. 2003 Mar, 46 (3): 347-51.
Adverse Drug Reaction News July 2003 Vol 5 No.2

OXALIPLATIN AND INFUSION RELATED ADRS

latinum-type anti-neoplastic agents such as cisplatin, carboplatin are known to cause hypersensitivity and anaphylactic-like reactions when administered intravenously. These reactions have also been reported to oxaliplatin, a relatively new member of this drug class. Oxaliplatin (Eloxatin, Sanofi-Synthelabo) was licensed in Singapore in 1998 and is approved for the first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil and folinic acid. Local reports Between May 1998 to May 2003, the Pharmacovigilance (PV) Unit has received 20 local ADRs suspected to be associated with oxaliplatin. Oxaliplatin was reported to be the sole suspected agent in 17 of these 20 reports. The adverse reactions reported include difficulty in breathing, stridor, flushing, tachycardia and angioedema. Many of these reactions occurred within minutes of the infusion or during the infusion. See Table 1 for some of the case details. Adrenaline, corticosteroids and antihistamines have been employed to alleviate some of these symptoms.

Label amendments The local package insert of Eloxatin will be amended to reflect the information that anaphylactic-like reactions such as difficulty in breathing, stridor, flushing, skin rash (particularly urticaria), conjunctivitis, rhinitis, bronchospasm, angioedema, hypotension and anaphylactic shock may occur within minutes of Eloxatin administration

Table 1: Examples of case reports of infusion related ADRs to oxaliplatin

Patient Female, 39 yrs, Chinese

ADRs

Other drugs

Outcome Information not available

The patient developed breathlessness after oxaliplatin Albumin, infusion and during Tomudex infusion. Blurred vision and dexamethasone, Kytril involuntary eye movements were also reported. Oxaliplatin and Tomudex were suspected. Flushing, tachycardia 15 mins after the start of infusion. Facial flushing 10 mins after the start of infusion, followed by vomiting, diarrhoea and breathlessness. Acute breathlessness and stridor during infusion. Reactions lasted for 30 mins. Rash, flushing, bronchospasm. Flushing, dyspnoea, chills, epigastric pain. Dexamethasone, Zofran Dexamethasone, fluorouracil, folinic acid, Zofran Dexamethasone, Kytril, Tomudex Fluorouracil, folinic acid, Kytril Kytril

Female, 55 yrs, Chinese Female, 69 yrs, Eurasian Female, 69 yrs Female, 70 yrs, Chinese Male, 40 yrs, Chinese Male, 62 yrs, Chinese Male, 64 yrs, Chinese

Recovered Recovered

Recovered Recovered Not yet recovered at the time of reporting Recovered Recovered Recovered Recovered

Acute breathlessness 1.5 hrs after the end of infusion. Reactions lasted for 15 mins. Acute difficulty in breathing at the end of infusion. Reactions lasted for 30 mins.

Dexamethasone, Navoban, Tomudex Dexamethasone, Navoban, Tomudex Dexamethasone, Leucovorin, Kytril Atenolol, fluorouracil, Leucovorin, nifedipine

Female, Chinese Angioedema of face and upper limbs. Male, 60 yrs, Chinese Diffuse rash occurred during infusion.

Adverse Drug Reaction News July 2003 Vol 5 No.2

Findings of the WHIMS... continued from page 1

Results
The WHIMS is a double-blind, placebo controlled trial. It began enrolling participants from the WHI oestrogen plus progestin trial in May 1996. It enrolled 4,532 postmenopausal women greater than 65 years of age with an average follow up of 4.05 years. Participants received either 1 daily tablet of 0.625 mg of conjugated equine oestrogen plus 2.5 mg of medroxyprogesterone (n=2,229) or a matching placebo (n=2,303). Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the oestrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% CI, 1.21-3.48; 45 vs 22 per 10,000 person-years; p=0.01). Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10,000 person-years; p=0.72).

they should be aware that there are currently many non-HRT alternatives which are effective in the prevention and treatment of osteoporosis. HSA continues to advise women to have their therapy and health regularly reviewed by their physicians. They should discuss their individual benefit and risk profile with their physicians who will be in the best position to advise them whether they should continue with HRT and what the alternative therapies are. HSA further advises physicians that oestrogen and oestrogen with progestin products have never been approved for prevention of Alzheimer Disease or memory deficit
Reference: Shumaker SA, Legault C. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: A randomised controlled trial. JAMA. 2003 May, 289 (20): 2651-62.

Comments
The WHIMS is the largest among randomised clinical trials todate, which assesses the effects of oestrogen plus progestin in dementia and mild cognitive impairment. The WHIMS results are specific to the use of conjugated equine oestrogen plus medroxyprogesterone acetate, and may not apply to other oestrogen/progestin combinations, doses, or routes of administration. However, no current evidence is available showing that other oestrogen plus progestin therapies would lead to substantially different outcomes. The WHIMS trial was restricted to women aged 65 years or older. Some investigators have suggested that for hormone therapy to prevent probable dementia, women must initiate its use around the menopause. This alternative hypothesis could not be tested in the WHIMS. It is noted that, within the age distribution included in the WHIMS, probable dementia occurred at all ages and almost 50% of the study participants were 65 to 70 years at age of study onset.

TAMOXIFEN & UTERINE SARCOMA

Warnings of an increased incidence of uterine malignancies

he local package insert for tamoxifen (Nolvadex , AstraZenca) was recently amended to include additional information on the increased rare risk of uterine sarcoma (mostly malignant mixed Mullerian tumours) as well as the previously noted increased risk of endometrial adenocarcinoma. Uterine sarcoma is rare, and is estimated to occur at 0.17 per 1000 women-years versus 0.01 to 0.02 for placebo. In Singapore, there are 270 cases of uterine sarcoma over the period 1968 1997. Of these, 50 were malignant mixed Mullerian tumours. Since 1978, when tamoxifen was first marketed in the US, there have been 159 cases of uterine sarcoma reported worldwide in women taking the drug. The incidence rate of endometrial adenocarcinoma is 2.2 per 1000 women-years versus 0.71 for placebo as observed during long-term followup of women enrolled in clinical trials of tamoxifen. The underlying mechanism is unknown, but may be related to the oestrogen-like effect of tamoxifen References:

HSAs advisory
As a result of these findings, HSA has issued an updated advisory which reinforced the public advisory issued in October 2002 which was to address the concerns which had risen from the results of the earlier WHI trial. (Please see http://www.hsa.gov.sg for further details). The advisory emphasises that for women who are taking HRT for short-term treatment of menopausal symptoms, the benefits of HRT are likely to outweigh the risk. For women whose sole indication for using HRT is the prevention of osteoporosis,

1. 2.

FDA Medwatch, Nolvadex (http://www.fda.gov/medwatch/ SAFETY/2002/safety02.htm#nolvad) Wysowski DK. Uterine sarcoma associated with tamoxifen use. NEJM. 6 June 2002, 346 (23): 1832-33

Adverse Drug Reaction News is produced by the Centre for Pharmaceutical Administration, HSA and the Pharmacovigilance Advisory Committe

Editor-in-Chief
Ms Chan Cheng Leng BSc (Pharm) Hons

Editorial Board
Clinical Prof. Goh Chee Leok Prof. Edmund Lee Jon Deoon A/Prof. Chia Kee Seng Clinical A/Prof. Chng Hiok Hee Dr Gilbert Lau Kwang Fatt Dr Lee Kheng Hock

Enquiries, comments and suggestions to:

Pharmacovigilance Unit Centre for Pharmaceutical Administration Health Sciences Authority 2 Jalan Bukit Merah Singapore 169547 Tel: (65) 6325 5604 Fax: (65) 6325 5448 Website: http://www.hsa.gov.sg Email: HSA_DRUGSAFETY@hsa.gov.sg

Executive Editor
Ms Ang Pei San BSc (Pharm)

Its contents are not to be reproduced in part or in whole, without prior written approval to the editor.Whilst every effort is made in compiling the content of this publication, the publishers, editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements.The mention of any product by the authors does not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2003 Health Sciences Authority of Singapore. All Rights Reserved.

Adverse Drug Reaction News July 2003 Vol 5 No.2