Sunteți pe pagina 1din 4

August 2002 Vol 4 No.

ISSN : 0219-2152

ADVERSE DRUG REACTION NEWS


ORAL COMBINED HORMONE REPLACEMENT THERAPY
Study concludes oral HRT not beneficial for the prevention of coronary heart disease in postmenopausal women.

HSA
Health Sciences Authority

Published by the Expert Panel on Adverse Drug Reactions and the Centre for Pharmaceutical Administration, HSA

Editorial Note
he Health Sciences Authority (HSA) and the Expert Panel on ADR would like to take this opportunity to thank all our doctors and pharmacists who reported the adverse drug reactions (ADRs) of Slim 10 to the Pharmacovigilance (PV) Unit.

Slim 10 was marketed as a Chinese Proprietary Medicine for slimming in December 2001. It was withdrawn on 19th April 2002 following confirmation of adulteration of the product with undeclared substances. An estimated 20,000 bottles of Slim 10 had been sold. The first ADR report of acute hepatitis to Slim 10 was received by the PV Unit in late March 2002. Three other ADR reports, two of hyperthyroidism and one of menstrual irregularities were subsequently reported in early April 2002. Based on these reports, HSA initiated an investigation into the product which revealed it to be adulterated with nicotinamide, fenfluramine and thyroid gland components. Since then, HSA has initiated enforcement action against the parties responsible for the import, sale and distribution of the adulterated product. The cooperation of our healthcare professionals in alerting HSA to a potential drug safety problem has enabled us to take timely regulatory action to remove Slim 10 from the market thereby significantly reducing the risk of exposure to consumers and consequently the incidence of adverse effects I

he US Womens Health Initiative (WHI) trial for women with intact uterus has been halted prematurely based on health risks that exceeded health benefits over an average follow-up of 5.2 years. This was a randomized controlled primary prevention trial (planned duration of 8.5 years) designed to assess the major health benefits and risks of the most commonly used combined hormone preparation (0.625 mg conjugated oestrogen plus 2.5 mg medroxyprogesterone) in the United States. About 16,000 postmenopausal women aged 50 79 years with an intact uterus at baseline were recruited into the trial between the period 1993 1998. The key findings after five years relate to an increase in risk of I Breast cancer (from 30 to 38 per 10,000 women years) I Coronary heart disease (from 30 to 37 cases per 10,000 women years) I Stroke (from 21 to 29 cases per 10,000 women years) The benefits were reductions in I Colorectal cancer (from 16 to 10 per 10,000 women years) and I Hip fracture (from 15 to 10 cases per 10,000 women years)
Continued on page 4

Ms Chan Cheng Leng


Editor-in-Chief

CONTENTS
Oral combined HRT On-line ADR reporting 3rd generation OC & thromboembolism Sibutramine (Reductil) Kava-kava & liver toxicities Epoetin alfa & pure red cell aplasia 1 2 2 3 3 4

Provide us with your full name and email address to receive HSA drug safety information. Email us at HSA_DRUGSAFETY@hsa.gov.sg
Volume 4 Number 2 2002

ON-LINE ADR REPORTING


he Pharmacovigilance (PV) Unit is pleased to announce the implementation of the on-line ADR reporting which is now available at the Health Sciences Authority (HSA)s website. This new platform of reporting allows our healthcare professionals to report ADRs directly to the PV unit. The reporter inputs the necessary data into the website and submits it through the Internet; this information is then translated as an e-mail to HSA_DrugSafety mail box of the officers in-charge. A pilot run has been conducted and the quality of the transmitted information was clear and instantaneous. This mode of reporting reduces the possibility of reports getting lost as well as delays in receipt of reports. The online ADR reporting form is an addition to the other standard modes of reporting which include reporting through e-mail (HSA_DRUGSAFETY@hsa.gov.sg), conventional mail, fax or telephone call to the PV Unit. Check out the online ADR reporting form at http://www.hsa.gov.sg/ADR_online. The online ADR reporting form is at http://www.hsa.gov.sg/ ADR_online. It can also be found at the HSA website under e-services and the pharmacovigilance webpages I

THIRD GENERATION ORAL CONTRACEPTIVES AND VENOUS THROMBOEMBOLISM (VTE)


Although the risk of VTE with the use of third generation oral contraceptives remains small, women should be advised that this group of drugs is associated with an increased risk of VTE when compared to the older ones.
I

associated with COCs containing desogestrel or gestodene with 30 mcg of ethinylestradiol (third generation COCs) compared to COCs containing levonorgestrel with the same amount of ethinylestradiol (second generation COCs). For COCs containing desogestrel or gestodene with 20 mcg of ethinylestradiol, the epidemiological data do not suggest a lower risk of VTE than for those containing 30 mcg of ethinylestradiol The estimates of the overall relative risk for VTE for the third generation COCs compared to the older ones vary considerably among epidemiological studies. On the basis of a careful evaluation of all available data, the best estimate of the relative risk is in the range of 1.5 2.0 The increased risk of VTE associated with COCs is less than the risk of VTE associated with pregnancy

he risk of developing venous thromboembolism (VTE) is a recognised complication associated with the use of combined oral contraceptives (COCs). Over the years, there has been ongoing debate as to whether third generation COCs (OCs containing gestodene or desogestrel) are associated with a higher risk of VTE than second generation COCs (OCs containing levonorgestrel or norethisterone). The European Committee for Proprietary Medicinal Products (CPMP) has published the outcome of its assessment of the risk of VTE associated with the use of third generation COCs in September 2001. This assessment was based on the reviews of epidemiological studies and studies on blood clotting mechanisms from the period 1995 to September 2001.

In summary, CPMP concludes that:


I

VTE is a rare adverse effect of all COCs. The level of this risk is low and the overall balance of benefits and risks remains favourable with all COCs The risk of VTE is highest during the first year that a woman ever uses any COC Evidence suggests that there is a small increased risk of VTE
I

The risk of VTE can be expressed as follows when taken in relative perspective: Risk Factor Healthy women between 15 44 yrs old not taking COCs Women taking second generation COCs Incidence of VTE 5-10 cases per 100,000 women years 20 cases per 100,000 women years

Women taking third generation COCs 30-40 cases per 100,000 women years Pregnancy 60 per 100,000 pregnancies

Volume 4 Number 2 2002

UPDATED REPORT ON SIBUTRAMINE (REDUCTIL)


The risk/benefit profile of sibutramine remains positive when used accordingly to labelled indications.
n March 2002, the Italian regulatory authority temporarily suspended the sale of sibutramine (Reductil, Abbott), an antiobesity drug, due to the occurrences of adverse drug reactions including two reports of death in Italy suspected to be associated with sibutramine. The Italian authority also initiated a request to the central European Committee for Proprietary Medicinal Products (CPMP) to reassess the efficacy and safety of sibutramine.

CPMPs report
The CPMP has recently finalised its view on sibutramine in June 2002. It has given a positive opinion on sibutramine, reaffirming the favourable risk/benefit profile of sibutramine for the treatment of obesity. The opinion of the CPMP was supported by analysis of data that included clinical studies of sibutramine, dating back to 1989 in about 12,000 obese patients. To-date, none of the other regulatory agencies including the Medicines Control Agency, UK, the Food & Drug Administration, USA and the Therapeutics Goods Administration, Australia has taken any regulatory actions against the marketing authorisation of the drug.

Use of sibutramine
Physicians are reminded that sibutramine should only be prescribed to patients who have a body mass index (BMI) > 30 kg/m2 or patients with BMI > 27 kg/m2 with obesity related risk factors such as type II diabetes and dyslipidaemia who have not responded adequately to an appropriately designed weight reduction programme. Treatment must also be discontinued if a 5% weight reduction is not achieved within three months. In addition, sibutramine should only be administered as a component of a therapeutic approach to weight loss on the long-term, under the supervision of a physician experienced in obesity treatment. The drug has also been approved for adjunctive treatment of obesity for up to one year only. Sibutramine can cause elevations in blood pressure and heart rate in some patients. Hence it is necessary to monitor the blood pressure and pulse rate regularly especially during the initiation of therapy. The drug should be discontinued if blood pressure levels exceed 140/90 mmHg at two consecutive readings. It is contraindicated in patients with inadequately controlled hypertension and in patients with history of heart diseases such as congestive heart failure and irregular rhythms. Detailed information regarding the use of sibutramine can be found in the product information leaflet of Reductil. All healthcare professionals are encouraged to report any adverse drug reactions suspected to be associated to Reductil to the Pharmacovigilance Unit I

HSAs review
Pending CPMPs outcome of the review, HSA had reviewed the safety data of sibutramine in March 2002 and concluded that the risk/benefit profile of sibutramine remains positive and it would not be necessary to take similar regulatory action to suspend the marketing approval of the drug. HSAs stand was posted on its website in March 2002 at http:// w w w. h s a . g o v. s g / h s a / c p a / CPA_information_whatsnew.htm.

KAVA-KAVA AND LIVER TOXICITIES


Kava-kava health supplements are no longer available in Singapore.
ava-kava containing health supplements were voluntarily withdrawn in Singapore in January 2002. This precautionary measure was taken pending a decision by the German regulatory authoritys review of reports of serious liver injuries suspected to be associated with the product. No such adverse effects have been reported in Singapore.

notified the marketing authorisation holders that all kavakava and kavaine containing products will be withdrawn from the German market due to hepatotoxic risks and insufficiently proven efficacy of these products. The kava-kava products that have been associated with liver toxicities relate to the chemically extracted ingredients of kava marketed as health supplements. The decision was based on an in-depth review of all the reports of liver toxicities. To-date, there are more than 40 cases of liver toxicity with suspected links to consumption of kava-kava. Of these cases, six led to complete liver failure that required an organ transplant and three cases resulted in death. In the light of confirmation of the liver toxicity risk and to enhance safeguards, HSA is proceeding to gazette kava-kava and its active constituents as poisons under the Poisons Act. This will prohibit the importation and sale of health products containing kava-kava I
Volume 4 Number 2 2002

Kava-kava (Piper methysticum) is a plant indigenous to the islands in the South Pacific. Supplements containing the herbal ingredient kava are promoted for relaxation (e.g. to relieve stress, anxiety and tension), sleeplessness and for ailments affecting the bladder and digestive tracts.

Regulatory decisions
Recently, in June 2002, BfArM, the German drug regulatory authority has finalised its decision on kava-kava and has

Continued from page 1

Oral Combined Hormone Replacement Therapy


This new data confirms and adds to information that is already known about the benefits and risks of oral combined HRT in women with intact uterus. The results of the trial confirms and quantifies the small increase in risk of breast cancer (significant only after the fifth year of therapy onwards) and provides new information on stroke. It confirms the lack of protection from coronary heart disease and shows instead a small increase in risk. It also confirms the protection against hip fracture and reveals a reduced incidence of colorectal cancer. On the whole, the percentage of women who experienced adverse effects from the combined HRT was small and therefore the risk to the individual women in the trial was small. There is another arm of the WHI trial which is still ongoing and it involves women who had a hysterectomy and are treated with oestrogen alone. This trial has not been halted as the balance of risks and benefits in the unopposed-oestrogen component remains uncertain and there were no significant adverse events in this study group. The trial will go on as planned for the duration of 8.5 years. In UK, a major trial, the Womens International Study of Long Duration Oestrogen after Menopause (WISDOM) which began in 1999 will continue but no new patients will be recruited until an international team commissioned by the British Medical Research Council has reviewed the findings of the WHI trial. The WISDOM trial which was planned till 2012 was intended to cover over 20,000 postmenopausal women from UK, Australia and New Zealand. It sought to find out if HRT lowers or increases the chances of developing diseases and conditions such as heart attacks, breast cancer, osteoporosis and dementia. The HRTs studied involve the combined HRTs and the oestrogen alone preparations. HSA has initiated communication with the product license holders of the relevant oral combined HRT preparations in Singapore to update the new findings in the product information leaflets. HSA in consultation with medical experts in the management of HRT has issued a public advisory on the matter. Please refer to http://app.internet.gov.sg/scripts/hsa/ communications/pressreleases.asp for more information. Healthcare professionals may also refer to the websites from other regulatory agencies for more information on the topic:

EPREX (EPOETIN ALFA) AND REPORTS OF PURE RED CELL APLASIA


Majority of reports of pure red cell aplasia are associated with the subcutaneous route of injection.
poetin alfa (Eprex, JanssenCilag) is indicated for the treatment of anaemia associated with chronic renal failure (CRF), cancer chemotherapy, autologous blood donation and during major elective orthopaedic surgery.

Pure red cell aplasia (erythroblastopenia) has been reported in CRF patients between 1-92 months from the initiation of Eprex therapy (median onset is 11 months). From 1998 through April 2002, there have been 124 such cases of suspected pure red cell aplasia reported worldwide of which 104 are reported to have been confirmed by bone marrow examination. Antibodies to erythropoietin have been observed in 63 (out of 79 for whom results were available) Eprex treated patients diagnosed with PRCA. Most of the worldwide reports of PRCA are associated with the subcutaneous (SC) route of administration, the predominant route of administration practised in most countries. The estimated worldwide Eprex exposure is 16 x 105 patient-years, giving a worldwide reporting incidence rate for suspected PRCA of 7.5 per 100,000 patient-years. Based on the companys investigations, no single trigger has been identified todate and a number of factors may have contributed to the development of immunogenicity. Eprex is approved to be administered by subcutaneous and intravenous injection. Available scientific information suggests that the subcutaneous route of administration for some medicines, such as Eprex,

may increase the likelihood of the body producing antibodies that could reduce the effectiveness of the medicine and possibly lead to events such as PRCA. Whilst the company continues with its investigations, Janssen-Cilag is recommending that the product be administered by the IV route in CRF patients, where feasible. The company advises that in patients with worsening anaemia, other causes (eg., iron, folate or vitamin B 12 deficiency; aluminium intoxication; infection or inflammation; blood loss or haemolysis) should be excluded. If PRCA is suspected it should be confirmed with bone marrow examination and/or antibody testing. Epoetin alfa should be discontinued, and patients should NOT be switched to another erythropoietin. PRCA may respond to immunosuppressive therapy and spontaneous resolution has occurred occasionally. In many of the cases, the patients become transfusion dependent. HSA is aware of several local cases of PRCA associated with Eprex usage, however the causality to Eprex has not been established as yet. Healthcare professionals are encouraged to report the ADRs to Pharmacovigilance Unit should they come across any such cases. Antibody testing can be arranged through Janssen-Cilag at telephone 62658922. HSA will be closely following the investigations by the company I

Adverse Drug Reaction News is produced by the Expert Panel on Adverse Drug Reactions and the Centre for Pharmaceutical Administration, Health Sciences Authority Editor-in-Chief:
Ms Chan Cheng Leng, BSc Pharm (Hons)

Editorial Board:
Clinical Professor Goh Chee Leok, Clinical Assoc. Professor Chng Hiok Hee, Dr Gilbert Lau, Clinical Professor Ng Han Seong, Professor Vernon Oh

Australia Therapeutic Goods Administration http://www.health.gov.au/tga/new/new.htm UK Committee of Safety of Medicine h t t p : / / w w w. m c a . g o v. u k / o u r w o r k / monitorsafequalmed/safetymessages US Food and Drug Administration http://www.fda.gov/cder/whatsnew.htm

Enquiries, comments and suggestions to: Ms Chan Cheng Leng, Pharmacovigilance Unit, Centre for Pharmaceutical Administration, Health Sciences Authority 2 Jalan Bukit Merah, Singapore 169547, Tel: 6325 5604, Fax: 6325 5448 Website: http://www.hsa.gov.sg/cpa Email: HSA_DRUGSAFETY@hsa.gov.sg
Its contents are not to be reproduced in part or in whole, without prior written approval to the editor. The mentioning of any product by the author does not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2002 Health Sciences Authority of Singapore. All Rights Reserved.

Volume 4 Number 2 2002

S-ar putea să vă placă și