Review of adverse events related to chinese medicines

Review of Adverse Events Related to Chinese Medicines
in Hong Kong, July 2004 - June 2005
Dr Anna Wong1 Dr Constance Chan2 Introduction

Investigation on Chinese medicine-related adverse events is important for monitoring the safety of Chinese medicines. At present, the Department of Health (DH) receives reports of adverse events suspected to be related to the use of Chinese medicines through various channels. Upon receipt of the report, a multidisciplinary team of the DH will start investigation. The team comprises public health physicians, Chinese medicine practitioners (CMPs), Chinese medicine experts and pharmacists. Assistance will be sought from the Government Laboratory to perform analytic tests on the Chinese medicines involved. The information so gathered would guide the formulation and implementation of public health measures to ensure their safe use. In September 2004, an article reviewing the adverse events reported in the period between January 2000 and June 2004 was published in the Public Health and Epidemiology Bulletin.1 This paper is a review of cases reported to the DH from July Method
All suspected Chinese medicine-related adverse events reported to the DH from July 2004 to June 2005 were studied. Relevant data on patients' demographics, Chinese medicines incriminated, causes and outcome of the adverse events were analyzed. Results
A total of 80 suspected cases was reported to the DH. After investigation, 39 cases were found to be unlikely due to use of Chinese medicines either because there were other diagnoses made for patients' presentations or the relationship with use of Chinese medicine could not be established. Another four cases were regarded as inconclusive due to insufficient information. For the remaining 37 cases, 38 patients were involved, of whom 15 were male and 23 were female. The patients' age ranged from nine days to 83 years, with a median age of 50.5 years. Public hospitals were the major source of reporting (28 cases). Other sources included other public agencies, private doctors, the media and the public. Among these 38 patients, 26 patients required hospitalization, of whom six patients were admitted to intensive care unit and In terms of the type of involved medicines, 21 cases were found related to Chinese herbal medicines, 15 cases were related to proprietary Chinese medicines (pCm) and one case involved both. Chinese herbal medicines usually refer to the dried form of the herbal medicines. Those commonly used in Hong Kong are listed in Schedule 1 and Schedule 2 of the Chinese Medicine Ordinance (Chapter 549). For pCm, they refer to proprietary products composed solely of Chinese herbal medicines or any materials of herbal, animal or mineral origin customarily used by the Chinese as active ingredients, that are formulated in a finished dose form. In 17 cases, the patients took Chinese medicines without prior consultation with CMPs while another 19 cases consumed Chinese medicines that were prescribed by CMPs. For one case, it was unsure whether the patient got his medicines from the Majority (30 cases, 81%) used Chinese medicines for treatment of a variety of conditions ranging from minor ailments to acute or longstanding diseases while five of them used Chinese medicines for weight reduction and two for general health Although the majority (28 cases, 76%) bought the Chinese medicines in Hong Kong, a significant portion (eight cases, 22%) purchased the medicines outside, mainly in Mainland China. In one case, the source of Chinese medicines could not be ascertained as the patient refused to disclose further information. The most frequently incriminated Chinese medicines were aconitine-containing (eight cases) which involved either processed Radix Aconiti (製川烏), processed Radix Aconiti Kusnezoffii (製草烏) and/or processed Radix Aconiti Lateralis (製附子). This was followed by aristolochic acid-containing herbs (four cases) which involved Radix Aristolochiae Fangchi (廣防己) and Herba Aristolochiae Mollissimae (尋骨風). Table 1 summarizes the Chinese medicines incriminated, the toxic components of the medicines and the causes for the adverse events. Table 1 Summary of Adverse Events Related to Chinese Medicines
Reported to the DH, July 2004 - June 2005
Incriminated
Toxic or Potent
Chinese Medicine
Components
Erroneous
Misuse Others
Substitution
Chinese Herbal Medicines
Kusnezoffii (製草烏) and/or Processed Radix Aconiti Lateralis (製附子) Radix Aristolochiae Fangchi (廣防己) Herba Aristolochiae Mollissimae including gold and bird's nest prepared into a paste Proprietary Chinese
Medicines
Rheumatic Capsules (特效李三連蛇骨風濕丸) Wilfordii Capsule (雷公籐多甙膠囊) Note: * Number of cases (number of patients) The same case involved both Chinese herbal medicines and proprietary Chinese medicines. Major Causes of Adverse Events
Quality defect was one of the main causes of adverse events for this series. Among these, adulteration of pCm products with western medicines accounted for most of the cases (ten cases). Western medicines were added to the products illegally to enhance the apparent efficacy of the products. These were mainly steroid and slimming agents. All patients presented with the adverse effects that are known side effects of the Three patients developed Cushingoid features after consuming Chinese medicines that contained steroid for a long time. They took the Chinese medicines for treating eczema, shortness of breath and joint pain respectively. Another three patients who took Chinese medicines for slimming purpose developed known problems of the adulterated western medicines. The medicines involved were N-nitrosofenfluramine, sibutramine and fenfluramine which led to acute liver failure requiring liver transplantation, convulsion and valvular heart disease respectively. The other ingredients adulterated in four cases were sulfamethazine, tetrahydropalmatine, diclofenac, chlorpromazine, and rosiglitazone. Sulfamethazine caused methaemo-globinaemia; rosiglitazone caused oedema and the others led to Another major cause for the adverse events in this series was misuse of the Chinese medicines. There were three main problems, namely, overdose, excessive long duration of use and inappropriate decoction. Among the 12 cases due to misuse, one third involved self-prescription without proper consultation with health care professionals. The rest were due to inappropriate formulation or improper decoction. More than half of these cases (seven cases) involved aconitine-containing herbs and the main reason was overdose. One of the patients required admission to intensive care unit. All the patients recovered. Aconitine-containing herbs should be decocted for one to two hours before boiling with other herbs.6,7 This is an important step to reduce its toxicity.2,7 Those self-prescribed were not aware of this crucial step. Chinese Medicines Containing Strychnine and Brucine Two patients suffered from toxic effects of Semen Strychni (馬錢子) overdose. The herb could cause adverse effects which include headache, dizziness, irritability, muscle spasm, mental confusion, tachypnoea, dilated pupils, arrhythmia and circulatory failure.7 One of them learnt from a Chinese medicine book that Semen Strychni (馬錢子) was good for his trigger finger. As a result, he self-prescribed Semen Strychni (馬錢子) for three doses with each dose one to four grams, which exceeded the recommended dosage of 0.3-0.6 gram.8 Another patient was a CMP who mistook a self-made pill containing Semen Strychni (馬錢子) for another self-made one. Both pills were only prepared for his own consumption. These two patients In one case, a five-year-old boy suffered from adverse effects after consumption of Fructus Xanthii (蒼耳子). He later recovered. When used for children, the dosage of Fructus Xanthii should be adjusted accordingly. In this case, the dosage used was relatively high for a child which was believed to be the reason for the toxic effects. Moreover, during investigation, it was also found that the herb in the market was not properly fried and the spikes which contain higher concentration of the toxins had not Rhizoma Dioscoreae Bulbiferae (黃藥子) In one case, a patient developed liver derangement after prescribed with 70 doses of Rhizoma Dioscoreae Bulbiferae (黃藥子). All the 70 doses exceeded the recommended dosage. Rhizoma Dioscoreae Bulbiferae (黃藥子) is known to be hepatotoxic. The patient gradually recovered. Erroneous substitution of Chinese herbal medicines with a more toxic herb is not uncommon. This is partly because the naming of Chinese medicines is sometimes confusing. The same Chinese medicine may have several names while one name may mean totally different herbs. Another reason is that the appearance of some Chinese In this series, the substitution cases were mainly the mixing up of Radix Aristolochiae Fangchi (廣防己) and Radix Stephaniae Tetrandrae (防己) (three cases). Both herbs have similar names, appearance and indications.9 Actually, they are from different families of plants. The former is of Family Aristolochiaceae (馬兜玲科) and the latter is of Family Menispermaceae (防己科). Radix Aristolochiae Fangchi (廣防己) contains aristolochic acid while Radix Stephaniae Tetrandrae (防己) does not. Aristolochic acid (AA)-containing herbs were banned for import and sale in Hong Kong on 1 June 2004 due to its renal toxicity and carcinogenic effects 10-12. One of the patients recovered after treatment. The other two patients had other underlying renal diseases and their renal function remained abnormal. The AA-containing herb was thought to aggravate their renal problems. Adverse events could also be a result of other causes like allergic reaction, intrinsic toxicity of the Chinese medicines or drug interaction. Two cases were related to the use of Ganoderma Lucidum spores (靈芝孢子). One patient developed tongue swelling after taking the product which was thought to be due to allergic reaction. Another patient developed diarrhoea and vomiting after One patient took an AA-containing herb Herba Aristolochiae Mollissimae (尋骨風) prescribed by a CMP in Mainland China where its use is not banned. He developed Another patient presented with mucositis, facial pigmentation and telangiectasia which are known side effects of the herb Radix Tripterygii Wilfordii (雷公籐) that the One patient had renal toxicity after taking a slimming agent containing anthraquinone for five weeks followed by a non-steroidal anti-inflammatory drug (NSAID), diclofenac for two days for pain relief. Literature review showed a case report by Queen Mary Hospital and Princess Margaret Hospital published in 2004, revealing that renal toxicity of NSAID may be aggravated by anthraquinone.14 Discussion
Adulteration of western medicines accounted for a large proportion of the cases. In the reporting year, there were ten such cases. At present, there is a routine surveillance system to screen for western medicines in pCm. Every pCm product imported to Hong Kong for the first time will be screened and products on sale in the market will be sampled for testing for adulteration. Those containing western medicine ingredients are regarded as unregistered pharmaceutical products under the Pharmacy and Poisons Ordinance and will be recalled. Measures have been taken to deal with the quality problems of herbs. In view of the importance of proper use and processing of the herb Fructus Xanthii (蒼耳子), a guideline was drawn up by the DH in January 2005 in consultation with the Chinese Medicines Board and the Chinese Medicine Practitioners Board of the Chinese Medicine Council of Hong Kong, and was issued to all CMPs and traders in January 2005 so as to promote the safe use and handling of the herb.15 In this series, four cases were due to erroneous substitution. At present, a licensing system is in place for those traders who are involved in the manufacture, wholesale and retail of Chinese medicines. Chinese medicine traders have to comply with the requirements including proper storage, labelling and standard naming of herbs. Herb dispensing has to be conducted or supervised by qualified persons. These measures help reducing the problem of erroneous substitution. The Chinese medicine traders associations are also concerned about this long-standing problem. They took the initiative to conduct researches and published a book “Hong Kong Commonly Confused Chinese Medicines” in 2005 which illustrates the differences of Chinese medicines commonly confused in Hong Kong. The book can be downloaded from the website. They have also collaborated with the DH to organize publicity programmes to heighten the awareness of the professions and trade, Misuse of medicines remained a major problem. One third of the misuse cases involved self prescription. There are possibly some misconceptions among the public. Firstly, it is a common belief that Chinese medicines are derived from natural source and the effects and side-effects of Chinese medicines are usually slower and milder. Secondly, some may think that since Chinese medicines have been used for a long time, they are very safe and should be free from any unknown adverse effects. These misconceptions may lead to a less prudent use by the public. In fact, Chinese medicines can be harmful and even fatal if inappropriately used. More public education on safe use of Chinese medicines is needed. Inappropriate formulation by CMPs was another cause leading to misuse. Besides taking public health actions to protect the public from further occurrence, the DH would disseminate information to CMPs and doctors through publication of review articles. In addition, guidelines and briefing sessions would be arranged for CMPs and Chinese medicine traders on how the Chinese medicines should be handled and used Up till now, there is still limited information on the interaction between Chinese and western medicines. We need to accumulate more knowledge of this kind in order to pave way for the collaboration of the two disciplines, which is one of the initiatives of the Government. For the case involving possible interaction between anthraquinone in Chinese medicines and NSAID, all doctors in Hong Kong have been encouraged through the Public Health and Epidemiology Bulletin issued in September 2004 to report cases of renal failure suspected to be related to the interaction between NSAID Conclusion
Chinese medicines, as part of our culture, serve us for thousands of year. The reported adverse events should not eclipse the importance of Chinese medicines. Systematic collection, investigation and analysis of adverse events are important for monitoring the safe use of Chinese medicines. A reporting system for Chinese medicine-related adverse events has been put in place and an Adverse Drug Reaction (ADR)*. Reporting Arrangement has been further enhanced by the DH in January 2005 to receive reporting from both Chinese and western medicine practitioners. The support of doctors and CMPs in reporting of cases to the DH is pledged as the investigation results will be translated to effective measures and strategies to .
*The World Health Organization defines Adverse Drug Reaction (ADR) as “a reaction to drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.” .
References
1. Sin J, Chan C. Review of adverse events related to Chinese medicines in Hong Kong, January 2000-June 2004. Public Health and Epidemiology Bulletin. 2004;13(4):60-6. 2. 有毒中藥現代研究與合理應用.人民衛生出版社.杜貴友,方文賢主編 (2003 年第 1 版) 3. Martindale. A complete drug reference. 33rd edition. 4. British National Formulary (March 2004). 5. Graham M. Woolf et al. Acute Hepatitis Associated with the Chinese Herbal Product Jin Bu Huan. Annals of Internal Medicine 1994;121:729-35. 6.毒性/烈性中藥應用常識.中醫藥發展籌傋委員會及香港衞生署出版 (1997 年 3 月) 7. 中華本草 (上海科學技術出版社) 1999 年版 8. Pharmacopoeia of the People's Republic of China (2005 edition). 9. 香港容易混淆中藥. 香港浸會大學中醫藥學院編著; 香港中藥聯商會督印 (2005) 10. Chen W, Chen Y. Li A. The clinical and pathological manifestations of aristolochic acid nephropathy – the report of 58 cases. Zhonghua Yi Xue Za Zhi 2001;25:1101-5. 11. Nortier JL, Martinez M-C, Schmeiser HH, et al. Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi). NEJM 2000;342:1686-92. 12. Working Party on Herbal Medicinal Products. Position Paper on the Risks Associated with the Use of Herbal Products containing Aristolochia Species. The European Agency of the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. 31 October 2000. 13. Zhongyao Jiqi Zhiji Buliang Fanying Dadian (中藥及其製劑不良反應大典). Liaoning Science and Technology Publishing House. First edition (May 2002). 14. Li FK, Lai CK et al. Aggravation of non-steroidal anti-inflammatory drug-induced hepatitis and acute renal failure by slimming drug containing anthraquinones. Nephrology Dialysis Transplantation 15. Guideline on Proper Use of Fructus Xanthii. Department of Health of HKSAR (January 2005) Reporting of Chinese medicine-related adverse events and ADR could be done with forms which could be downloaded from the following websites respectively: 1Medical and Health Officer 2Assistant Director of Health

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