Jebm_1056_lr

Journal of Evidence-Based Medicine ISSN 1756-5391
Recommendations for reporting adverse drug reactions
and adverse events of traditional Chinese medicine
Taixiang Wu1, Hongcai Shang2, Zhaoxiang Bian3, Junhua Zhang2, Tingqian Li1, Youping Li1and Boli Zhang2 1 Chinese Evidence-Based Medicine Centre, Chinese Clinical Trial Registry, West China Hospital, Sichuan University, Chengdu, China2 Evidence-Based Medicine Centre, Tianjin University of Traditional Chinese Medicine, The First Hospital Affiliated with Tianjin University ofTraditional Chinese Medicine, China3 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Keywords
Abstract
Clearly report adverse effect or adverse event occurred in the clinical practice isvery important for understanding the potential risk of using a drug for treatment Correspondence
of diseases, and with other advantages. This document aims to help healthcare providers to organize, report, and publish information on ADR/AE occurrences and to identify the nature of the ADR/AE in TCM and integrative medicine practice.
Tianjin University of Traditional Chinese This document provides recommendations on constructing a title, basic factors Nankai District, Anshan Xi Dao Number 312, of writing an abstract and the text of ADR/AE reporting. In each part, there are some samples could be references for the development of a report and ADR/AE.
We welcome any comments for improving this recommendation.
Fax: +86-22-23051183Email: zhangbolipr@163.com Along with clinical trials and systematic review, reporting Center for ADR Monitoring and provincial and local centers of adverse drug reactions (ADRs) is needed to assess the for ADR monitoring. Clinicians and others can use this sys- effects and safety of drugs used in clinical practice. ADR tem from any site via Internet. According to the regulation reports have special value in assessing drug safety, and can about ADR/AE made by State Food and Drug Administration compensate for the limitations of clinical trials in detecting (SFDA), any severe AE needs to be reported and the Cen- ter for ADR Monitoring will play the rule in identification An ADR is a harmful reaction, not related to the pur- of ADR and AE. However, the policy of AE reporting does pose of using a drug, which arises when a proven drug is not increase the transparency of AEs to the public. Ideally, administered at an approved dose according to established this information should be available to the public via acces- procedures. An adverse event (AE) is any individual event sible media. Publishing AEs in medical journals and at the in which a drug hurts a patient or harms the patient’s health.
same time submitting the report to an ADR monitoring center AEs encompass both ADRs and harms resulting from qual- should be encouraged. This will alert healthcare providers ity problems or incorrect use. In assessing drug safety and and public about the event. Aroson describes following clinical practice, the nature of any AE usually need to be advantages of publishing reports of ADR/AEs in medical identified. This identification can sometimes be very diffi- cult, however, so a professional institute such as Center for ADR Monitoring is needed. China has established a complete r Reports of previously unknown interactions will be helpful monitoring system for ADRs, which includes the national for safer use of the drugs in the future; JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM r Provide new ideas about possible uses of a drug in a new P (patient): The conventional medicine name of disease affecting the patient, together with the type of TCM “Zheng” r Monitor the use of drugs and suggest a proper treatment is required if the drug is required to be used according to the “Zheng.” Also include the number, gender, and age of the r Help determine the pharmaceutical mechanisms of drugs; r Generates a high number of case reports that can be used I/C (interventions/companion drugs): The names of the to establish a dose-effective relationship between drug and TCM drug and any companion drugs used, and the means of administering the drugs, should be included.
r Identify risk factors for ADR, such as age or liver and O (outcomes): Specify whether and ADR or another AE occurred. If unable to identify whether the AE was an ADR r Introduce new diagnostic techniques for ADR; and or an AE induced by poor drug quality or incorrect drug r Provide evidence of ADR for systematic review.
use, or in the case of multiple kinds of AE, use of the term Therefore, correctly and clearly reporting the complete information about ADR/AEs is very important. Healthcareproviders should take responsibility for this task.
Examples
Aroson’s suggestions on good publication practices for ADR was published in the British Medical Journal in 2003 A male patient with neurasthenia suffered general ADR (1, 2) and resulted in wide attention.
after oral intake Tall Gastrodia Tuber (Tianma).
Traditional Chinese medicine (TCM) is often thought of A postpartum woman suffered general ADR induced as being very safe. However, as the problems reported for through oral intake of Tall Gastrodia Tuber with chicken Chinese herbal neuropathy (3–5) show, TCM is not risk free.
Several reported AEs from TCM injections in recent years A 35-year-old male suffered general allergy after Heartleaf have drawn public attention throughout China. We attempted Houttuynia Herb (Yuxincao) injection to treat a urinary tract to identify the causes of these AEs, but we found that most infection with TCM sign “Shi Re Xia Zhu.” of the ADR/AE reports published in medical journals lack A child suffered ADR after intravenous administration of some key information. We were thus unable to distinguish Shuanghuanglian injection combined with Ribavirin and Lin- ADRs from AEs resulting from incorrect TCM drug use. It comycin to treat an upper respiratory tract infection with was clear that there is an urgent need to make guidelines for reporting ADR/AEs. Therefore, a working group has been es- A chronic hepatitis patient with TCM sign Shi Re Lei tablished of methodologists and experts in TCM, integrative Yun suffered a general rash after Yin Zhi Huang injection TCM, and Western medicine from the Chinese Evidence- followed by diammonium glycyrrhizinate injection.
Based Medicine Centre, Tianjin University of Traditional A child with an acute virus upper respiratory infection Chinese Medicine, and the School of Chinese Medicine at suffered diarrhea after Chuan Hu Ning injection.
Hong Kong Baptist University. The group developed “Rec-ommendations for Reporting Adverse Drug Reactions and Abstract
Adverse Events of Traditional Chinese Medicine” throughdiscussion on the basis of Aroson’s guidelines and the guide- An ADR/AE report is a type of case report, so a brief sum- lines for reporting ADR/AE disseminated by the National mary is needed for inclusion in a database. An abstract should Center for ADR Monitoring of China. In our recommenda- tions, the characteristics of the TCM drug and the environ- (1) The specific type of ADR/AE; if the AE can be identified, ment in which it is used are considered. The aim is to help an accurate term should be used, such as “ADR,” “AE induced healthcare providers to organize, report, and publish infor- mation on ADR/AE occurrences, and to identify the nature (2) The TCM drug’s name, dose, means of administration, of the ADR/AE. We sincerely call for comments to improve treatment duration, and any other drug(s) used at the same time.
(3) The patient’s age, gender, and any risk factors.
Constructing the title of a ADR/AE
(4) The evidence of the TCM drugs caused the ADR.
(5) The measure(s) used to treat the AE.
(6) The mechanism of AE (if known).
A title should include some necessary information for help- (7) The AE’s implications for use of the TCM drug.
ing readers understand a report’s main contents via a quick browse. The ADR/AE report title should be written according The former four parts are mandatory contents for an JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM Example 1
A 27-year-old postpartum woman suffered skin itching and red urticaria on her limbs after drinking chicken soup We report a case of ADR resulting from intravenous transfu- with Tianma. One hour later the urticaria disappeared. On the second day she drank the soup again, and one hour later coin- The primary disease of the patient suffering ADR was sized urticaria spots appeared on her face, body and limbs.
intracranial infection and demyelinating encephalopathy. A She experienced severe itching with chest pain, shortness of 45-years-old female patient had a sulfonamides allergic his- breath, and fever. She was sent to the hospital by her family tory. The ADR occurred during intravenous transfusion, and included pain in the front chest zone, cardio flutter, suffo- It was clear that the allergic reaction resulted from eating cating, dyspnea, pallid face, cyanotic lips, and cold limbs.
The ADR symptoms disappeared by when transfusion of theYu Xin Cao injection was halted, oxygen was given, anddexamethasone 10 mg was injected transfused liquid.
Introduction
There was an obvious relationship between the AE and intravenous transfusion of Yu Xin Cao injection, so the event In brief describe the treated disease and TCM indication “zheng” of the suspended TCM drug, and the target popula-tion, contraindications, main contents, application methods,and main ADRs.
Example 2
Review previously published case reports of similar inci- We report a case of allergic reaction induced by Shuang dents, and specify the objectives of the current report.
Note: it is not necessary to describe the pharmaceutical A 26-year-old male patient with bronchitis was treated with penicillin (8 million IU) and Shuang Huang Lian injec-tion (60 ml/day by intravenous transfusion). On the secondday, the patient exhibited bean-size rash and itching all over Example 1
his body. The patient had no penicillin allergic history. We The main components of Shuang Huang Lian injection are stopped Shuang Huang Lian injection and continued peni- extracts from Honeysuckle Flower, Baical Skullcap Root, cillin treatment, and the rash disappeared within one and half and Weeping Forsythiae Capsule; some manufacturers state that the product contains diclofinac. Shuan Huang Lian’s There was a clear relationship between the allergic reaction functions are to clear fever, counteract poison (qin re jie and use of the Shuang Huang Lian injection.
du), dispel wind (qin xuan feng re), and relieve pain. Itsindications include viral and bacterial upper respiratory tract Example 3
infection, pneumonia, tonsillitis, and pharyngitis. It can beadministered through intravenous injection and dripping, or We report a death caused by incorrect use of the Shuang by muscle injection of 10–20 ml, one to two times a day. For intravenous transfusion, the dose should be 1 ml/kg of body The patient was a 41-year-old woman treated for fever at weight; for the muscle injection, 2–4 ml/time, —one to two a village clinic with 8 million IU penicillin by intravenous transfusion. Ten minutes later, the patient was given a 60 ml The main ADR risk of Shuang Huang Lian injection is Shuang Huang Lian injection by quick intravenous transfu- allergy, and the main allergens are chlorogenic acid and sion. Two hours after the start of the drip, when 20% of the isochlorogenic acid from the honeysuckle flower. Some re- liquid remained, the patient suffered shock. She died on the ports about allergy induced by intravenous transfusion of way of to be sent to the city hospital by laid down on the back Shuang Huang Lian injection have been published. We re- port a case of general severe allergy induced by intravenous It is clear that the death resulted from incorrect drug use.
transfusion of Shuang Huang Lian injection to treat acute First the drugs given were not matched to the patient’s condi- upper respiratory tract infection with “feng re zheng.” tion; second, the interval between the penicillin and ShuangHuang Lian injections was too short; third, the drip speedwas too high; and finally, shock was treated incorrectly.
Example 2
Tianma is mainly used for treatment of headache, vertigo, Example 4
numbness in the limbs, infantile convulsion, epilepsy, con- This report concerns an allergic event in a postpartum vulsion, and tetanus; its effects are particularly strong for woman, which resulted from incorrectly taking Tianma.
“gan yang shang kang”-induced headache and vertigo. The JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM classic TCM manual Materia Medica Spreads out Righteous- characteristics of the environment where the patient received ness points out “only if Tianma is used together with other treatment, including season, temperature, weather, and clinic herbs can its effects be realized.” Tianma requires a prepa- ration that is specific to the disease and its “zheng,” such (7) Information about the suspended TCM drug, including as “Banxia Baichu Tianma Tang decoction” (Pinellia Tuber, manufacturer, number of manufacture, expiration date, in- Largehead Atractylodes Rhizome and Tall Gastrodia Tuber dicated method of use, details of administration, physical decoction), “Tianma Gouteng Yin decoction” (Tall Gastro- and chemical characteristics, whether the drug is an injec- dia Tuber with Gambir Plant decoction), or “Tianma wan.” tion, solvent name and the rate of solution, and physical and There is no evidence to indicate whether Tianma alone has chemical characteristics of the injection after dilution.
(8) Presentation of the ADR/AE, including: Another classic TCM book, Compendium of Materia Med- ica, recorded this ADR for Tianma: “long term intake of Tianma will result in a red rash.” The Truth of Materia Med- r Time of TCM drug administration, and subsequent re- ica said: “Tianma’s nature is not dry, but it is in fact a “windy” agent. If a patient with blood deficiency (xue xu) without r The patient’s reaction when given the TCM drug again “windy,” fever and headache, dry mouth, and no urine, never (if the TCM drug was not given a second time, the reason use Tianma.” Modern pharmacological experiments demon- strate that Tianma can be toxic at a dose of 40 grams or more; r The results of diagnostic tests for diagnosis of ADR/AE the poisoning latency is 1–6 hours. The AEs of Tianma in- and drug analysis, e.g., liver function tests, blood cell count, clude dizziness, nausea, chest pain, and skin rash and itching.
In some persons, it may cause edema of the face or the entire body, or even alopecia. These AEs have occurred not only r The final result, e.g., recovery, remission, no improve- when Tianma was used alone, but also with complex prepa- ment, worse, disability (sequelae) or death (including the rations containing Tianma, such as Banxia Baichu Tianma If available, the following information for analysis of We report a case of a postpartum woman who suffered a general allergic reaction after taking Tianma.
r Drug concentration in the blood, including each element of the drug and the metabolism time curve of the main ingre-dients. The concentration of the drugs should be expressed Case report text
The following should be included in the text: r Animal or in vitro research evidence.
(1) The patient’s demographic information, including age, A table is recommended to express the above information.
gender, weight, race or nationality, and marital status.
Following is a case published in a medical journal, in (2) The patient’s current disease history in detail, including which the authors described the progress of the ADR and temperature, pulse, breath frequency, blood pressure, symp- rescue clearly and in detail. We suggest some additional in- toms and extent of the disease, and laboratory indexes if formation [in square brackets and italics] that would improve possible. Describe the TCM sign (“zheng”) for the drug. The patient’s TCM symptoms and sign should also be reported.
A patient named xxx, female, 41 years old [nationality, (3) The patient’s allergic history, including reactions to address including county and village, occupation], admin- drugs, foods, and natural materials such as pollen, and family istrated in 6 August 2006 because of gastrointestinal type members’ allergic history and any genetic diseases.
cold [include more descriptive language such as: came to (4) The patient’s life history, including habits such as drink- the village clinic due to abdomen pain and diarrhea. include ing alcohol and smoking. Negative occurrences such as hos- data such as stool examination results, blood cell count, and pital visits due to excessive drinking should be noted.
abdomen image.] In village clinic, she was received 60 ml (5) Information about treatment of the disease before the Shuang Huang Lian injection (Made by Duo Duo Parma ADR/AE, including drug name(s), method of administration, Lit., lot number 060521045) in 5% glucose injection by in- duration of treatment, and speed of injection or transfusion.
travenous transfusion [the dilution of the Shuang Huan Lian (6) Sometimes the environment may contribute to a reaction.
injection, drip speed, and physical and chemical characteris- For example, if the patient was treated in a newly painted tics should be reported here]. Until 20 minutes of dripping, ward and was very sensitive to the paint, a skin allergic the patient suddenly appeared dyspnea, chills, headache, suf- reaction or asthma may occur. In this situation, a differen- focating, limbs convulsions, temperature raised to be 38.3 tial diagnosis is needed. Therefore, a detailed report of the ◦C. It was doubted as allergic shock [The allergic shock JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM Table 1 List of recommendations for reporting TCM-induced ADR/AEs
Oral, intravenous injection, intravenous drip, muscle injection If the patient had multiple presentations, “ADR”, “Allergic reaction” or “Adverse Event” can be used.
Disease name in conventional medicine, type of TCM sign (“zheng”), number of patients, ages, and gender Name of the ADR/AE, whether the patient had multiple presentations; a general designation term (“ADR,” “allergic reaction,” or “AE”) can be used.
Suspended TCM drug name, dose, means of administration, duration of therapy, and other drugs given concurrently Patient’s age, gender, race and health status Evidence that the suspended TCM drug The method used to identify the relationship of the TCM drug to the ADR/AE needs to match the recommended standard.
Any other drugs used before or during use of the suspended Requirements for safe use of the TCM drug, including risk Indications of the TCM drug including disease name in conventional medicine, TCM sign (“zheng”) and indications, contraindications, contents (including names of original herb ADR(s) listed in the Indication of the TCM drug Age, gender, weight, race, marital status, occupation Where the patient was born and where he or she currently lives; habits, particularly special dietary habits, smoking, The conventional medicine diagnosis, including symptoms, presentation and severity of the disease, and laboratory results, if possible. TCM sign (“zheng”), main TCM symptoms, and basis of TCM diagnosis should be described if there are any TCM sign requirements for using the TCM Allergies to drugs and natural materials, family members’ Any therapy apart from the TCM drug before ADR/AE occurrence; whether an allergy test was performed Season, temperature, weather status, clinic or ward conditions Manufacturer, product number, indicated expiration date, Oral administration, intravenous injection, intravenous transfusion, or muscle injection; dose, and time of use Name, dose, dilution if injection was used; water volume and Color, odor, solid material or liquid, method of opening ampoule or injection before and after dilution of the drug.
JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM Table 1 Continued
Detailed presentation of ADR/AE, duration of use of TCM drug, response after stopping use of the drug (include stop time), reaction when given the drug again (if the drug was not given Any tests used to diagnose ADR/AE and their results, as well Drugs given or approaches taken, including transfer to other hospitals and methods used there, time spent in the transfer Recovery, remission, no improvement, worsened condition, Analysis of the correlation between ADR/AE and the TCM drug Published or unpublished case reports, or data from the Center Include the accuracy of the diagnostic test used to identify the ADR/AE, and mechanism and cause of the ADR/AE Discuss prevention and management of ADR/AEs, implications for clinical practice, and any hypotheses raised which need to should be diagnosed based on both the low blood pressure identification of ADR/AE recommended by the World Health and disturbance of consciousness] and stop transfusion im- Organization and the National Center of ADR Monitoring of mediately, given dexamethasone 5 mg and chlorpheniramine China are acceptable. Since the components of TCM drugs 10 mg by muscle injection. Then the patient was emergently are very complex and have variable doses, the cause of the sent to The First People’s Hospital of Laishan district, Yan ADR factor may be one or several herbs, and the interaction Tai for rescue. [The method of patient transfer, the measure between TCM drugs and conventional medicines may be used to treat the shock, and the time spent in transit should the cause of the AE. The summary should also cover other be reported.] 20 minutes later, the patient appeared jet like possible excluded reason(s) for the ADR/AE, particularly vomiting, chills, and trembling, the temperature raised to be drug interactions. AEs caused by incorrect drug use should 39.7 ◦C, unconsciousness, incoherent speak. After injecting phenergan 25 mg and dexamethasone 5 mg the symptoms (2) A review published and unpublished case reports on did not remised, the patient was sent to the Yu Huang Ding ADR/AEs, or data from a center of ADR monitoring or other Hospital and she was no response for calling, short breath- ing, the body was cool and wet, limbs vibrate independently, (3) Possible mechanisms of the ADR/AE, taking into ac- did not cooperate for nervous system examination. The ECG count evidence from formal clinical trials, animal experi- shows sinus tachycardia. She was immediately sent to the ments, or in vitro research, and diagnosis of ADR/AE include Department of Respiratory Medicine for emergency rescue treatment by continue supply oxygen and monitoring ECG, (4) Implications for practice and research: blood pressure, oxygen saturation, quickly extending blood r Treatment and management methods of ADR/AE based volume, hormone therapy. In the progress of rescue, the pa- tient presented irritable, convulsions, vomiting, finally, she r Proper clinical use of the TCM drug and methods for Discussion
The discussion section should include the following:(1) A brief summary of the case, assessing the relationship Based on current evidence, the AE was an ADR to the Shuang between the ADR/AE and the suspended TCM drug, and Huang Lian injection. The dose and usage of the drug fol- explaining why the TCM drug is thought to be the cause lowed established protocols exactly, and the Center of ADR of the reaction, while other drugs are not. The methods for Monitoring has confirmed there was no contamination with JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University
Recommendations for reporting ADRs and AE of TCM foreign matter, and irregular perform the transfusion and high treatment methods for shock share the blame for the fatal dripping speed In addition, the AE occurred 20 minutes after starting transfusion of the Shuang Huang Lian injection.
Table 1 summarizes our recommendations for reporting Allergic reactions induced by Shuang Huang Lian injec- tions and AEs caused by incorrect use or quality problemshave been reported in recent years, but there was no previous References
evidence that the allergic shock induced by Shuang HuangLian injection directly caused death.
1. Aronson JK. Anecdotes as evidence. BMJ 2003; 326(7403): 1346.
2. Aronson JK. Publishing histories of adverse reactions to This serious ADR illustrates two key points for use of medicaments anecdotally: the PHARMA guidelines for reporting Shuang Huang Lian injection and treatment of allergies: suspected adverse drug reactions. Drug Safety 2008; 31(4): 355–6.
Although there is no role of allergy test for Shuang Huang 3. Lampert N, Xu Y. Chinese herbal nephropathy. Lancet 2002; Lian injection, but, if the health care provider had performed the test, the possibility of an ADR would clearly have been 4. Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial much reduced. We suggest that some TCM injections, in- carcinoma associated with the use of a Chinese herb (Aristolochia cluding Shuang Huang Lian, be included in the allergy test fangchi). New England Journal of Medicine 2000; 342(23): If, when the patient began to show shock symptoms (in- 5. Lord GM, Cook T, Arlt VM, Schmeiser HH, Williams G, Pusey cluding a drop in blood pressure and impaired conscious- CD. Urothelial malignant disease and Chinese herbal ness), epinephrine had been injected immediately, followed nephropathy. Lancet 2001; 358(9292): 1515–6.
by dexamethasone and fluids, and if the venous pathway had 6. Ying AQ, Wang JD, An QL. A case of death induced by the ADR been kept clear, the outcome might have been much bet- of Shuang Huang Lian injection. Chinese Pharmaceutical Affairs ter. The Shuang Huang Lian injection caused shock, but the JEBM 3 (2010) 11–17 c 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University

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