Major Adverse Drug Reactions Research Articles

Avoiding adverse drug reactions to Chinese medicine injections

A total of 109 varieties of Chinese medicine injections (CMI) have been approved by the State Food and Drug Administration of China, all of which have the potential to induce adverse drug reactions (ADRs). Major ADRs include systemic anaphylaxis, anaphylactic shock, acute intravascular hemolysis, hepatorenal damage, skin lesion, cardiac damage, respiratory system injury, and gastrointestinal disorders. Contributing factors of ADRs include healthcare workers' inadequate attention to ADRs of CMI, complex ingredients, allergic uncertainties, and inappropriate drug use in children and the aged. To decrease ADRs resulting from CMI, it is essential to improve the selection of drug indications, delivery of proper dosage regimens, compliance with drug instructions, and selection of solvents for the drugs.

Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients

Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.

The Influence of Adverse Drug Reactions on First-line Anti-tuberculosis Chemotherapy in the Elderly Patients

Background: Pulmonary tuberculosis (TB) is still common disease among the elderly patients in Korea where the overall incidence of TB is decreasing. Adverse drug reactions (ADR) associated with anti-TB drugs occurs frequently. Especially the aged tends to have more frequent ADRs than younger ones. These ADRs can cause significant morbidity, compromise therapeutic effects of drugs and even induce drug resistance. Therefore we evaluated the effect of ADRs on the first-line anti-TB drugs in elderly patients with active pulmonary TB. Methods: We retrospectively reviewed the charts and radiological findings of the patients with 65 and older who were bacteriologically confirmed as active TB and treated with standard anti-TB drugs for at least 6 months. Major ADR was defined with temporary or continuous stop of any first- line drugs intake. Results: An ADR was noted in 54% of all patients. The incidence of major ADR was 32% in all elderly patients. Dermatologic ADR (9%) was the most common among the major ADRs. GI trouble (8%), arthralgia (6%), visual change (6%), hepatotoxicity (4%), and fever (1%) were also note d. The drugs responsible for major ADR were ethambutol (62%), pyrazinamide (35%), rifampin (18%) and isoniazid (9%). Major ADRs were associated with higher ESR level at the initiation of anti-TB drugs. Conclusion: First-line anti-TB drugs in elderly patients frequently caused the major ADRs. Therefore the elderly patients receiving anti-TB drugs should be closely monitored and better tolerable therapy should be considered as part of a TB research agenda.

How Safe is Intravenous N‐Acetylcysteine for the Treatment of Paracetamol Poisoning?

ObjectiveParacetamol poisoning remains one of the most common and potentially lethal ingestions. N‐acetylcysteine (NAC) has been proven to be a highly effective antidote. The aim of this study was to determine the rate of adverse drug reactions (ADR) to intravenous (IV) NAC. Our hypothesis was that IV NAC for the treatment of paracetamol toxicity has a low rate of adverse events.MethodsThis was an observational cohort study undertaken by explicit retrospective medical record review. It included patients who presented to the emergency department with paracetamol overdose over the ten‐year period from July 1995 to June 2004. The primary outcome measure was the occurrence of an ADR during NAC administration. Adverse drug reactions were classified as minor (including flushing, urticaria, pruritus, bronchospasm, tachycardia, and non‐ischaemic chest pain) and major (including hypotension, angio‐oedema and death). Data analysis was by descriptive statistics and chi‐square analysis using univariate analysis, Fisher's exact test and Mann‐Whitney U‐test. Inter‐rater agreement was checked for 9% of the sample.ResultsThere were 470 cases of paracetamol poisoning. Of these, 320 received IV NAC. Thirty‐six (11%, 95% CI 8–15%) of these patients developed ADRs. There were two major ADRs, one hypotension and one angio‐oedema (0.6%, 95% CI 0.02–2%). Two patients died during hospitalisation, but neither had an ADR to NAC. The most common ADRs were urticaria (20), flushing (15), bronchospasm (12), and pruritus (3). None of the variables analysed was a clinically significant predictor of increased ADR risk.ConclusionAdverse drug reactions after IV NAC infusion occur commonly, but most are minor. Treatment of paracetamol poisoning with IV NAC appears to be safe, however a large prospective study would be required to confirm this.

Allergic adverse reactions to sulfonamides.

Antimicrobial sulfonamides were the first antimicrobial agents used effectively to treat infectious diseases. However, because they may cause severe adverse drug reactions (ADRs) and because more effective agents have since been developed, sulfonamides now are used for only a few indications in specific groups, such as AIDS patients. Skin reactions, from benign rash to potentially lethal toxidermias, are the most frequent ADRs to sulfonamides. Other major ADRs include acute liver injury, pulmonary reactions, and blood dyscrasias. Although the mechanisms involved have not been fully elucidated, reactive metabolites appear to play a pivotal role. The hydroxylamine and nitroso metabolites of sulfamethoxazole, the most frequently used sulfonamide today, can bind covalently to proteins because of their chemical reactivity, resulting in the induction of specific adverse immune responses. Therefore, changes in the activity of metabolic and detoxification pathways are associated with a greater risk for developing allergic reactions to sulfonamides. Allergies to sulfonamides, particularly sulfamethoxazole (often used in combination with trimethoprim as co-trimoxazole), are more frequent in AIDS patients, but the reason for this increased risk is not fully understood. No valid tools are available to predict which patients have a greater risk for developing allergies to sulfonamides. Diagnosis is essential to avoid a possible evolution toward severe reactions and readministration of the offending drug. In patients who absolutely require further treatment, successful desensitization may be achieved.

Latest Industry Information on the Safety Profile of Levofloxacin in Japan

This paper focuses on the development of four major adverse drug reactions (ADRs) associated with some fluoroquinolones: convulsions, phototoxicity, cardiac effects, and hepatotoxicity. CNS adverse events have been linked to fluoroquinolone administration, including seizures, which are more likely with co-administration of NSAIDs. Only 61 cases of convulsions have been reported with levofloxacin, with 33 of those affected having received NSAIDs. The assumed rate of serious convulsions was as low as 1/65,000 with NSAIDs and 1/260,000 without NSAIDs. Levofloxacin has a very low phototoxicity-inducing potential confirmed by pre-clinical animal studies and the results of post-marketing surveillance (PMS). Pre-clinical results demonstrated that levofloxacin was 20 times less phototoxic than sparfloxacin and PMS data show that serious phototoxicity develops in only 1 in 1.8 million cases treated with levofloxacin. While many fluoroquinolones are associated with cardiac effects, pre-clinical data has shown that compared with sparfloxacin and grepafloxacin, levofloxacin has no effect on myocardial conduction. PMS data further support the safety of levofloxacin in this regard. While trovafloxacin is associated with serious hepatic problems, PMS data demonstrates that levofloxacin has a very low incidence of 1/100,000 hepatic effects. These results were confirmed in a prospective study that confirmed a low 1.3% incidence rate for all ADRs associated with levofloxacin.

Lamotrigine-related rash: an audit

s 423 Lamotrigine-related rash: an audit I. Wang*, G. Mawer? J University of Bradford, Bradford, UK; t David Lewis Centre for Epilepsy Cheshire, UK; $ institute of Neurology National Hospital for Neurology and Neurosurgery, London, UK Purpose: 1. To estimate the incidence of serious and non-serious rashes associated with lamotrigine (LTG) treatment. 2. To identify risk factors for LTG-related rash. 3. To assess the effectiveness of the recommendation by the manufacturers to reduce starting dose. Methods: Case records were surveyed in five tertiary referral epilepsy centres in the UK. The causality of the rash was assessed using the WHO method. Risk factors for LTG-related rash were identified by logistic regression. The incidences of rash before and after reduction in starting dose were compared by Chi-square. Results and discussion: 1050 patients were included. The incidences of serious and non-serious rash were 1.1% (95% CI = 0.5% to 1.8%) and 7% (95% CI = 5.5% to 8.6%). This study confirms previous reports that concurrent sodium valproate and a high starting daily dose increase the risk of LTG-related rash, while concurrent enzyme inducers reduce it. Furthermore, female patients were twice as likely to develop rash than males. Some clinicians ignored the recommendation to start LTG at a lower dose, consequently, there was no reduction in the incidence of LTG-related rash since the manufacturer recommended reducing the starting dose of LTG. The post-marketing surveillance of gabapentin, lamotrigine and vigabatrin in patients with chronic epilepsy I. Wang*, G. Mawet-+ & J. Sander* *School of Pharmacy, University of Bradford, Bradford, UK; + David Lewis School of Epilepsy Cheshire, UK; $ Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK Purpose: A post-marketing surveillance study of gabapentin (GBP), lamotrigine (LTG) and vigabatrin (VGB) investigated adverse drug reactions (ADRs) and mortality. Methods: Case records were surveyed in five tertiary referral epilepsy centres in the UK. Adverse events were recorded and compared within and between the drugs. All deaths were followed and standardized mortality ratios (SMRs) calculated. Serious ADRs were assessed individually. Results and discussion: 1375 patients were included in the statistical analyses. ADRs to GBP were generally mild but one case of leucopenia was identified. Skin rash was the major ADR to LTG but rare cases of hepatic failure, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation and renal failure were also identified. Psychiatric/behavioural disturbance was the major ADR to VGB but one case of visual field constriction was identified. No death could be directly attributed to the use of the new drugs. The SMRs were slightly higher than that reported in the literature. This probably reflects the severity of epilepsy in the study population. Beneficial effect of levetiracetam (UCB L059) on juvenile myoclonic epilepsy resistant to valproate and lamotrigine Kate Smith, Tim Betts & Cathy Fox Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital, Birmingham B 15 2QZ, UK Levetiracetam (UCB L059) is a new antiepileptic drug (an enantiomer of piracetam) currently undergoing evaluation and already of proven efficacy in patients with partial onset epilepsy. We have examined the effect of this drug on a sub-group of nine patients with juvenile myoclonic epilepsy resistant to conventional therapy with sodium valproate and lamotrigine. Seven of these patients have become totally seizure-free-the other two almost completely so (still in dose escalation). This intriguing result is worthy of further study particularly because Levetiracetam has an acceptable side effect profile.

Pharmacology of immunosuppressive drugs.

Immunosuppressive therapy of solid organ transplantation has become more potent, effective and selective since the results of earlier use of prednisone and azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate mofetil have been important additions to the effective antirejection armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and prednisone are all effective immunosuppressive agents and are the cornerstone of immunosuppressive protocols used posttransplant. However, the use of these agents is hindered by a 20% rate of rejection, lack of selectivity and a high rate of major adverse drug reactions which ultimately lead to a decrease in patient and graft survival. A number of clinical trials are underway to compare efficacy, safety and tolerability of different combination protocols to improve patient and allograft survival and decrease adverse drug reactions. Clinical knowledge of the pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and therapeutic drug monitoring of antirejection agents is essential for designing an effective immunosuppressive protocol for individual solid organ transplant recipients. The clinical application of pharmacotherapeutic principles into the clinical practice will improve both long-term patient and allograft survival while minimizing systemic toxicity of immunosuppressive drugs.

Retrospective study of vigabatrin and psychiatric behavioural disturbances

Vigabatrin (VGB) is an effective add-on anti-epileptic drug. The major serious adverse drug reactions (ADRs) are behavioural and psychiatric disturbances. This study does not support the view that a previous history of behavioural and psychiatric features increases the risk of behavioural/psychiatric ADRs (relative risk 1.23, 95% CI 0.57-2.66, P = 0.61). The results suggest that a low starting does of vigabatrin does not reduce the risk of psychiatric and behavioural ADRs (P = 0.31) or prevent a more overt psychotic reaction from occurring.

Age Effects on Patient Drug Attribution Judgments

Data were obtained on patients' attribution of symptoms using two different post-marketing surveillance methods. In the patient-initiated method, outpatients were randomly assigned to have a printed notice conspicuously attached to the outside of their medication bags; the "outsert" requested the patients to monitor themselves during the next 2 weeks and to report via a toll-free telephone number any new or unusual symptoms. In the staff-initiated method, other patients filling the same target drug prescriptions did not receive any outsert but were identified at the pharmacy for a telephone interview 10 to 14 days later. The target drugs were chosen from two classes for which the major adverse drug reactions (ADRs) are well identified: oral antibiotics and tricyclic antidepressants. During the interview, for each reported symptom the patient was asked whether it might have been caused by the target drug. Results indicated that older patients, irrespective of the surveillance method or the drug class, appear to be capable of discriminating probable ADRs at least as well as or possibly better than younger patients.

Epidemiology of Adverse Drug Reactions in the Newborn

A prospective study on the epidemiology of adverse drug reactions (ADR) in the 200 neonates consecutively admitted to a newborn intensive care unit had shown that 136 ADR occurred in 60 babies (incidence = 30%). 20 of these ADR (14.7%) were major (life-threatening), 34 (25%) were moderate (prolonged hospital stay) and 82 (60.3%) were minor (resolved spontaneously, no therapy required). Respiratory depression, cardiac arrhythmias, renal failure, metabolic abnormalities (hyperglycemia, electrolyte imbalance) and gastrointestinal bleeding were the most common major and moderate ADR. Hematologic (eosinophilia, thrombocytopenia) and metabolic (lipemia, hyperglycemia) were the most frequent minor ADR. The case fatality rate is 5%. Most commonly suspected drugs associated with the ADR were cardiovascular drugs (tolazoline, digoxin, methoxamine), antibiotics, diuretics and components of intravenous nutrition solutions.

Adverse Drug Reaction Profiles

To the Editor.— I want to compliment Kramer et al (242:623, 1979) on their article on adverse drug reactions. They have created an excellent and thorough system. Unfortunately, I do not believe that development of a system is the total answer to a difficult problem. The adverse drug reaction reporting problem is of a more basic nature. As mentioned by the authors, medical inpatients generally have the highest incidence of adverse drug reactions. Major adverse drug reactions frequently result in a hospitalization or occur during hospitalization. The burden for development and maintenance of accurate systems for reporting and creating profiles on adverse drug reactions thus falls on the hospitals. All too frequently hospitals have no real program for reporting adverse drug reactions. Adverse drug reaction profiles are frequently created by asking the patient: Are you allergic to any medication? This often leads to poor, inaccurate, and unsubstantiated adverse drug reaction

Adverse Reactions in Changing From Phenformin Therapy

To the Editor.— Since the recent ban on the use of phenformin hydrochloride by the Food and Drug Administration, we have observed two major adverse drug reactions in patients being switched to tolazamide (Tolinase). Report of Cases.— Case1.—An 83-year-old man was previously treated with phenformin hydrochloride (DBI-TD), 50 mg orally three times a day for four years. Four days after changing to tolazamide, 250 mg orally three times a day, he came to the emergency room of the Medical Center Hospital of Vermont with a history of profuse diaphoresis, confusion, slurred speech, and severe shaking (possibly grand mal seizure, although verification is lacking). While being transported to the emergency room, rescue squad attendants gave the patient a glucose solution to drink. On arrival, the patient was oriented with irregular pulse of 88 beats per minute and blood pressure of 250/120 mm Hg. Monitoring by ECG showed frequent premature ventricular