Australian Adverse Drug Reaction Research Articles

Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics

Reports of neuroleptic malignant syndrome (NMS) induced by second-generation antipsychotic drugs highlight a propensity for atypical clinical presentations. To systematically compare the clinical profile of NMS induced by first- (1G-NMS) and second-generation antipsychotic drugs (2G-NMS). The Australian Adverse Drug Reaction Advisory Committee (ADRAC) database was searched to identify individuals with NMS reported between April 1994 and September 2010. The clinical characteristics of 208 people with NMS induced by monotherapy with first- or second-generation antipsychotic drugs, as well as presenting features of NMS, were compared. The individuals with 2G-NMS were younger and more likely to have a psychotic disorder diagnosis. The features of NMS in the two groups were very similar, except that people with 2G-NMS were less likely to present with rigidity or extrapyramidal signs compared with those with 1G-NMS. This difference was due to the lower rates of rigidity in those with clozapine-induced NMS. Mortality was considerably lower for those with 2G-NMS (3.0%) compared with 1G-NMS (16.3%), and the former were more likely to have received supportive treatment. The clinical profile of 2G-NMS is largely similar to 1G-NMS, with clozapine-induced NMS being differentiated by the relative lack of rigidity as a feature. Mortality is lower for 2G-NMS.

The effect of regularization on drug-reaction relationships

The least-squares method is a standard approach used in data fitting that has important applications in many areas in science and engineering including many finance problems. In the case when the problem under consideration involves large-scale sparse matrices regularization methods are used to obtain more stable solutions by relaxing the data fitting. In this article, a new regularization algorithm is introduced based on the Karush–Kuhn–Tucker conditions and the Fisher–Burmeister function. The Newton method is used for solving corresponding systems of equations. The advantages of the proposed method has been demonstrated in the establishment of drug-reaction relationships based on the Australian Adverse Drug Reaction Advisory Committee database.

Prolonged QT Interval, Syncope, and Delirium with Galantamine

To describe a case of QT interval prolongation, syncope, and delirium associated with galantamine use and to analyze similar cases related to acetylcholinesterase inhibitors (AChIs) reported to the Australian Adverse Drug Reaction Advisory Committee (ADRAC). An 85-year-old man with dementia was treated with prolonged release galantamine 8 mg daily for 1.5 years. Three months prior to the current admission, he had a syncopal episode with low blood pressure and bradycardia. Two months later, galantamine was withdrawn, but within 2 weeks, the man developed marked cognitive, behavioral, and functional deterioration and galantamine was restarted. Three weeks later, he developed syncope, delirium, hypotension, and prolonged QT interval with serious cardiac arrhythmias, in addition to vomiting and diarrhea. A complete blood cell count and biochemistry panel performed on admission were normal. No infection was detected. Galantamine and irbesartan were ceased. The delirium fully resolved in 6 days, and the QT interval shortened from 503 to 443 msec (corrected by Bazett's formula) 4 days after discontinuation of galantamine and remained normal. In the ADRAC reports, galantamine was associated with 18 cases of delirium/confusion, 8 of syncope, 13 of bradycardia, 6 of other arrhythmias or conduction abnormalities, and 6 of hypotension. Donepezil was associated with 56, 15, 26, 15, and 5, and rivastigmine with 21, 8, 6, 2, and 2, respectively, of these reactions. Five fatal outcomes were reported in association with galantamine, 11 with donepezil, and 3 with rivastigmine, including 3, 6, and 0 sudden deaths, respectively. This case, along with previously published reports and cases identified from the ADRAC database, illustrates that AChIs may lead to delirium, syncope, hypotension, and life-threatening arrhythmias. The Naranjo probability scale indicated that galantamine was the probable cause of QT interval prolongation, syncope, and delirium in this patient. Administration of galantamine and other AChIs requires vigilance and assessment of risk factors that may precipitate QT interval prolongation, syncope, and delirium.

The study of drug–reaction relationships using global optimization techniques

In this paper we develop an optimization approach for the study of adverse drug reaction (ADR) problems. This approach is based on drug–reaction relationships represented in the form of a vector of weights, which can be defined as a solution to some global optimization problem. Although it can be used for solving many ADR problems, we concentrate on two of them here: the accurate identification of drugs that are responsible for reactions that have occurred, and drug–drug interactions. Based on drug–reaction relationships, we formulate these problems as an optimization problem. The approach is applied to cardiovascularn-type reactions from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. Software based on this approach has been developed and could have beneficial use in prescribing.

Emergence of Adverse Reactions to Tramadol in Children and Adolescents at a Paediatric Hospital

ABSTRACTBackgroundThe use of tramadol at The Royal Children's Hospital, Melbourne has dramatically increased. This has coincided with the emergence of adverse drug reactions (ADRs).AimTo investigate potential adverse reactions to tramadol in children and adolescents as compared with adults.MethodThe ADR program at the hospital detects both spontaneously reported ADRs and those identified by medical records coding reports. For this study, reported reactions to tramadol were retrieved from the hospital's ADR database. Comparison with reports from the Australian Adverse Drug Reaction Advisory Committee and the literature was made.Results8 ADR reports implicating tramadol in patients aged from 14 months to 22 years were identified.ConclusionSome insight was gained into the possible adverse effects of tramadol in children and adolescents, which are similar to the reported profile of adverse reactions in adults. Further pharmacovigilance studies are required to expand on these findings and provide direction to ensure the safe use of tramadol in this age group.

Adverse Drug Reaction Reporting: Attitudes of Australian Hospital Pharmacists and Doctors

ABSTRACTAimTo determine the level of knowledge of the Australian adverse drug reaction (ADR) reporting system in hospital pharmacists and doctors, and the factors that influence ADR reporting.MethodA self‐administered anonymous, postal questionnaire was sent to 803 doctors in Western Australia and 1323 hospital pharmacists between June and September 2001.ResultsResponse rates from doctors and pharmacists were 35% and 43%, respectively. Pharmacists were more likely than doctors to know how to report ADRs (98% vs 57%; p < 0.001) and to support screening of ADR reports before submission to the Adverse Drug Reactions Advisory Committee (ADRAC) (80% vs 68%; p = 0.003). Factors that encouraged ADR reporting were serious or unusual ADRs or reactions to new drugs. Factors that discouraged ADR reporting were trivial or well known reactions, an uncertain association or insufficient time. Hypothetical ADRs (n = 10) that should have been reported to ADRAC were more likely to be reported by pharmacists (mean = 6.6; 95% CI = 6.4–6.7) than doctors (mean = 5.2; 95% CI = 4.9–5.5; p < 0.001).ConclusionHospital pharmacists are familiar with the ADR reporting system and are more likely than doctors to report ADRs to ADRAC. An appropriately resourced team approach could reduce barriers to ADR reporting and improve the quality and quantity of post‐marketing surveillance data in Australia.

A fuzzy derivative approach to classification of outcomes from the ADRAC database

AbstractThe Australian Adverse Drug Reaction Advisory Committee (ADRAC) database has been collected and maintained by the Therapeutic Goods Administration. In this paper we study a part of his database (Card2) which contains records having just reactions from the Cardiovascular group. Drug‐reaction relationships are presented by a vector of degrees which shows the degree of association of a drug with each class of reactions. In this work we examine these relationships in the classification of reaction outcomes. A modified version of the fuzzy derivative method (FDM2) is used for classification.

The role of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) in monitoring drug safety

The Australian adverse drug reaction reporting system is acknowledged as one of the best in the world. Despite its small population of less than 20 million people, Australia's current ADR reporting rate of over 12 000 reports per year places it in the top few nations in terms of reports per capita. The ADRAC program has been in operation for over 30 years. Australia was a founding member of the WHO International Drug Monitoring Programme which commenced in 1968 and currently there are about 153 000 reports in the ADRAC database. Reports from health professionals have uncovered a number of significant safety problems over the years. Of particular importance are flucloxacillin-induced hepatitis, amoxycillin/clavulanate-induced hepatitis, and the association of cystitis with tiaprofenic acid. The number and quality of the reports has allowed an understanding of the characteristics of the reactions and, using ADRAC reporters as a major source of cases, case-control studies have been completed which have identified risk factors. ADRAC's review of Australian reports has highlighted many important associations that have been disseminated through the Australian Adverse Drug Reactions Bulletin.

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.

Myocarditis and cardiomyopathy associated with clozapine

Clozapine is effective for resistant schizophrenia. After two sudden deaths in physically well young men soon after starting clozapine, we investigated the cardiovascular complications for this drug. From January, 1993, to March, 1999, 8000 patients started clozapine treatment in Australia, and were registered with a mandatory monitoring service. We identified cases of myocarditis and cardiomyopathy from voluntary reports to the Australian Adverse Drug Reaction Committee and sought details of the relevant diagnostic studies, necropsies that had been done in suspicious cases, or both. 23 cases (20 men, three women, mean age 36 years [SD 9]) were identified: 15 of myocarditis and eight of cardiomyopathy associated with clozapine treatment. Six patients died. All cases of myocarditis (five deaths) occurred within 3 weeks of starting clozapine. Cardiomyopathy (one death) was diagnosed up to 36 months after clozapine was started. Necropsy results showed mainly eosinophilic infiltrates with myocytolysis, consistent with an acute drug reaction. Clozapine therapy may be associated with potentially fatal myocarditis and cardiomyopathy in physically healthy young adults with schizophrenia.

Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic?

The clinico-pathological entity of flucloxacillin-associated cholestatic hepatitis is described and the recognition and documentation of cholestasis associated with flucloxacillin and with related isoxazolyl-penicillins (cloxacillin, dicloxacillin) is examined on an international basis, with particular reference to Australia. Data were obtained from the literature, from the Australian adverse drug reaction monitoring agency and from the Collaborative Centre for International Drug Monitoring (World Health Organisation) in Sweden. Approximately 600 cases of flucloxacillin-associated cholestatic hepatitis were collected, as well as 164 cases associated with other isoxazolyl penicillins. Jaundice and pruritus may first appear several weeks after administration of the drug has ceased and typically are severe and protracted. Liver tests may be abnormal for months after symptomatic recovery. Death is uncommon. Liver pathology shows centrizonal bile stasis with portal tract inflammation and variable loss of bile ducts. Approximately 1 in 15,000 users of flucloxacillin will develop the reaction. Increasing age (> 55 years) and prolonged intake (> 14 days) are particular risk factors. Cholestasis associated with cloxacillin/dicloxacillin appears to be similar in nature but is less well defined. Recognition and reporting of the reaction have been uncommon in the United Kingdom inter alia and high in Sweden and Australia, although estimates of risk have been similar. In Australia, the remarkably high rate of reports appears to be the result of sustained publicity for the reaction. There is only a trickle of reports of cholestatic hepatitis in association with the use of cloxacillin and dicloxacillin from the USA and Canada. The high level of awareness of the reaction and consequential regulatory action so far have not resulted in a diminution of its occurrence in Australia.

Drug-induced pulmonary disease.

To review some of the types of drug-induced pulmonary disease reported in Australia. Reports of pulmonary side effects made to the Australian Adverse Drug Reaction Advisory Committee between December 1972 and March 1991. Reports of drug-induced pulmonary disease from other countries are also reviewed. Only reports involving large patient numbers are included in the review to limit the bias likely from limited patient numbers. The incidence of adverse responses to a range of commonly used drugs from other countries is compared with reports to the Australian Adverse Drug Reaction Advisory Committee in the last 19 years. Of adverse drug reactions reported in Australia in the last 19 years 7.7% were of a pulmonary side effect and 55% of these involved a syndrome of airway dysfunction. Bronchospasm and cough were the two most common symptoms of airway dysfunction and beta-blocking drugs and radio contrast media were the drug groups most commonly reported to cause them. These figures are similar to data reported from other countries. Some of the more commonly occurring types of drug-induced disease affecting either the airways or the lung interstices are reviewed. Medical practitioners should maintain a high index of clinical suspicion that any unexplained pulmonary disease could be caused by a drug. Most of these reactions are reversible if the drug is withdrawn in time and if additional appropriate measures are taken as required.

Cholestatic jaundice associated with Captopril therapy

Captopril has attained widespread use as an effective agent in the treatment of heart failure and hypertension. Dermatological, renal and haematological toxicity associated with its use has been widely described and is usually well recognized. There have been comparatively few reports implicating it as causing hepatic drug reactions. Most descriptions have emphasized strongly cholestatic features, although a mixed hepatocellular cholestatic picture and predominant hepatocellular reactions have been reported. Between November 1972 and June 1990 only five cases of possible Captopril-associated hepatic dysfunction were reported to the Australian Adverse Drug Reaction Advisory Committee. Cases reported suggest equal sex distribution, latent period to development of abnormality between 1 week and 20 months, with slow resolution of jaundice and biochemical abnormality from 1 week to 6 months after withdrawal of the drug. One case of hepatic coma and death with massive acute hepatic necrosis on biopsy has been reported. Not uncommonly the accompanying systemic features suggest a syndrome of drug hypersensitivity. We report a case of Captopril-induced cholestatic jaundice in which the abnormality occurred 2 weeks after commencement of the drug and resolved slowly upon discontinuation. The case illustrates two important points: first, the importance of taking a full history, obtaining detailed information about previous drug administration in patients admitted with jaundice; and second, in the case of Captopril-induced liver disease, the jaundice may persist for many weeks after drug withdrawal.