Australian Adverse Drug Reactions Advisory 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.

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) will cease to exist

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) will cease to exist

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of peripheral neuropathy associated with pyridoxine

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of peripheral neuropathy associated with pyridoxine

Australian Reports of Bleeding Complications Associated with Antithrombotic Drug Combinations

ABSTRACTBackgroundThe Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received numerous reports of bleeding complications associated with the combined use of antithrombotic drugs (anticoagulants and/or antiplatelet drugs).AimTo review the ADRAC reports of major bleeding complications and determine the antithrombotic drug combinations implicated; and to establish the relevance of the voluntary ADRAC reporting data by comparing with published reports.MethodADRAC reports over a 6 year period from 1 January 2000 to 31 December 2006 were reviewed on the antithrombotic drugs involved, and the severity and nature of bleeding complications. Data were collated on patient demographics, and comorbidities.ResultsBleeding complications related to the combined use of antithrombotic drugs were described in 188 ADRAC reports over the 6 year period. 17.5% of the reports had a fatal outcome. The median age of patients was 76 years, 47% were men and the principal comorbid condition was renal impairment (8.5%). The antithrombotic drug combinations associated with the risk of mortality included aspirin and/or clopidogrel and heparins; aspirin and/or clopidogrel and warfarin; aspirin and/or clopidogrel co‐prescribed with heparins and glycoprotein IIb/IIIa inhibitors; aspirin and heparins co‐prescribed with tissue plasminogen activator drugs. Bleeding was reported to occur in the upper gastrointestinal tract (26%), central nervous system (21%) and retroperitoneal space (16%). Of the reports of cerebral haemorrhage, 14 reports (35%) were associated with mortality.ConclusionADRAC reports of major bleeding complications involving vital organs were associated with the combined use of anticoagulant and/or antiplatelet drugs and were frequently reported in older patients. These observations were supported by similar findings in published reports. These data highlight the risk associated with the use of antithrombotic drug combinations and the need for care in the clinical monitoring of patients.

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.

The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate

To estimate the incidence of pancytopenia in patients taking leflunomide with or without methotrexate in Australia. Review of spontaneous reports to the Australian Adverse Drug Reactions Advisory Committee (ADRAC); estimation of incidence using national prescription reimbursement data; concomitant exposure to methotrexate was estimated using three sources of information. ADRAC received 11 reports of pancytopenia (meeting predefined criteria) associated with the use of leflunomide during its first 31 months of marketing. In nine reports, the patients were also taking methotrexate. Estimates of incidence in patients taking leflunomide alone ranged from 1 in 3698 to 1 in 4582 patients exposed; for patients also taking methotrexate the estimates ranged from 1 in 575 to 1 in 822. Use of methotrexate with leflunomide increases the risk of pancytopenia compared with use of leflunomide alone. The haematological toxicity of the combination requires further study.

The Australian Adverse Drug Reactions Advisory Committee is currently aware of 49 cases

The Australian Adverse Drug Reactions Advisory Committee is currently aware of 49 cases

The Australian Adverse Drug Reactions Advisory Committee is currently aware of 49 cases

The Australian Adverse Drug Reactions Advisory Committee is currently aware of 49 cases

Risk Factors for Rhabdomyolysis with Simvastatin and Atorvastatin

To assess the frequency of risk factors for rhabdomyolysis with simvastatin and atorvastatin in cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). Reports meeting the definition of rhabdomyolysis were reviewed for risk factors including age > or = 70 years, dose > or = 40 mg, hepatic dysfunction, diabetes mellitus, hyperkalaemia, hypothyroidism and the use of concomitant interacting medications. Only one report associated with simvastatin and five reports associated with atorvastatin did not list any risk factors for rhabdomyolysis. Interacting medicines featured in 77% of reports of rhabdomyolysis associated with simvastatin and 44% of reports associated with atorvastatin. A comparison of the age profile for reports of atorvastatin- and simvastatin-associated rhabdomyolysis with that for all adverse drug reaction reports received, and for all reports of muscle disorders, suggested a trend towards an increasing risk of rhabdomyolysis with increasing age with simvastatin but not with atorvastatin. Similarly, comparing prescribed tablet strengths from Pharmaceutical Benefits Scheme data with the HMG-CoA reductase inhibitor ('statin') doses in reports of rhabdomyolysis suggested a dose-related risk with simvastatin, but a less increased risk with high-dose atorvastatin. Risk factors for rhabdomyolysis featured in nearly all of the reports of statin-associated rhabdomyolysis and the majority of reports listed multiple risk factors, although dependence on risk factors appeared to be stronger with simvastatin than atorvastatin. The multiplication of risk factors in patients taking simvastatin and atorvastatin should be minimised.

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.

Four reports of gambling associated with cabergoline [Cabaser] have been reported to the Australian Adverse Drug Reactions Advisory Committee

Four reports of gambling associated with cabergoline [Cabaser] have been reported to the Australian Adverse Drug Reactions Advisory Committee

Unintended pregnancies with the etonogestrel implant (Implanon): a case series from postmarketing experience in Australia

This paper describes a case series of over 200 unintended pregnancies associated with the etonogestrel implant, Implanon. These cases have been reported to the Australian Adverse Drug Reactions Advisory Committee during the first 3 years of marketing in this country. Of 218 cases included, 45 had insufficient data to assess the reason for contraceptive failure and 46 women were determined to have been already pregnant prior to Implanon insertion. Of the remaining 127 cases, the most common reason for unintended pregnancy was failure to insert the implant in 84 women. Other reasons included incorrect timing of insertion (19 cases), expulsion of Implanon (3 cases) and interaction with hepatic enzyme-inducing medicines (8 cases). The remaining 13 cases were classified as product/method failures once other reasons had been excluded. Using the 204,486 Implanon devices subsidized in this period to estimate the population exposed and the 218 pregnancies reported, the approximate failure rate in postmarketing use was 1 in 1000 insertions. These findings (and reports to medical indemnity insurers) have resulted in the development of guidelines and training for doctors inserting Implanon in Australia.

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of fetal abnormalities associated with isotretinoin,

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of fetal abnormalities associated with isotretinoin,

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of fetal abnormalities associated with isotretinoin,

The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of fetal abnormalities associated with isotretinoin,

Factors Influencing Adverse Drug Reaction Reporting in New South Wales Teaching Hospitals

Aim: To identify predisposing and enabling factors which influence adverse drug reaction reporting by medical, nursing and pharmacy staff in New South Wales teaching hospitals.Method: A questionnaire was distributed to all doctors, nurses and pharmacists in four New South Wales teaching hospitals. Health promotion concepts were used to provide a framework for interpreting results.Results: 4808 questionnaires were distributed and 1125 (23% response rate) were returned. Approximately 16% of respondents reported that they had reported an adverse drug reaction at least once to the Australian Adverse Drug Reactions Advisory Committee. 82% routinely asked patients about previous adverse drug reactions on admission and 95% of these respondents documented the adverse drug reaction in the medical record. Only 36% knew how to report an adverse drug reaction in their hospital. Most claimed awareness of recognised goals of adverse drug reaction reporting but many also identified erroneous goals. They were more likely to report an adverse drug reaction if it was serious or related to a new product. Predisposing factors relating to knowledge were identified as barriers to reporting by about one‐third of respondents. Factors relating to attitudes and beliefs were not identified as barriers. Disabling factors included excessive workload, forms not readily available and insufficient data.Conclusion: Knowledge appears to be a greater influence on adverse drug reaction reporting than attitudes and beliefs. Simple enabling processes, such as making forms more accessible or encouraging computerised reporting, might result in more reports. Educational initiatives should target nurses and junior medical officers.

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.