Monitoring of Suspected Adverse Drug Reactions in Oncology Unit ...

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International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 Spontaneous reporting schemes The thalidomide tragedy led to the institution, in many countries, of national schemes for voluntary collection of adverse drug reaction reports, of which the UK Committee on Safety of Medicines adverse reactions reporting scheme (outlined later) is one. Spontaneous reporting schemes cannot provide estimates of risk because the true number of cases is invariably under estimated and the denominator is not known. To be successful, reports should be made despite uncertainty about a causal relationship, irrespective of whether or not the reaction is well recognized and regardless of other drugs having been giving concurrently. The development of pharmacist reporting of adverse drug reactions [van Grootheest AC and de Jong-van den Berg, 2005; Major E, 2002; Davis S, et al, 1999; Lee A, et al, 1997] Adverse reactions cause considerable morbidity and mortality and have a significant impact on health care costs. Reports suggest that ADRs are responsible for 5% of all hospital admissions, with between 0.1 and 0.3% of hospital patients suffering fatal ADRs. Following the thalidomide disaster in 1961, the Committee on Safety of Medicines was formed and the ‘Yellow Card Scheme’ was introduced in the UK in 1964. The scheme is a spontaneous reporting system (based on yellow colored cards on which suspected ADRs are to be reported by health professionals) that was developed to act as an early warning system for the identification of ADRs. It is intended to provide information on the safely of a medicine throughout its lifespan. The success of the scheme is dependent upon the vigilance of health professionals. The yellow card scheme solicits reports on all serious reactions to all medicines licensed in the UK, as well as all reports on new ‘inverted black triangle’ medicines regardless of the seriousness of the reaction. A black triangle status is assigned to all new medicines and are described as being intensively monitored while this classification continues. The black triangle status remains in place until the safety/efficacy ratio that was established in premarketing clinical trials is adequately assessed. This period can be as short as two years but sometimes can last for upto five years. The British ‘Yellow card system’ is one of the most successful spontaneous ADR reporting systems in the world today. In the early 1990s, the number of reports received by the CSM was falling, particularly in the hospital setting. A pilot study to evaluate the potential contribution of hospital pharmacists was conducted in the Northern Region and showed a 45% overall increase in ADR reporting, with a 54% increase in the reporting of serious drug reactions. Hospital pharmacists became recognized contributors to the Yellow Card Scheme on 1 April 1997. In the first year of the scheme, hospital pharmacists reported a higher proportion of serious ADRs then doctors did, but fewer for black triangle drugs. Reporting was facilitated in hospitals where education on the scheme was provided, where there was a designated ADR Pharmacist and where there was a written procedure for reporting ADRs. From 1997 to 2002, the total number of reports submitted by pharmacists was 8,395, accounting for 8.5% of the total UK reports for that period. There is, however, still reluctance to reporting which needs to be addressed through education and increasing awareness and ownership of the scheme. Prevention of adverse drug reactions – role of the patient [van Grootheest K and de Jong-van den Berg L, 2004; van Grootheest K et al, 2003; Egberts GPG, et al, 1996] The prevention of ADRs should be a collective responsibility of the pharmaceutical industry, the doctor and the patient. Patients themselves can play a significant role in the prevention of adverse reactions. In particular, ensuring a high level of compliance with medication instructions can maximize therapeutic effects and avoid or minimize the possible occurrence of potentially adverse reactions. Inadequate compliance can lead to toxicity or treatment failure (this is clearly exemplified in anticonvulsant, anticoagulant and immunosuppressive therapy) and consequently to increased treatment costs and / or possible fatal outcome for the patient. Patients should also reject the belief that there is a “Pill for every ill” and avoid indiscriminate self-medication and doctor hopping. Causality assessment of adverse drug reactions [Diemont WL, 2005; Merle L, et al, 2005; Brown SD Jr and Landry FJ, 2001] The establishment of a causal relationship between specific drug and a clinical event is a fundamental problem in pharmacovigilance. Firstly, ADRs frequently mimic other disease and secondly many of the symptoms attributed to ADRs occur commonly in healthy individuals who are not taking any medication. There is some evidence that patients themselves are capable of correctly distinguishing probable ADRs, Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 6
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 from other types of adverse clinical event. When a patient is prescribed a new drug he should also be given information on possible ADRs, including how to recognize them, and what to do if one occurs. For instance, patients taking warfarin should know that if they notice unusual bruising or black stools, they should seek medical help at once. When a suspected adverse reaction has occurred it may be helpful to try to assess whether it is definitely, probably or possibly due to the drug. The Naranjo’s adverse drug reactions probability scale criteria [Naranjo CA, et al, 1992] has been extensively used for this purpose. This is based on ten questions each of which can be answered as ‘Yes’, ‘No’ or ‘Don’t know’ and the responses are scored as follows: 1) Are there previous conclusive reports on this reaction? Yes [+1] No [0] Don’t know [0] 2) Did the ADR appear after the suspected drug was administered? Yes [+2] No [-1] Don’t know [0] 3) Did the ADR improve when the drug was discontinued? Yes [+1] No [0] Don’t know [0] 4) Did the ADR appear with re-challenge? Yes [+2] No [-1] Don’t know [0] 5) Are there alternative causes for the ADR? Yes [-1] No [+2] Don’t know [0] 6) Did the reaction appear when placebo was given? Yes [-1] No [+1] Don’t know [0] 7) Was the drug detected in blood at toxic levels? Yes [+1] No [0] Don’t know [0] 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Yes [+1] No [0] Don’t know [0] 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? Yes [+1] No [0] Don’t know [0] 10) Was the ADR confirmed by any objective evidence? Yes [+1] No [0] Don’t know [0] The scores may range between –4 to +13 and the causality is assessed to be Definite if composite score is > 9, Probable if between 5 to 8, Possible if between 1 to 4 and Unlikely if < 0. In our study, we have utilized the World Health Organization-Uppsala Monitoring Centre criteria for standardized case causality assessment, details of which have been provided in Annex 2. Review of major groups of anticancer drugs and their toxicities [Chu E et al, 2007; Brunton LL et al, 2006; Shepherd GM, 2003; Skeel TR, 1999] Nitrogen mustards and other alkylating agents (covalent DNA binding drugs) All of the alkylating agents form strong electrophiles through the formation of carbonium ion intermediates. This results in the formation of covalent linkages by alykylation of various nucleophile moieties. The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA mainly through the 7 nitrogen atom of guanine although other moieties are also alkylated. The formation of one covalent bond with nucleophiles can result in mutagenesis or teratogenesis but the formation of two of these bonds through cross-linking can produce cytotoxicity. Bifunctional alkylating agents (those Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 7
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