Toxic Signal Detection in Pharmacovigilance of Anticancer Drugs in Cancer Treatment

Abstract

Background & Objective Pharmacovigilance (PV) is a continuous and ongoing process which allows assessing the safety of medicinal product through its life cycle. Pharmacovigilance collects, records, codes Adverse Drug Events (ADEs) / Adverse drug reactions (ADRs) analyses and assesses the reports, promotes the safe use of drugs, creates appropriate structures, and means of communication needed to perform its tasks. Spontaneous individual case safety reports gatherings are the main asset for early discovery of unknown ADR to drugs once they are introduced to the general public. The objective of the study was to identify possible significant signal associated with paclitaxel, docetaxel, cisplatin, carboplatin, cyclophoshphamide and vincristine by searching database of Canada Adverse Drug Reaction Monitoring Program (CADRMP) Patient and Methods A total of 10429 reports of patients between January 1970 to March 2010 were downloaded from Canada Adverse reaction Monitoring Program website. These reports contained information of adverse events associated with all other drugs inclusive of paclitaxel, docetaxel, cisplatin, carboplatin, cyclophoshphamide and vincristine. Adverse drug reaction (ADR) signal detection were determined by proportional reporting ratio (PRR), reporting odds ratio (ROR), PRR calculated by chi-square statistics, 95% confidence interval of PRR, observed to expected (O/E) ratio and De Mouchel method calculated PRR. Information component (IC) was given by Bayesian confidence propagation neural network. (As per regulatory criteria, PRR ≥ 2, ROR ≥ 1, Chi-square statistics calculated PRR ≥ 4 and lower bound limit of 95% CI of PRR ≥ 1 to consider particular adverse drug reaction as a signal. Further by BCPNN method, if IC − 2SD ≤ 0 then that drug-ADR pair considered as no signal; if 0 < IC − 2SD ≤1.5, then that drug-ADR pair considered as weak signal; if 1.5 < IC−2SD ≤ 3.0, then that drug-ADR pair considered as middle signal; if IC − 2SD > 3.0, then that drug-ADR pair considered as strong signal). Results For paclitaxel, the PRR was found to be 4.26 and by the Du Mouchel Method it was 4.39. The PRR calculated by chi-square statistics was 77.71, whereas the lower and upper limits of 95% CI of PRR was found to be 1.10 and 1.79, respectively. The O/E ratio was found to be 3.86 and ROR was found to be 4.41. In docetaxel analysis, the PRR was found to be 4.13 and by the Du Mouchel Method it was 3.67. The PRR calculated by chi-square statistics was 205.09, whereas the lower and upper limits of 95% CI of PRR was found to be 1.21 and 1.62, respectively. TheO/E ratio was found to be 3.67 and ROR was found to be 4.38. For cisplatin, the PRR was found to be 53.44 and by the Du Mouchel Method it was 20.7977. The PRR calculated by chi-square statistics was 544.70, whereas the lower and upper limits of 95% CI of PRR was found to be 3.67 and 4.57, respectively. The O/E ratio was found to be 20.9130 and ROR was found to be 55.03 whereas for cyclophoshphamide signal analysis, the PRR was found to be 4.73 and by the Du Mouchel Method it was 3.97. The PRR calculated by chi-square statistics was 236.02, whereas the lower and upper limits of 95% CI of PRR was found to be 1.34 and 1.76, respectively. The O/E ratio was found to be 3.93 and ROR was found to be 4.97. Vincristine also showed signal for peripheral neuropathy. In this group, the PRR was found to be 25.10 and by the Du Mouchel Method it was 16.43. The PRR calculated by chi-square statistics was 623.36, whereas the lower and upper limits of 95% CI of PRR was found to be 2.85 and 3.58, respectively. The O/E ratio was found to be 16.43 and ROR was found to be 26.63. For carboplatin, the PRR was found to be 7.04412 and by the Du Mouchel Method it was 16.4360. The PRR calculated by chi-square statistics were 623.36645, whereas the lower and upper limits of 95% CI of PRR was found to be 2.9167 and 3.6475, respectively. The O/E ratio was found to be 16.43854 and reporting odds ratio was found to be 7.6065. Similar value was obtained for PRR calculated by chi-square test using SAS software for all drugs which was statistically significant (p < 0.001). The value of information components(IC)-2SD was for 0.64, 1.72, 2.91, 1.68, 3.58 and 2.1995 for paclitaxel, docetaxel, cisplatin, cyclophoshphamide, vincristine and carboplatin respectively which indicates weak signal of tachycardia associated with paclitaxel, middle signal for flushing associated with docetaxel, ototoxicity associated with cisplatin (nearer to strong signal), neutropenia associated with cyclophosphamide and pruritis associated with carboplatin whereas strong signal for peripheral neuropathy associated with vincristine. Conclusion The therapeutic class specific signal has been detected for tachycardia associated with paclitaxel, flushing associated with docetaxel, ototoxicity associated with cisplatin, neutropenia associated with cyclophosphamide, peripheral neuropathy associated with vincristine and pruritis associated with carboplatin. Hence, it is recommended that treating physician should anticipate and counsel the patient adequately prior to starting of above therapy to minimize side effects. Further, treating physician should also prescribe prophylactic medications along with listed anticancer drugs for cancer treatment to minimize respective adverse effects. The frequency of tachycardia-associated with paclitaxel, flushing-associated with docetaxel, neutropenia associated with cyclophoshphamide, peripheral neuropathy associated with vincristine and pruritis associated with carboplatin were more common in females as compared to males whereas ototoxicity-associated with cisplatin were more common in males ascompared to females. The frequency of tachycardia-associated with paclitaxel, flushingassociated with docetaxel, neutropenia associated with cyclophoshphamide, peripheral neuropathy associated with vincristine and pruritis associated with carboplatin more prominent with adults (19-60 years age) as compared to geriatrics and pediatrics except ototoxicityassociated with cisplatin which was more prevalent in pediatric population (0-18 years).