PVmap™ of the Week

ProSanos has initiated a program to publicly provide a limited set of PVmaps™ generated from the FDA's Adverse Event database. A different map will be posted each week focusing on a drug and adverse event combination that is a current topic of discussion within the industry or in the published literature. For more information about PVmaps or the PVmap of the Week program, .

Hematologic Effects of Piperacillin (4/15/07)
The April 2007 issue of Drug Safety includes a comprehensive review of piperacillin-induced neutropenia.³³ The article systematically considers this rare adverse event in the context of the inhibition of granulopoiesis by members of the penicillin class. We generated a Drug-focused PVmap to investigate this relationship.

The PVmap above uses the publicly-available data from the FDA via its Adverse Event Reporting System (AERS) with data covering the period from 2001 through the first quarter of 2006. This is a Drug-focused PVmap that shows the adverse events most strongly associated with Piperacillin in the upper right hand corner of the graph. A striking feature of this map is a signal of similar strength for thrombocytopenia, as well as neutropenia. Both signals appear both under hematological terms and under laboratory terms as well (platelet count decreased and white blood cell count decreased). Rare thrombocytopenia has been previously associated with piperacillin through two mechanisms, overall bone marrow suppression,³⁴ and an immune-mediated reaction.³⁵

For any drug where hematologic toxicity is under investigation, it is helpful to investigate whether there might be an alternative explanation for the adverse events, such as the use of cancer chemotherapy drugs or other known bone-marrow suppressants. Such an investigation can be quickly performed by running a Potential Interactions PVMap:

In the case of piperacillin shown here, heparin appears but accounts for only 18 of 179 cases. None of the other associated drugs named on this map is a frequent bone-marrow suppressant. If, instead, we had seen a number of hematotoxic drugs or anti-platelet agents on this map, we would need to consider the possibility that the signal for hematologic adverse events was due to a "bystander effect". That, by itself, would not prove that the drug under study is innocent but would provide evidence to be considered, along with screening for individual cases where other drugs known to cause thrombocytopenia were present or absent.

About drug-focused PVmaps
Above is a Drug-focused PVmap, allowing you to visualize which adverse events are most highly associated with a particular drug of interest. In the map directly above, the drug is piperacillin and the red dots represent Adverse Events reported in the AERS database to be associated with piperacillin. On the horizontal axis of this graph is the reporting ratio that compares the number of cases of a particular adverse event with the number expected due to chance alone. The vertical axis expresses the statistical significance of the finding. Dots above the horizontal blue line and to the right of the vertical blue line represent "significant signals". The adverse events with the strongest association to piperacillin appear at the top and to the right on the PVmap.

Potential Interaction PVmaps
The second PVmap shown in the case study above is a Potential Interactions PVmap that allows you to visualize which concomitant drugs are most highly associated with a particular drug-event combination. In this case, the drug is piperacillin and the adverse event is the MedDRA term neutropenia. The red dots represent other drugs reported in the AERS database to have been co-prescribed along with piperacillin when neutropenia was reported as an adverse event. On the horizontal axis of this graph is the reporting ratio, which compares the number of times that a co-prescribed drug is reported with the specified drug-event combination, compared to the number expected due to chance alone. The vertical axis expresses the statistical significance of the finding. Dots above the horizontal blue line and to the right of the vertical blue line represent "significant signals". The drugs with the strongest association to piperacillin and neutropenia appear at the top and to the right on the PVmap.

Sponsor companies have used ProSanos PVMaps for multiple therapeutic areas. To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with the authors of cited references, and this article does not imply endorsement of their findings, content, or offerings.
2. Potential risks highlighted by drug safety analysis must be balanced against the clinical benefit attained by the use of a pharmaceutical product in a given clinical situation. Nothing in these analyses is intended to influence the practice of medicine, nor to weigh the benefits of one product over another.
3. Whether the reporting ratio of an adverse event is high enough to influence the decision to use a given product or products can only be determined by a complete analysis of the benefits, risks, and therapeutic alternatives.
4. Use of the publicly available FDA AERS data does not imply endorsement or agreement of the findings by the FDA Center for Drug Evaluation and Research.
5. There are many factors that can influence how the adverse events are reported in the AERS database and may impact the resulting safety signal. These include but are not limited to: publicity and media attention, litigation, length of time drug is on the market, whether the event in question has been previously attributed to the drug, the source of the report, etc.
6. AERS data must often be "cleaned" prior to analysis. This process may include de-duplication, reconciliation of misspelled product names, mapping of adverse events terms, and other manipulations which could introduce bias into the analysis.
7. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

33. Scheetz MH, McKoy JM, Parada JP, et al. Systematic Review of Piperacillin-Induced Neutropenia. Drug Safety 2007;30(4):295-306.
34. Kumar A, Choudhuri G, Aggarwal R. Piperacillin induced bone marrow suppression: a case report. BMC Clin Pharmacol. 2003 Jun 5;3:2.
35. Perez-Vazquez A, Pastor JM, Riancho JA. Immune thrombocytopenia caused by piperacillin/tazobactam. Clin Infect Dis. 1998 Sep;27(3):650-1.