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. On a regular basis, we will post a map 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, .

Pentoxifylline and Acute Generalized Exanthematous Pustulosis (4/14/2008)
Severe skin reactions represent an important and challenging class of drug safety issues. This week's PVmap of the week illustrates the opportunities and challenges of data analysis in this area.

The International Journal of Dermatology recently published a case report describing acute generalized exanthematous pustulosis (AGEP) in a patient who had recently begun pentoxifylline therapy for vascular retinopathy⁵⁹. Pentoxifylline, currently a generic drug in the US, is used to decrease blood viscosity in patients at risk for a variety of thrombotic conditions. Labeled adverse events related to skin conditions include pruritus, rash, urticaria, and angioedema, but not AGEP.

The MedDRA coding system includes a Preferred Term for acute generalized exanthematous pustulosis. We first generated an Event-focused PVmap to display the drugs that exhibit signals of disproportionate reporting for this MedDRA Preferred Term in the FDA Adverse Event Reporting System (AERS) database for the period from the first quarter of 2007. The authors of the Int. J. Dermatol. article stated, "To our knowledge, no other cases of AGEP induced by pentoxifylline have been described until now." We confirmed that no case reports associating AGEP with pentoxifylline are included in the AERS database. Following up on their remark that pentoxifylline is a member of a class of xanthine drugs, we then used "Highlight Points" to identify reports that include other drugs of the Chemical group in the ATC (Anatomic-Therapeutic-Chemical) hierarchy designated as "Xanthines". A zoomed-in view of the highlighted map is shown below.

The map includes seven reports that mention theophylline, a chemically-related drug. One report (the lower dot) mentions aminophylline, and another report mentions bamifylline. Bamifylline is not marketed in the US but is used as an asthma drug in Europe. None of these associations with AGEP is statistically significant, as they all fall well below the Statistical Unexpectedness threshold of 4.1 for this adverse event. (The Statistical Unexpectedness threshold is not visible in this zoomed-in portion of the map).

While MedDRA includes a term for AGEP, it is relatively rare with only 442 occurrences in the AERS database from 1997 to 2007 (as shown by the "Na=442" in the map above). The authors note that "AGEP is difficult to distinguish from other pustular dermatoses." We therefore wondered whether a broader search under pentoxifylline might yield additional suspicious cases. One of the hallmarks of AGEP is fever. We therefore generated a Potential Syndromes PVMap for pentoxifylline and the MedDRA PT pyrexia, and again used "Highlight Points" to identify any reports that contained MedDRA terms in the SMQ "Severe cutaneous adverse reactions".

Though again not statistically significant, the PVmap contained cases associated with mouth ulceration, oral mucosal ulceration (probably not relevant), blister, skin necrosis, skin exfoliation, dermatitis bullous, and stevens-johnson syndrome. These terms appear in association with pentoxifylline and pyrexia. A logical next step would be to compare detailed narrative information for those latter five cases against the diagnostic criteria for AGEP.

In investigating a drug-event combination, particularly for a skin reaction, some important questions are: Is this a class effect? If so, how broad is it? And how should cases be defined? The latter question may be particularly important, given that cases can be reported by a variety of healthcare professionals and lay persons who are not necessarily conversant in subtle diagnoses of dermatologic conditions. Here we have illustrated the database search and visualization capabilities of the CLÆRITY software that may be useful in rapidly shedding light on these questions by identifying case reports of interest for the investigation of a particular drug-event combination.

Event-focused PVmaps
The first PVmap shown above is an Event-focused PVmap, allowing you to visualize which drugs are most highly associated with a particular adverse event (rather than the other way around). In this case, the adverse event is the MedDRA term for AGEP and the red dots represent drugs reported in the AERS database to be associated with AGEP. On the horizontal axis of this graph is the reporting ratio, which compares the number of times that a drug is reported with the specified adverse event to the number expected due to chance alone. The vertical axis expresses the statistical significance of the finding. The drugs with the strongest association to AGEP appear at the top and to the right on the PVmap.

Potential Syndromes PVmaps
The second map above is a Potential Syndromes PVmap, allowing you to visualize what adverse events are significantly associated with a specified drug/adverse event combination. In this case, the drug/adverse event combination involves pentoxifylline reported with pyrexia. The red dots on the first map represent co-occurring adverse events when the drug/adverse event combination appeared. On the horizontal axis of this graph is the reporting ratio, which compares the frequency of the adverse event co-occurring with pentoxifylline in a case of pyrexia, with the frequency expected due to chance alone. The vertical axis expresses the statistical significance of the finding. Dots above the dotted line and to the right of the central line represent "significant signals". The adverse events that are most highly associated with the drug/event combination of interest appear at the top and to the right of 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. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

59. Patrizi A, Tabanelli M, Antonucci A, et al. Acute generalized exanthematous pustulosis induced by pentoxifylline. Int J Dermatol 2007:46;1310-12.