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, .

Hyponatremia and Psychotropics (1/14/2008)
A presentation at the latest International Society of Pharmacovigilance meeting⁵⁷ reported on an AMSP Project study of the association between hyponatremia and psychotropic drugs.⁵⁸ The AMSP (Arzneimittelsicherheit in der Psychiatrie) Project has been ongoing for several years and has been assessing adverse drug reactions associated with psychotropic medications among inpatients in 55 hospitals in Germany, Belgium, Austria, Switzerland, and Hungary. We thought it would be interesting to examine an Event-Focused PVmap for hyponatraemia in light of the main findings of the AMSP study to see how US-focused data compares with these European findings.

The map below displays drugs which exhibit signals of disproportionate reporting for the MedDRA Preferred Term hyponatraemia in the FDA Adverse Event Reporting System (AERS) database for the period from the first quarter of 1997 until the first quarter of 2007:

The AMSP investigators reported that "the majority of cases involved oxcarbazepine (31.8%), followed by diuretics (27.2%), antiarrhythmics (24.2%), carbamazepine (22.7%), and venlafaxine (16.7%)." The PVmap displays Statistical Unexpectedness on its vertical axis rather than case count, but agrees with the AMSP study in that oxcarbazepine is the top-ranked drug, followed by the diuretics hydrochlorothiazide, spironolactone, and furosemide, with indapamide, amiloride and other diuretics appearing further down. Interestingly, the antiarrhythmics do not appear prominently. Carbamazepine holds its place, while venlafaxine (yellow-highlighted dot) is statistically significant but not as prominent in our AERS-based data as it was in the AMSP list. Desmopressin, paroxetine, and citalopram figure more prominently in the AERS data than in the AMSP results.

In common with the AMSP study, we also find a high degree of coadministration of carbamazepine and diuretics, particularly hydrochlorothiazide (in 90 of 450 cases), as shown in this Potential Interactions PVmap for carbamazepine and hyponatraemia:

Thus we see both similarities and differences between the AMSP and the PVmap results. A number of factors could explain the differences, including drug-utilization differences between Europe and the US, and between hospital-based vs. spontaneous-report data. The AMSP study went well beyond a statistical survey and included both a rigorous case definition (serum sodium < 130 mmol/L) and review of individual cases for assessment of causality. Still, many of the main drug-event associations described in this study can be quickly and easily visualized in AERS data using PVmaps. In particular, the strong association between oxcarbazepine or carbamazepine and hyponatremia appears to hold true on both sides of the Atlantic.

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 hyponatraemia and the red dots represent drugs reported in the AERS database to be associated with hyponatremia. 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. 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 hyponatremia appear at the top and to the right on the PVmap.

Potential Interactions PVmaps
The second map above is a Potential Interactions PVmap, allowing you to visualize what concomitant drugs are significantly associated with a specified drug/adverse event combination. In this case, the drug/adverse event combination involves carbamazepine reported with hyponatraemia. The red dots on the first map represent concomitant drugs in use when the drug / adverse event combination occurred. On the horizontal axis of this graph is the reporting ratio, which compares the use of the concomitant drug with carbamazepine in a case of hyponatremia, with the use of the concomitant drug 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 concomitant drugs 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

57. ADR News from ISoP. Reactions Weekly 10 November 2007;1177:2-3.
58. Van der Velden JW, Jaquenoud Sirot E, Grohmann R. Hyponatraemia during psychotropic medication: results from the international AMSP Project. Drug Safety 2007 30(10): 922.