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, .

Infliximab and hypokalemia: Is there a relationship? (3/4/2007)
Infliximab (marketed as Remicade^®) is used to treat Crohn's disease, rheumatoid arthritis, and other autoimmune disorders. A recently published case report describes fairly strong evidence for an association of symptomatic hypokalemia with infliximab²³. Symptoms included severe muscle weakness which rendered the patient unable to walk, and both the symptoms and the hypokalemia resolved when infliximab was discontinued ("positive de-challenge"). The patient was also on azathioprine, mesalamine, and ciprofloxacin.

This case report was the subject of an analysis by Dr. Manfred Hauben²⁴. He replied to the journal with a letter, assessing the possible contribution of concomitant administration of steroid pre-medication, as well as other pathological or pharmacological factors, to the reported events.

To illustrate the issues raised by this case report, ProSanos first produced a drug-focused PVmap to visually investigate whether a statistically significant number of hypokalemia cases in infliximab patients had been reported to the FDA via its Adverse Event Reporting System (AERS) using data covering the period from 2001 through the first quarter of 2006. The Drug-focused PVmap for infliximab (not shown here) shows no statistical evidence for an association with hypokalemia (MedDRA term hypokalaemia). There are 71 cases of this drug-event combination, which is very close to the number expected within the AERS database due to coincidence alone (Reporting Ratio=0.898, Statistical Unexpectedness=0.7043).

To investigate the possibility that reports of hypokalemia with infliximab are related to concomitant steroids, we next produced a Potential Interactions PVmap using the same AERS data. This PVmap (displayed above) visually investigates the association of concomitant medications with the drug-event combination infliximab and hypokalaemia. The most significantly associated concomitant drugs appear in the upper right region of the graph. These associations can represent either drug interactions or bystander effects. A 'bystander effect' is a case where a drug does not necessarily have a causal relationship to a particular adverse event, but is frequently co-prescribed along with other drugs that do.

As shown in the map above, a number of terms for steroids, including prednisone, prednisone tab and medrol are significantly associated with infliximab and hypokalemia. This striking graphical display confirms the plausibility of infliximab as a bystander in this case, given the known association of steroids with hypokalemia. As with all data mining, this evidence is hypothesis-corroborating but not conclusive. A full understanding of the relevant case or case series, including pharmacological and clinical as well as statistical considerations, is crucial for informed decision making.

An important benefit of using data mining for drug safety investigation is to generate hypotheses, and to confirm their reasonableness prior to further study. Today's Map of the Week case study is a good example of this type of investigation.

Potential Interactions PVmaps
This 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 is the drug infliximab reported with hypokalaemia. The red dots on the map represent concomitant drugs in use when the drug / adverse event combination infliximab / hypokalaemia occurred. On the horizontal axis of this graph is the reporting ratio, which compares the use of the concomitant drug during infliximab / hypokalaemia 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

23. Karamanolis G, Tzathas C, Triantafyllou K, et al. Symptomatic Hypokalemia Associated with Infliximab in a Patient with Crohn's Disease. Inflamm Bowel Dis 2006;12(10):1010-1011.
24. Hauben M. Hypokalemia Associated with Infliximab: A Pharmacovigilance Perspective. Inflamm Bowel Dis 2007 Feb 2: E-publication ahead of print.