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, .
Levetiracetam and Behavior Abnormalities (6/11/07)
A recent article in Medscape Medical News50 discussed a label change
for the juvenile epilepsy drug levetiracetam (marketed as KEPPRA®),
to incorporate findings from clinical trials regarding behavior abnormalities in
patients taking the drug.51
A total of 109 MedDRA preferred terms were found above the detection threshold
for PVmaps. The top 7 signals for levetiracetam are related to the indication
for the drug as a treatment for epilepsy. The eighth signal is aggression
(93 reports), which was one of the commonly-noted behavior changes in the clinical
trials. Other behavior-related MedDRA preferred terms for signals of
disproportionate reporting detected by PVmaps for levetiracetam include
hostility (rank 19, 23 reports), abnormal behaviour (rank 22,
49 reports), irritability (rank 27, 48 reports), psychotic disorder
(rank 28, 33 reports), abnormal behaviour nos (rank 29, 27 reports),
psychotic disorder nos (rank 30, 24 reports), suicidal ideation
(rank 37, 55 reports), anger (rank 39, 30 reports), hallucination
auditory (rank 48, 19 reports), depression (rank 63, 81 reports),
hallucination nos (rank 65, 22 reports), suicide attempt (rank
81, 39 reports), agitation (rank 84, 51 reports), paranoia (rank
85, 20 reports), acute psychosis (rank 88, 7 reports), and homicidal
ideation (rank 105, 10 reports).
If we use the "Zoom" feature to zoom in on the center of the PVmap
(below the top signals, but above the statistical unexpectedness line), the
signals related to behavior abnormalities are clearly visible:
The safety-related label change for levetiracetam was made on the basis of data
from a double-blind, controlled clinical trial. When a safety signal appears in
a controlled clinical trial, which is considered the "gold standard" for
medical evidence, can data mining in an observational database such as AERS contribute
useful information? The AERS database reflects "real-world" experience
with a drug, and includes situations that may not be reflected in clinical trials.
A wider demographic spectrum of patients may be included, with a wider variety of
medical comorbidities and concomitant medications. Dosing and duration of
treatment may differ from clinical trial conditions, and off-label use may be
significant. Related conditions and precursor conditions may appear under
different MedDRA terms than those captured in the trial data.
For the case of levetiracetam, the finding of behavior changes using PVmaps
corroborates the results of the clinical trials. In other cases with other drugs,
the clinical trial results and postmarket experience may differ significantly, due
to extended duration of treatment, off-label use, or a variety of other factors.
When both clinical-trial data and real-world observational data are available,
there is an opportunity to evaluate the similarities and differences between the
two, and to gain a deeper understanding of the safety profile of a drug under
various conditions of use in various populations.
About Drug-focused PVmaps
Above is a Drug-focused PVmap, which allows you to visualize which adverse events
are most highly associated with a particular drug of interest. In the map directly
above, the drug is levetiracetam and the red dots represent Adverse Events reported
in the AERS database to be associated with levetiracetam. 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 levetiracetam 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
- ProSanos is not affiliated with the authors of cited references and this
article does not imply endorsement of their findings, content, or offerings.
- 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.
- 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.
- 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.
- 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.
- 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.
- PVmaps has been evaluated as a safety signal investigation tool for over two years.
References
- Waknine Y. FDA Safety Changes: Keppra,
Naropin, Rebetol. Medscape Medical News. Accessed on the Internet at www.medscape.com/viewarticle/549821,
June 6, 2007.
- KEPPRA® (levetiracetam) [Prescribing Information]. Accessed
on the Internet at www.fda.gov/medwatch/SAFETY/2007/Mar_PI/Keppra_PI.pdf,
June 6, 2007.
