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, .
Bradycardia and the Tizanidine - Ciprofloxacin Interaction (4/22/2007)
Within the past few weeks, Acorda Therapeutics and the FDA issued a warning to
healthcare professionals36 regarding an interaction between tizanidine
(marketed as ZANAFLEX®) and inhibitors of CYP1A2 such as ciprofloxacin and
fluvoxamine. Tizanidine is a muscle relaxant used to treat spasticity
associated with a number of conditions. In the presence of ciprofloxacin or
other potent CYP1A2 inhibitors, serum concentrations of tizanidine are greatly
increased, potentially exaggerating the sedative and hypotensive effects of the
drug.37
The primary evidence for this drug interaction comes from pharmacokinetics
rather than clinical observation, though one case report appears in the
literature.38 We investigated whether further clinical evidence for
this drug interaction can be found in the FDA Adverse Event Reporting System
(AERS) database, using PVmaps as the tool for this investigation. We first
produced a Drug-focused PVmap (not shown), to obtain a list of statistically
significant adverse events associated with tizanidine reported to the FDA via its
Adverse Event Reporting System (AERS) using data covering the period from 2001
through the first quarter of 2006. In order to identify signs of a potential drug
interaction, we looked for sentinel events which are MedDRA terms that
may indicate exaggerated effects of tizanidine. Among potential sentinel events,
sedation appears on the drug-focused PVmap for tizanidine ranked #7,
with hypotension at #17, hypotension nos at #22, and
bradycardia at #26.
We then produced Potential Interactions PVmaps for tizanidine in association
with each of these events.
The Potential Interactions PVmap above shows concomitant medications
that are significantly associated with tizanidine and sedation. This PVmap shows
a number of sedating painkillers, tranquilizers, and other medications that would
be expected in patients with pain and spasticity. Ciprofloxacin and fluvoxamine
do not show a statistically-significant association with tizanidine and sedation.
Sedation is common with tizanidine as well as with a number of commonly
co-prescribed medications, so it is not surprising to find that this is not a
good sentinel event for detecting this drug interaction.
In the Potential Interactions PVmap for tizanidine and hypotension (above),
ciprofloxacin appears above the statistical significance line. It is notable on
this map, since it is not strongly associated with hypotension on its own.
Ciprofloxacin is at the top of the Potential Interactions PVmap for
tizanidine and bradycardia. Bradycardia serves as an even
better sentinel event for this drug interaction. If the drug interaction between
tizanidine and ciprofloxacin were not already known, the prominence of
ciprofloxacin on these maps—in the absence of other
anti-infectives—could be indicative of the possibility of
cytochrome-mediated changes in pharmacokinetics. Further maps, such as a
Co-prescribed Drugs PVmap, could be generated in order to rule out a bystander
effect.
During this investigation, we generated several PVmaps in order to identify
sentinel events and investigate evidence of a drug interaction. The ability to
rapidly generate and review PVmaps in real time supports the iterative nature of
drug safety investigations.
Potential Interactions PVmaps
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 is the drug
tizanidine reported with adverse events such as sedation. The red dots
on the first map represent concomitant drugs in use when the drug / adverse
event combination tizanidine / sedation occurred. On the horizontal
axis of this graph is the reporting ratio, which compares the use of the
concomitant drug during tizanidine / sedation 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
- 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
- Updated Safety Information: Contraindications
to the Use of Tizanidine. Accessed on the Internet at http://www.fda.gov/medwatch/safety/2007/Zanaflex_DHCP_3-27-2007.pdf,
11 April 2007.
- Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly
increases concentrations and hypotensive effect of tizanidine by inhibiting
its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther.
2004 Dec;76(6):598-606.
- Momo K, Homma M, Kohda Y, et al. Drug interaction of tizanidine and
ciprofloxacin: case report. Clin Pharmacol Ther. 2006 Dec;80(6):717-9.
