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FDA's
Center for Veterinary Medicine (CVM)
RIMADYL®
Report
December
1, 1999
FDA's Center for Veterinary Medicine (CVM) has recently
compiled and reviewed adverse drug experience (ADE) reports
received for 1998. During this period, the Center received
a substantial number of ADE reports for carprofen (trade
name Rimadyl®) and consumer inquiries regarding the
safety of this product.
CVM has released the "1998 Annual Adverse Drug Experience
(ADE) Summary" which includes information about ADEs to
all veterinary drugs, including Rimadyl®. This ADE
summary is on our Home Page . Copies are also available
from CVM's Communications Staff at FDA/Center for
Veterinary Medicine, HFV-12, 7500 Standish Place, Rockville,
MD 20855, 301-594-1755. FDA also published a descriptive
overview of the 1998 ADE reports in the November/December
issue of the FDA Veterinarian. This report also is available
from the Communications Staff and our Home Page at the
above address.
FDA approved Rimadyl® for dogs on October 25, 1996,
after a comprehensive review of the product´s safety
and efficacy. Rimadyl® is a non-steroidal anti-inflammatory
drug (NSAID) indicated for use in relief of pain and inflammation
associated with osteoarthritis in dogs. NSAIDs are commonly
used in human medicine for relief of pain and include
such drugs as aspirin, ibuprofen, and naproxen. Rimadyl®
is one of two NSAID products currently approved for use
in dogs. The active ingredient in Rimadyl®, carprofen,
is not approved for use in humans. The drug is available
by veterinary prescription only. The approved drug sponsor
is Pfizer Animal Health of Exton, PA.
Pre-approval studies for Rimadyl® included a clinical
trial involving 297 dogs administered either the drug
or a placebo for 14 days. Similar adverse clinical signs
were observed in both the carprofen and placebo-treated
groups. These signs included an increase in vomiting,
diarrhea, lethargy, behavioral changes, constipation,
and an increase in liver enzymes. Safety studies revealed
no remarkable side effects associated with long-term drug
administration. Based on the studies submitted to CVM,
the risk of Rimadyl® was thought to be negligible.
Of all the ADE reports CVM received in 1998, thirty-nine
percent (39%) or 3626 involved Rimadyl®. The number
of ADE reports received by CVM for Rimadyl® is considerably
more than that received for other animal drugs. For any
one ADE report, there is no absolute certainty that the
suspected drug caused the effect. The adverse effects
in these reports are consistent with those expected for
NSAIDs. They typically involve the gastrointestinal system,
renal/urinary system, hematopoietic (blood) system, neurological
system, and the liver. Approximately 13% of the 1998 Rimadyl®
ADE reports for dogs involved death of the dog, either
on their own or by means of euthanasia.
In spite of the high standards for safety and effectiveness
that exist for FDA approval, not everything is known about
a drug when it is first marketed. Due to the limited number
of animals and controlled nature of pre-marketing clinical
trials, only the most common adverse effects will be observed.
Uncommon effects or problems may
not be discovered until after the drug has been widely
used.
Based on adverse experience reports received since Rimadyl®
was marketed, a number of actions have been taken to provide
the most current product safety information to veterinarians
and dog owners. In 1997, shortly after Rimadyl® was
marketed, CVM began receiving ADE reports involving the
drug. In May 1997, CVM asked Pfizer to change the adverse
reaction section of the label.
CVM also asked Pfizer to send a "Dear Doctor" letter to
veterinarians informing them of the adverse effects reported
with product use. In August 1997, Pfizer mailed a "Dear
Doctor" letter to all veterinarians who had purchased
the product. By September 1997, Pfizer had revised Rimadyl®
labeling to include an extensive adverse reaction section.
The possibility of a fatal outcome was mentioned elsewhere
on the label, but death was also added to the adverse
reactions section in the spring of 1999. In addition,
at CVM´s request, Pfizer developed and distributed
an information sheet containing safety information for
veterinarians to give to owners at the time Rimadyl®
is dispensed.
A number of factors might contribute to the high number
of ADE reports received for Rimadyl®:
type of drug - NSAIDs as a pharmaceutical class are commonly
associated with adverse affects on a variety of body systems,
particularly the gastrointestinal system. Adverse effects
on the kidney and liver have also been documented.
wide use -- Rimadyl® has been administered to 2.5
million dogs over its first two years of marketing. This
represents a high level of use for a recently approved
drug.
duration of use -- Rimadyl® is intended for daily
administration to dogs, possibly on a long-term basis.
While Rimadyl®-related adverse effects are reported
to occur shortly after drug initiation, long-term use
may result in a higher risk for adverse effects. A substantial
portion of dogs receive Rimadyl®
continuously for more than 30 days.
senior dog use - Over 85% of Rimadyl® ADE reports
involved dogs greater than six years of age. Rimadyl®
is intended for use in osteoarthritis, a disease condition
more pronounced in older dogs. Older dogs in general may
be more susceptible to carprofen-related adverse effects.
marketing of the drug -- Pfizer´s direct-to-consumer
marketing strategy and professional support encourages
the submission of a higher number of ADE reports. For
instance, Rimadyl® is one of the few animal drugs
that provides a toll-free number on the label for reporting
ADE reports to the drug
company, which facilitates reporting.
Most of the ADEs reported by owners directly to CVM involved
owners of dogs who said they were not aware of the potential
adverse effects associated with Rimadyl® use. Adequate
communication between the veterinarian and client should
result in an awareness of the risk and benefit of drug
use and alternate therapies
that are available. Additionally, communication should
establish the importance of evaluation of the dog prior
to Rimadyl® initiation and the necessity of periodic
follow-up evaluations if drug use is continued long-term.
Animal owners have told CVM that adequate communication
is not occurring in many
instances.
CVM will continue to evaluate ADE reports received for
Rimadyl® compared to the benefits of NSAID therapy.
In many dogs, the use of NSAIDs is not an elective therapeutic
choice, but the primary therapy available for maintaining
an acceptable standard of life due to the long-term debilitating
effects of osteoarthritis.
As an NSAID with potentially serious side effects, however,
the use of Rimadyl® should be carefully considered
before being incorporated in any therapeutic plan. Moreover,
dog owners should have an active role in making that decision.
CVM, along with drug sponsors, is actively pursuing a
number of avenues to improve the management of NSAID safety
issues in order to minimize the risks and maximize the
benefits of using these products in dogs.
