EDITORIAL
Putting Some Muscle into Osteoarthritis
Kenneth D. Brandt, MD
15 July 1997 | Volume 127 Issue 2 | Pages 154-156
Osteoarthritis, the most common joint disease, results from the complex interplay of biochemical, metabolic, and biomechanical factors and is characterized, in part, by the progressive loss of articular cartilage. Aggrecan and collagen, the major molecular constituents of articular cartilage, confer stiffness on compression and tensile strength, respectively. Evidence that the metabolic turnover rates of these molecules are increased in osteoarthritic cartilage has led investigators to search for enzymes responsible for their degradation in the hope that pharmacologic inhibitors might be developed to prevent the development or slow the progression of osteoarthritis.
In vitro, several matrix metalloproteinases (MMPs) degrade the core protein of aggrecan through the cleavage of the interglobular domain between Asn341 and Phe342. However, the predominant fragment of the core protein found in the synovial fluid of patients with osteoarthritis and in the medium of chondrocyte cultures after stimulation with interleukin-1 is generated by cleavage between Glu373 and Ala374, suggesting that in vivo proteolysis at the more distal site is important in the breakdown of cartilage in osteoarthritis. Efforts to produce primary Glu373 -Ala374 cleavage with a large number of proteases have been unsuccessful; this suggests that an unidentified enzyme, "aggrecanase," is responsible for this cleavage [1]. Recent evidence [2] suggests that aggrecanase may be a novel MMP.
The predominant collagen in articular cartilage, type II collagen, is responsible for the structural integrity of the tissue. Chondrocytes can produce three collagenases that are capable of cleaving the triple helical region of this collagen: MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3). The last of these represents a major product of cartilage stimulated with interleukin-1, and it hydrolyzes type II collagen much more efficiently than do the other collagenases in cartilage [3]. Whether pharmacologic inhibition of collagenase or other MMPs would ameliorate cartilage breakdown in patients with osteoarthritis-and whether this inhibition can be accomplished without major adverse effects-remains to be determined. The possibility is currently being tested.
Tetracyclines have been shown to inhibit several cartilage MMPs. Doxycycline is a more effective inhibitor of MMP-13 than of the other cartilage collagenases, gelatinase or stromelysin [4]. Oral administration of this drug reduces joint damage in animal models of osteoarthritis [5]. Doxycycline not only inhibits active MMPs by chelating zinc at the catalytic site but also reduces levels of total collagenase and total gelatinase in osteoarthritic cartilage, apparently by affecting enzyme stability through the chelation of intramolecular calcium [6]. Tetracyclines also reduce the stability of messenger RNA for nitric oxide synthase [7]. Because nitric oxide can activate latent MMPs in cartilage [8], this may provide an additional reason for the efficacy of doxycycline in animal models of osteoarthritis. On the basis of the above observations, a placebo-controlled trial of this drug in humans with osteoarthritis has been initiated.
Although advances in our understanding of the biochemical changes underlying the breakdown of cartilage may lead to new pharmacologic agents for osteoarthritis, all of the tissues of the involved joint are abnormal. We should not dismiss the possibility that pharmacologic, biological, or physical measures that modify disease processes in subchondral bone, synovium, joint capsule, ligaments, or periarticular muscles will be more effective than a "chondroprotective" drug. The role of the neuromuscular system in protecting against joint damage deserves consideration in this respect.
In the dog, transection of the anterior cruciate ligament leads to osteoarthritis of the knee, although full-thickness loss of cartilage requires years to develop. However, if sensory input from the hind limb is interrupted before the induction of joint instability (for example, by ipsilateral L4 -S1 dorsal root ganglionectomy), blocking proprioceptive impulses transmitted by neurons whose axons ascend in the dorsal column of the spinal cord, end-stage osteoarthritis is seen within only weeks. This striking acceleration of joint breakdown is associated with increased extension of the unstable limb at touchdown, which causes greater stresses on the knee than in the neurologically intact cruciate-deficient dog [9]. The pathology is very similar to that of the severe joint degeneration that characterizes the secondary form of osteoarthritis seen in neuropathic (Charcot) arthropathy in humans.
Of note, a deficit in proprioception has been documented in humans who have (apparently) primary osteoarthritis of the knee. Whether this deficit is due to a primary neurologic abnormality or to damage to mechanoreceptors in or around the involved joint is unclear, but persons with clinical and radiographic evidence of unilateral osteoarthritis of the knee exhibit impaired proprioception in both lower extremities; this suggests an underlying, generalized neurologic defect [10]. Because a proprioception deficit puts the joint at risk by impairing protective muscular reflexes, this observation requires follow-up.
Even in the neurologically normal person, periarticular muscle weakness poses a threat to the joint. Quadriceps weakness is common in patients with osteoarthritis of the knee, and muscle strengthening exercise can reduce joint pain and improve function [11]. Although this quadriceps weakness is generally presumed to be due to muscle atrophy caused by reduced loading of the painful extremity, it may be seen in persons with radiographic evidence of osteoarthritis of the knee who have no history of recent knee pain and no loss of quadriceps mass. In some cases, it may be due to reflex inhibition of the quadriceps, with altered afferent input from the diseased joint resulting in abnormal efferent output to the muscle [12].
However, there is more to this story. Among persons with medial tibiofemoral compartment osteoarthritis, a decrease in pain led to an increase in adductor and flexor moments at the knee [13]; this suggests that the alleviation of joint pain could increase loading of damaged cartilage. The concept of "analgesic arthropathy" is not new; for years, there has been concern that drugs that relieve joint pain may lead to detrimental overloading of the arthritic joint. Furthermore, some nonsteroidal anti-inflammatory drugs (NSAIDs) used for osteoarthritis pain inhibit proteoglycan synthesis [14] and could, theoretically, blunt the repair capacity of the chondrocyte. However, evidence that any NSAID accelerates progression of osteoarthritis in humans is far from clear cut.
Even if relief of joint pain were to increase joint loading, some have suggested that it may not be the magnitude of the load as much as the rate of loading that is the important determinant of joint damage [15]. Within physiologic limits, impulsive loads (in which the rate of loading is high) are more damaging to articular cartilage and subchondral bone than are forces of greater magnitude applied more gradually (Radin E. Personal communication). Very rapid application of load does not allow sufficient time for the periarticular muscles, the major shock absorbers protecting the joint, to absorb the load [16].
It has been suggested that normal persons walking at the same speed use various strategies to decelerate the leg at the end of the swing phase of gait [17]. Some persons use the braking action of their quadriceps to control the effect of gravity on the rate of descent of the leg, whereas deceleration of the leg by quadriceps contraction may be less effective in other persons, in whom the rate of descent is slowed only by contact with the ground. The large heel-strike transient that develops under the latter condition may generate contact forces in the knee that are several times greater than those produced when effective quadriceps contraction occurs before heel strike [18]. The basis for the differences in gait patterns among normal persons is unknown, but these differences could reflect individual differences in the central neurologic mechanisms that coordinate limb movements during gait.
Whether a quadricps-deficient pattern of gait leads to osteoarthritis of the knee is still unclear. However, preliminary analyses of a cohort of elderly persons living in the community suggest that persons who have quadriceps weakness at baseline are more likely than those with greater initial strength to exhibit progression of radiographic changes of osteoarthritis of the knee (Slemenda C, Brandt KD. Unpublished data). Regardless of its cause, weakness could impair protective reflexes originating from proprioceptive nerve endings in muscle spindles or mechanoreceptors within the joint.
Considerable effort is being expended on the development of drugs to counteract the underlying pathologic changes of osteoarthritis. It remains to be seen whether any drug that modifies chondrocyte metabolism will modify the pathology of osteoarthritis if the mechanical environment of the joint remains abnormal. Drug development should not preclude evaluation of the possibility that physical measures that improve neuromuscular function (for example, coordination or periarticular muscle strength) may have a favorable effect on the pathology and symptoms of osteoarthritis. Indeed, improvement in joint mechanics could enhance the efficacy of a disease-modifying drug. Even in elderly persons, quadriceps strength can be increased through training [19]. Although it may not be possible to completely reverse the neuropathologic changes that are responsible for initiating joint damage (for example, a deficit in proprioception), persons with such defects may be trained to alter their movement patterns to protect their joints from traumatic injury.
Acknowledgment: The author thanks Kathie Lane for expert secretarial assistance.
Grant Support: In part by grants AR20582 and AR43348 from the National Institutes of Health.
Requests for Reprints: Kenneth D. Brandt, MD, Rheumatology Division, 541 Clinical Drive, Room 492, Indianapolis, IN 46202.
Author and Article Information
TopAuthor & Article InfoReferences
Indiana University School of Medicine Indianapolis, IN 46202-5103
References
TopAuthor & Article InfoReferences
1. Fosang AJ, Last K, Maciewicz RA. Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metailoproteinase and aggrecanase activities can be independent. J Clin Invest. 1996;98:2292-9.[Abstract/Free Full Text]
2. Arner EC, Decicco CP, Pratta MA, Copeland RA, Trzaskos JM, Magolda RL, et al. Characterization of soluble bovine cartilage "aggrecanase" [Abstract]. Transactions of the Orthopaedic Research Society. 1997;22:103.
3. Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. J Clin Invest. 1996;97:2011-9.[Abstract/Free Full Text]
4. Smith GN, Hasty KA, Mickler EA, Brandt KD. Specificity of doxycycline inhibition of MMPs: relation to MMP structure [Abstract]. Transactions of the Orthopaedic Research Society. 1997;22:105.
5. Yu LP Jr, Smith GN Jr, Brandt KD, Myers SL, O'Connor BL, Brandt DA. Reduction of the severity of the canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum. 1992;35:1150-9.[Medline]
6. Smith GN Jr, Brandt KD, Hasty KA. Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity. Arthritis Rheum. 1996;39:235-44.[Medline]
7. Amin AR, Attur MG, Thakker GD, Patel PD, Vyes PR, Patel RN, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases Proc Natl Acad Sci U S A. 1996;93:14014-9.
8. Murrell GA, Jang D. Williams RJ. Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun. 1995;206:15-21.[Medline]
9. Vilensky J, O'Connor B, Brandt K, Dunn E, Rogers P. Serial kinematic analysis of the canine hind limb joints after deafferentation and anterior cruciate ligament transection. Osteoarthritis and Cartilage. 1997;5:173-82.[Medline]
10. Sharma L, Pai Y. The relationship between impaired proprioception and osteoarthritis. Curr Opin Rheumatol. 1997;9:253-8.[Medline]
11. Fisher NM, Kame VD Jr, Rouse L, Pendergast DR. Quantitative evaluation of a home exercise program on muscle and functional capacity of patients with osteoarthritis. Am J Phys Med Rehabil. 1994;3:413-20.
12. Hurley MV, Newham DJ. The influence of arthrogenous muscle inhibition on quadriceps rehabilitation of patients with early, unilateral osteoarthritic knees. Br J Rheumatol. 1993;32:127-31.[Medline]
13. Hurwitz D, Sum J, Andriacchi TP, Schnitzer TJ, Andersson G. The effects of osteoarthritis knee pain on joint loading [Abstract]. Transactions of the Orthopaedic Research Society. 1997;22:723.
14. Palmoski MJ, Brandt KD. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum. 1980;23:1010-20.[Medline]
15. Radin EL, Boyd RD, Martin RB, Burr DB, Caterson B, Goodwin C. Mechanical factors influencing cartilage damage. In: Peyron JG, ed. Osteoarthritis: Current Clinical and Fundamental Problems. Paris: Geigy; 1985:90-9.
16. Hill AV. Production and absorption of work by muscle. Science. 1960;131:897-903.
17. Jefferson RJ, Collins JJ, Whittle MW, Radin EL, O'Connor JJ. The role of the quadriceps in controlling impulsive forces around heel strike. Proc Inst Mech Eng [H]. 1990;204:21-8.[Medline]
18. Radin EL, Yang KH, Riegger C, Kish VL, O'Connor JJ. Relationship between lower limb dynamics and knee joint pain. J Orthop Res. 1991;9:398-405.[Medline]
19. Mikesky AE, Topp R, Wigglesworth JK, Harsha DM, Edwards JE. Efficacy of a home-based training program for older adults using elastic tubing Eur J Appl Physiol. 1994;69:316-20.
This article has been cited by other articles:
K J Sims, C A Richardson, and S G Brauer
Investigation of hip abductor activation in subjects with clinical unilateral hip osteoarthritis
Ann. Rheum. Dis, August 1, 2002; 61(8): 687 - 692.
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Do NSAIDs such as Rimadyl make arthritis worse ?
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Do NSAIDs such as Rimadyl make arthritis worse ?
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veterinary NSAIDs
by guest » Mon Aug 02, 2004 8:22 pm
AVMA Home | AVMA Journals Home | JAVMA online | Current JAVMA NewsApril
15, 2004 Minimizing the risk factors associated with veterinary NSAIDs
FDA-CVM offers suggestions based on postmarketing experience
Veterinary practitioners must weigh the serious risks associated with
nonsteroidal, anti-inflammatory drug usage. Specific strategies can be
implemented to reduce the likelihood of harming patients. Moreover,
practitioners can educate their clients by communicating the serious
risks that accompany the benefits of those medications.
Vital to the mission of the Food and Drug Administration's Center for
Veterinary Medicine of fostering public and animal health is its pre-
and postapproval regulation of drug labeling. Label content is
painstakingly crafted during products' approval negotiations and is
based on thorough review of all scientific data submitted to support
claims of safety and effectiveness. That content is amended, as needed,
to communicate postmarketing experience that reflects what happens to
patients in the real world.
Postmarketing experience is reported to the CVM by drug sponsors, as
required by the Code of Federal Regulations governing approved drug
applications. The companies report adverse drug experiences upon
notification by veterinary practitioners, pet owners, and other
stakeholders. The reports are stored in the CVM's Adverse Drug
Experience database and analyzed by clinical veterinarians. They review
the reports and classify the likelihood that clinical signs are or are
not linked to the use of a veterinary drug product.
The four most commonly reported clinical signs are vomiting, anorexia,
depression, and diarrhea. Further down the list of adverse events are
gastric ulceration, intestinal ulceration, renal failure, hepatic
failure, and death. Many of those injuries result from product misuse
and could be prevented by understanding the risks imposed by NSAIDs.
Another safeguard is exercising more judicious use of these products in
such ways as screening patients for hydration and for hepatic or renal
disease, and avoiding any overlapping treatment with other NSAID
products.
Drug risk information is communicated to veterinary practitioners and to
the public through the product labeling. Labeling includes the package
insert, the vial or bottle label, the carton label, the client
information sheet, and some types of promotional materials. Drugs that
come with client information sheets are intended to be dispensed to
clients with the client information sheet accompanying the prescription.
In many cases of adverse drug experiences, pet owners report they never
received the client information sheet from their veterinarian. In the
Jan. 15, 2004, JAVMA, staff at the CVM published an article titled
"Emerging issues regarding informed consent." That article reported
evidence that pet owners are increasingly concerned about risks and
benefits of commonly prescribed veterinary drugs. The article stated
that most of the calls received by the CVM concerning adverse drug
experiences now come from consumers rather than veterinarians.
All FDA-approved veterinary NSAID products have similar risk information
on their labels, including the following:
The products are for use in dogs only.
All dogs should undergo a thorough history and physical examination
before the initiation of NSAID therapy.
Appropriate laboratory tests should be considered to establish
hematologic and serum biochemical baseline data prior to, and
periodically during, administration of any NSAID.
The products may be associated with gastrointestinal, hepatic, and renal
toxicosis.
Concomitant use with other anti-inflammatory drugs, such as other NSAIDs
and corticosteroids, should be avoided or closely monitored.
Patients at greatest risk for renal toxicosis are those that are
dehydrated, are on concomitant diuretic treatment, or have renal,
cardiovascular, and/or hepatic dysfunction.
Many NSAIDs possess the potential to produce GI ulceration.
The risk information is there for good reason. Adverse events reported
to the CVM have included substantial numbers of reports of renal
toxicosis in cats (an extralabel use), and gastric and duodenal
ulceration and perforations. GI injuries occur most commonly in dogs
when higher-than-label doses are administered, following surgical
procedures, and after treatment with more than one product, or when
treatments with different products overlap.
For example, suppose a referring veterinarian treated a patient for
osteoarthritis with product A, and the referral practice treats the
patient with a "postsurgical pain" dose of product B. Did the latter
ensure an adequate washout period for the patient to eliminate product
A? Did they provide fluid support during surgery? The most common
factors predisposing patients to injury are overdose, surgical
anesthesia, and in-tandem administration of another NSAID and/or
corticosteroid.
The following practices could help veterinarians administering NSAIDs to
reduce the likelihood of adverse drug experiences and injuries:
Some products have two dosage levels—one for long-term use for
patients with osteoarthritis; another, higher dosage for short-term,
postoperative pain. Choose dosages strictly according to body weight.
Individualize dosing by titrating the dose to desired effect. (Nies AS.
Principles of therapeutics. In: Hardman JG, Limbird LL, eds. Goodman &
Gilman's the pharmacological basis of therapeutics. 10th ed. New York:
McGraw-Hill Book Co, 2001; 45-65.)
The NSAIDs can be nephrotoxic and hepatotoxic. Screen patients for renal
and hepatic disease, and monitor patients during treatment.
Optimize patients' hydration status. Provide parenteral fluids for
surgical patients. Do not administer NSAIDs to patients that are
dehydrated.
Allow an adequate washout period for patients to eliminate the last
NSAID or corticosteroid they were treated with prior to administering a
new NSAID. The duration that constitutes "adequate" has yet to be
determined. Contact product manufacturers to determine current
recommendations.
Most important—read the label. Understand the risk. Make informed
treatment decisions. Provide client information sheets. Communicate the
important risk information to clients.
If client information sheets did not arrive with a shipment of an NSAID
product, contact the distributor and the manufacturer and request that
they immediately send that information. We encourage you to report this
problem to the CVM as well.
The CVM has a Web site that explains its monitoring program for adverse
events associated with the use of drugs in animals, and provides
reported reactions for veterinary drugs:
www.fda.gov/cvm/index/ade/adetoc.htm. Veterinarians and pet owners can
report adverse drug experiences to the CVM by calling us at (888)
FDA-VETS.
–Dr. Thomas J. Moskal, Office of Surveillance and Compliance, FDA
Center for Veterinary Medicine
Return to top
AVMA Journals | JAVMA News | Discussion Groups | Veterinary Career
Center
Professional Resources | Member Center | Care for Animals | AVMA Home
American Veterinary Medical Association
Copyright © 2004
AVMA Home | AVMA Journals Home | JAVMA online | Current JAVMA NewsApril
15, 2004 Minimizing the risk factors associated with veterinary NSAIDs
FDA-CVM offers suggestions based on postmarketing experience
Veterinary practitioners must weigh the serious risks associated with
nonsteroidal, anti-inflammatory drug usage. Specific strategies can be
implemented to reduce the likelihood of harming patients. Moreover,
practitioners can educate their clients by communicating the serious
risks that accompany the benefits of those medications.
Vital to the mission of the Food and Drug Administration's Center for
Veterinary Medicine of fostering public and animal health is its pre-
and postapproval regulation of drug labeling. Label content is
painstakingly crafted during products' approval negotiations and is
based on thorough review of all scientific data submitted to support
claims of safety and effectiveness. That content is amended, as needed,
to communicate postmarketing experience that reflects what happens to
patients in the real world.
Postmarketing experience is reported to the CVM by drug sponsors, as
required by the Code of Federal Regulations governing approved drug
applications. The companies report adverse drug experiences upon
notification by veterinary practitioners, pet owners, and other
stakeholders. The reports are stored in the CVM's Adverse Drug
Experience database and analyzed by clinical veterinarians. They review
the reports and classify the likelihood that clinical signs are or are
not linked to the use of a veterinary drug product.
The four most commonly reported clinical signs are vomiting, anorexia,
depression, and diarrhea. Further down the list of adverse events are
gastric ulceration, intestinal ulceration, renal failure, hepatic
failure, and death. Many of those injuries result from product misuse
and could be prevented by understanding the risks imposed by NSAIDs.
Another safeguard is exercising more judicious use of these products in
such ways as screening patients for hydration and for hepatic or renal
disease, and avoiding any overlapping treatment with other NSAID
products.
Drug risk information is communicated to veterinary practitioners and to
the public through the product labeling. Labeling includes the package
insert, the vial or bottle label, the carton label, the client
information sheet, and some types of promotional materials. Drugs that
come with client information sheets are intended to be dispensed to
clients with the client information sheet accompanying the prescription.
In many cases of adverse drug experiences, pet owners report they never
received the client information sheet from their veterinarian. In the
Jan. 15, 2004, JAVMA, staff at the CVM published an article titled
"Emerging issues regarding informed consent." That article reported
evidence that pet owners are increasingly concerned about risks and
benefits of commonly prescribed veterinary drugs. The article stated
that most of the calls received by the CVM concerning adverse drug
experiences now come from consumers rather than veterinarians.
All FDA-approved veterinary NSAID products have similar risk information
on their labels, including the following:
The products are for use in dogs only.
All dogs should undergo a thorough history and physical examination
before the initiation of NSAID therapy.
Appropriate laboratory tests should be considered to establish
hematologic and serum biochemical baseline data prior to, and
periodically during, administration of any NSAID.
The products may be associated with gastrointestinal, hepatic, and renal
toxicosis.
Concomitant use with other anti-inflammatory drugs, such as other NSAIDs
and corticosteroids, should be avoided or closely monitored.
Patients at greatest risk for renal toxicosis are those that are
dehydrated, are on concomitant diuretic treatment, or have renal,
cardiovascular, and/or hepatic dysfunction.
Many NSAIDs possess the potential to produce GI ulceration.
The risk information is there for good reason. Adverse events reported
to the CVM have included substantial numbers of reports of renal
toxicosis in cats (an extralabel use), and gastric and duodenal
ulceration and perforations. GI injuries occur most commonly in dogs
when higher-than-label doses are administered, following surgical
procedures, and after treatment with more than one product, or when
treatments with different products overlap.
For example, suppose a referring veterinarian treated a patient for
osteoarthritis with product A, and the referral practice treats the
patient with a "postsurgical pain" dose of product B. Did the latter
ensure an adequate washout period for the patient to eliminate product
A? Did they provide fluid support during surgery? The most common
factors predisposing patients to injury are overdose, surgical
anesthesia, and in-tandem administration of another NSAID and/or
corticosteroid.
The following practices could help veterinarians administering NSAIDs to
reduce the likelihood of adverse drug experiences and injuries:
Some products have two dosage levels—one for long-term use for
patients with osteoarthritis; another, higher dosage for short-term,
postoperative pain. Choose dosages strictly according to body weight.
Individualize dosing by titrating the dose to desired effect. (Nies AS.
Principles of therapeutics. In: Hardman JG, Limbird LL, eds. Goodman &
Gilman's the pharmacological basis of therapeutics. 10th ed. New York:
McGraw-Hill Book Co, 2001; 45-65.)
The NSAIDs can be nephrotoxic and hepatotoxic. Screen patients for renal
and hepatic disease, and monitor patients during treatment.
Optimize patients' hydration status. Provide parenteral fluids for
surgical patients. Do not administer NSAIDs to patients that are
dehydrated.
Allow an adequate washout period for patients to eliminate the last
NSAID or corticosteroid they were treated with prior to administering a
new NSAID. The duration that constitutes "adequate" has yet to be
determined. Contact product manufacturers to determine current
recommendations.
Most important—read the label. Understand the risk. Make informed
treatment decisions. Provide client information sheets. Communicate the
important risk information to clients.
If client information sheets did not arrive with a shipment of an NSAID
product, contact the distributor and the manufacturer and request that
they immediately send that information. We encourage you to report this
problem to the CVM as well.
The CVM has a Web site that explains its monitoring program for adverse
events associated with the use of drugs in animals, and provides
reported reactions for veterinary drugs:
www.fda.gov/cvm/index/ade/adetoc.htm. Veterinarians and pet owners can
report adverse drug experiences to the CVM by calling us at (888)
FDA-VETS.
–Dr. Thomas J. Moskal, Office of Surveillance and Compliance, FDA
Center for Veterinary Medicine
Return to top
AVMA Journals | JAVMA News | Discussion Groups | Veterinary Career
Center
Professional Resources | Member Center | Care for Animals | AVMA Home
American Veterinary Medical Association
Copyright © 2004
15, 2004 Minimizing the risk factors associated with veterinary NSAIDs
FDA-CVM offers suggestions based on postmarketing experience
Veterinary practitioners must weigh the serious risks associated with
nonsteroidal, anti-inflammatory drug usage. Specific strategies can be
implemented to reduce the likelihood of harming patients. Moreover,
practitioners can educate their clients by communicating the serious
risks that accompany the benefits of those medications.
Vital to the mission of the Food and Drug Administration's Center for
Veterinary Medicine of fostering public and animal health is its pre-
and postapproval regulation of drug labeling. Label content is
painstakingly crafted during products' approval negotiations and is
based on thorough review of all scientific data submitted to support
claims of safety and effectiveness. That content is amended, as needed,
to communicate postmarketing experience that reflects what happens to
patients in the real world.
Postmarketing experience is reported to the CVM by drug sponsors, as
required by the Code of Federal Regulations governing approved drug
applications. The companies report adverse drug experiences upon
notification by veterinary practitioners, pet owners, and other
stakeholders. The reports are stored in the CVM's Adverse Drug
Experience database and analyzed by clinical veterinarians. They review
the reports and classify the likelihood that clinical signs are or are
not linked to the use of a veterinary drug product.
The four most commonly reported clinical signs are vomiting, anorexia,
depression, and diarrhea. Further down the list of adverse events are
gastric ulceration, intestinal ulceration, renal failure, hepatic
failure, and death. Many of those injuries result from product misuse
and could be prevented by understanding the risks imposed by NSAIDs.
Another safeguard is exercising more judicious use of these products in
such ways as screening patients for hydration and for hepatic or renal
disease, and avoiding any overlapping treatment with other NSAID
products.
Drug risk information is communicated to veterinary practitioners and to
the public through the product labeling. Labeling includes the package
insert, the vial or bottle label, the carton label, the client
information sheet, and some types of promotional materials. Drugs that
come with client information sheets are intended to be dispensed to
clients with the client information sheet accompanying the prescription.
In many cases of adverse drug experiences, pet owners report they never
received the client information sheet from their veterinarian. In the
Jan. 15, 2004, JAVMA, staff at the CVM published an article titled
"Emerging issues regarding informed consent." That article reported
evidence that pet owners are increasingly concerned about risks and
benefits of commonly prescribed veterinary drugs. The article stated
that most of the calls received by the CVM concerning adverse drug
experiences now come from consumers rather than veterinarians.
All FDA-approved veterinary NSAID products have similar risk information
on their labels, including the following:
The products are for use in dogs only.
All dogs should undergo a thorough history and physical examination
before the initiation of NSAID therapy.
Appropriate laboratory tests should be considered to establish
hematologic and serum biochemical baseline data prior to, and
periodically during, administration of any NSAID.
The products may be associated with gastrointestinal, hepatic, and renal
toxicosis.
Concomitant use with other anti-inflammatory drugs, such as other NSAIDs
and corticosteroids, should be avoided or closely monitored.
Patients at greatest risk for renal toxicosis are those that are
dehydrated, are on concomitant diuretic treatment, or have renal,
cardiovascular, and/or hepatic dysfunction.
Many NSAIDs possess the potential to produce GI ulceration.
The risk information is there for good reason. Adverse events reported
to the CVM have included substantial numbers of reports of renal
toxicosis in cats (an extralabel use), and gastric and duodenal
ulceration and perforations. GI injuries occur most commonly in dogs
when higher-than-label doses are administered, following surgical
procedures, and after treatment with more than one product, or when
treatments with different products overlap.
For example, suppose a referring veterinarian treated a patient for
osteoarthritis with product A, and the referral practice treats the
patient with a "postsurgical pain" dose of product B. Did the latter
ensure an adequate washout period for the patient to eliminate product
A? Did they provide fluid support during surgery? The most common
factors predisposing patients to injury are overdose, surgical
anesthesia, and in-tandem administration of another NSAID and/or
corticosteroid.
The following practices could help veterinarians administering NSAIDs to
reduce the likelihood of adverse drug experiences and injuries:
Some products have two dosage levels—one for long-term use for
patients with osteoarthritis; another, higher dosage for short-term,
postoperative pain. Choose dosages strictly according to body weight.
Individualize dosing by titrating the dose to desired effect. (Nies AS.
Principles of therapeutics. In: Hardman JG, Limbird LL, eds. Goodman &
Gilman's the pharmacological basis of therapeutics. 10th ed. New York:
McGraw-Hill Book Co, 2001; 45-65.)
The NSAIDs can be nephrotoxic and hepatotoxic. Screen patients for renal
and hepatic disease, and monitor patients during treatment.
Optimize patients' hydration status. Provide parenteral fluids for
surgical patients. Do not administer NSAIDs to patients that are
dehydrated.
Allow an adequate washout period for patients to eliminate the last
NSAID or corticosteroid they were treated with prior to administering a
new NSAID. The duration that constitutes "adequate" has yet to be
determined. Contact product manufacturers to determine current
recommendations.
Most important—read the label. Understand the risk. Make informed
treatment decisions. Provide client information sheets. Communicate the
important risk information to clients.
If client information sheets did not arrive with a shipment of an NSAID
product, contact the distributor and the manufacturer and request that
they immediately send that information. We encourage you to report this
problem to the CVM as well.
The CVM has a Web site that explains its monitoring program for adverse
events associated with the use of drugs in animals, and provides
reported reactions for veterinary drugs:
www.fda.gov/cvm/index/ade/adetoc.htm. Veterinarians and pet owners can
report adverse drug experiences to the CVM by calling us at (888)
FDA-VETS.
–Dr. Thomas J. Moskal, Office of Surveillance and Compliance, FDA
Center for Veterinary Medicine
Return to top
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Center
Professional Resources | Member Center | Care for Animals | AVMA Home
American Veterinary Medical Association
Copyright © 2004
AVMA Home | AVMA Journals Home | JAVMA online | Current JAVMA NewsApril
15, 2004 Minimizing the risk factors associated with veterinary NSAIDs
FDA-CVM offers suggestions based on postmarketing experience
Veterinary practitioners must weigh the serious risks associated with
nonsteroidal, anti-inflammatory drug usage. Specific strategies can be
implemented to reduce the likelihood of harming patients. Moreover,
practitioners can educate their clients by communicating the serious
risks that accompany the benefits of those medications.
Vital to the mission of the Food and Drug Administration's Center for
Veterinary Medicine of fostering public and animal health is its pre-
and postapproval regulation of drug labeling. Label content is
painstakingly crafted during products' approval negotiations and is
based on thorough review of all scientific data submitted to support
claims of safety and effectiveness. That content is amended, as needed,
to communicate postmarketing experience that reflects what happens to
patients in the real world.
Postmarketing experience is reported to the CVM by drug sponsors, as
required by the Code of Federal Regulations governing approved drug
applications. The companies report adverse drug experiences upon
notification by veterinary practitioners, pet owners, and other
stakeholders. The reports are stored in the CVM's Adverse Drug
Experience database and analyzed by clinical veterinarians. They review
the reports and classify the likelihood that clinical signs are or are
not linked to the use of a veterinary drug product.
The four most commonly reported clinical signs are vomiting, anorexia,
depression, and diarrhea. Further down the list of adverse events are
gastric ulceration, intestinal ulceration, renal failure, hepatic
failure, and death. Many of those injuries result from product misuse
and could be prevented by understanding the risks imposed by NSAIDs.
Another safeguard is exercising more judicious use of these products in
such ways as screening patients for hydration and for hepatic or renal
disease, and avoiding any overlapping treatment with other NSAID
products.
Drug risk information is communicated to veterinary practitioners and to
the public through the product labeling. Labeling includes the package
insert, the vial or bottle label, the carton label, the client
information sheet, and some types of promotional materials. Drugs that
come with client information sheets are intended to be dispensed to
clients with the client information sheet accompanying the prescription.
In many cases of adverse drug experiences, pet owners report they never
received the client information sheet from their veterinarian. In the
Jan. 15, 2004, JAVMA, staff at the CVM published an article titled
"Emerging issues regarding informed consent." That article reported
evidence that pet owners are increasingly concerned about risks and
benefits of commonly prescribed veterinary drugs. The article stated
that most of the calls received by the CVM concerning adverse drug
experiences now come from consumers rather than veterinarians.
All FDA-approved veterinary NSAID products have similar risk information
on their labels, including the following:
The products are for use in dogs only.
All dogs should undergo a thorough history and physical examination
before the initiation of NSAID therapy.
Appropriate laboratory tests should be considered to establish
hematologic and serum biochemical baseline data prior to, and
periodically during, administration of any NSAID.
The products may be associated with gastrointestinal, hepatic, and renal
toxicosis.
Concomitant use with other anti-inflammatory drugs, such as other NSAIDs
and corticosteroids, should be avoided or closely monitored.
Patients at greatest risk for renal toxicosis are those that are
dehydrated, are on concomitant diuretic treatment, or have renal,
cardiovascular, and/or hepatic dysfunction.
Many NSAIDs possess the potential to produce GI ulceration.
The risk information is there for good reason. Adverse events reported
to the CVM have included substantial numbers of reports of renal
toxicosis in cats (an extralabel use), and gastric and duodenal
ulceration and perforations. GI injuries occur most commonly in dogs
when higher-than-label doses are administered, following surgical
procedures, and after treatment with more than one product, or when
treatments with different products overlap.
For example, suppose a referring veterinarian treated a patient for
osteoarthritis with product A, and the referral practice treats the
patient with a "postsurgical pain" dose of product B. Did the latter
ensure an adequate washout period for the patient to eliminate product
A? Did they provide fluid support during surgery? The most common
factors predisposing patients to injury are overdose, surgical
anesthesia, and in-tandem administration of another NSAID and/or
corticosteroid.
The following practices could help veterinarians administering NSAIDs to
reduce the likelihood of adverse drug experiences and injuries:
Some products have two dosage levels—one for long-term use for
patients with osteoarthritis; another, higher dosage for short-term,
postoperative pain. Choose dosages strictly according to body weight.
Individualize dosing by titrating the dose to desired effect. (Nies AS.
Principles of therapeutics. In: Hardman JG, Limbird LL, eds. Goodman &
Gilman's the pharmacological basis of therapeutics. 10th ed. New York:
McGraw-Hill Book Co, 2001; 45-65.)
The NSAIDs can be nephrotoxic and hepatotoxic. Screen patients for renal
and hepatic disease, and monitor patients during treatment.
Optimize patients' hydration status. Provide parenteral fluids for
surgical patients. Do not administer NSAIDs to patients that are
dehydrated.
Allow an adequate washout period for patients to eliminate the last
NSAID or corticosteroid they were treated with prior to administering a
new NSAID. The duration that constitutes "adequate" has yet to be
determined. Contact product manufacturers to determine current
recommendations.
Most important—read the label. Understand the risk. Make informed
treatment decisions. Provide client information sheets. Communicate the
important risk information to clients.
If client information sheets did not arrive with a shipment of an NSAID
product, contact the distributor and the manufacturer and request that
they immediately send that information. We encourage you to report this
problem to the CVM as well.
The CVM has a Web site that explains its monitoring program for adverse
events associated with the use of drugs in animals, and provides
reported reactions for veterinary drugs:
www.fda.gov/cvm/index/ade/adetoc.htm. Veterinarians and pet owners can
report adverse drug experiences to the CVM by calling us at (888)
FDA-VETS.
–Dr. Thomas J. Moskal, Office of Surveillance and Compliance, FDA
Center for Veterinary Medicine
Return to top
AVMA Journals | JAVMA News | Discussion Groups | Veterinary Career
Center
Professional Resources | Member Center | Care for Animals | AVMA Home
American Veterinary Medical Association
Copyright © 2004
- guest
Pfizer Rimadyl lawsuit in news
by guest » Mon Aug 23, 2004 1:03 pm
The Post and Courier, Charleston, SC had the following article in today's
edition -
http://charleston.net/ - the article is not available unless you are
"registered" with the newspaper.
Story last updated at 7:07 a.m. Monday, August 23, 2004
Concern cited about pet drugs
Settlement fails to bring closure after death of dog
BY PHILLIP CASTON
Of The Post and Courier Staff More than a year after settlement of a lawsuit
brought against pharmaceutical company Pfizer Inc. by Johns Island resident
Jean Townsend, she now has her money but not the closure she wants.Townsend
filed the 1999 lawsuit two years after her chocolate Labrador retriever George
suffered life-threatening side effects of the drug Rimadyl. The dog was
euthanized because of severe internal bleeding and liver failure about two weeks after
Townsend began giving him pills to treat arthritis. She said neither she nor
her veterinarian were made aware of all the drug's potential dangers."It is
devastating to live with the realization that I gave my beloved pet medicine to
help him when, in fact, it was killing him," the Clark Hills Circle resident
said Sunday.Some 300 other pet owners across the nation later joined Townsend's
lawsuit. As part of the settlement, Pfizer offered to pay about $1,000 to each
plaintiff whose pet suffered adverse side effects to Rimadyl. Townsend hopes
to see other similar suits filed in other states, she said. She'd also like to
see veterinarians conduct blood screening work on animals before prescribing
Rimadyl or similar drugs and fully inform pet owners of all possible side
effects. "If you know what to look for, then you can take action immediately,"
Townsend said.After her dog died, Townsend notified Pfizer, which offered a
$249.33 settlement under the condition that she keep the incident confidential, she
said. Townsend declined the offer.Researching the drug on the Internet,
Townsend found dozens of dog owners throughout the country who had similar
experiences with Rimadyl. She and several owners launched a campaign to educate dog
owners about the drug's side effects, she said. After meeting with Food and Drug
Administration representatives and Pfizer officials and being unsatisfied
with their efforts to inform dog owners of the dangers, Townsend filed suit. She
sought $734 for the cost of veterinary care for George.In 1999, because of the
number of complaints about the drug, the FDA issued a public statement
warning of the drug's effects. When the FDA gave Pfizer an ultimatum that the
company must mention death as a possible side effect in its TV commercials for
Rimadyl, the company dropped the TV ads completely.Shortly after the lawsuit and
the FDA's statement, Pfizer decided to change the packaging of the drug and
include a client information sheet for customers that lists side effects and what
to do if they occur.According to FDA records and estimates, since Pfizer
introduced Rimadyl in 1997, the FDA has received reports of about 1,000 dogs that
died or were euthanized and 7,000 more that had bad reactions after being given
the drug.Townsend donated her settlement to a local veterinarian for pet
owners who can't afford surgery."Of course, no amount of money would ever replace
the loss of my friend, George, and the loss of so many other beloved
companions," Townsend said. "We, as pet owners, have the right to know as much about
the good and bad sides of veterinary medicines as we do the medicines we give
ourselves."Staff writer Adam Ferrell contributed to this report. >>
Please, if you have the time, write the reporters to thank them for the
article. Their e-mail addresses are:
pcaston@postandcourier.com
aferrell@postandcourier.com
If you want to respond by writing a Letter to the Editor - the address is:
letters@postandcourier.com - please be sure to include your name, address and
a telephone number.
Thanks.
Jean
(Always for George - Always for the Rimadyl Dogs)
http://hometown.aol.com/luswinton/myhom ... orial.html
edition -
http://charleston.net/ - the article is not available unless you are
"registered" with the newspaper.
Story last updated at 7:07 a.m. Monday, August 23, 2004
Concern cited about pet drugs
Settlement fails to bring closure after death of dog
BY PHILLIP CASTON
Of The Post and Courier Staff More than a year after settlement of a lawsuit
brought against pharmaceutical company Pfizer Inc. by Johns Island resident
Jean Townsend, she now has her money but not the closure she wants.Townsend
filed the 1999 lawsuit two years after her chocolate Labrador retriever George
suffered life-threatening side effects of the drug Rimadyl. The dog was
euthanized because of severe internal bleeding and liver failure about two weeks after
Townsend began giving him pills to treat arthritis. She said neither she nor
her veterinarian were made aware of all the drug's potential dangers."It is
devastating to live with the realization that I gave my beloved pet medicine to
help him when, in fact, it was killing him," the Clark Hills Circle resident
said Sunday.Some 300 other pet owners across the nation later joined Townsend's
lawsuit. As part of the settlement, Pfizer offered to pay about $1,000 to each
plaintiff whose pet suffered adverse side effects to Rimadyl. Townsend hopes
to see other similar suits filed in other states, she said. She'd also like to
see veterinarians conduct blood screening work on animals before prescribing
Rimadyl or similar drugs and fully inform pet owners of all possible side
effects. "If you know what to look for, then you can take action immediately,"
Townsend said.After her dog died, Townsend notified Pfizer, which offered a
$249.33 settlement under the condition that she keep the incident confidential, she
said. Townsend declined the offer.Researching the drug on the Internet,
Townsend found dozens of dog owners throughout the country who had similar
experiences with Rimadyl. She and several owners launched a campaign to educate dog
owners about the drug's side effects, she said. After meeting with Food and Drug
Administration representatives and Pfizer officials and being unsatisfied
with their efforts to inform dog owners of the dangers, Townsend filed suit. She
sought $734 for the cost of veterinary care for George.In 1999, because of the
number of complaints about the drug, the FDA issued a public statement
warning of the drug's effects. When the FDA gave Pfizer an ultimatum that the
company must mention death as a possible side effect in its TV commercials for
Rimadyl, the company dropped the TV ads completely.Shortly after the lawsuit and
the FDA's statement, Pfizer decided to change the packaging of the drug and
include a client information sheet for customers that lists side effects and what
to do if they occur.According to FDA records and estimates, since Pfizer
introduced Rimadyl in 1997, the FDA has received reports of about 1,000 dogs that
died or were euthanized and 7,000 more that had bad reactions after being given
the drug.Townsend donated her settlement to a local veterinarian for pet
owners who can't afford surgery."Of course, no amount of money would ever replace
the loss of my friend, George, and the loss of so many other beloved
companions," Townsend said. "We, as pet owners, have the right to know as much about
the good and bad sides of veterinary medicines as we do the medicines we give
ourselves."Staff writer Adam Ferrell contributed to this report. >>
Please, if you have the time, write the reporters to thank them for the
article. Their e-mail addresses are:
pcaston@postandcourier.com
aferrell@postandcourier.com
If you want to respond by writing a Letter to the Editor - the address is:
letters@postandcourier.com - please be sure to include your name, address and
a telephone number.
Thanks.
Jean
(Always for George - Always for the Rimadyl Dogs)
http://hometown.aol.com/luswinton/myhom ... orial.html
- guest
Is Rimadyl your best friend's friend? Or foe?
by guest » Mon Aug 23, 2004 1:43 pm
Is Rimadyl your best friend's friend? Or foe?
http://wcvb-tvpet.ip2m.com/index.cfm?pt ... cat_id=106
September 25, 2001 4:28 PM
--------------------------------------------------------------------------------
About half of the 52.9 million dogs in America might one day be candidates for Rimadyl. The acceptance of this nonsteroidal anti-inflammatory drug has been staggering; 4 million dogs have popped this pill since its January, 1997 introduction.
Rimadyl is used to relieve pain in the shorter term as a post surgical analgesic. It is used in the longer term for osteoarthritis (and associated joint problems), which afflict more than 8 million dogs.
Before Rimadyl hit the market, vets prescribed aspirin or steroids. Long-term usage of steroids created severe side effects, while "Aspirin is cheap but otherwise doesn’t cut it for dogs. Their systems can’t tolerate aspirin," says Dr. Jon Dee, a Board-certified veterinary surgeon in Hollywood, Fla.
Rimadyl, it seemed, was a better option. It promised to be far more tolerant to canine gastrointestinal systems than aspirin, and it produced fewer side effects than steroids.
With so many dogs so desperate for pain relief, it’s no wonder that word of Rimadyl’s benefits spread quickly on the Internet. At dog parks across the country, everyone was talking about a great new hope called Rimadyl.
However, it turns out that Rimadyl can produce serious side-effects -- and it can even lead to a dog’s death.
The Rimadyl drama has been played out on the Internet and in the media. Inaccurate reporting has left pet owners confused.
The Rimadyl buzz
The marketing campaign for Rimadyl hadn’t even begun. Internet buzz alone prompted an immediate onslaught the very day Rimadyl hit the market in January 1997.
That day may have been the busiest morning ever at Blum Animal Hospital in Chicago. The phone rang off the hook. People were clamoring for the drug.
"In my 32 years of practice, I’ve never seen anything like it," says Blum Chief of Staff Dr. Sheldon Rubin. "We didn’t even have the drug (at the clinic) yet. We took names on a waiting list like we were offering tickets to a rock concert or Cubs game."
Within months after the drug’s release, Peter and Cindy Schramm happened to have an appointment with Dr. Rubin. Bernie, their 8-year-old Pembroke Welsh Corgi, had osteoarthritis so bad he could no longer climb stairs.
"Bernie’s personality changed; he didn’t even want to be petted; he was in constant pain," said Cindy. "We were desperate. Poor Bernie was only just past middle age."
Around the same time in John’s Island, S.C., Jean Townsend (the owner of 10 dogs) didn’t know what to do for George, her Chocolate Labrador, whose osteoarthritis was also worsening. George was probably about 11 or 12 years old, although Townsend wasn’t sure since he’d been a stray.
For the owners of both George and Bernie, the answer seemed to be Rimadyl.
Within days, Bernie was his old self, bounding up and down stairs -- at least as much as any Corgi can bound. Once again he loved to be petted.
Meanwhile, Bernie’s owners say the drug brought him back to life.
The results for George were less dramatic, but Townsend noticed at least some improvement. She continued giving George Rimadyl for about a month. Then, one morning, George suddenly got very sick. He could barely move and couldn’t keep food down.
The dog’s condition worsened, and within days he was being cared for by vets around the clock. He was no longer able to stand and could barely keep his head up. "I looked into his eyes and George told me ‘enough.’ We ended his suffering on October 13, 1997," Townsend says.
A necropsy (an autopsy for animals) revealed acute internal hemorrhaging. Veterinarians agreed that Rimadyl contributed significantly to George’s death. In fact, Townsend was so convinced that she leveled a class action lawsuit again Pfizer Animal Health, the Exton, Pa. manufacturer of Rimadyl.
Pets vs. Pfizer
Townsend isn’t alone. The FDA Center for Veterinary Medicine (CVM) reports 4,596 complaints filed by users of Rimadyl. Meanwhile, Rimadyl has been an alleged contributing factor in 651 suspected canine deaths. This is a record number of complaints about a drug for pets. In fact, of all the complaints filed in 1998, 43 percent targeted Rimadyl.
The CVM does agree that Rimadyl has enjoyed one of the most successful introductions of any drug in the history of veterinary medicine. Since veterinarians are generally tentative about jumping on the new drug bandwagon, that’s a significant endorsement
Rimadyl was first expected to be marketed for use in people. In 1988, it won FDA approval, but developer Roche Laboratories decided the market for such drugs was overcrowded and they dropped it. Knowing that a desperate public clamored for an effective and safe drug for pain relief for dogs, Pfizer saw a niche. After all, pet drugs are a big business – more than $3 billion is spent annually on drugs for companion animals.
Pfizer wasn’t about to depend on word of mouth to promote its new product. The company spent millions on marketing.
The Rimadyl marketing blitz
Part of Pfizer’s marketing plan included a rash of (now-cancelled) television ads that featured elderly dogs, once hobbled by osteoarthritis, running and jumping pain free.
"Watching those TV ads made Rimadyl seem like the fountain of youth," says Robert Sinclair, of West Bloomfield, Mich.
In print ads, the headline read, "Give your dog relief from arthritis pain, and give your children back their favorite companion."
Officials at Pfizer won’t say exactly how much money they’ve spent on marketing Rimadyl but it certainly sets a record for dollars spent to launch a drug for dogs. Most importantly, the campaign reached consumers in record numbers.
Of course, some pet owners swear the ads were factual. "Those ads were absolutely true," says Louise Clements of Meridian, Idaho. Brass, her 14-year-old Pembroke Welsh Corgi, couldn’t walk down two steps to do relieve herself outdoors due to osteoarthritis. Within 48 hours of taking Rimadyl, Brass was acting like pretty much like a puppy again. "It was our own little miracle," Clements says.
On the other hand, Misty, Robert Sinclair’s 17-year-old toy poodle, was put on Rimadyl in October of 1997. Misty’s arthritis improved but by her third week on the drug she was having other serious medical problems. At first, Sinclair and his wife, Jayne, thought their dog might be experiencing congestive heart failure. "The vets never said anything about side effects," Jayne says.
As poor Misty languished, the Sinclairs went online frantically trying to figure out what was going wrong. They became convinced that Rimadyl was playing a role in their dog’s decline. By now, the Center for Veterinary Medicine’s Web site listed potential adverse reactions to Rimadyl. The side effects matched the symptoms Misty was having. But the Sinclairs’ efforts came too late. Misty went downhill, suffering far more than the pain she was given Rimadyl to relieve. Finally, the little pooch was put out of her misery.
The Sinclairs are certain Rimadyl caused their dog’s demise. "Old age is not a disease," Bob says. "I was horrified."
"Many of the dogs on Rimadyl are old, and may have had pre-existing liver or renal disease or weren’t carefully prescreened," says Board-certified orthopedic veterinarian Dr. Steve Budsberg, professor of surgery at the University of Georgia College of Veterinary Medicine, Athens. "Being older, they may have underlying problems (that are) not easily detected, even with appropriate and thorough testing. Also, it may be difficult to predict idiosyncratic (individually unique) medical problems that seem to potentially occur with Rimadyl," Budsberg said.
According to Pfizer, fewer than one percent of all Rimadyl users have reported Rimadyl-induced side-effects. In 1998, it was suspected that Rimadyl was a factor in far less than one percent of dog deaths.
"That’s pretty darn good," says Dr. Eli Ehrenpreis, assistant professor of clinical medicine at the University of Chicago. Far more humans die each year from drugs like aspirin that are designed to combat osteoporosis and inflammation.
"Rimadyl is in a serious class of potent drugs and should carefully be considered," according to Dr. Edward Kanara of Pfizer.
Almost immediately after Rimadyl’s release, the CVM began to document the drug’s side effects. Just five months after the drug’s release, officials requested that Pfizer change the Rimadyl package insert to list adverse drug reactions. Pfizer complied. The company also sent a letter to vets that outlined the latest information available. Pfizer also made several additional changes to the Rimadyl package insert.
By April of 1999, Rimadyl was believed to cause 49 adverse side effects, from mild gastrointestinal upset (diarrhea and/or vomiting) to changes in behavior to serious liver or renal dysfunction. Pfizer’s package insert was also changed to read, "In rare situations, death has been associated with some of the adverse reactions."
Dr. Bill Keller of the CVM says Pfizer has been "due diligent, very responsible about making appropriate label changes."
However, not everyone sees it that way. Robert Sinclair says, "A dog is no more a statistic than a child. Pfizer spent millions on their TV ads, but they sure didn’t spend millions informing us of the possible dangers (of Rimadyl)."
The FDA also asked Pfizer to include death as a possible side effect in the TV campaign. Pfizer didn’t want their heartening 30-second TV ads with a bounding, tail-wagging dog to culminate with that warning, so they cancelled the ads.
Pfizer has made offers to reimburse veterinary costs related to treatments for at least some pet owners. However, many say Pfizer will only reimburse vet bills if various conditions -- such as releasing Pfizer from all blame -- are met. Kanara says there may have been some miscommunication early on but denies Pfizer is now demanding any "conditions."
But reimbursement can only go so far. Nancy Friedman, a retired Chicago nurse, says she spent $2,500 on Bravo, her 8-year-old Rottweiler, that subsequently "crashed" as an adverse response to Rimadyl. "My initial reaction is that no amount of money can replace Bravo -- period," says Friedman. "This should never have happened. I was duped by their ad campaign."
B.A.R.K.S. is better than Rimadyl’s bite
Robert Sinclair is one of the more outspoken voices in a loose-knit group called B.A.R.K.S. (Be Aware of Rimadyl’s Known Side Effects). Sinclair says some vets are motivated to push Rimadyl because its manufacturer, Pfizer Animal Health, offers incentives for selling big volume. "To push this dangerous drug is a game of Rimadyl roulette," he says.
Veterinarians and Pfizer have confirmed these incentives do exist. Rewards for points earned on sales include Palm Pilots, Zip drives for computers, veterinary books and tuition for continuing education.
Dr. Sheldon Rubin doubts Sinclair’s theory. Rubin has been a private veterinary practitioner in Chicago for 32 years. He says other pharmaceutical companies (in addition to Pfizer) offer similar programs tied to sales. He adds, "I can’t imagine a veterinary professional making a decision about a drug based on receiving a book or a Palm Pilot," he says.
Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, points out that human doctors are also offered incentives. "As far as I know, Pfizer has done nothing that hints at being unethical," he says.
Not the first time
But Rimadyl this isn’t the first drug for pets that has entered the market followed by a near immediate wave of side effects or adverse reactions.
A drug called Heartgard was introduced in 1988. It was designed to fight mosquito-transmitted heartworm disease. Heartgard and a similar drug, Interceptor, both contained an active ingredient called ivermectin that created several serious adverse reactions. Most dramatically, it killed collies.
Keller of the CVM explains that clinical trials for animal drugs are done differently than tests for human drugs. Fewer dogs are required as test subjects than the number of people needed to test human drugs. Approximately 500 dogs were involved in the Rimadyl trials.
"The reality is cost," says Keller. "If clinical trials for animals had the same requirements as trials for people, we wouldn’t have drugs for pets coming to market." The biggest difference between the response over adverse reactions to Heartgard in 1988 and the Rimadyl situation is the Internet. Complaints can now be filed directly to the CVM with a click of a mouse, instead of weaving through government bureaucratic paperwork. Also, owners of dogs that have had problems, such as members of B.A.R.K.S., correspond via e-mail. Many listservs link dog owners whose pets have experienced problems with Rimadyl, and local breed clubs host pet chats that discuss the issue on a nightly basis. Some of these discussions involve nothing but gossip and scare tactics, but much of what’s available is legitimate. B.A.R.K.S. even produced a 10-minute video produced called "Rimadyl Update." The video is now available for $4. (Send to Cheryl Walton, c/o B.A.R.K.S., Advance Multimedia, 26600 Telegraph Rd., Suite 181, Southfield, MI 48034).
The Rimadyl fervor has launched a media onslaught. Although Rimadyl was the first nonsteroidal anti-inflammatory drug of its kind, the backlash has spread to other potentially dangerous pet medications. EtoGesic, a similar drug, was released about year later with less fanfare. Sure enough, about a year after reports of adverse reactions began to pile up for Rimadyl, complaints began to trickle in for EtoGesic.
Still, some pet owners and veterinarians swear by Rimadyl. Dr. Jon Dee, the surgeon from Hollywood, Fla., has prescribed more Rimadyl than almost any other vet in the United States. He used Rimadyl two years before it received FDA approval. As far as Dee knows, none of his canine clients has suffered a reaction more serious than gastrointestinal upset. In fact, Dee used Rimadyl for two years on his own Yellow Labrador, who suffered from degenerative joint disease.
Sheree Parks, of San Diego, is a Rimadyl believer. Nolan, her family’s 12-year-old Golden Retriever, began taking the pill in March of 1999 and hasn’t missed one since. "His pain was enormous; he could barely move," adds Parks. "Friends were telling us to euthanize Nolan. We tried Cosequin (Glucosamine/Chondroitin Sulfate, a nutritional supplement). It worked for a while but ultimately provided no relief. Even acupuncture was no longer helping. It’s not only the extra time we have with Nolan that matters, it’s that Nolan is now enjoying quality life without pain. "If it wasn’t for Rimadyl, Nolan would now be dead," Parks says.
"Rimadyl is a tool, the best one now available to ease pain of osteoarthritis," says Dee. "Like any tool, it can be used wisely or unwisely."
The business of pet health care
Americans have more than 115 million pets and spend in excess of $3 billion a year on drugs for their care. With pet spending increasing at a rate of 20 percent annually, this makes animal health one of the fastest growing segments of the entire pharmaceutical industry.
Even the typically standoffish Food and Drug Administration boasts about its association with the burgeoning pet market. The FDA proudly hurried to write its own press releases to tout two products it approved in 1999: Clomicalm, a drug for dogs that suffer separation anxiety, and Anipryl, which eases the effects of Canine Cognitive Syndrome, a disease much like Alzheimer’s.
Still, the majority of pet drugs used by vets haven’t specifically been tested for treating pets (but have been FDA tested and approved on people).
Off-label prescriptions have been a longstanding veterinary practice. Examples range from stalwarts such as Prednisolone -- a corticosteroid used for a variety of ailments from allergies to autoimmune disease -- to fairly recent products, such as Prozac, used for several purposes including aggression in dogs.
But because pet owners are uniformed about drugs and their side effects, many pets suffer.
Whom do you blame? Are vets at fault for not communicating with clients? Are pharmaceutical companies at fault for not informing consumers of all known information about drugs for pets? Or can pet owners be at fault?
"It’s not a matter of fault, it’s also human nature. Now that pets have become members of our families, we’re desperate to get them well," explains Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, and a vet in private practice for 41 years.
"It’s human nature to minimize any risks in your own mind-- you don’t hear what the veterinarian is really telling you. I have a spouse who’s been through cancer (treatments). I’ve been there; I understand how this can happen," he says.
But not all vets tell clients about potential adverse reactions; they’re either rushed or they just don’t know the potential side effects. When Bravo, a Rottweiller, became ill after taking Rimadyl in February 1999, Nancy Friedman of Chicago never thought about an adverse drug reaction. She figured Bravo, a Rottweiler Champion show dog, just picked up a bug at a dog show.
However, her health-care professional should have thought about the possibility of an adverse drug reaction before placing Bravo on Rimadyl a second time several months later. Bravo became ill quickly and soon died. The CVM later concurred Rimadyl was likely to have precipitated her dog’s death, Friedman says.
"Pfizer has been walking a pharmaceutical tightrope," says Ross Becker, publisher of Good Dog! magazine, a sort of Consumer Reports for canines. He’s been following this story from the beginning. "What bothers pet owners most is that they weren’t warned about side effects. It’s clear, there are too many holes in the current system -- there’s got to be a better way to inform consumers about the drugs their pets are taking."
But Pfizer is taking the necessary steps to warn pet owners. This February, it released a page of information about Rimadyl that is included in prepackaged seven- and 30-day supplies of the drug.
Seda says this information about potential adverse reactions, interactions with other drugs, and dosage and administration, is easier to understand than the complicated medical jargon consumers receive for their own drugs.
Pfizer plans to create similar user-friendly disclosures for its other animal drugs. "We answer tough questions that consumers should ask about any drug prescribed for their pet," says Dr. Edward Kanara, director of technical services for Pfizer.
However, apparently, not all pharmaceutical companies are as willing. For example, Novartis, a major player in animal health, refused to comment on the issue.
But voluntary disclosures aren’t enough to please some pet owners. Jean Townsend of John’s Island, S.C., leveled a class-action lawsuit against Pfizer, after her dog died allegedly as a result of using Rimadyl.
Together, Townsend and Sinclair attended a CVM meeting in April, and called for the FDA to create federal legislation. Such regulations would mandate that pharmaceutical companies and the veterinary industry provide consumers with all known information about drugs prescribed for their pets.
Although Seda of the American Veterinary Medical Association says he wants to find ways to better inform pet owners, he doesn’t want a government agency to oversee the veterinary industry. And he’s not alone. That government agency doesn’t want to do it either. Dr. Bill Keller of the CVM says there are "resource limitations," meaning budget restraints.
On drugs that the FDA has recently approved for animals, pharmaceutical manufacturers include at least most of the information we read on labels for human drugs. The problem is that many pet drugs are dispensed by vets in little plastic bottles without any information. Meanwhile, vets continue to prescribe vast array of medications off label. Vets also continue to prescribe longtime animal drugs where current facts about side effects and contraindications are not documented.
"Vets have a responsibility to provide whatever information is known about a drug, everything from whether it should be refrigerated to whether there are any potential serious side effects," Sinclair says.
"At the very least you’d think the FDA could mandate that vets and pharmaceutical companies find a way to provide easy-to-understand owner information for all drugs approved over the past five years, or the past 10 years," Sinclair says. "Drug companies could follow Pfizer’s lead with all prepackaged products. Computer programs are now available -- and with demand others will no doubt step up to the plate -- so vets can print out information whenever they dispense in those little plastic vials."
"Currently, the FDA takes nearly a year to provide summaries and information to the public about adverse drug reactions," he adds.
Becker, at Good Dog! magazine, agrees. "The FDA managed to find a way to fully inform people about their drugs, you bet they ought to do the same for companion animals. Pets can’t read or ask questions, it’s our responsibility.
"I believe we all learned several lessons from the Rimadyl story. All drugs have potential side effects, and people need to ask questions about medications. If your vet doesn’t take the time to answer, consider another vet. If your vet doesn’t know the answer, wait for one. Potentially saving your pet’s life is worth it," Becker concludes.
By Steve Dale, Tribune Media Services syndicated columnist
© 2000 Tribune Media Services WebPoint®
http://wcvb-tvpet.ip2m.com/index.cfm?pt ... cat_id=106
September 25, 2001 4:28 PM
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About half of the 52.9 million dogs in America might one day be candidates for Rimadyl. The acceptance of this nonsteroidal anti-inflammatory drug has been staggering; 4 million dogs have popped this pill since its January, 1997 introduction.
Rimadyl is used to relieve pain in the shorter term as a post surgical analgesic. It is used in the longer term for osteoarthritis (and associated joint problems), which afflict more than 8 million dogs.
Before Rimadyl hit the market, vets prescribed aspirin or steroids. Long-term usage of steroids created severe side effects, while "Aspirin is cheap but otherwise doesn’t cut it for dogs. Their systems can’t tolerate aspirin," says Dr. Jon Dee, a Board-certified veterinary surgeon in Hollywood, Fla.
Rimadyl, it seemed, was a better option. It promised to be far more tolerant to canine gastrointestinal systems than aspirin, and it produced fewer side effects than steroids.
With so many dogs so desperate for pain relief, it’s no wonder that word of Rimadyl’s benefits spread quickly on the Internet. At dog parks across the country, everyone was talking about a great new hope called Rimadyl.
However, it turns out that Rimadyl can produce serious side-effects -- and it can even lead to a dog’s death.
The Rimadyl drama has been played out on the Internet and in the media. Inaccurate reporting has left pet owners confused.
The Rimadyl buzz
The marketing campaign for Rimadyl hadn’t even begun. Internet buzz alone prompted an immediate onslaught the very day Rimadyl hit the market in January 1997.
That day may have been the busiest morning ever at Blum Animal Hospital in Chicago. The phone rang off the hook. People were clamoring for the drug.
"In my 32 years of practice, I’ve never seen anything like it," says Blum Chief of Staff Dr. Sheldon Rubin. "We didn’t even have the drug (at the clinic) yet. We took names on a waiting list like we were offering tickets to a rock concert or Cubs game."
Within months after the drug’s release, Peter and Cindy Schramm happened to have an appointment with Dr. Rubin. Bernie, their 8-year-old Pembroke Welsh Corgi, had osteoarthritis so bad he could no longer climb stairs.
"Bernie’s personality changed; he didn’t even want to be petted; he was in constant pain," said Cindy. "We were desperate. Poor Bernie was only just past middle age."
Around the same time in John’s Island, S.C., Jean Townsend (the owner of 10 dogs) didn’t know what to do for George, her Chocolate Labrador, whose osteoarthritis was also worsening. George was probably about 11 or 12 years old, although Townsend wasn’t sure since he’d been a stray.
For the owners of both George and Bernie, the answer seemed to be Rimadyl.
Within days, Bernie was his old self, bounding up and down stairs -- at least as much as any Corgi can bound. Once again he loved to be petted.
Meanwhile, Bernie’s owners say the drug brought him back to life.
The results for George were less dramatic, but Townsend noticed at least some improvement. She continued giving George Rimadyl for about a month. Then, one morning, George suddenly got very sick. He could barely move and couldn’t keep food down.
The dog’s condition worsened, and within days he was being cared for by vets around the clock. He was no longer able to stand and could barely keep his head up. "I looked into his eyes and George told me ‘enough.’ We ended his suffering on October 13, 1997," Townsend says.
A necropsy (an autopsy for animals) revealed acute internal hemorrhaging. Veterinarians agreed that Rimadyl contributed significantly to George’s death. In fact, Townsend was so convinced that she leveled a class action lawsuit again Pfizer Animal Health, the Exton, Pa. manufacturer of Rimadyl.
Pets vs. Pfizer
Townsend isn’t alone. The FDA Center for Veterinary Medicine (CVM) reports 4,596 complaints filed by users of Rimadyl. Meanwhile, Rimadyl has been an alleged contributing factor in 651 suspected canine deaths. This is a record number of complaints about a drug for pets. In fact, of all the complaints filed in 1998, 43 percent targeted Rimadyl.
The CVM does agree that Rimadyl has enjoyed one of the most successful introductions of any drug in the history of veterinary medicine. Since veterinarians are generally tentative about jumping on the new drug bandwagon, that’s a significant endorsement
Rimadyl was first expected to be marketed for use in people. In 1988, it won FDA approval, but developer Roche Laboratories decided the market for such drugs was overcrowded and they dropped it. Knowing that a desperate public clamored for an effective and safe drug for pain relief for dogs, Pfizer saw a niche. After all, pet drugs are a big business – more than $3 billion is spent annually on drugs for companion animals.
Pfizer wasn’t about to depend on word of mouth to promote its new product. The company spent millions on marketing.
The Rimadyl marketing blitz
Part of Pfizer’s marketing plan included a rash of (now-cancelled) television ads that featured elderly dogs, once hobbled by osteoarthritis, running and jumping pain free.
"Watching those TV ads made Rimadyl seem like the fountain of youth," says Robert Sinclair, of West Bloomfield, Mich.
In print ads, the headline read, "Give your dog relief from arthritis pain, and give your children back their favorite companion."
Officials at Pfizer won’t say exactly how much money they’ve spent on marketing Rimadyl but it certainly sets a record for dollars spent to launch a drug for dogs. Most importantly, the campaign reached consumers in record numbers.
Of course, some pet owners swear the ads were factual. "Those ads were absolutely true," says Louise Clements of Meridian, Idaho. Brass, her 14-year-old Pembroke Welsh Corgi, couldn’t walk down two steps to do relieve herself outdoors due to osteoarthritis. Within 48 hours of taking Rimadyl, Brass was acting like pretty much like a puppy again. "It was our own little miracle," Clements says.
On the other hand, Misty, Robert Sinclair’s 17-year-old toy poodle, was put on Rimadyl in October of 1997. Misty’s arthritis improved but by her third week on the drug she was having other serious medical problems. At first, Sinclair and his wife, Jayne, thought their dog might be experiencing congestive heart failure. "The vets never said anything about side effects," Jayne says.
As poor Misty languished, the Sinclairs went online frantically trying to figure out what was going wrong. They became convinced that Rimadyl was playing a role in their dog’s decline. By now, the Center for Veterinary Medicine’s Web site listed potential adverse reactions to Rimadyl. The side effects matched the symptoms Misty was having. But the Sinclairs’ efforts came too late. Misty went downhill, suffering far more than the pain she was given Rimadyl to relieve. Finally, the little pooch was put out of her misery.
The Sinclairs are certain Rimadyl caused their dog’s demise. "Old age is not a disease," Bob says. "I was horrified."
"Many of the dogs on Rimadyl are old, and may have had pre-existing liver or renal disease or weren’t carefully prescreened," says Board-certified orthopedic veterinarian Dr. Steve Budsberg, professor of surgery at the University of Georgia College of Veterinary Medicine, Athens. "Being older, they may have underlying problems (that are) not easily detected, even with appropriate and thorough testing. Also, it may be difficult to predict idiosyncratic (individually unique) medical problems that seem to potentially occur with Rimadyl," Budsberg said.
According to Pfizer, fewer than one percent of all Rimadyl users have reported Rimadyl-induced side-effects. In 1998, it was suspected that Rimadyl was a factor in far less than one percent of dog deaths.
"That’s pretty darn good," says Dr. Eli Ehrenpreis, assistant professor of clinical medicine at the University of Chicago. Far more humans die each year from drugs like aspirin that are designed to combat osteoporosis and inflammation.
"Rimadyl is in a serious class of potent drugs and should carefully be considered," according to Dr. Edward Kanara of Pfizer.
Almost immediately after Rimadyl’s release, the CVM began to document the drug’s side effects. Just five months after the drug’s release, officials requested that Pfizer change the Rimadyl package insert to list adverse drug reactions. Pfizer complied. The company also sent a letter to vets that outlined the latest information available. Pfizer also made several additional changes to the Rimadyl package insert.
By April of 1999, Rimadyl was believed to cause 49 adverse side effects, from mild gastrointestinal upset (diarrhea and/or vomiting) to changes in behavior to serious liver or renal dysfunction. Pfizer’s package insert was also changed to read, "In rare situations, death has been associated with some of the adverse reactions."
Dr. Bill Keller of the CVM says Pfizer has been "due diligent, very responsible about making appropriate label changes."
However, not everyone sees it that way. Robert Sinclair says, "A dog is no more a statistic than a child. Pfizer spent millions on their TV ads, but they sure didn’t spend millions informing us of the possible dangers (of Rimadyl)."
The FDA also asked Pfizer to include death as a possible side effect in the TV campaign. Pfizer didn’t want their heartening 30-second TV ads with a bounding, tail-wagging dog to culminate with that warning, so they cancelled the ads.
Pfizer has made offers to reimburse veterinary costs related to treatments for at least some pet owners. However, many say Pfizer will only reimburse vet bills if various conditions -- such as releasing Pfizer from all blame -- are met. Kanara says there may have been some miscommunication early on but denies Pfizer is now demanding any "conditions."
But reimbursement can only go so far. Nancy Friedman, a retired Chicago nurse, says she spent $2,500 on Bravo, her 8-year-old Rottweiler, that subsequently "crashed" as an adverse response to Rimadyl. "My initial reaction is that no amount of money can replace Bravo -- period," says Friedman. "This should never have happened. I was duped by their ad campaign."
B.A.R.K.S. is better than Rimadyl’s bite
Robert Sinclair is one of the more outspoken voices in a loose-knit group called B.A.R.K.S. (Be Aware of Rimadyl’s Known Side Effects). Sinclair says some vets are motivated to push Rimadyl because its manufacturer, Pfizer Animal Health, offers incentives for selling big volume. "To push this dangerous drug is a game of Rimadyl roulette," he says.
Veterinarians and Pfizer have confirmed these incentives do exist. Rewards for points earned on sales include Palm Pilots, Zip drives for computers, veterinary books and tuition for continuing education.
Dr. Sheldon Rubin doubts Sinclair’s theory. Rubin has been a private veterinary practitioner in Chicago for 32 years. He says other pharmaceutical companies (in addition to Pfizer) offer similar programs tied to sales. He adds, "I can’t imagine a veterinary professional making a decision about a drug based on receiving a book or a Palm Pilot," he says.
Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, points out that human doctors are also offered incentives. "As far as I know, Pfizer has done nothing that hints at being unethical," he says.
Not the first time
But Rimadyl this isn’t the first drug for pets that has entered the market followed by a near immediate wave of side effects or adverse reactions.
A drug called Heartgard was introduced in 1988. It was designed to fight mosquito-transmitted heartworm disease. Heartgard and a similar drug, Interceptor, both contained an active ingredient called ivermectin that created several serious adverse reactions. Most dramatically, it killed collies.
Keller of the CVM explains that clinical trials for animal drugs are done differently than tests for human drugs. Fewer dogs are required as test subjects than the number of people needed to test human drugs. Approximately 500 dogs were involved in the Rimadyl trials.
"The reality is cost," says Keller. "If clinical trials for animals had the same requirements as trials for people, we wouldn’t have drugs for pets coming to market." The biggest difference between the response over adverse reactions to Heartgard in 1988 and the Rimadyl situation is the Internet. Complaints can now be filed directly to the CVM with a click of a mouse, instead of weaving through government bureaucratic paperwork. Also, owners of dogs that have had problems, such as members of B.A.R.K.S., correspond via e-mail. Many listservs link dog owners whose pets have experienced problems with Rimadyl, and local breed clubs host pet chats that discuss the issue on a nightly basis. Some of these discussions involve nothing but gossip and scare tactics, but much of what’s available is legitimate. B.A.R.K.S. even produced a 10-minute video produced called "Rimadyl Update." The video is now available for $4. (Send to Cheryl Walton, c/o B.A.R.K.S., Advance Multimedia, 26600 Telegraph Rd., Suite 181, Southfield, MI 48034).
The Rimadyl fervor has launched a media onslaught. Although Rimadyl was the first nonsteroidal anti-inflammatory drug of its kind, the backlash has spread to other potentially dangerous pet medications. EtoGesic, a similar drug, was released about year later with less fanfare. Sure enough, about a year after reports of adverse reactions began to pile up for Rimadyl, complaints began to trickle in for EtoGesic.
Still, some pet owners and veterinarians swear by Rimadyl. Dr. Jon Dee, the surgeon from Hollywood, Fla., has prescribed more Rimadyl than almost any other vet in the United States. He used Rimadyl two years before it received FDA approval. As far as Dee knows, none of his canine clients has suffered a reaction more serious than gastrointestinal upset. In fact, Dee used Rimadyl for two years on his own Yellow Labrador, who suffered from degenerative joint disease.
Sheree Parks, of San Diego, is a Rimadyl believer. Nolan, her family’s 12-year-old Golden Retriever, began taking the pill in March of 1999 and hasn’t missed one since. "His pain was enormous; he could barely move," adds Parks. "Friends were telling us to euthanize Nolan. We tried Cosequin (Glucosamine/Chondroitin Sulfate, a nutritional supplement). It worked for a while but ultimately provided no relief. Even acupuncture was no longer helping. It’s not only the extra time we have with Nolan that matters, it’s that Nolan is now enjoying quality life without pain. "If it wasn’t for Rimadyl, Nolan would now be dead," Parks says.
"Rimadyl is a tool, the best one now available to ease pain of osteoarthritis," says Dee. "Like any tool, it can be used wisely or unwisely."
The business of pet health care
Americans have more than 115 million pets and spend in excess of $3 billion a year on drugs for their care. With pet spending increasing at a rate of 20 percent annually, this makes animal health one of the fastest growing segments of the entire pharmaceutical industry.
Even the typically standoffish Food and Drug Administration boasts about its association with the burgeoning pet market. The FDA proudly hurried to write its own press releases to tout two products it approved in 1999: Clomicalm, a drug for dogs that suffer separation anxiety, and Anipryl, which eases the effects of Canine Cognitive Syndrome, a disease much like Alzheimer’s.
Still, the majority of pet drugs used by vets haven’t specifically been tested for treating pets (but have been FDA tested and approved on people).
Off-label prescriptions have been a longstanding veterinary practice. Examples range from stalwarts such as Prednisolone -- a corticosteroid used for a variety of ailments from allergies to autoimmune disease -- to fairly recent products, such as Prozac, used for several purposes including aggression in dogs.
But because pet owners are uniformed about drugs and their side effects, many pets suffer.
Whom do you blame? Are vets at fault for not communicating with clients? Are pharmaceutical companies at fault for not informing consumers of all known information about drugs for pets? Or can pet owners be at fault?
"It’s not a matter of fault, it’s also human nature. Now that pets have become members of our families, we’re desperate to get them well," explains Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, and a vet in private practice for 41 years.
"It’s human nature to minimize any risks in your own mind-- you don’t hear what the veterinarian is really telling you. I have a spouse who’s been through cancer (treatments). I’ve been there; I understand how this can happen," he says.
But not all vets tell clients about potential adverse reactions; they’re either rushed or they just don’t know the potential side effects. When Bravo, a Rottweiller, became ill after taking Rimadyl in February 1999, Nancy Friedman of Chicago never thought about an adverse drug reaction. She figured Bravo, a Rottweiler Champion show dog, just picked up a bug at a dog show.
However, her health-care professional should have thought about the possibility of an adverse drug reaction before placing Bravo on Rimadyl a second time several months later. Bravo became ill quickly and soon died. The CVM later concurred Rimadyl was likely to have precipitated her dog’s death, Friedman says.
"Pfizer has been walking a pharmaceutical tightrope," says Ross Becker, publisher of Good Dog! magazine, a sort of Consumer Reports for canines. He’s been following this story from the beginning. "What bothers pet owners most is that they weren’t warned about side effects. It’s clear, there are too many holes in the current system -- there’s got to be a better way to inform consumers about the drugs their pets are taking."
But Pfizer is taking the necessary steps to warn pet owners. This February, it released a page of information about Rimadyl that is included in prepackaged seven- and 30-day supplies of the drug.
Seda says this information about potential adverse reactions, interactions with other drugs, and dosage and administration, is easier to understand than the complicated medical jargon consumers receive for their own drugs.
Pfizer plans to create similar user-friendly disclosures for its other animal drugs. "We answer tough questions that consumers should ask about any drug prescribed for their pet," says Dr. Edward Kanara, director of technical services for Pfizer.
However, apparently, not all pharmaceutical companies are as willing. For example, Novartis, a major player in animal health, refused to comment on the issue.
But voluntary disclosures aren’t enough to please some pet owners. Jean Townsend of John’s Island, S.C., leveled a class-action lawsuit against Pfizer, after her dog died allegedly as a result of using Rimadyl.
Together, Townsend and Sinclair attended a CVM meeting in April, and called for the FDA to create federal legislation. Such regulations would mandate that pharmaceutical companies and the veterinary industry provide consumers with all known information about drugs prescribed for their pets.
Although Seda of the American Veterinary Medical Association says he wants to find ways to better inform pet owners, he doesn’t want a government agency to oversee the veterinary industry. And he’s not alone. That government agency doesn’t want to do it either. Dr. Bill Keller of the CVM says there are "resource limitations," meaning budget restraints.
On drugs that the FDA has recently approved for animals, pharmaceutical manufacturers include at least most of the information we read on labels for human drugs. The problem is that many pet drugs are dispensed by vets in little plastic bottles without any information. Meanwhile, vets continue to prescribe vast array of medications off label. Vets also continue to prescribe longtime animal drugs where current facts about side effects and contraindications are not documented.
"Vets have a responsibility to provide whatever information is known about a drug, everything from whether it should be refrigerated to whether there are any potential serious side effects," Sinclair says.
"At the very least you’d think the FDA could mandate that vets and pharmaceutical companies find a way to provide easy-to-understand owner information for all drugs approved over the past five years, or the past 10 years," Sinclair says. "Drug companies could follow Pfizer’s lead with all prepackaged products. Computer programs are now available -- and with demand others will no doubt step up to the plate -- so vets can print out information whenever they dispense in those little plastic vials."
"Currently, the FDA takes nearly a year to provide summaries and information to the public about adverse drug reactions," he adds.
Becker, at Good Dog! magazine, agrees. "The FDA managed to find a way to fully inform people about their drugs, you bet they ought to do the same for companion animals. Pets can’t read or ask questions, it’s our responsibility.
"I believe we all learned several lessons from the Rimadyl story. All drugs have potential side effects, and people need to ask questions about medications. If your vet doesn’t take the time to answer, consider another vet. If your vet doesn’t know the answer, wait for one. Potentially saving your pet’s life is worth it," Becker concludes.
By Steve Dale, Tribune Media Services syndicated columnist
© 2000 Tribune Media Services WebPoint®
- guest
FDA and Pfizer Strive for Right Response to Rimadyl
by malernee » Tue Aug 24, 2004 1:22 am
Drug Bites Man: Most Arthritic Dogs Do Great on This Pill, Except Those That Die
A Surprised FDA and Pfizer Strive for Right Response for Remedy Gone Awry
What to Say in the TV Ads
By Chris Adams, Staff Reporter of The Wall Street Journal
The Wall Street Journal, 3/13/00
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You might call it a made-for-TV drug. Approved for human use in the U.S. but not marketed that way, an arthritis medicine called Rimadyl languished for nearly 10 years in developmental limbo, then emerged in a surprising new form: Instead of a human drug, it was now a drug for arthritic dogs. And it became a hit.
With the aid of slick commercials featuring once-lame dogs bounding happily about, Rimadyl changed the way veterinarians treated dogs. "Clients would walk in and say, `What about this Rimadyl?'" says George Siemering, who practices in Springfield, Va.
Today, those TV spots are gone. The reason has to do with dogs like Montana.
A six-year-old Siberian husky with stiff back legs, Montana hobbled out of a vet's office in Brooklyn, N.Y., six months ago accompanied by his human, Angela Giglio, and a supply of Rimadyl pills. At first, the drug appeared to work. But then Montana lost his appetite. He went limp, wobbling instead of walking. Finally he didn't walk at all. He ate leaves, vomited, had seizures and, eventually, was put to sleep. An autopsy showed the sort of liver damage associated with a bad drug reaction.
Pet drugs are big business -- an estimated $3 billion world-wide -- and Rimadyl is one of the bestsellers. It has been given to more than four million dogs in the U.S. and more abroad, brought Pfizer Inc. tens of millions of dollars in sales, and pleased many veterinarians and dog owners. But the drug has also stirred a controversy, with other pet owners complaining that nobody warned them of its risks.
Montana's owner, Ms. Giglio, is among them. After she informed Pfizer and the Food and Drug Administration of her relatively youthful dog's death, Pfizer offered her $440 "as a gesture of good will" and to cover part of the medical costs. Insulted by the offer and a stipulation that she agree to tell no one about the payment except her tax preparer, she refused to sign and didn't take the money. "There's just no way in my conscience or heart I can release them from blame," she says.
After reports of bad reactions and deaths started streaming in to the FDA, the agency suggested that Pfizer mention "death" as a possible side effect in a warning letter to vets, on labels and in TV ads. Pfizer eventually did use the word with vets and on labels, but when given an ultimatum about the commercials -- mention "death" in the audio or end the ads -- Pfizer chose to drop them.
Pfizer's director of animal-products technical services, Edward W. Kanara, says that when reports started coming in, "we acted extremely promptly based on the information we had." Pfizer points out that reported adverse events involve less than 1% of treated dogs.
Since Rimadyl's 1997 launch, the FDA has received reports of about 1,000 dogs that died or were put to sleep and 7,000 more that had bad reactions after taking the drug, records and official estimates indicate. The FDA says such events are significantly underreported.
While the numbers include cases "possibly" related to Rimadyl, it is hard to be sure. Many dogs given the arthritis drug are older, and few are autopsied after they die. Pfizer says it analyzed cases of Rimadyl-treated dogs that died in 1998 and found a link to Rimadyl to be "likely" in 12% of cases and "not likely" in 22%; it says there was too little information for a judgment about the others.
Despite these problems, the FDA says Rimadyl deserves to be on the market, provided vets take the proper precautions. These include advising dog owners what bad reactions to watch for and periodically doing liver-function or other lab tests.
Within a few weeks, Pfizer will begin affixing a safety sheet directly to packages of Rimadyl pills. It is the first time either FDA officials or Pfizer can recall such a step being taken in the world of animal drugs.
Rimadyl -- generically carprofen -- is an anti-inflammatory medicine. Developer Roche Laboratories expected to market it for people in 1988 and received FDA approval, but shelved the plan after concluding the market for such drugs was too crowded. In addition, some outside experts expressed concerns; a commentary in a pharmaceutical journal noted unusual liver-function readings in 14% to 20% of test subjects and opined that "until additional data on carprofen are available, older compounds should probably be tried initially."
The idea of switching the product to the animal-drug track soon arose. A couple of corporate transactions later, it ended up in the hands of Pfizer's animal-drug unit. There, it was treated to the kind of sophisticated marketing Pfizer does well. A survey of 885 dog owners was done. Besides shedding light on favorite dog names (Jake, Ginger, Lady), the poll revealed that one-fifth of dog owners would be willing to spend "whatever it took" to buy an aging dog an extra year or two of life. No fewer than 53% agreed that "my dog is a better companion than other members of my family."
The FDA requires safety and efficacy testing for animal drugs just as for human ones, but animal-drug tests are smaller. Pfizer says about 500 dogs got Rimadyl in various trials, which is no more than a fifth of the number of subjects in comparable human-drug trials. Some dogs showed unusual liver-function readings and one young beagle on a high dose died, but for the most part, the FDA and Pfizer didn't find side effects alarming. The drug was approved for an early-1997 launch. That same year, the FDA made it easier to market drugs directly to consumers on TV.
Soon, Pfizer was running commercials in which a once-stiff yellow Labrador retriever named Lady bounded over a fallen tree as she fetched tennis balls beside a lake. In another ad, a dog leapt through a window and slid down a banister. There were also full-page magazine ads and a public-relations campaign, whose results, the PR firm later said, included 1,785 print stories, 856 radio reports and 245 TV news reports "generating 25.5 million positive impressions on the product." Early on, vets were floored by the drug's effects.
"The results in some cases have been pretty darn close to miraculous," says David Whitten of the Hilldale Veterinary Hospital in Southfield, Mich. "I'm using this drug on my own dog. It has been effective. But as with all medications, side effects are certainly a problem." Indeed, within months of the launch, vets at Colorado State University in Fort Collins noticed troubling reactions. Labrador retrievers seemed particularly affected. Since the safety studies for Rimadyl had emphasized testing on young beagles, Pfizer went back to conduct another, small test just on Labs; it says that test showed no particular problem.
Bill Keller, an FDA veterinary-medicine official, notes that "any time you take a product from the investigation and put it into actual practice, you're going to see things you didn't expect." But reports about Rimadyl came in by the hundreds. The FDA had received just over 3,000 animal-drug bad-reaction reports in 1996, the year before Rimadyl's launch; in 1998, the drug's first full year, Rimadyl alone produced more than that many. They swamped the FDA's tiny Center for Veterinary Medicine in Rockville, Md. Pfizer was scrambling as well. "Basically, their response," says Dr. Keller, " was `Tell us what you want us to do. We love the fact that it's selling so well, but we don't know what to do with all these adverse reactions.'"
The FDA and Pfizer discussed a "Dear Doctor" letter to be sent to vets. FDA records show the agency found parts of an early Pfizer draft "unacceptable as they are promotional in tone. . . ." It was revised. The records also show Pfizer disagreed with the FDA's suggestion that the letter cite "death" as a possible side effect. To get the letter out, the FDA told Pfizer it was "agreeing to your exclusion of the 'death' syndrome from the letter at this time. However, we will revisit the 'death' syndrome issue and other potential side effects for possible inclusion in labeling at a later date." So the term didn't appear in the first warning Pfizer sent, in mid-1997.
Meanwhile, dog owners were asking for Rimadyl. "It was their advertising that sold me on the drug," says Michelle Walsh, a Phoenix woman who says her miniature schnauzer was given it and later died. Not that vets needed much convincing. They saw clear benefits from the drug. On top of that, they could get points from Pfizer for each Rimadyl purchase they made; points were redeemable for PalmPilots, Zip drives for PCs and other equipment.
Although Pfizer's letter told vets to explain to owners the signs of a bad reaction to Rimadyl, such as vomiting, lethargy or diarrhea, it is evident that a great many didn't. The FDA's Dr. Keller says, "There are a lot of veterinarians who don't think they need to take the time, or who forget, or for whatever reason are not providing animal owners with this information."
Donna Allen, whose chow-mix, Maggie, started on Rimadyl last summer, says, " All my vet did was give me this little bag of pills, with no information." She says Maggie "didn't want to take it, but I made her." After four weeks, Maggie began to vomit violently, Ms. Allen says. The dog vanished from their home outside Birmingham, Ala., and later was found lying in a ditch. Ms. Allen loaded her into a truck and sped 35 miles to a veterinary clinic, but the five-year-old dog died. Her vet wouldn't implicate Rimadyl in the death until Ms. Allen urged him to send the dog's internal organs to the University of Illinois vet school, where an examination showed liver toxicity. Maggie was buried under a marker adorned with the figure of an angel. And Ms. Allen took to the streets, delivering a letter to all the vets in the area urging them to "understand that Rimadyl helps certain dogs, but it is poison to other dogs."
As the complaints poured in, the FDA told Pfizer it would have to revisit the label issue. Pfizer had referred to "fatal outcomes" on the label as a possible effect of the drug class to which Rimadyl belonged, but not specifically of this drug. Now the agency asked that Pfizer cite "death" prominently as a possible side effect of the drug. Describing the back and forth with Pfizer, the FDA's Dr. Keller says, "They did it. They weren't enthusiastic about it, but they have always been cooperative. And that's part of the nature of the game we play with industry."
But the FDA also wanted the word "death" in the audio of commercials. Pfizer indicated this "would be devastating to the product," FDA minutes of a February 1999 meeting show. A company spokesman says that "putting 'death' on a 30-second commercial and in proper context was something we didn't think was possible." Rather than do so, it eventually pulled the commercials. Pfizer says it now will do traditional marketing to vets, making sure they know the proper way to use the drug.
Another "Dear Doctor" letter will soon go out, and the company will start attaching a safety sheet to pill packages. Pfizer acknowledges it has a perception problem with some dog owners; a consumer group, for instance, has mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects. The company is contacting dog owners who have told their stories on the Internet, and it is offering to pay medical and diagnostic expenses for some dogs who may have been harmed by Rimadyl.
But Pfizer stands firmly behind the value of the drug, of which it says sales have continued to grow. Most vets also remain strongly behind Rimadyl. Owners, too, generally say they think the drug is important -- they just want to know the risks. Atlantan Roger Williams gave his mixed-breed terrier, William, Rimadyl for more than a year and believes it contributed to the dog's death. "But if I had to do it all over, I would give my dog Rimadyl again," he says. "The difference is I would have known what to expect. Without Rimadyl, William was miserable. And what's the point of living another three years if you're miserable?"
A Surprised FDA and Pfizer Strive for Right Response for Remedy Gone Awry
What to Say in the TV Ads
By Chris Adams, Staff Reporter of The Wall Street Journal
The Wall Street Journal, 3/13/00
--------------------------------------------------------------------------------
You might call it a made-for-TV drug. Approved for human use in the U.S. but not marketed that way, an arthritis medicine called Rimadyl languished for nearly 10 years in developmental limbo, then emerged in a surprising new form: Instead of a human drug, it was now a drug for arthritic dogs. And it became a hit.
With the aid of slick commercials featuring once-lame dogs bounding happily about, Rimadyl changed the way veterinarians treated dogs. "Clients would walk in and say, `What about this Rimadyl?'" says George Siemering, who practices in Springfield, Va.
Today, those TV spots are gone. The reason has to do with dogs like Montana.
A six-year-old Siberian husky with stiff back legs, Montana hobbled out of a vet's office in Brooklyn, N.Y., six months ago accompanied by his human, Angela Giglio, and a supply of Rimadyl pills. At first, the drug appeared to work. But then Montana lost his appetite. He went limp, wobbling instead of walking. Finally he didn't walk at all. He ate leaves, vomited, had seizures and, eventually, was put to sleep. An autopsy showed the sort of liver damage associated with a bad drug reaction.
Pet drugs are big business -- an estimated $3 billion world-wide -- and Rimadyl is one of the bestsellers. It has been given to more than four million dogs in the U.S. and more abroad, brought Pfizer Inc. tens of millions of dollars in sales, and pleased many veterinarians and dog owners. But the drug has also stirred a controversy, with other pet owners complaining that nobody warned them of its risks.
Montana's owner, Ms. Giglio, is among them. After she informed Pfizer and the Food and Drug Administration of her relatively youthful dog's death, Pfizer offered her $440 "as a gesture of good will" and to cover part of the medical costs. Insulted by the offer and a stipulation that she agree to tell no one about the payment except her tax preparer, she refused to sign and didn't take the money. "There's just no way in my conscience or heart I can release them from blame," she says.
After reports of bad reactions and deaths started streaming in to the FDA, the agency suggested that Pfizer mention "death" as a possible side effect in a warning letter to vets, on labels and in TV ads. Pfizer eventually did use the word with vets and on labels, but when given an ultimatum about the commercials -- mention "death" in the audio or end the ads -- Pfizer chose to drop them.
Pfizer's director of animal-products technical services, Edward W. Kanara, says that when reports started coming in, "we acted extremely promptly based on the information we had." Pfizer points out that reported adverse events involve less than 1% of treated dogs.
Since Rimadyl's 1997 launch, the FDA has received reports of about 1,000 dogs that died or were put to sleep and 7,000 more that had bad reactions after taking the drug, records and official estimates indicate. The FDA says such events are significantly underreported.
While the numbers include cases "possibly" related to Rimadyl, it is hard to be sure. Many dogs given the arthritis drug are older, and few are autopsied after they die. Pfizer says it analyzed cases of Rimadyl-treated dogs that died in 1998 and found a link to Rimadyl to be "likely" in 12% of cases and "not likely" in 22%; it says there was too little information for a judgment about the others.
Despite these problems, the FDA says Rimadyl deserves to be on the market, provided vets take the proper precautions. These include advising dog owners what bad reactions to watch for and periodically doing liver-function or other lab tests.
Within a few weeks, Pfizer will begin affixing a safety sheet directly to packages of Rimadyl pills. It is the first time either FDA officials or Pfizer can recall such a step being taken in the world of animal drugs.
Rimadyl -- generically carprofen -- is an anti-inflammatory medicine. Developer Roche Laboratories expected to market it for people in 1988 and received FDA approval, but shelved the plan after concluding the market for such drugs was too crowded. In addition, some outside experts expressed concerns; a commentary in a pharmaceutical journal noted unusual liver-function readings in 14% to 20% of test subjects and opined that "until additional data on carprofen are available, older compounds should probably be tried initially."
The idea of switching the product to the animal-drug track soon arose. A couple of corporate transactions later, it ended up in the hands of Pfizer's animal-drug unit. There, it was treated to the kind of sophisticated marketing Pfizer does well. A survey of 885 dog owners was done. Besides shedding light on favorite dog names (Jake, Ginger, Lady), the poll revealed that one-fifth of dog owners would be willing to spend "whatever it took" to buy an aging dog an extra year or two of life. No fewer than 53% agreed that "my dog is a better companion than other members of my family."
The FDA requires safety and efficacy testing for animal drugs just as for human ones, but animal-drug tests are smaller. Pfizer says about 500 dogs got Rimadyl in various trials, which is no more than a fifth of the number of subjects in comparable human-drug trials. Some dogs showed unusual liver-function readings and one young beagle on a high dose died, but for the most part, the FDA and Pfizer didn't find side effects alarming. The drug was approved for an early-1997 launch. That same year, the FDA made it easier to market drugs directly to consumers on TV.
Soon, Pfizer was running commercials in which a once-stiff yellow Labrador retriever named Lady bounded over a fallen tree as she fetched tennis balls beside a lake. In another ad, a dog leapt through a window and slid down a banister. There were also full-page magazine ads and a public-relations campaign, whose results, the PR firm later said, included 1,785 print stories, 856 radio reports and 245 TV news reports "generating 25.5 million positive impressions on the product." Early on, vets were floored by the drug's effects.
"The results in some cases have been pretty darn close to miraculous," says David Whitten of the Hilldale Veterinary Hospital in Southfield, Mich. "I'm using this drug on my own dog. It has been effective. But as with all medications, side effects are certainly a problem." Indeed, within months of the launch, vets at Colorado State University in Fort Collins noticed troubling reactions. Labrador retrievers seemed particularly affected. Since the safety studies for Rimadyl had emphasized testing on young beagles, Pfizer went back to conduct another, small test just on Labs; it says that test showed no particular problem.
Bill Keller, an FDA veterinary-medicine official, notes that "any time you take a product from the investigation and put it into actual practice, you're going to see things you didn't expect." But reports about Rimadyl came in by the hundreds. The FDA had received just over 3,000 animal-drug bad-reaction reports in 1996, the year before Rimadyl's launch; in 1998, the drug's first full year, Rimadyl alone produced more than that many. They swamped the FDA's tiny Center for Veterinary Medicine in Rockville, Md. Pfizer was scrambling as well. "Basically, their response," says Dr. Keller, " was `Tell us what you want us to do. We love the fact that it's selling so well, but we don't know what to do with all these adverse reactions.'"
The FDA and Pfizer discussed a "Dear Doctor" letter to be sent to vets. FDA records show the agency found parts of an early Pfizer draft "unacceptable as they are promotional in tone. . . ." It was revised. The records also show Pfizer disagreed with the FDA's suggestion that the letter cite "death" as a possible side effect. To get the letter out, the FDA told Pfizer it was "agreeing to your exclusion of the 'death' syndrome from the letter at this time. However, we will revisit the 'death' syndrome issue and other potential side effects for possible inclusion in labeling at a later date." So the term didn't appear in the first warning Pfizer sent, in mid-1997.
Meanwhile, dog owners were asking for Rimadyl. "It was their advertising that sold me on the drug," says Michelle Walsh, a Phoenix woman who says her miniature schnauzer was given it and later died. Not that vets needed much convincing. They saw clear benefits from the drug. On top of that, they could get points from Pfizer for each Rimadyl purchase they made; points were redeemable for PalmPilots, Zip drives for PCs and other equipment.
Although Pfizer's letter told vets to explain to owners the signs of a bad reaction to Rimadyl, such as vomiting, lethargy or diarrhea, it is evident that a great many didn't. The FDA's Dr. Keller says, "There are a lot of veterinarians who don't think they need to take the time, or who forget, or for whatever reason are not providing animal owners with this information."
Donna Allen, whose chow-mix, Maggie, started on Rimadyl last summer, says, " All my vet did was give me this little bag of pills, with no information." She says Maggie "didn't want to take it, but I made her." After four weeks, Maggie began to vomit violently, Ms. Allen says. The dog vanished from their home outside Birmingham, Ala., and later was found lying in a ditch. Ms. Allen loaded her into a truck and sped 35 miles to a veterinary clinic, but the five-year-old dog died. Her vet wouldn't implicate Rimadyl in the death until Ms. Allen urged him to send the dog's internal organs to the University of Illinois vet school, where an examination showed liver toxicity. Maggie was buried under a marker adorned with the figure of an angel. And Ms. Allen took to the streets, delivering a letter to all the vets in the area urging them to "understand that Rimadyl helps certain dogs, but it is poison to other dogs."
As the complaints poured in, the FDA told Pfizer it would have to revisit the label issue. Pfizer had referred to "fatal outcomes" on the label as a possible effect of the drug class to which Rimadyl belonged, but not specifically of this drug. Now the agency asked that Pfizer cite "death" prominently as a possible side effect of the drug. Describing the back and forth with Pfizer, the FDA's Dr. Keller says, "They did it. They weren't enthusiastic about it, but they have always been cooperative. And that's part of the nature of the game we play with industry."
But the FDA also wanted the word "death" in the audio of commercials. Pfizer indicated this "would be devastating to the product," FDA minutes of a February 1999 meeting show. A company spokesman says that "putting 'death' on a 30-second commercial and in proper context was something we didn't think was possible." Rather than do so, it eventually pulled the commercials. Pfizer says it now will do traditional marketing to vets, making sure they know the proper way to use the drug.
Another "Dear Doctor" letter will soon go out, and the company will start attaching a safety sheet to pill packages. Pfizer acknowledges it has a perception problem with some dog owners; a consumer group, for instance, has mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects. The company is contacting dog owners who have told their stories on the Internet, and it is offering to pay medical and diagnostic expenses for some dogs who may have been harmed by Rimadyl.
But Pfizer stands firmly behind the value of the drug, of which it says sales have continued to grow. Most vets also remain strongly behind Rimadyl. Owners, too, generally say they think the drug is important -- they just want to know the risks. Atlantan Roger Williams gave his mixed-breed terrier, William, Rimadyl for more than a year and believes it contributed to the dog's death. "But if I had to do it all over, I would give my dog Rimadyl again," he says. "The difference is I would have known what to expect. Without Rimadyl, William was miserable. And what's the point of living another three years if you're miserable?"
- malernee
- Site Admin
- Posts: 462
- Joined: Wed Aug 13, 2003 5:56 pm
NSAID rimady law suite dermaxx handout
by guest » Fri Sep 03, 2004 6:09 pm
This law suit was about failure to warn, lack of informned consent.
I am posting the warning letter I give to all clients about NSAIDs. Dr Dawn Booth says she thinks Rimadyl might be the safest of all NSAIDs. Except for my opinion about Rimadyl, the rest of the information in this handout came from Dr Dawn Booth. The makers of Dermaxx have a good handout.
Warning Concerning Arthritis Medications
All Non Steroid Anti-inflammatory Drugs Can Kill
Rimadyl, Etogesic, Dermaxx, Metacam and Zubrin all belong to a class of drugs called non-steroid anti-inflammatory Drugs. The action of these drugs is similar to aspirin, in that they inhibit inflammatory substances called prostaglandins (PGEs), which cause pain, inflammation, and fever. These drugs are safer than aspirin because they are more selective for the harmful prostaglandins, COX 2 PGEs, and spare certain prostaglandins, COX 1 PGEs, which are essential to protect the G.I. tract, kidneys and other organs.
(This may be an over-simplification)
There is risk of liver failure with all NSAIDs. Liver necrosis in Labrador Retrievers caused by Rimadyl have been reported in the largest numbers. The manufacturer of Rimadyl alleges these reactions are attributed to the facts that Labs are the most common Breed, and Rimadyl was the first and most commonly prescribed NSAID. Rimadyl may be getting a bad rap. Until more information is available, the staff of Critter Fixer Pet Hospital prefers to exercise caution, and not to use this drug. All NSAIDs have the potential to cause liver failure. Blood tests before administration of NSAIDs cannot predict this liver reaction. The risk of this reaction is small. (1:10,000 with Rimadyl)
NSAIDs are relatively new to Veterinary Medicine. Veterinarians have little clinical experience with these drugs. Although every manufacturer has data that alleges their drug is safer than the others, No credible non-manufacturer sponsored data exists which accurately compares these drugs.
NSAIDs Dos and Don’ts
Do ask your Vet for a written warning about side effects, and read this warning. Ask to see the manufacturers package insert.
Do Test your pet for kidney problems before starting NSAIDs. This is especially important in older pets, which are prone to kidney failure. A urinalysis and blood test (Specific gravity, BUN, Creatinine) are essential.
Do Monitor kidney and liver function if your pet is on these drugs for a prolonged period of time. Monitoring is recommended whenever the dosage is increased.
Do Give Zantac or other antacid medication daily to prevent duodenal ulcers, which is a common side effect of all NSAIDs. Unfortunately this will not prevent gastric ulcers.
Do Give Polysulfated glucosamines, PSGAs, (Adequan, Glycoflex, or Cosequin) with prolonged use of NSAIDs for arthritis and degenerative joint disease.
NSAIDs relieve pain, but unfortunately over a long period of time NSAIDs can
contribute to cartilage degeneration. PSGAs help cartilage to heal.
NSAIDs can cause g.i. ulceration. PSGAs are part of the protectant lining of the g.i
tract. NSAIDs are better tolerated with PSGAs. PSGAs also protect the kidney.
Do Stop the medication at the first signs of gastric upset, nausea, and lack of appetite, vomiting or diarrhea.
Don’ts
Do not mix NSAIDs. Do not give NSAIDs with steroids like dexamethazone, prednisolone, Vetalog or Depomedrol. Gastrointestinal ulceration and bleeding can result.
A 3 – 5 day withdrawal period ( wash out)is necessary if you switch from one drug to another.
Do not give NSAIDs in patients with known impaired gastrointestinal, kidney, cardiovascular, or coagulation functions.
If liver enzymes are elevated use only at a lowered dose, and with liver treatment medication (i.e. SAM – E)
Do not give NSAIDs with Enalapril or other ACE inhibitors, Lasix, or with nephrotoxic drugs like aminoglycoside antibiotics or psychotropic drugs. (Prozac, Clomiclam)
Do not give NSAIDs in dogs with Cushing’s disease or other diseases where the patient is predisposed to thromboembolisms. (blood clots)
Do Not use NSAIDs in trauma patients or critical care patients due to potential clotting problems and nephrotoxicity.
A final note:
Relief from pain by NSAIDs is an individual response. If your pet does not get adequate relief from pain and return to normal function with one NSAID it is worth trying a different NSAID.
Reactions to NSAIDs are comparable. If your pet has an adverse reaction to one NSAID, another NSAID should not be used. Another Class of pain reliever drugs should be used.
I am posting the warning letter I give to all clients about NSAIDs. Dr Dawn Booth says she thinks Rimadyl might be the safest of all NSAIDs. Except for my opinion about Rimadyl, the rest of the information in this handout came from Dr Dawn Booth. The makers of Dermaxx have a good handout.
Warning Concerning Arthritis Medications
All Non Steroid Anti-inflammatory Drugs Can Kill
Rimadyl, Etogesic, Dermaxx, Metacam and Zubrin all belong to a class of drugs called non-steroid anti-inflammatory Drugs. The action of these drugs is similar to aspirin, in that they inhibit inflammatory substances called prostaglandins (PGEs), which cause pain, inflammation, and fever. These drugs are safer than aspirin because they are more selective for the harmful prostaglandins, COX 2 PGEs, and spare certain prostaglandins, COX 1 PGEs, which are essential to protect the G.I. tract, kidneys and other organs.
(This may be an over-simplification)
There is risk of liver failure with all NSAIDs. Liver necrosis in Labrador Retrievers caused by Rimadyl have been reported in the largest numbers. The manufacturer of Rimadyl alleges these reactions are attributed to the facts that Labs are the most common Breed, and Rimadyl was the first and most commonly prescribed NSAID. Rimadyl may be getting a bad rap. Until more information is available, the staff of Critter Fixer Pet Hospital prefers to exercise caution, and not to use this drug. All NSAIDs have the potential to cause liver failure. Blood tests before administration of NSAIDs cannot predict this liver reaction. The risk of this reaction is small. (1:10,000 with Rimadyl)
NSAIDs are relatively new to Veterinary Medicine. Veterinarians have little clinical experience with these drugs. Although every manufacturer has data that alleges their drug is safer than the others, No credible non-manufacturer sponsored data exists which accurately compares these drugs.
NSAIDs Dos and Don’ts
Do ask your Vet for a written warning about side effects, and read this warning. Ask to see the manufacturers package insert.
Do Test your pet for kidney problems before starting NSAIDs. This is especially important in older pets, which are prone to kidney failure. A urinalysis and blood test (Specific gravity, BUN, Creatinine) are essential.
Do Monitor kidney and liver function if your pet is on these drugs for a prolonged period of time. Monitoring is recommended whenever the dosage is increased.
Do Give Zantac or other antacid medication daily to prevent duodenal ulcers, which is a common side effect of all NSAIDs. Unfortunately this will not prevent gastric ulcers.
Do Give Polysulfated glucosamines, PSGAs, (Adequan, Glycoflex, or Cosequin) with prolonged use of NSAIDs for arthritis and degenerative joint disease.
NSAIDs relieve pain, but unfortunately over a long period of time NSAIDs can
contribute to cartilage degeneration. PSGAs help cartilage to heal.
NSAIDs can cause g.i. ulceration. PSGAs are part of the protectant lining of the g.i
tract. NSAIDs are better tolerated with PSGAs. PSGAs also protect the kidney.
Do Stop the medication at the first signs of gastric upset, nausea, and lack of appetite, vomiting or diarrhea.
Don’ts
Do not mix NSAIDs. Do not give NSAIDs with steroids like dexamethazone, prednisolone, Vetalog or Depomedrol. Gastrointestinal ulceration and bleeding can result.
A 3 – 5 day withdrawal period ( wash out)is necessary if you switch from one drug to another.
Do not give NSAIDs in patients with known impaired gastrointestinal, kidney, cardiovascular, or coagulation functions.
If liver enzymes are elevated use only at a lowered dose, and with liver treatment medication (i.e. SAM – E)
Do not give NSAIDs with Enalapril or other ACE inhibitors, Lasix, or with nephrotoxic drugs like aminoglycoside antibiotics or psychotropic drugs. (Prozac, Clomiclam)
Do not give NSAIDs in dogs with Cushing’s disease or other diseases where the patient is predisposed to thromboembolisms. (blood clots)
Do Not use NSAIDs in trauma patients or critical care patients due to potential clotting problems and nephrotoxicity.
A final note:
Relief from pain by NSAIDs is an individual response. If your pet does not get adequate relief from pain and return to normal function with one NSAID it is worth trying a different NSAID.
Reactions to NSAIDs are comparable. If your pet has an adverse reaction to one NSAID, another NSAID should not be used. Another Class of pain reliever drugs should be used.
- guest
Is Rimadyl your best friend's friend? Or foe?
by malernee » Wed Oct 20, 2004 6:22 pm
About half of the 52.9 million dogs in America might one day be candidates for Rimadyl. The acceptance of this nonsteroidal anti-inflammatory drug has been staggering; 4 million dogs have popped this pill since its January, 1997 introduction.
Rimadyl is used to relieve pain in the shorter term as a post surgical analgesic. It is used in the longer term for osteoarthritis (and associated joint problems), which afflict more than 8 million dogs.
Before Rimadyl hit the market, vets prescribed aspirin or steroids. Long-term usage of steroids created severe side effects, while "Aspirin is cheap but otherwise doesn’t cut it for dogs. Their systems can’t tolerate aspirin," says Dr. Jon Dee, a Board-certified veterinary surgeon in Hollywood, Fla.
Rimadyl, it seemed, was a better option. It promised to be far more tolerant to canine gastrointestinal systems than aspirin, and it produced fewer side effects than steroids.
With so many dogs so desperate for pain relief, it’s no wonder that word of Rimadyl’s benefits spread quickly on the Internet. At dog parks across the country, everyone was talking about a great new hope called Rimadyl.
However, it turns out that Rimadyl can produce serious side-effects -- and it can even lead to a dog’s death.
The Rimadyl drama has been played out on the Internet and in the media. Inaccurate reporting has left pet owners confused.
The Rimadyl buzz
The marketing campaign for Rimadyl hadn’t even begun. Internet buzz alone prompted an immediate onslaught the very day Rimadyl hit the market in January 1997.
That day may have been the busiest morning ever at Blum Animal Hospital in Chicago. The phone rang off the hook. People were clamoring for the drug.
"In my 32 years of practice, I’ve never seen anything like it," says Blum Chief of Staff Dr. Sheldon Rubin. "We didn’t even have the drug (at the clinic) yet. We took names on a waiting list like we were offering tickets to a rock concert or Cubs game."
Within months after the drug’s release, Peter and Cindy Schramm happened to have an appointment with Dr. Rubin. Bernie, their 8-year-old Pembroke Welsh Corgi, had osteoarthritis so bad he could no longer climb stairs.
"Bernie’s personality changed; he didn’t even want to be petted; he was in constant pain," said Cindy. "We were desperate. Poor Bernie was only just past middle age."
Around the same time in John’s Island, S.C., Jean Townsend (the owner of 10 dogs) didn’t know what to do for George, her Chocolate Labrador, whose osteoarthritis was also worsening. George was probably about 11 or 12 years old, although Townsend wasn’t sure since he’d been a stray.
For the owners of both George and Bernie, the answer seemed to be Rimadyl.
Within days, Bernie was his old self, bounding up and down stairs -- at least as much as any Corgi can bound. Once again he loved to be petted.
Meanwhile, Bernie’s owners say the drug brought him back to life.
The results for George were less dramatic, but Townsend noticed at least some improvement. She continued giving George Rimadyl for about a month. Then, one morning, George suddenly got very sick. He could barely move and couldn’t keep food down.
The dog’s condition worsened, and within days he was being cared for by vets around the clock. He was no longer able to stand and could barely keep his head up. "I looked into his eyes and George told me ‘enough.’ We ended his suffering on October 13, 1997," Townsend says.
A necropsy (an autopsy for animals) revealed acute internal hemorrhaging. Veterinarians agreed that Rimadyl contributed significantly to George’s death. In fact, Townsend was so convinced that she leveled a class action lawsuit again Pfizer Animal Health, the Exton, Pa. manufacturer of Rimadyl.
Pets vs. Pfizer
Townsend isn’t alone. The FDA Center for Veterinary Medicine (CVM) reports 4,596 complaints filed by users of Rimadyl. Meanwhile, Rimadyl has been an alleged contributing factor in 651 suspected canine deaths. This is a record number of complaints about a drug for pets. In fact, of all the complaints filed in 1998, 43 percent targeted Rimadyl.
The CVM does agree that Rimadyl has enjoyed one of the most successful introductions of any drug in the history of veterinary medicine. Since veterinarians are generally tentative about jumping on the new drug bandwagon, that’s a significant endorsement
Rimadyl was first expected to be marketed for use in people. In 1988, it won FDA approval, but developer Roche Laboratories decided the market for such drugs was overcrowded and they dropped it. Knowing that a desperate public clamored for an effective and safe drug for pain relief for dogs, Pfizer saw a niche. After all, pet drugs are a big business – more than $3 billion is spent annually on drugs for companion animals.
Pfizer wasn’t about to depend on word of mouth to promote its new product. The company spent millions on marketing.
The Rimadyl marketing blitz
Part of Pfizer’s marketing plan included a rash of (now-cancelled) television ads that featured elderly dogs, once hobbled by osteoarthritis, running and jumping pain free.
"Watching those TV ads made Rimadyl seem like the fountain of youth," says Robert Sinclair, of West Bloomfield, Mich.
In print ads, the headline read, "Give your dog relief from arthritis pain, and give your children back their favorite companion."
Officials at Pfizer won’t say exactly how much money they’ve spent on marketing Rimadyl but it certainly sets a record for dollars spent to launch a drug for dogs. Most importantly, the campaign reached consumers in record numbers.
Of course, some pet owners swear the ads were factual. "Those ads were absolutely true," says Louise Clements of Meridian, Idaho. Brass, her 14-year-old Pembroke Welsh Corgi, couldn’t walk down two steps to do relieve herself outdoors due to osteoarthritis. Within 48 hours of taking Rimadyl, Brass was acting like pretty much like a puppy again. "It was our own little miracle," Clements says.
On the other hand, Misty, Robert Sinclair’s 17-year-old toy poodle, was put on Rimadyl in October of 1997. Misty’s arthritis improved but by her third week on the drug she was having other serious medical problems. At first, Sinclair and his wife, Jayne, thought their dog might be experiencing congestive heart failure. "The vets never said anything about side effects," Jayne says.
As poor Misty languished, the Sinclairs went online frantically trying to figure out what was going wrong. They became convinced that Rimadyl was playing a role in their dog’s decline. By now, the Center for Veterinary Medicine’s Web site listed potential adverse reactions to Rimadyl. The side effects matched the symptoms Misty was having. But the Sinclairs’ efforts came too late. Misty went downhill, suffering far more than the pain she was given Rimadyl to relieve. Finally, the little pooch was put out of her misery.
The Sinclairs are certain Rimadyl caused their dog’s demise. "Old age is not a disease," Bob says. "I was horrified."
"Many of the dogs on Rimadyl are old, and may have had pre-existing liver or renal disease or weren’t carefully prescreened," says Board-certified orthopedic veterinarian Dr. Steve Budsberg, professor of surgery at the University of Georgia College of Veterinary Medicine, Athens. "Being older, they may have underlying problems (that are) not easily detected, even with appropriate and thorough testing. Also, it may be difficult to predict idiosyncratic (individually unique) medical problems that seem to potentially occur with Rimadyl," Budsberg said.
According to Pfizer, fewer than one percent of all Rimadyl users have reported Rimadyl-induced side-effects. In 1998, it was suspected that Rimadyl was a factor in far less than one percent of dog deaths.
"That’s pretty darn good," says Dr. Eli Ehrenpreis, assistant professor of clinical medicine at the University of Chicago. Far more humans die each year from drugs like aspirin that are designed to combat osteoporosis and inflammation.
"Rimadyl is in a serious class of potent drugs and should carefully be considered," according to Dr. Edward Kanara of Pfizer.
Almost immediately after Rimadyl’s release, the CVM began to document the drug’s side effects. Just five months after the drug’s release, officials requested that Pfizer change the Rimadyl package insert to list adverse drug reactions. Pfizer complied. The company also sent a letter to vets that outlined the latest information available. Pfizer also made several additional changes to the Rimadyl package insert.
By April of 1999, Rimadyl was believed to cause 49 adverse side effects, from mild gastrointestinal upset (diarrhea and/or vomiting) to changes in behavior to serious liver or renal dysfunction. Pfizer’s package insert was also changed to read, "In rare situations, death has been associated with some of the adverse reactions."
Dr. Bill Keller of the CVM says Pfizer has been "due diligent, very responsible about making appropriate label changes."
However, not everyone sees it that way. Robert Sinclair says, "A dog is no more a statistic than a child. Pfizer spent millions on their TV ads, but they sure didn’t spend millions informing us of the possible dangers (of Rimadyl)."
The FDA also asked Pfizer to include death as a possible side effect in the TV campaign. Pfizer didn’t want their heartening 30-second TV ads with a bounding, tail-wagging dog to culminate with that warning, so they cancelled the ads.
Pfizer has made offers to reimburse veterinary costs related to treatments for at least some pet owners. However, many say Pfizer will only reimburse vet bills if various conditions -- such as releasing Pfizer from all blame -- are met. Kanara says there may have been some miscommunication early on but denies Pfizer is now demanding any "conditions."
But reimbursement can only go so far. Nancy Friedman, a retired Chicago nurse, says she spent $2,500 on Bravo, her 8-year-old Rottweiler, that subsequently "crashed" as an adverse response to Rimadyl. "My initial reaction is that no amount of money can replace Bravo -- period," says Friedman. "This should never have happened. I was duped by their ad campaign."
B.A.R.K.S. is better than Rimadyl’s bite
Robert Sinclair is one of the more outspoken voices in a loose-knit group called B.A.R.K.S. (Be Aware of Rimadyl’s Known Side Effects). Sinclair says some vets are motivated to push Rimadyl because its manufacturer, Pfizer Animal Health, offers incentives for selling big volume. "To push this dangerous drug is a game of Rimadyl roulette," he says.
Veterinarians and Pfizer have confirmed these incentives do exist. Rewards for points earned on sales include Palm Pilots, Zip drives for computers, veterinary books and tuition for continuing education.
Dr. Sheldon Rubin doubts Sinclair’s theory. Rubin has been a private veterinary practitioner in Chicago for 32 years. He says other pharmaceutical companies (in addition to Pfizer) offer similar programs tied to sales. He adds, "I can’t imagine a veterinary professional making a decision about a drug based on receiving a book or a Palm Pilot," he says.
Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, points out that human doctors are also offered incentives. "As far as I know, Pfizer has done nothing that hints at being unethical," he says.
Not the first time
But Rimadyl this isn’t the first drug for pets that has entered the market followed by a near immediate wave of side effects or adverse reactions.
A drug called Heartgard was introduced in 1988. It was designed to fight mosquito-transmitted heartworm disease. Heartgard and a similar drug, Interceptor, both contained an active ingredient called ivermectin that created several serious adverse reactions. Most dramatically, it killed collies.
Keller of the CVM explains that clinical trials for animal drugs are done differently than tests for human drugs. Fewer dogs are required as test subjects than the number of people needed to test human drugs. Approximately 500 dogs were involved in the Rimadyl trials.
"The reality is cost," says Keller. "If clinical trials for animals had the same requirements as trials for people, we wouldn’t have drugs for pets coming to market." The biggest difference between the response over adverse reactions to Heartgard in 1988 and the Rimadyl situation is the Internet. Complaints can now be filed directly to the CVM with a click of a mouse, instead of weaving through government bureaucratic paperwork. Also, owners of dogs that have had problems, such as members of B.A.R.K.S., correspond via e-mail. Many listservs link dog owners whose pets have experienced problems with Rimadyl, and local breed clubs host pet chats that discuss the issue on a nightly basis. Some of these discussions involve nothing but gossip and scare tactics, but much of what’s available is legitimate. B.A.R.K.S. even produced a 10-minute video produced called "Rimadyl Update." The video is now available for $4. (Send to Cheryl Walton, c/o B.A.R.K.S., Advance Multimedia, 26600 Telegraph Rd., Suite 181, Southfield, MI 48034).
The Rimadyl fervor has launched a media onslaught. Although Rimadyl was the first nonsteroidal anti-inflammatory drug of its kind, the backlash has spread to other potentially dangerous pet medications. EtoGesic, a similar drug, was released about year later with less fanfare. Sure enough, about a year after reports of adverse reactions began to pile up for Rimadyl, complaints began to trickle in for EtoGesic.
Still, some pet owners and veterinarians swear by Rimadyl. Dr. Jon Dee, the surgeon from Hollywood, Fla., has prescribed more Rimadyl than almost any other vet in the United States. He used Rimadyl two years before it received FDA approval. As far as Dee knows, none of his canine clients has suffered a reaction more serious than gastrointestinal upset. In fact, Dee used Rimadyl for two years on his own Yellow Labrador, who suffered from degenerative joint disease.
Sheree Parks, of San Diego, is a Rimadyl believer. Nolan, her family’s 12-year-old Golden Retriever, began taking the pill in March of 1999 and hasn’t missed one since. "His pain was enormous; he could barely move," adds Parks. "Friends were telling us to euthanize Nolan. We tried Cosequin (Glucosamine/Chondroitin Sulfate, a nutritional supplement). It worked for a while but ultimately provided no relief. Even acupuncture was no longer helping. It’s not only the extra time we have with Nolan that matters, it’s that Nolan is now enjoying quality life without pain. "If it wasn’t for Rimadyl, Nolan would now be dead," Parks says.
"Rimadyl is a tool, the best one now available to ease pain of osteoarthritis," says Dee. "Like any tool, it can be used wisely or unwisely."
The business of pet health care
Americans have more than 115 million pets and spend in excess of $3 billion a year on drugs for their care. With pet spending increasing at a rate of 20 percent annually, this makes animal health one of the fastest growing segments of the entire pharmaceutical industry.
Even the typically standoffish Food and Drug Administration boasts about its association with the burgeoning pet market. The FDA proudly hurried to write its own press releases to tout two products it approved in 1999: Clomicalm, a drug for dogs that suffer separation anxiety, and Anipryl, which eases the effects of Canine Cognitive Syndrome, a disease much like Alzheimer’s.
Still, the majority of pet drugs used by vets haven’t specifically been tested for treating pets (but have been FDA tested and approved on people).
Off-label prescriptions have been a longstanding veterinary practice. Examples range from stalwarts such as Prednisolone -- a corticosteroid used for a variety of ailments from allergies to autoimmune disease -- to fairly recent products, such as Prozac, used for several purposes including aggression in dogs.
But because pet owners are uniformed about drugs and their side effects, many pets suffer.
Whom do you blame? Are vets at fault for not communicating with clients? Are pharmaceutical companies at fault for not informing consumers of all known information about drugs for pets? Or can pet owners be at fault?
"It’s not a matter of fault, it’s also human nature. Now that pets have become members of our families, we’re desperate to get them well," explains Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, and a vet in private practice for 41 years.
"It’s human nature to minimize any risks in your own mind-- you don’t hear what the veterinarian is really telling you. I have a spouse who’s been through cancer (treatments). I’ve been there; I understand how this can happen," he says.
But not all vets tell clients about potential adverse reactions; they’re either rushed or they just don’t know the potential side effects. When Bravo, a Rottweiller, became ill after taking Rimadyl in February 1999, Nancy Friedman of Chicago never thought about an adverse drug reaction. She figured Bravo, a Rottweiler Champion show dog, just picked up a bug at a dog show.
However, her health-care professional should have thought about the possibility of an adverse drug reaction before placing Bravo on Rimadyl a second time several months later. Bravo became ill quickly and soon died. The CVM later concurred Rimadyl was likely to have precipitated her dog’s death, Friedman says.
"Pfizer has been walking a pharmaceutical tightrope," says Ross Becker, publisher of Good Dog! magazine, a sort of Consumer Reports for canines. He’s been following this story from the beginning. "What bothers pet owners most is that they weren’t warned about side effects. It’s clear, there are too many holes in the current system -- there’s got to be a better way to inform consumers about the drugs their pets are taking."
But Pfizer is taking the necessary steps to warn pet owners. This February, it released a page of information about Rimadyl that is included in prepackaged seven- and 30-day supplies of the drug.
Seda says this information about potential adverse reactions, interactions with other drugs, and dosage and administration, is easier to understand than the complicated medical jargon consumers receive for their own drugs.
Pfizer plans to create similar user-friendly disclosures for its other animal drugs. "We answer tough questions that consumers should ask about any drug prescribed for their pet," says Dr. Edward Kanara, director of technical services for Pfizer.
However, apparently, not all pharmaceutical companies are as willing. For example, Novartis, a major player in animal health, refused to comment on the issue.
But voluntary disclosures aren’t enough to please some pet owners. Jean Townsend of John’s Island, S.C., leveled a class-action lawsuit against Pfizer, after her dog died allegedly as a result of using Rimadyl.
Together, Townsend and Sinclair attended a CVM meeting in April, and called for the FDA to create federal legislation. Such regulations would mandate that pharmaceutical companies and the veterinary industry provide consumers with all known information about drugs prescribed for their pets.
Although Seda of the American Veterinary Medical Association says he wants to find ways to better inform pet owners, he doesn’t want a government agency to oversee the veterinary industry. And he’s not alone. That government agency doesn’t want to do it either. Dr. Bill Keller of the CVM says there are "resource limitations," meaning budget restraints.
On drugs that the FDA has recently approved for animals, pharmaceutical manufacturers include at least most of the information we read on labels for human drugs. The problem is that many pet drugs are dispensed by vets in little plastic bottles without any information. Meanwhile, vets continue to prescribe vast array of medications off label. Vets also continue to prescribe longtime animal drugs where current facts about side effects and contraindications are not documented.
"Vets have a responsibility to provide whatever information is known about a drug, everything from whether it should be refrigerated to whether there are any potential serious side effects," Sinclair says.
"At the very least you’d think the FDA could mandate that vets and pharmaceutical companies find a way to provide easy-to-understand owner information for all drugs approved over the past five years, or the past 10 years," Sinclair says. "Drug companies could follow Pfizer’s lead with all prepackaged products. Computer programs are now available -- and with demand others will no doubt step up to the plate -- so vets can print out information whenever they dispense in those little plastic vials."
"Currently, the FDA takes nearly a year to provide summaries and information to the public about adverse drug reactions," he adds.
Becker, at Good Dog! magazine, agrees. "The FDA managed to find a way to fully inform people about their drugs, you bet they ought to do the same for companion animals. Pets can’t read or ask questions, it’s our responsibility.
"I believe we all learned several lessons from the Rimadyl story. All drugs have potential side effects, and people need to ask questions about medications. If your vet doesn’t take the time to answer, consider another vet. If your vet doesn’t know the answer, wait for one. Potentially saving your pet’s life is worth it," Becker concludes.
By Steve Dale, Tribune Media Services syndicated columnist
http://kntv-tvpet.ip2m.com/index.cfm?pt ... cat_id=106
Rimadyl is used to relieve pain in the shorter term as a post surgical analgesic. It is used in the longer term for osteoarthritis (and associated joint problems), which afflict more than 8 million dogs.
Before Rimadyl hit the market, vets prescribed aspirin or steroids. Long-term usage of steroids created severe side effects, while "Aspirin is cheap but otherwise doesn’t cut it for dogs. Their systems can’t tolerate aspirin," says Dr. Jon Dee, a Board-certified veterinary surgeon in Hollywood, Fla.
Rimadyl, it seemed, was a better option. It promised to be far more tolerant to canine gastrointestinal systems than aspirin, and it produced fewer side effects than steroids.
With so many dogs so desperate for pain relief, it’s no wonder that word of Rimadyl’s benefits spread quickly on the Internet. At dog parks across the country, everyone was talking about a great new hope called Rimadyl.
However, it turns out that Rimadyl can produce serious side-effects -- and it can even lead to a dog’s death.
The Rimadyl drama has been played out on the Internet and in the media. Inaccurate reporting has left pet owners confused.
The Rimadyl buzz
The marketing campaign for Rimadyl hadn’t even begun. Internet buzz alone prompted an immediate onslaught the very day Rimadyl hit the market in January 1997.
That day may have been the busiest morning ever at Blum Animal Hospital in Chicago. The phone rang off the hook. People were clamoring for the drug.
"In my 32 years of practice, I’ve never seen anything like it," says Blum Chief of Staff Dr. Sheldon Rubin. "We didn’t even have the drug (at the clinic) yet. We took names on a waiting list like we were offering tickets to a rock concert or Cubs game."
Within months after the drug’s release, Peter and Cindy Schramm happened to have an appointment with Dr. Rubin. Bernie, their 8-year-old Pembroke Welsh Corgi, had osteoarthritis so bad he could no longer climb stairs.
"Bernie’s personality changed; he didn’t even want to be petted; he was in constant pain," said Cindy. "We were desperate. Poor Bernie was only just past middle age."
Around the same time in John’s Island, S.C., Jean Townsend (the owner of 10 dogs) didn’t know what to do for George, her Chocolate Labrador, whose osteoarthritis was also worsening. George was probably about 11 or 12 years old, although Townsend wasn’t sure since he’d been a stray.
For the owners of both George and Bernie, the answer seemed to be Rimadyl.
Within days, Bernie was his old self, bounding up and down stairs -- at least as much as any Corgi can bound. Once again he loved to be petted.
Meanwhile, Bernie’s owners say the drug brought him back to life.
The results for George were less dramatic, but Townsend noticed at least some improvement. She continued giving George Rimadyl for about a month. Then, one morning, George suddenly got very sick. He could barely move and couldn’t keep food down.
The dog’s condition worsened, and within days he was being cared for by vets around the clock. He was no longer able to stand and could barely keep his head up. "I looked into his eyes and George told me ‘enough.’ We ended his suffering on October 13, 1997," Townsend says.
A necropsy (an autopsy for animals) revealed acute internal hemorrhaging. Veterinarians agreed that Rimadyl contributed significantly to George’s death. In fact, Townsend was so convinced that she leveled a class action lawsuit again Pfizer Animal Health, the Exton, Pa. manufacturer of Rimadyl.
Pets vs. Pfizer
Townsend isn’t alone. The FDA Center for Veterinary Medicine (CVM) reports 4,596 complaints filed by users of Rimadyl. Meanwhile, Rimadyl has been an alleged contributing factor in 651 suspected canine deaths. This is a record number of complaints about a drug for pets. In fact, of all the complaints filed in 1998, 43 percent targeted Rimadyl.
The CVM does agree that Rimadyl has enjoyed one of the most successful introductions of any drug in the history of veterinary medicine. Since veterinarians are generally tentative about jumping on the new drug bandwagon, that’s a significant endorsement
Rimadyl was first expected to be marketed for use in people. In 1988, it won FDA approval, but developer Roche Laboratories decided the market for such drugs was overcrowded and they dropped it. Knowing that a desperate public clamored for an effective and safe drug for pain relief for dogs, Pfizer saw a niche. After all, pet drugs are a big business – more than $3 billion is spent annually on drugs for companion animals.
Pfizer wasn’t about to depend on word of mouth to promote its new product. The company spent millions on marketing.
The Rimadyl marketing blitz
Part of Pfizer’s marketing plan included a rash of (now-cancelled) television ads that featured elderly dogs, once hobbled by osteoarthritis, running and jumping pain free.
"Watching those TV ads made Rimadyl seem like the fountain of youth," says Robert Sinclair, of West Bloomfield, Mich.
In print ads, the headline read, "Give your dog relief from arthritis pain, and give your children back their favorite companion."
Officials at Pfizer won’t say exactly how much money they’ve spent on marketing Rimadyl but it certainly sets a record for dollars spent to launch a drug for dogs. Most importantly, the campaign reached consumers in record numbers.
Of course, some pet owners swear the ads were factual. "Those ads were absolutely true," says Louise Clements of Meridian, Idaho. Brass, her 14-year-old Pembroke Welsh Corgi, couldn’t walk down two steps to do relieve herself outdoors due to osteoarthritis. Within 48 hours of taking Rimadyl, Brass was acting like pretty much like a puppy again. "It was our own little miracle," Clements says.
On the other hand, Misty, Robert Sinclair’s 17-year-old toy poodle, was put on Rimadyl in October of 1997. Misty’s arthritis improved but by her third week on the drug she was having other serious medical problems. At first, Sinclair and his wife, Jayne, thought their dog might be experiencing congestive heart failure. "The vets never said anything about side effects," Jayne says.
As poor Misty languished, the Sinclairs went online frantically trying to figure out what was going wrong. They became convinced that Rimadyl was playing a role in their dog’s decline. By now, the Center for Veterinary Medicine’s Web site listed potential adverse reactions to Rimadyl. The side effects matched the symptoms Misty was having. But the Sinclairs’ efforts came too late. Misty went downhill, suffering far more than the pain she was given Rimadyl to relieve. Finally, the little pooch was put out of her misery.
The Sinclairs are certain Rimadyl caused their dog’s demise. "Old age is not a disease," Bob says. "I was horrified."
"Many of the dogs on Rimadyl are old, and may have had pre-existing liver or renal disease or weren’t carefully prescreened," says Board-certified orthopedic veterinarian Dr. Steve Budsberg, professor of surgery at the University of Georgia College of Veterinary Medicine, Athens. "Being older, they may have underlying problems (that are) not easily detected, even with appropriate and thorough testing. Also, it may be difficult to predict idiosyncratic (individually unique) medical problems that seem to potentially occur with Rimadyl," Budsberg said.
According to Pfizer, fewer than one percent of all Rimadyl users have reported Rimadyl-induced side-effects. In 1998, it was suspected that Rimadyl was a factor in far less than one percent of dog deaths.
"That’s pretty darn good," says Dr. Eli Ehrenpreis, assistant professor of clinical medicine at the University of Chicago. Far more humans die each year from drugs like aspirin that are designed to combat osteoporosis and inflammation.
"Rimadyl is in a serious class of potent drugs and should carefully be considered," according to Dr. Edward Kanara of Pfizer.
Almost immediately after Rimadyl’s release, the CVM began to document the drug’s side effects. Just five months after the drug’s release, officials requested that Pfizer change the Rimadyl package insert to list adverse drug reactions. Pfizer complied. The company also sent a letter to vets that outlined the latest information available. Pfizer also made several additional changes to the Rimadyl package insert.
By April of 1999, Rimadyl was believed to cause 49 adverse side effects, from mild gastrointestinal upset (diarrhea and/or vomiting) to changes in behavior to serious liver or renal dysfunction. Pfizer’s package insert was also changed to read, "In rare situations, death has been associated with some of the adverse reactions."
Dr. Bill Keller of the CVM says Pfizer has been "due diligent, very responsible about making appropriate label changes."
However, not everyone sees it that way. Robert Sinclair says, "A dog is no more a statistic than a child. Pfizer spent millions on their TV ads, but they sure didn’t spend millions informing us of the possible dangers (of Rimadyl)."
The FDA also asked Pfizer to include death as a possible side effect in the TV campaign. Pfizer didn’t want their heartening 30-second TV ads with a bounding, tail-wagging dog to culminate with that warning, so they cancelled the ads.
Pfizer has made offers to reimburse veterinary costs related to treatments for at least some pet owners. However, many say Pfizer will only reimburse vet bills if various conditions -- such as releasing Pfizer from all blame -- are met. Kanara says there may have been some miscommunication early on but denies Pfizer is now demanding any "conditions."
But reimbursement can only go so far. Nancy Friedman, a retired Chicago nurse, says she spent $2,500 on Bravo, her 8-year-old Rottweiler, that subsequently "crashed" as an adverse response to Rimadyl. "My initial reaction is that no amount of money can replace Bravo -- period," says Friedman. "This should never have happened. I was duped by their ad campaign."
B.A.R.K.S. is better than Rimadyl’s bite
Robert Sinclair is one of the more outspoken voices in a loose-knit group called B.A.R.K.S. (Be Aware of Rimadyl’s Known Side Effects). Sinclair says some vets are motivated to push Rimadyl because its manufacturer, Pfizer Animal Health, offers incentives for selling big volume. "To push this dangerous drug is a game of Rimadyl roulette," he says.
Veterinarians and Pfizer have confirmed these incentives do exist. Rewards for points earned on sales include Palm Pilots, Zip drives for computers, veterinary books and tuition for continuing education.
Dr. Sheldon Rubin doubts Sinclair’s theory. Rubin has been a private veterinary practitioner in Chicago for 32 years. He says other pharmaceutical companies (in addition to Pfizer) offer similar programs tied to sales. He adds, "I can’t imagine a veterinary professional making a decision about a drug based on receiving a book or a Palm Pilot," he says.
Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, points out that human doctors are also offered incentives. "As far as I know, Pfizer has done nothing that hints at being unethical," he says.
Not the first time
But Rimadyl this isn’t the first drug for pets that has entered the market followed by a near immediate wave of side effects or adverse reactions.
A drug called Heartgard was introduced in 1988. It was designed to fight mosquito-transmitted heartworm disease. Heartgard and a similar drug, Interceptor, both contained an active ingredient called ivermectin that created several serious adverse reactions. Most dramatically, it killed collies.
Keller of the CVM explains that clinical trials for animal drugs are done differently than tests for human drugs. Fewer dogs are required as test subjects than the number of people needed to test human drugs. Approximately 500 dogs were involved in the Rimadyl trials.
"The reality is cost," says Keller. "If clinical trials for animals had the same requirements as trials for people, we wouldn’t have drugs for pets coming to market." The biggest difference between the response over adverse reactions to Heartgard in 1988 and the Rimadyl situation is the Internet. Complaints can now be filed directly to the CVM with a click of a mouse, instead of weaving through government bureaucratic paperwork. Also, owners of dogs that have had problems, such as members of B.A.R.K.S., correspond via e-mail. Many listservs link dog owners whose pets have experienced problems with Rimadyl, and local breed clubs host pet chats that discuss the issue on a nightly basis. Some of these discussions involve nothing but gossip and scare tactics, but much of what’s available is legitimate. B.A.R.K.S. even produced a 10-minute video produced called "Rimadyl Update." The video is now available for $4. (Send to Cheryl Walton, c/o B.A.R.K.S., Advance Multimedia, 26600 Telegraph Rd., Suite 181, Southfield, MI 48034).
The Rimadyl fervor has launched a media onslaught. Although Rimadyl was the first nonsteroidal anti-inflammatory drug of its kind, the backlash has spread to other potentially dangerous pet medications. EtoGesic, a similar drug, was released about year later with less fanfare. Sure enough, about a year after reports of adverse reactions began to pile up for Rimadyl, complaints began to trickle in for EtoGesic.
Still, some pet owners and veterinarians swear by Rimadyl. Dr. Jon Dee, the surgeon from Hollywood, Fla., has prescribed more Rimadyl than almost any other vet in the United States. He used Rimadyl two years before it received FDA approval. As far as Dee knows, none of his canine clients has suffered a reaction more serious than gastrointestinal upset. In fact, Dee used Rimadyl for two years on his own Yellow Labrador, who suffered from degenerative joint disease.
Sheree Parks, of San Diego, is a Rimadyl believer. Nolan, her family’s 12-year-old Golden Retriever, began taking the pill in March of 1999 and hasn’t missed one since. "His pain was enormous; he could barely move," adds Parks. "Friends were telling us to euthanize Nolan. We tried Cosequin (Glucosamine/Chondroitin Sulfate, a nutritional supplement). It worked for a while but ultimately provided no relief. Even acupuncture was no longer helping. It’s not only the extra time we have with Nolan that matters, it’s that Nolan is now enjoying quality life without pain. "If it wasn’t for Rimadyl, Nolan would now be dead," Parks says.
"Rimadyl is a tool, the best one now available to ease pain of osteoarthritis," says Dee. "Like any tool, it can be used wisely or unwisely."
The business of pet health care
Americans have more than 115 million pets and spend in excess of $3 billion a year on drugs for their care. With pet spending increasing at a rate of 20 percent annually, this makes animal health one of the fastest growing segments of the entire pharmaceutical industry.
Even the typically standoffish Food and Drug Administration boasts about its association with the burgeoning pet market. The FDA proudly hurried to write its own press releases to tout two products it approved in 1999: Clomicalm, a drug for dogs that suffer separation anxiety, and Anipryl, which eases the effects of Canine Cognitive Syndrome, a disease much like Alzheimer’s.
Still, the majority of pet drugs used by vets haven’t specifically been tested for treating pets (but have been FDA tested and approved on people).
Off-label prescriptions have been a longstanding veterinary practice. Examples range from stalwarts such as Prednisolone -- a corticosteroid used for a variety of ailments from allergies to autoimmune disease -- to fairly recent products, such as Prozac, used for several purposes including aggression in dogs.
But because pet owners are uniformed about drugs and their side effects, many pets suffer.
Whom do you blame? Are vets at fault for not communicating with clients? Are pharmaceutical companies at fault for not informing consumers of all known information about drugs for pets? Or can pet owners be at fault?
"It’s not a matter of fault, it’s also human nature. Now that pets have become members of our families, we’re desperate to get them well," explains Dr. Leonard Seda, president of the Schaumburg, Ill.-based American Veterinary Medical Association, and a vet in private practice for 41 years.
"It’s human nature to minimize any risks in your own mind-- you don’t hear what the veterinarian is really telling you. I have a spouse who’s been through cancer (treatments). I’ve been there; I understand how this can happen," he says.
But not all vets tell clients about potential adverse reactions; they’re either rushed or they just don’t know the potential side effects. When Bravo, a Rottweiller, became ill after taking Rimadyl in February 1999, Nancy Friedman of Chicago never thought about an adverse drug reaction. She figured Bravo, a Rottweiler Champion show dog, just picked up a bug at a dog show.
However, her health-care professional should have thought about the possibility of an adverse drug reaction before placing Bravo on Rimadyl a second time several months later. Bravo became ill quickly and soon died. The CVM later concurred Rimadyl was likely to have precipitated her dog’s death, Friedman says.
"Pfizer has been walking a pharmaceutical tightrope," says Ross Becker, publisher of Good Dog! magazine, a sort of Consumer Reports for canines. He’s been following this story from the beginning. "What bothers pet owners most is that they weren’t warned about side effects. It’s clear, there are too many holes in the current system -- there’s got to be a better way to inform consumers about the drugs their pets are taking."
But Pfizer is taking the necessary steps to warn pet owners. This February, it released a page of information about Rimadyl that is included in prepackaged seven- and 30-day supplies of the drug.
Seda says this information about potential adverse reactions, interactions with other drugs, and dosage and administration, is easier to understand than the complicated medical jargon consumers receive for their own drugs.
Pfizer plans to create similar user-friendly disclosures for its other animal drugs. "We answer tough questions that consumers should ask about any drug prescribed for their pet," says Dr. Edward Kanara, director of technical services for Pfizer.
However, apparently, not all pharmaceutical companies are as willing. For example, Novartis, a major player in animal health, refused to comment on the issue.
But voluntary disclosures aren’t enough to please some pet owners. Jean Townsend of John’s Island, S.C., leveled a class-action lawsuit against Pfizer, after her dog died allegedly as a result of using Rimadyl.
Together, Townsend and Sinclair attended a CVM meeting in April, and called for the FDA to create federal legislation. Such regulations would mandate that pharmaceutical companies and the veterinary industry provide consumers with all known information about drugs prescribed for their pets.
Although Seda of the American Veterinary Medical Association says he wants to find ways to better inform pet owners, he doesn’t want a government agency to oversee the veterinary industry. And he’s not alone. That government agency doesn’t want to do it either. Dr. Bill Keller of the CVM says there are "resource limitations," meaning budget restraints.
On drugs that the FDA has recently approved for animals, pharmaceutical manufacturers include at least most of the information we read on labels for human drugs. The problem is that many pet drugs are dispensed by vets in little plastic bottles without any information. Meanwhile, vets continue to prescribe vast array of medications off label. Vets also continue to prescribe longtime animal drugs where current facts about side effects and contraindications are not documented.
"Vets have a responsibility to provide whatever information is known about a drug, everything from whether it should be refrigerated to whether there are any potential serious side effects," Sinclair says.
"At the very least you’d think the FDA could mandate that vets and pharmaceutical companies find a way to provide easy-to-understand owner information for all drugs approved over the past five years, or the past 10 years," Sinclair says. "Drug companies could follow Pfizer’s lead with all prepackaged products. Computer programs are now available -- and with demand others will no doubt step up to the plate -- so vets can print out information whenever they dispense in those little plastic vials."
"Currently, the FDA takes nearly a year to provide summaries and information to the public about adverse drug reactions," he adds.
Becker, at Good Dog! magazine, agrees. "The FDA managed to find a way to fully inform people about their drugs, you bet they ought to do the same for companion animals. Pets can’t read or ask questions, it’s our responsibility.
"I believe we all learned several lessons from the Rimadyl story. All drugs have potential side effects, and people need to ask questions about medications. If your vet doesn’t take the time to answer, consider another vet. If your vet doesn’t know the answer, wait for one. Potentially saving your pet’s life is worth it," Becker concludes.
By Steve Dale, Tribune Media Services syndicated columnist
http://kntv-tvpet.ip2m.com/index.cfm?pt ... cat_id=106
- malernee
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Non-steroidal anti-inflammatory drugs systematic RCT
by malernee » Fri Nov 26, 2004 10:22 pm
Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials -- Bjordal et al., 10.1136/bmj.38273.626655.63
-- BMJ
Address:http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38273.626655.63v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=NSAIDs&andorexactfulltext=and&searchid=1101513454613_21459&stored_search=&FIRSTINDEX=30&sortspec=relevance&resourcetype=1,2,3,4
Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials
Jan Magnus Bjordal 1, Anne Elisabeth Ljunggren 1, Atle Klovning 1, Lars
Slørdal 2
1 Department of Public Health and Primary Health Care, University of
Bergen, 5018 Bergen, Norway
2 Department of Laboratory Medicine, Children's and Women's Health,
Norwegian University of Science and Technology, 7489 Trondheim, Norway
Objective To estimate the analgesic efficacy of non-steroidal
anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2
inhibitors (coxibs), in patients with osteoarthritis of the knee.
Design Systematic review and meta-analysis of randomised placebo
controlled trials.
Studies reviewed 23 trials including 10 845 patients, median age of 62.5
years. 7807 patients received adequate doses of NSAIDs and 3038 received
placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm
visual analogue scale (VAS), and average duration of symptoms was 8.2
years.
Main outcome measure Change in overall intensity of pain.
Results Methodological quality of trials was acceptable, but 13 trials
excluded patients before randomisation if they did not respond to
NSAIDs. One trial provided long term data for pain that showed no
significant effect of NSAIDs compared with placebo at one to four years.
The pooled difference for pain on visual analogue scale in all included
trials was 10.1 mm (95% confidence interval 7.4 to 12.
or 15.6% better
than placebo after 2-13 weeks. The results were heterogeneous, and the
effect size for pain reduction was 0.32 (0.24 to 0.39) in a random
effects model. In 10 trials that did not exclude non-responders to NSAID
treatment the results were homogeneous, with an effect size for pain
reduction of 0.23 (0.15 to 0.31).
Conclusion NSAIDs can reduce short term pain in osteoarthritis of the
knee slightly better than placebo, but the current analysis does not
support long term use of NSAIDs for this condition. As serious adverse
effects are associated with oral NSAIDs, only limited use can be
recommended.
© 2004 BMJ Publishing Group Ltd
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials -- Bjordal et al., 10.1136/bmj.38273.626655.63
-- BMJ
Address:http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38273.626655.63v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=NSAIDs&andorexactfulltext=and&searchid=1101513454613_21459&stored_search=&FIRSTINDEX=30&sortspec=relevance&resourcetype=1,2,3,4
Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis of randomised
placebo controlled trials
Jan Magnus Bjordal 1, Anne Elisabeth Ljunggren 1, Atle Klovning 1, Lars
Slørdal 2
1 Department of Public Health and Primary Health Care, University of
Bergen, 5018 Bergen, Norway
2 Department of Laboratory Medicine, Children's and Women's Health,
Norwegian University of Science and Technology, 7489 Trondheim, Norway
Objective To estimate the analgesic efficacy of non-steroidal
anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2
inhibitors (coxibs), in patients with osteoarthritis of the knee.
Design Systematic review and meta-analysis of randomised placebo
controlled trials.
Studies reviewed 23 trials including 10 845 patients, median age of 62.5
years. 7807 patients received adequate doses of NSAIDs and 3038 received
placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm
visual analogue scale (VAS), and average duration of symptoms was 8.2
years.
Main outcome measure Change in overall intensity of pain.
Results Methodological quality of trials was acceptable, but 13 trials
excluded patients before randomisation if they did not respond to
NSAIDs. One trial provided long term data for pain that showed no
significant effect of NSAIDs compared with placebo at one to four years.
The pooled difference for pain on visual analogue scale in all included
trials was 10.1 mm (95% confidence interval 7.4 to 12.
or 15.6% better
than placebo after 2-13 weeks. The results were heterogeneous, and the
effect size for pain reduction was 0.32 (0.24 to 0.39) in a random
effects model. In 10 trials that did not exclude non-responders to NSAID
treatment the results were homogeneous, with an effect size for pain
reduction of 0.23 (0.15 to 0.31).
Conclusion NSAIDs can reduce short term pain in osteoarthritis of the
knee slightly better than placebo, but the current analysis does not
support long term use of NSAIDs for this condition. As serious adverse
effects are associated with oral NSAIDs, only limited use can be
recommended.
© 2004 BMJ Publishing Group Ltd
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Is drug regulation failing?
by malernee » Sat Nov 27, 2004 6:16 pm
BMJ 2004;329 (27 November), doi:10.1136/bmj.329.7477.0-g
Editor's choice
Is drug regulation failing?
Something is rotten at the heart of the FDA. The United States Food and Drug Administration, mired in controversy over the last 12 months, now faces an extraordinary charge of attempting to discredit a whistleblower. As this week's issue reveals, David Graham, the FDA's associate director of drug safety, was so bothered about the difficulties of presenting his data on rofecoxib (Vioxx) in the Lancet that he took his case to the Government Accountability Group, a public interest group that protects whistleblowers. What was extraordinary, reports Jeanne Lenzer on p 1255, was that an FDA manager then called the accountability group to rubbish Graham's account and accuse him of scientific misconduct. In a quandary, the accountability group checked both sides of the story, and found that Graham's version was perfectly credible, while the FDA agent's version failed every test of credibility. It says something of the turmoil within the FDA that when Graham returned to work after giving his damning testimony at Senate hearings—he described the approval of rofecoxib as the "single greatest drug safety catastrophe in the history of the world"—he received a standing ovation from his colleagues (p 1253).
His testimony raises serious questions about the ability of the FDA to fulfil its role as regulator. The dangers of rofecoxib were apparent eight years ago and not acted upon, the harms suppressed. What has now unfolded may be the most serious example of regulatory failings about drug related harm since the thalidomide scandal, suggests Graham. Apart from questions around scientific credibility and accusations of being too close to industry ( BMJ 2004;329: 189[Free Full Text]), the FDA has spent much of the year defending itself against allegations that its decision not to offer over the counter emergency contraception—imaginatively named plan B—was politically motivated ( BMJ 2004;328: 1219[Free Full Text]). Ray Moynihan offers another example that will test the FDA's decision making, this time around indication creep, with its fast track review of testosterone patches for hypoactive sexual disorder (p 1255, p 1294). The patches increase sexual activity by one "episode"—or less—per month.
Not that UK regulators need be smug. This year's paroxetine saga has tarred the Medicines and Healthcare products Regulatory Agency with the brush of industry bias ( BMJ 2004;329: 865[Free Full Text]), and I was surprised to discover the extent to which senior policy makers at a meeting to discuss futures for the NHS saw the drug industry as an essential financer of research and development with barely an acknowledgement of issues of transparency, competing interests, and disentangling the relationship between drug companies and drug regulators. The FDA and MRHA are two of the world's leading drug regulators and their reputations have taken a battering. When will they show that their primary role is to protect the public and not to protect industry?
Kamran Abbasi, acting editor
Editor's choice
Is drug regulation failing?
Something is rotten at the heart of the FDA. The United States Food and Drug Administration, mired in controversy over the last 12 months, now faces an extraordinary charge of attempting to discredit a whistleblower. As this week's issue reveals, David Graham, the FDA's associate director of drug safety, was so bothered about the difficulties of presenting his data on rofecoxib (Vioxx) in the Lancet that he took his case to the Government Accountability Group, a public interest group that protects whistleblowers. What was extraordinary, reports Jeanne Lenzer on p 1255, was that an FDA manager then called the accountability group to rubbish Graham's account and accuse him of scientific misconduct. In a quandary, the accountability group checked both sides of the story, and found that Graham's version was perfectly credible, while the FDA agent's version failed every test of credibility. It says something of the turmoil within the FDA that when Graham returned to work after giving his damning testimony at Senate hearings—he described the approval of rofecoxib as the "single greatest drug safety catastrophe in the history of the world"—he received a standing ovation from his colleagues (p 1253).
His testimony raises serious questions about the ability of the FDA to fulfil its role as regulator. The dangers of rofecoxib were apparent eight years ago and not acted upon, the harms suppressed. What has now unfolded may be the most serious example of regulatory failings about drug related harm since the thalidomide scandal, suggests Graham. Apart from questions around scientific credibility and accusations of being too close to industry ( BMJ 2004;329: 189[Free Full Text]), the FDA has spent much of the year defending itself against allegations that its decision not to offer over the counter emergency contraception—imaginatively named plan B—was politically motivated ( BMJ 2004;328: 1219[Free Full Text]). Ray Moynihan offers another example that will test the FDA's decision making, this time around indication creep, with its fast track review of testosterone patches for hypoactive sexual disorder (p 1255, p 1294). The patches increase sexual activity by one "episode"—or less—per month.
Not that UK regulators need be smug. This year's paroxetine saga has tarred the Medicines and Healthcare products Regulatory Agency with the brush of industry bias ( BMJ 2004;329: 865[Free Full Text]), and I was surprised to discover the extent to which senior policy makers at a meeting to discuss futures for the NHS saw the drug industry as an essential financer of research and development with barely an acknowledgement of issues of transparency, competing interests, and disentangling the relationship between drug companies and drug regulators. The FDA and MRHA are two of the world's leading drug regulators and their reputations have taken a battering. When will they show that their primary role is to protect the public and not to protect industry?
Kamran Abbasi, acting editor
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fda review not for pet COX-2 inhibitors drugs Linda Grassie
by malernee » Wed Dec 15, 2004 9:49 am
Dear Dr. Malernee:
Thank you for sharing your views about reviewing COX-2 inhibitors approved for pets.
At this time, FDA does not plan to include the veterinary products in the panel review of the human products.
FDA's Center for Veterinary Medicine is constantly screening the data for new Adverse Drug Experiences (ADEs), including cardiac ADEs. But, we do not receive many ADEs involving cardiac or brain infarction signs for COX-2 inhibitors or other drugs.
As you know, there are considerable differences between the diagnostic procedures for pets and humans and the reporting of ADEs from veterinary and human drugs. It is extremely common for physicians to diagnose myocardial infarctions and strokes and extremely uncommon for veterinarians to diagnose them. Most veterinarians do not order MRIs or CT scans that are very common diagnostic tools for humans.
Please be assured that we will continue to monitor these and other veterinary drugs and to look for signals of unusual frequency and severity. If you or your colleagues are aware of such ADEs, please report them to CVM. This is a link to information on reporting ADEs to us -- http://www.fda.gov/cvm/index/ade/adereporting.htm
Thank you again for sharing your views.
Sincerely yours,
Linda A. Grassie
Communications Staff
FDA/Center for Veterinary Medicine
Thank you for sharing your views about reviewing COX-2 inhibitors approved for pets.
At this time, FDA does not plan to include the veterinary products in the panel review of the human products.
FDA's Center for Veterinary Medicine is constantly screening the data for new Adverse Drug Experiences (ADEs), including cardiac ADEs. But, we do not receive many ADEs involving cardiac or brain infarction signs for COX-2 inhibitors or other drugs.
As you know, there are considerable differences between the diagnostic procedures for pets and humans and the reporting of ADEs from veterinary and human drugs. It is extremely common for physicians to diagnose myocardial infarctions and strokes and extremely uncommon for veterinarians to diagnose them. Most veterinarians do not order MRIs or CT scans that are very common diagnostic tools for humans.
Please be assured that we will continue to monitor these and other veterinary drugs and to look for signals of unusual frequency and severity. If you or your colleagues are aware of such ADEs, please report them to CVM. This is a link to information on reporting ADEs to us -- http://www.fda.gov/cvm/index/ade/adereporting.htm
Thank you again for sharing your views.
Sincerely yours,
Linda A. Grassie
Communications Staff
FDA/Center for Veterinary Medicine
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are cox2s safer than other nsaids ?
by malernee » Wed Dec 15, 2004 10:06 am
There is conflicting information on the GI safety of cox2s compared to NSAIDS.
http://www.fda.gov/bbs/topics/ANSWERS/2 ... 01151.html
Celecoxib Long-term Arthritis Safety Study (CLASS).
>>FDA agreed with its Advisory Committee recommendations of February 7, 2001
that CLASS did not show a safety advantage in upper gastrointestinal (GI)
events for Celebrex compared to either ibuprofen or diclofenac. Inclusion of
patients on low-dose aspirin in the study was valuable for safety assessment of
Celebrex in this important population of arthritis sufferers. However, the use of
aspirin (a drug known to cause stomach ulcers and bleeding) may have obscured
the ability to accurately compare the GI safety of Celebrex to other
nonsteroidal anti-inflammatory drugs. The agency concluded that the drug labeling for
Celebrex should continue to include the standard warning for doctors and their
patients about risks associated with all NSAIDS, including risks of GI
ulceration, bleeding and perforation. The labeling advises physicians prescribing
and patients taking these drugs to be alert for ulceration and bleeding that can
occur with or without warning.>>
Another assessment(reported in JAMA, vol. 286 no.19) of CLASS made this
claim:
>The authors of the CLASS trial1 reported that celecoxib caused fewer
symptomatic ulcers and ulcer complications than did diclofenac or ibuprofen at 6
months of follow-up.1 We are concerned that subsequent information from the trial,
which is available on the US Food and Drug Administration (FDA) Web site,
appears to contradict these conclusions. As described on the FDA Web site, the
published CLASS trial differs from the original protocol in primary outcomes,
statistical analysis, trial duration, and conclusions. In particular, the
unpublished data show that by week 65, celecoxib was associated with a similar
number of ulcer complications as diclofenac and ibuprofen.>>
http://jama.ama-assn.org/cgi/content/ex ... =&HITS=10&
hits=10&RESULTFORMAT=&fulltext=Celebrex&searchid=1103111735292_946&
stored_search=&FIRSTINDEX=0&journalcode=jama
http://www.fda.gov/bbs/topics/ANSWERS/2 ... 01151.html
Celecoxib Long-term Arthritis Safety Study (CLASS).
>>FDA agreed with its Advisory Committee recommendations of February 7, 2001
that CLASS did not show a safety advantage in upper gastrointestinal (GI)
events for Celebrex compared to either ibuprofen or diclofenac. Inclusion of
patients on low-dose aspirin in the study was valuable for safety assessment of
Celebrex in this important population of arthritis sufferers. However, the use of
aspirin (a drug known to cause stomach ulcers and bleeding) may have obscured
the ability to accurately compare the GI safety of Celebrex to other
nonsteroidal anti-inflammatory drugs. The agency concluded that the drug labeling for
Celebrex should continue to include the standard warning for doctors and their
patients about risks associated with all NSAIDS, including risks of GI
ulceration, bleeding and perforation. The labeling advises physicians prescribing
and patients taking these drugs to be alert for ulceration and bleeding that can
occur with or without warning.>>
Another assessment(reported in JAMA, vol. 286 no.19) of CLASS made this
claim:
>The authors of the CLASS trial1 reported that celecoxib caused fewer
symptomatic ulcers and ulcer complications than did diclofenac or ibuprofen at 6
months of follow-up.1 We are concerned that subsequent information from the trial,
which is available on the US Food and Drug Administration (FDA) Web site,
appears to contradict these conclusions. As described on the FDA Web site, the
published CLASS trial differs from the original protocol in primary outcomes,
statistical analysis, trial duration, and conclusions. In particular, the
unpublished data show that by week 65, celecoxib was associated with a similar
number of ulcer complications as diclofenac and ibuprofen.>>
http://jama.ama-assn.org/cgi/content/ex ... =&HITS=10&
hits=10&RESULTFORMAT=&fulltext=Celebrex&searchid=1103111735292_946&
stored_search=&FIRSTINDEX=0&journalcode=jama
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fda marcia larkins dvm COX-2 inhibitors in pets letter
by malernee » Wed Dec 15, 2004 11:06 am
Dear Dr. Malernee,
This is to acknowledge the receipt of your email in which you expressed your concerns about the use of COX-2 inhibitors in pets. Linda Grassie of the Communications Staff has provided a response to your comments.
If I can be of any further assistance you can contact me by email or by phone.
Marcia K. Larkins D.V.M.
Ombudsman
Center for Veterinary Medicine
(Voice) 301-827-4535
(Fax) 301-827-5505
-----Original Message-----
From: Artjamie@aol.com [mailto:Artjamie@aol.com]
Sent: Friday, December 10, 2004 7:53 PM
To: mlarkins@cvm.fda.gov; lindagrassie@fda.gov; tmoskal@cvm.fda.gov
Subject: pet COX-2 inhibitors
The FDA is convening a panel in February to review all COX-2 inhibitors. That review should include those COX-2 inhibitors approved for pets. Most are sold to be given daily for long term osteoarthritis treatment. Do you really want these drugs used this way? If so lets see some data they are safe and efficacious.
art malernee dvm
This is to acknowledge the receipt of your email in which you expressed your concerns about the use of COX-2 inhibitors in pets. Linda Grassie of the Communications Staff has provided a response to your comments.
If I can be of any further assistance you can contact me by email or by phone.
Marcia K. Larkins D.V.M.
Ombudsman
Center for Veterinary Medicine
(Voice) 301-827-4535
(Fax) 301-827-5505
-----Original Message-----
From: Artjamie@aol.com [mailto:Artjamie@aol.com]
Sent: Friday, December 10, 2004 7:53 PM
To: mlarkins@cvm.fda.gov; lindagrassie@fda.gov; tmoskal@cvm.fda.gov
Subject: pet COX-2 inhibitors
The FDA is convening a panel in February to review all COX-2 inhibitors. That review should include those COX-2 inhibitors approved for pets. Most are sold to be given daily for long term osteoarthritis treatment. Do you really want these drugs used this way? If so lets see some data they are safe and efficacious.
art malernee dvm
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half a pfizer study
by malernee » Sun Dec 19, 2004 8:07 pm
This is a prime example of the way clinical trial results can be
manipulated. Since the results of the first six months of the Celebrex
study were favorable to Celebrex but the entire study was not, they only
reported the results for the first six months. By the time this was
discovered, everyone had already swallowed the 'safer for the stomach'
hype whole. As a matter of fact, the first widely publicized deaths
from the human cox 2 inhibitors were from sudden GI perforation. There
have been a number of deaths reported for the doggie cox 2 NSAID
Deramaxx from GI perforation.
manipulated. Since the results of the first six months of the Celebrex
study were favorable to Celebrex but the entire study was not, they only
reported the results for the first six months. By the time this was
discovered, everyone had already swallowed the 'safer for the stomach'
hype whole. As a matter of fact, the first widely publicized deaths
from the human cox 2 inhibitors were from sudden GI perforation. There
have been a number of deaths reported for the doggie cox 2 NSAID
Deramaxx from GI perforation.
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COX-2 enzyme is a “cardioprotective protein
by malernee » Sat Dec 25, 2004 7:05 am
Dec. 17, 2004
Public Citizen to Call on FDA to Ban Celebrex and Bextra
Statement of Dr. Sidney Wolfe, Director of Public Citizen’s Health Research Group
Even before today’s announcement by Pfizer about the heart attack risks associated with Celebrex, Public Citizen’s Health Research Group was preparing a petition to the U.S. Food and Drug Administration (FDA) to ban both Celebrex and the other Pfizer COX-2 drug, Bextra. In February 2001, we testified at an FDA advisory committee hearing that the cardiac risks of Celebrex (and Vioxx) demanded a black box warning for both drugs. Two months later, in the April 2001 issue of our newsletter Worst Pills, Best Pills News (now online at www.worstpills.org), we urged patients not to use either drug because there are safer alternatives.
Today’s announcement by Pfizer is quite misleading because the company states that “These clinical trial results are new. The cardiovascular findings in one of the studies (APC) are unexpected.” Four years ago, after reviewing the results of the Pfizer-funded CLASS study, an FDA physician stated that “the incidence of adverse events related to cardiac ischemia (decreased blood flow to the heart) was higher in the celecoxib [Celebrex] group ... and was most pronounced in the group of patients not taking ASA (aspirin)” as a cardiovascular protective drug. In these patients, the rate of heart attack was also highest in the celecoxib group (0.2 percent) compared with users of the other two drugs (0.1 percent). For all patients, on and off aspirin, there was a higher incidence of atrial fibrillation, a type of heart rhythm disturbance, in the celecoxib group compared to those taking ibuprofen or diclofenac. Again this was more pronounced in the group not taking aspirin. Dr. Throckmorton concluded by stating that “the data do not exclude a less apparent pro-thrombotic [blood clot-forming] effect of celecoxib, reflected in the relative rates of cardiac adverse events related to ischemia.”
Even earlier evidence of the danger of Celebrex was published more than four years ago. In a study in the Aug. 29, 2000, Proceedings of the National Academy of Sciences, the ability of rabbits to withstand temporary experimental coronary artery occlusion (experimental heart attack) was significantly impaired by treatment with celecoxib (Celebrex), which completely blocked the cardioprotective effects of the COX-2 enzyme. The authors of that study concluded that COX-2 enzyme is a “cardioprotective protein.” Therefore, it is implied, drugs that block this cardioprotective enzyme, such as COX-2 inhibitors, may neutralize the protective effects of this important enzyme.
The FDA should remove Celebrex and Bextra from the market immediately.
Please visit www.worstpills.org for more information.
Public Citizen to Call on FDA to Ban Celebrex and Bextra
Statement of Dr. Sidney Wolfe, Director of Public Citizen’s Health Research Group
Even before today’s announcement by Pfizer about the heart attack risks associated with Celebrex, Public Citizen’s Health Research Group was preparing a petition to the U.S. Food and Drug Administration (FDA) to ban both Celebrex and the other Pfizer COX-2 drug, Bextra. In February 2001, we testified at an FDA advisory committee hearing that the cardiac risks of Celebrex (and Vioxx) demanded a black box warning for both drugs. Two months later, in the April 2001 issue of our newsletter Worst Pills, Best Pills News (now online at www.worstpills.org), we urged patients not to use either drug because there are safer alternatives.
Today’s announcement by Pfizer is quite misleading because the company states that “These clinical trial results are new. The cardiovascular findings in one of the studies (APC) are unexpected.” Four years ago, after reviewing the results of the Pfizer-funded CLASS study, an FDA physician stated that “the incidence of adverse events related to cardiac ischemia (decreased blood flow to the heart) was higher in the celecoxib [Celebrex] group ... and was most pronounced in the group of patients not taking ASA (aspirin)” as a cardiovascular protective drug. In these patients, the rate of heart attack was also highest in the celecoxib group (0.2 percent) compared with users of the other two drugs (0.1 percent). For all patients, on and off aspirin, there was a higher incidence of atrial fibrillation, a type of heart rhythm disturbance, in the celecoxib group compared to those taking ibuprofen or diclofenac. Again this was more pronounced in the group not taking aspirin. Dr. Throckmorton concluded by stating that “the data do not exclude a less apparent pro-thrombotic [blood clot-forming] effect of celecoxib, reflected in the relative rates of cardiac adverse events related to ischemia.”
Even earlier evidence of the danger of Celebrex was published more than four years ago. In a study in the Aug. 29, 2000, Proceedings of the National Academy of Sciences, the ability of rabbits to withstand temporary experimental coronary artery occlusion (experimental heart attack) was significantly impaired by treatment with celecoxib (Celebrex), which completely blocked the cardioprotective effects of the COX-2 enzyme. The authors of that study concluded that COX-2 enzyme is a “cardioprotective protein.” Therefore, it is implied, drugs that block this cardioprotective enzyme, such as COX-2 inhibitors, may neutralize the protective effects of this important enzyme.
The FDA should remove Celebrex and Bextra from the market immediately.
Please visit www.worstpills.org for more information.
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nyt article MEDICINE'S DATA GAP
by malernee » Thu Dec 30, 2004 6:36 am
MEDICINE'S DATA GAP
Doctors, Too, Ask: Is This Drug Right?
By BARRY MEIER
Published: December 30, 2004
cross the country, doctors are struggling to decide which pain relievers to prescribe now that they know that popular drugs like Vioxx and Celebrex pose potentially serious heart risks. "We are desperately in need of information," said Dr. Stephen Brenner, an internist in New Haven. Yet for at least two years, doctors at the Mayo Clinic, the federal Veterans Affairs Department and the Kaiser Permanente health plan have been sharply limiting their use of Vioxx and Celebrex.
That is because those three institutions, after undertaking separate reviews of test data available on various painkillers, reached the same conclusion: For most patients, Vioxx, Celebrex and a related drug, Bextra, did not work any better than older pain relievers or provide any safety benefits beyond them.
A growing number of health care organizations have in recent years taken rigorous steps to close one of medicine's biggest information gaps. They are scrutinizing findings about all drugs, new and old, available to treat a particular health condition to determine which work best at the lowest cost.
Such evidence-based reviews, as they are known, are an effort to separate scientific wheat from chaff by examining not just the quantity, but also the quality of clinical trials and studies on a given drug. They also seek to determine how a drug's risks and benefits stack up against competing treatments. These reviews have been applied to every major category of medication, from blood pressure treatment to antidepressants.
Practitioners like Dr. Brenner do not typically consult such reviews when deciding which drugs to prescribe, but instead rely on their own experience. But that may change as government agencies and academic centers disseminate drug review research more broadly.
The drive to base medical practice on such reviews is not new, but it is taking on more urgency as health care costs rise and many newer drugs prove to be only marginally better, if that, than older ones.
Dr. Eric L. Matteson, a rheumatologist with the Mayo Clinic, said such reviews also help to counterbalance the forces that influence doctors in writing prescriptions, like drug company pitches, medical specialists championing certain medicines and patients eager to get the latest drug advertised on television.
"The pressures to prescribe are enormous," Dr. Matteson said. "You constantly have people at your door."
One of the leading institutions doing drug class reviews is the Evidence-based Practice Center at Oregon Health and Science University in Portland. In recent years, some states have started to use reviews produced by the center to draw up lists for preferred drugs that their Medicaid programs will cover.
Today, about 12 states, including Washington, Oregon and Missouri, use the center's reports to differing degrees.
Earlier this month, the federal government announced that it was planning to spend $15 million in coming years to pay for evidence-based reviews that will compare the effectiveness of various procedures and drugs used to treat 10 of the most common health conditions, including stroke, arthritis, pneumonia, diabetes and ulcers. The studies will be made available to doctors and the public as well as to government and private health plans.
Physicians like Dr. Brenner may welcome the help in deciding which painkillers are appropriate for certain patients. In recent weeks, studies have linked Vioxx, Bextra and Celebrex - all of which are in the class of drugs known as COX-2 inhibitors - to increased heart risks under certain conditions. In late September, Vioxx was withdrawn from the market by its manufacturer, Merck. Pfizer, the maker of Bextra and Celebrex, continues to sell both drugs but has limited marketing.
Another recent study has suggested that an older pain reliever, naproxen, which is sold as Aleve, might also increase heart attacks, though several experts said the Aleve data was less troubling because the numbers appeared too small to be statistically significant. Drug companies say they support the idea of evidence-based medicine. But they also contend that the Oregon center's approach is more about cutting costs than about science.
"What Oregon is doing is hiding a cost-cutting agenda that they are marketing widely under the rubric of evidence-based medicine," said Dr. Mark Horn, the medical director for the government relations group at Pfizer. Dr. Mark Helfand, the director of the Oregon center, dismissed that suggestion.
And Dr. Matteson said he had heard similar complaints about the Mayo Clinic's work from drug company representatives. "We've had plenty of criticism from the representatives of different companies that market these drugs to us that we are just looking at the bottom line and not to the patient's best interest," he said.
Advocates of evidence-based reviews say they can help make sense of the incomplete and conflicting state of knowledge about different drugs used for the same problem. Newer drugs, for example, are typically tested more extensively than older ones, and not all drugs in the same class are tested against each other. Moreover, the quality of clinical drug trials run on each drug and their relevance to medical practice can also vary sharply.
Those advocates have also long called upon pharmaceutical companies to disclose all clinical trials run on a drug so that all evidence about the drug is available to the public. Legislation to require companies to register their drug trials was recently introduced in Congress.
To do an analysis, researchers try to pull together published and unpublished clinical trials and studies about all drugs in a treatment class by doing extensive literature reviews and asking pharmaceutical companies for data. They analyze the studies to determine their scientific rigor, eliminating those that they believe do not make the cut. Even clinical trials, which are considered the most thorough because they test medications under controlled conditions, can be flawed or misleading because of their design.
"The biggest contribution that we make is in laying out the evidence," Dr. Helfand said.
Because responses to pain relievers varies among individuals, a drug that works for one patient might not work for another. But after reviewing all relevant data, the Oregon group and others doing similar studies decided that Vioxx, Celebrex and Bextra did not relieve arthritis-related pain any better than other drugs they had been tested against, like ibuprofen, which is also a nonsteroidal anti-inflammatory drug, or Nsaid.
In terms of safety, Vioxx showed the strongest evidence of reducing the incidence of stomach bleeding associated with older Nsaids. Stomach bleeding is a problem that is generally limited to older patients or those with a history of gastrointestinal problems.
So even as the prescribing of COX-2 drugs by doctors in general was increasing, the use of these drugs by doctors working for organizations doing evidence-based studies was falling.
Doctors working for the Veterans Affairs Department have been curtailing their use of COX-2 drugs since late 2001. The Mayo Clinic decided two years ago to cut down its use of the medications by 50 percent.
Those groups and Kaiser Permanente, which also sharply limited its COX-2 prescriptions, saved money. Their actions may have also saved lives. A study conducted by an F.D.A. researcher that was released in September found that Kaiser patients relied on high doses of Vioxx, which can increase the risk of heart attacks, less than half as often as the general population.
In undertaking its drug review, Veterans Affairs also re-examined the value of a lesser-known pain reliever, etodolac, and began using it more. The drug was first sold in 1991 as Lodine by a company that is now part of GlaxoSmithKline. Like many older medications, however, it was not extensively tested.
A study based on a review of V.A. patient records that was published last month in a medical journal, Gastroenterology, found that the rate of stomach bleeding caused by etodolac was substantially lower than that caused by naproxen and comparable to that of Vioxx.
Dr. Byron Cryer, a researcher at the University of Texas Southwestern Medical School in Dallas who led the study, said his group was reviewing those same patient records in effort to determine whether etodolac increased heart risks. Dr. Cryer said that analysis should be completed in about a month.
Dr. David Campen, a medical director at Kaiser, said that his organization had not yet changed its prescribing guidelines for Celebrex, which was reported to pose heart risks during a trial of the drug as a cancer treatment.
The Mayo system, which operates hospitals and clinics in several states, meanwhile, has decided to reduce its use of the COX-2 drug even further.
Previously, any patient over 60 qualified for Celebrex, Dr. Matteson said. But earlier this month, a group of Mayo Clinic doctors, epidemiologists and pharmacists, after reviewing old and new test data, decided to limit the drug's use to patients at risk of stomach bleeding or to others with highly specific conditions.
Doctors, Too, Ask: Is This Drug Right?
By BARRY MEIER
Published: December 30, 2004
cross the country, doctors are struggling to decide which pain relievers to prescribe now that they know that popular drugs like Vioxx and Celebrex pose potentially serious heart risks. "We are desperately in need of information," said Dr. Stephen Brenner, an internist in New Haven. Yet for at least two years, doctors at the Mayo Clinic, the federal Veterans Affairs Department and the Kaiser Permanente health plan have been sharply limiting their use of Vioxx and Celebrex.
That is because those three institutions, after undertaking separate reviews of test data available on various painkillers, reached the same conclusion: For most patients, Vioxx, Celebrex and a related drug, Bextra, did not work any better than older pain relievers or provide any safety benefits beyond them.
A growing number of health care organizations have in recent years taken rigorous steps to close one of medicine's biggest information gaps. They are scrutinizing findings about all drugs, new and old, available to treat a particular health condition to determine which work best at the lowest cost.
Such evidence-based reviews, as they are known, are an effort to separate scientific wheat from chaff by examining not just the quantity, but also the quality of clinical trials and studies on a given drug. They also seek to determine how a drug's risks and benefits stack up against competing treatments. These reviews have been applied to every major category of medication, from blood pressure treatment to antidepressants.
Practitioners like Dr. Brenner do not typically consult such reviews when deciding which drugs to prescribe, but instead rely on their own experience. But that may change as government agencies and academic centers disseminate drug review research more broadly.
The drive to base medical practice on such reviews is not new, but it is taking on more urgency as health care costs rise and many newer drugs prove to be only marginally better, if that, than older ones.
Dr. Eric L. Matteson, a rheumatologist with the Mayo Clinic, said such reviews also help to counterbalance the forces that influence doctors in writing prescriptions, like drug company pitches, medical specialists championing certain medicines and patients eager to get the latest drug advertised on television.
"The pressures to prescribe are enormous," Dr. Matteson said. "You constantly have people at your door."
One of the leading institutions doing drug class reviews is the Evidence-based Practice Center at Oregon Health and Science University in Portland. In recent years, some states have started to use reviews produced by the center to draw up lists for preferred drugs that their Medicaid programs will cover.
Today, about 12 states, including Washington, Oregon and Missouri, use the center's reports to differing degrees.
Earlier this month, the federal government announced that it was planning to spend $15 million in coming years to pay for evidence-based reviews that will compare the effectiveness of various procedures and drugs used to treat 10 of the most common health conditions, including stroke, arthritis, pneumonia, diabetes and ulcers. The studies will be made available to doctors and the public as well as to government and private health plans.
Physicians like Dr. Brenner may welcome the help in deciding which painkillers are appropriate for certain patients. In recent weeks, studies have linked Vioxx, Bextra and Celebrex - all of which are in the class of drugs known as COX-2 inhibitors - to increased heart risks under certain conditions. In late September, Vioxx was withdrawn from the market by its manufacturer, Merck. Pfizer, the maker of Bextra and Celebrex, continues to sell both drugs but has limited marketing.
Another recent study has suggested that an older pain reliever, naproxen, which is sold as Aleve, might also increase heart attacks, though several experts said the Aleve data was less troubling because the numbers appeared too small to be statistically significant. Drug companies say they support the idea of evidence-based medicine. But they also contend that the Oregon center's approach is more about cutting costs than about science.
"What Oregon is doing is hiding a cost-cutting agenda that they are marketing widely under the rubric of evidence-based medicine," said Dr. Mark Horn, the medical director for the government relations group at Pfizer. Dr. Mark Helfand, the director of the Oregon center, dismissed that suggestion.
And Dr. Matteson said he had heard similar complaints about the Mayo Clinic's work from drug company representatives. "We've had plenty of criticism from the representatives of different companies that market these drugs to us that we are just looking at the bottom line and not to the patient's best interest," he said.
Advocates of evidence-based reviews say they can help make sense of the incomplete and conflicting state of knowledge about different drugs used for the same problem. Newer drugs, for example, are typically tested more extensively than older ones, and not all drugs in the same class are tested against each other. Moreover, the quality of clinical drug trials run on each drug and their relevance to medical practice can also vary sharply.
Those advocates have also long called upon pharmaceutical companies to disclose all clinical trials run on a drug so that all evidence about the drug is available to the public. Legislation to require companies to register their drug trials was recently introduced in Congress.
To do an analysis, researchers try to pull together published and unpublished clinical trials and studies about all drugs in a treatment class by doing extensive literature reviews and asking pharmaceutical companies for data. They analyze the studies to determine their scientific rigor, eliminating those that they believe do not make the cut. Even clinical trials, which are considered the most thorough because they test medications under controlled conditions, can be flawed or misleading because of their design.
"The biggest contribution that we make is in laying out the evidence," Dr. Helfand said.
Because responses to pain relievers varies among individuals, a drug that works for one patient might not work for another. But after reviewing all relevant data, the Oregon group and others doing similar studies decided that Vioxx, Celebrex and Bextra did not relieve arthritis-related pain any better than other drugs they had been tested against, like ibuprofen, which is also a nonsteroidal anti-inflammatory drug, or Nsaid.
In terms of safety, Vioxx showed the strongest evidence of reducing the incidence of stomach bleeding associated with older Nsaids. Stomach bleeding is a problem that is generally limited to older patients or those with a history of gastrointestinal problems.
So even as the prescribing of COX-2 drugs by doctors in general was increasing, the use of these drugs by doctors working for organizations doing evidence-based studies was falling.
Doctors working for the Veterans Affairs Department have been curtailing their use of COX-2 drugs since late 2001. The Mayo Clinic decided two years ago to cut down its use of the medications by 50 percent.
Those groups and Kaiser Permanente, which also sharply limited its COX-2 prescriptions, saved money. Their actions may have also saved lives. A study conducted by an F.D.A. researcher that was released in September found that Kaiser patients relied on high doses of Vioxx, which can increase the risk of heart attacks, less than half as often as the general population.
In undertaking its drug review, Veterans Affairs also re-examined the value of a lesser-known pain reliever, etodolac, and began using it more. The drug was first sold in 1991 as Lodine by a company that is now part of GlaxoSmithKline. Like many older medications, however, it was not extensively tested.
A study based on a review of V.A. patient records that was published last month in a medical journal, Gastroenterology, found that the rate of stomach bleeding caused by etodolac was substantially lower than that caused by naproxen and comparable to that of Vioxx.
Dr. Byron Cryer, a researcher at the University of Texas Southwestern Medical School in Dallas who led the study, said his group was reviewing those same patient records in effort to determine whether etodolac increased heart risks. Dr. Cryer said that analysis should be completed in about a month.
Dr. David Campen, a medical director at Kaiser, said that his organization had not yet changed its prescribing guidelines for Celebrex, which was reported to pose heart risks during a trial of the drug as a cancer treatment.
The Mayo system, which operates hospitals and clinics in several states, meanwhile, has decided to reduce its use of the COX-2 drug even further.
Previously, any patient over 60 qualified for Celebrex, Dr. Matteson said. But earlier this month, a group of Mayo Clinic doctors, epidemiologists and pharmacists, after reviewing old and new test data, decided to limit the drug's use to patients at risk of stomach bleeding or to others with highly specific conditions.
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