Pharmacokinetics: The
absolute bioavailabillty of PREVICOX™ (firocoxib) is approximately 38%
when administered as a 5 mg/kg oral dose to fasted adult dogs. Firocoxib
is rapidly cleared from the blood via hepatic metabolism and fecal
excretion (CLsystemic = ~0.4 L/hr/kg). Despite a high level of plasma
protein binding (96%), firocoxib exhibits a large volume of distribution
(Vdk of total drug = ~4.6 L/kg) and a
terminal elimination half life of 7.8 hours (%CV = 30%). The oral drug
absorption process is highly variable among subjects. Co-administration
of PREVICOX™ with food delays drug absorption (Tmax from 1 to 5 hours)
and decreases peak concentrations (Cmax from 1.3 to 0.9 mcg/mL).
However, food does not affect the overall oral bioavailability at the
recommended dose.
Indications: PREVICOX™ (firocoxib)
Chewable Tablets are indicated for the control of pain and inflammation
associated with osteoarthritis in dogs.
Dosage and Administration:
Always provide Client Information Sheet with prescription. The
recommended dosage of PREVICOX™ (firocoxib) for oral administration in
dogs is 2.27 mg/lb (5 mg/kg) body weight once daily. The tablets are
scored and dosage should be calculated in half tablet increments.
PREVICOX™ Chewable Tablets can be administered with or without food.
Contraindications: Dogs with
hypersensitivity to firocoxib or other NSAIDs should not receive
PREVICOX™ Chewable Tablets.
Warnings: Not for use in
humans. Keep this and all medications out of the reach of children.
Consult a physician in case of accidental ingestion by humans.
For oral use in dogs only. Use
of this product at doses above the recommended 2.27 mg/lb (5.0 mg/kg) in
puppies less than seven months of age has been associated with serious
adverse reactions, including death.
All dogs should undergo a thorough history and physical
examination before the initiation of NSAID therapy. Appropriate
laboratory testing to establish hematological and serum baseline data is
recommended prior to and periodically during administration of any NSAID.
Owners should be advised to observe for signs of
potential drug toxicity (see Adverse Reactions and Animal Safety) and be
given a Client Information Sheet about PREVICOX™ Chewable Tablets.
Precautions: This product
cannot be dosed accurately in dogs less than seven pounds in body
weight.
Consider appropriate washout times when switching from
one NSAID to another.
As a class, cyclooxygenase inhibitory NSAIDs may be
associated with renal and gastrointestinal toxicity. Sensitivity to
drug-associated adverse events varies with the individual patient.
Patients at greatest risk for renal toxicity are those that are
dehydrated, on concomitant diuretic therapy, or those with existing
renal, cardiovascular, and/or hepatic dysfunction. Concurrent
administration of potentially nephrotoxic drugs should be carefully
approached. NSAIDs may inhibit the prostaglandins that maintain normal
homeostatic function. Such antiprostaglandin effects may result in
clinically significant disease in patients with underlying or
pre-existing disease that has not been previously diagnosed. Since many
NSAIDs possess the potential to produce gastrointestinal ulcerations,
concomitant use with other anti-inflammatory drugs, such as NSAIDs or
corticosteroids, should be avoided or closely monitored. The concomitant
use of protein bound drugs with PREVICOX™ Chewable Tablets has not been
studied in dogs. Commonly used protein-bound drugs include cardiac,
anticonvulsant, and behavioral medications. The influence of concomitant
drugs that may inhibit the metabolism of PREVICOX™ Chewable Tablets has
not been evaluated. Drug compatibility should be monitored in patients
requiring adjunctive therapy.
The safe use of PREVICOX™ Chewable Tablets in pregnant,
lactating or breeding dogs has not been evaluated.
Adverse Reactions: In
controlled field studies, 128 dogs (ages 11 months to 15 years) were
evaluated for safety when given PREVICOX™ Chewable Tablets at a dose of
5.0 mg/kg orally once daily far 30 days. The following adverse reactions
were observed. Dogs may have experienced more than one of the observed
adverse reactions during the study.
Adverse Reactions Seen in U.S. Field
Studies
|
Adverse Reactions |
Previcox™
n=128 |
Active Control
n=121 |
|
Vomiting |
5 |
8 |
|
Diarrhea |
1 |
10 |
|
Decreased Appetite or Anorexia |
3 |
3 |
|
Lethargy |
1 |
3 |
|
Pain |
2 |
1 |
|
Somnolence |
1 |
1 |
|
Hyperactivity |
1 |
0 |
PREVICOX™ (firocoxib) Chewable Tablets were safely used
during field studies concomitantly with other therapies, including
vaccines, anthelmintics, and antibiotics.
Clinical Pharmacology:
Mode of action: PREVICOX™ (firocoxib) is a cyclooxygenase-inhibiting (coxib)
class, non-narcotic, non-steroidal anti-inflammatory drug (NSAID) with
anti-inflammatory and analgesic properties. There are two main
cyclooxygenase enzymes, COX-1 and COX-2, and a newly discovered third
enzyme, COX-3, which has yet to be fully characterized. Cyclooxygenase-1
(COX-1) is the enzyme responsible for facilitating constitutive
physiologic processes, e.g., platelet aggregation, gastric mucosal
protection, and renal perfusion. It also is constitutively expressed in
the brain, spinal cord, and reproductive tract. Cyclooxygenase-2 (COX-2)
is responsible for the synthesis of inflammatory mediators, but it is
also constitutively expressed in the brain, spinal cord and kldneys.
Cyclooxygenase-3 (COX-3) is also constitutively expressed in the canine
and human brain and also the human heart. Results from
in vitro studies showed firocoxib to be highly
selective for the COX-2 enzyme when canine blood was exposed to drug
concentrations comparable to those observed following a once daily 5
mg/kg oral dose in dogs. However, the clinical significance of these
findings has not been established.
Effectiveness: Two hundred
and forty-nine dogs of various breeds, ranging in age from 11 months to
20 years, and weighing 13 to 175 lbs, were randomly administered
PREVICOX™ or an active control drug in two field studies. Dogs were
assessed for lameness, pain on manipulation, range of motion, joint
swelling, and overall improvement in a non-inferiority evaluation of
PREVICOX™ compared with the active control. At the study's end, 87% of
the owners rated PREVICOX™-treated dogs as improved. Eighty-eight
percent of dogs treated with PREVICOX™ were also judged improved by the
veterinarians. Dogs treated with PREVICOX™ showed a level of improvement
in veterinarian-assessed lameness, pain on palpation, range of motion,
and owner-assessed improvement that was comparable to the active
control. The level of improvement in PREVICOX™-treated dogs in limb
weight bearing on the force plate gait analysis assessment was
comparable t the active control.
Palatability: PREVICOX™
Chewable Tablets were rated both convenient to administer (97.2%) and
palatable to the dog (68.5%) by owners in multi-center field studies
involving client-owned dogs of various breeds and sizes.
Animal Safety: In a target
animal safety study, firocoxib was administered orally to healthy adult
Beagle dogs (eight dogs per group) at 5, 15, and 25 mg/kg (1, 3, and 5
times the recommended total dally dose) for 180 days. At the indicated
dose of 5 mg/kg, there were no treatment related adverse events.
Decreased appetite, vomiting, and diarrhea were seen in dogs in all dose
groups, including unmedicated controls, although vomiting and diarrhea
were seen more often in dogs in the 5X dose group. One dog in the 3X
dose group was diagnosed with juvenile polyarteritis of unknown etiology
after exhibiting recurrent episodes of vomiting and diarrhea, lethargy,
pain, anorexia, ataxia, proprioceptive deficits, decreased albumin
levels, decreased and then elevated platelet counts, increased bleeding
times, and elevated liver enzymes. On histopathologic examination, a
mild ileal ulcer was found in one 5X dog. This dog also had a decreased
serum albumin which returned to normal by study completion. One control
and three 5X dogs had focal areas of inflammation in the pylorus or
small intestine. Vacuolization without inflammatory cell infiltrates was
noted in the thalamic region of the brain in three control, one 3X, and
three 5X dogs. Mean ALP was within the normal range for all groups but
was greater in the 3X and 5X dose groups than in the control group.
Transient decreases in serum albumin were seen in multiple animals in
the 3X and 5X dose groups, and in one control animal.
In a separate safety study, firocoxib was administered
orally to healthy juvenile (10-13 weeks of age) Beagle dogs at 5, 15,
and 25 mg/kg (1, 3, and 5 times the recommended total daily dose) for
180 days. At the indicated (1X) dose of 5 mg/kg, on histopathologic
examination, three out of six dogs had minimal periportal hepatic fatty
change. On histopathologic examination, one control, one 1X, and two 5X
dogs had diffuse slight hepatic fatty change. These animals showed no
clinical signs and had no liver enzyme elevations. In the 3X dose group,
one dog was euthanized because of poor clinical condition (Day 63). This
dog also had a mildly decreased serum albumin. At study completion, out
of five surviving and clinically normal 3X dogs, three had minimal
periportal hepatic fatty change. Of twelve dogs in the 5X dose group,
one died (Day 82) and three moribund dogs were euthanized (Days 38, 78,
and 79) because of anorexia, poor weight gain, depression, and in one
dog, vomiting. One of the euthanized dogs had ingested a rope toy. Two
of these 5X dogs had mildly elevated liver enzymes. At necropsy all five
of the dogs that died or were euthanized had moderate periportal or
severe panzonal hepatic fatty change; two had duodenal ulceration; and
two had pancreatic edema. Of two other clinically normal 5X dogs (out of
four euthanized as comparators to the clinically affected dogs), one had
slight and one had moderate periportal hepatic fatty change. Drug
treatment was discontinued for four dogs in the 5X group. These dogs
survived the remaining 14 weeks of the study. On average, the dogs in
the 3X and 5X dose groups did not gain as much weight as control dogs.
Rate of weight gain was measured (instead of weight loss) because these
were young growing dogs. Thalamic vacuolation was seen in three of six
dogs in the 3X dose group, five of twelve dogs in the 5X dose group, and
to a lesser degree in two unmedicated controls. Diarrhea was seen in all
dose groups, including unmedicated controls.
In a separate dose tolerance safety study involving a
total of six dogs (two control dogs and four treated dogs), firocoxib
was administered to four healthy adult Beagle dogs at 50 mg/kg (ten
times the recommended daily dose) for twenty-two days. All dogs survived
to the end of the study. Three of the four treated dogs developed small
intestinal erosion or ulceration. Treated dogs that developed small
intestinal erosion or ulceration had a higher incidence of vomiting,
diarrhea, and decreased food consumption than control dogs. One of these
dogs had severe duodenal ulceration, with hepatic fatty change and
associated vomiting, diarrhea, anorexia, weight loss, ketonuria, and
mild elevations in AST and ALT. All four treated dogs exhibited
progressively decreasing serum albumin that, with the exception of one
dog that developed hypoalbuminemia, remained within normal range. Mild
weight loss also occurred in the treated group. One of the two control
dogs and three of the four treated dogs exhibited transient increases in
ALP that remained within normal range.
Storage: Store at room
temperature, between 59°-86° F (15°-30° C). Brief periods up to 104° F
(40° C) are permitted.
How Supplied: PREVICOX™ is
available as round, beige to tan, half-scored tablets in two strengths,
containing 57 mg or 227 mg firocoxib. Each tablet strength is supplied
in 10 count and 30 count blister packages and 60 count bottles.