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 (Vd_k 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.

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