Zubrin (tepoxalin) 200 mg, 90 Tablets

Intervet/Schering-Plough Animal Health

(tepoxalin)

Rapidly-Disintegrating Tablets

NON-STEROIDAL ANTI-INFLAMMATORY DRUG

NADA #141-193, Approved by FDA

FOR ORAL USE IN DOGS ONLY

CAUTION Federal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION Tepoxalin, 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide, has a melting range of 125° to 130°C, a molecular formula of C₂₀H₂₀CIN₃O₃, and a molecular weight of 385.84 g/mol. Tepoxalin is insoluble in water but soluble in alcohol and most organic solvents.

Tepoxalin is a white, crystalline, tasteless material. It is micronized and formulated into rapidly-disintegrating tablets. When administered orally, the tablets disintegrate in the mouth within seconds after placement on the tongue, allowing the contents to be subsequently swallowed.

CLINICAL PHARMACOLOGY Tepoxalin is a non-steroidal anti-inflammatory drug (NSAID) with antipyretic,¹ analgesic and anti-inflammatory activity. The mechanism of action of tepoxalin, like other NSAIDs, is believed to be associated with the inhibition of cyclooxygenase activity. Additionally, tepoxalin has been shown to be an inhibitor of lipoxygenase and is thus classified as a dual inhibitor of arachidonic acid metabolism.²

PHARMACOKINETICS IN THE DOG Tepoxalin is rapidly absorbed after oral administration. Its half-life in plasma is short due to conversion to an active metabolite. The active metabolite has a long half-life, which justifies once-daily dosing of ZUBRIN^® Tablets. Twelve fed dogs (6 male, 6 female) were administered ZUBRIN Tablets for 7 consecutive days. Tepoxalin therapy was initiated at 20 mg/kg on the first day (Day 0) followed by 10 mg/kg once daily for the next 6 days. Based on the results, there is no strong evidence of accumulation of tepoxalin, as demonstrated by comparisons of mean C_max, mean T_1/2, and mean AUC on Day 1 and Day 6 (see Table 1). Parent drug accumulation was also not apparent in safety studies where tepoxalin was administered at high doses, twice daily, for one to several months. However, as expected with a compound associated with a long terminal elimination half-life and a 2X initial dose on Day 0, levels of active metabolite were higher on the second day of dosing (Day 1) than on the first (Day 0). In most dogs given a 2X dose on Day 0 and a 1X dose thereafter, levels of active metabolite were similar on Day 1 and Day 6. Clinical signs of toxicity, as demonstrated in safety studies, were dose related rather than related to the duration of dosing (see SAFETY section).

Table 1. Summary of Mean Tepoxalin Pharmacokinetic Parameters in Dogs (+ Standard Deviation)

*Where AUC represents the area under the concentration/time curve over either one complete dosing interval (active metabolite) or to the last quantifiable concentration (tepoxalin).

**Standard deviation.

There is substantial intrasubject and intersubject variability associated with the pharmacokinetics of tepoxalin. As a result of the highly variable kinetics, it is recommended that when time to onset of pain relief is critical, therapy be initiated at a dose of 20 mg/kg to improve the likelihood that systemic drug concentrations rapidly and consistently exceed the minimum effective concentration of this compound and its active metabolite. This may be particularly important in an acute or peracute exacerbation of an osteoarthritic condition, when time to onset of pain relief is critical.

Tepoxalin is lipophilic, and it is effectively insoluble in water. Administration with food is expected to facilitate the solubilization of tepoxalin within the gastrointestinal fluids, thereby increasing its extent of oral absorption. An increase in drug bioavailability in the presence of food was suggested from the data conducted on six Beagle dogs to examine the impact of food on product bioavailability. For this reason, it is recommended that ZUBRIN Tablets be administered with food or within 1 to 2 hours after feeding.

Based on the total 14C analysis and radio-HPLC analysis, metabolic elimination of tepoxalin is rapid and extensive. The excretion pathway of radioactivity derived from a 14C-tepoxalin dose in the dog is almost exclusively in the feces (only ~1% of the radioactive dose, identified as unknown metabolites other than the active tepoxalin pyrazole acid, is recovered in urine).

INDICATIONS ZUBRIN^® 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.

Dosage: Administer 10 mg/kg (4.5 mg/lb) or 20 mg/kg (9.1 mg/lb) on the initial day of treatment, followed by a daily maintenance dose of 10 mg/kg. Due to observed variability in tepoxalin metabolism, a higher initial dose of 20 mg/kg may be given to increase the likelihood that plasma active metabolite levels will reach a minimum effective concentration following the first oral administration. This could be beneficial to dogs that show signs of severe osteoarthritic pain. The duration of treatment at 10 mg/kg should be based on clinical response and patient tolerance of drug treatment.

Administration: Place the rapidly-disintegrating tablet into the dog's mouth. Keep the mouth closed for a sufficient amount of time (~4 seconds) to ensure tablet dispersion.

ZUBRIN^® Tablets should be administered either with food or within 1 to 2 hours after feeding.

Due to tablet sizes, dogs weighing less than 3 kg (6.6 lbs) cannot be accurately dosed.

CONTRAINDICATIONS ZUBRIN^® Tablets should not be used in dogs exhibiting previous hypersensitivity to tepoxalin.

WARNINGS Animal safety: For oral use in dogs only. All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests should be conducted to establish hematological and serum biochemical baseline data before and periodically during administration of any NSAID. Owners should be advised to observe for signs of potential drug toxicity (see Client Information About ZUBRIN^® Tablets and ADVERSE REACTIONS).

User safety: Keep out of reach of children. Not for human use. Consult a physician in cases of accidental ingestion by humans.

For technical assistance or to report suspected adverse reactions, call 1-800-224-5318.

PRECAUTIONS

1. As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal and renal toxicity. When NSAIDs inhibit prostaglandins that cause inflammation, they may also inhibit prostaglandins that maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically significant disease in patients with underlying or preexisting disease more often than in healthy patients. Sensitivity to drug-associated adverse effects varies with the individual patient. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction.

2. Treatment with ZUBRIN^® Tablets should be terminated if signs such as inappetance, vomiting, fecal abnormalities, anemia, icterus, or lethargy are observed. Dogs treated with NSAIDs, including tepoxalin, should be evaluated periodically to ensure that the drug is still necessary and well tolerated. Owners should be advised to observe for signs of potential drug toxicity.

3. Since many NSAIDs possess the potential to induce gastric ulceration, concomitant use of ZUBRIN Tablets with any other anti-inflammatory drugs, such as other NSAIDs and corticosteroids, should be avoided or closely monitored.

4. Studies to determine the effect of ZUBRIN Tablets when administered concomitantly with other protein-bound drugs have not been conducted. Drug compatibility should be monitored closely in patients receiving adjunctive therapy.

5. The safety of ZUBRIN Tablets has not been investigated in breeding, pregnant, or lactating dogs, or in dogs younger than 6 months of age.

6. A significant number of patients receiving ZUBRIN Tablets are older animals. Prior to administration of this or any NSAID, it is advisable to conduct a geriatric examination and to consider appropriate laboratory tests to establish hematological and serum biochemical baseline data.

ADVERSE REACTIONS Field study: In the controlled field study, 101 dogs (age range 6 months to 18 years) were evaluated for safety when given ZUBRIN^® Tablets at a dose of 20 mg/kg on the first day, followed by daily administration of 10 mg/kg for 6 additional days. Table 2 shows the number of dogs displaying each clinical observation.

Table 2. Adverse Reactions Observed in Dogs That Participated in the Field Study Treated With ZUBRIN Tablets or Active Control for 7 Days

*Dogs may have experienced more than one of the observations during the study.

**Two days after the completion of the field study, one 9-year-old Labrador Retriever became seriously ill and subsequently died. Necropsy results showed multiple gastric ulcerations (3-8 mm), anemia, and severe diffuse gastroenteritis. The dog's death could not be definitively attributed to the administration of tepoxalin.

Field safety study: ZUBRIN Tablets were administered for 4 weeks in an uncontrolled field study to 107 adult dogs (age range 1 to 17 years), using the initial dose of 20 mg/kg on the first day, followed by daily administration of 10 mg/kg. The results of the field safety analysis yielded a higher number of gastrointestinal abnormalities compared with the 7-day field study. Table 3 shows the number of dogs displaying each clinical observation.

Table 3. Adverse Reactions Observed in Dogs That Participated in a Field Safety Study Treated With ZUBRIN Tablets for 28 Days

*Dogs may have experienced more than one of the observations during the study.

**This dog was a 12-year-old German Shepherd (with pretreatment elevated liver enzymes and WBC count) that experienced vomiting, diarrhea, inappetance, and GI blood loss during the study (from Days 3-12). ZUBRIN Tablet treatment was continued until Day 14, despite signs of NSAID intolerance and progressive systemic illness. IM steroids were administered after tepoxalin treatment was discontinued. Rapid clinical deterioration and death ensued.

This table does not include one dog that died following surgery for splenic torsion. This 8.5-year-old dog vomited repeatedly during the first 4 days of ZUBRIN Tablet treatment. Three days after termination of therapy, the dog presented with continuous vomiting and splenic torsion, followed by death the following morning. While the cause of death was definitively due to a splenic torsion, the investigator was unsure whether the splenic torsion initiated the dog's vomiting, or the vomiting initiated the splenic torsion.

EFFECTIVENESS A 7-day, controlled, masked field study evaluated the effectiveness of ZUBRIN^® Tablets in 62 dogs with osteoarthritis at the recommended dose (20 mg/kg on Day 0, followed by 10 mg/kg/day for 6 more days). Scored parameters included ambulation, weight-bearing, pain and resistance to palpation and forced movement, general attitude, and overall improvement. Pretreatment results were compared with results on Day 6. Results of the study showed statistically significant improvement for all parameters from Day 0 to Day 6 within the ZUBRIN Tablet group.

SAFETY Tepoxalin was administered to healthy adult dogs at doses of 0, 20, 100, or 300 mg/kg/day in one safety study for 6 months. In addition, a 1-year safety study evaluated 32 dogs using 0, 10, 30, or 100 mg/kg/day of tepoxalin. Pale yellow to white material was frequently observed in the feces of tepoxalin-treated dogs in both studies from 30 to 300 mg/kg/day. The material was probably tepoxalin that was not absorbed from the gastrointestinal tract.

Six-month study: In the 6-month study (56 dogs), two female dogs in the 300 mg/kg/day group had mild to moderate decreases in total protein, albumin, and calcium which were considered to be related to treatment (one dog at 6, 14, and 27 weeks and one dog at 27 weeks). One of the dogs developed neutrophilic leukocytosis, anemia, decreased serum total protein, decreased albumin, and decreased calcium as a result of chronic gastric ulceration. In the 20 mg/kg/day dose group, one dog showed RBC, Hb, and HCT decreases at Week 14 that returned to predosage levels by Week 27.

At 13 weeks, six dogs per treatment group were necropsied. Dogs in all dose groups showed evidence of gastric irritation (mucosal hemorrhage and congestion) after 13 weeks: one in the 0 mg/kg group, one in the 20 mg/kg group, three in the 100 mg/kg group, and two dogs in the 300 mg/kg group. One of the two dogs that received the highest dose (300 mg/kg) showed gastric ulceration at the mid-study necropsy. The ulcers were confirmed histologically. At the end of the 6-month study, the remaining eight dogs per group were necropsied. Necropsy results demonstrated gross gastric lesions in no dogs in the 0 mg/kg/day group, one dog in the 20 mg/kg/day group, two dogs in the 100 mg/kg/day group, and four dogs in the 300 mg/kg/day group. Gastric ulceration was confirmed by histopathology in the highest-dose group (300 mg/kg/day) in two of the four dogs with gross gastrointestinal abnormalities. Dogs with gross lesions in the lower dose groups showed histological evidence of gastric irritation (mucosal hemorrhage and congestion) after 6 months of treatment with tepoxalin.

One-year study: In the 1-year study (32 dogs), tepoxalin at 100 mg/kg/day caused gastric ulceration in two (of eight) dogs. Gastric mucosal hemorrhage was noted in a third dog. Emesis occurred more frequently in the 100 mg/kg/day group.

Field safety study: An uncontrolled field study demonstrated the safety of tepoxalin under field conditions in 107 adult dogs (age range 1 to 17 years) diagnosed with osteoarthritis. ZUBRIN^® Tablets were administered for 28 consecutive days. Ninety-seven dogs completed the 28-day course of therapy. Of the 10 dogs that discontinued therapy before the completion of the study, seven were related to the occurrence of adverse reactions. In five of these seven cases, discontinuation of therapy resulted in resolution of the adverse reaction. In two cases, death ensued after termination of therapy and the association with tepoxalin administration could not be ruled out (see ADVERSE REACTIONS).

HOW SUPPLIED ZUBRIN^® Tablets are supplied in boxes containing 3, 6, 9, or 10 foil blisters each or in pouches containing 1, 2, or 3 blisters. Each foil blister contains 10 rapidly-disintegrating tablets of 50, 100, or 200 mg tepoxalin.

STORAGE Store between 2° and 30°C (36° and 86°F).

Made in the United Kingdom for Schering-Plough Animal Health Corp., Summit, NJ 07901 USA

REFERENCES:

1. Data on file.

2. Argentieri, DC, Ritchie, DM, et al. A Dual Cyclooxygenase/5-Lipoxygenase Inhibitor of Arachidonic Acid Metabolism With Potent Antiinflammatory Activity and A Favorable Gastrointestinal Profile. J Pharmacol Exp Ther. December 1994;271(3):1399-1408.

U.S. Patent No. 4,826,868

Copyright 2002, 2006, Schering-Plough Animal Health Corp. All rights reserved.

26572746 Rev. 10/06

NAC No.: 10472203