Equine & Livestock

The relative bioavailability study was a randomized, two period, two sequence crossover study in thirty horses. Each horse received a single tablet (57 mg firocoxib) and a single tube of paste (56.7 mg firocoxib). Blood samples were collected at 15 minutes, 45 minutes, 1,1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96 and 120 hours following each treatment. Samples were analyzed by LC-MS/MS for firocoxib concentrations. The results of the relative bioavailability study are summarized in Table2. The Cmax and AUC last of EQUIOX X Tablets were within the adjusted 90% CI for safety and effectiveness and met the criteria established for successfully demonstrating that EQUIOX X Tablets will be safe and effective. Therefore, EQUIOX X Tablets and EQUIOX X Oral Paste are acceptable as pharmaceutical alternatives. There was a substantial difference in the Tmax (time to maximum plasma concentration) between EQUIOX X Oral Paste and EQUIOX X Tablets. The Tmax ranged from 0.25-4 hours for EQUIOX X Oral Paste and 0.25-12 hours for EQUIOX X Tablets. The difference in the rate and extent of absorption was greatest within the first three hours after administration. The mean terminal elimination half-life of EQUIOX X Oral Paste (45.45hours) was similar to that of EQUIOX X Tablet (4 4.49 hours). Table 2: Relative Bioavailability Results for EQUIOX X Oral Paste (Reference) and EQUIOX X Tablets (Test) (n=30 horses) Parameter Units Reference Geometric Mean Test Geometric Mean Test / Reference Lower 90% CI Upper 90% CI Cmax ng /mL 78.4 4 5 8.85 0.75 67.9 2 82.8 8 AUC last hr *ng /mL 2 515.7 7 2 3 3 6.3 2 0.9 3 8 6.3 7 9 9.85 Cmax= maximum observed plasma concentration AUClast = Area Under the Curve to the last quantifiable time point CI= Confidence Interval Mode of Action: EQUIOX X (firocoxib) is a cyclooxygenase-inhibiting (coxib) class, non-narcotic, non-steroidal anti- inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic activity1 in animal models. Based on in vitro horse data, firocoxib is a selective inhibitor of prostaglandin biosynthesis through inhibition of the inducible cyclooxygenase-2- isoenzyme (COX- 2)2,3. Firocoxib selectivity for the constitutive isoenzyme, cyclooxygenase-1 (COX-1) is relatively low. However, the clinical significance of these in vitro selectivity findings has not been established. Effectiveness: Two hundred fifty-three client-owned horses of various breeds, ranging in age from 2 to 37 years and weighing from 595 to 1638 lbs, were randomly administered EQUIOX X Oral Paste or an active control drug in multi-center field studies. Two hundred forty horses were evaluated for effectiveness and 252 horses were evaluated for safety. Horses were assessed for lameness, pain on manipulation, range of motion, joint swelling, and overall clinical improvement in a non- inferiority evaluation of EQUIOX X Oral Paste compared to an active control. At study's end, 84.4% of horses treated with EQUIOX X Oral Paste were judged improved on veterinarians' clinical assessment, and 73.8%were also rated improved by owners. Horses treated with EQUIOX X Oral Paste showed improvement in veterinarian-assessed lameness, pain on manipulation, range of motion, and joint swelling that was comparable to the active control. The effectiveness of EQUIOX X Tablets was established in a relative bioavailability study comparing EQUIOX X Tablets and EQUIOX X Oral Paste. Therefore, additional field studies were not performed to support the effectiveness of EQUIOX X Tablets. (See CLINICAL PHARMACOLOGY, Relative Bioavailability Study). Animal Safety: In a target animal safety study conducted to support the approval of EQUIOX X Oral Paste, firocoxib was administered orally to healthy adult horses (two male castrates and four females per group) at 0, 0.1, 0.3 and 0.5 mg firocoxib/kg body weight (1, 3 and 5X the recommended dose) for 30 days. Administration of firocoxib at 0.3 and 0.5 mg/kg body weight was associated with an increased incidence of oral ulcers as compared to the control group but, no oral ulcers were noted with 0.1mg/kg. There were no other drug-related adverse findings in this study. In another target animal safety study, firocoxib was administered orally to healthy adult horses (four males or male castrates and four females per group) at 0, 0.1, 0.3 and 0.5 mg firocoxib/kg body weight (1, 3 and 5X the recommended dose) for 42 days. Administration of firocoxib at 0.1, 0.3 and 0.5mg/kg body weight was associated with delayed healing of pre-existing oral (lip, tongue, gingival) ulcers. In addition, the incidence of oral ulcers was higher in all treated groups as compared to the control group. Clinical chemistry and coagulation abnormalities were seen in several horses in the 0.5 mg/kg (5X) group. One 5X male horse developed a mildly elevated BUN and creatinine over the course of the study, prolonged buccal mucosal bleeding time (BMBT),and a dilated pelvis of the right kidney. Another 5X male had a similar mild increase in creatinine during the study but did not have any gross abnormal findings. One female in the 5X group had a prolonged BMBT, bilateral tubulointerstitial nephropathy and bilateral papillary necrosis. Tubulointerstitial nephropathy occurred in one 3X female, two 3X male horses, and the 5X female horse discussed above with the prolonged BMBT. Papillary necrosis was present in one 1X male horse and the 5X female horse discussed above. Despite the gross and microscopic renal lesions, all of the horses were clinically healthy and had normal hematology, clinical chemistry and urinalysis values. In another target animal safety study, firocoxib was administered orally to healthy adult horses (three females, two male castrates and one male per group) at 0,0.25mg/kg, 0.75 mg/kg and 1.25 mg/kg (2.5, 7.5 and 12.5X the recommended dose of 0.1 mg/kg) for 92 days. An additional group of three females, two male castrates and one male per group, was dosed at 1.25mg/kg for 92 days but was monitored until Days 147-149. There were treatment-related adverse events in all treated groups. These consisted of ulcers of the lips, gingiva and tongue and erosions of the skin of the mandible and head. Gross and microscopic lesions of the kidneys consistent with tubulointerstitial nephropathy were seen in all treated groups. Papillary necrosis was seen in the 2.5X and 12.5X groups. In addition, several 12.5X horses had elevated liver enzymes (GGT, SDH, AST and ALT). One 2.5X horse had increased urine GGT and urine protein levels which was due to renal hemorrhage and nephropathy. Gastric ulcers of the margo plicatus and glandular area were more prevalent in the 2.5X and 7.5X groups, but not seen in the 12.5X group. The group of horses that were monitored until Days 147-149 showed partial to full recovery from oral and skin ulcers, but no recovery from tubulointerstitial nephropathy. In a target animal safety study conducted to assess the safety of EQUIOX X Injection followed by EQUIOX X Oral Paste in the horse, thirty-two clinically healthy adult horses received EQUIOX X Injection intravenously once daily for five days at doses of either 0 mg/kg (control group); 0.09 mg/kg (1X); 0.27 mg/kg (3X); or 0.45 mg/kg (5X the recommended dose).This was followed by once daily oral administration of EQUIOX X Oral paste for nine days at doses of either 0 mg/kg (control group); 0.1 mg/kg (1X); 0.3 mg/kg (3X); or 0.5 mg/kg (5X the recommended dose). This sequence (five days of EQUIOX X Injection followed by nine days EQUIOX X Oral Paste, for a total of 14 days) was repeated three times for a total treatment duration of 42 days (3X the recommended treatment duration of 14 days). Two male 5X horses demonstrated a white focus in the renal cortex which correlated with tubulointerstitial nephropathy microscopically. The presence of tubulointerstitial nephropathy was considered treatment- related. One horse from the control group and two horses from the 5X group had injection site swellings during treatment. Injection site changes characterized by inflammatory cell influx and rarely tissue necrosis were seen in all study groups including the control group.There was a dose-dependent increase in the incidence of oral ulcers and erosions. Elevated hepatic enzymes (GGT or AST) were noted in all study groups at one or more time points. One male 5X horse with an elevated GGT value on Day 42 was noted to have tubulointerstitial nephropathy at the time of necropsy. For all horses, these hepatic enzyme elevations generally returned to the reference range by the next timepoint. The safety of EQUIOX X Tablets was supported by a relative bioavailability study comparing EQUIOX X Tablets and EQUIOX X Oral Paste (see CLINICAL PHARMACOLOGY, Relative Bioavailability Study), pharmacovigilance information, and target animal safety data for existing firocoxib containing products in horses. No additional target animal safety studies were conducted with EQUIOX X Tablets. Storage Information: Store at room temperature, between 59°-86°F (15°-30° C). Brief periods up to 104° F (40° C) are permitted. How Supplied: EQUIOX X Oral Paste is available in packs of 20 individually-boxed syringes and packs of 72 individually wrapped syringes. Each syringe contains 6.93 grams of EQUIOX X paste, suf ficient to treat a 1250 lb. horse. EQUIOX X Tablets are available as round, beige to tan, half-scored tablets, containing 57 mg firocoxib. EQUIOX X Tablets are supplied in 60 and 180 count bottles. 1 McCann ME, Rickes EL, Hora DF, Cunningham PK et al. In vitro effects and in vivo ef ficacy of a novel cyclooxygenase-2 inhibitor in cats with lipopolysaccharide- induced pyrexia. Am J Vet Res. 2005 Jul;66 (7):1278-84. 2 McCann ME, Anderson DR, Brideau C et al. In vitro activity and in vivo ef ficacy of a novel COX-2 inhibitor in the horse. Proceedings of the Academy of Veterinary Internal Medicine. 2002. Abstract 114, p.789. 3 Data on file Made in France. EQUIOX X ® is a registered trademark of Boehringer Ingelheim Animal Health USA Inc. ©2022 Boehringer Ingelheim Animal Health USA Inc. All rights reserved. US-EQU-0357-2022

• Cover