Etodolac: what the FDA reviewed for dog products

EtoGesic® Tablets NADA 141-108, Original approval, July 22, 1998; sponsor Boehringer lngelheim Animal Health USA Inc.; species: Dogs; foi_id 2215; FDA PDF

Indication

Management of pain and inflammation associated with osteoarthritis in dogs.

Dose regimen

10 to 15 mg/kg (4.5 to 6.8 mg/lb), oral, once daily, Effectiveness shown at approximately 15 mg/kg/day for 8 days; 4.5 mg/kg/day gave suboptimal efficacy.

The recommended dose of EtoGesicTM; tablets for dogs is 10 to 15 mg/kg body weight (4.5 to 6.8 mg/lb) given orally once daily.

Pharmacokinetics

Target-animal safety

dose multiples 1 – 1.5X, 3 – 4.5X, 6 – 9X; duration 26 weeks; animals 4 dogs/sex/group.

Sixteen male and sixteen female beagle dogs were randomly assigned (4 dogs/sex/group) to the four treatment groups. At the start of the study, the dogs ranged from 8.2-11.3 kg in weight and were 10 months of age.

Effectiveness

Combined dose-determination and placebo-controlled clinical field study (P440-C2) at four university orthopedic sites in client-owned dogs with osteoarthritis from chronic hip dysplasia; placebo vs 135 mg/day (~4.5 mg/kg/day) vs 450 mg/day (~15 mg/kg/day) orally for 8 days; force-plate vertical impulse area plus subjective mobility scores.; n = 100 completed and analyzed; primary endpoint: Change in force-plate vertical impulse area of the most affected rear leg from pretreatment; limb disuse, pain on palpation and weight-bearing scores.; result: Vertical impulse area change: placebo 0.04, 135 mg 0.13, 450 mg 0.22 (units 100 x N x sec/kg); both doses significantly improved from pretreatment and 450 mg significantly greater than placebo (P < 0.05); ~15 mg/kg/day for 8 days concluded effective, 4.5 mg/kg/day suboptimal.

One hundred sixteen client-owned dogs from four separate locations entered the study. The dogs were of various breeds, ranged in weight from 26 to 43 kg (57 to 95 lb), and were 1 to 10 years of age. A total of 100 dogs completed the study and were used in the statistical analysis.

Adverse reactions

Extraction notes: PK table (Table 3) prints Cmax units as 'mg/mL' and AUC as 'AUC0-¥' (mangled infinity symbol); values copied as printed. Target animal safety uses the six-month study (15/45/90 mg/kg/day); the one-year study (10/40/80 mg/kg/day, 0.7-1X to 5.3-8X) is captured as an additional finding, and a 9.5-week study at ~15 mg/kg found excessive surgical hemorrhage in 5 of 6 treated vs 2 of 6 control dogs. Adverse reactions are percentages of dogs in the field study (Table 2, number of dogs=116). The 'EtoGesicTM;' rendering and '45or90mg/kg/day' spacing are source artifacts.

EtoGesic® Tablets NADA 141-108, Supplemental approval, May 08, 2003; sponsor Boehringer lngelheim Animal Health USA Inc.; species: Canine; foi_id 637; FDA PDF

Indication

Management of pain and inflammation associated with osteoarthritis in dogs

Dose regimen

10 to 15 mg/kg body weight (4.5 to 6.8 mg/lb), Oral, Once daily

10 to 15 mg/kg body weight (4.5 to 6.8 mg/lb) given orally once daily.

Extraction notes: Supplemental NADA (May 8, 2003) that only adds a 500 mg tablet size to the existing 150 mg and 300 mg tablets. The summary states that no new effectiveness or target animal safety data were required because the minimum and maximum doses are unchanged; approval was based on manufacturing, labeling, dissolution and stability data, with reference to the original FOI summary of July 22, 1998. Category II change, no marketing exclusivity. No study content to extract; validator warning expected.

Etogesic® Sterile Injectable Solution NADA 141-274, Original approval, September 07, 2007; sponsor Boehringer lngelheim Animal Health USA Inc.; species: Dogs; foi_id 833; FDA PDF

Indication

Control of pain and inflammation associated with osteoarthritis in dogs.

Dose regimen

4.5 to 6.8 mg/lb (10 to 15 mg/kg), dorsoscapular subcutaneous injection, single injection, If needed, the daily dose of ETOGESIC Tablets may be given 24 hours after the injectable.

The recommended dose of ETOGESIC Injectable is 4.5 to 6.8 mg/lb (10 to 15 mg/kg) body weight as a dorsoscapular subcutaneous (SQ) injection. If needed, the daily dose of ETOGESIC Tablets may be given 24 hours after the injectable.

Pharmacokinetics

Target-animal safety

dose multiples 2X; duration single subcutaneous injection; injection sites examined for eight days; animals 8 females and 8 males.

Sixteen Beagles (8 fe males and 8 males) at least 12 months of age.

Effectiveness

Blood-level bioequivalence (GLP) two-treatment, two-sequence crossover in 36 fasted beagles: 15 mg/kg ETOGESIC Injectable subcutaneously vs ETOGESIC Tablets (minimum 10 mg/kg, dose-normalized to 15 mg/kg), 14-day washout; clinical effectiveness relies on the approved tablets (NADA 141-108).; n = 36; primary endpoint: AUC0-LOQ (total exposure) and AUC0-4 (early exposure surrogate for onset of pain relief); Cmax evaluated for safety.; result: Injectable and tablet equivalent for AUC0-LOQ (ratio 1.08, 0.98-1.19) and AUC0-4 (0.99, 0.92-1.06) but not Cmax (0.83, 0.73-1.02; lower after SC); products judged therapeutically equivalent.

The study was designed as a two-treatment, two- sequence crossover evaluation using 36 dogs, with a 14-day washout interval between treatments.

Adverse reactions

Extraction notes: This NADA rests on bioequivalence to the approved tablets; 'No additional animal safety data beyond injection site toleration were required', so target_animal_safety captures the 2X (30 mg/kg) injection-site tolerance study (8 etodolac, 8 saline) rather than a systemic margin-of-safety study (see NADA 141-108). Adverse reactions are from the uncontrolled crossover BE study (no placebo arm). PK from Table 2 (crossover, harmonic mean for T1/2) and Table 9 (bioaccumulation, 14 female beagles); the Table 9 AUC row is fragmented in the text ('109 ± 75 NA NA AUC0-∞ , mcg•hr/mL') and quoted as printed. Two non-GLP formulation-comparison injection-site studies reported delayed firm nodules in some dogs.