Desoxycorticosterone Pivalate: what the FDA reviewed for dog products

Zycortal® Suspension NADA 141-444, Original approval, February 17, 2016; sponsor Dechra Veterinary Products LLC; species: Dogs; foi_id 936; FDA PDF

Indication

Replacement therapy for mineralocorticoid deficiency in dogs with primary hypoadrenocorticism (Addison's disease)

Dose regimen

2.2 mg/kg (1 mg/lb), subcutaneous injection, every 25 days initially; subsequent dose and interval individualized, Long-term administration; tailor dose and interval to clinical response and Na+/K+ normalization; concurrent glucocorticoid replacement

Therefore, based on published study results and the study comparing intramuscular and subcutaneous routes of administration, the starting dosage of 2.2 mg/kg (1 mg/lb) of DOCP, administered by subcutaneous injection every 25 days, was selected.

Pharmacokinetics

Target-animal safety

dose multiples 1X (2.2 mg/kg), 3X (6.6 mg/kg), 5X (11 mg/kg); duration 6 months, once every 21 days subcutaneously (9 total doses); animals 4 M / 4 F per group.

To evaluate the safety of desoxycorticosterone pivalate in dogs when administered subcutaneously once every 21 days for 6 months. b. Study Animals Male and female Beagle dogs, approximately 5.5 to 6 months of age, weighing between 7.3 to 9.7 kg. c. Treatment Groups Table 4: Treatment Groups Treatment Group Dose (mg/kg) Number and Sex of Dogs 1 Negative control Saline (0 mg/kg) 4 M / 4 F 2 1X DOCP (2.2 mg/kg) 4 M / 4 F 3 3X DOCP (6.6 mg/kg) 4 M / 4 F 4 5X DOCP (11 mg/kg) 4 M / 4 F

Effectiveness

Multi-center, randomized, active-controlled non-inferiority field study: ZYCORTAL 2.2 mg/kg SC (113 dogs) vs FDA-approved DOCP active control 2.2 mg/kg IM (39 dogs), dose and interval individualized, all dogs on glucocorticoid replacement; evaluated through Day 180; n = 152 enrolled; 135 evaluable (101 ZYCORTAL, 34 active control); primary endpoint: Treatment success at Day 90±14: clinically normal or reduced clinical signs AND Na+/K+ within reference range or Na+/K+ ratio 27-32; non-inferiority margin 15%; result: Success 86.2% ZYCORTAL vs 85.1% active control; upper bound of 95% CI for difference 13.6% (<15%), supporting non-inferiority; success 88.3% vs 86.9% at Day 180

Of the 152 dogs enrolled in the study, 135 dogs (101 ZYCORTAL Suspension and 34 active control) were included in the statistical analysis for Day 90 effectiveness. The percent success was 86.2% and 85.1% in the ZYCORTAL Suspension and active control groups, respectively. The upper bound of the 95% confidence interval for the difference of success rates between the active control and ZYCORTAL Suspension groups at Day 90 ± 14 was 13.6%, lower than the acceptance margin of 15%, thus supporting a conclusion of non-inferiority.

Adverse reactions

Extraction notes: PK values are from flattened Table 1 rows (SC and IM at 5X dose, 11 mg/kg, n=6 crossover); the text states the half-life estimates are only approximate. Adverse reaction denominators (Table 3): ZYCORTAL n=113, active control (IM DOCP) n=39. Active control was an FDA-approved DOCP product, not placebo.

Percorten™-V NADA 141-029, Original approval, January 12, 1998; sponsor Elanco US Inc.; species: dogs; foi_id 3622; FDA PDF

Indication

Replacement therapy for the mineralocorticoid deficit in dogs with primary adrenocortical insufficiency.

Dose regimen

1.0 mg per pound of body weight (starting dose); most patients maintained on 0.75 to 1.0 mg/lb, Intramuscular injection (25 mg/mL suspension; avoid inadvertent intravenous injection), every 25 days initially; maintenance every 21 to 30 days, Dose individualized on patient response; monitor serum sodium and potassium; glucocorticoid replacement must be supplied separately

Begin treatment at a dose of 1.0 mg per pound of body weight every 25 days. In some patients, the dose may be reduced. Serum sodium and potassium levels should be monitored to assure the animal is properly compensated. Most patients are well controlled with a dosage of 0.75 to 1.0 mg per pound of body weight, given every 21 to 30 days.

Target-animal safety

dose multiples 1X, 3X, 5X; duration Six months (18 doses: first three days of each 28-day interval); 0, 2.2, 6.6 and 11 mg/kg; animals 12 males and 12 females (six per group, three of each sex).

DOCP was administered by intramuscular injection at 1X, 3X and 5X the intended labeled dose for three consecutive days at the beginning of each 28-day dosing interval for six months. Animals: Five-month old pure bred Beagle dogs. Groups of six dogs (three of each sex) were assigned to each treatment group (total 12 males and 12 females).

Effectiveness

First multi-location clinical field trial (May 1989-May 1990) in dogs with definitively diagnosed primary hypoadrenocorticism; each animal its own control vs Day 0; initial dose 1 mg/lb IM every 25 days, 75 days (3 injections); n = 69 enrolled; 49 (71%) completed; primary endpoint: Serum sodium, potassium, chloride, BUN, creatinine, Na/K ratio and body weight on Days 0, 14, 25, 39, 50, 64, 75; clinician final evaluation Day 75; result: Electrolytes, BUN and Na/K ratio returned to normal by Day 14 and remained normal; body weight increased; DOCP judged effective in 96% (51/53) of cases; a second field trial (21 dogs, 18 completed) judged DOCP effective in all cases

Animals: A total of 69 dogs were enrolled in this study and 49 (71%) completed the trial;

Adverse reactions

Extraction notes: Original approval. Adverse reactions are from Table 2 of the first field trial (clinical signs observed, number of cases among 69 enrolled dogs; no control group, so control is null); the two-column table was flattened so each quote contains neighbouring rows. Both field trials are uncontrolled (each dog its own control). TAS doses 0, 2.2, 6.6, 11 mg/kg = 0X, 1X, 3X, 5X.