Cyclosporine: what the FDA reviewed for dog products

Optimmune® NADA 141-052, Original approval, August 02, 1995; sponsor Intervet, Inc.; species: Dogs; foi_id 583; FDA PDF

Indication

Treatment of chronic keratoconjunctivitis sicca (KCS) in dogs.

Dose regimen

1/4 inch strip of ointment to the affected eye(s), Ophthalmic (topical), directly on the cornea or into the conjunctival sac, every 12 hours, 0.2% cyclosporine USP ophthalmic ointment; continual therapy is needed to maintain the effect (regression on withdrawal shown in the field study).

The ingredients of OPTIMMUNE® are formulated into a topical ophthalmic ointment. A 1/4 inch strip is to be administered every 12 hours to the affected eye(s). The ointment may be placed directly on the cornea or into the conjuctival sac.

Target-animal safety

dose multiples 1X (0.2%), 10X (2%); duration 26 consecutive weeks, twice daily, 7 days/week, each eye; animals 12 male, 12 female young adult Beagles.

A blinded chronic (26 week) laboratory safety study during which cyclosporine ophthalmic ointment was administered twice daily at 0, 1X, and 10X the daily use concentration of 0.2%. b. Animals: Twenty-four young adult Beagle dogs (12 male, 12 female)

Effectiveness

Dose confirmation study #1330C-61-V91-092: blinded, placebo-controlled multicenter clinical field study (11 board-certified veterinary ophthalmologists, 9 states) of 1/4 inch 0.2% cyclosporine ointment every 12 hours for 84 days in dogs with chronic KCS (STT ≤ 10 mm/min with conjunctivitis), followed by treatment withdrawal (up to 6 weeks) and retreatment (up to 4 weeks) phases.; n = 132 enrolled, 124 analyzed; primary endpoint: Schirmer Tear Test values and numerically scored conjunctival, corneal and internal ocular findings on Days 7, 21, 42 and 84; investigator overall assessment; result: Mean STT response favored cyclosporine (mixed-model ANOVA); investigator overall improvement on Day 84 in 81% of left eyes (vs 46% placebo) and 81% of right eyes (vs 48%); clinical regression in all but one cyclosporine eye on withdrawal and improvement in all but two dogs on retreatment.

A total of 132 client owned animals of various breeds, ages, and sex were enrolled and 124 cases were analyzed in this study.

Adverse reactions

Extraction notes: Original NADA (1995). The General Information section has no species field; 'Dogs' is taken from the indication. No pharmacokinetic data. Effectiveness uses the pivotal dose-confirmation field study; the dose-response study (#V89-032, 90 dogs, 0.05/0.1/0.2/0.4% vs placebo for 42 days; 0.2% gave the greatest mean STT change of 7.50 mm/min by Day 42), the formulation bridging study (23 dogs, preservative-free formulation) and the open corroborative field study (80 dogs; STT increases of 8.4 and 9.1 mm/min; 88%/94% eyes improved) are not separately recorded. Target animal safety is the 26-week GLP Battelle study (SCH 36547) with 1X = 0.2% and 10X = 2% ointment; the group sizes are 4M, 4F per group. Result percentages for effectiveness are stated in prose in the source.

Atopica™ NADA 141-218, Original approval, August 15, 2003; sponsor Elanco US Inc.; species: Dogs; foi_id 749; FDA PDF

Indication

Control of atopic dermatitis in dogs weighing at least 4 lbs body weight

Dose regimen

5 mg/kg/day (3.3-6.7 mg/kg/day) initial, Oral (gelatin capsules); given fasted in the field study (1 hour before or 2 hours after a meal), Single daily dose for 30 days, then taper to every other day or two times a week, Taper to the minimum frequency that maintains the desired therapeutic effect

The initial daily dose of ATOPICA is 5 mg/kg/day (3.3-6.7 mg/kg/day) as a single daily dose for 30 days. Following this initial daily treatment period, the dose of ATOPICA may be tapered by decreasing the frequency of dosing to every other day or two times a week until a minimum frequency is reached which will maintain the desired therapeutic effect.

Target-animal safety

dose multiples 0X, 1X (6.7 mg/kg/day maximum exposure; constant or tapered), 3X (20 mg/kg/day; constant or tapered), 5X (33.3 mg/kg/day; constant or tapered); duration 90 days, once daily orally in fasted dogs (taper groups reduced at Days 30 and 60); animals 22 male and 22 female.

Twen ty two male and 22 female Beagle dogs approximately 6 months of age. 11 (d) Control and Treatment Groups: Groups 2, 4, and 6 received a constant dose of 5 mg cyclosporine/kg/day while Groups 3, 5 and 7 had their dose tapered throughout the study, as shown in the table below.

Effectiveness

Phase 1: multicenter (US/Canada), placebo-controlled, randomized, double-masked field study, 5 mg/kg/day vs placebo for 28 days; Phase 2: open-label dose-tapering for up to 16 weeks; 269 dogs enrolled; n = 94 cyclosporine, 98 placebo (Phase 1); primary endpoint: CADESI lesion score and pruritus score change from Visit 1 to Visit 2 (28 days); result: Mean CADESI decreased 45% with cyclosporine (76.94 to 42.18) vs increased 9% with placebo (75.02 to 82.18), p<0.0001; pruritus improved in 74% vs 24%

At Visit 2 after 28 days of treatment, the cyclosporine-treated group showed improvement with the average CADESI score decreasing by 45%. The placebo group worsened over the same period with the average CADESI score increasing by 9% (see tables below). There was a significant difference in CADESI score between the treated and the control group at the end of study Visit 2 (p<0.000l) using an analysis of variance. Table 3. Means and Standard Deviations of Field Study CADESI Scores Treatment Visit N Mean SD Min Max Cyclosporine 1 94 76.94 51.56 26 290 2 94 42.18 38.75 0 214 Placebo 1 98 75.02 42.98 25 263 2 98 82.18 50.86 7 246

Adverse reactions

Extraction notes: No pharmacokinetic parameters are reported (only that blood cyclosporine levels did not correlate with response). TAS is the 90-day GLP study with constant (1X/3X/5X) and taper groups; the design quote reproduces PDF artifacts verbatim ('Twen ty two', stray page number '11'); a 52-week study (1X/3X/9X, 32 Beagles) and vaccination/methylprednisolone interaction studies are also summarized. Adverse reactions are clinical observations over the whole field study (all 265 dogs received cyclosporine in Phase 1 or 2), so no placebo column exists; the 'p<0.000l' in the effectiveness quote is a PDF typo (letter l) reproduced verbatim.

Optimmune® NADA 141-052, Supplemental approval, August 26, 1997; sponsor Intervet, Inc.; species: dogs; foi_id 2513; FDA PDF

Indication

Management of chronic keratoconjunctivitis sicca (KCS) and chronic superficial keratitis (CSK) in dogs (this supplement adds the CSK claim and changes 'treatment' of KCS to 'management').

Dose regimen

1/4 inch strip of ointment, Topical ophthalmic (directly on the cornea or into the conjunctival sac of the affected eye(s)), every 12 hours, Dogs with CSK will most likely require lifelong consistent therapy

A 1/4 inch strip is to be administered every 12 hours to the affected eye(s). The ointment may be placed directly on the cornea or into the conjunctival sac. Dogs afflicted with CSK will most likely require lifelong consistent therapy.

Effectiveness

Multicenter, historical-controlled clinical field study in dogs with bilateral CSK (7 European referral ophthalmology clinics; 6 contributed to the efficacy analysis); ~1 cm (1/4 inch) ribbon of 0.2% cyclosporine ointment twice daily for 42 days, then 3-week post-treatment phase; n = 36 enrolled; 32 in efficacy analysis; primary endpoint: Severity of vascularization, pigmented opacity and granulation tissue vs baseline on Days 7, 21, 42; investigator overall response; result: Vascularization and granulation tissue significantly reduced from baseline on Days 7, 21 and 42; pigmented opacity did not improve; investigators rated 90.3% of treated eyes improved after 42 days; ~39% unchanged and 50% worsened within 21 days after withdrawal

Animals: A total of thirty-six (36) cases treated with cyclosporine were enrolled in this clinical field trial and thirty-two (32) were included in the efficacy analysis.

Adverse reactions

Extraction notes: Supplemental approval. No new target animal safety study: 'Target animal safety was established in the original NADA approved on August 2, 1995.' Historical control only (no concurrent control group), so adverse_reactions control is null.

MODULIS® for Dogs NADA 200-743, Original approval, March 21, 2023; sponsor Ceva Sante Animale; species: Dogs; foi_id 13657; FDA PDF

Indication

Control of atopic dermatitis in dogs weighing at least 4 lbs (1.8 kg).

Dose regimen

5 mg/kg/day, Oral, single daily dose, for 30 days, then may be tapered to every other day or twice weekly to the minimum frequency maintaining effect; give at least one hour before or two hours after a meal

The initial dose of MODULIS® for Dogs is 5 mg/kg/day as a single daily dose for 30 days. Following this initial daily treatment period, the dose of MODULIS® for Dogs may be tapered by decreasing the frequency of dosing to every other day or twice weekly, until a minimum frequency is reached which will maintain the desired therapeutic effect.

Pharmacokinetics

Effectiveness

Blood-level bioequivalence study (not a clinical effectiveness study): randomized, masked, two-period, two-sequence, single-dose crossover in fasted beagle dogs, 14-day washout; 50 mg MODULIS oral solution vs 50 mg ATOPICA capsule; n = 30; primary endpoint: CMAX and AUC (average bioequivalence; 90% CI of geometric mean ratios within 0.80-1.25); result: Bioequivalence demonstrated; no serious adverse events reported

The in vivo blood-level study was conducted in 30 healthy, fasted dogs.

Adverse reactions

Extraction notes: Generic (ANADA) approval via suitability petition (oral solution vs RLNAD capsule). No effectiveness or target animal safety studies were required; the 'effectiveness' entry is the pivotal bioequivalence study. PK table columns: Parameter | Generic mean | RLNAD mean | Ratio | Lower 90% CI | Upper 90% CI (dagger = geometric mean).

Sporimune™ NADA 200-627, Original approval, November 01, 2018; sponsor Dechra Veterinary Products LLC; species: Dogs; foi_id 5781; FDA PDF

Indication

Control of atopic dermatitis in dogs weighing at least 4 lbs (1.8 kg).

Dose regimen

5 mg/kg/day (3.3-6.7 mg/kg/day), oral (capsule), at least one hour before or two hours after a meal, single daily dose for 30 days, then taper to every other day or twice weekly, initial 30 days daily; then reduce frequency to the minimum that maintains the therapeutic effect

The initial dose of Cyclosporine Capsules, USP MODIFIED is 5 mg/kg/day (3.3-6.7 mg/kg/day) as a single daily dose for 30 days. Following the initial daily treatment period, the dose of Cyclosporine Capsules, USP MODIFIED may be tapered by decreasing the frequency of dosing to every other day or twice weekly, until a minimum frequency is reached which will maintain the desired therapeutic effect.

Pharmacokinetics

Extraction notes: ANADA (generic of Atopica, NADA 141-218): 'CVM did not require effectiveness studies for this approval' and 'CVM did not require target animal safety studies for this approval', so those blocks are null. Approval rests on a 50 mg capsule blood-level bioequivalence study (AUC ratio 0.95, 90% bounds 85.95-105.77%; Cmax ratio 0.94, 80.44-110.69%) plus a capsule-rupture biowaiver for the 10, 25 and 100 mg strengths. No significant adverse events were recorded in the BE study; no adverse-reaction table exists.