Fluoxetine hydrochloride: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Fluoxetine hydrochloride, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Reconcile® (NADA/ANADA 141-272)
Reconcile® NADA 141-272, Original approval, January 19, 2007; sponsor Pegasus Laboratories, Inc.; species: Dogs; foi_id 831; FDA PDF
Indication
Treatment of canine separation anxiety in conjunction with a behavior modification plan
Dose regimen
1-2 mg/kg, oral (chewable tablet), once daily, In conjunction with behavior modification; 56-day treatment in the pivotal field study; do not exceed the recommended dose
The oral administration of 1-2 mg/kg of RECONCILE chewable tablets once daily is effective for the treatment of separation anxiety when administered in conjunction with behavior modification in dogs.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 3 to 12.9 hours (fluoxetine, range) | Study D00901: single oral dose, 12 Beagle dogs, crossover of chewable tablet vs gelatin capsule | The plasma half-life (T1/2) for fluoxetine in dogs ranged from 3 to 12.9 hours and the T1/2 for norfluoxetine ranged from 33 to 64 hours. |
| half-life | 33 to 64 hours (norfluoxetine metabolite, range) | Study D00901: single oral dose, 12 Beagle dogs | The plasma half-life (T1/2) for fluoxetine in dogs ranged from 3 to 12.9 hours and the T1/2 for norfluoxetine ranged from 33 to 64 hours. |
| auc | 1340 ng*hr/mL (fluoxetine AUC0-last, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 1162; tablet/capsule ratio 1.15 (90% CL 1.08-1.28); Table 7 row order: tablet, capsule, ratio, LCL, UCL | AUC0-last ng*hr/m L 1340 1162 1.15 1.08 1.28 |
| cmax | 126.6 ng/mL (fluoxetine, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 112.4; ratio 1.13 | Cmax ng/m L 126.6 112.4 1.13 1.03 1.25 |
| tmax | 1.7 hr (fluoxetine, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 1.8 hr | Tmax hr 1.7 1.8 0.94 |
| half-life | 6.2 hr (fluoxetine mean, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 6 hr | T1/2 hr 6.2 6 1.03 |
| bioavailability | 1.15 (relative; chewable tablet/capsule AUC ratio; CL 1.08-1.28) | Study D00901, 90% confidence limits; tablets more bioavailable than the capsules used in the toxicity study | AUC0-last ng*hr/m L 1340 1162 1.15 1.08 1.28 |
| cmax | 138 ng/mL (norfluoxetine, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 126 | Cmax ng/m L 138 126 1.10 1.03 1.14 |
| tmax | 12.8 hr (norfluoxetine, RECONCILE chewable tablets) | Single oral dose, 12 Beagles; capsule 16.3 hr | Tmax hr 12.8 16.3 0.79 |
| half-life | 48 hr (norfluoxetine mean, both formulations) | Single oral dose, 12 Beagles | T1/2 hr 48 48 1.00 |
Target-animal safety
dose multiples 0.5X (1 mg/kg/day capsule; 0.43X tablet-equivalent), 2.25X (4.5 mg/kg/day capsule; 1.96X tablet-equivalent), 10X (20 mg/kg/day capsule; 8.70X tablet-equivalent; reduced to 10 mg/kg/day from Day 180); duration 1 year once daily, plus 2-month recovery phase (2 dogs/sex/group); animals 4/gender control, 5/gender per treated group.
Purpose: To determine the potential cumulative toxicity and reversibility of any toxicology of fluoxetine hydrochloride with chronic administration to Beagle dogs. Animals: Test animals were adult laboratory Beagle dogs (4/gender in the control group, 5/gender in the treated group)
| Finding | Quote |
|---|---|
| 3 of 5 females at 20 mg/kg died or were euthanized in first 6 months; high dose reduced to 10 mg/kg/day | Three of five female dogs in the 20 mg/kg group died or were euthanatized during the first six months of the study. |
| Seizures in one dog at 1 mg/kg (0.87 mg/kg tablet-equivalent) and two dogs at 20 mg/kg | One dog in the 1 mg/kg group (equivalent to 0.87 mg/kg/day of RECONCILE chewable tablets) and two dogs in the 20 mg/kg group (equivalent to 17.4 mg/kg/day of RECONCILE chewable tablets) experienced a seizure. |
| Anorexia, tremors, decreased pupillary light response, mydriasis, vomiting and decreased weight gain in all treated groups, most frequent at high dose | Anorexia, tremors, decreased pupillary light response, mydriasis, vomiting, and decreased weight gain were observed in all treatment groups, but occurred more frequently in the high dose group. |
| Phospholipidosis in lung, liver, adrenals, lymph nodes, spleen, retina and white blood cells of all groups, reversible on recovery | Evidence of phospholipidosis was noted in the lung, liver, adrenal glands, lymph nodes, spleen, retina, and white blood cells of all groups, which resolved during the recovery period. |
| Dose-dependent mild bradycardia in the two higher dose groups; no consistent hematology/chemistry/urinalysis effects | Bradycardia was absent on the electrocardiogram in the control and lowest dose groups, but was mildly present in a dose-dependent manner in the two higher dose groups. |
| Narrow margin of safety and variable individual response (seizure at 0.43X the maximum dose) | This study demonstrated that fluoxetine has a variable individual safety response and a narrow margin of safety, as one dog who received the equivalent of 0.87 mg/kg/day (0.43 times the maximum recommended RECONCILE chewable tablets dose of 2 mg/kg/day) experienced a seizure. |
Effectiveness
Study T8E420001: multi-centered, double-masked, placebo-controlled, parallel-arm field study; RECONCILE 1-2 mg/kg once daily vs control tablets, both arms with formal behavior modification; 14-day pre-treatment observation then 56 days of treatment; 96 RECONCILE and 92 control dogs evaluable; n = 229 enrolled (117 RECONCILE, 112 control); primary endpoint: Incidence of dogs with improved global separation anxiety severity score relative to pre-treatment, assessed weekly by owners; result: Incidence of improved global SA score statistically higher for RECONCILE at every treatment week except week 3 (p=0.004-0.025); improvement also in destructive behavior, vocalization and restlessness; 70% voluntary tablet acceptance. A second field study without behavior modification (T8E180101, 198 dogs) showed no clinically significant benefit and was used for safety only.
Two hundred and twenty nine (229) healthy, client-owned dogs were enrolled in the study. Of those 229, 112 dogs received the control tablets and 117 received RECONCILE chewable tablets.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Calm/Lethargy/Depression | 53 (45.3%) | 19 (17.0%) | Calm /Lethargy/Depression 53 45.3 19 17.0 |
| Anorexia/Decreased Appetite | 34 (29.1%) | 12 (10.7%) | Anorexia/Decreased Appetite 34 29.1 12 10.7 |
| Shaking/Shivering/Tremor | 19 (16.2%) | 4 (3.6%) | Shaking/Shivering/Tremor 19 16.2 4 3.6 |
| Vomiting | 17 (14.5%) | 10 (8.9%) | Vomiting 17 14.5 10 8.9 |
| Restlessness/Hyperactivity | 16 (13.7%) | 7 (6.3%) | Restlessness/Hyperactivity 16 13.7 7 6.3 |
| Seizures | 3 (2.6%) | 1 (0.9%) | Seizures 3 2.6 1 0.9 |
Extraction notes: Adverse reactions from Table 3 (Study T8E420001; N=117 RECONCILE, N=112 control), preserved as 'term n % n %' rows. Weight loss >=5% occurred in 32.1% of RECONCILE vs 15.7% of control dogs. Toxicity study doses were capsule doses; tablet-equivalent multiples derived via the 1.15 AUC ratio.
Reproduce: foi_structured_search(query="Fluoxetine hydrochloride") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).