Phenobarbital: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Phenobarbital, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- FIDOQUEL™-CA1 (NADA/ANADA 141-578)
FIDOQUEL™-CA1 NADA 141-578, Original approval, September 06, 2023; sponsor Genus Lifesciences Inc.; species: Dogs; foi_id 14500; FDA PDF
Indication
Control of seizures associated with idiopathic epilepsy in dogs (conditional approval).
Dose regimen
2.5 mg/kg (5 mg/kg/day) minimum, titrated to effect up to 5 mg/kg (10 mg/kg/day), oral (tablet), twice a day, chronic; adjusted on monitoring of the individual patient's clinical response
The conditional dose for the indication for the control of seizures associated with idiopathic epilepsy in dogs is a minimum dosage of 2.5 mg/kg (5 mg/kg/day) administered orally twice a day. The dose may be titrated to effect to a maximum dosage of 5 mg/kg (10 mg/kg/day).
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | 15-35 μg/mL | therapeutic serum phenobarbital concentration range cited from the 2015 ACVIM consensus statement (not a sponsor study) | The panel stated that the most effective and safe therapeutic range for phenobarbital serum concentration is 15-35 μg/mL, although effectiveness can be seen at lower concentrations. |
| other | greater than 85% dissolved within 15 minutes | in vitro dissolution of FIDOQUEL-CA1 and commercially available phenobarbital oral formulations, used to bridge published safety data | The dissolution of FIDOQUEL™-CA1 and the commercially available oral formulations of phenobarbital was rapid with greater than 85% dissolved within 15 minutes. |
Target-animal safety
dose multiples 5 mg/kg BID, 15 mg/kg BID, 25 mg/kg BID; duration margin of safety study terminated after 2 weeks because of acute toxicity and mortality in the two higher dose groups; remainder of safety is a weight-of-evidence literature review.
A weight of evidence approach was used to determine the safety of FIDOQUEL™-CA1. To bridge safety data from the published literature, FIDOQUEL™-CA1 was compared to the commercially available oral formulations of phenobarbital with qualitative and quantitative comparisons of the formulations and dissolution data.
| Finding | Quote |
|---|---|
| Margin of safety study at 5, 15 and 25 mg/kg twice daily was terminated after 2 weeks due to acute toxicities and mortality at the high doses. | A margin of safety study, using twice daily phenobarbital doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg, was terminated after 2 weeks due to acute toxicities and mortality in the high dose groups. |
| CNS toxicity (severe sedation, ataxia, recumbency progressing to moribund) after three doses in the two highest groups; 5 mg/kg dogs did well. | The toxicities observed in the two highest dose groups were CNS-related, including severe sedation and ataxia |
| Dogs in the lowest dose group (5 mg/kg twice daily) did well throughout the two weeks. | Dogs in the lowest dose group (5 mg/kg), did well throughout the two weeks of the study. |
| Literature: most consistent toxicoses are lethargy/sedation, ataxia, polyphagia and polyuria/polydipsia, usually diminishing within 10 days to 2 weeks. | The most consistently reported toxicoses, generally seen either initially after the start of treatment or when the initial dose is too high, are lethargy/sedation, ataxia, polyphagia, and polyuria/polydipsia. These adverse findings usually diminish within 10 days to 2 weeks of the start of therapy because tolerance to these effects generally develops. |
| Literature: liver is the target organ (ALP, ALT, GGT, GLDH increases), reversible with dose reduction; serious hepatotoxicity rare and linked to chronic use or serum levels > 35 mcg/ml. | Serious liver toxicity is rare and more likely associated with chronic use or phenobarbital serum concentrations > 35 mcg/ml. |
| Poison control data: serious adverse events in 50 of 1083 dogs (4.6%), 43 of them at > 25 mg/kg (> 5X); lowest dose with a serious event 14.3 mg/kg (2.9X). | Serious adverse events were reported in 50 of 1083 dogs (4.6%), and 43 of these 50 dogs received doses > 25 mg/kg (> 5X). The lowest dose associated with a serious adverse event was 14.3 mg/kg which represents a dose level of 2.9X the highest recommended dose. |
Effectiveness
Reasonable expectation of effectiveness (conditional approval) based on published literature: two consensus statements (ACVIM 2016, IVETF 2015), four randomized prospective comparator field studies (Schwartz-Porsche 1985, Boothe 2012, Tipold 2015, Fredsø 2016) and two retrospective record studies; no sponsor field study; n = 311 (pooled across 8 phenobarbital monotherapy studies in the ACVIM consensus review); primary endpoint: Seizure reduction (>50% reduction, seizure freedom) on phenobarbital monotherapy; result: ACVIM review: 82% (258/311) had > 50% seizure reduction, 31% (93/311) seizure-free, 15% (48/311) no improvement. Boothe 2012: seizure eradication 17/20 (85%) on phenobarbital vs 12/23 (52%) on bromide. Tipold 2015: 83% (73/88) with >= 50% reduction and 58.0% (51/88) complete eradication on phenobarbital starting at 2 mg/kg BID
The American College of Veterinary Internal Medicine (ACVIM) consensus statement reviewed 8 studies including a total of 311 dogs where seizure reduction was evaluated following phenobarbital monotherapy. Over the 8 studies, 82% of the dogs (258/311 dogs) had > 50% seizure reduction, 31% (93/311) were seizure-free, and 15% (48/311) of dogs did not improve.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Side effects on phenobarbital in 54-Labrador retrospective study (Heynold 1997): fatigue, ataxia, polyphagia, itching, aggressiveness | 13 dogs (fatigue 10, ataxia 2, polyphagia 1, itching 1, aggressiveness 1) | Twenty-four dogs showed no side effects of phenobarbital treatment, whereas 13 dogs presented with fatigue (n = 10), ataxia (n = 2), polyphagia (n = 1), itching (n = 1), or periods of aggressiveness (n = 1). | |
| Serious adverse events (respiratory/cardiac arrest, coma, euthanasia, death) in poison control centre cases of phenobarbital ingestion | 50 of 1083 (4.6%) | Serious adverse events were reported in 50 of 1083 dogs (4.6%), and 43 of these 50 dogs received doses > 25 mg/kg (> 5X). | |
| Owner withdrawals due to adverse events (Tipold 2015, phenobarbital vs imepitoin) | Five dogs in each group | Five dogs in each group were withdrawn by the owners due to adverse events. |
Extraction notes: Conditional approval (2023) under section 571; effectiveness and safety are literature-based. No pharmacokinetic study values are given; the two PK entries are a cited therapeutic serum range and the in vitro dissolution bridging statement. The margin-of-safety study is described in two sentences only (no n, no group multiples), so dose_multiples list the absolute doses. 'Twenty-four' and 'thirty-seven' are spelled out in the Heynold quote; treated counts use only the numerals present.
Reproduce: foi_structured_search(query="Phenobarbital") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).