Difloxacin Hydrochloride: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Difloxacin 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
- Dicural® Tablets (NADA/ANADA 141-096)
Dicural® Tablets NADA 141-096, Original approval, November 20, 1997; sponsor Boehringer lngelheim Animal Health USA Inc.; species: Dogs; foi_id 2557; FDA PDF
Indication
Management of diseases in dogs associated with bacteria susceptible to difloxacin; clinical efficacy confirmed in skin and soft tissue infections (wounds, abscesses) and urinary tract infections (cystitis).
Dose regimen
5 to 10 mg/kg (2.3 to 4.6 mg/lb), oral (tablet), once a day, 2-3 days beyond cessation of clinical signs to a maximum of 30 days; urinary tract infections at least 10 consecutive days
The dose range of difloxacin in dogs is 5 to 10 mg/kg (2.3 to 4.6 mg/lb) once a day for 2-3 days beyond cessation of clinical signs to a maximum of 30 days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | 14.5 mcg·hr/mL (tablet); 16.2 mcg·hr/mL (capsule) | AUCinfinity, single oral 5 mg/kg, fasted, two-period crossover, 2 groups of 10 dogs; columns Tablet, Capsule | AUCinfinity mcg·hr/mL 14.5 16.2 |
| half-life | 9.3 hr (tablet); 9.4 hr (capsule) | elimination T1/2, single oral 5 mg/kg, fasted; columns Tablet, Capsule | Elimination Half-Life (T1/2) hr 9.3 9.4 |
| cmax | 1.8 mcg/mL (tablet); 2.1 mcg/mL (capsule) | single oral 5 mg/kg, fasted; columns Tablet, Capsule | Maximum Concentration (Cmax) mcg/mL 1.8 2.1 |
| tmax | 2.8 hr (tablet); 2.3 hr (capsule) | single oral 5 mg/kg, fasted; columns Tablet, Capsule | Maximum Time (Tmax) hr 2.8 2.3 |
| cmax | 2.4 mcg/mL at 1.5 hours | 14C-difloxacin base 10 mg/kg oral gavage, fasted, 6 beagles | After oral administration of a 10 mg base/kg dose, both the total radioactivity and parent drug levels in the plasma peaked at 2.4 mcg/mL by 1.5 hours. |
| other | 16% of dose in urine, 80% in feces within five days | excretion of 14C after oral 10 mg/kg | Within five days after oral administration of 14C-difloxacin base, 16% of the 14C dose was excreted in the urine and 80% was eliminated in the feces. |
| clearance | renal clearance <5% of total systemic clearance | after IV 14C-difloxacin; biliary secretion and enterohepatic cycling important | Renal clearance accounted for less than 5% of the total systemic clearance. |
| other | 1.39 +/- 0.44 µg/mL (mean plasma concentration three hours post-dose, 5 mg/kg/day) | 3-month oral dosing, mean of hour-3 samples on days 0, 6, 28, 56 and 84; columns dose, observed mean +/- SD, dose-normalized, %CV; no accumulation with repeated dosing | 5 1.39 +/- 0.44 16.68 31.5 |
Target-animal safety
dose multiples 1X (5 mg/kg/day), 3X (15 mg/kg/day), 5X (25 mg/kg/day; 2.5X the 10 mg/kg upper label dose); duration 30 days; animals four/sex/group (plus four/sex placebo controls).
Dogs were dosed at levels of at 5, 15 or 25 mg/kg of body weight/day (mg/kg) for 30 days. A control group (four/sex) received placebo tablets for 30 days.
| Finding | Quote |
|---|---|
| Diarrhea and transient erythema/edema of ears, face, lips and periocular skin | Antemortem observations included diarrhea and transient erythema/edema. Erythema and edema (red/warm) were observed on the ears, face, lips, and around the eyes. |
| No radiocarpal joint flattening in skeletally mature dogs | There were no confirmed occurrences of flattening (hyperextension) of the radiocarpal joint. |
| No quinolone-type articular cartilage lesions in mature dogs | There were no articular cartilage lesions characteristic of quinolone-induced arthropathy of juvenile dogs. |
| 10-day 50 mg/kg/day study: difloxacin glucuronide particles in gall bladder bile of 3 of 4 dogs, with orange emesis/feces | Gross necropsy revealed granular-like particles of the glucuronide ester of difloxacin in the bile within the gall bladder in three of the four dogs administered 50 mg/kg/day BW for 10 days. |
| 13-week juvenile study: dose-related radiocarpal joint hyperextension above 5 mg/kg | An increased incidence of bilateral flattening (hyperextension) of the radiocarpal joint was noted at dose levels greater than 5 mg/kg and was dose related. |
| 13-week juvenile study: articular cartilage lesions mainly at 50 and 125 mg/kg | Drug-related effects were found in the articular cartilage of the femur and proximal tibia, principally in the animals given 50 or 125 mg/kg. |
Effectiveness
Multi-center (18 veterinarians, 4 US regions) randomized clinical field trial of difloxacin tablets 5.0 mg/kg once daily vs enrofloxacin 2.5 mg/kg twice daily (positive control) for 5-10 days in dogs with dermal and urinary tract infections; n = 141 difloxacin; 131 enrofloxacin; primary endpoint: Bacterial elimination (urinary tract) and resolution of clinical signs (dermal) at day 5 and 3-5 days post-treatment; result: Difloxacin: urinary E. coli 20/20 (100%), Proteus 5/5 (100%), Staph 6/7 (86%); dermal Staph 36/38 (95%), E. coli 1/1, Klebsiella 1/2 (50%). Enrofloxacin: urinary E. coli 9/10 (90%), dermal Staph 32/34 (94%). Laboratory dose titration selected 5.0 mg/kg; tablet shown bioequivalent to capsule
Difloxacin was administered to 141 dogs of various breeds, weights and ages. The variety of breeds depicted the U.S. canine population. Body weights and ages ranged from 1.4 to 55.9 kg and 9 months to 16 years, respectively. No breed, weight or age susceptibilities were observed. Enrofloxacin was used in a group of 131 dogs, as a positive control for comparative purposes.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Side effects (emesis, anorexia, diarrhea, inappetance) | 17/141 (12.1%) | Nineteen of 131 (14.5%) (enrofloxacin) | Nineteen of 131 (14.5%) enrofloxacin-treated dogs and 17 of 141 (12.1%) difloxacin-treated dogs were noted by the investigators to have experienced side effects such as: emesis, anorexia, diarrhea and inappetance. |
Extraction notes: 1997 original approval. Bioequivalence table (Table 1) rows are quoted as extracted, values in order Tablet then Capsule. Table 3 steady-state row columns: dose (mg/kg), observed hour-3 mean +/- SD, dose-normalized mean, %CV. TAS entry is the 30-day margin-of-safety study in skeletally mature beagles; the 10-day 50 mg/kg tolerance study and 13-week juvenile (3.5-3.8 month) toxicity study (0-125 mg/kg) are captured as additional findings. Field-trial Table 4 was flattened; results were read from the row values.
Reproduce: foi_structured_search(query="Difloxacin Hydrochloride") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).