DICURAL® tablets Rx Fort Dodge DIFLOXACIN HYDROCHLORIDE FOR ORAL USE IN DOGS ONLY NADA 141-096 Approved by FDA
Federal law prohibits the extra-label use of this drug in food-producing animals.
DESCRIPTION: Difloxacin hydrochloride [3-quinolinecarboxylic acid 6-fluoro-1-(4-fluorophenyl)-1 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo- monohydrochloride] is a fluoroquinolone with broad spectrum antimicrobial activity against gram-positive and gram-negative microorganisms. Difloxacin is poorly water soluble at neutral pH [octanol/water partition coefficient (P) = 8.3 in water 7.2 at pH 7.0]. Its water solubility is improved under acidic conditions (P = 2.1 at pH 5.0) and difloxacin is highly water soluble under basic conditions (P = 0.33 at pH 9.0). Accordingly the molecule has two ionizable sites: a carboxylic acid group (pKa=4.33) and a methyl substituted nitrogen group (pKa=9.05).
FIGURE 1. Chemical structure of difloxacin
INDICATIONS: DICURAL® (difloxacin hydrochloride) tablets are indicated for the management of diseases in dogs associated with bacteria susceptible to difloxacin.
EFFICACY CONFIRMATION: Clinical efficacy was confirmed in skin and soft tissue infections (wounds and abscesses) and urinary tract infections (cystitis). Specific pathogens isolated in clinical field trials are listed in table 4 in the MICROBIOLOGY section.
DOSAGE AND ADMINISTRATION: The dose range of difloxacin in dogs is 5 to 10 mg/kg body weight (2.3 to 4.6 mg/lb) once a day for two to three days beyond the cessation of clinical signs to a maximum of 30 days (see DRUG INTERACTIONS). The determination of dosage for any particular patient must take into consideration such factors as the severity and nature of the infection the susceptibility of the causative organism and the integrity of the host-defense mechanisms. The dose of 5 mg/kg of body weight administered once daily should be used for the routine treatment of infection caused by susceptible organism(s) in an otherwise healthy dog. The dosage may be increased to the upper limit of the dose range (10 mg/kg) if deemed necessary. Antibiotic susceptibility of the pathogenic organism(s) should be determined prior to use of difloxacin. However therapy with DICURAL® tablets may be initiated before results of these tests are known. Once test results become available continue with appropriate therapy. For the treatment of skin and soft tissue infections DICURAL® tablets should be given for two (2) to three (3) days beyond the cessation of clinical signs to a maximum of 30 days. For the treatment of urinary tract infections DICURAL® tablets should be administered for at least 10 consecutive days. If no improvement is noted within five (5) days the diagnosis should be re-evaluated and a different course of therapy considered. table 1. Dose table for DICURAL® tablets for Dogs
tablet Color
tablet Strength (Difloxacin Base)
Daily Dose
5 mg/kg
10 mg/kg
Blue
11.4 mg
2.3 kg (5 lb)
1.1 kg (2.5 lb)
White
45.4 mg
9 kg (20 lb)
4.5 kg (10 lb)
Orange
136 mg
27 kg (60 lb)
13.5 kg (30 lb)
CLINICAL PHARMACOLOGY: Pharmacokinetics in healthy adult dogs: Difloxacin hydrochloride oral bioavailability exceeds 80% when administered by gavage to fasted dogs. Linear pharmacokinetics have been demonstrated for oral difloxacin up to 60 mg/kg/day. Approximately 90% of the total radioactivity in plasma is attributable to the parent compound following both oral and intravenous administration of 14C-difloxacin. Difloxacin is associated with two major metabolites: the ester glucuronide and the desmethyl derivative of difloxacin. Difloxacin elimination occurs primarily through glucuronidation with subsequent biliary secretion. However the glucuronide metabolite may be hydrolyzed in the gastrointestinal tract and the resulting parent compound reabsorbed. Approximately 80% of an intravenous dose is eliminated in the feces. Renal clearance accounts for less than 5% of difloxacin total body clearance. Pharmacokinetic estimates for difloxacin tablets following oral administration to fasted dogs are shown in table 2. No statistically significant gender effects were observed. The effect of food on difloxacin oral bioavailability has not been determined (see DRUG INTERACTIONS).
table 2. Plasma pharmacokinetics following administration of difloxacin tablets (5 mg/kg body weight) to dogs (n=20).
Pharmacokinetic Measure
Mean Value
Peak Plasma Concentration (CMAX)
1.8 µg/mL
Time to Reach CMAX (TMAX)
2.8 hours
Elimination Half-life (T½)
9.3 hours
Area Under the Plasma Curve (AUC0-∞)
14.5 µg·hr/mL
Total Body Clearance/Fa (CL/F)
375 mL/kg/hr
Steady State Volume of Distribution/Fb
3.8 L/kg
Volume of Distribution (area)/Fc
4.7 L/kg
a)Total body clearance/F = Dose/AUC b)Steady state volume of distribution/F = Dose·AUMC/AUC2 c)Volume of distribution (area)/F = Vdb = (T1/2) (CL/F)/0.693 Blood concentration versus time profiles for difloxacin after a single 5 mg/kg or 10 mg/kg dose of DICURAL® tablets are presented in Figure 2. Negligible accumulation occurs with once daily administration.
Difloxacin Concentrations After a Single Oral Dose
FIGURE 2: Difloxacin concentration after oral administration of a single DICURAL® tablet. Profile for the 10 mg/kg dose was based upon the mean concentrations observed following a single 5 mg/kg dose.
The affinity of difloxacin for canine plasma proteins is low (plasma protein binding = 46% to 52%). Accordingly difloxacin readily diffuses into peripheral tissues. This is evidenced by the levels of 14C activity in tissues following oral administration of 10 mg/kg 14C-difloxacin hydrochloride (table 3). These results are consistent with difloxacin's lipophilic properties and its large volume of distribution.
table 3. Levels of 14C radioactivity (expressed as µg equivalents of difloxacin per gram or mL) in tissues at 2 6 and 24 hours following administration of a single oral dose of radiolabeled difloxacin free base at 10 mg/kg.
Body System
2 hours (n=2)
6 hours (n=1)
24 hours (n=1)
Hematopoietic
Whole Blood
2.3
1.1
0.6
Plasma
2.6
1.2
0.8
Bone
6.5
7.2
6.5
Lymph Node
3.1
2.5
1.7
Liver
10.7
7.8
4.6
Spleen
3.5
1.1
1.1
Urogenital
Urine*
22.6
21.0
10.7
Kidney
5.0
2.8
1.5
Bladder Wall
3.0
1.8
1.7
Testes
3.1
1.6
0.8
Prostate
3.4
1.5
1.4
Gastrointestinal
Stomach
66.7
8.5
9.9
Small Intestine
18.3
38.7
16.4
Cardiopulmonary
Lung
3.2
0.9
0.8
Heart
3.8
1.6
1.1
Other Tissues
Muscle
4.1
1.2
1.1
Fat
0.7
0.8
0.8
*Based on percent of dose with urine output at 50 mL/kg/day Considering the comparability of 14C radioactivity in tissues and plasma AUC CMAX and the MIC of the targeted pathogen(s) can be used as a guide for clinical dose adjustment.
MICROBIOLOGY: Difloxacin has broad spectrum activity against gram-negative and gram-positive bacteria. It is bactericidal and exerts its antibacterial effect through interference with the bacterial enzyme DNA gyrase which is needed for the maintenance and synthesis of bacterial DNA. The minimum inhibitory concentrations (MICs) of pathogens isolated in clinical field trials conducted in the United States between 1991 and 1993 were determined using National Committee for Clinical Laboratory Standards (NCCLS). The following table (table 4) provides the minimum inhibitory concentrations of difloxacin for the bacteria isolated during clinical field trials:
table 4. MIC values* (µg/mL) of difloxacin for bacterial pathogens isolated from skin and soft tissue infections and urinary tract infections in dogs enrolled in clinical studies conducted during 1991-1993.
Bacteria Name
No. of Isolates
MIC50
MIC90
MIC Range
Enterobacter spp.
9
0.11
3.66
£0.05-3.66
Escherichia coli
28
£0.05
0.11
£0.05-7.3
Klebsiella spp.
8
0.11
0.11
0.11-0.23
Pasteurella spp.
8
£0.05
£0.05
£0.05
Proteus spp.
15
0.92
1.83
0.11-1.83
Pseudomonas spp.
5
0.11
0.92
£0.05-0.92
Staphylococcus spp.
193
0.23
0.46
£0.05-1.83
Streptococcus spp.
56
1.83
3.66
0.11-7.3
*The correlation between the in vitro susceptibility data (MIC values) and clinical response has not been confirmed. The MIC tests were performed using difloxacin hydrochloride and an adjustment was made to represent the results as difloxacin (free base). A study was conducted to determine the in vitro activity of difloxacin against 300 canine clinical isolates from multiple geographic locations across the United States during 1995-1996. MICs were determined using National Committee for Clinical Laboratory Standards. The study results are summarized in table 5.
table 5. MIC values* (µg/mL) of difloxacin for canine bacterial isolates collected during a comprehensive study conducted in the United States during 1995 - 1996.
Bacteria Name
Number of Isolates
MIC50
MIC90
MIC Range
Escherichia coli
78
0.11
0.23
0.01 - >0.91
Klebsiella pneumoniae
20
0.46
0.46
0.03 - >0.91
Proteus spp.
38
0.91
0.91
0.46 - 1.82
Staphylococcus intermedius
164
0.91
0.91
0.11 - >0.91
*The correlation between the in vitro susceptibility data (MIC values) and clinical response has not been confirmed. The MIC tests were performed using difloxacin hydrochloride and an adjustment was made to represent the results as difloxacin (free base).
DRUG INTERACTIONS: Compounds (e.g. sucralfate antacids and multivitamins) containing divalent and trivalent cations (e.g. iron aluminum calcium magnesium and zinc) may substantially interfere with the absorption of quinolones from the intestinal tract resulting in a decrease in product bioavailability. Therefore the concomitant oral administration of quinolones with foods supplements or other preparations containing these compounds should be avoided. Difloxacin hydrochloride has been administered to dogs concurrently with other animal health products under field conditions with no adverse effects observed. Concurrent therapies included heartworm prevention thyroid hormone augmentation ectoparasiticides anesthetics anti-seizure compounds topical antibiotics/anti-inflammatory and antihistamine medication.
CONTRAINDICATIONS: Difloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested the dog being particularly sensitive to this side effect. Difloxacin is contraindicated in immature dogs during the rapid growth phase (between 2 and 8 months of age in small and medium*sized breeds and up to 18 months of age in large and giant breeds).
PRECAUTIONS: Quinolone-class drugs should be used with caution in animals with known or suspected central nervous system (CNS) disorders. In such animals quinolones have in rare instances been associated with CNS stimulation which may lead to convulsive seizures. Quinolones have been shown to produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The safety of DICURAL® tablets in breeding or pregnant dogs has not been determined. DICURAL® tablets should not be used in dogs known to be hypersensitive to quinolones.
HUMAN WARNINGS: For use in animals only. Keep out of the reach of children. Avoid contact with eyes. In case of contact immediately flush eyes with copious amounts of water for 15 minutes. In case of dermal contact wash skin with soap and water. Consult a physician if irritation persists following ocular or dermal exposure. Individuals with a history of hypersensitivity to quinolones should avoid this product. In humans there is a risk of user photosensitization within a few hours after excessive exposure to quinolones. If excessive accidental exposure occurs avoid direct sunlight.
TARGET ANIMAL SAFETY: Difloxacin administered to 9.5 to 11.5 month-old 9.5 to 17.6 kg beagles at doses of 5 15 or 25 mg/kg for 30 consecutive days supports an adequate safety margin for the product. There was no ante or post-mortem evidence of quinolone-induced arthropathy. However transient erythema/edema on the facial area diarrhea and decreased appetite and weight loss were observed in some dogs. In 15 to 16 week-old Beagle puppies dosed at 0 5 25 35 50 and 125 mg/kg/day for 90 days lameness and articular cartilage lesions in the femur and proximal tibia were noted in the 50 mg/kg and 125 mg/kg groups. Clinical lameness was not observed in any group below 50 mg/kg. Articular cartilage lesions were also noted in the 5 25 and 35 mg/kg/day groups (see CONTRAINDICATIONS).
ADVERSE REACTIONS: Various breeds of dogs aged 9 months to 16 years were admitted into the clinical study and received 5 mg/kg/day for up to 10 days. DICURAL® tablets were well tolerated. Potential adverse reactions recorded in clinical cases involved the gastrointestinal tract (e.g. anorexia emesis diarrhea and inappetence) which were self-limiting and did not require additional treatment.
STORAGE CONDITIONS: Store DICURAL® tablets between 15°C and 30°C (59°F and 86°F); avoid excessive heat (40°C/104°F).
Prescription items are NON-RETURNABLE and NON-REFUNDABLE.
