MARBOQUIN- marbofloxacin_tablet, chewable

CLINICAL PHARMACOLOGY:
Marbofloxacin is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration to fasted animals. Divalent cations are generally known to diminish the absorption of fluoroquinolones. The effects of concomitant feeding on the absorption of marbofloxacin have not been determined. (See Drug Interactions 1 In vitro Marbofloxacin plasma concentrations were determined over time in healthy adult beagle dogs (6 dogs per dosage group) following single oral doses of 1. 25 mg/lb or 2. Absorption of orally administered marbofloxacin increases proportionally over the dose range of 1. Marbofloxacin plasma concentrations were determined overtime in 7 healthy adult male cats following a single oral dose of 2. Plasma pharmacokinetic parameters following oral dosing of dogs and cats are summarized in Figures 2 and 3 and in Table 2. Based on the terminal elimination half-life and the dosing interval, steady-state levels are reached after the third dose and are expected to be approximately 25% greater in dogs and 35% greater in cats than those achieved after a single dose. Marbofloxacin is widely distributed in canine tissues. Tissue concentrations of marbofloxacin were determined in healthy male beagle dogs (4 dogs per time period) at 2, 18 and 24 hours after a single oral dose (1. 5 mg/lb) and are summarized in Tables 3a and 3b. Table 1: Mean pharmacokinetic parameters following intravenous administration of marbofloxacin to 6 adult beagle dogs at a dosage of 2. Parameter Estimate +/- SD SD = standard deviation Total body clearance, (mL/h ∙ kg) 94 +/- 8 Volume of distribution at steady state, V ss 1. 08 AUC 0-inf 59 +/- 5 Terminal plasma elimination half-life, t 1/2 9. 7 Table 2: Mean pharmacokinetic parameters following oral administration of marbofloxacin tablets to adult beagle dogs at a nominal dosage of 1. 5 mg/lb and to cats at 2. mean actual dosages administered to dogs were 1. 22 mg/lb and 2. 56 mg/lb, respectively, and the mean actual dosage administered to cats was 2. Parameter Dog SD = standard deviation Dog Cat Time of maximum concentration, T max 1. 6 Maximum concentration, C max 2. 7 AUC 0-inf 31. 6 64 +/- 8 70 +/- 6 Terminal plasma elimination half-life, t 1/2 10. 1 Figure 2: *See Table 4 Microbiology Figure 3: *See Table 5 Microbiology Table 3a: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 1. 25 mg/lb SD = standard deviation Tissue Marbofloxacin Concentrations (µg/g +/- SD) bladder 4. 19 bone marrow 3. 2 feces 15 +/- 9 48 +/- 40 26 +/- 11 jejunum 3. 19 lymph node 5. 2 prostate 5. 08 Table 3b: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 2. Tissue Marbofloxacin Concentrations (µg/g +/- SD) SD = standard deviation bladder 12 +/- 4 6 +/- 7 1. 4 bone marrow 4. 3 feces 18 +/- 3 52 +/- 17 47 +/- 28 jejunum 7. 3 kidney 12. 2 lymph node 8. 06 muscle 7. 12 prostate 11 +/- 3 2. 09 Figure 2 Figure 3 The primary action of fluoroquinolones is to inhibit the bacterial enzyme, DNA gyrase. In susceptible organisms, fluoroquinolones are rapidly bactericidal at relatively low concentrations. Marbofloxacin is bactericidal against a broad range of gram-negative and gram-positive organisms. The minimum inhibitory concentrations (MICs) of pathogens isolated in clinical field studies performed in the United States were determined using National Committee for Clinical Laboratory Standards (NCCLS) standards, and are shown in Tables 4 and 5. MIC Values The correlation between in vitro Organism No. of Isolates MIC 50 MIC 90 MIC Range Staphylococcus intermedius 135 0. 125-2 Escherichia coli 61 0. 015-2 Proteus mirabilis 35 0. 25 Beta-hemolytic Streptococcus, 25 1 2 0. 5-16 Streptococcus, enterococcus 16 1 4 0. 008-4 Pasteurella multocida 13 0. 5 Staphylococcus aureus 12 0. 5 Enterococcus faecalis 11 2 2 1-4 Klebsiella pneumoniae 11 0. 06 Pseudomonas 9 MIC 50 90 0. 06-1 Pseudomonas aeruginosa 7 0. 25-1 Table 5: MIC Values The correlation between in vitro Organism No. of Isolates MIC 50 MIC 90 MIC Range Pasteurella multocida 135 0. 25 Beta-hemolytic Streptococcus 22 1 1 0. 06-1 Staphylococcus aureus 21 0. 125-1 Corynebacterium 14 0. 25-2 Staphylococcus intermedius 11 0. 5 Enterococcus faecalis 10 2. 0 Escherichia coli 10 0. 03 Bacillus 10 0.
Microbiology:
The primary action of fluoroquinolones is to inhibit the bacterial enzyme, DNA gyrase. In susceptible organisms, fluoroquinolones are rapidly bactericidal at relatively low concentrations. Marbofloxacin is bactericidal against a broad range of gram-negative and gram-positive organisms. The minimum inhibitory concentrations (MICs) of pathogens isolated in clinical field studies performed in the United States were determined using National Committee for Clinical Laboratory Standards (NCCLS) standards, and are shown in Tables 4 and 5. Table 4. MIC Values The correlation between in vitro Organism No. of Isolates MIC 50 MIC 90 MIC Range Staphylococcus intermedius 135 0.25 0.25 0.125-2 Escherichia coli 61 0.03 0.06 0.015-2 Proteus mirabilis 35 0.06 0.125 0.03-0.25 Beta-hemolytic Streptococcus, 25 1 2 0.5-16 Streptococcus, enterococcus 16 1 4 0.008-4 Pasteurella multocida 13 0.015 0.06 <=0.008-0.5 Staphylococcus aureus 12 0.25 0.25 0.25-0.5 Enterococcus faecalis 11 2 2 1-4 Klebsiella pneumoniae 11 0.06 0.06 0.01 -0.06 Pseudomonas 9 MIC 50 90 0.06-1 Pseudomonas aeruginosa 7 0.25-1 Table 5: MIC Values The correlation between in vitro Organism No. of Isolates MIC 50 MIC 90 MIC Range Pasteurella multocida 135 0.03 0.06 <=0.008-0.25 Beta-hemolytic Streptococcus 22 1 1 0.06-1 Staphylococcus aureus 21 0.25 0.5 0.125-1 Corynebacterium 14 0.5 1 0.25-2 Staphylococcus intermedius 11 0.25 0.5 0.03-0.5 Enterococcus faecalis 10 2.0 2.0 1.0-2.0 Escherichia coli 10 0.03 0.03 0.015-0.03 Bacillus 10 0.25 0.25 0.125-0.25

INDICATIONS AND USAGE:
Marboquin registered
EFFECTIVENESS CONFIRMATION:
Clinical effectiveness was confirmed in bacterial skin and soft tissue infections in dogs and cats and urinary tract infections (cystitis) in dogs associated with bacteria susceptible to marbofloxacin. Bacterial pathogens isolated in clinical field studies are provided in the Microbiology

The recommended dosage for oral administration to dogs and cats is 1. 25 mg marbofloxacin per lb of body weight once daily, but the dosage may be safely increased to 2. For the treatment of skin and soft tissue infections, Marboquin Chewable Tablets should be given for 2en dash3 days beyond the cessation of clinical signs for a maximum of 30 days. For the treatment of urinary tract infections, Marboquin Chewable Tablets should be administered for at least 10 days. If no improvement is noted within 5 days, the diagnosis should be re-evaluated and a different course of therapy considered. Drug Interactions: Compounds (e. , sucralfate, antacids, and mineral supplements) containing divalent and trivalent cations (e. , iron, aluminum, calcium, magnesium, and zinc) can interfere with the absorption of quinolones which may result 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.

The following clinical signs were reported during the course of clinical field studies in dogs receiving marbofloxacin at dosages up to 2.5 mg/lb daily: decreased or loss of appetite (5.4%), decreased activity (4.4%), and vomiting (2.9%). The following signs were reported in less than 1% of cases in dogs: increased thirst, soft stool/diarrhea, behavioral changes, shivering/shaking/tremors, and ataxia. One dog which had a seizure the day before study enrollment experienced a seizure while on marbofloxacin therapy. The following clinical signs were reported during clinical field studies in cats receiving 1.25 mg/lb/day: diarrhea (2.1%) and soft stool (1.4%). Vomiting was reported in less than 1% of cases in cats.

Marbofloxacin 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. Marbofloxacin is contraindicated in immature dogs during the rapid growth phase (small and medium breeds up to 8 months of age, large breeds up to 12 months of age and giant breeds up to 18 months of age). Marbofloxacin is contraindicated in cats under 12 months of age. Marbofloxacin is contraindicated in dogs and cats known to be hypersensitive to quinolones.

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

TARGET ANIMAL SAFETY
Dogs: The toxicity of marbofloxacin was assessed in 12- to 14-month-old beagle dogs administered marbofloxacin at 2. 5 mg/lb/day for 42 days. Vomiting, reddened skin (usually involving the ears) and reddened mucous membranes were occasionally observed in all groups, including controls, but were noted most frequently in the 12. 5 mg/lb group. Decreased food consumption and weight loss were significant in the 7. 5 mg/lb and 12. 5 mg/lb groups. No clinical lameness was noted in any of the treated animals. Minimal to slight lesions in the articular cartilage were observed in 1/8 placebo-treated animals and in 3/8 animals given 12. 5 mg marbofloxacin/lb. Macroscopically, these lesions were vesicles, raised areas, or depressed, light-colored areas. Microscopically, these lesions were characterized by the presence of one or more of the following: fissuring, erosion, chondrocyte proliferation, fibrillation, or vertical splitting of the articular cartilage. These cartilage lesions in treated dogs were similar to those in control dogs, and were not typical of those produced by fluoroquinolones. In addition to the above pathologic alterations, red areas of articular cartilage were noted macroscopically in 0/8 placebo-treated dogs and in 2/8 dogs from each of the three marbofloxacin-treated groups. These areas usually correlated microscopically with areas of vascularity of the articular surface, but could not be confirmed microscopically in all animals. They consisted of large blood vessels in mature fibrous connective tissue, with no indication of active vascularization due to drug-induced damage. They were considered most likely to be developmental anomalies or normal variations of the joint surface and were not considered to be related to drug treatment. Marbofloxacin was administered to 12- to 14-month-old beagle dogs at a dosage of 25 mg/lb/day for 12 days. Decreased food consumption, vomiting, dehydration, excessive salivation, tremors, reddened skin, facial swelling, decreased activity and weight loss were seen in treated dogs. No clinical lameness was noted. As in the 42 day study, grossly visible, focal, red areas of articular cartilage were seen. These findings were noted in 2/6 placebo-treated dogs and in 4/6 marbofloxacin-treated dogs. The foci were areas of fibrocartilage with prominent vascularization or increased vascularization of subchondral bone. Due to the appearance microscopically and macroscopically, these red foci were described as likely to be developmental anomalies or normal variations in articular cartilage. Marbofloxacin administered to 3- to 4-month-old, large breed, purpose-bred mongrel dogs at a dosage of 5 mg/lb/day for 14 days resulted in marked lameness in all dogs due to articular cartilage lesions. Lameness was accompanied by decreased appetite and activity. Cats: Marbofloxacin was administered for 42 consecutive days to 24 cats approximately 8 months old (8 cats per treatment group) at the dosages of 2. 5 mg/lb/day (5. 5 mg/kg/day). Treatment with marbofloxacin did not produce adverse effects on body weights, food consumption, serum chemistry, urinalysis or organ weight parameters. Decreased segmented neutrophil counts were observed in some cats in all treatment groups, including the placebo group, but mean counts were significantly lower in the marbofloxacin-treated groups. In some cats, absolute neutrophil counts were below normal reference values (as low as 615 neutrophils/µL in a marbofloxacin-treated cat and as low as 882 neutrophils/µL in a placebo-treated cat). Other hematological observations were not adversely affected. Clinical signs were occasionally noted in cats in the highest dosage group: excessive salivation in 4/8 cats and redness of ear pinnae in 2/8 cats. Macroscopic changes in the articular cartilage of femurs were seen in one cat receiving 7. 5 mg/lb and in 3 cats receiving 12. Microscopically, these gross lesions were related to a focal or multifocal chondropathy. Microscopic chondropathy not associated with macroscopic observations was also present in one cat treated with 2. 5 mg/lb daily (1X the upper end of the dose range) and one additional cat treated with 7. 5 mg/lb daily. There was no evidence of lameness during the course of the study. A perivascular to diffuse dermatitis was seen microscopically in one mid-dose cat and 4 high-dose cats. Funduscopic exam by a board-certified ophthalmologist and histologic examination of retina and optic nerve by ocular pathologists revealed no lesions in any of the treatment groups. Marbofloxacin was also administered orally to 6 cats approximately 8 months of age for 14 consecutive days at a dosage of 25 mg/lb/day (55 mg/kg/day). Clinical signs associated with drug intolerance were excessive salivation in 5/6 cats and redness of ear pinnae in all cats after 8 days of treatment. Emesis was noted occasionally in several cats and diminished activity was noted in one cat. Decreased food intake was noted in some animals, primarily males, when compared to controls. Perivascular to diffuse dermatitis was seen microscopically in the pinnae of all treated animals and in the standard skin samples of several animals. There was focal or multifocal articular chondropathy in 2/6 treated animals. One treated cat had a duodenal mucosal erosion and one treated cat had a pyloric ulcer. There were no observations of lameness and no adverse effects on hematology, clinical chemistry, urinalysis, or organ weight parameters. Funduscopic examination by a board-certified ophthalmologist and histologic examination of retina and optic nerve by ocular pathologists revealed no lesions. A study was conducted to investigate the effect of marbofloxacin on articular cartilage of skeletally mature cats 12-14 months of age. Forty cats were randomly assigned to 4 groups of 10 cats each. Groups received placebo or marbofloxacin at dosages of 1. 5 mg/lb/day (2. 5 mg/kg/day) for 42 consecutive days. There were no treatment-related pathological changes in the joints or other tissues. Emesis and soft stools was noted in all treatment groups, including placebo, and increased in frequency with increasing dose and duration of treatment. Emesis was more apparent in the high-dose males.
REFERENCES:
1. Schneider M, et al: To report suspected adverse drug events, for technical assistance or to obtain a copy of the Safety Data Sheet, contact Dechra Veterinary Products at (866) 933-2472. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae Approved by FDA under ANADA # 200-733

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