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Summer
Skin Relief
PROMOTION
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INJECTABLE CEPHALOSPORIN
• One injection for up to 14 days of continuous antibiotic therapy*
• Quickly treats common skin infections in dogs and cats
• First-time resolution† and 100% compliance
ORAL CEPHALOSPORIN
• When an oral option is preferred, your choice for treatment of
common canine skin infections
• Long half-life results in once-daily dosing for improved compliance
• Tablets are film coated, odorless and scored for easier administration
FLUOROQUINOLONE
• The fluoroquinolone with the longest half-life for convenient,
once-daily dosing
• Highest known tissue concentrations in the skin, kidney and
lung of the dog compared with other veterinary-approved
fluoroquinolones at the lowest recommended dose 1,2
IMPORTANT SAFETY INFORMATION:
People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to CONVENIA
and SIMPLICEF. Do not use these products in animals with a history of allergic reactions to penicillins or
cephalosporins. Side effects of CONVENIA for both dogs and cats include vomiting, diarrhea, decreased
appetite/anorexia and lethargy. Please see full Prescribing Information for CONVENIA and SIMPLICEF.
ZENIQUIN is not recommended for use in immature cats or dogs during the rapid growth phase, or in
cats or dogs known to be hypersensitive to fluoroquinolones. People with a history of hypersensitivity to
fluoroquinolones should avoid this product. See full Prescribing Information.
*In clinical studies, a single injection of CONVENIA was clinically equivalent to a 14-day antibiotic regimen.
†In a U.S. efficacy study, only 14% of dogs treated for skin infections required a second injection.
1
ZENIQUIN U.S. Prescribing Information NADA #141-151. 2013.
2
Scheer M. Concentrations of active ingredient in the serum and in tissues after oral and parenteral administration of Baytril. Vet Med Rev. 1987;2:104-118.
Summer
Skin Relief
Purchase across the portfolio.
Earn higher rewards.
PROMOTION
Relief for your patients.
Rewards for your practice.
1. Qualify on at least two Zoetis anti-infectives by purchasing
a minimum of $500 per product during the promotion period.
2.
You will accumulate the following
rebate percentage, to be applied
to all qualifying purchases within
the promotion period:
As you buy across the
portfolio, the rebate for your
total purchase increases.
3. The rebate percentage
accumulated during the offer
period will be applied to all
qualifying products purchased
from Zoetis or an authorized
distributor.
4. You will receive your rebate in
the form of an account credit.
CONVENIA
5%
All trademarks are the property of Zoetis Services LLC or a related company or a licensor unless otherwise noted. ©2016 Zoetis Services LLC. All rights reserved. AIF-00348
5%
CONVENIA
SIMPLICEF
TOTAL REBATE
CONVENIA
ZENIQUIN
TOTAL REBATE
SIMPLICEF
ZENIQUIN
TOTAL REBATE
CONVENIA
SIMPLICEF
ZENIQUIN
ZENIQUIN
5%
5% + 5% = 10%
5% + 5% = 10%
5% + 5% = 10%
TOTAL REBATE
5% + 5% + 5% = 15%
Rebates apply to qualifying
purchases placed and invoiced from
June 1–July 15, 2016
SIMPLICEF
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(cefovecin sodium)
Antimicrobial for Subcutaneous Injection in Dogs and Cats Only
CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.
DESCRIPTION: Cefovecin sodium is a semi-synthetic broad-spectrum antibacterial agent from the
cephalosporin class of chemotherapeutic agents. Cefovecin is the non-proprietary designation for
(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[(2S)-tetrahydro-2furanyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monosodium salt.
Figure 1: Chemical structure of cefovecin sodium.
Cats
A total of 291 cats, ranging in age from 2.4 months (1 cat) to 21 years, were included in the
field study safety analysis. Adverse reactions reported in cats treated with CONVENIA and
the active control are summarized in Table 3.
Table 3: Number of Cats* with Adverse Reactions Reported During the Field Study with
CONVENIA.
Adverse Reaction
Vomiting
Diarrhea
Anorexia/Decreased Appetite
Lethargy
Hyper/Acting Strange
Inappropriate Urination
CONVENIA
(n=147)
10
7
6
6
1
1
Active Control
(n=144)
14
26
6
6
1
0
*Some
Each mL of CONVENIA reconstituted lyophile contains cefovecin sodium equivalent to 80 mg
cefovecin, methylparaben 1.8 mg (preservative), propylparaben 0.2 mg (preservative), sodium
citrate dihydrate 5.8 mg and citric acid monohydrate 0.1 mg, sodium hydroxide or hydrochloric
acid as required to adjust pH.
INDICATIONS:
Dogs
CONVENIA is indicated for the treatment of skin infections (secondary superficial pyoderma,
abscesses, and wounds) in dogs caused by susceptible strains of Staphylococcus intermedius
and Streptococcus canis (Group G).
Cats
CONVENIA is indicated for the treatment of skin infections (wounds and abscesses) in cats
caused by susceptible strains of Pasteurella multocida.
DOSAGE AND ADMINISTRATION:
Dogs
CONVENIA should be administered as a single subcutaneous injection of 3.6 mg/lb (8 mg/kg) body
weight. A second subcutaneous injection of 3.6 mg/lb (8 mg/kg) may be administered if response
to therapy is not complete. The decision for a second injection for any individual dog should take
into consideration such factors as progress toward clinical resolution, the susceptibility of the
causative organisms, and the integrity of the dog’s host-defense mechanisms. Therapeutic drug
concentrations after the first injection are maintained for 7 days for S. intermedius infections and
for 14 days for S. canis (Group G) infections. Maximum treatment should not exceed 2 injections.
Cats
CONVENIA should be administered as a single, one-time subcutaneous injection at a dose of
3.6 mg/lb (8 mg/kg) body weight. After an injection of CONVENIA, therapeutic concentrations
are maintained for approximately 7 days for Pasteurella multocida infections.
General Dosing Information
A sample of the lesion should be obtained for culture and susceptibility testing prior to beginning
antimicrobial therapy. Once results become available, continue with appropriate therapy. If
acceptable response to treatment is not observed, or if no improvement is seen within 3 to 4 days,
then the diagnosis should be re-evaluated and appropriate alternative therapy considered.
CONVENIA may persist in the body for up to 65 days. The effect of remaining concentrations
of cefovecin on any subsequent antimicrobial therapies has not been determined.
Fluoroquinolone and aminoglycoside antimicrobials have been reported to be compatible
with cephalosporin antimicrobial agents.1,2,3
Table 1: Dose Table for CONVENIA at 8 mg/kg Body Weight.
Weight of Animal
5 lb
10 lb
15 lb
20 lb
40 lb
80 lb
Volume of CONVENIA
(3.6 mg/lb or 0.045 mL/lb)
0.23 mL
0.45 mL
0.67 mL
0.90 mL
1.80 mL
3.60 mL
PREPARATION OF SOLUTION FOR INJECTION: To deliver the appropriate dose, aseptically
reconstitute CONVENIA with 10 mL sterile water for injection. Shake and allow vial to sit until
all material is visually dissolved. The resulting solution contains cefovecin sodium equivalent to
80 mg/mL cefovecin. CONVENIA is light sensitive. The vial should be stored in the original carton
and refrigerated when not in use. Use the entire contents of the vial within 56 days of reconstitution.
CONTRAINDICATIONS: CONVENIA is contraindicated in dogs and cats with known allergy to
cefovecin or to β-lactam (penicillins and cephalosporins) group antimicrobials. Anaphylaxis
has been reported with the use of this product in foreign market experience. If an allergic
reaction or anaphylaxis occurs, CONVENIA should not be administered again and appropriate
therapy should be instituted. Anaphylaxis may require treatment with epinephrine and other
emergency measures, including oxygen, intravenous fluids, intravenous antihistamine,
corticosteroids, and airway management, as clinically indicated. Adverse reactions may
require prolonged treatment due to the prolonged systemic drug clearance (65 days).
WARNINGS: Not for use in humans. Keep this and all drugs out of reach of children. Consult a
physician in case of accidental human exposure. For subcutaneous use in dogs and cats only.
Antimicrobial drugs, including penicillins and cephalosporins, can cause allergic reactions in
sensitized individuals. To minimize the possibility of allergic reactions, those handling such
antimicrobials, including cefovecin, are advised to avoid direct contact of the product with
the skin and mucous membranes.
PRECAUTIONS: Prescribing antibacterial drugs in the absence of a proven or strongly
suspected bacterial infection is unlikely to provide benefit to treated animals and may
increase the risk of the development of drug-resistant animal pathogens.
The safe use of CONVENIA in dogs or cats less than 4 months of age (see Animal Safety) and
in breeding or lactating animals has not been determined. Safety has not been established
for IM or IV administration. The long-term effects on injection sites have not been determined.
CONVENIA is slowly eliminated from the body, approximately 65 days is needed to eliminate
97% of the administered dose from the body. Animals experiencing an adverse reaction may
need to be monitored for this duration.
CONVENIA has been shown in an experimental in vitro system to result in an increase in free
concentrations of carprofen, furosemide, doxycycline, and ketoconazole. Concurrent use of these or
other drugs that have a high degree of protein-binding (e.g. NSAIDs, propofol, cardiac, anticonvulsant,
and behavioral medications) may compete with cefovecin-binding and cause adverse reactions.
Positive direct Coombs’ test results and false positive reactions for glucose in the
urine have been reported during treatment with some cephalosporin antimicrobials.
Cephalosporin antimicrobials may also cause falsely elevated urine protein determinations.
Some antimicrobials, including cephalosporins, can cause lowered albumin values due to
interference with certain testing methods.
Occasionally, cephalosporins and NSAIDs have been associated with myelotoxicity, thereby creating
a toxic neutropenia4. Other hematological reactions seen with cephalosporins include neutropenia,
anemia, hypoprothrombinemia, thrombocytopenia, prolonged prothrombin time (PT) and partial
thromboplastin time (PTT), platelet dysfunction and transient increases in serum aminotransferases.
ADVERSE REACTIONS:
Dogs
A total of 320 dogs, ranging in age from 8 weeks to 19 years, were included in a field study
safety analysis. Adverse reactions reported in dogs treated with CONVENIA and the active
control are summarized in Table 2.
Table 2: Number of Dogs* with Adverse Reactions Reported During the Field Study with
CONVENIA.
Adverse Reaction
Lethargy
Anorexia/Decreased Appetite
Vomiting
Diarrhea
Blood in Feces
Dehydration
Flatulence
Increased Borborygmi
CONVENIA
(n=157)
2
5
6
6
1
0
1
1
Active Control
(n=163)
7
8
12
7
2
1
0
0
*Some dogs may have experienced more than one adverse reaction or more than one
occurrence of the same adverse reaction during the study.
Mild to moderate elevations in serum -glutamyl transferase or serum alanine
aminotransferase were noted post-treatment in several of the CONVENIA-treated dogs. No
clinical abnormalities were noted with these findings.
One CONVENIA-treated dog in a separate field study experienced diarrhea post-treatment
lasting 4 weeks. The diarrhea resolved.
cats may have experienced more than one adverse reaction or more than one
occurrence of the same adverse reaction during the study.
Four CONVENIA cases had mildly elevated post-study ALT (1 case was elevated pre-study).
No clinical abnormalities were noted with these findings.
Twenty-four CONVENIA cases had normal pre-study BUN values and elevated post-study
BUN values (37 – 39 mg/dL post-study). There were 6 CONVENIA cases with normal pre- and
mildly to moderately elevated post-study creatinine values. Two of these cases also had an
elevated post-study BUN. No clinical abnormalities were noted with these findings.
One CONVENIA-treated cat in a separate field study experienced diarrhea post-treatment
lasting 42 days. The diarrhea resolved.
FOREIGN MARKET EXPERIENCE: The following adverse events were reported voluntarily
during post-approval use of the product in dogs and cats in foreign markets: death, tremors/
ataxia, seizures, anaphylaxis, acute pulmonary edema, facial edema, injection site reactions
(alopecia, scabs, necrosis, and erythema), hemolytic anemia, salivation, pruritus, lethargy,
vomiting, diarrhea, and inappetance.
For a copy of the Material Safety Data Sheet (MSDS) or to report a suspected adverse
reaction call Zoetis Inc. at 1-888-963-8471.
CLINICAL PHARMACOLOGY:
Pharmacokinetics
Cefovecin is rapidly and completely absorbed following subcutaneous administration. Non-linear
kinetics is exhibited (plasma concentrations do not increase proportionally with dose). Cefovecin
does not undergo hepatic metabolism and the majority of a dose is excreted unchanged in the
urine. Elimination also occurs from excretion of unchanged drug in the bile. Cefovecin is a highly
protein-bound molecule in dog plasma (98.5%) and cat plasma (99.8%) and may compete with
other highly protein-bound drugs for plasma protein-binding sites that could result in transient,
higher free drug concentrations of either compound. Pharmacokinetic parameters following
subcutaneous dosing at 8 mg/kg in the dog and cat are summarized in Table 4.
Table 4: Pharmacokinetic Parameters Reflecting Total Drug Concentrations in Plasma
(mean ± standard deviation or range) Following an 8 mg/kg Intravenous or Subcutaneous
Dose of Cefovecin in Dogs and Cats.
MEAN ± SD1 or (Range)
PARAMETER
Terminal plasma elimination half-life, T1/2 (h)*h
AUC0-inf (μg·h/mL)*g
Time of maximum concentration, Tmax (h)*h
Maximum concentration, Cmax (μg/mL)*a
Vdss (L/kg)**g
CLtotal (mL/h/kg)**g
Dogs
Catsp
133 ± 16
10400 ± 1900p
6.2 (0.5-12.0)
121 ± 51
0.122 ± 0.011
0.76 ± 0.13p
166 ± 18
22700 ± 3450
2.0 (0.5-6.0)
141 ± 12
0.090 ± 0.010
0.350 ± 0.40
SD = standard deviation
= a phase effect was observed, only data for the first phase are provided (n=6); all other data
provided are derived from 12 animals
* = SC
** = IV
a
= arithmetic mean
h
= harmonic mean
g
= geometric mean
Population Pharmacokinetics
Dogs
Cefovecin plasma concentrations in the dog have been characterized by the use of population
pharmacokinetic (PPK) data. Plasma cefovecin concentration data were pooled from 7
laboratory pharmacokinetic studies, each involving young, normal healthy Beagle dogs. The
final dataset contained 591 concentration records from 39 dogs. The simulations from the model
provide the mean population estimate and the 5th and 95th percentile of the population estimates
of total and free cefovecin concentrations over time. Figure 2 shows the predicted free plasma
concentrations following administration of 8 mg/kg body weight to dogs. Based upon these
predicted concentrations, 95% of the canine population will have active (free) drug concentrations
> the MIC90 of S. canis (0.06 μg/mL) for approximately 14 days and free concentrations
> the MIC90 for S. intermedius (0.25 μg/mL) for approximately 7 days following a single
8 mg/kg subcutaneous injection of cefovecin. (See MICROBIOLOGY).
Figure 2: Population Predicted Free Concentration of Cefovecin in Plasma Following a
Single Subcutaneous Injection of 8 mg/kg Body Weight in Dogs (solid line is population
prediction, dotted lines are the 5th and 95th percentiles for the population prediction).
MICROBIOLOGY: CONVENIA is a cephalosporin antibiotic. Like other β-lactam
antimicrobials, CONVENIA exerts its inhibitory effect by interfering with bacterial
cell wall synthesis. This interference is primarily due to its covalent binding to the
penicillin-binding proteins (PBPs) (ie, transpeptidase and carboxypeptidase), which
are essential for synthesis of the bacterial cell wall. For E. coli, the in vitro activity of
CONVENIA is comparable to other cephalosporins, but due to the high-affinity proteinbinding, the in vivo free concentration of cefovecin does not reach the MIC90 for
E. coli (1.0 μg/mL). CONVENIA is not active against Pseudomonas spp. or enterococci.
Dogs
The minimum inhibitory concentration (MIC) values for cefovecin against label-claim pathogens
isolated from skin infections in dogs enrolled in a 2001-2003 field effectiveness study are presented
in Table 5. All MICs were determined in accordance with the Clinical and Laboratory Standards
Institute (CLSI) standards.
Table 5: Activity of CONVENIA against Pathogens Isolated from Dogs Treated with
CONVENIA in Field Studies in the US During 2001-2003.
Disease
Skin
Infections
Pathogen
Microbiological Number Sample
MIC50 MIC90 MIC
Collection
of
Treatment
Relative μg/mL μg/mL Range
Isolates (Time
Outcome
μg/mL
to Treatment)
Staphylococcus Success
intermedius
Failure
44
Pre-Treatment 0.12
4
Pre-Treatment
Streptococcus Success
canis (Group G)
Failure
16
Pre-Treatment ≤ 0.06 ≤ 0.06 ≤ 0.06
2
Pre-Treatment
Cats
Cefovecin plasma concentrations in the cat have been characterized by the use of PPK data.
Plasma cefovecin concentration data were pooled from 4 laboratory pharmacokinetic studies.
The final dataset contained 338 concentration records from 22 cats. The simulations from the
model provide the mean population estimate as well as the 5th and 95th percentile of the population
estimates of total and free cefovecin concentrations over time. Figure 3 displays the predicted free
plasma concentrations following administration of 8 mg/kg body weight to cats. Based upon these
predicted concentrations, 95% of the feline population will have active (free) drug concentrations > the
MIC90 of Pasteurella multocida (0.06 μg/mL) for approximately 7 days when administered a single 8
mg/kg subcutaneous injection of cefovecin. (See MICROBIOLOGY).
Figure 3: Population Predicted Free Concentration of Cefovecin in Plasma Following a
Single Subcutaneous Injection of 8 mg/kg Body Weight in Cats (solid line is population
prediction, dotted lines are the 5th and 95th percentiles for the population prediction).
≤ 0.06 - 2
0.12 - 2
≤ 0.06
Cats
The MIC values for cefovecin against Pasteurella multocida isolated from skin infections
(wounds and abscesses) in cats enrolled in a 2001-2003 field effectiveness study are
presented in Table 6. All MICs were determined in accordance with the CLSI standards.
Table 6: Activity of CONVENIA against Pathogens Isolated from Cats Treated with
CONVENIA in Field Studies in the US During 2001-2003.
Microbiological Number Sample
MIC50 MIC90
Collection
of
Treatment
Relative μg/mL μg/mL
Isolates (Time
Outcome
to Treatment)
57
Pre-Treatment ≤ 0.06 ≤ 0.06
Skin
Pasteurella Success
Infections multocida Failure
1
Pre-Treatment
Disease
Pathogen
MIC
Range
μg/mL
≤ 0.06 - 0.12
≤ 0.06
EFFECTIVENESS:
Dogs
In a double-masked, 1:1 randomized canine field study conducted in the United States, the
effectiveness of CONVENIA was compared to a cephalosporin active control. In this study, 320
dogs with superficial secondary pyoderma, abscesses, or infected wounds were treated with
either a single injection of CONVENIA (n=157) at 3.6 mg/lb (8 mg/kg) body weight or with an oral
active control antibiotic (n=163), administered twice daily for 14 days. In this study, dogs could
receive a second course of therapy 14 days after the initial treatment. Of the 320 enrolled dogs,
22 of 157 dogs received 2 treatments of CONVENIA and 35 of 163 dogs received 2 courses of
treatment with the active control. In the study, 118 of the 157 enrolled cases were evaluable for
effectiveness for CONVENIA, and 117 of the 163 enrolled cases were evaluable for effectiveness of
the active control antibiotic. CONVENIA was non-inferior to the active control. Table 7 summarizes
the clinical success rates obtained 28 days after the initiation of the final course of therapy.
Table 7: Clinical Success Rates by Treatment Group 28 Days after the Initiation of the
Final Course of Therapy.
Type of Infection
1
p
0.25
Skin (secondary superficial pyoderma,
abscesses, and infected wounds)
Dogs
CONVENIA
(n=118)
Active Control
(n=117)
109 (92.4%)
108 (92.3%)
CONVENIA was administered concomitantly with other commonly used veterinary products
such as heartworm preventatives, flea control products, sedatives/tranquilizers, anesthetic
agents, routine immunizations, antihistamines, thyroid hormone supplementation, and nonsteroidal anti-inflammatory drugs during the field study.
Cats
In a double-masked, 1:1 randomized cat field study conducted in the United States, the
effectiveness of CONVENIA was compared to an active control. In this study, 291 cats with
infected wounds or abscesses were treated with either a single injection of CONVENIA (n=147)
at 3.6 mg/lb (8 mg/kg) body weight or with an oral active control antibiotic (n=144), administered
once daily for 14 days. CONVENIA was non-inferior to the active control. The clinical success
rates were obtained 28 days after the initiation of therapy and are presented in Table 8.
Table 8: Clinical Success Rates by Treatment Group 28 Days after the Initiation of Therapy.
Cats
Type of Infection
CONVENIA
(n=89)
Active Control
(n=88)
Skin (wounds and abscesses)
86 (96.6%)
80 (90.9%)
CONVENIA was used concomitantly with other commonly used veterinary products such as
heartworm preventatives, flea control products, sedatives/tranquilizers, anesthetic agents,
and vaccines during the field study.
ANIMAL SAFETY:
Dogs
CONVENIA administered to healthy 4-month-old dogs at doses of 12 mg/kg (1.5X), 36 mg/kg (4.5X),
and 60 mg/kg (7.5X) every 7 days by dorsoscapular subcutaneous injections was well-tolerated for
a total of 5 doses. Vomiting and diarrhea were seen in all treatment groups, with the incidence of
vomiting and the incidence and duration of diarrhea increasing in a dose-related manner. Injection
site irritation and transient edema occurred with increasing frequency in a dose-related manner and
with repeat injections. Two injection site reactions included a seroma over the shoulder and swelling
lasting > 30 days. Dogs dosed at 36 mg/kg had a significant (P=0.0088) increase in BUN (all means
remained within the normal range) compared to the controls. One dog dosed at 60 mg/kg exhibited
a glomerulopathy on histopathology, and 1 dog in this same group had minimal peliosis hepatis.
At an exaggerated dose of 180 mg/kg (22.5X) in dogs, CONVENIA caused some injection site
irritation, vocalization, and edema. Edema resolved within 8-24 hours.
Cats
CONVENIA administered to healthy 4-month-old cats at doses of 12 mg/kg (1.5X), 36 mg/kg (4.5X),
and 60 mg/kg (7.5X) every 7 days by dorsoscapular subcutaneous injections was well-tolerated for
a total of 5 doses. Vomiting and diarrhea were observed in cats, with the incidence of vomiting and
the incidence and duration of diarrhea increasing in a dose-related manner. The mean albumin
values for all the CONVENIA-treated cats were significantly lower (P ≤ 0.05) than the control values
(all means remained within the normal range) for all time periods. The mean alkaline phosphatase
values in the 60 mg/kg group were significantly higher (P ≤ 0.0291) than the control values for all time
periods. Injection-site irritation and transient edema occurred with increasing frequency in a doserelated manner and with repeat injections. One cat in the 12 mg/kg group had a mild renal tubular and
interstitial fibrosis, and 1 cat in the 12 mg/kg group had mild glomerulosclerosis on histopathology.
At an exaggerated dose of 180 mg/kg (22.5X), CONVENIA was associated with injection site irritation,
vocalization, and edema. Edema resolved within 8-24 hours. On day 10, cats had lower mean white
blood cell counts compared to the controls. One cat had a small amount of bilirubinuria on day 10.
STORAGE INFORMATION:
Store the powder and the reconstituted product in the original carton, refrigerated at 2° to 8° C
(36° to 46° F). Use the entire contents of the vial within 56 days of reconstitution. PROTECT FROM
LIGHT. After each use it is important to return the unused portion back to the refrigerator in the
original carton. As with other cephalosporins, the color of the solution may vary from clear to
amber at reconstitution and may darken over time. If stored as recommended, solution color does
not adversely affect potency.
HOW SUPPLIED:
CONVENIA is available as a 10 mL multi-use vial containing 800 milligrams of cefovecin as
a lyophilized cake.
REFERENCES:
1
Pillai SK, Moellering RC, Eliopoulos GM. Antimicrobial combinations. In: Lorian V, ed.
Antibiotics in laboratory medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins,
2005;365-440.
2
Fish DN, Choi MK, Jung R. Synergic activity of cephalosporins plus fluoroquinolones against
Pseudomonas aeruginosa with resistance to one or both drugs. J Antimicrob Chemother
2002;50:1045-1049.
3
Mayer I, Nagy E. Investigation of the synergic effects of aminoglycoside-fluoroquinolone and
third-generation cephalosporin combinations against clinical isolates of Pseudomonas spp.
J Antimicrob Chemother 1999;43:651-657.
4
Birchard SJ, Sherding RG. Saunders manual of small animal practice. 2nd ed. Philadelphia:
PA: WB Saunders Co, 2000;166.
NADA# 141-285, Approved by FDA
Distributed by
Zoetis Inc.
January 2013
Kalamazoo, MI 49007
PAA035845A&P
For Oral Use In Dogs Only
CAUTION: Federal (USA) law restricts this drug to use by or on
the order of a licensed veterinarian.
DESCRIPTION
Cefpodoxime proxetil is an orally administered, extended
spectrum, semi-synthetic cephalosporin antibiotic. The chemical
name is:
(+/-)-1-Hydroxyethyl(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)
glyoxylamido]-3-methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]
oct-2-ene-2-carboxylate, 72-(Z)-(O-methyloxime), isopropyl
carbonate (ester) [87239-81-4].
Cefpodoxime proxetil Chemical Structure:
Cefpodoxime proxetil is a prodrug; its active metabolite is
cefpodoxime. All doses of SIMPLICEF (cefpodoxime proxetil)
tablets are expressed in terms of the active cefpodoxime moiety.
SIMPLICEF is available as:
100 mg Tablet, each reddish-orange, elliptical, scored tablet
contains cefpodoxime proxetil equivalent to 100 mg of cefpodoxime.
200 mg Tablet, each light orange, round rectangle, scored tablet
contains cefpodoxime proxetil equivalent to 200 mg of cefpodoxime.
INDICATION
SIMPLICEF tablets are indicated for the treatment of skin
infections (wounds and abscesses) in dogs caused by susceptible
strains of Staphylococcus intermedius, Staphylococcus aureus,
Streptococcus canis (group G, ß hemolytic), Escherichia coli,
Pasteurella multocida, and Proteus mirabilis.
DOSAGE AND ADMINISTRATION
Dose range: The dose range of SIMPLICEF (cefpodoxime proxetil)
tablets is 5-10 mg/kg (2.3-4.5 mg/lb) body weight, administered
orally, once a day. The dose may be given with or without food.
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 organisms, and
the integrity of the patient’s host-defense mechanisms. Obtain
a sample of the pathogenic organism for culture and sensitivity
testing prior to beginning antimicrobial therapy. Once results
become available, continue with appropriate therapy.
Duration: SIMPLICEF tablets should be administered once daily
for 5-7 days or for 2-3 days beyond the cessation of clinical
signs, up to a maximum of 28 days. Treatment of acute infections
should not be continued for more than 3-4 days if no response to
therapy is seen.
Dosing Charts: For daily oral administration of SIMPLICEF at
5 mg/kg (Table 1) and 10 mg/kg (Table 2).
Table 1. Dose Table for SIMPLICEF Tablets at 5 mg/kg Total
Daily Dosage
Weight of Dog (lbs)
Daily Dose
22
44
No. of 100 mg tablets
0.5 1
No. of 200 mg tablets
66
1.5
Weight of Dog (kgs)
Daily Dose
10
20
No. of 100 mg tablets
0.5 1
No. of 200 mg tablets
30
1.5
88
1
40
1
132
1
1
60
1
1
Table 2. Dose Table for SIMPLICEF Tablets at 10 mg/kg Total
Daily Dosage
Daily Dose
No. of 100 mg tablets
No. of 200 mg tablets
Weight of Dog (lbs)
11
22
44
0.5 1
1
Daily Dose
No. of 100 mg tablets
No. of 200 mg tablets
Weight of Dog (kgs)
5
10
20
0.5 1
1
66
1
1
30
1
1
88
132
2
3
40
60
2
3
CONTRAINDICATIONS
Cefpodoxime proxetil is contraindicated in dogs with known
allergy to cefpodoxime or to the ß-lactam (penicillins and
cephalosporins) group of antibiotics.
WARNINGS
Not for human use. Keep this and all drugs out of reach of children.
Antimicrobial drugs, including penicillins and cephalosporins,
can cause allergic reactions in sensitized individuals. To
minimize the possibility of allergic reactions, those handling such
antimicrobials, including cefpodoxime, are advised to avoid direct
contact of the product with the skin and mucous membranes.
PRECAUTIONS
The safety of cefpodoxime proxetil in dogs used for breeding,
pregnant dogs, or lactating bitches has not been demonstrated.
As with other cephalosporins, cefpodoxime proxetil may
occasionally induce a positive direct Coombs’ test.
ADVERSE REACTIONS
A total of 216 dogs of various breeds and ages ranging from
2 months to 15 years were included in the field study safety
analysis. The following table shows the number of dogs
displaying each clinical observation.
Table 3. Abnormal Health Findings in the U.S. Field Study1
Clinical Observation SIMPLICEF
Active
(n=118)
Control (n=98)
Vomiting
2
4
Diarrhea
1
1
Increased water
0
2
drinking
Decreased appetite
1
1
1
Dogs may have experienced more than one of the observations
during the study.
To report a suspected adverse reaction call 1-888-963-8471.
To request a material safety data sheet (MSDS) for SIMPLICEF
tablets, call 1-888-963-8471.
CLINICAL PHARMACOLOGY
Pharmacokinetics/Pharmacodynamics: Cefpodoxime proxetil
is a prodrug that is absorbed from and de-esterified in the
gastrointestinal tract to its active metabolite, cefpodoxime.
Following oral administration to fasting Beagles, oral
bioavailability was 63.1 ± 5.3%.
Figure 1. Canine Plasma Concentration of Cefpodoxime After a
Single Oral Dose of 10 mg/kg Cefpodoxime Proxetil Tablets
Cefpodoxime is distributed in the body with an apparent volume
of distribution of 151 ± 27 mL/kg. Like other ß-lactam antibiotics,
cefpodoxime is eliminated from the body primarily in the urine,
with an apparent elimination half-life of approximately 5-6 hours
after oral administration. This is similar to the 4.7 hour apparent
elimination half-life observed after intravenous dosing. Following
intravenous administration of 10 mg/kg, the average total body
clearance (ClB) was 22.7 ± 4.19 mL/hr/kg.
Table 4. Summary of Pharmacokinetic Parameters Obtained
after a Single Oral Dose of 10 mg Cefpodoxime/kg BW,
Administered as a Tablet
PK Parameter
Unit
Tablet (SD)
AUC0-∞
mcg•hr/mL
145 (77.6)
AUC0-LOQ
mcg•hr/mL
142 (77.5)
Maximum concentration
(Cmax)
mcg/mL
16.4 (11.8)
Terminal plasma
elimination half-life (t1/2,z)
hr
5.61 (1.15)
Time of maximum
concentration (tmax)
hr
2.21 (0.542)
Mean residence time
(MRT0-∞)
hr
9.21 (1.97)
Microbiology: Like other ß-lactam antibiotics, cefpodoxime
exerts its inhibitory effect by interfering with bacterial cell
wall synthesis. This interference is primarily due to its
covalently binding to the penicillin-binding proteins (PBPs) (i.e.
transpeptidase and/or carboxypeptidase), which are essential
for synthesis of the bacterial cell wall. Therefore, cefpodoxime
is bactericidal. Cefpodoxime is stable in the presence of many
common ß-lactamase enzymes. As a result, many organisms
resistant to other ß-lactam antibiotics (penicillins and some
cephalosporins) due to the production of ß-lactamases may
be susceptible to cefpodoxime.
Cefpodoxime has a broad spectrum of clinically useful
antibacterial activity that includes staphylococci, streptococci,
and Gram-negative species (including Pasteurella, Escherichia,
and Proteus). The compound is not active against most obligate
anaerobes, Pseudomonas spp., or enterococci. The minimum
inhibitory concentrations (MICs) for cefpodoxime against Grampositive and Gram-negative pathogens isolated from canine skin
infections (wounds and abscesses) in a 2002 U.S. field study are
presented in Table 5. All MICs were determined in accordance
with the National Committee for Clinical Laboratory Standards
(NCCLS). Appropriate quality control (QC) ranges for in vitro
susceptibility testing are presented in Table 6.
Table 5. Cefpodoxime Minimum Inhibitory Concentration Values
(mcg/mL) from a 2002 Field Study Evaluating Skin Infections
(wounds and abscesses) of Canines in the United States.
Organism*
# of
Isolates
MIC50
MIC90
Range
Staphylococcus
118
0.12
0.50
0.12->32.0
intermedius
Streptococcus
33
≤0.03
≤0.03
≤0.03†
canis (group G, ß
hemolytic)
Escherichia coli
41
0.25
0.50
0.12->32.0
Pasteurella
32
≤0.03
≤0.03
≤0.03-0.12
multocida
Proteus mirabilis
14
≤0.03
0.06
≤0.03-0.06
Staphylococcus
19
2.0
2.0
0.12-2.0
aureus
†
No Range, all isolates yielded the same value.
* Veterinary specific interpretive criteria have not been established
for the above listed canine pathogens by the NCCLS at this time.
Table 6. Acceptable Quality Control Ranges for Cefpodoxime
QC ATCC strain
KB Disk
Diffusion Method
Drug
concentration
Zone
diameter
Broth
Micro-dilution
Method
MIC
Escherichia coli
10 mcg
23-28 mma 0.25-1 mcg/mLa
25922
Staphylococcus
10 mcg
19-25 mma
aureus 25923
Staphylococcus
1-8 mcg/mLa
aureus 29213
Streptococcus
10 mcg
28-34 mmb
0.03pneumoniae
0.12 mcg/mLb
49619
a
These ranges are for quality control strains used to monitor
accuracy of minimum inhibitory concentrations (MICs) of nonfastidious organisms using cation-adjusted Mueller-Hinton agar
or broth medium. The dilution range should encompass the
QC ranges of these strains in the broth micro-dilution method.
b
These ranges are for quality control strains used to monitor
accuracy of minimum inhibitory concentrations (MICs) of
fastidious organisms. When susceptibility testing is performed
for Streptococcus canis (group G, ß hemolytic), Streptococcus
pneumoniae ATCC 49619 should be included as a QC strain
in the presence of 5% lysed sheep blood (KB disk diffusion
method) or 2.5% lysed horse blood (broth micro-dilution method).
EFFECTIVENESS
The clinical effectiveness of SIMPLICEF (cefpodoxime proxetil)
was established in a multi-location (23 site) field study. In
this study, 216 dogs with infected wounds or abscesses were
treated with either SIMPLICEF (n=118) once daily at 5 mg/
kg (2.3 mg/lb) body weight or with a active control antibiotic
(n=98) administered twice daily for 5-7 days. In this study,
SIMPLICEF was considered noninferior to the active control
(88.7% versus 88.4% respectfully) in the treatment of canine
skin infections (wounds and abscesses) caused by susceptible
strains of Staphylococcus intermedius, Staphylococcus aureus,
Streptococcus canis (group G, ß hemolytic), Escherichia coli,
Pasteurella multocida, and Proteus mirabilis.
ANIMAL SAFETY
In target animal safety studies, cefpodoxime was well tolerated
at exaggerated daily oral doses of 100 mg/kg/day (10 times
the maximum label dose) for 13 weeks in adult dogs and for
28 days in puppies (18- 23 days of age). Therefore, once daily
administration of cefpodoxime oral tablets at the maximum
labeled dose of 10 mg/kg for up to 28 days was shown to be safe
in adult dogs and puppies.
Blood dyscrasia including neutropenias, may be seen following
high doses of cephalosporins. Cephalosporin administration
should be discontinued in such cases.
STORAGE INFORMATION
Store tablets at controlled room temperature 20° to 25°C (68° to
77°F). Replace cap securely after each opening.
HOW SUPPLIED
SIMPLICEF tablets are available in the following strengths
(cefpodoxime equivalent), colors, and sizes:
100 mg (reddish-orange, elliptical, scored, debossed with 5228)
Bottles of 100
Bottles of 250
200 mg (light orange, round rectangle, scored, debossed with 5229)
Bottles of 100
Bottles of 250
NADA # 141-232, Approved by FDA
Manufactured by:
Sandoz
Kundl, Austria
Product of India
Distributed by:
Zoetis Inc.
Kalamazoo, MI 49007
Revised June 2013
46104787A&P
®
cats only
Figure 2: Mean plasma concentrations (µg/mL) following single oral administration
of marbofloxacin to adult beagle dogs at dosages of 1.25 mg/lb or 2.5 mg/lb.
* See Table 4 in Microbiology section for MIC data.
®
Tablets
For oral use in dogs and cats only
CAUTION: Federal law restricts this drug to use by or on the order of a licensed
veterinarian.
Federal law prohibits the extralabel use of this drug in
food-producing animals.
DESCRIPTION: Marbofloxacin is a synthetic broad-spectrum antibacterial agent
from the fluoroquinolone class of chemotherapeutic agents. Marbofloxacin is
the non-proprietary designation for 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2] benzoxadiazine-6-carboxylic acid. The
empirical formula is C17H19FN4O4 and the molecular weight is 362.36. The compound is soluble in water; however, solubility decreases in alkaline conditions. The
N-octanol/water partition coefficient (Kow) is 0.835 measured at pH 7 and 25°C.
Figure 1: Chemical structure of marbofloxacin
O
O
F
N
* See Table 5 in Microbiology section for MIC data.
OH
N
H3 C
N
O
N
CH3
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.) In the dog, approximately 40%
of an oral dose of marbofloxacin is excreted unchanged in the urine1. Excretion in
the feces, also as unchanged drug, is the other major route of elimination in dogs.
Ten to 15% of marbofloxacin is metabolized by the liver in dogs.
In vitro plasma protein binding of marbofloxacin in dogs was 9.1% and in cats was
7.3%. In the cat, approximately 70% of an oral dose is excreted in the urine as
marbofloxacin and metabolites with approximately 85% of the excreted material as
unchanged drug. Pharmacokinetic parameters related to intravenous dosing were
estimated in a study of 6 healthy adult beagle dogs, and are summarized in Table 1.
The absolute bioavailability following dosing of oral tablets to the same animals
was 94%.
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
2.5 mg/lb. Absorption of orally administered marbofloxacin increases proportionally over the dose range of 1.25 to 2.5 mg/lb. Marbofloxacin plasma concentrations
were determined over time in 7 healthy adult male cats following a single oral dose
of 2.5 mg/lb. 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 (1.25 or 2.5 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 2.5 mg/lb.
Estimate ± SD*
Parameter
n= 6
Total body clearance, (mL/h•kg)
Volume of distribution at steady state, Vss, (L/kg)
AUC0-inf (µg•h/mL)
Terminal plasma elimination half-life, t1/2(h)
94 ± 8
1.19 ± 0.08
59 ± 5
9.5 ± 0.7
* SD = standard deviation
Table 2: Mean pharmacokinetic parameters following oral administration of
marbofloxacin tablets to adult beagle dogs at a nominal dosage of 1.25 mg/lb or
2.5 mg/lb and to cats at 2.5 mg/lb.†
Parameter
Figure 3: Mean plasma concentrations (µg/mL) following single oral administration
of marbofloxacin to adult cats at a dosage of 2.5 mg/lb.
Dog
Estimate ± SD*
(1.25 mg/lb)
n= 6
Time of maximum concentration, Tmax(h)
1.5 ± 0.3
2.0 ± 0.2
Maximum concentration, Cmax, (µg/mL)
31.2 ± 1.6
AUC0-inf (µg•h/mL)
Terminal plasma elimination half-life, t1/2(h) 10.7 ± 1.6
Dog
Estimate ± SD*
(2.5 mg/lb)
n= 6
Cat
Estimate ± SD*
(2.5 mg/lb)
n=7
1.8 ± 0.3
4.2 ± 0.5
64 ± 8
10.9 ± 0.6
1.2 ± 0.6
4.8 ± 0.7
70 ± 6
12.7 ± 1.1
† 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 2.82 mg/lb.
* SD = standard deviation
Table 3a: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 1.25 mg/lb*.
Tissue
Marbofloxacin Concentrations (µg/g ± SD)
2 hours
18 hours
24 hours
(n=4)
(n=4)
(n=4)
bladder
bone marrow
feces
jejunum
kidney
lung
lymph node
muscle
prostate
skin
4.8 ± 1.1
3.1 ± 0.5
15 ± 9
3.6 ± 0.5
7.1 ±1.7
3.0 ± 0.5
5.5 ± 1.1
4.1 ± 0.3
5.6 ± 1.4
1.9 ± 0.6
2.6 ± 1.5
1.5 ± 1.5
48 ± 40
1.3 ± 1.0
1.4 ± 0.5
0.8 ± 0.2
1.3 ± 0.3
1.0 ± 0.3
1.8 ± 0.6
0.41 ± 0.13
1.11 ± 0.19
0.7 ± 0.2
26 ± 11
0.7 ± 0.3
0.9 ± 0.3
0.57 ± 0.19
1.0 ± 0.3
0.7 ± 0.2
1.1 ± 0.4
0.32 ± 0.08
* SD = standard deviation
Table 3b: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 2.5 mg/lb.
Tissue
Marbofloxacin Concentrations (µg/g ± SD*)
2 hours
18 hours
24 hours
(n=4)
(n=4)
(n=4)
bladder
bone marrow
feces
jejunum
kidney
lung
lymph node
muscle
prostate
skin
12 ± 4
4.6 ± 1.5
18 ± 3
7.8 ± 1.1
12.7 ±1.7
5.48 ± 0.17
8.3 ± 0.7
7.5 ± 0.5
11 ± 3
3.20 ± 0.33
6±7
1.28 ± 0.13
52 ± 17
2.0 ± 0.3
2.7 ± 0.3
1.45 ± 0.19
2.3 ± 0.5
1.8 ± 0.3
2.7 ± 1.0
0.705 ± 0.013
1.8 ± 0.4
0.9 ± 0.3
47 ± 28
1.1 ± 0.3
1.6 ± 0.2
1.0 ± 0.2
2.03 ± 0.06
1.20 ± 0.12
2.0 ± 0.5
0.46 ± 0.09
* SD = standard deviation
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.
13910600 A&P
Table 4: MIC Values* (µg/mL) of marbofloxacin against pathogens isolated from
Vomiting, reddened skin (usually involving the ears) and reddened mucous memTable 4: MIC Values* (µg/mL) of marbofloxacin against pathogens isolated from
skin, soft tissue and urinary tract infections in dogs enrolled in clinical studies conbranes were occasionally observed in all groups, including controls, but were
branes were occasionally observed in all groups, including controls, but were
skin, soft tissue and urinary tract infections in dogs enrolled in clinical studies conducted during 1994–1996.
noted most frequently in the 12.5 mg/lb group. Decreased food consumption and
noted most frequently in the 12.5 mg/lb group. Decreased food consumption and
ducted during 1994–1996.
weight
loss were significant in the 7.5 mg/lb and 12.5 mg/lb groups. No cliniweight loss were significant in the 7.5 mg/lb and 12.5 mg/lb groups. No cliniNo. ofNo. of
cal
lameness
was noted
in anyinof
theoftreated
animals.
Minimal
to slight
lesions
lameness
was noted
any
the treated
animals.
Minimal
to slight
lesions
Organism
Isolates
MIC Range in thecal
Organism
Isolates MIC50MIC50 MIC90MIC90 MIC Range
articular
cartilage
were
observed
in
1/8
placebo-treated
animals
and
in the articular cartilage were observed in 1/8 placebo-treated animals in
and in
Staphylococcus
intermedius
135
0.25
0.25
0.125–2
3/8
animals
given
12.5
mg
marbofloxacin/lb.
Macroscopically,
these
lesions
were
Staphylococcus intermedius
135
0.25
0.25
0.125–2
3/8 animals given 12.5 mg marbofloxacin/lb. Macroscopically, these lesions were
Escherichia
coli coli
61 61
0.03 0.03 0.06 0.06 0.015–2
vesicles,
raised
areas,
or depressed,
light-colored
areas.
Microscopically,
thesethese
Escherichia
0.015–2
vesicles,
raised
areas,
or depressed,
light-colored
areas.
Microscopically,
Proteus
mirabilis
35
0.06
0.125
0.03–0.25
lesions
werewere
characterized
by the
of one
more
of theoffollowing:
fis- fisProteus mirabilis
35
0.06
0.125
0.03–0.25
lesions
characterized
bypresence
the presence
of or
one
or more
the following:
Beta-hemolytic
Streptococcus,
suring,
erosion,
chondrocyte
proliferation,
fibrillation,
or
vertical
splitting
of
the
Beta-hemolytic Streptococcus,
suring, erosion, chondrocyte proliferation, fibrillation, or vertical splitting of the
(not Group
A or Group
B) B)
25 25
1
2
0.5–16
articular
cartilage.
These
cartilage
lesions
in treated
dogsdogs
werewere
similar
to those
(not Group
A or Group
1
2
0.5–16
articular
cartilage.
These
cartilage
lesions
in treated
similar
to those
Streptococcus,
in
control
dogs,dogs,
and were
not typical
of those
produced
by fluoroquinolones.
Streptococcus,
in control
and were
not typical
of those
produced
by fluoroquinolones.
GroupGroup
D enterococcus
16
1
4
0.008–4
In
addition
to
the
above
pathologic
alterations,
red
areas
of
articular
cartilage
D enterococcus
16
1
4
0.008–4
In addition to the above pathologic alterations, red areas of articular cartilage
Pasteurella
multocida
13 13
0.0150.015 0.06 0.06 ≤0.008–0.5
notednoted
macroscopically
in 0/8inplacebo-treated
dogsdogs
and in
2/8indogs
fromfrom
Pasteurella
multocida
≤0.008–0.5 werewere
macroscopically
0/8 placebo-treated
and
2/8 dogs
Staphylococcus
aureus
12 12
0.25 0.25 0.25 0.25 0.25–0.5
of theofthree
marbofloxacin-treated
groups.
These
areasareas
usually
correlated
Staphylococcus
aureus
0.25–0.5 eacheach
the three
marbofloxacin-treated
groups.
These
usually
correlated
Enterococcus
faecalis
11 11
2
2
1–4 1–4
microscopically
with with
areasareas
of vascularity
of theofarticular
surface,
but could
not be
Enterococcus
faecalis
2
2
microscopically
of vascularity
the articular
surface,
but could
not be
Klebsiella
pneumoniae
11
0.06
0.06
0.01–0.06
confirmed
microscopically
in
all
animals.
They
consisted
of
large
blood
vessels
in in
Klebsiella pneumoniae
11
0.06
0.06
0.01–0.06
confirmed microscopically in all animals. They consisted of large blood vessels
Pseudomonas
spp.
9
**
**
0.06–1
mature
fibrous
connective
tissue,
with
no
indication
of
active
vascularization
due
Pseudomonas spp.
9
**
**
0.06–1
mature fibrous connective tissue, with no indication of active vascularization due
Pseudomonas
aeruginosa
7
** **
** ** 0.25–1
to drug-induced
damage.
TheyThey
werewere
considered
mostmost
likelylikely
to betodevelopmental
Pseudomonas
aeruginosa
7
0.25–1
to drug-induced
damage.
considered
be developmental
anomalies
or normal
variations
of theofjoint
surface
and were
not considered
to beto be
anomalies
or
normal
variations
the
joint
surface
and
were
not considered
* The correlation
between
in
vitro
susceptibility
data
(MIC)
and
clinical
response
has
not
been
* The correlation between in vitro susceptibility data (MIC) and clinical response has not been related to drug treatment.
related
to
drug
treatment.
determined.
determined.
Marbofloxacin
was administered
to 12-toto1214-month-old
beagle
dogsdogs
at a dosage
** MIC
and MIC
Marbofloxacin
was administered
to 14-month-old
beagle
at a dosage
90 not calculated due to insufficient number of isolates.
**50MIC
50 and MIC90 not calculated due to insufficient number of isolates.
of 25 of
mg/lb/day
for 12for
days.
Decreased
food food
consumption,
vomiting,
dehydration,
25 mg/lb/day
12 days.
Decreased
consumption,
vomiting,
dehydration,
excessive
salivation,
tremors,
reddened
skin,
facial
swelling,
decreased
activity
TableTable
5: MIC5:Values*
(µg/mL)
of marbofloxacin
against
pathogens
isolated
from from
excessive salivation, tremors, reddened skin, facial swelling, decreased activity
MIC Values*
(µg/mL)
of marbofloxacin
against
pathogens
isolated
and weight
loss were
seenseen
in treated
dogs.dogs.
No clinical
lameness
was was
noted.
As inAs in
skin and
infections
in cats
in clinical
studies
conducted
in 1995
weight
loss were
in treated
No clinical
lameness
noted.
skinsoft
andtissue
soft tissue
infections
in enrolled
cats enrolled
in clinical
studies
conducted
in 1995 the 42and
day
grossly
visible,
focal,focal,
red areas
of articular
cartilage
werewere
seen.seen.
and 1998.
the
42study,
day study,
grossly
visible,
red areas
of articular
cartilage
and 1998.
TheseThese
findings
werewere
notednoted
in 2/6inplacebo-treated
dogsdogs
and in
4/6inmarbofloxacinNo. ofNo. of
findings
2/6 placebo-treated
and
4/6 marbofloxacintreated
dogs.dogs.
The foci
areasareas
of fibrocartilage
with with
prominent
vascularizaOrganism
Isolates
treated
Thewere
foci were
of fibrocartilage
prominent
vascularizaMIC Range tion or
Organism
Isolates MIC50MIC50 MIC90MIC90 MIC Range
increased
vascularization
of
subchondral
bone.
Due
to
the
appearance
tion
or
increased
vascularization
of
subchondral
bone.
Due
to
the appearance
Pasteurella
multocida
135
0.03
0.06
≤0.008–0.25
Pasteurella multocida
135
0.03
0.06
≤0.008–0.25 microscopically
and macroscopically,
thesethese
red foci
described
as likely
to beto be
microscopically
and macroscopically,
red were
foci were
described
as likely
Beta-hemolytic
Streptococcus
1
1
0.06–1
Beta-hemolytic
Streptococcus 22 22
1
1
0.06–1
developmental
anomalies
or normal
variations
in articular
cartilage.
developmental
anomalies
or normal
variations
in articular
cartilage.
Staphylococcus
aureus
21
0.25
0.5
0.125–1
Staphylococcus aureus
21
0.25
0.5
0.125–1
Marbofloxacin
administered
to 3- to
to 34-month-old,
largelarge
breed,
purpose-bred
mon-monMarbofloxacin
administered
to 4-month-old,
breed,
purpose-bred
Corynebacterium
spp. spp.
14 14
0.5 0.5
1
0.25–2
Corynebacterium
1
0.25–2
grel dogs
at a dosage
of 5 mg/lb/day
for 14for
days
resulted
in marked
lameness
in all
grel
dogs
at
a
dosage
of
5
mg/lb/day
14
days
resulted
in
marked
lameness
Staphylococcus
intermedius
11
0.25
0.5
0.03–0.5
Staphylococcus intermedius
11
0.25
0.5
0.03–0.5 dogs due to articular cartilage lesions. Lameness was accompanied by decreasedin all
dogs
due
to
articular
cartilage
lesions.
Lameness
was
accompanied
by
decreased
Enterococcus
faecalis
10
2.0
2.0
1.0–2.0
Enterococcus faecalis
10
2.0
2.0
1.0–2.0 appetite and activity.
appetite and activity.
Escherichia
coli coli
10 10
0.03 0.03 0.03 0.03 0.015–0.03
Escherichia
0.015–0.03
Marbofloxacin
was administered
for 42for
consecutive
daysdays
to 24to
cats
approxiBacillus
spp.
10
0.25
0.25
0.125–0.25
Marbofloxacin
was administered
42 consecutive
24 cats
approxiBacillus spp.
10
0.25
0.25
0.125–0.25 Cats:Cats:
mately
8 months
old (8old
cats
per treatment
group)
at theatdosages
of 2.5,of7.5
and
mately
8
months
(8
cats
per
treatment
group)
the
dosages
2.5,
7.5 and
* The correlation
between
in
vitro
susceptibility
data
(MIC)
and
clinical
response
has
not
been
* The correlation between in vitro susceptibility data (MIC) and clinical response has not been 12.5 mg/lb/day
(5.5, 16.5
Treatment
with with
marbofloxacin
did did
12.5 mg/lb/day
(5.5, and
16.527.5
and mg/kg/day).
27.5 mg/kg/day).
Treatment
marbofloxacin
determined.
determined.
not produce
adverse
effects
on body
weights,
food food
consumption,
serum
chemnot produce
adverse
effects
on body
weights,
consumption,
serum
chemurinalysis
or organ
weight
parameters.
Decreased
segmented
neutrophil
INDICATIONS
AND AND
USAGE:
Zeniquin
(marbofloxacin)
tablets
are indicated
for the
urinalysis
or organ
weight
parameters.
Decreased
segmented
neutrophil
INDICATIONS
USAGE:
Zeniquin
(marbofloxacin)
tablets
are indicated
for the istry,istry,
counts
were
observed
in
some
cats
in
all
treatment
groups,
including
the
placebo
treatment
of infections
in dogs
and cats
with bacteria
susceptible
to to
counts were observed in some cats in all treatment groups, including the placebo
treatment
of infections
in dogs
and associated
cats associated
with bacteria
susceptible
group,
but mean
counts
werewere
significantly
lowerlower
in theinmarbofloxacin-treated
marbofloxacin.
group,
but mean
counts
significantly
the marbofloxacin-treated
marbofloxacin.
In some
cats,cats,
absolute
neutrophil
counts
werewere
below
normal
reference
groups.
In some
absolute
neutrophil
counts
below
normal
reference
CONTRAINDICATIONS:
Marbofloxacin
and other
quinolones
have have
beenbeen
shown
to to groups.
CONTRAINDICATIONS:
Marbofloxacin
and other
quinolones
shown
(as low
615
in a marbofloxacin-treated
cat and
values
(asas
low
asneutrophils/µL
615 neutrophils/µL
in a marbofloxacin-treated
cat as
andlow
as as
low as
causecause
arthropathy
in immature
animals
of most
species
tested,
the dog
par- par- values
arthropathy
in immature
animals
of most
species
tested,
thebeing
dog being
882 neutrophils/µL
in a placebo-treated
cat). cat).
OtherOther
hematological
observations
882
neutrophils/µL
in
a
placebo-treated
hematological
observations
ticularly
sensitive
to
this
side
effect.
Marbofloxacin
is
contraindicated
in
immature
ticularly sensitive to this side effect. Marbofloxacin is contraindicated in immature were not adversely affected. Clinical signs were occasionally noted in cats in the
were not adversely affected. Clinical signs were occasionally noted in cats in the
dogs dogs
duringduring
the rapid
growth
phasephase
(small(small
and medium
breeds
up toup
8 months
of of
the rapid
growth
and medium
breeds
to 8 months
highest dosage
group:
excessive
salivation
in 4/8incats
and redness
of earofpinnae
dosage
group:
excessive
salivation
4/8 cats
and redness
ear pinnae
age, large
breeds
up to up
12 to
months
of ageofand
breeds
up toup
18 to
months
of age).
age, large
breeds
12 months
agegiant
and giant
breeds
18 months
of age). in 2/8highest
Macroscopic
changes
in theinarticular
cartilage
of femurs
werewere
seenseen
incats.
2/8 cats.
Macroscopic
changes
the articular
cartilage
of femurs
Marbofloxacin
is contraindicated
in cats
12 months
of age.
is is
Marbofloxacin
is contraindicated
in under
cats under
12 months
of Marbofloxacin
age. Marbofloxacin
in oneincat
receiving
7.5 mg/lb
and in
3 cats
receiving
12.5 mg/lb.
Microscopically,
one
cat
receiving
7.5
mg/lb
and
in
3
cats
receiving
12.5
mg/lb.
Microscopically,
contraindicated
in
dogs
and
cats
known
to
be
hypersensitive
to
quinolones.
contraindicated in dogs and cats known to be hypersensitive to quinolones.
thesethese
grossgross
lesions
werewere
related
to a focal
or multifocal
chondropathy.
Microlesions
related
to a focal
or multifocal
chondropathy.
MicroWARNING:
For use
animals
only. only.
KeepKeep
out ofout
reach
of children.
AvoidAvoid
contact
WARNING:
Forinuse
in animals
of reach
of children.
contact scopic
chondropathy
not associated
with with
macroscopic
observations
was was
also also
scopic
chondropathy
not
associated
macroscopic
observations
with eyes.
In
case
of
contact,
immediately
flush
eyes
with
copious
amounts
of
with eyes. In case of contact, immediately flush eyes with copious amounts of
present
in one
with with
2.5 mg/lb
dailydaily
(1X the
end of
theofdose
present
incat
onetreated
cat treated
2.5 mg/lb
(1Xupper
the upper
end
the dose
waterwater
for 15for
minutes.
In case
of dermal
contact,
washwash
skin with
and water.
15 minutes.
In case
of dermal
contact,
skin soap
with soap
and water. range)
and one
cat treated
with with
7.5 mg/lb
daily.daily.
ThereThere
was was
no evidence
range)
andadditional
one additional
cat treated
7.5 mg/lb
no evidence
Consult
a
physician
if
irritation
persists
following
ocular
or
dermal
exposure.
Consult a physician if irritation persists following ocular or dermal exposure.
of lameness
during
the course
of theofstudy.
A perivascular
to diffuse
dermatitis
of lameness
during
the course
the study.
A perivascular
to diffuse
dermatitis
Individuals
with awith
history
of hypersensitivity
to fluoroquinolones
should
avoidavoid
this this was seen
Individuals
a history
of hypersensitivity
to fluoroquinolones
should
microscopically
in
one
mid-dose
cat
and
4
high-dose
cats.
Fundu
scopic
was seen microscopically in one mid-dose cat and 4 high-dose cats. Fundu
scopic
product.
In humans,
therethere
is a risk
user
withinwithin
a fewahours
product.
In humans,
is aofrisk
of photosensitization
user photosensitization
few hours
examexam
by a board-certified
ophthalmologist
and histologic
examination
of retina
by
a
board-certified
ophthalmologist
and
histologic
examination
of
retina
after after
excessive
exposure
to
quinolones.
If
excessive
accidental
exposure
occurs,
excessive exposure to quinolones. If excessive accidental exposure occurs, and optic
nervenerve
by ocular
pathologists
revealed
no lesions
in any
theoftreatment
and optic
by ocular
pathologists
revealed
no lesions
inof
any
the treatment
avoidavoid
directdirect
sunlight.
sunlight.
groups.
groups.
PRECAUTIONS:
Quinolones
should
be
used
with
caution
in
animals
with
known
PRECAUTIONS: Quinolones should be used with caution in animals with known
Marbofloxacin
was also
orallyorally
to 6 cats
approximately
8 months
of of
Marbofloxacin
was administered
also administered
to 6 cats
approximately
8 months
or suspected
central
nervous
system
(CNS)(CNS)
disorders.
In such
animals,
quinoor suspected
central
nervous
system
disorders.
In such
animals,
quinoage for
consecutive
daysdays
at a dosage
of 25of
mg/lb/day
(55 mg/kg/day).
Clinical
age14for
14 consecutive
at a dosage
25 mg/lb/day
(55 mg/kg/day).
Clinical
loneslones
have,have,
in rare
instances,
been
associated
with
CNS
stimulation
which
may
in rare instances, been associated with CNS stimulation which may
signssigns
associated
with with
drug drug
intolerance
werewere
excessive
salivation
in 5/6incats
and and
associated
intolerance
excessive
salivation
5/6 cats
lead to
convulsive
seizures.
Quinolones
have have
beenbeen
shown
to produce
erosions
lead
to convulsive
seizures.
Quinolones
shown
to produce
erosions
redness
of earofpinnae
in all in
cats
afterafter
8 days
of treatment.
Emesis
was was
notednoted
occaredness
ear
pinnae
all
cats
8
days
of
treatment.
Emesis
occaof cartilage
of weight-bearing
jointsjoints
and other
signssigns
of arthropathy
in immature
of cartilage
of weight-bearing
and other
of arthropathy
in immature
sionally
in several
cats cats
and diminished
activity
was was
notednoted
in one
sionally
in several
and diminished
activity
in cat.
one Decreased
cat. Decreased
animals
of
various
species.
The
use
of
fluoroquinolones
in
cats
has
been
reported
animals of various species. The use of fluoroquinolones in cats has been reported food food
intakeintake
was noted
in some
animals,
primarily
males,
whenwhen
compared
to conwas noted
in some
animals,
primarily
males,
compared
to conto adversely
affectaffect
the retina.
SuchSuch
products
should
be used
with caution
in cats.
to adversely
the retina.
products
should
be used
with caution
in cats. trols.trols.
Perivascular
to diffuse
dermatitis
was was
seenseen
microscopically
in theinpinnae
of of
Perivascular
to
diffuse
dermatitis
microscopically
the
The safety
of marbofloxacin
in animals
used used
for breeding
purposes,
pregnant,
or or all treated animals and in the standard skin samples of several animals. Therepinnae
The safety
of marbofloxacin
in animals
for breeding
purposes,
pregnant,
was was
all
treated
animals
and
in
the
standard
skin
samples
of
several
animals.
There
lactating
has not
demonstrated.
lactating
hasbeen
not been
demonstrated.
focalfocal
or multifocal
articular
chondropathy
in 2/6intreated
animals.
One treated
cat cat
or multifocal
articular
chondropathy
2/6 treated
animals.
One treated
ADVERSE
REACTIONS:
The following
clinical
signssigns
werewere
reported
during
the the
had ahad
duodenal
mucosal
erosion
and one
cat had
pyloric
ulcer.ulcer.
There
ADVERSE
REACTIONS:
The following
clinical
reported
during
a duodenal
mucosal
erosion
and treated
one treated
cat ahad
a pyloric
There
course
of clinical
field studies
in dogs
receiving
marbofloxacin
at dosages
up toup to werewere
no observations
of lameness
and no
effects
on hematology,
clinical
course
of clinical
field studies
in dogs
receiving
marbofloxacin
at dosages
no observations
of lameness
andadverse
no adverse
effects
on hematology,
clinical
2.5 mg/lb
daily:daily:
decreased
or loss
appetite
(5.4%),
decreased
activity
(4.4%),
chemistry,
urinalysis,
or organ
weight
parameters.
Fundu
scopic
examination
by by
2.5 mg/lb
decreased
orof
loss
of appetite
(5.4%),
decreased
activity
(4.4%),
chemistry,
urinalysis,
or organ
weight
parameters.
Fundu
scopic
examination
and vomiting
(2.9%).
The
following
signs
were
reported
in
less
than
1%
of
cases
in
ophthalmologist
and histologic
examination
of retina
and optic
and vomiting (2.9%). The following signs were reported in less than 1% of cases in a board-certified
a board-certified
ophthalmologist
and histologic
examination
of retina
and optic
dogs:dogs:
increased
thirst,thirst,
soft stool/diarrhea,
behavioral
changes,
shivering/shaking/
by ocular
pathologists
revealed
no lesions.
increased
soft stool/diarrhea,
behavioral
changes,
shivering/shaking/ nervenerve
by ocular
pathologists
revealed
no lesions.
tremors,
and ataxia.
One dog
had ahad
seizure
the day
studystudy
enrollment
tremors,
and ataxia.
Onewhich
dog which
a seizure
thebefore
day before
enrollment A study
was conducted
to investigate
the effect
of marbofloxacin
on articular
A study
was conducted
to investigate
the effect
of marbofloxacin
on articular
experienced
a seizure
whilewhile
on marbofloxacin
therapy.
experienced
a seizure
on marbofloxacin
therapy.
cartilage
of skeletally
mature
cats cats
12–1412–14
months
of age.
FortyForty
cats cats
werewere
randomly
cartilage
of skeletally
mature
months
of age.
randomly
The following
clinical
signssigns
werewere
reported
during
clinical
field studies
in cats
assigned
to 4 groups
of 10of
cats
each.each.
Groups
received
placebo
or marbofloxacin
at at
The following
clinical
reported
during
clinical
field studies
in cats
assigned
to 4 groups
10 cats
Groups
received
placebo
or marbofloxacin
receiving
1.25 mg/lb/day:
diarrhea
(2.1%)(2.1%)
and soft
(1.4%).
Vomiting
was was
dosages
of 1.25,
3.75 or
7.5ormg/lb/day
(2.75,(2.75,
8.25 or
16.5
for 42for
consecureceiving
1.25 mg/lb/day:
diarrhea
andstool
soft stool
(1.4%).
Vomiting
dosages
of 1.25,
3.75
7.5 mg/lb/day
8.25
or mg/kg/day)
16.5 mg/kg/day)
42 consecureported
in lessinthan
cases
in cats.
tive days.
ThereThere
werewere
no treatment-related
pathological
changes
in theinjoints
or or
reported
less 1%
thanof1%
of cases
in cats.
tive days.
no treatment-related
pathological
changes
the joints
tissues.
Emesis
and soft
was noted
in allintreatment
groups,
including
DOSAGE
AND AND
ADMINISTRATION:
The recommended
dosage
for oral
tissues.
Emesis
andstools
soft stools
was noted
all treatment
groups,
including
DOSAGE
ADMINISTRATION:
The recommended
dosage
foradministraoral administra- otherother
and increased
in frequency
with with
increasing
dosedose
and duration
of treattion totion
dogs
and cats
1.25ismg
per lbper
of body
weight
onceonce
daily,daily,
but but placebo,
placebo,
and increased
in frequency
increasing
and duration
of treatto dogs
and is
cats
1.25marbofloxacin
mg marbofloxacin
lb of body
weight
ment.ment.
Emesis
was more
apparent
in theinhigh-dose
males.
the dosage
may be
safely
increased
to 2.5tomg/lb.
Emesis
was more
apparent
the high-dose
males.
the dosage
may
be safely
increased
2.5 mg/lb.
STORAGE
CONDITIONS:
StoreStore
below
30°C 30°C
(86°F).
For the
of skin
infections,
Zeniquin
tablets
should
be be
STORAGE
CONDITIONS:
below
(86°F).
Fortreatment
the treatment
ofand
skinsoft
andtissue
soft tissue
infections,
Zeniquin
tablets
should
givengiven
for 2–3
beyond
the cessation
of clinical
signssigns
for a for
maximum
of 30 of
days.
fordays
2–3 days
beyond
the cessation
of clinical
a maximum
30 days. HOWHOW
SUPPLIED:
SUPPLIED:
For the
of urinary
tract tract
infections,
Zeniquin
tablets
should
be adminisFortreatment
the treatment
of urinary
infections,
Zeniquin
tablets
should
be adminis- Zeniquin
tablets
are available
in theinfollowing
strengths
of marbofloxacin
and and
Zeniquin
tablets
are available
the following
strengths
of marbofloxacin
teredtered
for atfor
least
10 days.
If no improvement
is noted
withinwithin
5 days,
the diagnosis
at least
10 days.
If no improvement
is noted
5 days,
the diagnosis bottlebottle
sizes:sizes:
should
be re-evaluated
and aand
different
course
of therapy
considered.
should
be re-evaluated
a different
course
of therapy
considered.
25 mg25scored
tablets
supplied
in bottles
that contain
100 or
250
mg scored
tablets
supplied
in bottles
that contain
100
ortablets
250 tablets
50 mg50scored
tablets
supplied
in bottles
that contain
100 or
250
Drug Drug
Interactions:
Compounds
(e.g., (e.g.,
sucralfate,
antacids,
and mineral
supplemg scored
tablets
supplied
in bottles
that contain
100
ortablets
250 tablets
Interactions:
Compounds
sucralfate,
antacids,
and mineral
supple100 mg
tablets
supplied
in a 50
bottlebottle
ments)
containing
divalent
and trivalent
cations
(e.g., (e.g.,
iron, aluminum,
calcium,
100scored
mg scored
tablets
supplied
in tablet
a 50 tablet
ments)
containing
divalent
and trivalent
cations
iron, aluminum,
calcium,
tablets
supplied
in a 50
bottlebottle
magnesium,
and zinc)
can interfere
with the
of quinolones
whichwhich
may may 200 mg
200scored
mg scored
tablets
supplied
in tablet
a 50 tablet
magnesium,
and zinc)
can interfere
withabsorption
the absorption
of quinolones
resultresult
in a decrease
in product
bioavailability.
Therefore,
the concomitant
oral oral
in a decrease
in product
bioavailability.
Therefore,
the concomitant
REFERENCES:
REFERENCES:
administration
of quinolones
with foods,
supplements,
or other
preparations
con- con- 1. Schneider
administration
of quinolones
with foods,
supplements,
or other
preparations
M, etM,
al:et
Pharmacokinetics
of marbofloxacin
in dogs
afterafter
oral and
1. Schneider
al: Pharmacokinetics
of marbofloxacin
in dogs
oral and
taining
thesethese
compounds
should
be avoided.
taining
compounds
should
be avoided.
parenteral
administration.
J VetJPharmacol
Therap
19:56–61,
1996.1996.
parenteral
administration.
Vet Pharmacol
Therap
19:56–61,
EFFECTIVENESS
CONFIRMATION:
Clinical
effectiveness
was confirmed
in bacteEFFECTIVENESS
CONFIRMATION:
Clinical
effectiveness
was confirmed
in bacte- To report
suspected
adverse
effects,
and/or
obtain
a copy
of theofMSDS,
call call
To report
suspected
adverse
effects,
and/or
obtain
a copy
the MSDS,
rial skin
infections
in dogs
and cats
tract tract
infections
rialand
skinsoft
andtissue
soft tissue
infections
in dogs
and and
catsurinary
and urinary
infections
1-888-963-8471.
1-888-963-8471.
(cystitis)
in dogs
associated
with bacteria
susceptible
to marbofloxacin.
Bacterial
(cystitis)
in dogs
associated
with bacteria
susceptible
to marbofloxacin.
Bacterial NADA
#141-151,
Approved
by FDA
NADA
#141-151,
Approved
by FDA
pathogens
isolated
in clinical
field studies
are provided
in theinMicrobiology
sec- secpathogens
isolated
in clinical
field studies
are provided
the Microbiology
tion. tion.
TARGET
ANIMAL
SAFETY:
TARGET
ANIMAL
SAFETY:
Distributed
by: by:
Distributed
Dogs:Dogs:
The toxicity
of marbofloxacin
was assessed
in 12-into1214-month-old
beagle
Inc. Inc.
The toxicity
of marbofloxacin
was assessed
to 14-month-old
beagle ZoetisZoetis
A&P
13910600
13910600
Kalamazoo,
MI 49007
dogs dogs
administered
marbofloxacin
at 2.5,at7.5
for 42for
days.
Kalamazoo,
MI 49007
administered
marbofloxacin
2.5,and
7.512.5
andmg/lb/day
12.5 mg/lb/day
42 days.
Revised:
January
20132013
Revised:
January