Simplicef Tablets (200 mg) (Canada)

Cefpodoxime proxetil is a prodrug; its active metabolite is cefpodoxime. All doses of SIMPLICEF tablets are expressed in terms of the active cefpodoxime moiety.

Each SIMPLICEF tablet contains 200 mg of cefpodoxime (as cefpodoxime proxetil) per tablet.

Simplicef Tablets (200 mg) Indications

SIMPLICEF tablets are indicated for the treatment of skin infections (wounds and abscesses) in dogs caused by susceptible strains of Staphylococcus pseudintermedius, Staphylococcus aureus, Streptococcus canis (group G, β hemolytic), Escherichia coli, Pasteurella multocida, and Proteus mirabilis.

Dosage and Administration

Dosage: The recommended dosage for SIMPLICEF tablets is 5 mg/kg body weight (BW), administered orally, once a day and may be given with or without food. This dose can safely be increased to 10 mg/kg. However, this dosage level has not been evaluated to confirm an improvement in clinical resolution, in comparison with the 5 mg/kg dose. 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-defence 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. If acceptable response to treatment is not observed, or if no improvement is seen in 3 to 4 days, then the diagnosis should be re-evaluated and appropriate alternative therapy considered.

Dosing Charts: For daily oral administration of SIMPLICEF tablets at 5 mg/kg BW (Table 1) and 10 mg/kg BW (Table 2).

This product is not intended to be split to less than half of the original tablet size, therefore, this product may not be appropriate for treating dogs weighing less than 20 kg.

Table 1. Dose Table for SIMPLICEF Tablets at 5 mg/kg BW Total Daily Dosage

*1 Tablet equivalent to a daily dosage of 6.7 mg/kg BW.

** 1.5 Tablets equivalent to a daily dosage of 6 mg/kg BW.

Table 2. Dose Table for SIMPLICEF Tablets at 10 mg/kg BW Total Daily Dosage

Contraindications

SIMPLICEF tablets are contraindicated in dogs with known allergy to cefpodoxime or to the β-lactam (penicillins and cephalosporins) group of antibiotics.

CAUTIONS: The safety of SIMPLICEF tablets in dogs used for breeding, pregnant dogs, or lactating bitches has not been demonstrated. As with other cephalosporins, SIMPLICEF tablets may occasionally induce a positive direct Coombs’ test. Blood dyscrasia including neutropenias, may be seen following high doses of cephalosporins. Cephalosporin administration should be discontinued in such cases.

Warnings

Keep out of reach of children.

To limit the development of antimicrobial resistance:

- SIMPLICEF tablets should not be used in food-producing animals.

- The extra-label drug use of SIMPLICEF tablets is not recommended.

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.

To report adverse reactions in users or to obtain a copy of the material safety data sheet (MSDS) for this product call 1-800-461-0917.

Adverse Reactions

The most frequently reported adverse events were emesis (vomiting), anorexia, lethargy, diarrhea and allergic edema.

Anemia, hepatopathy and death, although very rare, have also been reported.

Adverse events most commonly requiring clinical intervention included lethargy, emesis, anorexia, allergic edema, anemia, diarrhea, pruritus, hepatopathy, urticaria and dermatitis.

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 BW SIMPLICEF Tablets

Cefpodoxime is distributed in the body with an apparent volume of distribution of 151 ± 27 mL/kg. Like other β-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 BW, the average total body clearance (Cl_B) was 22.7 ± 4.19 mL/hr/kg.

Table 3. Summary of Pharmacokinetic Parameters Obtained after a Single Oral Dose of 10 mg Cefpodoxime/kg BW, Administered as a Tablet

MICROBIOLOGY: Like other β-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 β-lactamase enzymes. As a result, many organisms resistant to other β-lactam antibiotics (penicillins and some cephalosporins) due to the production of β-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 Gram-positive and Gram-negative pathogens isolated from canine skin infections (wounds and abscesses) in a 2002 U.S. field study are presented in Table 4. All MICs and interpretive criteria were determined in accordance with the Clinical and Laboratory Standards Institute (CLSI). Diffusion tests to define the susceptibility of microorganisms were completed using paper disks containing 10 µg of cefpodoxime. Cefpodoxime MIC values and zone diameters for bacteria listed in the indications should be interpreted according to the susceptibility criteria recommended by the CLSI and presented in Table 5. Appropriate quality control (QC) ranges for in vitro susceptibility testing are presented in Table 6.

Table 4. Cefpodoxime Minimum Inhibitory Concentration Values (µg/mL) from a 2002 Field Study Evaluating Skin Infections (wounds and abscesses) of Canines in the United States

No Range, all isolates yielded the same value.

Table 5. CLSI Recommended Susceptibility Interpretive Breakpoint Criteria for Cefpodoxime MIC and Zone Diameters^a

^a CLSI breakpoint criteria defined for cefpodoxime sensitivity for bacteria listed in the indications.

^b Determined using paper disks containing 10 µg of cefpodoxime.

Table 6. Acceptable Quality Control Ranges for Cefpodoxime

^a These ranges are for quality control strains used to monitor accuracy of minimum inhibitory concentrations (MICs) of non-fastidious 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, β 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

A surgical wound experimental infection study in dogs showed a statistically significant difference in the reduction in colony counts of Escherichia coli at a dosage of 10 mg/kg of cefpodoxime proxetil compared to a 5 mg/kg dosage. However, the clinical significance of this finding is unknown. The clinical effectiveness of SIMPLICEF tablets was established in a multi-location U.S. field study (23 sites). In this study, 216 dogs with infected wounds or abscesses were treated with either SIMPLICEF tablets (n=118) once daily at 5 mg/kg BW or with an active control antibiotic (n=98) administered twice daily for 5-7 days. In this study, SIMPLICEF tablets were considered non inferior 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 pseudintermedius, Staphylococcus aureus, Streptococcus canis (group G, β hemolytic), Escherichia coli, Pasteurella multocida, and Proteus mirabilis.

ANIMAL SAFETY:

In target animal safety studies, SIMPLICEF tablets were 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 BW for up to 28 days was shown to be safe in adult dogs and puppies.

Storage

Store between 15 and 25°C. 200 mg tablets split at the scoreline may be stored at 15-25°C for 48 hours. Replace cap securely after each opening.

PRESENTATION: Each color-coded SIMPLICEF tablet contains 200 mg cefpodoxime (as cefpodoxime equivalent). Each tablet is light orange, oblong, scored and debossed with 5229.

The tablets are packaged in 100 and 250 count bottles. Not all pack sizes may be marketed.

Zoetis is a trademark and Simplicef is a registered trademark of Zoetis or its licensors, used under license by Zoetis Canada Inc.

Zoetis Canada Inc., Kirkland QC H9H 4M7

10022737-17-0

CPN: 1198455.3