Convenia [Cefovecin] for Cats & Dogs

By | 2012-01-29

Active substance / Generic: Cefovecin

Scientific discussion

This medicine is approved for use in the European Union

Convenia is a powder and solvent for solution for injection containing a third generation cephalosporin, cefovecin sodium, for use in dogs and cats.

The product is presented in a single pack size composed of one vial containing the freeze-dried active substance (cefovecin sodium), and a second vial containing the diluent. Reconstitution yields 10.6 ml of solution for injection.

The route of administration is subcutaneous.

The active substance of Convenia is cefovecin (as the sodium salt) (ATCvet code: QJ01DD91), a third generation cephalosporin with a broad-spectrum of activity against Gram-positive and Gram-negative bacteria. Cefovecin differs from other cephalosporins in that it is highly protein bound and has a long duration of activity. As with all cephalosporins, the bactericidal action of cefovecin results from the inhibition of bacterial cell wall synthesis.

The benefits of Convenia are its long duration of activity. The product is well tolerated and no side effects have been reported to date.

The approved indications are:

Dogs:

For the treatment of skin and soft tissue infections including pyoderma, wounds and abscesses associated with Staphylococcus intermedius, β-haemolytic Streptococci, Escherichia coli and/or Pasteurella multocida.

For the treatment of urinary tract infections associated with Escherichia coli and/or Proteus spp.

Cats:

For the treatment of skin and soft tissue abscesses and wounds associated with Pasteurella multocida, Fusobacterium spp., Bacteroides spp., Prevotella oralis, β-haemolytic Streptococci and/or Staphylococcus intermedius.

For the treatment of urinary tract infections associated with Escherichia coli.

Convenia: Quality Assessment

Convenia contains cefovecin sodium, a third generation cephalosporin, and is indicated for use in dogs and cats for the treatment of skin and soft tissue infections and for the treatment of urinary tract infections. It is administered subcutaneously. The product is presented in a single pack size composed of one vial containing the freeze-dried active substance (cefovecin sodium), and a second vial containing the diluent.

In general the quality aspects of the product have been well documented. The active substance and finished product are manufactured and controlled in the appropriate manner, in compliance with current EU and VICH guidelines. Satisfactory information has been provided to demonstrate that the manufacture and control processes routinely and consistently generate a product of uniform quality.

Cefovecin: Safety Assessment

Pharmacokinetics

In dogs, when cefovecin was administered as a single subcutaneous dose of 8 mg/kg bodyweight, absorption was rapid and extensive; peak plasma concentration at 6 hours was 120 µg/ml and bioavailability approximately 99%. Peak concentrations in tissue cage fluid of 31.9 µg/ml were measured 2 days after administration. No data on metabolism of cefovecin are available. Fourteen days after administration, the mean cefovecin concentration in plasma was 5.6 µg/ml. Plasma protein binding is high (96.0% to 98.7%) and the volume of distribution is low (0.1 1/kg). The elimination half-life is long – approximately 5.5 days. Cefovecin is primarily eliminated unchanged via the kidneys. At fourteen days after administration, urine concentrations were 2.9 µg/ml. In dogs, urinary cefovecin concentrations accounted for 60 % of the total administered dose 35 days post-dose.

In cats, the pharmacokinetics of cefovecin after subcutaneous administration is characterised by rapid and complete absorption. Following a single subcutaneous dose of 8 mg/kg bw, maximum cefovecin concentrations of 141 µg/ml in plasma were achieved approximately 2 hours post-dose. Bioavailability is approximately 99 %. No data on metabolism of cefovecin are available. Fourteen days after administration, the mean cefovecin concentration in plasma was 18 µg/ml. Cefovecin concentrations in plasma remained above 5 µg/ml for up to 32 days post-dose. Plasma protein binding is high (more than 99%) and the volume of distribution is low (0.09 1/kg). The elimination half-life is long -approximately 6.9 days. At ten and fourteen days after administration, urine concentrations were 1.3 µg/ml and 0.7 µg/ml, respectively. Cefovecin was shown to be predominantly eliminated unchanged via the kidneys over several weeks. In cats, about 50% of the administered radiolabelled dose was excreted in urine by 21 days post-dose. Urinary cefovecin concentrations of > 1 µg/ml were present for up to 14 days following a single subcutaneous administration.

Overall Conclusions On Safety

Cefovecin is a third generation cephalosporin with a broad-spectrum of bactericidal activity against Gram-positive and Gram-negative bacteria.

Cefovecin is of low acute toxicity in rats (oral and subcutaneous) and dogs (subcutaneous). A sensitisation test, however, revealed acute toxic effects in guinea pigs after intradermal injection, due to effects on their gut flora, and so the use in small herbivores (including guinea pigs and rabbits) is contraindicated.

No studies on reproductive toxicity have been submitted, thus the safety of use in dogs and cats during pregnancy and lactation has not been established. Since cephalosporins have been shown to impact on male fertility in rats, it is advised that treated animals should not be used for breeding for 12 weeks after the last administration.

Cephalosporins at high doses showed neurotoxic, and in some cases nephrotoxic effects, in humans. However, no such data have been observed in dogs, and the CVMP concluded that such effects would be unlikely in dogs or cats, as no such signs were seen in target animal safety studies.

Cefovecin is not irritating to skin and only minimally irritating to the eye. However, cefovecin has skin sensitisation potential. The CVMP noted the risk of hypersensitivity reactions to the susceptible user and appropriate user warning has been included in the SPC.

The potential exposure of the environment to excreted cefovecin residues will be minimal, and CVMP concluded that the use of this product does not pose a risk to the environment.

Cefovecin: Efficacy Assessment

Concerning skin and soft tissue infections, the data demonstrated that the proposed treatment dose (8 mg/kg) and interval (14 days) was efficacious. Concerning urinary tract infections, dose finding was based on PK/PD-analysis.

For dogs, the results of three field trials demonstrated the efficacy of cefovecin in the treatment of skin and soft tissue infections including pyoderma, wounds and abscesses associated with Staphylococcus intermedius, β-haemolytic Streptococci, Escherichia coli and/or Pasteurella multocida. The results of the European field trial demonstrated the efficacy of Convenia in the treatment of urinary tract infections associated with Escherichia coli and/or Proteus spp. Further supportive evidence for this claim was received from another trial carried out in the USA.

In cats, the efficacy in the treatment of skin and soft tissue abscesses and wounds associated with Pasteurella multocida, Fusobacterium spp., Bacteroides spp., Prevotella oralis, β-haemolytic Streptococci and/or Staphylococcus intermedius was demonstrated by the results of one field trial. The efficacy of Convenia in the treatment of urinary tract infections associated with E. coli was supported by sufficient data from one field trial.

Convenia: Benefit Risk Assessment

Convenia contains cefovecin sodium, a third generation cephalosporin, and is indicated for use in dogs and cats for the treatment of skin, tissue and urinary tract infections. It is administered subcutaneously. The product is presented in a single pack size composed of one vial containing the freeze-dried active substance (cefovecin sodium), and a second vial containing the diluent.

In general the quality aspects of the product have been well documented. The active substance and finished product are manufactured and controlled in the appropriate manner, in compliance with current EU and VICH guidelines. Satisfactory information has been provided to demonstrate that the manufacture and control processes routinely and consistently generate a product of uniform quality.

The starting materials of animal origin used in the production of the final product have all been declared in compliance with the current regulatory texts related to the TSE Note for Guidance (EMEA/410/01-Rev.2) and Commission Directive 2001/82/EC as amended.

Cefovecin is of low acute oral and parenteral toxicity and is considered non-mutagenic and non-carcinogenic. From the scientific literature certain cephalosporins have been shown to exert adverse effects on male fertility in rats. Considering the long term activity of the substance and period of spermiogenesis in dogs and cats, appropriate restrictions for use have, therefore, been included in the product literature.

Cefovecin proved to be non-irritant to intact skin and has a minimal irritating effect on eyes. Like other cephalosporins cefovecin has a potential to cause hypersensitivity or allergic reactions following injection, inhalation, ingestion or skin contact. Under field conditions, while handling the product, accidental skin or eye contact may occur. Adequate precautionary statements are, therefore, included in the product literature.

The environmental risk assessment concluded that cefovecin in the recommended posology would have minimal impact on the environment when used in the form of the final product.

In vitro data were provided demonstrating the susceptibility of bacteria involved in dogs and cats diseases against cefovecin, i.e., Staphylococcus intermedius, β-haemolytic Streptococci, Escherichia coli, Pasteurella multocida and Proteus spp in dogs and Pasteurella multocida, Bacteroides spp., Prevotella oralis, β-haemolytic Streptococci, Fusobacterium spp., Staphylococcus intermedius and Escherichia coli in cats respectively.

The potential for development of resistance was shown to be low. As cefovecin is a third generation cephalosporin, appropriate prudent use statements are included in the product literature.

Cefovecin is well tolerated in young and adult dogs and cats. The use in dogs and cats of less than 8 weeks old was contraindicated as such young animals were not included in the studies. No adverse reactions to the product have been reported to date and this is reflected in the product literature.

The concurrent use of other substances that have a high degree of protein binding (e.g., furosemide, ketoconazole or non-steroidal anti-inflammatory drugs ) may compete with cefovecin binding and so may cause adverse effects. An appropriate statement to this effect has, therefore, been included in the product literature.

Considering the long duration of activity of the product and the duration of a spermatogenetic cycle (8-9 weeks in cats and dogs), an appropriate statement has been included in the product literature “The safety of Convenia in dogs and cats has not been established during pregnancy and lactation. Treated animals should not be used for breeding for 12 weeks after the last administration.”.

Preclinical data were considered sufficient to confirm the proposed treatment dose of 8 mg/kg bodyweight. The repeated treatment in skin diseases with a dosing interval of 14 days was also adequately supported by the data provided.

For dogs, the results of three field trials demonstrated the efficacy of cefovecin in the treatment of skin and soft tissue infections including pyoderma, wounds and abscesses, associated with Staphylococcus intermedius, β-haemolytic Streptococci, Escherichia coli and/or Pasteurella multocida. Data from one pivotal and one supportive field trial have demonstrated efficacy in the treatment of urinary tract infections associated with Escherichia coli and/or Proteus spp in dogs.

For cats, the CVMP concluded that the efficacy in the treatment of skin and soft tissue abscesses and wounds associated with Pasteurella multocida, Fusobacterium spp., Bacteroides spp., Prevotella oralis, β-haemolytic Streptococci and/or Staphylococcus intermedius was demonstrated by the results of one clinical trial. The efficacy in the treatment of urinary tract infections associated with E. coli was supported by sufficient data from one field trial.

Based on the original and supplementary data presented, the Committee for Medicinal Products for Veterinary Use (CVMP) concluded that the quality, safety and efficacy of Convenia were considered to be in accordance with the requirements of Directive 2001/82/EC as amended.