Page 131 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

98 SECTION | I General

VetBooks.ir human drugs used in animals. Exceptions to this are those products, part of this process is to perform a summary
review, which includes a list of clinical signs for a partic-
drugs on the FDA’s Index of Legally Marketed
ular product in decreasing order of their reporting fre-
Unapproved New Animal Drugs for Minor Species (the
“Index”). These drugs are legally marketed for a specific quency. The clinical sign profile that is seen postapproval
use in certain minor species (FDA/CVM, 2014). Many is compared with the labeled adverse reactions for the
approved animal drugs can be identified by the presence product, and the development of a Postapproval
of a NADA number on the label, or a C-NADA number Experience (PAE) section may be proposed for addition
in the case of conditionally approved drugs, although to the drug labeling. The PAE section provides a listing
these identifiers on labeling are not currently required by of adverse experiences reported for the product, and the
regulation. Veterinarians and/or animal owners are CVM considers both frequency and severity of the events
encouraged to report ADEs for unapproved animal drugs, to determine their inclusion in this section of labeling.
including compounded products, to the CVM. This process contributes to the safe and effective use of
Although no form of premarket approval is currently animal drug products by updating the label and informing
required for devices used in veterinary medicine, FDA the end user about the potential risks associated with the
does have regulatory oversight over veterinary devices product. If ADEs during the postapproval period indicate
and can take appropriate regulatory action if a device is that the risks of the product outweigh its expected bene-
misbranded, mislabeled, or adulterated. A few examples fits, the FDA may take other types of regulatory action
of devices commonly used in animals include suture beyond label changes.
material, certain types of bandage materials, intravenous On occasion, ADE reports will help determine changes
catheters, anesthetic machines, and equipment as well as other than postapproval experience that may be needed
imaging equipment. It is the responsibility of the manu- for labeling. A well-known example is that of fluoroqui-
facturer and/or distributor of these articles to assure that nolones and retinal toxicity in cats. Enrofloxacin was
animal devices are safe, effective, and properly labeled. approved for use in cats in 1989 for the treatment of skin
Although not required by regulation, the CVM accepts infections caused by susceptible strains of Pasteurella
reports from manufacturers and distributors of veterinary multocida, Staphylococcus aureus, and Staphylococcus
devices of adverse events associated with marketed epidermidis, at an oral dose of 2.5 mg/kg twice daily.
devices. Most adverse event reports that the CVM This dosage regimen was changed by a supplemental
receives for animal devices are reported directly by veter- approval in 1997 to provide for a range of 5 20 mg/kg as
inarians or animal owners. a single daily dose or divided twice daily. No ocular
changes had been noted in preapproval TAS studies in
cats administered up to 25 mg/kg/day for 30 days, or in
Safety Signal Detection cats treated with up to 125 mg/kg for 5 days. Between
A safety signal is defined by the World Health 1992 and 1997, the CVM had received four reports of
Organization as “reported information on a possible blindness in cats treated with enrofloxacin, and between
causal relationship between an adverse event and a drug, 1997 and 2000, the CVM received an additional 52 feline
the relationship being unknown or incompletely documen- blindness reports (Hampshire et al., 2004). Most of the
ted previously” (WHO, 2017b). With the large volume of reports indicated that affected cats had been treated with
ADE reports that the CVM receives annually, drug safety greater than 5 mg/kg/day. In a postapproval study com-
reviewers cannot always review the reports individually. pleted by the drug’s sponsor, no changes in vision were
Accordingly, data mining strategies that involve the use seen in cats treated at the 5 mg/kg dose for up to 21 days;
of computer algorithms to analyze data in large, complex however, at doses of 20 mg/kg and higher, mild to severe
databases are being employed at the CVM to more effi- retinal degeneration was observed. In 2001, the sponsor
ciently identify safety signals. These methods do not changed the labeled dosage for cats to a maximum of
replace hands-on clinical review of the case reports that 5 mg/kg/day, and a PAE section was added to the label to
generated the signal and assessment of those cases to include the signs of blindness and retinal degeneration. In
determine the medical implications of the signal. Signals addition, a class statement was added to all fluoroquino-
that are detected are essentially hypotheses, not causal lones approved for use in cats, indicating that the use of
associations, and need to be confirmed by case series fluoroquinolones in cats has been reported to adversely
examination. Signal detection processes assist the CVM affect the retina and advising veterinary practitioners to
in detecting potential safety signals in large volumes of use these products with caution in cats (FDA/CVM,
data, helping to focus time and resources. 2001). Research published in 2011 indicated that fluoro-
If a safety signal is identified during the ADE review quinolones are substrates for the ABCG2 transporter,
process, a medical review of the case reports generating which is found in many tissues, including the blood-retina
the signal is completed. For more recently approved barrier. Four feline-specific amino acid changes in the