Source: http://www.regulations.gov/?_escaped_fragment_=documentDetail;D=FDA-2008-N-0326-0177
Timestamp: 2016-07-28 22:18:39
Document Index: 791491817

Matched Legal Cases: ['art 530', 'art 530', '§ 530', '§ 530', '§ 530', 'art 530', '§ 530', '§ 530', '§ 530', 'art 530', 'art 530', 'art 530', 'art 530', 'art 530', 'art 530', 'art 530', 'art 530', '§ 530', '§ 530', 'art 530']

Skip Navigation HomeHelpResourcesContact Us Advanced Search Start of Main Content New Animal Drugs; Orders of Prohibition: Cephalosporin Drugs; Extralabel Animal Drug Use This Rule document was issued by the Food and Drug Administration (FDA) For related information, Open Docket Folder Show agency attachment(s) DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. FDA-2008-N-0326]
SummaryThe Food and Drug Administration (FDA, the Agency) is issuing an order prohibiting certain extralabel uses of cephalosporin antimicrobial drugs in certain food-producing animals. We are issuing this order based on evidence that certain extralabel uses of these drugs in these animals will likely cause an adverse event in humans and, therefore, present a risk to the public health.
DatesThis rule becomes effective April 5, 2012. Submit either electronic or written comments on this document by March 6, 2012.
AddressesYou may submit comments, identified by Docket No. FDA-2008-N-0326, by any of the following methods:
Mail/Hand delivery/Courier (For paper, disk, or CD-ROM submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Instructions: All submissions received must include the Agency name and Docket No. FDA-2008-N-0326 for this rulemaking. All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For additional information on submitting comments, see the “Comments” heading of theSUPPLEMENTARY INFORMATIONsection of this document.
For Further Information ContactEric Nelson, Center for Veterinary Medicine (HFV-230), Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, (240) 276-9201, email: eric.nelson@fda.hhs.gov. Supplementary InformationI. BackgroundA. HistoryIn theFederal Registerof July 3, 2008 (73 FR 38110), FDA published an order prohibiting the extralabel use of cephalosporin antimicrobial drugs in food-producing animals, with a 60-day comment period and a 90-day effective date for the final order. The order, which was to take effect as a final rule on October 1, 2008, would have resulted in a change to part 530 (21 CFR part 530) in § 530.41 to list cephalosporins as prohibited from extralabel use in food-producing animals as provided for in § 530.25(f).
FDA considered the requests and, in theFederal Registerof August 18, 2008 (73 FR 48127), extended the comment period for the order for 60 days, until November 1, 2008. Accordingly, FDA also delayed the effective date of the final rule 60 days, until November 30, 2008.
The Agency received many substantive comments on the July 3, 2008, order of prohibition. Therefore, to allow more time to fully consider the comments, FDA decided to revoke the order so that it would not take effect November 30, 2008. Accordingly, in theFederal Registerof November 26, 2008 (73 FR 71923), FDA withdrew the final rule and indicated that if, after considering the comments and other relevant information the Agency decided to issue another order of prohibition addressing this matter, FDA would follow the procedures in § 530.25 that provide for a public comment period prior to implementing the new order.B. Comments on the July 3, 2008, Order of ProhibitionThe Agency received comments from approximately 170 organizations and individuals on the July 3, 2008, order of prohibition. Comments were received from a trade organization representing new animal drug manufacturers, several trade organizations representing food animal producers, several professional associations representing veterinarians, a consumer protection organization, several new animal drug manufacturers, and many individuals including food animal veterinarians, farmers, and ranchers. Only two of the commenters supported the July 3, 2008, order of prohibition as written. All others felt that the prohibition should be revised in some manner before enactment or that it was unnecessary and should not be enacted in any form. These comments can be summarized into two general categories:
The Agency is prohibiting these extralabel uses in food-producing major species because we believe such uses in these animals will likely cause an adverse event in humans and, therefore, present a risk to the public health. FDA may further restrict extralabel use of cephalosporin antimicrobial drugs in animals in the future if it has evidence that demonstrates that such use has caused or likely will cause an adverse event.II. Basis for Prohibiting the Extralabel Use of Cephalosporins With Certain ExceptionsA. AMDUCA and CephalosporinsThe Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) (Public Law 103-396) was signed into law October 22, 1994. It amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to permit licensed veterinarians to prescribe extralabel uses of approved human and animal drugs in animals. In theFederal Registerof November 7, 1996 (61 FR 57732), FDA published the implementing regulations (codified at part 530) for AMDUCA that include, among other things, a definition for the term “extralabel use” as well as provisions for prohibiting extralabel uses.
The sections in FDA's implementing regulations governing the prohibition of extralabel use of drugs in animals include §§ 530.21, 530.25, and 530.30. These sections describe the basis for issuing an order prohibiting an extralabel drug use in animals and the procedure to be followed in issuing such an order. FDA may issue a prohibition order if it finds that extralabel use of a drug in animals presents a risk to the public health. Under § 530.3(e), this means that FDA has evidence demonstrating that the use of the drug has caused, or likely will cause, an adverse event. Furthermore, as discussed in section III.B of this document, the regulations permit a prohibition order to be either a general ban on the extralabel use of the drug orclass of drugs, or a ban limited to one or more of the uses described in the definition of extralabel use cited previously.
Section 530.25 provides for a public comment period of not less than 60 days. It also provides that the order of prohibition become effective 90 days after the date of publication, unless FDA revokes or modifies the order, or extends the period of public comment. The list of drugs prohibited from extralabel use is found in § 530.41.
At this time, FDA is concerned that certain extralabel uses of cephalosporins in food-producing major species are likely to lead to the emergence and dissemination of cephalosporin-resistant strains of foodborne bacterial pathogens. If these drug-resistant bacterial strains infect humans, it is likely that cephalosporins will no longer be effective for treating disease in those people. The Agency is particularly concerned about the extralabel use of cephalosporin drugs that are not approved for use in food-producing major species because very little is known about their microbiological or toxicological effects when used in food-producing animals. Therefore, FDA is issuing an order prohibiting, with limited exceptions, the extralabel use of cephalosporins in food-producing major species because, as discussed in this document, the Agency has determined that such extralabel use likely will cause an adverse event and, therefore, presents a risk to the public health.B. Importance of Cephalosporins in Veterinary and Human MedicineCephalosporins are members of the beta-lactam (β-lactam) class of antimicrobials. Members of the cephalosporin class have a β-lactam ring fused to a sulfur-containing ring-expanded system (Ref. 1). These antimicrobials work by targeting synthesis of the bacterial cell wall, resulting in increased permeability and eventual hydrolysis of the cell.
Two cephalosporin drugs are currently approved for use in food-producing animal species: Ceftiofur and cephapirin. Injectable ceftiofur products are approved for the treatment and control of certain diseases, including: (1) The treatment of respiratory disease in cattle, swine, sheep, and goats; (2) the treatment of acute bovine interdigital necrobacillosis (foot rot) and acute bovine metritis; (3) the control of bovine respiratory disease; and (4) the control of early mortality associated with E. coli infections in day-old chicks and poults. In addition, ceftiofur is approved as an intramammary infusion for the treatment of clinical mastitis in lactating dairy cattle associated with coagulase-negative staphylococci, Streptococcus dysgalactiae, and E. coli. Cephapirin is only approved as an intramammary infusion for the treatment of lactating cows having bovine mastitis caused by susceptible strains of Streptococcus agalactiae and Staphylococcus aureus. C. Mechanism of Cephalosporin ResistanceIn general, there are three major mechanisms by which bacteria become resistant to antimicrobial agents:(1) Alteration of the antimicrobial target, (2) efflux of the antimicrobial or changes in permeability of the bacterial cell, and (3) inactivation of the antimicrobial agent itself. Gram-negative bacterial resistance to cephalosporins occurs mainly through inactivation of the cephalosporin by β-lactamases. These enzymes can be both innate and acquired (Ref. 5).
ESBLs present in bacteria of human health concern include members of the TEM, SHV, and CTX-M families. These enzymes are plasmid-mediated and have the potential to provide resistance to all cephalosporins. Different ESBLs hydrolyze different cephalosporins at different efficiencies and rates, thus leading to varying patterns of in vitro susceptibility. In 2010, the CLSI revisedthe cephalosporin resistance breakpoints to more accurately reflect in vivo susceptibility. Prior to this time, a particular ESBL strain that might not raise the minimum inhibitory concentration (MIC) for a given cephalosporin to a level above the breakpoint for resistance would commonly prove to be resistant in vivo (Ref. 5). Therefore, there were specific guidelines for screening bacterial isolates for the presence of ESBLs when MICs fell in the susceptible range. Any bacterial isolate which produced either an AmpC enzyme or an ESBL was reported to clinicians as resistant to all cephalosporins even though susceptibility testing may have shown in vitro susceptibility to some of the cephalosporins (Ref. 10).
Serious infections caused by cephalosporin-resistant bacteria may be empirically treated with ineffective antibacterial regimens, significantly increasing the likelihood of death. Urinary tract infections caused by community-acquired cephalosporin-resistant E. coli may be associated with bloodstream infections, and these infections may also be resistant to most or all antibiotics commonly used to treat such infections. Empirical treatment of such infections is often with a fluoroquinolone, amoxicillin-clavulanate, or a cephalosporin; however, these E. coli are likely to be resistant to all of these agents, making treatment of these infections more difficult (Ref. 11).D. Cephalosporin-Resistant Zoonotic Foodborne BacteriaIn regard to antimicrobial drug use in animals, the Agency considers the most significant risk to the public health associated with antimicrobial resistance to be human exposure to food containing antimicrobial-resistant bacteria resulting from the exposure of food-producing animals to antimicrobials, including cephalosporins. Resistance to certain cephalosporins is of particular public health concern in light of the evidence of cross-resistance among drugs in the cephalosporin class. Importantly, resistance to ceftiofur compromises the efficacy of ceftriaxone, a first-line therapy for treating salmonellosis in humans. A recent review of β-lactam resistance in bacteria of animal origin states that an emerging issue of concern is the increase in reports of CMY-2 and CTX-M β-lactamases (Ref. 6), which confer cephalosporin resistance and are transmissible between enteric bacteria. Acquired resistance to β-lactams in animal and human isolates has been observed in surveillance programs such as the U.S. National Antimicrobial Resistance Monitoring System (NARMS) and the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS).
Ceftiofur is not used in human medicine in the United States, but after the 2010 CLSI change in the cephalosporin breakpoint, resistance to this agent largely coincides with resistance to ceftriaxone, a third generation cephalosporin that is a critically important antimicrobial approved for use in humans (Ref. 23). As discussed earlier, this resistance trait conferred by the CMY-2 enzyme. CMY-2 provides resistance to first, second, and third generation cephalosporins. In addition to conferring ceftiofur and ceftriaxone resistance, CMY-2 also imparts resistance to several other β-lactams, including ampicillin and amoxicillin/clavulanate (Ref. 26). The prevalence and spread of CMY-2 is reflected in the surveillance data on ceftriaxone and ceftiofur susceptibility(Ref. 27) and supports the finding that cephalosporin use in food-producing animals is likely contributing to an increase in cephalosporin-resistant human pathogens.E. Extralabel Uses of Greatest Concern1. Dairy CattleThe U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) conducts both ante-mortem and post-mortem inspection of livestock and poultry presented for slaughter at each official establishment. As part of ante-mortem inspection, FSIS personnel inspect animals to determine whether they exhibit behaviors or conditions that are indicative of illegal chemical use. If such behaviors or symptoms are exhibited, the animals are tagged and further examined at post-mortem inspection. During post-mortem inspection, FSIS veterinarians examine carcasses and their organs to determine whether the animals they came from had pathological diseases or other conditions that could have warranted the use of drugs or other chemicals and whether there are any indications of illegal chemical use. In addition, FSIS conducts laboratory analysis of sample tissues that have been taken from carcasses that have pathologies or other conditions indicative of chemical use to determine whether they contain violative chemical residues. FSIS transmits to FDA information about the violative chemical residue found, including the name of the official establishment where the livestock or poultry was presented for slaughter.
During the 1-year period ending June 25, 2009, FSIS reported 113 instances of violative ceftiofur residues in dairy cows and an additional 22 instances of violative ceftiofur residues in other food-producing animals, including beef cattle and veal calves. The FSIS reports include quantitative drug residue levels for each violation. In most instances, the violative residue levels of ceftiofur detected in dairy cows were significantly above the allowable tolerance of 0.4 ppm (kidney) in tested tissues and are summarized as follows: Up to 2x above the tolerance = 12 violations
Over 20x above the tolerance = 38 violationsAn examination of 25 recent inspections of farms responsible for violative ceftiofur residues identified a number of factors that resulted in the misuse of ceftiofur animal drug products. These factors include, but were not limited to, the following: (1) Poor or nonexistent animal treatment records for adequately monitoring treated animals; (2) inadequate animal identification systems for monitoring treated animals; (3) animal owners' lack of knowledge regarding withdrawal times associated with the animal drug product; (4) the animal drug product was administered by a route not included in the approved labeling; (5) the animal drug product was administered at a dose higher than stated in the approved labeling; and (6) the animal drug product was administered to a type of animal (e.g., veal calves) not listed in the approved labeling. Most of the violations involved culled dairy cows. More than half of the violations involved ceftiofur residue levels more than 10 times the established tolerance level.
It is estimated that just over one million cases of human salmonellosis occur every year in the United States (Ref 36). Salmonella serovars Typhimurium and Newport are often multi-drug resistant and appear to be associated with more severe human disease than other serovars (Refs. 37, 38). These infections can lead to treatment failures, greater hospitalization or death rates, and higher costs than infections with susceptible strains. Consumption ofdairy products, as well as dairy farm contact, represents important risk factors for human S. Newport MDR-AmpC infection (Ref. 39). Additionally, a number of outbreaks of S. Newport MDR-AmpC have been linked to dairy product consumption (Refs. 40, 41). NARMS data indicate that in 2006, 42.6 percent of diagnostic Salmonella isolates from cattle were ceftiofur resistant. S. Typhimurium and S. Newport were the second and third most frequently isolated serovars from human infections in that year, and S. Newport was the third most frequently isolated serovar from cattle. Thirty-four percent of S. Newport isolated from humans and 32 percent of S. Newport isolated from cattle were resistant to ceftiofur, making this serovar the leading source of ceftiofur-resistant isolates for both hosts.2. PoultryFDA conducted inspections at U.S. poultry hatcheries in 2001 and examined records relating to the hatcheries' antimicrobial use during the 30-day period prior to inspection. FDA found that six of the eight hatcheries inspected that used ceftiofur during that period were doing so in an extralabel manner (Ref. 42). For example, ceftiofur was being administered at unapproved dosing levels or via unapproved methods of administration. In particular, ceftiofur was being administered via egg injection, rather than by the approved method of administering the drug to day-old chicks. The Agency is concerned that this extralabel use, particularly when employed in conjunction with automated technology, could result in levels of cephalosporin exposure in food-producing animals that are significantly higher than exposure levels from the approved uses. As a result, FDA believes human exposure to food containing cephalosporin-resistant bacteria would be significantly higher as well. Therefore, considering the large amount of food produced by the poultry industry each year, the Agency believes such extralabel use presents a risk to the public health.3. Other Extralabel Uses That Increase Drug ExposureOne of the goals of this order of prohibition is to reduce the amount of cephalosporins used in food-producing animals for uses that have not been evaluated for safety and approved by FDA. This is particularly important for uses that result in significant increases in cephalosporin drug exposure such as the injection of chick eggs previously noted. Other extralabel uses that significantly increase drug exposure include certain deviations from an approved dosage regimen. This would include higher doses and longer durations of administration than approved and extralabel routes of administration that facilitate mass dosing of large numbers of animals, such as through drinking water. A similar concern is the use of a cephalosporin drugs to prevent an extralabel disease or condition, particularly when such use involves entire flocks or herds of animals. FDA believes that exposing large numbers of animals to cephalosporin drugs when such use has been neither evaluated nor approved by FDA presents a risk to the public health.4. BiobulletsThe Agency received 35 comments on the July 3, 2008, order of prohibition that documented the extralabel use of ceftiofur in a compounded new animal drug product known as Biobullets. According to the manufacturer's Web site, Biobullets deliver a solid pellet of ceftiofur sodium (NADA 140-338) encased in a biodegradable bullet propelled by an air rifle into the muscle of cattle. Such use clearly represents an extralabel use because ceftiofur sodium is only approved for injection in liquid form by hypodermic needle. Since the rate and extent of dissolution and distribution of ceftiofur sodium in solid form delivered as an implant has not been established, the microbiological and toxicological profile of this extralabel use is unknown; thus, the safety of human food derived from animals treated in this manner is also unknown. Furthermore, based on these comments, and on past regulatory actions regarding Biobullets (Ref. 43), FDA continues to have concerns that the manufacture, distribution, and use of this product may violate the compounding and valid veterinary-client-patient-relationship provisions of AMDUCA and 21 CFR part 530.5. Human CephalosporinsAnother concern is the extralabel use in food-producing animals of cephalosporin drugs that are only approved for use in humans. The use of these human drug products in food-producing animals presents a risk to public health because, like Biobullets, the microbiological and toxicological profile of this extralabel use is unknown; thus, the safety of human food derived from animals treated with these drugs is also unknown. Also, since none of these drugs are approved for use in food-producing animals, there are no approved labels to guide the use of these drugs regarding, for example, dosing regimen or withdrawal period.
FDA has evidence of the extralabel use of human cephalosporins (cephalexin) by veterinarians for the treatment of cattle. This evidence was obtained during inspections of farms and veterinary hospitals by FDA investigators. Furthermore, one of the comments on the July 3, 2008, order of prohibition reported that cephalosporin drugs that are either being researched or approved for human use are being administered to food-producing animals, including via drinking water.III. Response to CommentsA. Revised Scope of the OrderMany of the comments received on the July 3, 2008, order of prohibition said the scope of the original order was too broad in that it unnecessarily prohibited certain extralabel uses that do not significantly contribute to the development of antimicrobial resistance.
As is recognized for the use of antimicrobial drugs in general, the use of cephalosporins provides selection pressure that favors expansion of resistant variants of bacteria. Given the importance of the cephalosporin class of drugs for treating disease in humans, FDA believes that preserving the effectiveness of such drugs is critical. Therefore, as stated in the July 2008 order of prohibition, FDA believes that it is necessary to take action to limit the extent to which extralabel use of cephalosporins in food-producing animals may be contributing to the emergence and dissemination of resistant variants. However, as noted earlier, FDA also agrees with many of the comments received on the July 3, 2008, order of prohibition that said the scope of the original order was too broad in that it unnecessarily prohibited certain extralabel uses that are not likely to cause an adverse event and present a risk to the public health. As discussed below, based on the comments and additional information submitted in response to the July 3 order, the Agency has reconsidered its position on the following three specific areas: extralabel use of cephapirin, extralabel use for unapproved indications, and extralabel use in food-producing minor species.1. CephapirinFDA considered the possibility of limiting the order of prohibition to certain generations of cephalosporins, or to certain individual cephalosporin drugs. FDA recognized that not all cephalosporin drugs necessarily posed the same level of risk. But given thepotential for confusion regarding the classification of individual cephalosporin drugs into various generations, FDA concluded in the July 3, 2008, final rule, that it would be problematic to define the scope of the prohibition based on cephalosporin “generation.” Although FDA continues to believe that a “generation-based” prohibition would be problematic, the Agency has given further consideration to excluding certain cephalosporin drugs from the order of prohibition. Therefore, based on the comments received on the July 3, 2008, order of prohibition, the Agency now believes that it is not necessary to prohibit the extralabel use of approved cephapirin drug products in food-producing animals.
Therefore, because the impact of cephapirin on antimicrobial resistance among bacteria of public health concern is substantially less than other, newer cephalosporins, and its unique dosage form restricts the extent of its extralabel use significantly, the Agency believes that it is appropriate to exclude cephapirin drug products from the prohibition order.2. Extralabel Indications for UsePeople often think of extralabel use only in terms of unapproved indications for use, that is, diseases or conditions not included in the approved labeling. However, as noted earlier, the definition of “extralabel use” includes several aspects of drug use not described in the approved labeling including, but not limited to:
For the reasons described previously, FDA does not at this time believe that extralabel use in food-producing majorspecies to treat or control an unapproved disease indication presents a risk to the public health as long as the drug is used at a labeled dose, frequency, duration, and route of administration approved for that species and production class.3. Food-Producing Minor SpeciesIn accordance with the act, minor species means animals other than cattle, swine, chickens, turkeys, horses, dogs, cats, and humans. Many comments requested that food-producing minor species, particularly small ruminants, be excluded from the order of prohibition. Most of these comments cited the limited availability of approved animal drug products for these species and several comments also noted that small ruminants represent only very limited uses of cephalosporin drug products compared to cattle, swine, and poultry. Based on these comments, the Agency reconsidered the decision to include food-producing minor species in the prohibition on the extralabel use of cephalosporin drugs in food-producing animals.
Please note that all the provisions of AMDUCA remain applicable to the exceptions noted above. This includes provisions making it unlawful for the permitted extralabel use of a cephalosporin drug to result in a residue above an established tolerance or safe level. See 21 U.S.C. 360b(a)(4)(B) and FDA regulations at 21 CFR 530.11.B. Legal StandardSeveral comments questioned the legal standard applied by FDA in implementing the order of prohibition. Some comments referred to the Agency's approach as involving the “precautionary principle,” an apparent reference to a principle used in the European Union in some environmental and regulatory decision-making. Two comments suggested that, in order to support an order of prohibition, it would be necessary for FDA to demonstrate “either a demonstrative negative impact on human health or an imminent danger to human health.” Some comments suggested that FDA must perform a risk assessment that would characterize the hazard, evaluate the risk, and ascertain the impact of any risk management recommendations associated with the order.
FDA rejects the apparent suggestion of one commenter, noted above, that an order of prohibition cannot be based on an adverse event in humans. Such a reading would be squarely inconsistent with the statutory provisions authorizing FDA to ban extralabel uses that present a risk to the public health. FDA addressed this issue in the preamble to the final AMDUCA implementing regulations, clarifying that “[t]he agency did not intend for the term `adverse event' to be interpreted as related only to animal ‘adverse drug reactions.’ ” (61 FR 57732 at 57737, November 7, 1996). Also, as made clear by the preamble, “* * * the primary focus will be on human health.” (61 FR at 57732 at 57737).
FDA also rejects the assertion by some commenters that FDA relied on the “precautionary principle.” As previously noted, the standard in the regulation does require the existence of evidence. In the preamble to the final rule, FDA addressed the question of what type of evidence would be necessary by saying that the risk determinations that would lead to prohibition of an extralabel use “typically will involve documented scientific information. However, the Agency believes that it is not limited to making risk determinations based solely on documented scientific information, but may use other suitable information as appropriate.” (61 FR 57732 and 57738; November 7, 1996). In other sections of this preamble, FDA provides a detailed description of the evidence supporting its conclusion that the extralabel use that is being prohibited by this revised order does in fact present a risk to the public health, including a likelihood that the use would, if not prohibited, ultimately lead to adverse events in humans resulting from the development of resistance to antibiotic drugs needed to treat human infections.IV. ConclusionsBased on information regarding cephalosporin resistance as discussed previously, FDA continues to believe, as it did in July of 2008, that it is likely that the extralabel use of cephalosporins in certain food-producing animal species is contributing to the emergence of cephalosporin-resistant zoonotic foodborne bacteria. Therefore, FDA has determined in accordance with the relevant provisions of 21 CFR part 530 that, with some exceptions, such extralabel use likely will cause an adverse event and, as such, presents a risk to the public health. As also noted earlier, FDA agrees with many of the comments received on the July 3, 2008, order of prohibition that said the scope of the original order was too broad and, in response, has narrowed the scope of this order accordingly. Specifically, this order prohibits all extralabel use of cephalosporin drugs in food-producing animals except for the following uses, provided they comply with AMDUCA and FDA's regulations implementing AMDUCA at 21 CFR part 530:
Minor Species: All extralabel use of a cephalosporin drug product is permitted in food-producing minor species provided such use complies with the requirements of AMDUCA and 21 CFR part 530.V. CommentsFDA is providing 60 days from the date of this publication for the public to comment on this document. For the effective date of the order, see theDATESsection of this document, unless the Agency revokes or modifies the order, or extends the comment period. Interested persons may submit to the Division of Dockets Management (seeADDRESSES) either electronic or written comments regarding this document. It is only necessary to send one set of comments. It is no longer necessary to send two copies of mailed comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.VI. Order of ProhibitionTherefore, I hereby issue the following order under 21 CFR 530.21 and 530.25. FDA finds that certain extralabel use of the cephalosporin class of antimicrobial drugs in food-producing animals likely will cause an adverse event, which constitutes a finding that extralabel use of these drugs presents a risk to the public health. Therefore, the Agency is prohibiting the extralabel use of the cephalosporin class of antimicrobial drugs as follows:
Cephalosporins (not including cephapirin) are prohibited from extralabel use in cattle, swine, chickens, or turkeys as follows: (1) For disease prevention purposes; (2) at unapproved doses, frequencies, durations, or routes of administration; and (3) if the drug is not approved for that species and production class.VII. ReferencesThe following references have been placed on display in the Dockets Management Branch (seeADDRESSES). You may view them between 9 a.m. and 4 p.m., Monday through Friday. FDA has verified the Web site addresses, but FDA is not responsible for any subsequent changes to the Web site after this document publishes in theFederal Register.
6. Li, X.Z. et al.β-Lactam Resistance and β-lactamases in Bacteria of Animal Origin. Veterinary Microbiology 121:197-214, 2007.
List of Subjects in 21 CFR Part 530Administrative practice and procedure, Advertising, Animal drugs, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs and redelegated to the Director of the Center for Veterinary Medicine, 21 CFR part 530 is amended as follows:Regulatory TextPart 530 Extralabel Drug Use in Animals
1. The authority citation for 21 CFR part 530 continues to read as follows:
Authority:15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b, 371, 379e.
2. In § 530.41, add paragraph (a)(13) to read as follows:
§ 530.41 Drugs prohibited for extralabel use in animals.
[FR Doc. 2012-35 Filed 1-4-12; 11:15 am]BILLING CODE 4160-01-P
Attachments View All (44) Return to top Ref 1 Livermore and Williams1991 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 2 Powers 2006 View Attachment: + View more information Authors: cvm Ref 4_Biedenbach et al 2006 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 3_MAXIPIME (cefepime HCl) Injection labeling 2011 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 5 Livermore 1995 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 6 Li et al 2007 View Attachment: + View more information Authors: cvm Ref 7 CDC NARMS Human Isolates Final Report 2008 2010 View Attachment: + View more information Authors: cvm Ref 8 Glenn et al 2011 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 9 Doi et al 2009 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 10 CLSI M100 S16 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 11 Livermore et al 2007 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 12 Lewis et al 2007 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 13 Castanheira et al 2008 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 14 Sjolund et al 2008 View Attachment: + View more information Authors: cvm Ref 15 McGettigan et al 2009 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 16 Sjolund-Karlsson et al 2010 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 17 Wittum et al 2010 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 18 Naseer and Sundsfjord 2011 View Attachment: + View more information Authors: cvm Ref 19 Sjolund-Karlsson et al 2011 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 20 Molbak 2004 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 21 USDA NARMS Animal Isolates 2009 2011 View Attachment: + View more information Authors: cvm Ref 22 FDA NARMS Executive Report 2009 2011 View Attachment: + View more information Authors: cvm Ref 23 FDA NARMS Executive Report 2007 2010 View Attachment: + View more information Authors: cvm Ref 24 CDC NARMS Human Isolates 2009 2011 View Attachment: + View more information Authors: cvm Ref 25 Dutil et al 2010 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 26 Zhao et al 2009 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 27 Zhao et al 2001 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 28 Lowrance et al 2007 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 29 Tragesser et al 2006 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 30 van den Bogaard and Stobberingh 2000 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 31 Cummings et al 2009 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 32 Cummings et al 2009 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 33 Cobbold et al 2006 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 34 Warnick et al 2003 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 35_Berge et al 2006 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 36 Scallan et al 2011 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 37 Varma et al 2005 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 38 Varma et al 2005 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 39 Varma et al 2006 View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 40 CDC Salm Newport MMWR View Attachment: + View more information Authors: cvmReason Restricted: This attachment is restricted to show metadata only because it contains copyrighted data. Ref 40_CDC Salm Newport MMWR View Attachment: + View more information Reason Restricted: This attachment is restricted to show metadata only. The reason is - duplicate Ref 41 CDC Salm Newport MMWR 2008 View Attachment: + View more information Ref 42 FDA CVM Summary of 2001 hatchery inspections 2002 View Attachment: + View more information Authors: cvm Ref 43 FDA Warning Letter on Biobullets 2011 View Attachment: + View more information Authors: cvm View document: No documents available. Attachments View All (0) Comment Now! Comment Period Closed Mar 6 2012, at 11:59 PM ET ID: FDA-2008-N-0326-0177 Tracking Number: View original printed format: Document Information Date Posted: Jan 6, 2012RIN: Not AssignedCFR: 21 CFR Part 530Federal Register Number: 2012-00035 Show More Details Submitter Information Comments107,650 Comments Received* N/A View Comment N/A View Comment N/A View Comment Docket Information This document is contained in FDA-2008-N-0326 Related Dockets: NoneRelated RINs: NoneRelated Documents: The Veterinary Pharmacy (TVP), Inc. - Request for ExtensionNew Animal Drugs; Cephalosporin Drugs; Extralabel Animal...New Animal Drugs; Cephalosporin Drugs; Extralabel Animal... Related Comments: View all * This count refers to the total comment/submissions received on this document, as of 11:59 PM yesterday. 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