On August 18, 1995, the Food and Drug Administration approved a new fluoroquinolone antibacterial drug, sarafloxacin hydrochloride, for use in chickens and turkeys. Sarafloxacin was the first fluoroquinolone approved for use in food-producing animals. It is a prescription drug distributed under the trade name Saraflox® WSP by Abbott Laboratories, North Chicago, Illinois. Saraflox® WSP is administered in drinking water to control mortality in broiler chickens and growing turkeys infected with Escherichia coli organisms susceptible to sarafloxacin. On October 12, 1995, FDA approved Saraflox® Injection, also manufactured by Abbott Laboratories, for control of early chick mortality associated with bacterial infection by E.Coli.
These approvals of fluoroquinolone products for food animal use followed lengthy consideration by FDA's Center for Veterinary Medicine (CVM) about possible microbial resistance to these drugs. Fluoroquinolones are the newest class of antimicrobial drugs developed for treating infections in people and animals. CVM approved enrofloxacin (another fluoroquinolone product) for use in companion animals in January 1989. Since then, some members of the human health community expressed concerns about the possible approval of fluoroquinolones in food animals. FDA held a joint meeting of the Agency's Veterinary Medicine and Anti-Infective Drugs advisory committees on May 11-12, 1994, to discuss this issue. Members of both committees concluded that FDA could approve fluoroquinolones found to be safe and effective for animal use.
CVM is interested in preserving the usefulness of these valuable new drugs and other fluoroquinolones by minimizing the potential for development of resistant pathogens. Part of the strategy to achieve this objective is to control unnecessary treatment of animals with fluoroquinolones. To facilitate accomplishment of this important objective, CVM is initiating an educational program to inform veterinarians and producers about the appropriate use of fluoroquinolones and is revising the Compliance Policy Guide 7125.06, Extra-label Use of Animal Drugs in Food-Producing Animals, to include regulatory guidance for these drugs.
To control the extra-label use of this class of drugs, FDA will assign a regulatory priority based on their actual use. The highest priority for regulatory action will be for extra-label use of fluoroquinolone products in major food-producing animal species (cattle, swine, chickens, and turkeys) that are not included in the approved labeling. For example, the highest priority for regulatory action would be assigned when a fluoroquinolone product only approved for use in chickens were used in a different major food-producing species such as cattle.
FDA is collaborating with the U. S. Department of Agriculture (USDA) and the Centers for Disease Control and Prevention (CDC) to develop a surveillance system to monitor antimicrobial susceptibility in enteric pathogens. Under the program, USDA will test Salmonella samples from animals for susceptibility to antimicrobial drug products. The CDC will conduct similar testing on Salmonella and E. coli. isolated from humans. The manufacturer, Abbott Laboratories, will test E. coli obtained from chickens and turkeys to monitor their susceptibility to sarafloxacin. The manufacturer will also provide geographically-based drug distribution information to CVM as part of their annual Drug Experience Reports. The information from the monitoring programs will be used to assess the development of fluoroquinolone-resistant organisms and make any adjustments in the extra-label drug use regulatory program.
Additional information on the approval of Saraflox WSP® is contained in the Federal Register of September 28, 1995. Questions regarding CVM's position on the extra-label drug use of fluoroquinolones may be directed to CVM's Office of Surveillance and Compliance at 7500 Standish Place, HFV-200, Rockville, MD 20855, or by calling (301) 594-1761.
FDA approved Monsanto Company's recombinant bovine somatotropin (rbST) product in November 1993 after a comprehensive review of the product's safety and efficacy, including human food safety. Monsanto's product, known as Posilac®, is the only rbST product approved for increasing milk production in dairy cattle. The product has been commercially available since February 4, 1994.
In a March 14, 1995 FDA TALK PAPER, the Agency stated that during the first year of commercial use a total of 806 adverse effects to the drug were reported to Monsanto and submitted to FDA. The following is an update on the adverse experiences to Posilac® reported to FDA during the next seven months of commercial use; from February 1, 1995 through August 25, 1995. During this period, FDA received 509 adverse experience reports (See table below.) It is important to note that a report of an adverse effect in relation to a drug does not itself establish that the effect was caused by the drug. FDA believes that 392 of the 509 reports were possibly associated with the use of Posilac®, and that the other 117 reports were not related to treatment with Posilac®. Also, all of the reported clinical manifestations are known to occur in dairy cattle not supplemented with Posilac®.
Of the 392 reports possibly related to the use of Posilac®, 100 included reproductive disorders, 77 involved digestive disorders, 69 included mastitis, 62 included injection site reactions, 54 included swelling of the udder or abnormal milk, 53 included foot or leg problems, and 44 involved increased somatic cell counts. In some cases, one report contained more than one condition.
The number and severity of the reported conditions raise no new animal health concerns about the safety of Posilac®. The numbers and types of reactions are similar to those found during clinical trials and indicated on the label. Also, there is no indication that the drug is any less effective than labeled. In addition, FDA and the States have found no indication of a change in the incidence of violative drug residues in milk since Posilac® has been in commercial use.
Based on the these reports of adverse reactions to Posilac®, FDA does not find any cause for concern. However, it is important for dairy farmers to continue to report all adverse reactions associated with the use of rbST. They may report such reactions to Monsanto, to FDA through their veterinarian, or directly to FDA's Center for Veterinary Medicine. CVM accepts collect calls during working hours, and an answering machine is available to record after-hours calls. The telephone numbers are (301) 594-1751 for collect calls during working hours, and (301) 594-0797 to leave a message on evenings and weekends.
SUMMARY OF ADVERSE REACTION REPORTS ON POSILAC
The following table summarizes the important clinical manifestations (CM) from the 392 adverse experience reports possibly related to the use of Posilac® from February 1 through August 25, 1995.
This summary is intended only as a general reference to the type of reactions that veterinarians and dairy farmers have voluntarily reported to the manufacturer or FDA. Therefore, the summary is not by itself a basis for determining drug association for a particular sign, safety or efficacy of the drug, or determining the frequency or incidence rate of a clinical manifestation. Each of the reports may contain one or more CMs, and as a result the number of CMs exceeds the number of reports. It is important to recognize that all of the reported clinical manifestations are known to occur in dairy cattle not supplemented with Posilac®.
|
Clinical Manifestation (CM) |
Number of Reports with the CM |
Estimated Number of Cows Reported with the CM |
| Mastitis (clinical) |
69 |
1,781 |
| Increased Somatic Cell Counts in Milk |
44 |
1,024 |
| Other Udder Abnormalities* |
54 |
943 |
| Reproductive Disorders** |
100 |
2,263 |
| Cardiovascular Disorders |
0 |
0 |
| Digestive Disorders*** |
77 |
5,923 |
| Foot or Leg Problems |
53 |
696 |
| Injection Site Reactions |
62 |
791 |
| Cattle Deaths**** |
8 |
22 |
* Includes udder swelling, udder edema, or abnormal milk.
** Includes decreased fertility, abortions, premature births, and retained placentas.
*** Includes anorexia, weight loss, and other digestive tract signs.
**** The most commonly reported CM for all dairy cattle drug products is death. This includes cows that were euthanized or slaughtered due to an illness, such as chronic mastitis.
1994 ADVERSE DRUG EXPERIENCE SUMMARY
This issue of the FDA Veterinarian contains a pull-out section of the second half of the 1994 Veterinary Adverse Drug Experience Summary. The first portion was included in the September/October issue.
[Editor's note: this electronic version of the FDA Veterinarian does not include the ADE summary. ADE information is available as a section in the On-Line Library elsewhere on this site. (Be warned that there is no link back to here)] This summary includes all domestic adverse drug experience reports submitted to the Center for Veterinary Medicine (CVM) for calendar year 1994 which the Center has determined to be at least possibly drug related. It is organized alphabetically by generic drug, and within each drug by species, and within each species by the general route of administration. The percentages represent the number of reports containing a sign divided by the total number of reports. Also, reported signs are truncated at twenty-two characters
The Center's adverse drug reaction review process takes into consideration confounding factors such as dosage, concomitant drug use, the medical and physical condition of the animals at the time of treatment, environmental and management information, product defects, etc. These complex factors, however, cannot be fully addressed in this summary. This summary is intended only as a general reference to the type of reactions that veterinarians, animal owners, and others have voluntarily reported to FDA or the manufacturer after drug use; therefore, it is not by itself a basis for:
This summary does not include product failure or adverse experience reports for biologics and topically applied, externally acting parasiticides. Such reports received by CVM are forwarded to the government agency that regulates the product in question. In addition, it does not include reports of drug product defect reports unless the report also contains adverse reaction information. The human reports involve human exposure to an animal drug.
An abbreviation table and additional information about the summary may be found on page I-1 of the September/October issue of the FDA Veterinarian.
CVM ESTABLISHES HOME PAGE ON THE WWW
The Center for Veterinary Medicine now has a Home Page on the World Wide Web (WWW). The Home Page will allow the public to have computer access to publications and information from the Center. The CVM Home Page may be found at:
http://www.cvm.fda.gov/
The CVM Home Page includes general information about the Center, organizational charts, specific information about each office, and telephone numbers for all Center employees. Also included in the CVM Home Page are Freedom of Information (FOI) Summaries for many new animal drugs, the FDA Approved Animal Drug Products Database, some CVM Guidelines, answers to Frequently Asked Questions (FAQs), information on CVM research activities and research plans, and the text of FDA and the Veterinarian.
This World Wide Web site is maintained for the Center for Veterinary Medicine by the Drug Information Laboratory at the Virginia-Maryland Regional College of Veterinary Medicine at the Virginia Polytechnic Institute, Blacksburg, VA. CVM is committed to the continued development and growth of this Home Page and additional information will be added in the future. Comments on what should be included in this Home Page are encouraged. Questions or comments on the CVM Home Page may be made through the e-mail address on the Home Page or to Ms. Deborah Brooks, CVM's Home Page Manager. Ms. Brooks may be reached on (301) 827-0215 or by e-mail at Brooks_D@A1.CVM.FDA.GOV.
CVM PUBLISHES GUIDE ON MASTER FILES
On July 26, 1995, CVM issued a Policy Letter announcing the Center's informal guidance document entitled "MASTER FILES -- Guidance for Industry for the Preparation and Submission of Veterinary Master Files." A master file (MF) is a voluntary submission to FDA that may be used to provide confidential, detailed information about the facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more veterinary drugs. Master files on file with CVM are generally referred to as veterinary master files (VMFs). This is to distinguish these files from those submitted to FDA's Center for Drug Evaluation and Research, which are referred to as drug master files (DMFs). The information in a VMF may be used to support an investigational new animal drug application (INADA), a new animal drug application (NADA), an abbreviated new animal drug application (ANADA), another VMF, an Export Application, or amendments or supplements to any of these.
A master file is not a substitute for an INADA, NADA, ANADA, or Export Application. It is not approved or disapproved. Instead, the submission is found acceptable or deficient in support of an INADA, NADA, ANADA, Export Application, or other master file.
The submission of a master file is not required by law or FDA regulation. Master files are generally created to allow a party other than the holder of the master file to reference material without disclosing to that party the contents of the file. When an applicant references its own material, the applicant should reference the material contained in its own INADA, NADA, or ANADA directly, rather than establishing a master file.
A master file is submitted solely at the discretion of the holder. All information submitted in a master file is considered confidential, and is reviewed only when the master file holder provides appropriate authorization permitting the FDA to refer to it on behalf of an applicant or sponsor.
This guidance document recognizes five distinct types of Veterinary Master Files (Types I - V) as well as public master files. It states that Type I VMFs are being eliminated, and that the Center will no longer accept new Type I VMFs or correspondence updating existing Type I VMFs. Also, the information in Type I VMFs currently on file can no longer be incorporated by reference into new applications, amendments, or supplements. Further definitions of the content of Type I -V VMFs and the mechanism by which Type I master files will be eliminated or recategorized are also included in the informal guidance document.
The informal guidance document also announces that a VMF will only be reviewed in conjunction with an application. Previously, CVM routinely reviewed submissions that were not necessarily linked to an application. The Center has concluded that the routine review and evaluation of VMFs not specifically referenced in applications may be a waste of resources, and will discontinue this practice.
Copies of the policy letter and the informal guidance document are available from the FDA Veterinarian. Comments and questions on the guidance document may be addressed to:
William G. Marnane
Center for Veterinary Medicine
Office of New Animal Drug Evaluation
HFV-143
7500 Standish Place
Rockville, MD 20855
This issue of the FDA Veterinarian contains the first in a series of questions and answers that are frequently asked about CVM's Veterinary Adverse Drug Experience (ADE) program. Readers who have additional questions on our ADE program or any other Center issue are encouraged to submit them to the following address: FDA/Center for Veterinary Medicine, 7500 Standish Place, HFV-12, Rockville, MD 20855 or telephone Linda Grassie at (301) 594-5909.
Q. What is an ADE?
A. An adverse drug experience (ADE) is either an undesired side effect, or the lack of a desired effect. CVM's official definition of an ADE is "any side effect, injury, toxicity, or sensitivity reaction (or failure to perform as expected) associated with the use of an animal drug, whether or not determined to be attributable to the drug."
Q. What are CVM's specific areas of interest?
A. The primary purpose of CVM's ADE monitoring system is to detect problems or "side effects" associated with the use of FDA approved animal drugs. During the research studies that lead to drug approval, only limited numbers of animals are treated. Because of this, effects or problems that only occur rarely may not be discovered until after the drug has been more widely marketed and used in a clinical setting.
Lack of effectiveness is an adverse experience. The majority of reports of this nature involve anthelmintics. These reports can be difficult to evaluate, but a group of similar reports will prompt further investigation.
CVM gives careful consideration to any reports of adverse experiences occurring in humans as a direct result of using or administering an animal drug or in other situations involving accidental human exposure.
In the July/August issue of the FDA Veterinarian, there was an article discussing the approval of minor use drugs (see pages 6-8). The article mentioned that Dr. Linda Kahn was CVM's liaison to the minor use drug program known as the National Research Support Project-Number 7 (NRSP-7).
Dr. Kahn has since left the Agency. The new FDA/CVM Liaison to NRSP-7 is Dr. Meg R. Oeller. Dr. Oeller may be contacted on 301-594-1650 or by writing to FDA/CVM, 7500 Standish Place, HFV-130, Rockville, MD 20855.
DESOXYCORTICOSTERONE PIVALATE (PERCORTEN ®-V). CIBA-GEIGY CORP. HAS FILED AN APPLICATION REQUESTING APPROVAL FOR EXPORT OF PERCORTEN ®-V TO CANADA. THE PRODUCT IS USED AS PARTIAL MINERALOCORTICOID REPLACEMENT THERAPY IN CASES OF ADRENOCORTICAL INSUFFICIENCY IN DOGS. Federal Register 8/11/95.
TRENBOLONE ACETATE AND ESTRADIOL BENZOATE (SYNTEX ® PLUS(TM)). Syntex Animal Health has filed an application requesting approval for export of SYNTEX ® PLUS(TM) to Canada. The product is used to increase weight gain and improve feed efficiency in feedlot steers and heifers. Federal Register 9/25/95.
NATAMYCIN (FAP 2234.) DuCoa L.P. has filed a petition proposing that the food additive regulations be amended to provide for the safe use of natamycin as a mold retardant of Aspergillus parasiticus, Penicillium rubrum, and Fusarium moniliforme in broiler chicken feed for up to 14 days when used at a level of 11 parts per million. Federal Register 9/20/95.
FOOD ADDITIVE REGULATIONS AMENDED
In the September 28, 1995 Federal Register, the FDA announced that the Agency is amending the food additive regulations for irradiation in the production, processing, and handling of animal feed and pet food to provide for the safe use of gamma radiation from cobalt-60 in an absorbed dose range of 2 kiloGrays (kGy) (0.2 Megarads) (Mrad) to 25 kGy (2.5 Mrad), for rendering complete poultry feeds or poultry feed ingredients salmonella negative. This action is in response to a food additive petition filed by Nordion International, Inc., Kanata, Ontario, Canada.
CONSENT DECREE SIGNED IN DRUG RESIDUE CASE
On July 5, 1995, a Consent Decree of Permanent Injunction was signed by David L. Hogan, owner of Hogan's Misty Meadow Dairy, Tillamook, Oregon. This dairy is primarily a producer of fluid milk, with a producing herd of 700 cows. In addition, the farm produces bull calves which are sold for slaughter or for further raising and then slaughter for human food.
The injunction action against Mr. Hogan was based on 16 residue incidents in veal during the period from March 1990 through June 1994. The illegal drug residues involved included streptomycin, neomycin, gentamicin, and oxytetracycline. The Consent Decree permanently restrained and enjoined Mr. Hogan from introducing or delivering for introduction into interstate commerce any cattle intended to be slaughtered for use as food or any edible tissues of cattle unless and until medicated cows and bulls are identified, medicated in accordance with approved labeling, and held for the proper withdrawal period. The Consent Decree also requires that calves intended for sale be segregated into a separate pen, medicated calves or calves fed colostrum or milk from a medicated cow be marked, medication be used in accordance with its approved labeling, withdrawal periods be followed, and written records be kept.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
These violations involved illegal residues of neomycin and oxytetracycline in calves, penicillin in bull calves, oxytetracycline in a steer, neomycin and tetracycline in a bull calf, sulfadimethoxine and gentamicin in a cull dairy cow, sulfamethazine in a cow, penicillin in a sow, oxytetracycline in a cull dairy cow, ivermectin and oxytetracycline in a heifer, penicillin in a cull dairy cow, and neomycin and oxytetracycline in beef calves.
The following firms received warning letters for deviations from the Good Manufacturing Practice (GMP) regulations:
Company
Schering-Plough Animal Health Corp.
(NADA 141-052)
Generic and (Brand) Names
Cyclosporine Ophthalmic Ointment
(Optimmune)® Rx
Indications
Dogs. For treatment of chronic keratoconjunctivitis sicca.
Routes/Remarks
OPHTHALMIC: Provides for 0.2 percent cyclosporine.
Federal Register 9/20/95
Company
Rhone Merieux, Inc.
(NADA 141-042)
Generic and (Brand) Names
Melarsomine Dihydrochloride Rx (Immiticide Sterile Powder)
Indications
Dogs. For treatment of heartworm.
Routes/Remarks
INJECTABLE: Provides for a vial of lyophilized powder containing 50 milligrams of dihydrochloride melarsomine to be reconstituted with the provided 2 milliliters of sterile water.
Federal Register 9/25/95.
Company
Abbott Labs.
(NADA 141-017)
Generic and (Brand) Names
Sarafloxacin Hydrochloride Water Soluble Powder
(SaraFlox ® WSP)
Indications
Turkeys and Broiler Chickens.
For control of mortality associated with E.coli organisms susceptible to sarafloxacin.
Routes/Remarks
ORAL: For medicated drinking water.
Chickens--20-40 ppm for five consecutive days as the only source of drinking water.
Turkeys--30 to 50 ppm for five consecutive days as the only source of drinking water.
Federal Register 9/28/95.
Company
Rhone-Merieux Canada, Inc.
(ANADA 200-144)
Generic and (Brand) Names
Oxytetracycline hydrochloride soluble powder
Indications
Chickens, Turkeys, and Swine. For treatment and/or control of certain diseases susceptible to oxytetracycline.
Routes/Remarks
ORAL: For medicated drinking water.
ANADA 200-144 is a generic copy of I.D. Russell's NADA 130-435 for Oxytet Soluble.
Federal Register 8/9/95.
Company
Halocarbon Labs., Division of Halocarbon Products Corp.
(ANADA 200-129)
Generic and (Brand) Names
Isoflurane Rx
Indications
Horses and Dogs. For induction and maintenance of general anesthesia.
Routes/Remarks
INHALANT: ANADA 200-129 is a generic copy of Anaquest's NADA 135-773 for AErrane® (isoflurane).
Federal Register 8/9/95.
Company
Mac Leod Pharmaceuticals, Inc
(ANADA 200-115)
Generic and (Brand) Names
Gentamicin Solution
Indications
Horses and Mares. For control of bacterial infections of the uterus (metritis) in horses and as an aid in improving conception in mares with uterine infections caused by bacteria sensitive to gentamicin.
Routes/Remarks
INTRAUTERINE: ANADA 200-115 is a generic copy of Schering's NADA for Gentocin® Solution, NADA 046-724.
Federal Register 8/30/95.
Generic and (Brand) Names
Flunixin Meglumine Injection
Indications
Horses. For alleviation of inflammation and pain associated with musculoskeletal disorders and visceral pain associated with colic.
Routes/Remarks
INJECTION: ANADA 200-142 is a generic copy of Schering-Plough's NADA 101-479 for Banamine® Injection.
Federal Register 9/20/95.
Company
Phoenix Pharmaceutical, Inc.
(ANADA 200-068)
Generic and (Brand) Names
Oxytetracycline Hydrochloride Injection
Indications
Cattle. For treatment of certain diseases caused by pathogens sensitive to oxytetracycline.
Routes/Remarks
INJECTION: ANADA 200-068 is a generic copy of Fermenta's NADA 108-063 for Medamycin-100®.
Federal Register 9/20/95.
Company
Fermenta Animal Health Co.
(ANADA 200-023)
Generic and (Brand) Names
Gentamicin Solution
Indications
Horses and Mares. For control of bacterial infections of the uterus (metritis) in horses, and as an aid in improving conception in mares with uterine infections caused by bacteria sensitive to gentamicin.
Routes/Remarks
INTRAUTERINE: ANADA 200-023 is a generic copy of Schering's NADA 046-724 for Gentocin® Solution.
Federal Register 9/21/95.
Company
Fermenta Animal Health Co
(ANADA 200-029)
Generic and (Brand) Names
Ketamine Hydrochloride Injection Rx
Indications
Cats and Non-Human Primates. In cats for restraint and to produce anesthesia that is suitable for diagnostic or minor surgical procedures that do not require skeletal muscle relaxation. In non-human primates for restraint.
Routes/Remarks
INJECTION: ANADA 200-029 is a generic copy of Fort DodgeLabs' NADA 045-290 for Vetalar®/Ketaset®.
Federal Register 9/25/95.
Company
Ciba-Geigy Animal Health
(NADA 140-915)
Generic and (Brand) Names
Milbemycin Oxime Tablets (INTERCEPTOR®) Rx
Indications
Dogs. For prevention of heartworm disease, control of adult hookworm infections, and removal and control of adult roundworm and whipworm infections.
Routes/Remarks
ORAL: Provides for 2.3-, 5.75-, 11.5-, and 23.0- milligram Interceptor® tablets. Supplement provides for use to treat puppies 4 weeks of age or greater and 2 lbs. of body weight or greater.
Federal Register 9/28/95.
Company
Merck Research Labs., Div. of Merck & Co.
(NADA 128-409)
Generic and (Brand) Names
Ivermectin (Ivomec® Injection)
Indications
Ranch-raised Foxes. For use as an antiparasitic (for treatment and control of ear mites).
Routes/Remarks
INJECTION: Provides for this additional use of 0.27 percent ivermectin. Approval is based in part on data and information in PMF 5307 established under the National Research Support Project No. 7.
Federal Register 8/30/95.
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