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• CVM APPROVES FIRST BEHAVIORAL DRUGS FOR DOGS

• UPDATE ON FY 98 APPROVALS

• UPDATE ON HUMAN FOOD SAFETY OF BST

• UPDATE ON BOVINE SOMATOTROPIN ADVERSE EXPERIENCES

• REGULATION OF CONTROLLED SUBSTANCES

• BLACKWELL ACCEPTS NEW POSITION WITH SURGEON GENERAL

• EVALUATION OF NEW TYPE C MEDICATED FEED METHODS FOR APPROVED TYPE A MEDICATED ARTICLES

• CELEBRATE NATIONAL PET WEEK IN MAY

• ANALYTICAL METHODS FOR THE DETERMINATION OF DIURETICS IN BOVINE MILK

• FINALIZED MINOR USES/MINOR SPECIES GUIDANCE AVAILABLE

• UPDATED NCIE ELECTRONIC SUBMISSION GUIDANCE AVAILABLE

• NEW VMAC CHAIRMAN

• VETERINARIAN SENTENCED IN ANIMAL DRUG SMUGGLING CASE

• ANNUAL MID-ATLANTIC CONFERENCE FOR BOVINE PRACTITIONERS

• CONSENT DECREE ENTERED IN ANIMAL DRUG COMPOUNDING CASE

• REGULATORY ACTIVITIES

• NEW ANIMAL DRUG APPROVALS

• ABBREVIATED NEW ANIMAL DRUG APPROVALS

• SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

CVM APPROVES FIRST BEHAVIORAL DRUGS FOR DOGS

FDA's Center for Veterinary Medicine (CVM) has approved two drugs to treat two different behavioral problems affecting some dogs. These drugs are ClomicalmTM Tablets (clomipramine hydrochloride) to be used as part of a comprehensive behavioral management program to treat separation anxiety in dogs greater than six months of age, and Anipryl® Tablets (selegiline hydrochloride, L-deprenyl hydrochloride) to control the clinical signs associated with canine Cognitive Dysfunction Syndrome (CDS).

Separation anxiety is a complex behavior disorder displayed when the owner or someone the dog is attached to leaves the dog. Dogs with separation anxiety may exhibit one or more of the following clinical signs: barking, destructive behavior, excessive salivation, and inappropriate elimination. Proper recognition of clinical signs, which comes from compiling a complete patient history and assessment of the dog's household environment, is essential to accurately diagnose and treat separation anxiety.

In clinical trials, ClomicalmTM Tablets, when used with behavior modification, were shown to reduce the signs of separation anxiety and increase the rate of improvement when compared to behavior modification alone.

Anipryl® Tablets control clinical signs of CDS, an age-related deterioration typified by multiple cognitive impairments which affect the dog's ability to function normally. Behavioral changes associated with CDS include disorientation, decreased activity level, abnormal sleep wake cycles, loss of house training, decreased or altered responsiveness to family members, and decreased or altered greeting behavior. In clinical trials, Anipryl® was shown to be effective in controlling clinical signs associated with CDS. However, onset, duration and magnitude of response varied with individual dogs.

The diagnosis of CDS in dogs is a diagnosis of exclusion, based on thorough behavioral and medical histories, in conjunction with appropriate testing and diagnosis. Periodic patient monitoring to evaluate the response and tolerance to the drug and for the presence of concurrent or emergent disease is recommended.

While ClomicalmTM Tablets and Anipryl® Tablets are safe for use in dogs at the recommended dosages, both products can cause side effects. The package inserts for both products also carry important Warning, Contraindication, and Precaution statements that should be considered prior to treatment. An important example is the fact that a dog should not be on both ClomicalmTM Tablets and Anipryl® Tablets at the same time. The use of these products together is contraindicated. A close veterinarian-client-patient relationship is recommended in order to monitor response to therapy and to watch for any side effects.

ClomicalmTM Tablets will be sold by Novartis Animal Health US, Inc. of Greensboro, NC. Anipryl® will be sold by Pfizer Animal Health, Inc. of Exton, PA. Both drugs will be available in tablet form and only on the order of a licensed veterinarian.

UPDATE ON FY 98 APPROVALS

CVM's Office of New Animal Drug Evaluation acted on 6,513 submissions for new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), investigational new animal drug files (INADs), and generic investigational new animal drug (JINADs) files in Fiscal Year (FY) 1998. Approximately 85 percent of these decisions were made within the statutory limit of 180 days for NADAs and ANADAs and the internally established time frame for INADs and JINADs. Of the 6,513 applications, 102 were for original applications (and reactivated originals) and 835 were for supplements to previously approved applications. In addition, 428 phased data submissions were completed by the Center during FY 1998. The on-time rate for these applications and substantial submissions was 75 percent.

Of the actions taken in FY 1998, FDA published 101 documents reflecting NADA and ANADA approvals in the Federal Register. These approvals included some very significant new product approvals, i.e., 10 new chemical entities, 10 products for use in new animal species, and 4 products available in new dosage forms. In addition, other approvals included 28 original generic approvals, 4 drug effectiveness study implementation (DESI) finalizations, 5 new product indications, and 3 additional production classes approved through supplements to existing approved drugs.

The new chemical entities approved in FY 98 included the ones listed in the table below.

A complete list of all FY 98 animal drug approvals is available from the FDA Veterinarian.

UPDATE ON HUMAN FOOD SAFETY OF BST

FDA's Center for Veterinary Medicine (CVM) has reexamined the human food safety of recombinant bovine somatotropin (rbST) in response to recent inquiries about the safety of this product. FDA's CVM approved Monsanto Company's rbST product, Posilac® in November 1993 after a comprehensive review of the product's safety and efficacy, including human food safety. CVM has issued a detailed report based on a careful audit of the human food safety sections of this approval. CVM's finding upholds the Agency's original conclusion that milk from cows treated with rbST is safe for human consumption.

The new concerns about the safety of Posilac® , currently the only rbST product approved for increasing milk production in dairy cattle in the U.S., were stimulated by the product's review for approval in Canada. In April 1998, while the review process was underway, the Health Protection Branch (HPB) of Health Canada prepared an internal memorandum, entitled "rBST (Nutrilac) 'GAPS Analysis' Report," which was critical of the review method used by the HPB, and identified areas of human food safety concern.

In particular, the Canadian report claimed that a 90-day oral toxicity study in rats had been "misreported" by FDA, and cited allegations of significant absorption of oral rbST based on serum antibody levels in the rats, and toxicity to the rats. Both the memorandum and the circumstances under which it was made public became highly controversial in Canada.

Following the publication of the Canadian document several groups and individuals in the United States raised questions about the safety of milk from rbST-treated cows. In response to these concerns, CVM prepared a "Report on the Food and Drug Administration's Review of the Safety of Recombinant Bovine Somatotropin." The Report affirmed the original review of the 90-day rat oral toxicity study, which concluded that there were no biologically significant observed effects in either the thyroid or the prostate.

In addition, CVM conducted a review of the report cited by Health Canada of the antibody response to oral rbST. While CVM concurred that oral exposure to high doses of rbST results in antibody production, there is no evidence for biologically significant absorption of intact rbST from the gastrointestinal tract.

The "Report on the Food and Drug Administration's Review of the Safety of Recombinant Bovine Somatotropin" is available on the CVM's Internet Home Page.

A copy of this report may also be obtained by calling or writing the FDA Veterinarian.

UPDATE ON BOVINE SOMATOTROPIN ADVERSE EXPERIENCES

Since FDA approved Monsanto Company's recombinant bovine somatotropin (rbST) product, Posilac® , in November 1993, FDA and Monsanto have closely monitored the safety and efficacy of Posilac® under commercial use conditions. As expected during a product's life-cycle, the frequency of ADE reports for Posilac® has diminished since initial marketing. The number and nature of the reports raise no new animal health concerns.

The attached table summarizes the important clinical manifestations (CM) from the adverse experience reports possibly related to the use of Posilac®^, submitted between February 4, 1994 and February 4, 1996 (first two years of marketing) and between February 4, 1994 and December 31, 1998 (1,235 reports for nearly 5 years of marketing).

Between February 4, 1994 and December 31, 1998, FDA received 1,981 adverse experience reports. 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 1,235 of the 1,981 reports were possibly associated with the use of Posilac® , and that the other 746 reports were not related to treatment with Posilac® .

Of the 1,235 reports possibly related to the use of Posilac® , 276 included reproductive events, 266 included mastitis, 246 involved injection site reactions, 240 included swelling of the udder or abnormal milk, 218 involved increased somatic cell counts, 194 involved digestive disorders, and 159 included foot or leg problems. In some cases, a single report contained multiple conditions.

SUMMARY OF ADVERSE EXPERIENCE REPORTS ON POSILAC®

This summary is intended only as a general reference to the type of reactions that veterinarians and dairy farmers have voluntarily reported. 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. The reported clinical manifestations are known to occur in dairy cattle not supplemented with Posilac® .

* Includes twinning, decreased fertility, abortions, premature births, and retained placentas.

** Includes udder swelling, udder edema, or abnormal milk.

*** Includes anorexia, weight loss, and other digestive tract signs.

**** The most commonly reported CM for all other dairy cattle drug products is death. This includes cows that were euthanized or slaughtered due to an illness, such as chronic mastitis.

REGULATION OF CONTROLLED SUBSTANCES

The CSA established five schedules that classify controlled substances according to their potential for abuse. Drugs are placed into categories according to how dangerous they are, how great their potential for abuse is, and whether they have any legitimate medical value.

Regulations for prescribing controlled substances are included in Title 21, Part 1306 of the Code of Federal Regulations (CFR). These regulations state that:

- No prescription for a controlled substance may be issued unless there is a legitimate medical reason.

- Narcotics under any schedule may not be prescribed for "detoxification" or "maintenance treatment."

- Prescribing practitioners as well as the pharmacists who fill the prescriptions, share the corresponding responsibilities to adhere to the laws and regulations of the Food and Drug Administration (FDA), DEA, the States in which they are practicing, and their licensing boards.

- In the event that discrepancies between Federal and State laws exist, the more stringent of the two must be followed.

Information about products in these schedules and prescribing restrictions follows.

Schedule I Products

The Food and Drug Administration (FDA) and the DEA have not recognized any legitimate medical purpose for such controlled substances. Examples of Schedule I products are heroin and marihuana. Issuance of prescriptions for Schedule I products is prohibited.

Schedule II Products

Examples of Schedule II products which are approved for use in animals include pentobarbital, oxymorphone, naloxone, fentanyl, butorphanol, and secobarbital. Except for butorphanol, which is available in both tablet and injectable form, all other Schedule II drugs are injectables. FDA has no evidence that these animal drug products are used illicitly.

Physical and psychological dependence on most of the Schedule II drugs is high, and normally results in withdrawal symptoms. Therefore, production of these drugs is controlled by DEA. FDA determines and advises DEA on whether production of these products needs to be curtailed or increased depending upon medical needs. FDA's Center for Veterinary Medicine (CVM) and Center for Drug Evaluation and Research (CDER) collaborate in this decision-making process. Refillingof prescriptions for Schedule II products is prohibited under Title 21, Part 1306.12 of the CFR.

Schedule III Products

Examples of Schedule III products include androgenic anabolic agents, such as boldenone, testosterone, and stanozolol. Since these drugs are formulated in both injectable and tablet dosage forms and have potential for abuse, they have not been exempted from CSA. Anabolic agents which are used as implants are unlikely to be abused, and therefore are exempted from Schedule II requirements of CSA. An example of these types of drugs is trenbolone acetate which is chemically and pharmacologically related to testosterone and defined as a controlled substance under Title 21, Part 1300.01(a)(4) of the CFR. Since it is only approved as an implant, trenbolone acetate is exempted from CSA requirements.

Schedule IV Products

Examples of Schedule IV products are benzodiazepines such as barbital, clonazepam, diazepam (Valium), and diethylpropion.

Under Title 21, Part 1306.22 of the CFR, no prescription for a controlled substance listed in Schedule III or IV may be filled or refilled more than six months after the date on which such prescription was issued, and no such prescription may be refilled more than five times.

Schedule V Products

Examples of Schedule V products include buprenorphine, cough syrup containing codeine, and lomotil. Although codeine is a Schedule II drug, the concentration permitted in cough syrup is low enough to classify it as a Schedule V product.

Anabolic steroids were added to Schedule III of CSA as a result of the passage of the Anabolic Steroid Control Act in February 1991. FDA retained the responsibility to assure that these products are safe and effective for use as labeled, and they are not counterfeit, adulterated, or misbranded. As mentioned above, anabolic steroids which are expressly intended for administration through implants to cattle or other non-human species, and which have been approved by FDA, are not currently regulated under CSA. It is felt that this dosage form is not likely to be abused by humans.

FDA and DEA work together to determine when other drugs, including animal drugs, should become controlled substances. Normally, decisions to classify animal drugs as controlled substances are based on concerns about diversion to and abuse by humans. An example of such FDA and DEA cooperation is recent activities regarding ketamine.

Ketamine hydrochloride, an anesthetic for human and veterinary use, is a legitimately manufactured product that is being abused with increasing frequency. On the street, the drug is often called "K" or "Special K." It produces effects similar to those produced by phencyclidine (PCP), and the visual effects of LSD. With repeated daily exposure, users can develop tolerance and psychological dependence, as is the case with most controlled substances. Veterinary clinics have been burglarized for ketamine. These are among the factors that have caused the FDA and DEA to re-evaluate the control status of the drug.

FDA recently recommended that ketamine should be placed into Schedule III. DEA plans to publish a proposed rule in the Federal Register to accomplish this scheduling action.

Under Federal law, all businesses which manufacture or distribute controlled drugs, all health professionals (including veterinarians) entitled to dispense, administer or prescribe them, and all pharmacies entitled to fill prescriptions must register with the DEA. Registrants must comply with a series of regulatory requirements relating to drug security, records accountability, and adherence to standards.

Questions related to the registration process may be directed to DEA's Office of Diversion Control, Registration Unit. This unit has a toll-free number available 24 hours a day. This number, 1-800-882-9539, is equipped with a voice mail system that may be used to request:

New applications for registration,

Renewal applications,

Duplicate certificates of registration,

DEA order forms, and

Changes of address.

Callers may speak with a Registration Assistant during normal business hours (8:30 a.m. to 6:00 p.m. EST).

BLACKWELL ACCEPTS NEW POSITION WITH SURGEON GENERAL

by Karen A. Kandra

Dr. Michael Blackwell describes himself as a "dyed in the wool FDAer", who is emotionally tied to his 22-year career at the Food and Drug Administration. However, on February 1, 1999, Dr. Blackwell left his post as Deputy Director of the Center for Veterinary Medicine, to become Chief of Staff with U.S. Surgeon General, Admiral David Satcher.

In his new assignment, Dr. Blackwell will assist Admiral Satcher and Deputy Surgeon General Rear Admiral Kenneth Moritsugu in managing the Commissioned Corps of the United States Public Health Service (PHS). His outstanding record and achievements in the PHS qualified Dr. Blackwell for selection as the first veterinarian to hold this prestigious position.

Since1994, Dr. Blackwell has served as CVM’s Deputy Director, and he is proud of many significant accomplishments during that time.

He assisted Director, Dr. Stephen Sundlof in handling the challenges facing the Center for Veterinary Medicine. As a career FDAer, Dr. Blackwell had the knowledge and experience necessary to oversee day-to-day Center operations. Along with Dr. Sundlof, the management team has strengthened relationships with stakeholders, making tremendous gains by increasing collaborative efforts with external customers.

To improve CVM’s service to its worldwide stakeholders and to address complex issues facing them, Dr. Blackwell helped change the scope of the Office of the Director. The Policy and Regulations Team was placed under that Office to handle such important functions as preparation of guidance documents and regulations. By adding special assistants in needed areas to perform duties formerly handled by other Offices, the Center is improving its ability to interact with both internal and external customers.

CVM can now utilize the science of epidemiology more formally in the regulatory process, thanks to the long-overdue establishment of an Epidemiology Team. Dr. Blackwell also contributed to the appointment of the first woman Office Director in CVM, and the first African American selected as Division Director. A work group appointed by Dr. Blackwell was formed to draft the CVM diversity policy to assist in hiring efforts to better ensure a diverse work place.

A major regret for Dr. Blackwell is that he will not be available to continue CVM’s unfinished business of cultural change within the organization where people feel empowered to help make good decisions for the public health. Dr. Blackwell helped implement this ongoing effort, which he hopes will give employees a high level of trust and increased job satisfaction.

Dr. Blackwell received significant personal recognition and awards while at CVM. On October 7, 1997, he was promoted to the Commissioned Corps rank of Rear Admiral and Assistant Surgeon General. From 1994 to 1998, Dr. Blackwell also served as the Chief Veterinary Officer in the Public Health Service and participated on many committees and work groups to help develop and implement public health policy for the Department of Health and Human Services and the Surgeon General.

Dr. Blackwell began his government career in 1977 as a Veterinary Medical Officer in the Bureau of Veterinary Medicine, and has served primarily in FDA, not only in CVM, but also in the Center for Devices and Radiological Health (CDRH). In addition, he also served at the National Institute for Occupational Safety and Health, and the Centers for Disease Control and Prevention.

When asked about his goals for his new assignment, Dr. Blackwell says he hopes to assist Drs. Satcher and Moritsugu to reestablish the Office of the Surgeon General and its role within the Department (DHHS). He believes it is important that the Department and the country prepare for a new era of threats, i.e., biological and chemical weapons of mass destruction. A key component of that effort will be to improve the Commissioned Corps’ inactive reserve force, and provide proper training that would keep individuals in a state of readiness to respond in the event of a national emergency.

The Office of the Surgeon General will be working to achieve three major priorities of Dr. Satcher:

1) A balanced community health system.

2) A global approach to disease prevention and health promotion.

3) Elimination of disparities in health care due to race or ethnicity.

Dr. Blackwell, your work is cut out for you -- we at CVM wish you all the best in your new position, and thank you for your major contributions to CVM.

EVALUATION OF NEW TYPE C MEDICATED FEED METHODS FOR APPROVED TYPE A MEDICATED ARTICLES

by Mary G. Leadbetter

The following information was presented at the 112th AOAC International Annual Meeting and Exposition, Montreal, Quebec, Canada, on September 13, 1998.

The Center for Veterinary Medicine (CVM) requires appropriate analytical test methods be provided as part of a New Animal Drug Application (NADA) for the approval of a Type A Medicated Article. The regulations covering medicated articles and feeds are provided in 21 CFR 558, NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS, and the GMP regulations are provided in 21 CFR 225 for MEDICATED FEEDS and 21 CFR 226 for TYPE A MEDICATED ARTICLES. The test methods to determine the concentration of the active ingredient in Type A Medicated Articles and Type C Medicated feeds are critical control procedures. These critical control test procedures are evaluated for completeness in written description, practicality and appropriateness. These methods are provided in Standard Operating Procedure (SOP) formats, which are more detailed than published procedures. The performance of the method must be supported by validation information that demonstrates the method can meet the appropriate criteria for recovery, precision, accuracy, linearity and specificity.

The sponsor releases the Type A Medicated Articles based on release specifications. Release specifications are needed to assess whether the product’s concentration or potency is within approved specified limits. The sponsor retains control and responsibility for the quality and accuracy of the results obtained from their testing facilities. However, Type C Medicated feeds are usually produced by feed mills from Type A Articles and are not routinely assayed before use. Some sponsors maintain Customer Service Laboratories, that will provide an analysis of medicated feeds. State feed laboratories assay medicated feed samples to check for agreement with the labeled concentration. Independent contract laboratories will also assay feed samples for customers.

Prior to approving new feed methods, CVM requires the sponsor to conduct additional testing of Type C Medicated feed methods because these test methods are used by testing laboratories not under the control of the sponsor. The analysts perform the analysis using the available test methods. In order to have well tested and validated medicated feed assay methods available, many Type C Medicated feed methods for new approvals undergo multi-laboratory evaluation to assure the practicality, transferability and performance of the method. This process is called a "method trial." At least three participating laboratories are needed, and include both contract and state feed laboratories. The method trial process assures that the instructions provided in the test method include sufficient detail so that a competent analyst can adequately perform the procedure based on the information provided in the method alone. The multi-laboratory evaluation is done to assure the transferability of the Type C Medicated feed methods. The evaluation of new alternate Type C Medicated feed methods for existing approved products requires similar information. However, the demonstration of transferability of new up-to-date test methods does not require a multi-laboratory evaluation. A one laboratory evaluation by an independent contract laboratory is sufficient. These methods are not considered confidential information and can be obtained from CVM. Alternately, the sponsor can choose to conduct an AOAC collaborative study.

A method validation report is submitted to CVM to begin the method evaluation process. The report provides a proposed detailed method description and the data to demonstrate the performance of the method. The evaluation criteria for Type C Medicated feed methods are the same whether the methods are submitted for an original approval or as new methods for existing approved Type A Medicated Articles. The evaluation criteria for the validation of the method are outlined below:

o Linear standard curve. Single point calibration techniques are acceptable only if the calibration curve is linear with an intercept close to zero.

o Recovery (Average). Eighty (80) to 110 percent of Labeled Concentration. The assay is tested at 50 percent of the lowest proposed concentration. Correction factors are usually unacceptable.

o Within Laboratory Coefficient of Variation. The results for replicate analysis, usually 5, feed matrix samples fortified at 1/2 and 1 times the lowest labeled concentration, and 1 and 2 times the highest labeled concentration. The results should give a Coefficient of Variation as a percent no greater that 5.0 percent for concentrations 10 ppm or greater, and no greater than 7.5 percent for concentrations less than 10 ppm.

o Background Interferences. Control feed matrix samples should have interferences equivalent to less than 10 percent of the lowest labeled concentration.

o Specificity. The effect (or non effect) of selected potential interfering substances. The response for the active ingredient should be clearly resolved from any other responses potentially present and should be readily distinguishable above the background signal.

o Proof of Recovery from Medicated Feed Samples. The recovery of the active ingredient from control feed matrix may not adequately reflect the performance of the method with medicated feed manufactured in commercial size mixers. The efficient isolation of the active ingredient from finished medicated feed samples should be demonstrated. Data are needed for the analysis of at least two commercial size batches; ideally one produced in a horizontal mixer and one produced in a vertical mixer. The batch size should be at least one-thousand pounds.

o Number of Samples per Day. Feed Laboratories have limited resources and a large workload. A reliable method that can process at least 7 to 10 individual samples in a day is desired.

o Ruggedness. The method should be rugged enough for routine use by reasonably experienced analysts. The method should not include a large number of critical steps. The number of individual operations necessary should be considered during method development, with all critical steps clearly identified.

o Practicality. The method should use the most common and reliable equipment, reagents, and materials. Unique or research instrumentation, large quantities of solvents, reagents, and supplies may render the method economically impractical for State Feed Laboratories.

o User Safety and Waste Disposal. The method should be developed with a consideration of worker safety and the disposal of hazardous chemicals. Chlorinated solvents should be avoided.

The current method trial process for new approvals consists of four stages. The first stage is the review and acceptance by the CVM of the method description and supporting performance data, and of the draft protocol for the laboratory evaluation. The second stage is the method demonstration at the laboratory designated by the sponsor. During the second stage, the method description and protocols for the laboratory evaluation are revised to address the observations and/or comments from participants. The third stage is an inter-laboratory testing of the method in each of the multiple participating laboratories. During the third stage, we request the sponsor to analyze the same sample set as analyzed by the participants. The fourth stage is the documentation of the trial. The documentation includes the submission of summary report prepared by the sponsor to which copies of the individual laboratory reports are attached. The report for the set of samples analyzed by the sponsor’s laboratory is included. If the data show the method can meet CVM performance criteria, the method is approved after the method description is evaluated and revised as needed based on the observations and comments of the participating analysts.

Many Type A Medicated Articles that were approved years ago no longer have test methods that can meet current standards. These methods often do not have adequate specificity and do not give an accurate estimation of the concentration of the active ingredient in the medicated matrix. For Type A Medicated Articles, the sponsor can submit and get approval for a more up-to-date test method by submitting a supplemental application for the test method. The test method must be in an SOP format supported by appropriate validation data, and include a bridging study to show the proposed test method performs as well or better than the approved test method. However, for Type C Medicated feed methods, additional supporting information is necessary. The transferability of the method must be demonstrated. Sponsors do not want to submit new up-to-date methods and also be required to undertake a multi-laboratory method trial. In addition, the sponsors are concerned about the possibility of having their current Type C Medicated feed assay limits as provided in 21 CFR 558.4 (d) re-evaluated.

Currently, we have two sponsors who have submitted new up-to-date Type C Medicated feed methods for existing products. Before the new methods were submitted, the sponsors contacted CVM’s Division of Manufacturing Technologies to discuss the approval requirements. The sponsors were concerned about the cost of a multi-laboratory evaluation and that CVM would re-evaluate the assay limits. However, CVM agreed not to re-evaluate the assay limits and to modify the requirements for transferability. These sponsors agreed to our proposal for a modified test of the transferability of the method. The method and supporting data would be evaluated for adequacy according to the criteria and procedure currently used in our method trial procedure. This is the same as stage 1 of the current method trial process. However, a multi-laboratory method trial would not be conducted. A one laboratory evaluation by an independent contract laboratory would be conducted by the sponsor with CVM’s agreement to the protocol. This combines stages 2 and 3 of our current process into one stage. In this process, the method demonstration would be optional. The third stage is the documentation stage, similar to the current stage 4. Any improvements in the test method should be discussed in the report prepared by the sponsor. In this way, the transferability of the method could be evaluated at a more reasonable cost to the sponsor. At this time, we are working with the two sponsors to develop the supporting data required and to provide more detailed SOPs that have all the instructions and information required.

Sponsors of older approved products have other options available to gain approval of improved test methods. The sponsor could choose to conduct an AOAC collaborative study through the AOAC or a multi-laboratory CVM method trial. However, with limited resources and a decline in participation by FDA field laboratories, sponsors are reluctant to expend the time or money required. We are testing the one laboratory evaluation approach to encourage sponsors to provide better test methods for Type C Medicated feed methods.

CELEBRATE NATIONAL PET WEEK IN MAY

National Pet Week is unique in that it focuses on the importance of the human-animal bond and responsible pet ownership. Growing public interest in how pets benefit humans is seen everywhere. In many cases, physicians are prescribing that patients spend time with pets to promote their own health and well-being. Pets can even lower blood pressure, and give patients a reason to live, taking their thoughts off their own problems as they care for a beloved pet.

CVM is proud to endorse this worthwhile campaign.

ANALYTICAL METHODS FOR THE DETERMINATION OF DIURETICS IN BOVINE MILK

by Badar Shaikh, Ph.D.

Diuretics are chemically heterogeneous compounds used as therapeutic agents in certain pathological conditions to eliminate bodily fluids. They not only promote renal excretion of water and salt but also affect the renal absorption and excretion of other ions, e.g., potassium, calcium, and magnesium. The diuretics, due to their variety of chemical structures, have different pharmacological properties and accordingly are classified into four groups: carbonic anhydrase inhibitors, loop, thiazide and thiazide type, and potassium sparing diuretics. The carbonic anhydrase inhibitors, e.g., acetazolamide, decrease the conversion of bicarbonate ion to carbonic acid resulting in an increase in sodium, potassium, and bicarbonate renal excretion. This also increases the pH of the urine. Furosemide has been reported to be the most potent and short-acting loop diuretic. It is widely used to treat edematous states of hepatic, cardiac, and renal origin. It is also a common drug of abuse in livestock shows since it reduces tissue water resulting in improved muscle tone appearance. The thiazide diuretics, chlorothiazide (CTZ), hydrochlorothiazide (HCTZ), and trichlormethiazide (TCMTZ) increase the excretion of potassium and can cause hypokalemia during long-term maintenance therapy. Therefore, thiazides are often given with potassium sparing diuretics such as amloride, in order to maintain electrolyte balance in the body. Trichlormethiazide is given in combination with dexamethasone. The combined diuretic activity of TCMTZ and the specific anti-inflammatory activity of dexamethasone are complementary in the reduction of physiological parturient edema of the mammary gland and associated structures. Because the two drugs are complementary in their action, effects are achieved with a minimum dosage of TCMTZ. The clinically determined saluretic potency of TCMTZ is estimated to be 10-20 times that of HCTZ and 100-200 times that of CTZ, resulting in a decrease in the incidences of hypokalemic manifestation (ref. 1). Diuretic toxic effects include bone marrow depression, altered carbohydrate metabolism, and elevated levels of urea, uric acid and sugar.

Furosemide and thiazide diuretics, CTZ, HCTZ, and TCMTZ are approved for use in dairy cattle for the treatment of post-parturient edema of the mammary gland and associated structures (ref. 2). Furosemide is also a common drug of abuse in livestock shows since it reduces tissue water resulting in improved muscle tone. The unauthorized use of these diuretics, or the failure to follow label directions for approved use in cattle, could lead to unacceptable residues in meat or milk destined for human consumption. Therefore, monitoring of the residues of these diuretic drugs in food is part of a general policy to prevent unapproved uses of diuretics. While there are no official tolerances for these drugs in milk, CVM has tentatively established the safe levels for furosemide, CTZ, HCTZ, and TCMTZ to be 10, 67, 67, and 7 ppb, respectively. The withdrawal time for furosemide is 48 hours and 72 hours for CTZ and HCTZ (ref. 2). Although not listed in the Code of Federal Regulations, the withdrawal time for TCMTZ is considered to be 72 hours, similar to other thiazides (ref. 3).

Accurate, precise and sensitive analytical methods for the determination of diuretics, furosemide, HCTZ, CTZ, and TCMTZ, in bovine milk were developed. These methods are specific and distinguish these compounds from each other and from other diuretics, drugs, and antibiotics used in dairy cattle. The diuretics were isolated from milk employing liquid-liquid extraction and cleanup procedures, followed by quantitative determination by high performance liquid chromatography using fluorescence (furosemide) and ultraviolet (UV) absorption detectors (thiazides). The initial procedure to remove the fat from the milk for the four diuretics was the same. It involved centrifugation of an aliquot of milk in a centrifuge set at 4 ⁰C followed by removal of the top fat layer or bottom skim milk. Further cleanup of milk for furosemide was less rigorous than for the other three thiazides. This is because furosemide is naturally fluorescent, while most endogenous interfering compounds in milk do not fluoresce.

For furosemide, the defatted milk was further deproteinated by mixing with acetonitrile and centrifugation. The supernatant was evaporated to remove acetonitrile and the remaining aqueous layer was directly analyzed by HPLC. The HPLC conditions included a reversed phase silicon column, a fluorescence detector set at 272 and 410 nm excitation and emission wavelengths, respectively, and an isocratic mobile phase of 30% acetonitrile in 0.01-M phosphate buffer, pH3 (ref. 4). The average recovery of furosemide at fortification levels of 5-20 ppb was 95% with 9% coefficient of variation (CV), reflecting good accuracy and precision. Furosemide incurred milk samples obtained from a cow administered intravenously with a single dose of 500-mg furosemide was analyzed to validate the overall method. Furosemide concentration in 8 and 24-hour post-dose milk samples were determined to be 150 and 5 ppb, respectively. No furosemide was detected in 32 and 48-hour milk samples.

For the three thiazides, the defatted milk was further treated with 5% lead acetate and acetonitrile. The sample was vortex mixed and centrifuged. The supernatant was removed and ethylacetate was added, mixed and centrifuged to separate the layers. The organic layer was removed and 10% sodium tungstate solution was added, vortex mixed and centrifuged again. The upper organic layer was removed and evaporated to dryness with nitrogen. The resulting residue was reconstituted in mobile phase and an aliquot injected into the HPLC column. The HPLC conditions included reversed phase polymer column, UV detector set at 225 nm, and a mobile phase mixture consisting of acetonitrile (ACN), tetrahydrofuron (THF), and 0.05 M phosphate buffer, pH 3. The thiazides, CTZ and HCTZ are more polar than TCMTZ and required less organic modifier in the mobile phase for their elution from the HPLC column. However, the lower percentage of organic solvent increased the retention of TCMTZ on the HPLC column. Therefore, two isocratic mobile phases, 14% ACN:THF (1:1) in 0.05M phosphate buffer for CTZ and HCTZ; and 30% ACN:THF (2:1) in 0.05 M potassium phosphate buffer, pH3, for TCMTZ were used for their analysis in the milk. Although a gradient mobile phase, consisting of ACN/buffer resolved the three thiazides, the addition of THF was essential to resolve CTZ from the endogenous interfering compounds in milk. However, the three phase mobile phase caused increased baseline shift during the gradient run, therefore, the use of gradient was abandoned. The average recoveries for CTZ and HCTZ at fortification levels of 35-140 ppb were 97 and 89%, respectively, with corresponding average CV’s of 6 and 5% (ref. 5). The average recovery for TCMTZ at fortification levels of 7-140 ppb was 101% with 13% CV (ref. 6). These recoveries and CV’s reflect good accuracy and precision for the overall method. Thiazide incurred milk samples obtained from cows treated with therapeutic doses (ref. 2) of the thiazides were analyzed to validate the overall methods. Both the HCTZ and TCMTZ were detected only in 8-hour post-dose milk samples at concentrations of 47 and 6 ppb, respectively. Chlorothiazide concentrations in 8, 24, and 32-hour post-dose samples were determined to be 430, 86, and 22 ppb.

The development of the above analytical methods allows for the first time the monitoring of residue levels of diuretics, furosemide, CTZ, HCTZ, and TCMTZ in bovine milk. These diuretics are approved for use in dairy cattle. The methods are accurate, precise, sensitive and specific enough to distinguish these compounds from each other, and other drugs and antibiotics used in dairy cattle. Additionally, the methods are simple, fast, and can be adopted easily in most laboratories, including state regulatory laboratories. These methods were applied to detect their concentrations in incurred milk collected from cows treated with therapeutic doses of these diuretics. The preliminary results suggest that these diuretics are rapidly depleted from cows, well before their withdrawal times. However, it must be noted that these data reflect the results from a single cow for each diuretic, and may not represent the rate of depletion from dairy cattle in general. A detailed study to ascertain the withdrawal time of furosemide, using a larger number of cows, is being undertaken to confirm the above preliminary results.

References

Veterinary Pharmaceuticals and Biologicals, 8^th ed., Veterinary Publishing Company, Lenexa, KS, USA, 1993/1994, p. 601.

Code of Federal Regulations , Food and Drugs, parts 520.420, 520.1010b, and 522.1150, U.S. GPO: Washington, DC, 1997.

Talbot, R.B., Fernandez, A.H., Melendez, L.V. (Eds.), List of FDA Approved Animal Products, Laboratory of Veterinary Medical Informatics, Information Series 87-1, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, 1987, 2.47.

Shaikh, B., Development and validation of a liquid chromatographic method for the determination of furosemide, a diuretic, in bovine milk. J. Agric. Food Chem. 1995, 43, 2117-2121.

Shaikh, B. and Rummel, N. Liquid chromatographic determination of chlorothiazide and hydrochlorothiazide diuretic drugs in bovine milk. J. Agric. Food Chem. 1998, 46, 1039-1043.

Shaikh, B. and Rummel, N. Determination of trichlormethiazide in bovine milk by high performance liquid chromatography. J. Chromatogr. B., 1998, 709, 137-143.

The author was CVM’s 1998 nominee for the FDA Excellence in Analytical Science Award

FINALIZED MINOR USES/MINOR SPECIES GUIDANCE AVAILABLE

The Food and Drug Administration has finalized guidance entitled "Guidance for Industry -- FDA Approval of Animal Drugs for Minor Uses and Minor Species." This guidance document (number 61), supersedes Guideline 26, "Guidelines for the Preparation of Data to Satisfy the Requirements of Section 512 of the Act Regarding Minor Use of Animal Drugs."

The purpose of this document is to provide specific guidance on the means for generating effectiveness and safety data to support the approval of minor use animal drugs. A minor animal drug use is defined as use in a minor species or use in any animal species for a condition that is rare or that occurs in limited geographic areas. Minor species are defined by exclusion, as any species other than major species. Major species are defined as cattle, swine, chickens, turkeys, horses, dogs, and cats. According to current regulations, sheep are a minor species except with respect to human food safety data collection requirements, for which sheep are considered major species. Other guidance addresses issues related to exotic and wildlife species.

This document represents the Agency's current thinking on drug approval for minor uses and minor species. It does not create or confer any rights for or on any person and does not operate to bind the FDA or public. An alternative approval may be used if such approach satisfies the requirements or the applicable statute, regulations, or both.

A copy of this guidance document may also be obtained by calling or writing the FDA Veterinarian.

Questions on this document may be directed to Dr. Meg Oeller, FDA/Center for Veterinary Medicine, HFV-130, 7500 Standish Place, Rockville, MD 20855, 301-827-7581 (mailto:moeller@cvm.fda.gov).

UPDATED NCIE ELECTRONIC SUBMISSION GUIDANCE AVAILABLE

This guidance, entitled "Guidance for Industry: Submitting a Notice of Claimed Investigational Exemption in Electronic Format to the Center for Veterinary Medicine via E-Mail," (guidance #59) updates an earlier guidance dated June 16, 1997. Starting September 8, 1997, CVM conducted a pilot program to determine the practicality of electronic submission and review as an alternative to the paper-based processes used in the past. The pilot project was conducted for six months and then extended until March 10, 1999, to allow for finalization of procedures. The current guidance document is based on the Center's and participating animal drug industry's experiences in the pilot project and incorporates those procedures into NCIEs electronic submission. It presents the procedures necessary for electronic NCIEs submitted to the Center to be accepted as the official original document.

The CVM standardized NCIE form, Form FDA 3458 (1/98), may be submitted via either electronic transmission or hard copy.

Copies of this guidance document and form may also be obtained by calling or writing the FDA Veterinarian.

NEW VMAC CHAIRMAN

Keith E. Sterner, D.V.M. has succeeded Dr. Donald Lein as the chairman of the Food and Drug Administration's (FDA's) Veterinary Medicine Advisory Committee (VMAC). Dr. Sterner presided over the VMAC meeting held January 25-26, 1999.

Dr. Sterner is a graduate of Michigan State University. He is co-owner of a mixed animal practice in Ionia, Michigan, treating mainly food animals. Dr. Sterner has been a member of VMAC since 1997 where he has represented the large animal specialty. He is a member of the American Veterinary Medical Association, the American Association of Bovine Practitioners, the National Mastitis Council, and the United States Animal Health Association, and other organizations. Dr. Sterner is past president, American Association of Bovine Practitioners; past president, National Mastitis Council; member, AVMA Task Force on Responsible Antimicrobial Use; vice chair, AVMA Council on Education; and past member, AVMA Drug Availability Committee. In 1991, the American Association of Bovine Practitioners honored Dr. Sterner as "Bovine Practitioner of the Year", and Michigan State University College of Veterinary Medicine presented him with the Distinguished Alumnus Award.

VETERINARIAN SENTENCED IN ANIMAL DRUG SMUGGLING CASE

Dr. Jerry M. Bonham, a veterinarian from Cordell, Oklahoma, was sentenced to eight months in Federal prison for conspiring to buy more than $64,000 in illegal animal drugs knowing they had been smuggled into the United States. Dr. Bonham owns the Bonham Cattle Company and the Cordell Animal Hospital in Cordell, Oklahoma.

Dr. Bonham pled guilty and was sentenced on Wednesday, December 16, 1998, by the Honorable Robin Cauthron in U.S. District Court in Oklahoma City. He was also fined $15,000, ordered to pay a $50 special assessment, and will be placed on two years supervised release after his prison term ends. Dr. Bonham was ordered to voluntarily report to the U.S. Bureau of Prisons to begin serving his sentence by noon, January 19, 1999. In addition, the Oklahoma Board of Veterinary Medical Examiners scheduled a hearing to review Dr. Bonham's veterinary license.

Dr. Bonham admitted that between at least 1988 and 1994 he purchased more than 1,000 bottles of Clenbuterol from a Canadian veterinarian and resold it to his veterinary customers so they could use it to illegally enhance the muscle mass of their lambs and cattle entered in various livestock shows. Dr. Bonham's actions posed a danger to the food supply because many of the animals entered in livestock shows are slaughtered for food.

Clenbuterol, which belongs to the family of compounds called Beta-agonists, has never been approved for use in food animals in the U.S. In Europe, human illness was associated with consumption of meat containing Clenbuterol residue. Symptoms from ingesting Clenbuterol-contaminated meat can include increased heart rate, muscular tremors, headache, dizziness, nausea, fever, and chills. Concerns over the abuse of Clenbuterol in food animals in the U.S. have led to strict enforcement against illegal sales and use.

Last May, FDA approved Ventipulmin® Syrup, which contains a small amount of Clenbuterol, as a restricted use prescription-only drug for treating horses affected with airway obstruction. When FDA approved Ventipulmin® , several controls were put in place to ensure that this drug would not be misused in food-producing animals.

Judge Cauthron said her sentence was designed to punish Dr. Bonham for threatening the food supply, abusing his veterinary license, and refusing to cooperate with the government in discovering the names of all those to whom he sold the drug. "I think what you have done is a very serious offense, both against the laws of the United States and against its people," Cauthron said. "I think that in order to provide the example to the public . . . it is necessary that you go to prison." She also said "I cannot forget what you have done to children, or young people who are out there legitimately trying to learn how to do things and how to do them right, and they have been taught a very wrong thing by your activities in this case."

Dr. Bonham's conviction follows an investigation by agents of the Food and Drug Administration's Office of Criminal Investigations and the U.S. Customs Service, which began their joint probe after six prize winning animals at the 1994 Tulsa State Fair tested positive for Clenbuterol. The case was prosecuted by the Justice Department's Office of Consumer Litigation.

ANNUAL MID-ATLANTIC CONFERENCE FOR BOVINE PRACTITIONERS

The pre-registration deadline is March 20, 1999, however, registration will be accepted at the door for one or both days. Cost (including meals) is $140 for both days, or $80 for one day. Veterinary students or technicians may attend at half price. Spouses are admitted free, but must pay for meals. The course is cosponsored by the Maryland Veterinary Medical Association, the Maryland Department of Agriculture, the American Association of Bovine Practitioners, District II, the Western Maryland Veterinary Medical Association, the Pennsylvania State University, and the Virginia-Maryland Regional College of Veterinary Medicine. For further information, please contact the MVMA office at (888) 884-6862.

CONSENT DECREE ENTERED IN ANIMAL DRUG COMPOUNDING CASE

Also under the Consent Decree, Mortar & Pestle's President, Stan Henderson, and Owner, Meri C. Russell, agreed not to engage in the business of manufacturing, processing, packing, or labeling drugs unless and until they register as a drug establishment and adopt and implement procedures adequate to ensure that their operations fully comply in all respects with good manufacturing practice, the Federal Food, Drug, and Cosmetic Act (the Act), and FDA regulations. In addition, Mr. Henderson and Ms. Russell agreed that they would not re-enter the business of compounding drugs unless and until they adopt and implement procedures adequate to ensure that their operations fully comply in all respects with FDA guidance regarding the compounding of drugs, the Act, and FDA regulations.

The government initiated this seizure action because Mortar & Pestle was not compounding animal drugs in compliance with the law and FDA's guidance and, therefore, the drugs were adulterated, misbranded, and unapproved under the Act. In 1996, FDA published a Compliance Policy Guide (CPG) outlining the criteria and boundaries for the compounding of animal drugs. This CPG states that FDA recognizes that circumstances exist when it may be necessary for a veterinarian to compound, or direct a pharmacist to compound an article that will result in an unapproved new animal drug. The Agency will exercise its regulatory discretion and ordinarily will not take regulatory action against violations of the Act resulting from the compounding of an unapproved new animal drug if the criteria described in the CPG are met. However, Mortar & Pestle was not following the stipulations in the CPG.

FDA urges any pharmacy that wishes to compound animal drugs to become thoroughly familiar with the CPG 608.400, "Compounding of Drugs for Use in Animals." Copies of this CPG may be obtained by calling or writing CVM's Communications Staff at FDA/Center for Veterinary Medicine, HFV-12, 7500 Standish Place, Rockville, MD 20855, 301-594-1755. Send one self-addressed adhesive label to assist in processing your request.

REGULATORY ACTIVITIES

• Rodney and Patricia Loomis, Mercer Livestock Auction, Inc., Mercer, PA
• Janet M. Slegers, Aspen Dairy, Chino, CA
• Ruby J. McNichol, McNichol's Dead and Crippled Livestock, Portersville, PA
• Andrew Stutzman, Kidron, OH
• Sam Knevelbaard, Knevelbaard Dairies, Corona, CA
• Marvin J. Lynn, Chippewa Falls, WI
• Manuel Zermeno, Pinecrest Jersey Farm, Oakdale, CA
• Sybrand Vander Dussen, Syann Dairy, Corona, CA
• John D. Mello, J.D. Mello Dairy, Hanford, CA
• Louis Da Rosa, Da Rosa and Son Dairy, Turlock, CA
• Loren Duescher, Duescher Hilltop Jerseys, Kewaunee, WI
• Chris M. Mellott, Mercersburg, PA
  

These violations involved illegal residues of penicillin in cows, sulfadimethoxine in dairy cows, streptomycin in a calf, gentamicin in a culled dairy cow, tetracycline in a dairy cow, gentamicin and sulfamethoxazole in a calf, and erythromycin in a cow.

Warning letters were also sent to the following firms/individuals which had a history of offering animals for sale for human food use which were adulterated with drug residues. These warning letters stated that these individuals/firms had offered animals for slaughter that contained illegal drug residues:

• Robert Weikert, Weikert's Livestock, Inc., Fairfield, PA
• Manuel Carmo, Carmo Dairy, Elk Grove, CA

These violations involved illegal residues of gentamicin, penicillin, neomycin, and sulfadimethoxine in cows.

NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Boehringer Ingelheim Vetmedica, Inc. (NADA 141-002)	Oxytetracycline Hydrochloride	Beef and Dairy calves. For control and treatment of oxytetracycline sensitive diseases, bacterial enteritis, and bacterial pneumonia.	ORAL: The NADA provides for use of 500 and 1000 milligram calf boluses to control and treat bacterial diseases caused by organisms sensitive to oxytetracycline, bacterial enteritis caused by Salmonella typhimurium and Escherichia coli, and bacterial pneumonia caused by Pasteurella multocida. Federal Register: 12/21/98.
Novartis Animal Health US, Inc. (NADA 141-120)	Clomipramine Hydrochloride (ClomicalmTM) Rx	Dogs. To be used as a part of a comprehensive behavioral management program to treat separation anxiety in dogs greater than6 months of age.	ORAL: The NADA provides for administration of tablets as a single daily dose or divided twice daily to dogs greater than 6 months of age at 0.9 to 1.8 mg per pound per day. Federal Register:1/12/99.
Elanco Animal Health, Division of Eli Lilly & Co. (NADA 140-926)	Narasin/Nicarbazin and Bacitracin Methylene Disalicylate (Maxiban®, BMD® )	Broiler chickens. For prevention of certain forms of coccidiosis and for increased rate of weight gain and improved feed efficiency.	MEDICATED FEED: The NADA provides for combining approved Narasin/nicarbazin (1:1 fixed ratio) and BMD® Type A medicated articles to make combination Drug Type C medicated broiler chicken feeds for prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E.acervulnia, E. maxima, E. brunetti, and E. mivati, and for increased rate of weight gain and improved feed efficiency. This NADA requires manufacture in a licensed feed mill. Federal Register:02/02/99.

ABBREVIATED NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Alpharma Inc. (ANADA 200-263)	Chlortetracycline and Monensin Sodium (ChlorMaxTM,Coban® )	Broiler Chickens. Used as an aid in the reduction of mortality due to E. coli infections susceptible to such treatments and as an aid in the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati.	MEDICATED FEED: The ANADA is a generic copy of Roche Vitamins, Inc.'s NADA 121-553. (Aureomycin-Coban). Federal Register: 12/21/98

SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Pfizer, Inc. (NADA 141-061)	Doramectin (Dectomax®)	Cattle. For added subcutaneous and intramuscular use to control infections and to protect from reinfection with C. oncophora for 14 days and O. radiatum for 28 days after treatment.	SUBCUTANEOUS AND INTRAMUSCULAR: The supplement provides a new persistent use which is in addition to the currently approved use in cattle for treatment and control of various gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice and mangemites, and to control infections and to protect from reinfection with O. osteragi for 21 days and C. punctata and D.viviparus for 28 days. In addition, a tolerance for doramectin and its residues in cattle muscle is established and an ADI is codified. Federal Register: 12/10/98.

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