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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 128-070 VALBAZEN® - original approval

I. GENERAL INFORMATION

NADA128-070
Sponsor:SmithKline Animal Health Products
Division of SmithKline Beckman Corporation
1600 Paoli Pike
West Chester, PA 19380
 
Generic Name:Albendazole
Trade Name:VALBAZEN®
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE

Cattle anthelmintic for the removal and control of the following endoparasites and infecting cattle:

  1. Liver flukes:Fasciola hepatica (adults)
  2. Tapeworms:Moniezia benedeni, M. expansa (heads and segments)
  3. Lungworms:Dictyocaulus viviparus (adults and 4th stage larvae)
  4. Stomach worms:
    Barberpole worm: Haemonchus contortus, H. placei (adults and 4th stage larvae)
    Brown stomach worm: Ostertagia ostertagi (adults, 4th stage larvae and 4th stage inhibited larvae)
    Small stomach worm: Trichostrongylus axei (adults and 4th stage larvae)
  5. Intestinal worms:
    Hookworm: Bunostomum phlebotomum (adults)
    Threadnecked intestinal worm: Nematodirus spathiger, N. helvetianus (adults and 4th stage larvae)
    Small intestinal worm: Cooperia oncophora, C. punctata (adults and 4th stage larvae)
    Bankrupt worm: T. colubriformis (adults)
    Nodular worm: Oesophagostomum radiatum (adults)

 

III. DOSAGE

A.DOSAGE FORM30% Paste (300 mg/g)
B.ROUTE OF ADMINISTRATIONOral
C.RECOMMENDED DOSAGES:Ten (10) mg of albendazole per kg of body weight (4.54 mg/lb) administered orally with a dispensing gun.

IV. EFFECTIVENESS

This NADA relies on adequate well-controlled studies demonstrating the anthelmintic effectiveness of albendazole in cattle included in the approved NADA 110-048 (Albendazole Suspension, 54 FR 25114, June 13, 1989). Based on dose titration data against F. hepatica contained in NADA 110-048, an optimum effective dose of 10 mg albendazole per kg body weight was determined. The present NADA relies on a trial conducted in cattle which demonstrates that the paste formulation has efficacy comparable to albendazole suspension when used at the same dose of 10 mg/kg body weight. This trial tested the efficacy against the most difficult parasite control; viz, F. hepatica, and it was demonstrated that the paste formulation was as effective as the suspension with respect to F. hepatica and the other parasites indicated on the labeling. This conclusion is further supported by a number of confirmatory studies which corroborate the efficacy against the other parasites.

A. Pivotal Efficacy

The following study was conducted to demonstrate that the paste formulation has similar biological efficacy to that of albendazole suspension when used at the same dose of 10 mg/kg body weight. F. hepatica was chosen as the test species since this is the most difficult parasite to control.

Formulation Comparison Study
W. J. Foreyt
Washington State University
Pullman, Washington
Study AX-5059
This trial was designed to compare a single oral dose of 10 mg/kg of albendazole in the paste formulation to the drench suspension. Thirty cattle from a fluke enzootic area in southern Idaho were selected based on the presence of fluke eggs in their feces. The cattle were divided into three groups of ten animals each. One group remained untreated and served as a control. The other groups were given either albendazole suspension or paste formulation as a single oral dose of 10 mg/kg. At necropsy, 37 to 38 days following treatment, the percent removal of the worms was recorded and is given below. No adverse reaction was observed.

% Removal

ParasitePasteSuspension
F. hepatica9987

B. Efficacy-Confirmation

The results from the above trial supported the conclusion that albendazole paste formulation, when given orally to cattle at 10 mg/kg body weight, has efficacy comparable to albendazole suspension against liver flukes. Additional support of the efficacy of albendazole paste formulation against adult and larval stages of gastrointestinal roundworms, lungworms, and tapeworms was ascertained by four investigators in seven controlled trials. Infections were acquired naturally in two of the trials and were experimentally induced in the remaining five trials. All of the cattle were necropsied at 6 to 14 days after treatment, and parasites were recovered and counted.

The investigator and efficacy against individual parasitic species are given in the following table.

Table 1 SUMMARY OF CONTROLLED EFFICACY STUDIES - PASTE FORMULATION

ParasiteNo. of Animals ControlNo. of Animals Treated% Removal (Range)Investigator
M. benedeni 7.5 mg/kg1010100Ciordia,Todd
D. viviparus 7.5 mg/kg303297 - 99Benz, Todd, Theodorides
H. contortus 7.5 mg/kg182093 - 98Todd
O. ostertagi 7.5 mg/kg283098 - 100Benz, Todd
T. axei 7.5 mg/kg283093 - 99Benz, Todd
T. colubriformis 7.5 mg/kg202099Benz, Todd
C. oncophora 7.5 mg/kg283099 - 100Benz, Todd
C. punctata 7.5 mg/kg101099Benz
N. helvetianus 7.5 mg/kg101097Todd
Oe. radiatum 7.5 mg/kg182099 - 100Benz, Todd

Location of Investigators in Table 1

  • Dr. G. Benz, Auburn, AL
  • Dr. H. Ciordia, Experiment, GA
  • Dr. V. Theodorides, W. Chester, PA
  • Dr. A. Todd, Madison, WI

C. Clinical Field Trials

Well-documented clinical studies were conducted in the United States according to an approved protocol which was modified to accommodate the parasite(s) of interest and local management conditions. Groups of cattle with at least a moderate worm infection, as determined by egg counts in their feces, were selected. Approximately the same numbers of animals were treated with albendazole or left untreated, as controls. Worm eggs in fecal samples were counted before and after treatment, and animals were visually observed for side effects. In two studies, the severity of the parasitic infection precluded leaving some of the animals untreated to serve as controls; therefore, in these two cases the entire group of infected cattle was treated.

Thirteen trials were conducted by eight investigators using albendazole paste formulation in nine states. Cattle of various breeds were treated and compared to untreated controls. Investigators, trial locations and numbers of animals in the trials are tabulated on the following pages. The results of these clinical field trials confirm the results of the controlled studies indicating elimination or reduction of fecal egg counts in virtually all treated cattle. The paste formulation at dosage levels ranging from 7.5 to 15 mg/kg was found to be safe and practical under field conditions.

Clinical field trials conducted by foreign investigators were also submitted. They confirm further the efficacy of albendazole against a broad spectrum of gastrointestinal roundworm, lungworm, tapeworm and liver fluke infections in cattle.

CLINICAL FIELD TRIALS WITH ALBENDAZOLE PASTE IN CATTLE LIVER FLUKES (15 MG/KG) - United States

Study #Investigator/LocationTotal No. of AnimalsNo. of TreatedNo. with Fluke eggs Before/After TreatmentNo. of ControlsNo. with Fluke eggs Before/After Treatment
AP-309Dr. D.S. Dennis
Roosevelt, UT
593019/82917/22
AP-331Dr. J. B. Malone
Baton Rouge, LA
1497519/37426/19
AP-5015Dr. R. B. Wescott
Pullman, WA
937357/212015/13
Study #Investigator/LocationTotal No. of AnimalsNo. of TreatedNo. with Tapeworm eggs Before/After TreatmentNo. of ControlsNo. with Tapeworm eggs Before/After Treatment
AP-345Dr. R. B. Wescott
Pullman, WA
494930/00 
AP-288Dr. A. D. Kelly
Plainville, KS
333333/00 
AP-311Dr. H. E. Jordan
Stillwater, OK
1216619/15513/13

CLINICAL FIELD TRIALS WITH ALBENDAZOLE PASTE IN CATTLE LUNGWORMS (7.5 MG/KG) -

Study #Investigator/LocationTotal No. of AnimalsNo. of TreatedNo. with Lungworm Larvae Before/After TreatmentNo. of ControlsNo. with Lungworm Larvae Before/After Treatment
AP-292Dr. J. J. Sheldon
Casa Grande, AZ
1005021/05020/4
AP-314Dr. J. J. Sheldon
Texarkana, TX
168847/18414/9
AP-345Dr. R. B. Wescott
Pullman, WA
494927/20 

CLINICAL FIELD TRIALS WITH ALBENDAZOLE PASTE IN CATTLE GASTROINTESTINAL NEMATODES (7.5 MG/KG) - United States

Study #Investigator/LocationTotal No. of AnimalsNo. of TreatedNo. with Nematode eggs Before/After TreatmentNo. of ControlsNo. with Nematode eggs Before/After Treatment
AP-285Dr. W. J. Foreyt
Stillwater, OK
995050/14949/49
AP-290Dr. K. S. Todd, Jr.
Urbana, IL
703526/03531/28
AP-292Dr. J. J. Sheldon
Casa Grande, AZ
1005046/05040/45
AP-296Dr. H. E. Jordan
Stillwater, OK
502524/32522/21
AP-308Dr. H. E. Jordan
Stillwater, OK
783933/43933/33
AP-311Dr. H. E. Jordan
Stillwater, OK
1216664/105550/51
AP-314Dr. J. J. Sheldon
Casa Grande, AZ
1688464/28462/66
AP-345Dr. R. B. Wescott
Pullman, WA
494947/00 
AP-5015*Dr. R. B. Wescott
Pullman, WA
937365/352015/19
AP-5058*Dr. J. B. Malone
Baton Rouge, LA
21118/3108/5

* 15 mg/kg

 

V. ANIMAL SAFETY

This NADA relies on safety studies that are included in approved NADA 110-048 (albendazole suspension, 54 FR 25114, June 13, 1989), and these studies indicated the maximum tolerated dose in cattle is 45 mg/kg; (i.e., 4.5 times the highest recommended therapeutic dose).

At doses higher that 45 mg/kg, toxic symptoms were: decreased activity and anorexia followed by severe watery diarrhea and in some cases, death. Pathologic changes consisted of fibrinous peritonitis and ascites, hydrothorax and acute pleuritis, congestion of the abomasum and acute enteritis.

No overt adverse reactions were observed in any of the efficacy or clinical field trials conducted with albendazole paste formulation (with doses ranging form 7.5 to 15 mg/kg) in cattle.

 

VI. HUMAN SAFETY

A. Safe Concentration for Albendazole Residues

The safe concentrations for total albendazole residues in the uncooked edible tissues of cattle were established based upon toxicity studies submitted under NADA 110-048. Those values are: 0.6 ppm in muscle, 1.2 ppm in liver, 1.8 ppm in kidney, and 2.4 ppm in fat.

B. Marker Residue, Target Tissue, and Rm (Tolerance) for Albendazole in Cattle

The residue and metabolism studies by which the marker residue and target tissue for albendazole were selected were conducted under NADA 110-048. That work led to the assignment of cattle liver as the target tissue and the 2-aminosulfone metabolite as the marker residue. The data also showed that, when total albendazole residues have depleted to the 1.2 ppm safe concentration in liver, the level of the 2-aminosulfone metabolite in that tissue is approximately 0.2 ppm. On that basis, the tolerance (Rm) in liver was set at 0.2 ppm.

C. Regulatory Methods for Residues

A regulatory method for the determination of the albendazole marker residues was developed under NADA 110-048. The determinative procedure is based on the measurement of the 2-aminosulfone metabolite by high performance liquid chromatography with fluorescence detection. The presence of the marker residue can be confirmed by a procedure using mass spectrometry.

The determinative and confirmatory procedures for albendazole are on display in the FDA's Freedom of Information Public Room (Room 12A-30, 5600 Fishers Lane, Rockville, MD 20857).

D. Marker Residue Depletion Study and Calculation of a Withdrawal Time

Under NADA 110-048, the sponsor established the intent to have a single withdrawal time for the various dosage forms of albendazole being developed. Twenty seven days was assigned as that withdrawal time as it was the longest of the withdrawal times determined in residue depletion studies with the individual dosage forms.

The residue depletion study with the paste formulation was conducted under this NADA in order to determine the time required for residues of the paste formulation to deplete to or below the 0.2 ppm tolerance. The study used 32 head of beef cattle, each of which received a single oral 10 mg/kg body weight dose of the albendazole paste formulation. The cattle were euthanized in groups of eight (four heifers and four steers per group) at 20, 24, 28 or 32 days post dosing.

The livers were collected at the time of slaughter and were assayed for the marker residue (the 2-aminosulfone metabolite) using the determinative procedure of the regulatory assay. The results are presented in the following table.

Residue Levels (ppb) of the Albendazole Marker Residue in the Livers of Cattle Following a 10 mg/kg Dose of the Paste Formulation of Albendazole

Days Post Dosing

 20242832
Number of Animals8888
Average ppb148 (±22)100 (±20)80.7(±16)63.5 (±7.8)

A statistical analysis of the depletion data using the upper tolerance limit containing a 99 percentile of the population with 95% confidence limits yielded a withdrawal time of 24 days. A withdrawal time of 27 days is used for labeling purposes with the paste formulation in order to have a single common withdrawal time for all of the oral dosage forms of albendazole.

E. Safety to Handler

Under NADA 110-048, studies were conducted which demonstrated that the drug would have no ill effects on persons handling it if the drug were used according to label recommendations.

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA satisfy the requirements of section 512 of the act and demonstrate that albendazole paste, when used under its proposed conditions of use, is safe and effective.

This albendazole paste provides for the same indications for use, drug dosage level and duration, and same class(es) of cattle as the albendazole suspension, NADA 110-048, approved on June 13, 1989 (54 FR 25114).

Based on work conducted under NADA 110-048, the safe concentration for albendazole residues, the marker residue, target tissue, Rm (tolerance) and approved analytical method were all established. For this albendazole paste, a residue depletion study in the target tissue liver following the labeled dosage of a single oral dose of 10 mg/kg using the approved analytical method demonstrated that the marker residue was well below the established limit in less time than the 27 day withdrawal set for the albendazole suspension. However, for consistency, both the albendazole paste and suspension bear the 27 day withdrawal.

The agency concludes that adequate directions for use by the laity have been written for the proposed over the counter use of this anthelmintic which is indicated for the removal and control of parasites commonly occurring in cattle, the same as the recently approved albendazole suspension that is marketed over the counter.

 

VIII. LABELING (Attached)

1. Cartridge label

Copies of applicable labels may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.