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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 139-858 TRAMISOL; X-TRA - original approval

Approval Date: June 16, 1988

I. GENERAL INFORMATION:

NADA139-858
Sponsor:American Cyanamid Company
Agricultural Division
Wayne, New Jersey 07470
Generic Name:levamisole resinate and famphur
Trade Name:TRAMISOL; X-TRA
Marketing Status:Over the Counter (OTC)
Description:The efficacy and safety of existing oral dosage forms of levamisole and famphur for cattle have been proven in NADAs 34-266, 39-356, 39-357, 44-015 and 126-237. This summary contains new data pertaining to the safety and effectiveness of an alternate dosage form of each of these two drugs when administered as a combination levamisole resinate/famphur paste via an oral dispensing device. All dose titration, dose confirmation, safety, bioavailability and residue depletion studies are summarized in this outline.

II. INDICATIONS FOR USE

For treatment of cattle infected with the following parasites:

  • STOMACH WORMS: Haemonchus, Trichostrongylus, Ostertagia
  • INTESTINAL WORMS: Trichostrongylus, Cooperia, Nematodirus, Bunostomum, Oesophagostomum
  • LUNGWORMS: Dictyocaulus
  • BITING LICE: Bovicola
  • SUCKING LICE: Linognathus, Solenoptes

It is not effective against lice eggs.

III. DOSAGE FORM

TRAMISOL X-TRA Combination Paste contains levamisole resinate (50%) and famphur as active ingredients packed in a polyethylene cartridge-type container. TRAMISOL X-TRA is formulated to provide 8 mg/kg (3.6 mg/lb) of body weight of levamisole HCl equivalent activity and 30 mg/kg (13.6 mg/lb) of body weight of famphur activity which has been demonstrated to be the optimum dose level for effective performance the product's anthelmintic and ectoparasitic label claims.

TRAMISOL X-TRA is administered to cattle in individual oral doses using the compatible GelGun ®oral dispensing device. The product has been designed so that each distinct depression of the Gel Gun trigger or "click" delivers a 0.18 g levamisole and 0.68 g famphur activity which is the appropriate dose for each 50 lb body weight. In practice TRAMISOL X-TRA is administered by setting the Gel Gun weight selector for the approximate weight of the animal to be treated, directing the nozzle of the cartridge through the interdental space and squeezing the trigger two times directing the paste over the tongue into the animal's throat.

IV. EFFECTIVENESS

For the levamisole/famphur combination drug the data establishes non-interference of each drug in the drug combination. The data documents that the combination drug is superior to famphur for endoparasites and to levamisole alone for the ectoparasites.

Famphur
Famphur is approved in cattle as a pour-on (NADA 34-697; 21 CFR 524.900) and as medicated feed (NADA 34-266; 21 CFR 558.254).

The efficacy of the famphur component of the levamisole/famphur combination paste was determined in 8 dose titration trials conducted in the fall of 1984 and early 1985. Five of these trials were conducted to evaluate the optimum dose of famphur against grubs and three trials were conducted to measure effectiveness against lice in cattle. A list of these trials is provided in the accompanying table.

(Eds. note: The following table consists of 6 columns.)

TABLE I TRIAL INFORMATION

LocationInvestigatorParasiteDateTermination DateNo. Animals
ArkansasDr. Tan Yazwinski
University of Arkansas, Fayetteville, AR
Grubs10/19/842/14/85100
NebraskaDr. John Campbell
University of Nebraska, North Platte, NE
Grubs10/31/843/27/85104
TexasDr. Carl Patrick
Texas Agriculture, Extension Service, Amarillo, TX
Grubs10/9/842/11/8545
VirginiaDr. Jim Roberts
Dept. of Entomology, VPI, Blacksburg, VA
Grubs9/26/843/15/8582
KentuckyDr. Fred Knapp
University of Kentucky, Lexington, KY
Grubs11/2/844/18/85100
NebraskaDr. John Campbell
University of Nebraska, North Platte, NE
Lice2/21/854/18/8530
WyomingDr. Jack Lloyd
University of Wyoming, Laramie, WY
Lice1/15/854/24/8570
VirginiaDr. Jim Roberts
Dept. of Entomology, VPI, Blacksburg, VA
Lice2/19/854/16/8518

Summary of Grub Trials
Five-trials were conducted in various regions of the United States and consisted of five treatment groups. The treatments were a negative control which received no grubicide, and a positive control that received WARBEX® Pour-On at 40 mg/kg. Three of the treatment groups received the combination paste in which the famphur was administered orally at 10, 20, and 30 mg/kg. All animals received a dose of levamisole at 8 mg/kg.

The trial locations adequately covered all regions of the United States along with the various breeds and crossbreeds of cattle to which this paste may be administered in the U.S. for control of grubs. The majority of the trials contained both heifers and steers. Both species of grub, Hypoderma lineatum, the common grub, and Hypoderma bovis, the northern cattle grub, were represented in almost all the trials. Various degrees of infection rates were present for dose titration and efficacy evaluation.

For statistical analysis of the data, transformation of the grub counts was necessary in order to minimize the heterogeneity of variance among the treatment groups. Treating the trials as replicates, the ANOVA on the transformed data was performed for a balanced, completely randomized design.

Treatment groups that received oral famphur at 30 mg/kg and WARBEX® Pour-On had significantly fewer grubs (p<0.05) than the negative control and demonstrated grub control superior to the two treatment groups that received oral famphur in the combination paste formulation at 10 and 20 mg/kg. There was no significant difference in grub control between the oral famphur dosed at 30 mg/kg in the combination paste formulation and the WARBEX Pour-On group.

The back transformed mean grub counts from the five trials for the negative control, groups that received oral famphur at 10, 20, and 30 mg/kg, and the WARBEX® Pour-On group were 8.6, 1.4, 1.5, 0.3 and 0.3, respectively. As compared to the negative control, the grub reduction for oral famphur administered at 10, 20, and 30 mg/kg and the WARBEX® Pour-On group was 84, 83, 97, and 97%, respectively.

Summary of Lice Trials
Three trials were conducted to evaluate the efficacy against lice with the combination paste. The three predominant lice species were evaluated, which included Linognathus vituli, the long nose cattle louse, Bovicola bovis, the cattle biting louse and Solenoptes capillatus, the little blue cattle louse. Animals in different treatment groups were maintained in separate pens to prevent cross infestations. All treatments were administered mid-winter in which peak lice infestations were present.

Animal numbers per treatment group, number of treatment groups, number of examinations per animal, and method of recording counts varied from one trial site to another. Thus the data from the trials were not combined for a statistical analysis.

In all three trials, famphur was effective against adult lice at oral dosages of 10, 20, and 30 mg/kg. There appeared to be very little difference among the three oral dosages since all three doses eliminated the adult lice populations on the cattle. One hundred percent reduction in adult lice was usually observable by 3 days posttreatment. Reinfestation occurred between 7 and 28 days posttreatment. This appeared to be dependent upon the severity of the lice infestation. The reinfestation of lice in the oral famphur treatment groups is attributed to egg hatch and new maturing nits. The oral famphur was effective at eliminating the adult population of all three predominant species of lice from the cattle. The WARBEX® Pour-On treatment eradicated the lice populations on all animals for the complete duration of each trial.

In summary, the optimum dose for famphur in the levamisole/famphur paste combination for efficacy against grubs and lice in cattle appears to be dependent on the results of the dose titration data against grubs. An oral dose of 30 mg/kg offered significantly (p<0.05) better control of grubs than the negative control group and was superior to the treatment groups in which oral famphur was administered at 10 and 20 mg/kg. The percent reduction as compared to the negative control was greater than 95%. This excellent percent control was obtained from results of dose titration field trials in which 84 animals were orally administered the combination paste at 30 mg famphur/kg body weight and under conditions of natural grub infections. The oral famphur administered at 30 mg/kg eliminated the adult lice populations on cattle. The data clearly demonstrated that a levamisole/famphur combination paste formulated to deliver oral famphur at 30 mg/kg is commercially acceptable for control of grubs and lice in cattle.

Levamisole
Levamisole is currently approved in cattle in several dosage forms as the hydrochloride salt (NADAs 39-356; 21 CFR 520.1242b, 39-357; 21 CFR 520.1242a, 44-015; 21 CFR 558.315 and 126-237; 21 CFR 520.1242f). Efficacy for the levamisole component of the levamisole resinate/famphur combination paste is supported by a bioavailability study with TRAMISOL GEL (NADA 126-237; 21 CFR 520.1242f).

Because of (1) the different modes of actions of famphur and levamisole, (2) lack of ectoparasites activity of levamisole, (3) limited activity of famphur against endoparasites at the proposed use level, (4) prior documentation of the correlation between effectiveness and blood levels on levamisole, and (5) the level of effectiveness of levamisole against endoparasites, the combination drug requirements were adequately documented by the pharmacokinetic parameters of a blood level study. That is, the data evaluates the effect of famphur on the bioavailabilityof levamisole.

Bioavailability Study
This study was conducted by Dr. T.R. Garces at the Agricultural Research Center of American Cyanamid Company. A comparison to TRAMISOL® Gel (NADA 126-237; 21 CFR 520.1242f) was done in a two phase crossover design with 6 animals per group. Blood samples were collected periodically for 24 hours posttreatment.

Statistical analysis of the data was conducted by use of Multivariate Analysis of Variance. Phase or animal effects were not significantly different as determined by Wilk's Lambola criteria. The treatment effect was significant at the 5% level. The administration of the levamisole/famphur paste at 8 mg levamisole hydrochloride equivalent and 30 mg famphur/kg indicates that the bioavailability of the levamisole in the combinations paste is as good as the TRAMISOL Gel.

Therefore, the present formulation of the levamisole/famphur paste will provide therapeutic levamisole blood levels to support the efficacy against the nine internal cattle nematodes that TRAMISOL® Gel has received approval for in NADA 126-237; 21 CFR 520.1242f.

V. ANIMAL SAFETY

The safety of levamisole HCl was previously established in cattle in 39-356, 39-357, 44-015 and 126-237. The resinate salt was the subject of safety studies in laboratory species and in swine in NADA 101-079; 21 CFR 520.1242d. The safety of famphur, when administered either as a pour-on (NADA 34-697; 21 CFR 524.900) or in medicated feed (NADA 34-266; 21 CFR 558.254), was also previously established in cattle. In addition, a formal safety study was conducted with the proposed levamisole/famphur combination paste administered orally at various multiples of the dose levels recommended on the proposed labeling. Four groups of cattle (three males and three females per group) were administered the paste to provide a levamisole (HCl equivalent) dose of 0, 8, 16, and 24 mg/kg and famphur at , 30, 60, and 90 mg/kg. The negative control, 1X, 2X, and 3X dosage of the recommended dose was used for the safety study. The animals were observed by a veterinarian who is experienced in the clinical observations of drug toxicities. Periodic blood samples were taken for various hematological and blood chemistry determinations. The animals remained in the same groups and received a similar dose of the paste 28 days following the initial treatment. The animals were sacrificed seven days following the second treatment for gross pathological and histological examination.

No clinical signs of toxicity were observed in the control animals. One animal receiving the lX dose exhibited muzzle foam following the initial treatment; however, no adverse clinical signs appeared in the six animals following the second treatment 28 days later.

Muzzle foam and tenesmus were observed in all animals receiving the 2X and 3X doses of the paste. Three animals in the 3X dose also displayed some head shaking and hyperexcitability. All clinical signs had dissipated within 24 hours posttreatment. Anorexia was observed in the 2X and 3X treated animals for the next two days. All appetites had returned to normal after three days posttreatment. Similar observations of clinical toxicities were made at the 28-day treatment period for both the 2X and 3X treated animals. The degree of severity of the clinical signs of drug toxicity exhibited by the cattle in both treatment phases were considered mild.

Mean blood chemistry results indicate that the values for total protein, serum glutamic oxalacetic transaminase (SGOT) and alkaline phosphatase were within acceptable normal limits for all the groups at all intervals. Statistically significant differences (p<0.05) compared to controls were observed in the calcium, phosphatase, albumin, uric acid, total bilirubin, blood urea nitrogen, and glucose in different groups at various time intervals. These differences are considered biologically insignificant, since the mean values were within the normal range for cattle and attributed to the inherent variability of blood chemistry values among animals. No relationship could be established between the sporadic animals. No relationship could be established between the sporadic significant differences in blood chemistries and clinical signs exhibited by the 2X and 3X dose groups or the gross and histopathological examinations of these animals.

The plasma cholinesterase values were significantly (p<0.05) depressed as compared to control levels for 14 days posttreatment in the 1X, 2X, and 3X treatment groups. This biological manifestation was expected since famphur is an organophosphate. These values returned to normal and there were no significant differences in plasma cholinesterase at 28 days posttreatment for all treatment groups.

The only significant difference observed in the hematological measurements was an increase in the number of lymphocytes in the 3X dose group at 28 days posttreatment and days posttreatment for the second treatment.

No gross pathology was observed on necropsy that would be attributed to drug treatment.

There were no histological lesions that could be attributed to drug induced damage found in any tissues examined.

In summary, the major treatment related effects were characterized by clinical responses in the animals treated with 2X and 3X doses of the levamisole/famphur paste. These clinical signs of toxicity are judged to be mild and transitory in nature, with no apparent pathogenesis to any major organ system. This was further substantiated by both gross and histopathological findings. The recommended dose of 8 mg levamisole HCl equivalent and 30 mg famphur/kg was demonstrated to be safe for use in cattle.

VI. HUMAN SAFETY:

1. Toxicity Tests
The toxicity data that support the use of levamisole and famphur in cattle are contained in the approved NADAs listed below.

Levamisole: NADAs 39-356; 21 CFR 520.1242b and 039-357; 21 CFR 520. 1242a

Famphur: NADA 34-266; 21 CFR 558.254

2. Safe Concentrations of Residue
The tolerance for famphur in edible tissues appears in 40 CFR 180.233 and is listed as 0.1 ppm of the parent drug plus its oxygen analog metabolite, famophoxon.

The tolerance for levamisole in the edible tissues of cattle is 0.1 ppm levamisole hydrochloride as listed in 21 CFR 556.350.

3. Residue Depletion Studies
Two residue depletion studies were conducted for the purpose of determining a withdrawal time for the levamisole/famphur combination. The first study involved 23 Hereford cattle with an average weight of 355 kg. Twenty of the cattle received a single oral dose of the levamisole/famphur paste at the recommended label dosage of 8 mg levamisole HCl equivalent and 30 mg famphur per kg body weight. The treated cattle were sacrificed in groups of four at 3, 6, 9, 12 and 15 days post treatment, and samples of muscle, liver, kidney and fat were collected. The remaining three cattle served to provide control tissue samples.

Samples of the four tissues were assayed for famphur and its oxygen analog, famophoxon, while only liver, the target tissue for levamisole, was assayed for that drug. Average residue values for famphur in fat and liver tissue and levamisole in liver tissue are shown below. The assay for famphur in muscle yielded no positive values while two out of four kidney samples at 3 days and one out of four samples at 6 days yielded positive responses near the tolerance. No tissue samples were positive for famophoxon.

(Eds. note: The following table consists of 4 columns.)

Days post DosingLiverFamphur(ppm)
Omental Fat
Levamisole(ppm)
Liver
30.070.671.85
60.070.450.155
90.0150.0350.037
120.0120.0150.029
15NM*0.008**0.016

* NM = None measured
** Value represents one positive response

The second residue depletion study was similar in format to the first and involved 20 treated and 3 control Hereford cattle having a weight range of 181 to 414 kg. The animals were dosed in the same fashion as in the first study but were sacrificed in groups of four at the shorter schedule of 2, 3, 4, 5 and 6 days post dosing. Samples of liver and omental fat were collected and assayed for famphur, famophoxon and levamisole (liver only). The average levels (ppm) of residues are shown below.

(Eds. note: The following table consists of 4 columns.)

Days post DosingLiverFamphur(ppm)
Omental Fat
Levamisole(ppm)
Liver
20.563.513.32
30.180.751.14
40.100.150.13
50.080.190.15
60.060.100.14

The analytical method for famphur in both studies was the official AOAC method which was modified to include the use of a disposable solid-phase silica gel column in the cleanup procedure. The method used for the assay of levamisole was the official AOAC method which was modified to include the use of solid-phase extraction with a disposable strong cation exchange column in the cleanup procedure. Both methods gave excellent recoveries at spiking levels of 0.05 ppm.

4. Withdrawal Time Calculation
The depletion data from the two residue studies described above were subjected to a statistical analysis using a 99% tolerance limit with 95% confidence. Withdrawal times were calculated based on the depletion of famphur in fat and liver and on levamisole in liver. That procedure yielded a withdrawal time of 19 days for the levamisole famphur combination based on the depletion of famphur in fat tissue in the first study.

5. Assay Noninterference Studies
The following studies were conducted to demonstrate that the presence of each drug in the levamisole/famphur combination did not have an adverse effect on the assay of the other drug. The results of this work confirmed that neither drug interfered with the assay for the other.

  1. Levamisole Assay
    The effect of the presence of famphur and famophoxon on the assay for levamisole was determined by analyzing control liver tissue (the target for levamisole) fortified with famphur and famophoxon each with levamisole at the following levels: 0.0, 0.5, 0.10, 3.0 and 5.0 ppm. The recoveries were generally in the acceptable range and confirmed that neither famphur nor famophoxon interfered with the assay for levamisole.
  2. Famphur and Famophoxon Assay
    The effect of levamisole on the determination of famphur and famophoxon was demonstrated by the use of control samples of fat and liver that had been fortified with levamisole at 1 ppm and famphur and famophoxon at 0.0, 0.05, 0.1, and 1.0 ppm each. The assays for famphur and famophoxon gave acceptable recoveries and confirmed that the presence of levamisole does not interfere with the assay.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that levamisole resinate/famphur combination paste when used under its proposed conditions of use are safe and effective.

For the purpose of a human food safety review, this original NADA for the combination product was treated as if it were a Category II supplemental NADA (42 FR 64367, December 22, 1977). Each of the active ingredients is presently approved for oral administration to the same production class of animals. Based on its review of the data submitted with this NADA and the data in the approved NADA's for the individual products, the Agency concluded that the qualitative composition of the residues of famphur and levamisole is not expected to change when the combination product is administered. Because of the new dosing form and dosing scheme for famphur and its use in the combination product, the sponsor submitted a residue depletion study to establish a withdrawal period for the combination product. The amount of residue of the drugs that remains at the end of the withdrawal time is not appreciably different than the amount found when the drugs are used separately. Although the dosage of the drugs in the combination is higher than for the drugs when used separately, the withdrawal time for the combination is longer, and the cumulative exposure is the same.

The Agency concludes that adequate directions for use by the lay persons have been written for the proposed over-the-counter use of this anthelmintic and ectoparasitic drug which is indicated for the treatment of endo- and ecto-parasites commonly occurring in cattle. Some of the adverse reactions, such as muzzle foam, salivation, etc., occasionally observed after the treatment can be readily recognized by persons involved in rearing cattle. A thorough review of the current safety data submitted under the subject NADA indicates that the incidence of adverse reactions with the combination product would not be different from those already observed either with levamisole or famphur in field-use condition. Moreover, a review of the Adverse Drug Reaction reports submitted during the past 5 to 6 years also indicates that the reported deaths in small number of animals (9 with levamisole and 7 with famphur) were unrelated to the treatment with either drug. Both levamisole resinate and famphur are presently marketed separately over-the-counter as endoparasitic and ectoparasitic drug products, respectively.

VIII. LABELING (Attached)

  1. TRAMISOL® X-TRA product label

Copies of this label 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.