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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-958 Equiphen Paste - original approval

Approval Date: May 14, 1993

I. GENERAL INFORMATION

NADA140-958
Sponsor:Luitpold Pharmaceuticals, Inc.
Generic Name:phenylbutazone paste
Trade Name:Equiphen Paste
Marketing Status:Prescription

 

II. INDICATIONS FOR USE

For relief of inflammatory conditions associated with the musculoskeletal system in horses.

 

III. DOSAGE

A. DOSAGE FORM: Each calibrated plastic syringe contains 12 grams of phenylbutazone in 60 grams of paste or 6 grams of phenylbutazone in 30 grams of paste for oral administration.

B. ROUTE OF ADMINISTRATION: Oral.

C. RECOMMENDED DOSAGES: 1 to 2 grams of phenylbutazone per 500 lbs of body weight, but do not exceed 4 grams daily. Use a relatively high dose for the first 48 hours, then reduce gradually to a maintenance dose. Maintain lowest dose capable of producing desired clinical response.GUIDELINES TO SUCCESSFUL THERAPY

  • Use a relatively high dose for the first 48 hours, then reduce gradually to a maintenance dose. Maintain lowest dose capable of producing desired clinical response.
  • Response to Equiphen Paste therapy is prompt, usually occurring within 24 hours. If no significant clinical response is evident after 5 days, re-evaluate diagnosis and therapeutic approach.
  • When administering Equiphen Paste, the oral cavity should be empty. Deposit paste on back of tongue by depressing plunger that has been previously set to deliver the correct dose.
  • Many chronic conditions will respond to Equiphen Paste therapy, but discontinuance of treatment may result in recurrence of symptoms.

 

IV. EFFECTIVENESS

The effectiveness of the drug product has been established by the National Academy of Sciences and the National Research Council (NAS/NRC). NAS/NRC determined the drug to be effective for the treatment of inflammation associated with musculoskeletal system in the horse. The Food and Drug Administration concurred with the NAS/NRC findings. These findings were published on December 23,1980 in 45 FR 84762.

  1. Pivotal Study

    1. Type of Study:

      As per 21 CFR 520.1720c (c) and 514.111, a study was conducted to demonstrate the comparative bioavailability of Luitpold's Equiphen Paste (test product) to the NAS/NRC reviewed standard product (Butazolidin Paste, Cooper's Animal Health).

    2. Names and Addresses of Investigators:

      Doyne Hamm, DVM - Study Director
      President RAH, Inc.
      Rt.13, Hunt Lane
      Fayetteville, AR. 71701

      E. Wynn Jones, FRCVS Ph.D., Q. A. Monitor
      Mississippi State University
      Starkville, MS.

    3. Design of The Investigation:

      The study was designed to demonstrate the comparative bioavailability of the test product (Equiphen Paste, Luitpold Pharmaceuticals, Inc.) and the NAS/NRC review standard product (Butazolidin Paste, Cooper's Animal Health).

      Twelve mature quarter horse type animals of mixed sex (6 females and 6 geldings) were utilized. The horses were randomly assigned into two groups of 3 females and 3 geldings each. The horses were determined to be healthy on the basis of physical examination and baseline hematologic data. Feed and hay were withheld for 24 hours prior to dosing and 12 hours after dosing to minimize potential variance due to adsorption of phenylbutazone to hay.

      The bioequivalency study was of a crossover design. Horses of Group 1 were dosed initially with the standard product, and horses of Group 2 were dosed with the test product. After a 14 day washout period, Group 1 horses received the test product, and Group 2 horses received the standard product.

      Both test and standard products were available as oral paste containing 12 grams of phenylbutazone per 60 grams of paste. The pastes were administered by the oral route.

      A dosage of 2 grams of phenylbutazone per 500 pounds of body weight was utilized in the study. The dosage of each formulation was weighed and administered in an individual syringe of known weight. The syringe was reweighed after dosing and the residue in the syringe was calculated and subtracted from the total dosage. This was done to hold variability in dosage to a minimum.

      The duration of the test for each replicate in the crossover study was 48 hours.

      The pertinent parameters measured included serum drug concentrations for phenylbutazone at 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 36, and 48 hours after dosing and the incidence of adverse reactions. Serum samples were collected, stored frozen, and shipped frozen to Luitpold Pharmaceuticals, Inc. The content of phenylbutazone in the samples was determined by High Performance Liquid Chromatography (HPLC). The chemist who performed the HPLC tests and calculations was unaware of the group assignments for the study.

    4. Results:

      Table 1 gives the mean serum concentrations of phenylbutazone at each time period for both the test product and the standard product. Concentrations are in micrograms per milliliter.

      (Eds. note: The following table consists of 3 columns.)

      TABLE 1

      TIME (HOURS)TEST PRODUCTSTANDARD PRODUCT
      00.00000.0000
      0.250.57170.3908
      0.501.38331.5725
      13.20172.9333
      27.92255.5783
      412.249210.2908
      615.042511.2250
      910.645011.9983
      1210.937511.0517
      245.58175.4408
      363.86582.2558
      481.15251.3408
    5. Statistical Analysis and Conclusions:
      The variables area under curve (AUC), maximum blood concentration (Cmax), and time to maximum concentration (Tmax) for the study were calculated and subjected to analysis of variance.

      Under conditions of this study, the 90% (percentage) confidence intervals for the difference between test and reference (standard) means were (3.27%, 19.73%) for AUC, (1.85%, 15.12%) for Cmax, (- 35.55%, - 12.87%) for Tmax, (5.56%, 26.11%) for AUMC, and (- 2.77%, 4.56%) for MRT . Using the (percentage) confidence intervals approach, the results support the claim of bioequivalence between Luitpold and Cooper's products.

      This study was performed prior to the Center for Veterinary Medicine's Bioequivalency Guideline dated April 12, 1990. However, the study design and statistical analysis meet the criteria outlined in the Guideline.

    6. Adverse Reactions:

      No adverse reactions were reported during the study.

  2. Corroborative Study:

    1. Type of Study:

      An open field study to evaluate palatability of phenylbutazone paste was conducted.

    2. Names and Addresses of Investigators:

      Dr. Jerry Pack
      P.O. Box 758
      Charles Town, W.V. 25414

      Dr. Doyne Hamm
      Rt. 13, Box 203
      Hunt Lane
      Fayetteville, AR. 72701

      Dr. Rick Arthur
      599 Elm
      Sierra Madre, CA. 91024

    3. Design of The Investigation:

      This was an open, uncontrolled study to evaluate the acceptability and palatability of Equiphen Paste.

      Horses requiring relief of inflammation associated with the musculoskeletal system were eligible for the study provided they had not received anti- inflammatory therapy within two weeks of entry into the study. Fifty-two (52) horses were treated in this study. Table 2 summarizes the demographic data.

      (Eds. note: The following table consists of 3 columns.)

      Table 2:
       Age:Mean
      Range 4 months to 23 years
       
      3.53 years
       Sex:
       
      Males8
      Females22
       Breed:
       
      Quarter Horse8
      Thoroughbred44

      Diagnosis was made on the basis of routine clinical evaluation. Of the 52 horses, 31 (60%) were diagnosed as having arthritis or joint related injuries, 16 (31 %) were diagnosed as having inflammatory conditions of the muscle, tendon, or bone (e.g. myositis, tendonitis, shinbuck), and 4 (8%) were diagnosed with miscellaneous inflammatory conditions. No diagnosis was specified in 1 horse. The route of administration for the study was oral.

      The dosage used was 1- 2 grams per 500 lbs of body weight daily.

      Duration of the therapy was left to the discretion of the clinician.

      Parameters measured in the study included a subjective grading of the clinical response, ease of administration, acceptability, loss of drug, and adverse reactions.

      (Eds. note: The following table consists of 3 columns.)

      TABLE 3:

      Variable: Clinical Response (graded subjectively 0-100%):


       
      Mean:80.8%
      Range:25-100%
       
      Variable: Ease of Administration:
       
      No difficulty52
      Moderate difficulty0
      Difficult0
      Variable: Acceptability: 
       
      Readily acceptable 50
      Attempted to spit out2
       
      Variable: Loss of Drug:
       
      No loss50
      Small part lost2
      Most lost0
      Variable: Adverse Reaction:None52
    4. Conclusions: Based on this study, Equiphen Paste is readily acceptable and palatable under conditions of field use.

 

V. ANIMAL SAFETY

Phenylbutazone Paste was reviewed by the NAS/NRC and found to be safe in horses at the recommended dosages reflected on the product labeling. Findings of the NAS/NRC were published December 23, 1980 in 45 FR 84762.

 

VI. HUMAN FOOD SAFETY

Data on human safety pertaining to consumption of drug residues in food were not required for approval of this NADA. The drug is approved for use only in horses that are not to be used for food, and the product labeling will contain the following statement: "WARNING: Not for use in horses intended for food."

Human safety relative to possession, handling, and administration is addressed by the following statement on the package labeling: "WARNING: Keep this and all medications out of the reach of children. "

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and Section 514.111 of the implementing regulations. The efficacy and safety of the drug product has been established by the National Academy of Science/National Research Council/Drug Effectiveness Study Implementation (NAS/NRC/DESI) which evaluated the drug as being effective for relief of inflammation associated with the musculoskeletal system of horses (45 FR 84762, December 20, 1980). The Food and Drug Administration concurred with those findings. The data herein indicate that the new animal drug is bioequivalent to the NAS/NRC/DESI reviewed standard product and is thus safe and effective.

This drug is restricted to use by or on the order of a licensed veterinarian because a veterinarian is needed for the diagnosis of the conditions for which the drug is intended.

The approval of this NADA is based on a demonstration of bioequivalency with a pre-'62 NAS/NRC (DESI) reviewed product; therefore, the product does not qualify for marketing exclusivity under Section 512(c)2(F)(ii) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(ii), since the application does not contain reports of new clinical or field investigations (other than bioequivalence) essential to the approval and conducted or sponsored by the applicant.

 

VIII. LABELING (Attached)

  1. Package insert for 30 & 60 gram paste.
  2. Container label for 30 & 60 gram paste.
  3. Carton label for 30 & 60 gram paste.
  4. Shipper label for 30 & 60 gram paste.

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

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855