Approval Date: May 30, 1995

Freedom of Information Summary
NADA 200-027

I. GENERAL INFORMATION:

NADA 200-027
Sponsor:

Planalquimica Industrial Ltd
Rua das Magnolias nr. 2405
Jardim das Bandeiras
CEP 13053-120
Campinas - Sao Paulo - Brazil

Generic Name: nicarbazin
Trade Name: Nicarmix (nicarbazin) 25%
Marketing Status: Over the Counter (OTC)
Effect of Supplement:  This supplement approves Nicarmix (nicarbazin) 25%, as manufactured by Planalquimica, as an equivalent to nicarbazin sold by Merck.


2. INDICATIONS:As an aid in preventing outbreaks of cecal (Eimeria tenella) and intestinal (E. acervulina, E. maxima, E. necatrix and E. brunetti) coccidiosis in chickens.



3. DOSAGE:

113.5 g/ton of Type C medicated feed is to be fed as the only ration from the time the chicks are placed on litter until past the time when coccidiosis is ordinarily a hazard.



4. TARGET ANIMAL SAFETY and DRUG EFFECTIVENESS:

A. PIVOTAL STUDY:

  1. Type of Study: Clinical end point bioequivalence study (broilers) - Experiment GPR-890302

    Test Product: NICARMIX (nicarbazin) 25% Type A medicated article (Planalquimica)

    Reference Product: NICARB® (nicarbazin) 25% Type A medicated article (Merck)

  2. Investigator:

    Larry R. McDougald, Ph.D.
    Director of Research
    Georgia Poultry Research, Inc.
    P.O. Box 5822
    Athens, Georgia 30604

    Statistician:

    Larry R. McDougald, Ph.D.
    Department of Poultry Science
    University of Georgia
    Athens, Georgia 30602

  3. General Design of Investigation:

    1. Purpose of Study:

      To compare the efficacy of nicarbazin manufactured by Planalquimica to that of nicarbazin sold by Merck in broiler chickens infected with E. tenella.

    2. Test Animals:

      Broiler pullets (female) Peterson X Arbor Acres obtained from Seaboard Farms Hatchery, Athens, Georgia. Six hundred birds were used for the study. They were randomized into cages of 10 birds at 12 days of age (15 replicate cages).

    3. Treatments:

      1. Uninfected, unmedicated
      2. Infected, unmedicated
      3. Infected, nicarbazin Planalquimica
      4. Infected, nicarbazin Merck

      A standard broiler mash was used in all treatments. Feed mixtures were assayed for drug content.

    4. Dosage Form:

      Type A medicated articles.

    5. Route of Administration and Dosage:

      Both drugs were administered orally in the feed at a rate of 113.5 g/ton for the duration of the trial.

    6. Test Duration:

      The trial started April 18, 1989 and ended April 26, 1989 (8 days). The birds were given designated treatments (Day -2) and infected at the age of 2 weeks (Day 0) with a culture of a recent field isolate of 100,000 E. tenella oocysts (FS 284, Virginia, 1988) administered orally. Six days (Day 6) later the experiment was terminated.

    7. Pertinent Parameters Measured:

      Mortality, cecal lesion scores, and average weight gain were the parameters measured.

  4. Results: 

    Table 1. Comparison of the efficacy of nicarbazin from two sources against
Eimeria tenella. Summary of weight gains, mortality and cecal lesion
scores. (Experiment GPR-890302)

                        Percent      Average Gain     Average Cecal
Treatment¹             Mortality      (g/bird)²       Lesion Score³
                
    
Unmedicated, 
Uninfected 
Controls                  0.0            205              0.00
 
Unmedicated, 
Infected Controls         8.0            149              3.49

Nicarbazin (0.0125%)
 (Planalquimica)          0.0            193              0.12

Nicarbazin (0.0125%)
 (Merck)                  0.0            195              0.01

    
¹Replicated in 15 cages of 10 birds each. 
²Average gain per survivor (g) from the time of inoculation (DO), to 6 days
postinoculation (D+6). 
³Average cecal lesion scores based on the average of 5 birds per cage. Lesions
were scored according to Johnson and Reid, 1970. Experimental Parasitology
28, 30-36.

  5. Conclusion:

    The results demonstrated no difference in the efficacy of nicarbazin Planalquimica and nicarbazin Merck against a recent field isolate of E. tenella in broiler chickens.

B. PIVOTAL STUDY:

  1. Type of Study: Clinical end point bioequivalence study (broilers) - Experiment GPR-881110

    Test Product: NICARMIX (nicarbazin) 25% Type A medicated article (Planalquimica)

    Reference Product: NICARB® (nicarbazin) 25% Type A medicated article (Merck)

  2. Investigator:

    Larry R. McDougald, Ph.D.
    Director of Research
    Georgia Poultry Research, Inc.
    P.O. Box 5822
    Athens, Georgia 30604

    Statistician:

    Larry R. McDougald, Ph.D.
    Department of Poultry Science
    University of Georgia
    Athens, Georgia 30602

  3. General Design of Investigation:

    1. Purpose of Study:

      To compare the efficacy of nicarbazin manufactured by Planalquimica to that of nicarbazin sold by Merck in broiler chickens infected with E. acervulina.

    2. Test Animals:

      One day old broiler cockerels (male) Peterson X Arbor Acres obtained from Seaboard Farms Hatchery, Athens, Georgia. Six hundred birds were used for the study. They were randomized into cages of 10 birds at 12 days of age (15 replicate cages).

    3. Treatments:

      1. Uninfected, unmedicated
      2. Infected, unmedicated
      3. Infected, nicarbazin Planalquimica
      4. Infected, nicarbazin Merck

      A standard broiler mash was used in all treatments. Feed mixtures were assayed for drug content.

    4. Dosage Form:

      Type A medicated articles.

    5. Route of Administration and Dosage:

      Both drugs were administered orally in the feed at a rate of 113.5 g/ton for the duration of the trial.

    6. Test Duration:

      The trial started June 25, 1989 and ended July 2, 1989 (8 days). The birds were given designated treatments (Day -2) and infected at the age of 2 weeks (Day 0) with a culture of a recent field isolate of 1,000,000 E. acervulina oocysts (FS 284, Virginia, 1988) administered orally. Six days (Day 6) later the experiment was terminated.

    7. Pertinent Parameters Measured:

      Mortality, cecal lesion scores, and average weight gain were the parameters measured.

  4. Results: 

    Table 2. Comparison of the efficacy of nicarbazin from two sources against
Eimeria acervulina.
Summary of weight gains, mortality and cecal lesion scores.
(ExperimentGPR-881110)

                     Percent     Average Gain    Average Intestinal
Treatment¹          Mortality     (g/bird)²        Lesion Score³

    
Unmedicated, 
Uninfected 
Controls               0.0           193               0.00

Unmedicated, 
Infected Controls      0.0            78               3.91

Nicarbazin (0.0125%)
 (Planalquimica)       0.0           155               0.76 
 
Nicarbazin (0.0125%)
 (Merck)               0.0           152               0.79 

    
¹Replicated in 15 cages of 10 birds each. 
²Average gain per survivor (g) from the time of inoculation (DO), to 6 days
postinoculation (D+6). 
³Average cecal lesion scores based on the average of 5 birds per cage. Lesions
were scored according to Johnson and Reid, 1970. Experimental Parasitology
28, 30-36.

  5. Conclusion:

    The results demonstrated no differences in the efficacy of both formulations against single infection of E. acervulina.

5. HUMAN FOOD SAFETY:

Tolerance

The tolerances established for the pioneer product apply to the generic product. A tolerance of 4 ppm is established for residue in uncooked chicken muscle, liver, skin, and kidney (21 CFR 556.445).

 

Withdrawal Period

The following study was conducted by Dr. Carey L. Quarles of Colorado Quality Research, Inc., Ft. Collins, CO, and Dr. Halina Kramer, Group Leader of Hazleton Laboratories America, Inc., Madison, WI.

Nicarbazin manufactured by Planalquimica, LTDA of Sao Paulo, Brazil was fed to broiler chickens (equal number of males and females) at a concentration of 0.0125% in the feed beginning at one day of age and continuing for 49 days. Four birds (equal number of each sex) were sacrificed at 24, 36, 48, 60, and 72 hours after removal of nicarbazin-containing feed, and tissues were collected for assay of nicarbazin residues. The sponsor used the HPLC assay that has been approved for regulatory use. The residues in muscle and skin/fat were below the accepted tolerance of 4 ppm nicarbazin (21 CFR 556.445) at all withdrawal times, and the liver residues were below the tolerance after 60 hours withdrawal.

Nicarbazin Residue Depletion in Chicken Tissue: Data Summary


                      ppm Nicarbazin¹ at Withdrawal Time (Hours)


Tissue²           24         36          48          60         72


Liver            6.62       4.53        4.31        3.08       2.49
               (±1.08)    (±0.83)     (±0.23)     (±0.27)    (±1.02)


Muscle           0.98       0.61        0.32        0.12       0.12
               (±0.088)   (±0.19)     (±0.086)    (±0.065)   (±0.089)


Skin/Fat        0.88        0.86        0.53        0.33       0.19
              (±0.042)    (±0.14)     (±0.081)    (±0.16)    (±0.13)


¹ Nicarbazin residue values represent an average of assays from 2 female and 2
male birds per tissue and withdrawal time.
²Tissues from birds receiving 0.0125% nicarbazin for 49 days, followed by
unmedicated feed for the indicated withdrawal time.

A statistical analysis of the depletion data for nicarbazin in liver using the upper tolerance limit containing a 99 percentile of the population with 95% confidence limits yielded a withdrawal period of four days.

Regulatory Methods for Residues

The determinative assay for measuring residues in liver from chickens treated with nicarbazin is by high performance liquid chromatography (HPLC) with UV detection. The regulatory method is provided in the AOAC reference: Lewis, J.L., Macy, T.D., & Garteiz, D.A. (1989) J. Assoc. Off. Anal. Chem. 72, 577-581.

 



6. AGENCY CONCLUSIONS:

This ANADA submitted under section 512(b) of the Federal Food, Drug, and Cosmetic Act satisfies the requirements of section 512(n) of the act and demonstrates that nicarbazin when used under the proposed conditions of use, is safe and effective for its labeled indications.



Attachments:

The following generic labeling and currently approved pioneer labeling are attached.

Facsimile Type A package label for generic nicarbazin - NICARMIX (nicarbazin) 25%

Facsimile Type C blue bird label for generic nicarbazin - NICARMIX (nicarbazin) 25%

Approved pioneer Type A package label - NICARB® (nicarbazin) 25%



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

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