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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-846 PRIME-X - original approval

Approval Date: June 21, 1994

I. GENERAL INFORMATION:

NADA 140-846
Sponsor: Wildlife Laboratories, Inc.
1401 Duff Drive, Suite 600
Fort Collins, Colorado 80524
Generic Name: melatonin implant
Trade Name: PRIME-X
Marketing Status:  

II. INDICATIONS FOR USE

PRIME-X is recommended for use in healthy male and female kit and adult female mink selected for accelerated priming: PRIME-X implanted mink complete autumn molt and prime 4-6 weeks earlier than normal.

III. DOSAGE FORM, ROUTE OF ADMINISTRATION AND RECOMMENDED DOSAGE:

The product is supplied as an silastic implant containing 2.7 mg (11.8% weight to weight) melatonin for subcutaneous administration at a dose rate of one implant per mink.

IV. EFFECTIVENESS:

PIVOTAL STUDIES

Dose Determination Study 1:

1) Type of Study: Dose Determination

2) Name and Address of Investigator:

A) Dr. Bruce Murphy
Dept. CRRA Faculty of Veterinary Medicine
3200 Sicotte Street
St-Hyacinthe, Quebec J2S7C6 - Canada

B) Location of trial:

Montgomery Fur Farm
Wetaskiwin, Alberta, Canada

3) General Design:

A. Purpose: Determine an effective dose of melatonin in silastic implant to induce early priming of fur in mink.

B. Test Animals:

1)  Species     Mustela vison 

Color       Demi buff

2)  Treatment Groups

a)  Group 1 

1)  10 male, 10 female 

2)  melatonin dose 0.78 mg (24.7% w/w)

b)  Group 2 

1)  10 male, 9 female 

2)  melatonin dose 1.95 mg (24.7% w/w)

c)  Group 3 

1)  8 male, 10 female 

2)  melatonin dose 3.91 mg (24.7% w/w)

d)  Group 4 

1)  10 male, 10 female 

2)  melatonin dose 7.82 mg (24.7% w/w)

3)  Control Group

a)  9 male, 10 female

4)  Age and Sex: kit male and female

C. Type of Control: No treatment (not implanted) with identical housing and maintenance D. Dosage Form: Single silastic subcutaneous implant containing 0.78 mg (24.7% w/w), 1.95 mg (24.7% w/w), 3.91 mg (24.7% w/w) and 7.82 w/w) melatonin per dose.

E. Route of Administration: Subcutaneous over shoulder area

F. Test Duration: Data for this study were collected between July 12, 1985 and December 3, 1985

G. Parameters Measured:

1) Adverse reactions at implant site
2) Feed consumption
3) Date pelted
4) Fur quality at pelt
5) Size at prime

4)Results:

All mink from Groups 1-4 (implanted July 12, 1985) were prime and pelted on October 17, 1985, with the exception of 1 mink from Group 1 implanted with 0.78 mg (24.7% w/w) melatonin, which failed to prime. Controls were prime and pelted on December 3, 1985. Feed consumption was monitored, and it was determined that implanted mink consumed an average of .55 pounds of feed per day while control mink consumed .48 pounds of feed per day. At pelting, the quality of pelts from implanted animals was equal to that of controls. Although obtained, serum melatonin data did not provide reliable data for analysis because of variation in the mean melatonin levels among the groups. This variation may have been due to an error in the method of analysis or due to the daily cyclic spikes in endogenous melatonin within the animals.

5) Adverse Reactions: There was one mortality recorded - kit no. 29 in dose group 1.95 mg (24.7% w/w) - due to cardiac puncture. There were no local reactions associated with the implants identified at pelting.

6) Conclusion: All dose levels (4) administered produced early priming in mink. The 0.78 mg (24.7% w/w) dose produced 90% efficacy while the 1.95 mg (24.7% w/w), 3.91 mg (24.7% w/w) and 7.82 mg (24.7% w/w) doses were equally effective, providing 100% effectiveness. A clinically revevant (sic) endpoint dose was not defined during this study. However, the study provided useful information concerning variables (such as surface area) which affect the dissipation of the melatonin from the implant, and therefore, efficacy of the drug.

Dose Determination Study 2:

1) Type of Study: Dose Determination

2) Name and address of Investigator:

Dr. Bruce Murphy
Dept. CRRA Faculty of Veterinary Medicine
3200 Sicotte Street
St-Hyacinthe, Quebec J2S7C6 - Canada
3) A) Las Charitas Ranch Argentina
B) El Pelito Ranch Argentina

4) General Design:

A) Purpose: Determine an effective dose of melatonin in silastic implant to induce early priming of fur in mink. Key variables in determining an effective dosage were identified as percent melatonin by weight and total dose of melatonin per implant.

B)  Test Animals:

1)  Species:    Mustela vison

2)  Treatment Group:

a)  Group 11 Las Charitas

1)  36 male, 32 female

2)  melatonin dose 0.13 mg (3.9% w/w)

b)  Group 12 Las Charitas

1)  25 male, 30 female

2)  melatonin dose 0.32 mg (3.9 % w/w)

c)  Group 13 Las Charitas

1)  27 male, 23 female

2)  melatonin dose 0.64 mg (3.9% w/w)

d)  Group 14 Las Charitas

1)  21 male, 25 female

2)  melatonin dose 1.26 mg (3.9% w/w)

e)  Group 15 El Pelito

1)  63 male, 51 female

2)  melatonin dose 5.19 mg (16.4% w/w)

a)  Las Charitas

1)  22 male, 21 female (no treatment)

2)  20 male, 23 female (treatment with placebos)

b)  El Pelito

1)  12 male, 24 female (no treatment)

 4)  Age and Sex: kit male and female mink

All control animals were housed and maintained the same as treated animals. C) Dosage Form: Single silastic subcutaneous implant containing 0.13 mg (3.9% w/w), 0.32 mg (3.9% w/w), 0.64 mg (3.9% w/w), 1.26 mg (3.9% w/w), or 5.19 mg (16.4% w/w) melatonin per dose. D) Route of Administration: Subcutaneous over shoulder area.

E) Test Duration: Data for this study were collected between the dates of December 18, 1985 and June 15, 1986. Implant dates were determined by officials at Las Charitas and El Pelito ranches based on their experience raising mink in the Southern hemisphere after consultation with the drug sponsor regarding use of the drug in the Northern hemisphere.

F) Parameters Measured:

1) Adverse Reactions
2) Pelting Date

5) Results: Melatonin doses of 0.13 mg (3.9% w/w) did not induce early priming of fur. A dose of 1.26 mg (3.9% w/w) melatonin induced prime furring in male and female kit mink two weeks earlier than controls. With the exception of 12 mink implanted with 5.19 mg (16.4% w/w) melatonin, all were pelted on May 5, 1986, compared to controls pelted on June 15, 1986. The twelve exceptions were reported pelted on June 4, 1986.

6) Adverse Reactions: None were observed.

7) Conclusion: Analysis of data provided to the NADA file indicates that the 5.19 mg (16.4% w/w) implant was an effective dose that produced priming of mink six weeks before control mink. Of 114 implanted mink, 102 (89.4%) were pelted on May 5, 1986, compared with the control mink which were pelted on June 15, 1986. The 1.26 mg (3.9% w/w) implant did not provide consistent results. Priming of implanted mink was only two weeks earlier than comparable control mink. Fractional doses of the 1.26 mg (3.9% w/w) implant [0.63 mg (3.9% w/w), 0.32 mg (3.9% w/w), and 0.13 mg (3.9 w/w)] did not produce early priming in any mink. This study provided additional data used to develop a dose of 2.7 mg (11.8% w/w).

Dose Determination Study 3:

1) Type of Study: Dose Determination

2) Name and address of Investigator:

Dr. Bruce Murphy
Dept. CRRA Faculty of Veterinary Medicine
3200 Sicotte Street
St-Hyacinthe, Quebec J2S7C6 - Canada

3) Location:

University of Saskatchewan
Saskatoon, Saskatchewan, Canada

4) General Design:

A) Purpose: To determine an in vivo release rate of melatonin from a silastic implant. This study was conducted using the dose of 2.7 mg (11.8% w/w) melatonin, the dose implanted in field studies, with removal of the implant at 8 and 12 weeks.

B)  Test Animals:

1)  Species: Domestic Ferret (Mustela putorius)

2)  Treatment Groups:

a)  Group 1-implant removal 4 weeks after implantation

1)  5 males

b)  Group 2-implant removal 8 weeks after implantation

1)  5 males

c)  Group 3-implant removal 12 weeks after implantation

1)  5 males

3)  Age and Sex: adult males

C) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8% w/w) melatonin per dose. D) Route of Administration: Subcutaneous over shoulder area.

E) Test Duration: Data for this study were collected between the dates of March 18, 1986, and June 10, 1985.

F) Parameters Measured:

1) Date of implant removal
2) Quantitative analysis of implant

5) Results: Silastic implants were rinsed in alcohol, air dried and frozen in liquid N2. Implants were pulverized and melatonin extracted and quantitated by spectrofluorimetry.

Analysis of the implants removed from ferrets at monthly intervals demonstrated a linear pattern of release through 4 weeks with 18% of the melatonin depleted by four weeks, 31% depleted by eight weeks, and 33% depleted by twelve weeks. The data suggests that complete dissipation of the melatonin will ensue by 274 days. There was a linear release pattern for 60 days post implantation (sic). The lack of a linear pattern after this point is not relevant to the development of the autumn molt and subsequent early priming because of the increased production of endogenous melatonin secondary to the shortening photoperiod.

6) Adverse Reactions: None were observed

General Summary of Dose Determination Studies

In developing the dose determination studies for melatonin implants, several variables were considered, including total dose of melatonin contained in an implant, the percent melatonin by weight, and surface area of the implant. Results of the study done in Canada (pivotal dose determination study 1) indicated that a 1.95 mg, 24.7% w/w, 0.032 square inches surface area dose was more effective than a 0.78 mg, 24.7% w/w, 0.019 square inches surface area dose in producing early priming of fur. Lower doses tested in that study were no more effective than the 1.95 mg, 24.7% w/w, 0.032 square inches surface area dose.

Pursuant to the results of that study, a second pivotal dose determination study was conducted in Argentina and it provided further information on the appropriate dose of the drug for mink. A dose of 5.19 mg, 16.4% w/w, 0.101 square inches surface area dose was as effective as the 1.95 mg, 24.7% w/w, 0.032 square iches (sic) surface area dose in producing early priming by six weeks of pelts. A 1.26 mg, 3.9% w/w, 0.101 square inches surface area dose was less effective than the 1.95 mg 24.7% w/w, 0.032 square inches surface area dose and the 5.19 mg, 16.4% w/w, 0.101 square inches surface area dose. It produced early priming of fur by only two weeks.

Based on these data, a dose of 2.7 mg melatonin at 11.8% w/w with a surface area of 0.074 square inches was chosen. This dose was within the range that produced early priming of fur by six weeks (i.e., 3.9%- 24.7% weight to weight, 1.95 mg to 5.19 mg melatonin per implant, and surface area of 0.032-0.101 square inches).

Pivotal Clinical Field Trial 1:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigator:

Mr. Tom Gibson Gibson
Fur Farm 26 Pioneer Road
Delta, Colorado 81416

3) Trial Location: Delta, Colorado

4) General Design:

A) Purpose: To demonstrate efficacy of the 2.7 mg (11.8% w/w) melatonin implant to induce early prime fur in ranched mink under actual field conditions of use.

   B)  Test Animals:
        1)  Species:    Mustela vison
        2)  Treatment Group:
        Color           Male        Female 
        White           237         413
        Demi-Buff       51          27 
        Silver Blue     119         122
        3)  Control Group:
        Color           Male        Female 
        White           160         93
        Demi-Buff       384         508 
        Silver Blue     86          93
        4)  Age and Sex: kit, male and female

C) Type of Control: No treatment (not implanted) with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8% w/w) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between July 14, 1986, and November 20, 1986.

G) Parameters Measured:

1) Date of Pelting
2) Pelt Size Distribution (% each size of total)
3) Pelt Quality Distribution (% each grade of total)

5) Results: Subcutaneous implantation of a single implant containing 2.7 mg (11.8% w/w) melatonin between July 14-20, 1986, produced early prime pelts in all implanted white mink between October 5-7, 1986. White controls were pelted 6 weeks later on November 20, 1986. White mink are normally pelted during the last half of November. Pelt quality was better among treated white male mink than among non-treated white males; whereas, there was no difference in quality among white females. There was no diference (sic) in pelt size between treated and control white mink. Treated silver blue mink were pelted on October 13 and 14, 1986, and the treated demi- buffs were pelted on October 24, 1986. Untreated color mink were pelted on November 20, 1994. However, eighty-eight percent of the non-implanted demi-buffs produced a higher quality pelt than the implanted demi-buffs, which all produced C grade or below average pelts. Implanted silver blue mink pelts were generally graded as equal to or better than non-implanted silver blue mink pelts.

6) Adverse Reactions: None were reported.

7) Conclusion: Implant treatment resulted in early priming, decreased quality of demi-buff pelts, and increased quality of white male pelts. Treatment did not affect pelt size.

8) Special Issues: Once a mink has reached its prime fur it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

Pivotal Clinical Field Trial 2:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigator:

Mr. Gary Lemon
River Ranch Fur Farm
Delta, Colorado 81416

3) Trial Location: Delta, Colorado

4) General Design:

A) Purpose: Demonstrate efficacy of 2.7 mg (11.8% w/w) implant to induce early prime fur in ranched mink under the actual conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Groups: White Mink

a)  359 males and 345 females

3)  Control Group: White Mink

a)  331 males and 193 females

4)  Age and Sex: kit, male and female

C) Type of Control: No treatment with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8% w/w) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between the dates of July 14, 1986 and November 20, 1986. Mink were implanted on July 14, 1986.

G) Parameters Measured:

1) Date of Pelting
2) Pelt Size Distribution (% each size of total)
3) Pelt Quality Distribution (% each grade of total)

5) Results: Subcutaneous implantation of a single implant containing 2.7 mg (11.8% w/w) melatonin produced early prime pelts in all treated mink on October 5-7, 1986, over 6 weeks earlier than controls that were pelted on November 20, 1986. White mink are normally pelted during the last half of November. Pelt size was comparable between implanted and control male and female mink respectively. There were 1.4 X more selects (highest quality) among implanted males than in control males. There were 1.9 X more implanted females graded select compared to control females.

7) Adverse Reactions: None were observed.

8) Conclusion: Implant treatment resulted in early pelt priming, and increased pelt quality; however, pelt size was not affected by implant treatment.

9) Special Issues: Once a mink has reached its prime fur it is economically advantageous to pelt the animals as soon as possible. Thusly, pelting dates usually closely follow priming dates and in most instances are the same date.

Pivotal Clinical Field Trial 3:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigator:

Mr. David Frisch
N5209 Rosedale Road
Deerbrook, Wisconsin 54424

3) Trial Location: Deerbrook, Wisconsin

4) General Design:

A) Purpose: Demonstrate efficacy of 2.7 mg (11.8% w/w) implant to induce early prime fur in ranched mink under the actual conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Group: Pink Color

a)  527 males and 19 females

3)  Control Group: Pink Color

a)  200 males and 709 females

4)  Age and Sex: kit male and female

C) Type of Control: No treatment with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8%) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between the dates of July 26, 1989, and December 5, 1989. The mink were implanted July 24-25, 1989.

G) Parameters Measured:

1) Date of Pelting
2) Auction House Grading
a) Pelt Quality
b) Size

5) Results: All implanted (treated) animals were prime and pelted more than 6 weeks earlier than controls (not treated). Pelt size among implanted and control male mink was comparable. Among females, the implanted mink were on average larger than the control mink.

6) Adverse Reactions: None were observed.

7) Conclusion: Implant treatment resulted in early pelt priming, and did not affect pelt quality or size.

8) Special Issues: Once a mink has reached its prime fur it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

Pivotal Clinical Field Trial 4:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigator:

Mr. David Frisch
N5209 Rosedale Road
Deerbrook, Wisconsin 54424

3) Trial Location: Deerbrook, Wisconsin

4) General Design:

A) Purpose: Demonstrate efficacy of 2.7 mg (11.8% w/w) implant to induce early prime fur in ranched mink under the actual conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Group: Ranch dark kit males

a)  48 males

3)  Control Group: Litter mates of Treatment Group

a)  46 males

4)  Age and Sex: kit males

C) Type of Control: No treatment with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8% w/w) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between the dates of July 25, 1989 and December 18, 1989. The mink were implanted on July 25, 1989.

G) Parameters Measured:

1) Date of Pelting
2) Auction House Grading
a) Pelt Quality
b) Size

5) Results: Subcutaneous implantation of a single implant containing 2.7 mg (11.8% w/w) melatonin produced early prime pelts approximately 6 weeks before controls in 100% of ranched mink. Pelt size and quality were comparable.

6) Adverse Reactions: None were observed.

7) Conclusion: Implant treatment resulted in early (approximately 6 weeks) pelt priming, and did not affect pelt quality or size.

8) Special Issues: Once a mink has reached its prime it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

CORROBORATIVE EFFICACY STUDIES

Corroborative Clinical Trial 1:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigators:

These field efficacy trials demonstrate the efficacy of the 2.7 mg (11.8%) implant under a variety of commercial ranch conditions.

A) Mr. Gale Alderman
Route 4
Tomah, WI 54660

B) Mr. Marvin and Mrs. Mary Bakko
M & M Mink Ranch
7721 State Road 92 Lake
Stevens, WA 98258

C) Mr. Ed Brecke
N246 Oriole Drive
Stetsonville, WI 54480

D) Mr. Walt Brown W. Brown
Fur Farm
Rural Route 3, Box 23A Arlington, SD 57212

E) Mr. David Frisch
Twin Spruce Fur Farm, Inc.
N5209 Rosedale Road
Deerbrook, WI 54424

F) Mr. Hans Haugen
Northwest Mink Ranches, Inc.
N4533 Zebro Road
Bruce, WI54819

G) Mr. George Kalmon
N3647 CTHE
Medford, WI 54451

3) Trial Location: Various (see list of investigators)

4) General Design:

A) Purpose: Demonstrate efficacy of 2.7 mg (11.8% w/w) implant to induce early prime fur in ranched mink under actual field conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Group consisted of 23,373 males and females

3)  Control Group consisted of 41,645 males and females

In the studies, remaining untreated mink on the ranch served as controls and were maintained under identical management conditions. The dates of priming of treated animals were compared to that of the untreated population managed under identical conditions.

4)  Age and Sex: Adult, kit, male and female

C) Type of Control: No treatment with identical housing and maintenance. D) Dosage Form: Subcutaneous silastic implant containing 2.7 mg (11.8% w/w) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between the dates of July 10, 1989, and November 5, 1989.

G) Parameters Measured:

1) Date of Pelting
2) Physical examination by veterinarian at pelting to evaluate the general heath of mink. Examination did not assess fur quality.

5) Results: The results of these studies are summarized in the table below. The animals were all implanted plus or minus 6 days of the time period recommended by the package insert for this product (July 7 - July 21). The treated animals were observed by veterinarians to detect any adverse effects on the general health of the mink. The 2.7 mg (11.8% w/w) melatonin implant produced accelerated pelt priming on 90% of 23,373 mink in trials conducted on seven commercial operating mink ranches. Group 89MN-2, Brown, reported decreased pelt quality in 1975 mink (8.5% of total study). Group 89MN-9, Kalmon, 300 dark mink were pelted six weeks later (12/7/89) than they should have been. Late pelting may have produced decreased pelt quality in this group. Ranch dark mink characteristically prime 15-30 days later than light colored mink.

(Eds. Note; The following table consists of 11 columns)

1989 INVESTIGATIONAL MELATONIN IMPLANT TRIALS IN MINK
Trial     Invest    St   Yrs   #Mink   Controls    Colors*      Date        Date      Adv      PE
  No.                    Exp   Implt                            Implt       Pelted    React    **
89MN-1    Frisch    WI   16    1450      1450      P,W,Ma,B,V   7/25-27     10/27-29   No       E
89MN-2    Brown     SD   15    1975       535      RW,Pa        7/14-17     11/3-5     No       E
89MN-3    Haugen    WI   25    4000      7310      W            7/25        10/18      No       E
89MN-6    Brecke    WI   22   11000     13500      Ma,Mu        7/10-25     10/16      No       E
89MN-7    Bakko     WA   11    1728      5300      BI           7/12-14     10/10      No       E
89MN-8    Alderman  WI   40    2800      6600      W,De         7/15        10/15-20   No       E
89MN-9    Kalmon    WI   10     100      7000      Mu           7/18-19     10/12      No       E
89MN-9    Kalmon    WI   10     300                D            7/18-19     12/7       No       E
*Colors: P (pink), W (white), Ma (Mahogany), B (Black), V (Violet),
 RW (Ranch Wild), Pa (Pastel), Mu (Mutation), BI (Blue Iris), De (Demi Buff)
**PE = Physical Exam; E = Excellent

6) Adverse Reactions: None were observed 7) Conclusion: Implant treatment resulted in early (4 to 6 weeks) pelt priming in 90% of 23,373 treated mink.

8) Special Issues: Once a mink has reached its prime fur it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

Corroborative Clinical Field Trial 2:

1) Type of Study: Field Efficacy Trial

2) Name and Address of Investigator:

Mr. Tom Gibson
Gibson Fur Farm
26 Pioneer Road
Delta, Colorado 81416

3) Trial Location: Delta, Colorado

4) General Design:

A) Purpose: To demonstrate efficacy of the 2.7 mg (11.8% w/w) melatonin implant to induce early prime fur in ranched mink under actual field conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Group:

Color   Number

Creole  17

3)  Control Group:Color   Number

Creole  8300

4)  Sex: male and female

C) Type of Control: No treatment (not implanted) with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 2.7 mg (11.8%) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Test Duration: Data for this study were collected between July 14, 1986, and November 20, 1986. Mink were implanted July 14-20, 1986, and implanted mink were pelted October 6-27, 1986, while control mink were pelted November 20, 1986.

G) Parameters Measured:

1) Date of Pelting
2) Pelt Size Distribution (% each size of total)
3) Pelt Quality Distribution (% each grade of total)

5) Results: All implanted (treated) animals were pelted at least 4 weeks earlier than controls (not treated). Implanted creole-colored mink all produced C grade or below average quality pelts, while 87% of the nonimplanted creole mink produced Select/A or the best or above average quality pelts and 13% produced C grade pelts.

6) Adverse Reactions: None were observed.

7) Conclusion: Although implanted creole mink were pelted earlier than non-implanted controls, they were generally of lesser quality than comparable non-implanted mink.

8) Special Issues: Once a mink has reached its prime it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

 

V. ANIMAL SAFETY:

The following study was a pivotal toxicity study providing information to support the safety of PRIME-X [2.7 mg (11.8% w/w) melatonin implants] in mink.

1) Type of Study: Subacute Toxicity

2) Name and Address of Investigator:

Dr. Bruce Murphy
Dept. CRRA Faculty of Veterinary Medicine
3200 Sicotte Street
St-Hyacinthe, Quebec J2S7C6 - Canada

3) Trial Location:

Montgomery Fur Farm
Wetaskiwin, Alberta, Canada

4) General Design:

A) Purpose: Demonstrate safety of the dose 78.2 mg (24.7% w/w) (29 x the proposed dose) melatonin in ranch dark mink under actual field conditions of use.

B)  Test Animals:

1)  Species: Mustela vison

2)  Treatment Group:

a.  5 males 

b.  5 females

3)  Control Group:

a.  9 males 

b.  10 females

4)  Age and Sex: 8-10 week old kits, demi-buff

a.  0.970 kg Males (average weight) 

b.  0.631 kg Female (average weight)

C) Type of Control: No treatment (not implanted) with identical housing and maintenance. D) Dosage Form: Single silastic subcutaneous implant containing 7.8 mg (24.7% w/w) of melatonin.

E) Route of Administration: Subcutaneous over shoulder area.

F) Dose Used: 10 implants each containing 7.82 mg (24.7% w/w) or 2.9X melatonin per implant were implanted for a total dose of 78.2 mg (24.7% w/w) or 29X melatonin.

1) Males: 80.6 mg/kg average dose
2) Females: 123.9 mg/kg average dose
G) Test Duration: Data for this study were collected between July 12, 1985, and December 3, 1985.

H) Parameters Measured

1) Body Weight (grams) Start and end of study
2) Pelting Date and Grade
3) Testicular Weight and Spermatogenesis rating
4) Gross pathology and histopathology - heart, adrenal, liver, spleen, kidney, ovaries, testes, brain, thyroid, thymus.

5) Results: On gross and histopathologic examination, advanced spermatogenesis was noted. In addition, an increase in weight was noted in male implanted mink when compared with controls. No other changes due to drug administration were observed. Sex, age, body weight, grade, testicular weight and spermatogenesis rating are summarized in the following tables:

(Eds. Note: The following table consists of 8 columns)

Sub-Acute Toxicity Test
DOSE: 10 X 7.82 MG IMPLANTS
DATE IMPLANTED: JULY 12, 1985 DATE PELTED: OCTOBER 17, 1985

NO.   SEX   AGE    ------BODY WGT-------    GRADEa    TESTES     SPERMATO
                   --------(GMS)--------               WGT       GEMESIS     
                   --Start         End--              (GMS)      RATINGb
                   (7/12/85)   (10/17/85)           
                   Implanted     Pelted
                  
102    M    Kit      1150        2099         MAJ      1.67         3
103    M    Kit      1070        2313         MAJ      1.55         3
104    M    Kit       920        2501         MAJ      1.73         3
105    M    Kit       850        2228         CAN      2.40         3
106    M    Kit       760        2493         CAN      0.74         3
 -     -     -       x=950      x=2327       x=3.6       -          -
50     F    Kit       700         100         CAN       N/A        N/A
51     F    Kit       620        1145         MAJ       N/A        N/A
52     F    Kit       670        1168         MAJ       N/A        N/A
53     F    Kit       575        1472         UL        N/A        N/A
54     F    Kit       640        1225         CAN       N/A        N/A
-   -   -           x=641      x=1224        x=3.2       -          -

aGrade Definition:
4 - Best Grade = (MAJ) Majestic
3 - Middle Grade = (CAN) Canada
2 - Lower Grade = (UL) Unlabeled
1 - Lowest Grade = (LG) or III

bSpermatogenesis ratings:
1 Spermatogonia
2 Spermatogonia/primary spermatocytes
3 Spermatids

(Eds. Note: The following table consists of 8 columns)

                  Sub-Acute Toxicity Test (cont'd)
                           DOSE: CONTROLS
      DATE ON TEST: JULY 12, 1985 DATE PELTED: DECEMBER 3, 1985

NO.   SEX   AGE    ------BODY WGT-------    GRADEa    TESTES     SPERMATO
                   --------(GMS)--------               WGT       GEMESIS     
                   --Start         End--              (GMS)      RATINGb
                   (7/12/85)   (12/3/85)           
                   Implanted     Pelted
                                                
63    M     Kit      950          1980        MAJ      1.59    3
62    M     Kit      800          2156        MAJ      0.83    2
61    M     Kit     1100          1725        CAN      1.92    3
60    M     Kit     1080          1925        UL       1.25    3
59    M     Kit      960          2156        UL       0.66    2
55    M     Kit      950          2241        CAN      2.41    3
56    M     Kit      850          2043        UL       1.17    3
57    M     Kit      925          1800        MAJ      0.99    3
58    M     Kit     1025          2000        CAN      3.49    3
--   --     --      x 961       x 2003      x 2.8    x 1.59  x 2.8
01    F     Kit      740          1400        MAJ       N/A   N/A
02    F     Kit     7800          1425        UL        N/A   N/A
03    F     Kit      775          1400        MAJ       N/A   N/A
04    F     Kit      800          1410        CAN       N/A   N/A
05    F     Kit      740          1440        MAJ       N/A   N/A
06    F     Kit      575          1040        CAN       N/A   N/A
07    F     Kit      650          1075        MAJ       N/A   N/A
08    F     Kit      640          1225        UL        N/A   N/A
09    F     Kit      750          1375        UL        N/A   N/A
10    F     Kit      590          1225        MAJ       N/A   N/A
--    --    --      x704         x1306       x3.2        --    --

aGrade Definition:
4 - Best Grade = (MAJ) Majestic
3 - Middle Grade = (CAN) Canada
2 - Lower Grade = (UL) Unlabeled
1 - Lowest Grade = (LG) or III

bSpermatogenesis ratings:
1 Spermatogonia
2 Spermatogonia/primary spermatocytes
3 Spermatids

At their respective pelting dates, treated males averaged 324 grams more than their control counterparts. Control females averaged 82 grams more than the treated (implanted) females. 6) Adverse Reactions: Elevated doses of melatonin produced advanced spermatogenesis in male mink when compared to controls.

7) Conclusion: Use of 10 implants containing 7.8 mg (24.7%) melatonin each in 5 males and 5 female ranched mink produced no signs of toxicity. On gross and histologic pathology examination, pelting dates and grade of fur were noted.

The difference in average weight gain (324 grams) between the implanted and non-treated male mink at pelting could be attributed to environmental or management factors which occurred after the treated mink were pelted but prior to pelting of the control animals. The 82 gram difference between implanted and non-treated females was not considered clinically significant. Advanced spermatogenesis was noted in melatonin implanted mink pelted on 10/17/85 and included the presence of mature spermatids in 100% of implanted male animals. Average testes weight of treated males at pelting on 10/17/85 was 1.62 grams. There were mature spermatids identified in 66.6% of the control mink. Average testes weight of the control mink pelted on 12/3/85 was 1.59 grams. Comparing the presence of mature spermatids and testes weight of melatonin implanted animals pelted on 10/17/85 to control animals pelted nearly 7 weeks later, it was evident that spermatogenesis was advanced by 7 weeks. Advanced spermatogenesis had no adverse effects on pelt quality. All melatonin implanted males with advanced spermatogenesis graded in the top two grades (Majestic and Canada). Control males pelted on 12/3/85 graded Majestic, Canada and Unlabeled.

8) Special Issues: Once a mink has reached its prime fur it is economically advantageous to pelt the animal as soon as possible. Thusly, pelting dates usually closely follow priming dates and in many instances are the same date.

Adverse Reactions in other Clinical Field Trials: Summary data from international and domestic trials conducted between June 13 and August 10, 1986, involved 13,619 kit males, 11,623 kit females, 25 adult males and 5,847 adult females implanted with 2.7 mg (11.8%) melatonin implants. The following adverse reactions were observed in those trials in which mink were implanted between June 13 and July 7: decreased pelt quality (7.7%), late priming or failure to prime early (kit male 6.8%, kit female 4.0%), occurrence or brown cast or metallic sheen and lack of undercoat which reduces value (kit male 4.6%, kit female 1.3%, adult female 25.5%), smaller pelts, and decreased weight gain (kit female 4.0%). One percent (1.0%) of kit males and 1.5% of kit females implanted between July 8 and August 10 were observed to have pelts with brown casts or metallic sheens. In summary, unfavorable early priming results were reported on 15.6% kit males, 9.3% kit females, and 25.5% adult females implanted between June 13 and July 7. Mink implanted from July 8 through August 10 reported unfavorable results for 1.0% kit males and 1.5% kit females. No adult females implanted between July 8 and August 10 reported unfavorable results. Of total kit males implanted, 4.3% were reported to have failed to prime or primed at a later date. Demi-buffs, in particular, were most often judged to be unsatisfactory. Diet, genetics, disease, environment, and premature implantation with melatonin may have been factors in the occurrence of these conditions. Furthermore, data derived from the dose determination studies, which provided for a 1.9X dose (5.19 mg) and 2.9X dose (7.82 mg), provided no evidence of adverse reactions related to the melatonin implant.

 

VI. HUMAN SAFETY:

Melatonin implants are not for use in domestic animals or animals to be consumed for food. Data on human safety, pertaining to consumption of drug residues in food, were not required for approval of this NADA. The drug is to be labeled for use in mink, which are nonfood animals.

 

VII. AGENCY CONCLUSIONS:

The data in support of this original NADA complies with the requirements of Section 512 of the Act and Section 514.111 of the implementing regulations. It demonstrates that PRIME-X [2.7 mg (11.8%) melatonin implants] when used under conditions specified in the label is safe and effective.

Under section 512(c)(2)(F)(i) of the Federal Food, Drug, and Cosmetic Act, this approval for non- food producing animals qualifies for FIVE years of marketing exclusivity beginning on the date of approval because no active ingredient (including any ester or salt of the active ingredient) has been approved in any other application.

The product is OTC. It is labeled for use during a very specific time of year and will be used by persons thoroughly familiar with the management of ranched mink. There is no diagnosis necessary prior to initiation of treatment. The label contains adequate directions for use.

 

VIII. LABELING (Attached)

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