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Veterinary Drugs

 
Product and
NADA/ANADA Number
Trade Name
Ingredients
melatonin implant
140-846
PRIME-X
melatonin implant

                                                                   
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Summary of 
FDA Information:

Approval Date: June 21, 1994 Freedom of
Information Summary NADA 140-846 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: OTC 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.

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