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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-014 SUPER-OV® - original approval

Date of Approval: August 13, 1993

I. GENERAL INFORMATION

NADA140-014
Sponsor:Ausa International Inc.
Rt. 8, Box 324-12,
Tyler, TX 75703.
Generic Name:Follicle stimulating hormone (FSH)
Trade Name:SUPER-OV®
Marketing Status: 

 

II. INDICATIONS FOR USE

SUPER-OV® is indicated for the induction of superovulation in cows for procedures requiring the production of multiple ova at a single estrus. SUPER-OV® is effective only in cows that are not pregnant and have a normal corpus luteum, i.e. those cows that are cycling normally.

 

III. PRODUCT INFORMATION

A.DOSAGE FORMSUPER-OV® is derived from porcine pituitary glands and is available in one package size: 75 unit (NIH-FSH-S1) vial of powdered drug. Each vial is reconstituted with one vial of SUPER-OV® DILUENT. A vial of diluent and powdered drug are packaged together.
B.ROUTE OF ADMINISTRATIONIntramuscular injection
C.RECOMMENDED DOSAGES:SUPER-OV® is administered at a dosage of 12.5 units (1.6 mL of the reconstituted solution) twice a day approximately 12 hours apart for 3 days, for a total dose of 75 units (NIH-FSH-S1). To effect regression of the corpus luteum, a prostaglandin should be administered according to the manufacturer's instructions at the time of the fifth SUPER-OV® injection.

 

IV. EFFECTIVENESS

A. Pivotal Studies

NOTE: Unless otherwise indicated, the principle investigator in the following studies was:

Lloyd E. Donaldson MVSc, MRCVS, MACVSc, PhD
Ausa International Inc.
Rt. 8, Box 324-12,
Tyler, TX 75703.

  1. Dose Determination (Unit and Duration) Studies

    1. DOSE TITRATION STUDY

      A dose titration of 3 levels was completed. Sixty commercial cows of dairy (Holstein) or mixed beef breeds, ranging in age from 2 to 8 years, were divided by breeds and subdivided into 3 treatment groups. These groups received a total FSH dose of 37.5, 75 or 150 units (NIH-FSH-S1). The total dose of FSH was equally divided over 8 intramuscular injections and was given at 12 hour intervals for 4 days. A control group (zero drug level) was not required for this study, because the difference between the low dose and higher doses was expected (and confirmed) to be statistically significant. In addition, the expected rate of multiple ovulations in the bovine is low(1).

      Estrus was induced with a 2 mL (500 mcg) dose of cloprostenol sodium administered at the time of the fifth SUPER-OV® injection. Cows were inseminated with one straw of semen from 4 to 22 hours after the detection of estrus. Routine nonsurgical embryo collections were performed 7 days following insemination.

      Parameters measured were total and transferable embryo production. These parameters were measured following a microscopic evaluation and grading of the ova and embryos collected.

      (1)Stephen J. Roberts, VETERINARY OBSTETRICS AND GENITAL DISEASES THERIOGENOLOGY (Woodstock, VT:Roberts, 1986), page 96.

      RESULTS

      TREATMENTBREED
      (NUMBER OF COWS)
      TRANSFERABLE
      EMBRYOS (S.D.)
      TOTAL OVA AND
      EMBRYOS (S.D.)
      37.5 unitsdairy (8)3.63 (4.69)5.13 (4.73)
      37.5 unitsbeef (12)1.67 (2.06)3.58 (3.70)
      37.5 unitsCombined (20)2.45 (3.40)4.20 (4.10)
      75 unitsdairy (8)4.88 (3.91)10.25 (4.40)
      75 unitsbeef (12)6.75 (5.94)13.42 (8.76)
      75 unitsCombined (20)6.00 (5.19)12.15 (7.36)
      150 unitsdairy (8)5.38 (4.66)8.00 (2.93)
      150 unitsbeef(12)5.25 (3.17)9.33(4.01)
      150 unitsCombined (20)5.30 (3.72)8.80 (3.60)

      The standard deviations were large indicating that the transferable and total embryo production data were not normally distributed. The data was transformed and an analysis of variance was used to evaluate the data. Treatment differences were significant for both transferable (p=0.0158) and total ova and embryos (p=0.0001). The 37.5 unit dose of SUPER-OV® produced fewer ova and embryos (2.5/4.2) than did the 75 (6.0/12.15) and 150 (5.3/8.8) unit doses. There were no breed differences in embryo production (P>0.05).

      CONCLUSIONS

      Based on the results of the study, 75 NIH units was selected as the appropriate dose because it performed better than 37.5 units and there was no improvement with the higher dose of 150 units. There were no differences detected in the response to treatment by breed of cattle.

    2. COMPARISON OF THE SUPEROVULATION RESPONSE IN COWS TREATED ONCE OR TWICE A DAY WITH A TOTAL DOSE OF 75 UNITS SUPER-OV® FOR THREE OR FOUR DAYS

      Additional investigators

      Douglas Eckery
      Kerry Powell
      Maritza Rodreguez
      Brigham Young University
      Provo, Utah 84602

      The purpose of the study was to compare the efficacy of the selected dose of SUPER-OV® (75 units FSH) administered over 3 or 4 days in either once or twice daily injections.

      Eighty heifers, about 2 years of age, were selected on the basis of body size from a large group of crossbred beef heifers (Brahma cross) housed in a feed lot. The heifers were observed for 2 weeks, and those seen in estrus were examined by rectal palpation and selected for study if their reproductive tracts appeared to be normal.

      The heifers were randomly allocated to treatments in a 2 x 2 factorial experiment with the variables being days of SUPER-OV® treatment (3 or 4) and number of times treated per day (1 or 2). Treatment was started between days 8 and 14 of their cycle. The total dose of SUPER-OV® was held constant at 75 units. In the 3 day, twice a day (morning and evening) group, animals received 12.5 units FSH at each injection (6 total injections, 75 total units FSH). In the 4 day, twice a day (morning and evening) group, animals received 9.4 units FSH at each injection (8 total injections, 75.2 total units FSH).

      The heifers received a prostaglandin (2 mL (500 mcg) of cloprostenol sodium) injection on the third day of treatment to induce estrus. Heifers were artificially inseminated 12 to 18 hours after observation of estrus. Animals not observed in estrus were bred 60 hours after the prostaglandin injection. Ova and embryos were collected 7 days after breeding by a technique equivalent to surgical embryo collection, but performed at slaughter, rather than in the standing animal.

      The primary response parameters were the number of transferable embryos and percent of transferable embryos (collected at slaughter).

      TREATMENT (N)NUMBER OF TRANSFERABLE MEAN (S.D.)PERCENT OF TRANSFERABLE MEAN (S.D.)TOTAL OVA AND EMBRYOS MEAN (S.D.)
      3 days, 1 injection
      N=14
      3.07 (5.94)29.84 (40.80)9.14 (9.64)
      3 days, 2 injections
      N=19
      4.58 (4.80)53.83 (36.75)10.68 (8.84)
      4 days, 1 injection
      N=20
      2.35 (2.92)40.03 (39.97)5.95 (6.57)
      4 days, 2 injections
      N=18
      2.78 (2.94)57.63 (35.59)6.11 (6.76)

      Not all animals entered in the study were acceptable at necropsy. Any animal that was not seen in estrus after superovulation and with ovaries that did not contain 7 day old corpora lutea at necropsy was excluded from analysis. No statistically significant treatment differences were found between number of days, number of injections per day, or the interaction of days and injections for the number of transferable embryos. No statistically significant treatment differences were found between number of days or the interaction of days and injections for the percent of transferable embryos. However, a statistically significant treatment difference was found between the number of injections per day (p= .03) with 2 injections per day better than 1 for the percent of transferable embryos.

      CONCLUSIONS

      In heifers receiving a total dose of 75 units of FSH, the animals dosed twice a day for 3 or 4 days had a statistically significant higher percent of transferable embryos than those animals dosed once a day for 3 or 4 days. No advantage was seen for 4 days of twice a day treatment over three days of twice a day treatment, therefore, 12.5 units of SUPER-OV® , administered twice a day for 3 days, for a total dose of 75 units, was selected as the appropriate dose.

    3. FSH AND PROSTAGLANDINS IN THE SUPEROVULATION OF CATTLE

      The purpose of this study was to determine if FSH and prostaglandins are both necessary for superovulation of cows and to determine whether the effects obtained differ between dairy (Holstein) and beef type cows.

      Forty commercial cows of dairy (Holstein) or mixed beef breeds, ranging in age from 2 to 8 years, were used. Animals were allocated to groups on the basis of a 2 x 2 factorial design with randomized sub-groups. Two levels of FSH (0 and 75 units) and 2 levels (0 and 2 mL (500 mcg)) of cloprostenol sodium were each administered alone and in combination with one another to groups of dairy (Holstein) only and beef only cattle (8 total treatment groups). Injections were administered intramuscularly. The total dose of FSH was equally divided over 8 injections and given at 12 hour intervals for a period of 4 days. The cloprostenol sodium was given at the time of the fifth FSH injection. Individual animal FSH superovulation treatment was begun from 8 to 13 days after estrus was observed and was continued for 4 days. There were 2 (1 beef and 1 dairy (Holstein)) untreated control groups included in the study (0 units FSH and 0 mL cloprostenol sodium).

      Cows were inseminated with one straw of semen 4 to 24 hours after the detection of estrus. Cows not detected in estrus were inseminated at the expected time relative to expected ovulation, if a positive response had been achieved. Ova and embryos were collected non-surgically 7 days after insemination. Parameters measured were total (ova and embryo) and transferable embryo production.

      RESULTS

      GROUP (Number of cows)TREATMENT
      FSH DOSE UNITS
      (prostaglandin dose)
      NUMBER OF
      TRANSFERABLE
      MEAN (S.D.)
      TOTAL OVA AND
      EMBRYOS
      MEAN (S.D.)
      Beef & Dairy (10)75 units (2 mL)5.4 (2.01)9.9 (4.53)
      Beef & Dairy (10)0 units (2 mL).3 (.48)0.5 (0.53)
      Beef & Dairy (10)75 units (0 mL)0 (0)0 (0)
      Beef & Dairy (1O)0 units (0 mL)0 (0)0 (0)

      Cattle type (i.e., beef or dairy) had no effect on embryo production (P=0.7363), therefore, the breeds could be combined by treatment group. The data was transformed for analysis. Both SUPER-OV® and cloprostenol sodium (a prostaglandin) had highly significant effects upon transferable and total embryo production (P< 0.0001) with highly significant interactions (P< 0.0001 ). There was no superovulatory response unless both treatments (FSH and prostaglandin) were used.

      CONCLUSIONS

      FSH and prostaglandins function together to achieve a superovulation response in cattle. Therefore, the product will carry the label statement that the 2 hormones should be administered together, as described under Dosage and Administration. There were no response differences noted between types of cattle.

B. SUPPORTIVE STUDIES

  1. FSH IN CATTLE FOR 3, 4, OR 5 DAYS

    The purpose of this study was to evaluate the effects of 3 durations of treatment with 1 level of FSH when used to produce superovulation in cows and to determine whether the effects obtained differ between Holstein and beef-type cows.

    Sixty commercial cows of dairy (Holstein) or mixed beef breeds, ranging in age from 2 to 8 years, were acquired. Animals were grouped by breed and randomly assigned to 1 of 3 groups. The cows received 2 FSH injections, beginning 8 to 13 days after estrus, each containing 9.375 units FSH, as a fixed dose, daily for a period of 3, 4, or 5 days. The FSH dose used (9.375 units twice a day) was determined in another study (DOSE TITRATION STUDY). Thus cows treated for 3 days received 56.25 units, cows treated for 4 days received 75 units, and cows treated for 5 days received 93.75 units of FSH. To induce estrus, cloprostenol sodium (500 micrograms, 2 mL) was administered concurrently with the fourth injection of FSH. Cows were inseminated 4 to 22 hours after the detection of estrus with 1 straw of frozen semen.

    Embryos were collected 7 days after insemination by the standard nonsurgical technique. Pertinent parameters measured were total and transferable embryo production.

    RESULTS

    TREATMENT
    N=20/GROUP
    TOTAL DOSENUMBER OF
    TRANSFERABLE
    MEAN (S.D.)
    TOTAL OVA AND
    EMBRYOS
    MEAN (S.D.)
    3 DAYS (N=20)56.25 units1.25 (1.74)3.95 (4.40)
    4 DAYS (N=20)75.00 units5.95 (4.53)11.05 (7.25}
    5 DAYS93.75 units5.55 (6.05)8.20 (5.98)
    BREEDNUMBER OF
    RANSFERABLE
    MEAN (S.D.)
    TOTAL OVA AND
    EMBRYOS
    MEAN (S.D.)
    Holstein (N=28)5.04 (4.94)7.54 (5.00)
    Beef (N=32)3.56 (4.83)7.91 (7.79)

    Duration of treatment has a highly significant effect on embryo production. Three days is less effective than 4 or 5 days at this fixed dose. There were no significant breed effects or significant interactions.

    CONCLUSIONS

    The study results indicated comparable efficacy for SUPER-OV® administered at a total dose of 75 units given over 4 days or a total dose of 93.75 units given over 5 days. This supports the choice of 75 units as the optimum total dose, since there is no advantage to an increased dose.

C. CLINICAL FIELD TRIALS FOR SUPER-OV®.

  1. PIVOTAL

    The purpose of this study was to evaluate the selected dose of 12.5 units of SUPER-OV® twice a day for 3 days for the superovulation of cattle by independent operators under field conditions. In addition, the effects of the three prostaglandin products used in the study were evaluated. A control group (zero level of drug) was not required for this study, because in the normal bovine the rate of ovulation 86.9%(1) of the time is a single ovum.

    In the 3 x 2 trial, 122 cows of various ages and of beef and dairy breeds were superovulated by 5 investigators (one investigator conducted studies at 2 separate sites). The parameters measured were total and transferable embryo production.

    Cows were superovulated with a total dose of 75 units of SUPER-OV® given intramuscularly in 6 equal doses 12 hours apart. The first treatment was given 8 to 13 days after estrus was observed. A prostaglandin injection was given concurrently with the fifth SUPER- OV® injection. Prostaglandins used in this study included dinoprost tromethamine (dose 25 to 50 mg), cloprostenol sodium (dose 500 micrograms), or fenprostalene (dose 1 mg). Cows were inseminated with one or two straws of frozen semen 4 to 22 hours after the detection of estrus. Ova and embryos were collected by standard non-surgical technique 7 days after insemination, and classified by their microscopic appearance as transferable embryos, non-transferable embryos, and unfertilized ova. The group classification of total ova and embryos include all those listed above.

    Three prostaglandin products were selected by the investigators and nothing was done to control this variable. The investigator used the prostaglandin that was normally used in the practice. The effects of the prostaglandin used on the transferable/total embryos produced are presented in Table 2 (the prostaglandin used was not reported in 1.6% Of the cases).

    One investigator, Dr. J. Wiltbank, superovulated cows at two locations and his results are listed separately at each location. Following is a list of the investigators who participated in the pivotal clinical field studies:

    (1) Stephen J. Roberts, VETERINARY OBSTETRICS AND GENITAL DISEASES THERIOGENOLOGY (Woodstock, VT:Roberts, 1986), page 96.

    NAMEFIRMSTREET ADDRESSCITYSTATEZIP
    Dr. B. WatsonABC EmbryonicsRt. 1 Box 1080, Church Rd.PetersburgVA23833
    Dr. L. StrelowNorth Central Embryo Service1060 West Rock Grove Rd.OrangevilleIL61060
    Dr. J. WiltbankDept. Animal ScienceBrigham Young UniversityProvoUT84602
    Dr. Jesse AdkinsPlum Tree RanchRoute 2, Box 69BuffaloTX75813
    Dr. S. Vredenberg Route 2 Box 277CForest GroveOR97116

    RESULTS

    TABLE 1. RESULTS BY INVESTIGATOR

    INVESTIGATORNUMBER OF COWS
    TREATED
    TRANSFERABLE
    EMBRYOS±S.D
    TOTAL EMBRYOS
    ±S.D
    WATSON136.2±8.411.2±8.6
    STRELOW276.2±6.27.7±7.3
    VREDENBERG168.4±6.311.9±8.1
    ADKINS126.1±3.710.3±5.5
    WILTBANK (UT)143.1±3.33.5±3.4
    WILTBANK (ID)402.4±3.33.7±4.9
    TOTAL1224.9±5.67.1±7.1
    TABLE 2. EFFECTS OF THE PROSTAGLANDIN ON SUPEROVULATION
    PROSTAGLANDINPERCENT OF COWS
    TREATED (N=122*)
    TRANSFERABLE
    EMBRYOS±S.D.
    TOTAL EMBRYOS
    ±S.D
    fenprostalene30.3 (37)2.3±3.43.6±5.0
    cloprostenol sodium18.9 (23)5.0±6.98.0±7.8
    dinoprost tromethamine49.2 (60)6.5±5.79.0±7.2

    * Percent calculated using N=122. 1.67% (2/122) did not indicate the prostaglandin used.

    These 122 cows produced a mean (±S.D.) of 4.9±5.6 transferable embryos from 7.1±7.1 total embryos. All 3 prostaglandins were not equally effective in the superovulation of cattle in these studies. A significantly reduced number of transferable embryos were produced when fenprostalene was used as the prostaglandin in the superovulation process. Therefore, the following statement is found on the label: There is an inherent failure rate in the superovulation of cattle. In studies, with multiple investigators, using 12.5 units of SUPER-OV® twice a day for 3 days, with dinoprost tromethamine or cloprostenol sodium as the luteolytic agent, 20-35 % of the cows treated failed to superovulate. In cows treated by a single investigator, with fenprostalene as the prostaglandin, a higher failure rate was observed. Higher doses of SUPER-OV® did not increase the success rate of the procedure and should not be used. See the SAFETY AND TOXICITY section.

    CONCLUSION

    SUPER-OV® administered at a total dose of 75 units divided into 6 equal doses and administered at 12 hour intervals over 3 days is a safe and effective superovulation drug. In a study of this size, we cannot definitively determine the role of prostaglandins in the variable response (measured by total and transferable embryos and ova) to superovulation, but in this study there is a trend of decreased response in those animals which received fenprostalene as the prostaglandin to induce luteolysis.

 

V. ANIMAL SAFETY

NOTE: Unless otherwise indicated, the principle investigator in the following studies was:

Lloyd E. Donaldson MVSc, MRCVS, MACVSc, PhD
Ausa International Inc.
Rt. 8, Box 324-12,
Tyler, TX 75703.

A. REPRODUCTIVE EFFECTS STUDY FOR SUPER-OV®

The purpose of this study was to evaluate the effects of superovulation in cows on the ability of the cows to become pregnant either by natural breeding or artificial insemination subsequent to superovulation.

Parameter measured was pregnancy rate.

  1. Natural Breeding

    Additional Investigators:

    Dr. D. Atteberry,
    5649 Shawnee Heights Road,
    Tecumseh, KS 66542

    Dr. S. Vredenberg,
    Route 2 Box 277c
    Forest Grove, OR 97116

    One hundred and five commercial cows of Holstein or mixed beef breeds, ranging in age from 2 to 8 years, were used.

    Superovulated cows came mainly from other study treatments, namely the dose-response study, efficacy studies, and the duration - efficacy studies. Fifty-one cows (29 beef and 32 Holstein) that had been superovulated comprised the superovulated group. Fifty-four cows (33 beef and 22 dairy) from an experimental herd that had not been superovulated were randomly selected and allocated to the experiment as controls.

    All cows, superovulated and control, were turned out in a single pasture with 4 bulls for 6 weeks. The bulls were semen tested and found to be normal. Each bull was seen successfully serving a cow. Cows were rectally palpated for pregnancy and were not rechecked. The pregnancy checks were used to determine those cows which cycled, were bred and conceived, and a pregnancy rate for the mating period.

    In a separate clinical setting in Dr. Vrendenberg's practice, 8 superovulated cows were bred back naturally.

    RESULTS

    The first cycle pregnancy rates for control and superovulated cows were 61.1% and 68.6% (P=0.548); on the second cycle 61.9% and 64.7% (P=0.873); and for the six weeks breeding 85.2% and 88.2% (P=0.863).

    No breed effects were detected, pregnancy rates being 90.2% and 81.2% (beef vs. Holstein, P=0.342)

    In the 8 cows bred in Dr. Vrendenberg's practice, 6 (75%) became pregnant on the first service and 2 (25%) on the second service.

  2. Artificial Breeding

    Eighteen cows that were superovulated with 75 units SUPER-OV® were bred back by artificial breeding at the first estrus subsequent to the superovulation. These cows were pure-bred beef cows that were entered into a commercial embryo transfer program.

    Twenty-eight cows were superovulated and rebred artificially by Dr. Atteberry under clinical conditions.

    RESULTS

    For the 46 cows, the pregnancy rate on the first insemination was 40/46 or 86.9%, and on second insemination 3/4 or 75.0%.

    CONCLUSIONS

    This study indicated that superovulation did not have a negative effect on fertility at the breeding, natural or artificial, subsequent to superovulation and that there were no breed effects in the natural breeding group. This study demonstrates that a single superovulation does not have an adverse effect on subsequent fertility, but does not address the issue of repeated superovulation on subsequent fertility. Therefore, the following statement is found on the label under the heading, WARNINGS:

    The long term effect of SUPER-OV® and the effect of SUPER-OV® on the fertility of cattle at higher than recommended doses, for extended periods, or for multiple treatments in an individual, has not been assessed.

B. THE EFFECTS OF SEVERAL DOSE LEVELS OF SUPER-OV® ON EMBRYO RECOVERY AND REPRODUCTIVE TRACT MORPHOLOGY.

The purpose of this study was to determine the effects of SUPER-OV® at 4 dose levels on the morphology of the reproductive tract, specifically ovarian weight and the number and size of corpora lutea and follicles and to relate these parameters to dose of SUPER-OV® and to embryo production.

Fifty-five heifers were selected from a group of beef heifers. They were examined by rectal palpation and were selected if their reproductive tracts appeared to be normal, and they were cycling. Thirty heifers were used in control groups. Twenty-five were used in the treatment groups. The groups are found in the following table.

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

SUPER-OV® DOSENUMBER OF COWSNUMBER OF
INJECTIONS PER DAY
NUMBER OF DAYS
TREATED
0 Units202 injections4 days
75 Units172 injections4 days
56 Units62 injections4 days
112 Units62 injections4 days
187 Units62 injections4 days

Groups receiving 1 of 4 different doses of SUPER-OV® (56, 75, 112, or 187 units) were compared with an untreated (no SUPER-OV®) control group. All of these groups received norgestomet ear implants to synchronize estrous cycles. To establish that norgestomet did not affect embryo production or the number of corpora lutea, two additional control groups were used. One group remained untreated (no SUPER-OV® or norgestomet) and one group received 75 units SUPER-OV® (no norgestomet). Heifers were implanted with a synthetic progestin (norgestomet) on day 1. On day 8 the cows were started on an injection series of 8 SUPER-OV® injections 12 hours apart. Cloprostenol sodium (3 mL (500 mcg)) was administered at the time of the fifth SUPER-OV® injection in order to induce estrus. On day 11 at the time of the seventh SUPER-OV® injection, the ear implants were removed. The heifers were bred by artificial insemination 4 to 22 hours after being observed in estrus, or at 60 hours post-cloprostenol injection, if no estrus was observed. Injection sites were marked and shaved in selected animals.

Control heifers were treated with SUPER-OV® diluent only, and 10 were treated with an ear implant. All were treated and bred as described for the treated groups. Ten heifers were treated with 75 units of SUPER-OV®, but did not receive an ear implant.

Seven days after breeding, cows were slaughtered. Injection sites were examined for signs of tissue reaction, and tissue samples were taken from 10 animals (3 diluent treated and 7 SUPER-OV® treated) for histologic examination. The reproductive tracts were collected for embryo recovery and examination of tissues.

Parameters measured included the number of corpora lutea, corpus luteum weight, number of follicles, and total and transferable embryo production. The reproductive tracts were examined grossly at necropsy.

RESULTS

There were no gross effects of SUPER-OV® detected on the reproductive tract (uterus, oviducts, cervix, or anterior vagina), except for those described below which were found in the temporary ovarian structures (follicles and corpora lutea). No samples were taken for histology from the reproductive organs.

The data from 2 cows were excluded because they were not seen in estrus and their ovarian morphology confirmed that they did not satisfy the terms of the study.

There was no norgestomet effect on number of corpora lutea, transferable embryos, or total embryos, and there were no significant interactions. Therefore, the data could be pooled for further analysis.

Progressively increased doses of SUPER-OV® changed ovarian morphology by increasing the number of corpora lutea and large follicles and decreasing corpus luteum size and the number of small follicles.

Controls (0 dose) produced fewer corpora lutea than all other doses and fewer transferable embryos (0.5±0.7) than 56 units (5.7±6.3) or 75 units (3.2±3.6).

Controls produced fewer total embryos (0.9±0.6) than all other doses. Doses of 56 (12.7±8.0) and 112 units (14.5±8.8) produced more total embryos than the 75 units dose (4.5±4.5), but a lower percentage of them were transferable as indicated in the text below.

The percent of transferable embryos (used as a measure of quality) was higher in the control (50±52%) and the 75 unit dose (71±28%) groups. The percent transferable embryos was lower in the other dose groups (56 units, 32±31%;112 units, 33±39%; 187 units, 45±51%).

Ovarian weight for 0 dose was less than for all other doses. The increase in ovarian weight with SUPER-OV® treatment was due to an increase in the number of corpora lutea and total corpus luteum weight. Total number of follicles (unadjusted for size of follicle) was unchanged by SUPER-OV® treatment.

Small follicles (2-5mm in diameter) on control (0 dose) ovaries were reduced by SUPER-OV® treatment. There were dose effects on follicles 6-7mm in diameter, particularly in the 75 unit dose. Numbers increased from 0.4±0.6 for controls to 2.8±2.4 for 75 units and 3.7±5.3 for 187 units. However, there were fewer of these follicles in the 112 unit treatment (0.7±1.2) than in the 75 or 187 unit treatments.

Follicles of the next size category (8-10mm) were increased in number by SUPER-OV® treatment, but larger follicles (diameter 11-15mm) were unaffected. There were increases in the number of largest follicles (>15mm in diameter) in cows treated with SUPER-OV® from 0.2±0.4 at 0 levels to 2.3±2.7 at 187 units.

The injection sites were inspected at post-mortem, about 8 days after the last injection. Three mild inflammatory reactions were seen and were attributed to infectious agents introduced by the needle. Ten injection sites were examined histologically, 3 diluent treated controls, and 7 SUPER-OV® treated animals. No abnormalities were found.

CONCLUSIONS

SUPER-OV® was tested at dose rates sufficient to cause overstimulation. SUPER-OV® at the dose rates tested (0 to 187 units) changed ovarian morphology by decreasing the individual corpus luteum weight and increasing the number of corpora lutea and large follicles (temporary ovarian structures). An increased ovarian weight and a reduced number of transferable embryos occurred at the higher doses.

SUPER-OV® at the elevated dose rates tested caused a reduction in transferable embryos. At the recommended dose SUPER-OV® is safe for the superovulation of cattle.

No evidence of irritation at the injection sites, attributable to SUPER-OV®, was detected in this study, therefore, this product does not warrant a trim-out statement on the label. There was also no evidence of a SUPER-OV® effect on the morphology of the permanent structures of the reproductive tract (uterus, oviducts, cervix, or anterior vagina).

C. 10X DRUG TOLERANCE TEST OF SUPER-OV® INTRAMUSCULARLY ADMINISTERED TO DAIRY CATTLE.

This study was conducted to demonstrate the target animal safety of SUPEROV® intended for use in dairy cows. Three nonpregnant clinically healthy dairy (Holstein) cows, judged to be reproductively normal, were used for the study. SUPER-OV® was administered at a dose of 93.75 units twice daily at 12 hour intervals for 4 consecutive days (750 total units), a dose which is 10 times the use rate of 75 units.

Animals were euthanized by intravenous injection of a euthanizing agent. One cow was necropsied on day 3 following estrus, one on day 9, and one on day 20 (assuming that estrus occurred 1 day following the last SUPER-OV® injection.

Parameters measured were complete physical examinations, body weights, clinical observations (including rectal temperatures, behavior, appetite, respiration), feed consumption, clinical pathology tests including comprehensive hematology and serum biochemistry, and postmortem examinations of reproductive tract and injection sites.

RESULTS

Reproductively, the cows were judged to be normal prior to treatment. Changes noted following treatment included only the temporary ovarian structures (follicles and corpora lutea), and not the structural parts of the reproductive tract (uterus, oviducts, cervix, vagina, and mammary gland). The numbers and sizes of the ovaries and their structures are found in the table below:

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

COW NUMBER
(NECROPSY DAY)
RIGHT OVARY
NUMBER OF
FOLLICLES (CL'S)
[OVARIAN WEIGHT]
LEFT OVARY
NUMBER OF
FOLLICLES (CL'S)
[OVARIAN WEIGHT]
707 (3 days)12 (1) [26 9]8 (0) [18 g]
47 (9 days)6 (1) [19 g]7 (0) [10 g]
633 (20 days)3 (2) [16.3 g]3 (1) [15.2 g]

No abnormalities were seen pre- or post-treatment in hematological values or serum profiles. Microscopic lesions of injection sites included a single observation of sarcocystis resulting from sarcosporidia parasites in this cow. One injection site was represented, microscopically, by a mild focal hemorrhage. Another injection site grossly had evidence of subcutaneous hemorrhage and edema, which was not confirmed microscopically.

CONCLUSIONS

The 10X (750 units FSH) dose administered over a 4 day period appeared to have no observable toxic effects based on the ante-mortem or post-mortem parameters evaluated in this study.

 

VI. HUMAN FOOD SAFETY

A. Toxicity studies

Follicle stimulating hormone is not orally active; therefore, residues of follicle stimulating hormone are safe for human consumption, and toxicological studies were not required.

B. Residue studies

As there was no requirement for toxicological testing, tissue residue studies were not required and there is no tolerance, withdrawal period, or regulatory method for SUPER-OV® (follicle stimulating hormone)

 

VII. PATENTS

Patent #4,780,451 entitled "Composition and method for producing superovulation in cattle" expires October 25, 2005. Patent # 5,162,306 entitled "Composition anhttp://wcms.fda.gov/ucm/resources/wcm/sitestudio/d method for producing superovulation in mammals" expires October 25, 2005.

 

VIII. AGENCY CONCLUSIONS

The data submitted in support of this original NADA satisfy the requirements of section 512 of the act and demonstrate that SUPER-OV® follicle stimulating hormone (FSH), when used under its proposed conditions of use is safe and effective.

The agency has granted an exemption under 21 CFR 201.1 05 from the requirement for "adequate directions for use" in section 502 (f)(1) of the act for the FSH injection for intramuscular administration. Therefore, labeling will restrict this drug to use by or on the order of a licensed veterinarian. This decision was based on the following factors: (a) the process of superovulation should be undertaken only by those trained and qualified to perform embryo recovery and possible transfer, (b) the manipulation of the cow for superovulation requires an extensive knowledge of anatomy, physiology, pharmacology (including the use of other prescription drugs), biochemistry, endocrinology, and the use of aseptic technique, and this knowledge base is part of the training of the licensed veterinarian, and (c) the drug requires reconstitution for use.

No slaughter withdrawal or milk discard period is required for the use of 75 units of follicle stimulating hormone in heifers and cows.

Under section 512(c)(2)(F)(ii) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(ii)), this approval qualifies for 3 years of marketing exclusivity beginning on the date of approval because the application contains reports of new clinical or field investigations (other than bioequivalence or residue studies) essential to the approval and conducted or sponsored by the applicant.

Patent #4,780,451 entitled "Composition and method for producing superovulation in cattle" expires October 25, 2005. Patent # 5,162,306 entitled "Composition and method for producing superovulation in mammals" expires October 25, 2005.

 

IX. LABELING

  1. SUPER-OV® Package Insert
  2. Superovulation of Cattle with SUPER-OV® Recommended Procedure
  3. SUPER-OV® Vial Label, Diluent Label, Package Label

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