Reproductive performance was evaluated in the following studies individually and from a pooled analysis:
Multi-lactation Chronic Animal Toxicity Study (TAS)
Multi-location SC Dose Response Clinical Study (4 Dose-SC)
Multi-location IM Single Dose Study (Single Dose-IM)
IM Dose Titration Study (Dose-IM)
IM/SC Bridging Study (IM/SC)
The experimental design and methods for each of these studies are described in Sections 6.b, 5.a, 6.e, 6.d, and 6.c, respectively. Location-specific practices were followed for vaccination programs, sire selection, management of reproductive problems, and calving management. All cows received a veterinary examination to evaluate reproductive health prior to initiation of the breeding program. All breeding was by artificial insemination. Estrus detection was by visual appraisal of standing estrus according to the following system: 1 = standing heat; 2 = bulling, sniffing, and attempting to mount other cows; 3 = bawling and restlessness; 4 = clear vaginal discharge, vulva lips swollen and/or flabby; 5 = metestrus bleeding; 6 = other, when 1-5 did not apply, explained in an observation column. Some locations may also have used heat detection aids such as heat mount detectors or tailhead chalking. Use of prostaglandins and gonadotropins to induce fertile estrus was not restricted in the IM studies and normal location practices were allowed. In the 4 Dose-SC study, use of any medication to alter the normal cycle was not allowed until after 120 days in milk. No restriction, however, was placed on the use of these products to treat a diagnosed ailment such as cystic ovarian disease or pyometra. Data were analyzed using all available information and again, separately, excluding those cows that received any medication intended to alter the estrous cycle. Since the trends regarding the effects of sometribove treatment on reproduction were the same in either case, only the overall analysis is discussed.
All locations participated in a routine herd health program. Pregnancy status was determined by rectal palpation by the herd veterinarian or other qualified person at regular intervals. This information was used to determine the conception date and to identify any loss of a previously diagnosed pregnancy. At parturition, a calving ease score was assigned, with increasing calving difficulty indicated by increasing score. Calving ease scores were as follows: 1 = an unassisted delivery in which progressive fetal expulsion continued throughout and labor did not exceed 3 or 5 hours for multiparous or primiparous cows, respectively; 2 = a multiparous or primiparous cow delivered a calf after prolonged or difficult unassisted labor of >3 or >5 hours, respectively; 3 = manual assistance (traction only) was required; 4 = delivery was assisted due to improper calf positioning for parturition; 5 = calving occurred unobserved. Scores were grouped into high (scores 2, 3, and 4) versus low (score 1) calving difficulty for analysis. All calves were weighed at birth.
Data from each of the five studies were analyzed separately by parity. Data were then pooled where appropriate, i.e., where similar sometribove doses and similar reproductive management techniques were used, and analyzed by parity to allow the most complete evaluation of the effects of sometribove on reproduction. In all IM studies (including the IM/SC Bridging Study), attempts to breed cows began at approximately 40 days after calving. Because of this, approximately 40 % of all cows on these studies received at least one insemination prior to the first sometribove administration. In the 4 Dose-SC study, all inseminations occurred after the first administration of sometribove. For this reason, pooling across the IM and SC studies was not possible. Thus, the data from clinical studies using the IM route of administration were pooled for the control and 500 mg doses (including only the IM injected cows from the IM/SC study) and analyzed as the "Pooled IM" studies, and the 4 Dose-SC study was analyzed separately. Finally, the TAS Study was evaluated separately from the other studies because of the higher doses used.
Reproductive variables were analyzed over several separate study periods. In the Pooled IM studies, where breeding was initiated prior to sometribove treatment, reproductive performance was evaluated in the pretreatment period to determine, among other things, whether breedings occurring within a few weeks of initiating sometribove treatment resulted in greater failure in conception rates. Reproductive performance in the Pooled IM studies was also evaluated from the initiation of sometribove treatment (i.e., approximately 60 days postpartum) until the breeding cut-off (i.e., days postpartum in which attempts to breed a cow ceased), which was set at 170 days in these studies. Finally, reproductive performance over the entire breeding period (pretreatment through 170 days postpartum) was evaluated. In the 4 Dose-SC study, breeding initiated after the start of sometribove treatment and continued until at least 305 days postpartum. Evaluation of reproductive performance in this study covered the periods from 60 to 180 days postpartum, and from 60-305 days postpartum. (For example, for the 60-180 day evaluation, if a cow conceived at 250 days postpartum, she was nevertheless classified as "open" in the analysis.) Finally, in both the Pooled IM and 4 Dose-SC analyses, reproductive performance across dose groups was evaluated during the first 28 days of sometribove treatment to determine whether negative effects, if any, were predominantly associated with the earliest period of treatment when treated cows usually had a reduction in energy balance compared to controls. It should be noted that individual cows were only included in the periods of analysis for variables in which they were "eligible." For example, in the Pooled IM studies, a cow conceiving to a full-term pregnancy prior to the initiation of sometribove treatment was excluded from the day 60 to 170 analyses for selected variables because she was already pregnant. However, if she lost the fetus prior to 170 days postpartum, she would have been included in the day 60 to 170 analyses for these variables because she was once again eligible for breeding.
A glossary of terms is included at the end of this Section (Table 65) and reflects most of the variables analyzed. Results of the analyses during the pretreatment period did not indicate that initiation of sometribove treatment shortly after breeding adversely affected conception or other reproduction indices. Effects during the first 28 days of treatment were not substantially different from those observed during the remainder of the breeding period.
The results of reproductive performance in the TAS study from days 60-140 postpartum in Year 1 and days 60-275 postpartum in Year 2, in the Pooled IM studies from day 60 to 170 postpartum, and the 4 Dose-SC study from days 60-180 postpartum in general were found to reflect the effects of sometribove treatment during the entire breeding period. Based on these data, both primiparous and multiparous cows experienced a reduction in pregnancy rates (see Table 61) and variables related to pregnancy rate (e.g., conception rate and successful calving rate). Primiparous cows had an increase in days open (see Table 62). Administration of sometribove was also associated with an increased rate of twinning and an increase in the incidence of cystic ovaries (Tables 63 and 64). Other parameters of reproductive performance, such as days to first estrus and insemination, interestrous interval, services per conception and incidence of fetal loss were not consistently affected by the administration of sometribove.
Conclusions
The product labeling states that treatment of cows with sometribove may result in reduced pregnancy rates and an increase in days open for primiparous cows. Also, the incidence of cystic ovaries and multiple births may increase. The labeling recommends the implementation of a comprehensive and ongoing herd reproductive health program preceding use of sometribove.
(Eds. note: The following table consists of 6 columns.)
Table 61. Pregnancy rates (full term).
TAS Study1
Dose 0 mg 600 mg 1800 mg 3000 mg P
Year 1; days 60-140 of lactation
Primiparous 100 % (3/3)2 43 % (3/7) 40 % (2/5) 20 % (1/5) .078
Multiparous 100 % (10/10) 45 % (5/11) 43 % (3/7) 50 % (6/12) .072
Year 2; days 60-275 of lactation
Primiparous 100 % (4/4) 100 % (2/2) 50 % (1/2) 0 % (0/1) .016
Multiparous 100 % (10/10) 17 % (1/6) 100 % (4/4) 75 % (6/8) .916
Pooled IM Analyses; days 60-170 of lactation3
Dose 0 mg 500 mg P
Primiparous 90 % (37/41) 63 % (30/48) .002
Multiparous 77 % (89/115) 70 % (90/129) .115
4 Dose-SC Study; days 60-180 of lactation1
Dose 0 mg 250 mg 500 mg 750 mg P
Primiparous 77 % (20/26) 63 % (17/27) 70 % (19/27) 80 % (20/25) .680
Multiparous 86 % (30/35) 62 % (21/34) 66 % (21/32) 66 % (23/35) .105
1 Linear trend in proportions across dosage levels
(Cochran-Armitage).
2 Number of cows pregnant full term divided by number of cows in
group.
3 Cochran-Mantel-Haenszel Chi-square test for difference between
control and treated.
(Eds. note: The following table consists of 7 columns.)
Table 62.
Days Open A (average number of days from calving to final
conception for cows pregnant to term).1
TAS Study Probability
Dose 0 mg 600 mg 1800 mg 3000 mg A2 B3
Year 1; days 60-140 of lactation
P4 77±13.2(3)5 101±13.2(3) 91±16.2(2) 125±22.9(1) .372 .180
M4 95± 8.5(10) 96±12.0(5) 86±15.5(3) 91±11.0(6) .945 .616
Year 2; days 60-275 of lactation
P 93±23.9(4) 196±33.9(2) 64±47.9(1) ± (0) .116 E
M 107ab±10.4(10) 223c±32.9(1) 84a±16.5(4) 135b±13.4(6) .006 .182
Pooled IM Analyses; days 60-170 of lactation
Dose 0 mg 500 mg A
P 89a±5.0(37) 105b±5.0(30) .024 --
M 101±4.2(89) 103±3.5(90) .646 --
4 Dose-SC Study; days 60-180 of lactation
Dose 0 mg 250 mg 500 mg 750 mg A B
P 102a±6.8(20) 112a±7.6(17) 103a±7.2(19) 131b±7.5(20) .024 .017
M 106±6.5(30) 115±7.7(21) 109±8.5(21) 110±7.6(23) .817 .836
a,b,c Means within a row with different superscripts are
significantly different (P< .10).
1 Least-squares analysis; results reported as least-squares
means ± SE of least-squares means.
2 A = Probability of dose main effect.
3 B = Probability of linear contrast (E = all doses are not
present).
4 P = Primiparous; M = Multiparous.
5 Number of cows included in analysis.
(Eds. note: The following table consists of 6 columns.)
Table 63. Rate of multiple births (full-term pregnancies). TAS Study1 Dose 0 mg 600 mg 1800 mg 3000 mg P Year 1; days 60-140 of lactation Primiparous 0.0 % (0/3)2 0.0 % (0/3) 0.0 % (0/2) 100.0 % (1/1) .025 Multiparous 0.0 % (0/10) 0.0 % (0/5) 0.0 % (0/3) 0.0 % (0/6) 1.000 Year 2; days 60-275 of lactation Primiparous 0.0 % (0/4) 0.0 % (0/2) 0.0 % (0/1) 0.0 % (0/0) 1.000 Multiparous 0.0 % (0/10) 100.0 % (1/1) 25.0 % (1/4) 16.7 % (1/6) .411 Pooled IM Analyses; days 60-170 of lactation3 Dose 0 mg 500 mg P Primiparous 2.9 % (1/34) 20.8 % (5/24) .016 Multiparous 1.2 % (1/86) 13.6 % (11/81) .003 4 Dose-SC Study; days 60-180 of lactation1 Dose 0 mg 250 mg 500 mg 750 mg P Primiparous 5.0 % (1/20) 5.9 % (1/17) 5.3 % (1/19) 10.0 % (2/20) .560 Multiparous 13.3 % (4/30) 4.8 % (1/21) 9.5 % (2/21) 13.6 % (3/22) .936 1 Linear trend in proportion across dosage levels (Cochran-Armitage). 2 Number of cows with multiple births (full term) divided by number of cows with full-term pregnancies. 3 Cochran-Mantel-Haenszel Chi-square test for difference between control and treated.
(Eds. note: The following table consists of 7 columns.)
Table 64.
Incidence of cystic ovaries (number of cases, number of cases per
100 cow days, and number of cows affected).
TAS Study
Dose 0 mg 600 mg 1800 mg 3000 mg P
Year 1; days 60-140 of lactation
P1 # cases 0 2 0 2
# /100 d2 0.00 0.53 0.00 0.51 .887
# cows3 0 (3)4 2 (7) 0 (5) 2 (5) .425
M1 # cases 1 3 4 0
# /100 d 0.42 0.50 1.32 0.00 .279
# cows3 1 (10) 2 (11) 2 (8) 0 (12) .390
Year 2; days 60-275 of lactation
P # cases 0 1 0 2
# /100 d 0.00 0.36 0.00 2.35 .087
# cows3 0 (4) 1 (2) 0 (2) 1 (1) .143
M # cases 3 13 1 2
# /100 d 0.64 1.62 1.02 0.31 .113
# cows3 2 (10) 2 (6) 1 (4) 2 (8) .916
Pooled IM Analyses; days 60-170 of lactation
Dose 0 mg 500 mg P
P # cases 3 14
# /100 d 0.21 0.48 .183
# cows5 3 (41) 9 (48) .108
M # cases 21 55
# /100 d 0.36 0.70 .018
# cows5 17 (117) 34 (130) .048
4 Dose-SC Study; days 60-180 of lactation
Dose 0 mg 250 mg 500 mg 750 mg P
P # cases 13 19 7 15
# /100 d 0.86 1.03 0.50 0.76 .694
# cows3 5 (26) 8 (27) 5 (27) 12 (25) .065
M # cases 10 11 21 17
# /100 d 0.50 0.42 0.97 0.74 .120
# cows3 6 (35) 7 (34) 10 (32) 9 (35) .265
1 P = primiparous; M = multiparous.
2 Poisson regression.
3 Linear trend in proportions across dosage levels
(Cochran-Armitage).
4 Number of cows included in analysis.
5 Cochran-Mantel-Haenszel Chi-square test for differences
between control and treated.
(Eds. note: The following table consists of 2 columns.)
Table 65. Glossary of Reproduction Terms
Number of Cows Total number of cows available for analysis.
Estrous Period Period of time the cow is receptive to breeding
activity. Generally defined by immobility during
mounting attempts of other cows. Activity is scored
(see below) and all scores within a 4 day period are
considered to be a single estrous period. The first
date of the 4 day period is used as the date of
estrus which is used to calculate interestrous
interval. The last date of the 4 day period is used
to assign estrous period to a particular study period.
Total Estrous Total number of estrous periods during a given time.
Periods This excludes estrous periods after conception in
full term pregnancies and after conception and up to
fetal loss in cows that later lost a pregnancy.
Average Number of The average number of estrous periods during a given
Estrous Periods time. Same exclusions as for Total Estrous Periods.
Interestrous Average number of days between all estrous periods.
Interval Same exclusions as for Total Estrous Periods.
First Interestrous Average number of days between the first estrous
Interval period and the second estrous period. Same
exclusions as for Total Estrous Periods.
Second Interestrous Average number of days between the second estrous
Interval period and the third estrous period. Same exclusions
as for Total Estrous Periods.
Expected Estrous Calculated by using the open days divided by 21.
Periods
Days to First Estrus Average number of days to first observation of
estrus. Definitions for estrous scores follow:
1 = Standing estrus.
2 = Bulling, sniffing and attempting to mount other cows.
3 = Bawling and restlessness.
4 = Clear vaginal discharge, vulva
lips swollen and/or flabby.
5 = Metestrus bleeding.
6 = Other; when 1-5 does not apply, explain in
observation column.
Total Inseminations The total number of inseminations for all cows within
a group.
Average Number of The average number of inseminations per cow within a
Inseminations group.
First Insemination The average number of days between the first and
Interval second insemination.
Second Insemination The average number of days between the second and
Interval third inseminations.
Inseminations/Estrus The average number of inseminations per estrous
period.
Missed Inseminations The total number of estrous periods for which there
is no insemination and no insemination occurs within
24 hours after the end of an estrous period.
Days to First Average number of days to first insemination.
Insemination
Days From First Average number of days from the first estrus to
Estrus to Pregnancy conception, resulting in full term pregnancy (250
days gestation).
Days From First Average number of days from the first insemination to
Insemination to conception, resulting in full term pregnancy.
Pregnancy
Days Between Average number of days between inseminations.
Inseminations Includes all inseminations excluding those occurring
after conception date resulting in full term
pregnancy.
Services/Conception Average number of inseminations per cow required to
attain full term pregnancy.
Days From Average number of days from the first injection of
Initiation of sometribove to conception, resulting in full term
Treatment to pregnancy.
Pregnancy
Days Open A Average number of days from calving to conception for
cows pregnant to term.
Days Open B Average number of days from calving to conception,
for cows pregnant full term, or to upper limit of
breeding period in days postpartum for cows not
pregnant full term (e.g., if breeding cut off was 180
days, cows not pregnant by this time were assigned
180 days open).
Median Days Open The value for days open for pregnant cows above and
below which there are an equal number of values.
Calving Interval Average number of days between successive
parturitions for full term pregnancies.
Days Carried Calf Average number of days cows were pregnant between
During Treatment conception date and the last injection date plus 14
days (end of last cycle) or the date of diagnosed
late fetal loss or early fetal loss whichever
occurred first.
Percent of Cows Number of cows inseminated divided by total number of
Inseminated cows available for breeding.
Conception Rate Number of cows that conceived (diagnosed pregnant by
palpation per rectum at any time after insemination)
divided by the number of cows that were inseminated.
Fertilization Rate Number of cows which conceived at least once divided
by the number of inseminations for cows which
conceived.
First Service The number of conceptions from the first insemination
Pregnancy Rate resulting in full term pregnancy divided by the
number of cows receiving the first insemination.
Second Service The number of conceptions from the second
Pregnancy Rate insemination resulting in full term pregnancy divided
by the number of cows receiving the second
insemination.
Third Service The number of conceptions from the third insemination
Pregnancy Rate resulting in full term pregnancy divided by the
number of cows receiving the third insemination.
Combined Pregnancy The number of conceptions from the first three
Rate inseminations combined resulting in full term
pregnancy divided by the number of cows receiving the
first three inseminations.
Pregnancy Rate Number of cows pregnant full term divided by the
number of cows in the group.
Full Term Pregnancy Gestation length >=250 days and < =314 days.
Unsuccessful Calving A cow which meets one of the following criteria:
1. Calves < 250 or > 314 days gestation.
2. Dies within 7 days of parturition or does not lactate
after parturition.
3. Calf dies within 24 hours after birth.
4. Cow was removed from herd within 7
days of parturition.
Unsuccessful Includes all cows in "unsuccessful calving" plus any
Reproduction cow that does not calve for any reason.
Successful Calving Number of cows delivering a calf at greater than or
Rate equal to 250 and less than or equal to 314 days of
gestation divided by the number of cows in the group.
Also the cow must have lived 7 days and the calf 24
hours postpartum. The cow must not have been removed
from the herd within 7 days postpartum.
Total Fetal Loss The sum of all fetal loss categories including early
fetal loss, late fetal loss, stillbirth and other
fetal loss.
Early Fetal Loss Pregnancy loss at < 70 days gestation.
Late Fetal Loss Pregnancy loss >=70 and < 250 days of gestation.
Stillbirth Pregnancy loss at >=250 and <=314 days of gestation.
Gestation >314 days. Calf dies within 24 hours after
birth.
Other Fetal Loss Pregnancy loss that does not fit into early fetal
loss, late fetal loss or stillbirth definitions
includes unexpected circumstances such as death of
the cow (natural or euthanized).
Cystic Ovary A cow is determined to have a cystic ovary if at
least one diagnosis of cystic ovary has been made
based on rectal palpation.
Incidence Rate of Duration of cystic ovarian condition divided by 30.
Cystic Ovaries
Conception Rate Number of cows that conceived at least once after a
After Cystic Ovary diagnosis of cystic ovary has been made divided by
the number of cows diagnosed with the condition.
Treatment Rate for The number of times a cow was treated (GnRH, HCG,
Cystic Ovaries Prostaglandins, Rupture) for a cystic ovary divided
by the number of cows diagnosed with the condition.
Insemination Passage of an insemination pipette and deposition of
semen in the reproductive tract of the female.
Excluded Cows for Cows receiving reproductive aids such as
PGF prostaglandins, HCG, or GnRH to induce a fertile
estrus were dropped from analysis of a given variable.
HCG Human Chorionic Gonadotropin. Used as a source of
luteinizing hormone for the treatment of cystic
ovaries or to induce ovulation.
GnRH Gonadotropin Releasing Hormone. Used to cause
endogenous release of luteinizing hormone for the
treatment of cystic ovaries or to induce ovulation.
P4 Kit Milk progesterone test. A test to determine the
concentration of progesterone in milk for the purpose
of confirming estrous behavior.
The effect of sometribove treatment on clinical mastitis, subclinical mastitis and somatic cell count (SCC) was evaluated from the following studies in separate and pooled analyses:
Multi-lactation Chronic Animal Toxicity Study (TAS)
Multi-location SC Dose Response Clinical Study (4 Dose-SC)
Multi-location IM Single Dose Study (Single Dose-IM)
IM Dose Titration Study (Dose-IM)
IM/SC Bridging Study (IM/SC)
The experimental design and sample collection schedule for each of these studies has been described (Sections 6.b, 5.a, 6.e, 6.d, 6.c, respectively).
Since the individual effectiveness trials lacked sufficient numbers of animals to examine any association between use of sometribove and effect on mastitis and milk somatic cell count, data from studies were pooled in order to augment animal numbers and increase the reliability of conclusions. As discussed in Sections 5.a and 6.e, data collected at one location (Utah) from the 4 Dose-SC study and the same location in the Single Dose-IM study were excluded from the clinical and subclinical mastitis analysis. Clinical mastitis was rarely treated during these trials, possibly affecting the incidence of mastitis and confounding any effects due to sometribove.
For clinical mastitis, data from the 4 Dose-SC, Single Dose-IM, Dose-IM and IM/SC studies (i.e., 8 trials) were pooled for analysis. The TAS study was excluded from the pooled analysis because of the higher doses used. A separate analysis of this study was carried out. For subclinical mastitis, data from the 4 Dose-SC study were pooled with the IM/SC study and the Dose-IM study. Finally, for somatic cell counts, several analyses were carried out on data from individual studies and on pooled data.
Detection of clinical mastitis.
In all studies, milkers were responsible for the detection of abnormal milk by the examination of foremilk from each quarter at each milking. There was some variation from location to location in routine practices and therapy related to mastitis. However, within a given location, control and sometribove-treated cows were assessed and administered therapy for mastitis by identical procedures.
Detection of subclinical mastitis.
Milk samples were obtained for determination of subclinical mastitis by microbiological culture once before initiation of treatment with sometribove and at approximately 8 week intervals during the treatment period.
Determination of SCC.
Milk samples for determination of SCC were taken once per week throughout the study for all of the studies. All determinations were done by independent laboratories.
Definitions.
Case Rate was the number of clinical mastitis cases per quarter per cow-day when a new case could be observed. Twenty-one (21) days must have elapsed between observations within a quarter or a new pathogen isolated for separate cases to be identified.
Days Affected Rate was the number of days affected per cow-day observed. Cases in more than one quarter on a given day were consolidated in this variable. Essentially, a yes/no response was created for each animal each day.
Results:
Clinical Mastitis
In the pooled analysis (excluding the TAS study), there was a total of 202911 quarter days when new cases could have been observed for 193 primiparous cows and 408468 quarter days when new cases could have been observed in 426 multiparous cows. Because of overlap, days observed were slightly smaller than one quarter of these values; primiparous cows were observed on 51069 days and multiparous cows on 103125 days.
Cochran-Mantel Haenszel (CMH) measures of general association were used to test for association, controlling various effects. Analyses were done (1) separately by parity, (2) controlling for parity, and (3) ignoring (collapsing) parity. There was an association between sometribove usage and the number of cows affected with clinical mastitis. Comparing the proposed use level (500 mg) to control, the relative risk of a treated animal showing signs of clinical mastitis during the treatment period was about 1.79 times that of a control animal (Table 66).
(Eds. note: The following table consists of 4 columns.)
Table 66. Pooled analysis (0 and 500 mg sometribove only)
-------- Relative risk (500 mg/0 mg)-----------
Parity handling Estimate 95 % Confidence 95 % Confidence
Lower Bound Upper Bound
Primiparous 1.969 0.944 4.098
Multiparous 1.745 1.214 2.506
Controlled for Parity 1.789 1.292 2.475
Poisson-based regression was used to estimate the probability of observing a new case on a quarter-day when a new case could be observed. Case Rate per cow-day could then be obtained by assuming independence of the quarters. The probability was then the sum of the probabilities in each of the four quarters in the udder, or four times the probability in any one quarter. Poisson-based regression was also used to estimate the probability that a cow would be affected with clinical mastitis on any given day. The regression coefficients were used to calculate predicted Case Rates and Days Affected Rates for a standard treatment period of 252 days. Case Rate was increased for primiparous cows, with an expected 0.21 cases per control animal and 0.37 cases in treated (500 mg) primiparous cows. Case Rate was also increased for multiparous cows, with an expected 0.36 cases of clinical mastitis in control animals and 0.54 cases in treated (500 mg) cows. The total Days Affected Rate for primiparous cows was not increased by treatment with sometribove. For multiparous cows, Days Affected Rate was increased from 1.49 in controls to 2.15 in treated (500 mg) animals. The results from this analysis are presented in Table 67. The P value reported in Table 67 refers to the probability associated with the regression, not to the comparison between the 0 and 500 mg dose group.
(Eds. note: The following table consists of 4 columns.)
Table 67.
Comparison of expected mastitis Cases and total Days Affected for
control and sometribove-treated cows -pooled analysis assuming a 252 day
standardized treatment period.
------- Study Groups -------
Parity Group Control Sometribove1 P
Primiparous Cows
Cases 0.21 0.37 0.0147
Days Affected 1.15 1.21 0.6779
Multiparous Cows
Cases 0.36 0.54 0.0021
Days Affected 1.49 2.15 0.0001
1 Expected results for the 500 mg/14 day dose group.
A separate analysis was conducted for the TAS study because the range of doses of sometribove was considerably different from the range in the remainder of the studies. Over two years of treatment, this study covered 32961 quarter days when new cases could be observed in 27 primiparous cows (8466 days with overlap). In 56 multiparous cows, there were 76823 quarter days when new cases could be observed, which covered 19820 days, considering overlap. Although there was numerical evidence for a dose related increase in Case Rate and Days Affected Rate in this study, the high background level of clinical mastitis resulted in no significant differences detected in the pooled analysis at the use level of the drug (500 mg) although the linear trend was significant (Table 68).
(Eds. note: The following table consists of 4 columns.)
Table 68.
Comparison of expected mastitis Cases and total Days Affected for
control and 500 mg sometribove-treated cows - TAS study assuming a 252 day
standardized treatment period.
----- Study Groups -----
Parity Group Control Sometribove P
Primiparous Cows
Cases 0.95 1.07 0.0784
Days Affected 3.50 4.33 < 0.0001
Multiparous Cows
Cases 0.97 1.13 < 0.0001
Days Affected 4.43 5.62 < 0.0001
The average duration of clinical cases of mastitis was evaluated between control and sometribove (all doses) treated cows in the 8 clinical trials and TAS study, with parities pooled (Table 69).
(Eds. note: The following table consists of 3 columns.)
Table 69.
Average duration (in days) of cases of clinical mastitis in
control and sometribove-treated cows.
Sometribove Dose (mg/14 days)
Trial 0 mg All Sometribove
Doses
Arizona IM 4.5 4.0
Arizona SC 4.0 5.9
Cornell IM 4.1 3.6
Cornell SC 2.0 4.1
Florida SC 2.0 3.3
Dardenne IM 5.2 4.3
Dose-IM 5.0 4.7
IM/SC 3.0 5.5
Weighted Average 4.5 4.6
of Clinical Trials
TAS Study (Year 1) 5.4 5.5
The average case duration in controls versus treated cows in these clinical trials was 4.5 versus 4.6 days; in the TAS study the average durations were 5.4 versus 5.5 days, respectively. Thus, the increased total days affected with clinical mastitis in sometribove-treated cows reflected the greater number of clinical mastitis cases and not increased average duration per case.
Subclinical Mastitis
Analysis of subclinical mastitis on a per cow basis indicated that treatment with sometribove significantly increased the number of animals with this condition. The relative risks for contracting subclinical mastitis for the 250, 500, and 750 mg groups were 1.56, 1.55, and 1.51, respectively, compared to controls (Table 70).
On a quarter basis, the results showed a general association between sometribove level and testing positive for subclinical mastitis (P=0.001) for all dose levels. The relative risks for testing positive for subclinical mastitis for the 250, 500, and 750 mg groups were 1.60, 1.81, and 1.52, respectively, compared to controls (Table 70). A separate analysis (results not shown) indicated that for the four microbiological categories evaluated (i.e., pathogen, coagulase negative Staphylococcus (CNS), environmental, and other), at the use level of the drug the "pathogen" and the "CNS" categories were statistically significant (P=.001) for general association.
(Eds. note: The following table consists of 4 columns.)
Table 70.
The effect of sometribove treatment at various dosages on the
relative risk for occurrence of subclinical mastitis compared to
controls.
------------ Sometribove Dose ------------
250 mg 500 mg 750 mg
Per cow basis
Relative risk 1.56 1.55 1.51
Probability <.001 <.001 .003
Per quarter basis
Relative risk 1.60 1.81 1.52
Probability .001 .001 .001
Somatic Cell Counts (SCC)
Several analyses were conducted on somatic cell count (SCC) data from the TAS, 4 Dose-SC (all four locations), Single Dose-IM (all four locations), Dose-IM, and IM/SC studies.
First, data from each study location were analyzed individually by parity. Sometribove treatment resulted in significantly higher SCC (P< 0.10) for the following location-parity groups: Dardenne IM (multiparous only), Cornell IM (multiparous only), Arizona IM (multiparous only), Dose-IM (multiparous only), Utah SQ (multiparous only), and TAS year one (primiparous only).
Data were then pooled for the Single Dose-IM (excluding the Utah location) study. Analyses showed that multiparous cows treated with 500 mg sometribove had significantly higher SCC than control multiparous cows. Also, when parities were pooled, SCC were statistically higher in treated cows (Table 71).
Results were also pooled from the 4 Dose-SC (excluding the Utah location), Dose-IM, and IM/SC studies. This analysis revealed no significant increase in SCC due to sometribove treatment (Table 72).
(Eds. note: The following table consists of 4 columns.)
Table 71. Least-squares means for log (base 10) transformed SCC data pooled
across Dardenne, Arizona, and Cornell IM clinical trials.
Sometribove Dose (mg)
Parity Group (n) 0 500 P
Primiparous (68) 4.88 4.94 .2875
Multiparous (223) 5.03 5.15 .0001
Pooled parities (291) 4.99 5.10 .0001
(Eds. note: The following table consists of 6 columns.)
Table 72. Least-squares means for log (base 10) transformed SCC data pooled across Arizona SC, Cornell SC, Florida SC, Dose-IM, and IM/SC trials.
-----Sometribove Dose (mg)----- Parity Group (n) Control 250 500 750 P Primiparous (126) 4.86 4.94 4.86 4.88 .6021 Multiparous (205) 4.97 5.05 5.03 5.05 .1997 Pooled parities (331) 4.93 5.01 4.97 4.99 .1391
Conclusions:
Administration of sometribove (500 mg/14 days): 1) increases the risk of clinical mastitis in both primiparous and multiparous cows; 2) increases the number of cases of clinical mastitis in both primiparous and multiparous cows; 3) increases the risk of subclinical mastitis in both parity groups; and 4) increases milk somatic cell counts in some herds. The product labeling advises of these effects to inform the user of risks associated on a per animal basis. Also, the labeling states that herd mastitis management practices should be thoroughly evaluated prior to initiating the use of sometribove.
FDA also concluded that the increase in clinical mastitis in sometribove-treated cows was not a public health concern with respect to antibiotic residues in milk being increased above tolerance due to therapeutic treatment of mastitis. Although the incidence of clinical mastitis was increased in treated cows, there was no indication that these cases of mastitis were more difficult to treat, as reflected by the similar average duration of cases between treated and control cows. When examined on a per unit milk basis, the increase in the incidence of clinical mastitis due to sometribove (approximately 0.1 case per cow per year) is about 4 to 9 times less than the effects due to other sources of variation, such as season, parity, stage of lactation, and herd-to-herd variation. For example, on a per unit milk basis, the increase in mastitis incidence from winter to summer is at least nine times greater than the increase due to sometribove treatment. Also, the increase in mastitis between early lactation (when sometribove would not be administered) compared to late lactation is at least seven times greater than the effect of sometribove. (See references by Smith et al. [1985, J. Dairy Science 68:1531]; Morse et al. [1988, J. Dairy Science 71:848]; and Hogan et al. [1989, J. Dairy Science 72:1547]).
Another important factor is that therapeutic drugs, such as antibiotics for the treatment of clinical mastitis, are to be used in food-producing animals only under approved conditions and with appropriate withdrawal periods (as established by FDA) to ensure that food products are safe for human consumption. State and Federal regulatory bodies currently monitor milk supplies for drug residues, and any milk that contains illegal residues is discarded. In addition, the dairy industry currently tests every tanker truck of milk for penicillin-like, beta-lactam drugs prior to processing. The beta-lactams are the most commonly used drugs for the treatment of mastitis so that even if an increase in use of these drugs--and an increase in illegal residues--occurred as a result of increased mastitis, any residues would result in the rejection of the milk before it could enter the market.
Allergic reactions are the most common side effect of the beta-lactam antibiotics, the predominant therapeutic treatment for clinical mastitis, and these agents are the most common cause of drug allergies. Three to 10 % of the human population is allergic to penicillin. Penicillin allergies develop following long-term (weeks) exposure to high doses (therapeutic). Once an individual is allergic to penicillin, smaller doses can cause an allergic reaction. Typically these reactions consist of a skin rash and are not considered to be significant health risks. In the last 25 years, there have been less than 10 cases of allergic reactions worldwide following the consumption of penicillin residues in milk (Dewdney et al., 1991, Food Chem. Toxicol. 21:477-483). All of these adverse reactions involved penicillin residues in the milk at levels well above FDA's current tolerance of 5 parts per billion (ppb). Currently, the commonly used screening test for beta-lactam residues in milk is the Bacillus stearothemophilus disc assay, which detects penicillin residues at >=3-5 ppb. This provides an indication of the magnitude of the public health concern for violative antibiotic residues in food.
In view of the much larger variation in the number of clinical mastitis cases due to other factors, the monitoring of milk for illegal drug residues, and the minuscule public health concern for beta-lactam antibiotic residues in milk, FDA concluded that the use of sometribove was not important in considering the overall incidence of mastitis per unit of milk produced and therefore not a public health concern.
FDA's Veterinary Medicine Advisory Committee and expert consultants were convened for an open public hearing to discuss the issue of increased mastitis in sometribove-treated cows and a potential increase in the risk of antibiotic residues in milk on March 31, 1993. After hearing presentations from interested parties, and after considering the data presented to the Committee, the Committee concluded that, while sometribove treatment might cause a statistically significant increase in mastitis, the increased risk to human health posed by mastitis and resultant use of antibiotics was insignificant.
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