An analysis of health observations from cows treated with sometribove was conducted using data from the following studies:
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 of each of these studies is described in Sections 6.b, 5.a, 6.e, 6.d, 6.c, respectively. Data were gathered from daily observations, log entries, calving reports, medication files, physical examinations, veterinary requests, animal release records, necropsy reports, and feed sheet records. Data were grouped by system, subsystem within system, and category within subsystem and then were analyzed at each of these levels. A listing of the system and subsystem groupings used is contained in Table 73. The categories within each subsystem are listed in the results tables described later.
(Eds. note: The following table consists of 2 columns.)
Table 73. Grouping of health observations used in analysis
System Subsystem
Circulatory/ Heart
Lymphatics Lymph Nodes
Hypovolemic Shock
Veins
Bovine Leukosis
Septicemia/Toxemia
Anemia
Digestive Rumen Motility
Other rumen abnormalities
Feces/stool
Abomasum
Cecum gas/dilatation
Intestine
Indigestion
Parasites (internal)/Coccidiosis
Reticulum
Genito-Urinary Uterus
Vulva/Vagina/Clitoris
Cervix
Ovary/Oviduct
Kidney/Bladder
Musculoskeletal Neck/shoulder/rib/back
Hip/Thigh/Hook/Pelvis/Gluteal/Pinbone
Leg
Hock
Knee/Carpus
Stifle
Foot/Hoof/Dew Claw/Fetlock/Pastern
Gait
Elbow
Metabolic Ketosis
Disorders Milk Fever/Hypocalcemia
Acidosis
Hypoglycemia
Respiratory Lung/Thorax
Upper Respiratory
Udder Disorders Udder
Teats
Eye and Eye
Conjunctiva Conjunctiva
Integumentary Swelling/edema/enlarged
Laceration/abrasion/lesion
Abscess/infection
Lump
Warts (except teats)
Dermatitis
Scar Tissue(except repro tract)
Miscellaneous Feed Intake
Body Temperature
Allergic Reaction
Abnormal Appearance
Drug Reaction
Mouth/Teeth
Miscellaneous injuries
Straining
Blood Transfusion
Head Tilt
Abnormal Suckling
Escaped/Loose
Foreign Objects in Feed
Total Days Medicated
Total Days Clinical Signs
Health observations were summarized and analyzed in five different periods:
Pretreatment period - from calving to the day before start of treatment;
Standardized treatment period - from start of treatment up through 18 cycles (16 cycles for TAS) which usually was equivalent to the period used in production analysis;
Entire treatment period - from start of treatment through day of last milking if cow was pregnant, 14 days after last injection date while still milking if cow was not pregnant, or a cow's removal date from study if it preceded either the last milk or treatment dates;
Dry period - from day after last milking until day before next calving or a cow's removal date from study if it preceded the next calving;
Lactation subsequent to treatment - from calving through 56 days, a cow's last milk if it preceded 56 days or a cow's removal date from study if it preceded either the last milk or 56 days.
Data were analyzed both within each of the individual studies listed above and as a pooled analysis of all of the studies excluding the TAS study. Separate analyses were performed for primiparous and multiparous cows. Table 74 lists the total number of cows and cow days when health incidents could be observed.
(Eds. note: The following table consists of 6 columns.)
Table 74. Health Observations
TAS; Primiparous Period Control 6001 18001 30001
N (# cows) 1st (full) 6 7 7 7
N (# cows) 2nd (pre) 4 2 2 1
N (# cows) 2nd (full) 4 2 2 1
N (# cows) 2nd (next) 4 2 1
total cow days 1st (full) 1331 1789 1522 1584
total cow days 2nd (pre) 244 118 117 57
total cow days 2nd (full) 920 653 421 247
total cow days 2nd (next) 53 34 19
TAS;Multiparous
N (# cows) 1st (full) 14 13 13 14
N (# cows) 2nd (pre) 10 6 5 8
N (# cows) 2nd (full) 10 6 5 8
N (# cows) 2nd (next) 10 1 5 7
total cow days 1st (full) 3192 3169 2839 3373
total cow days 2nd (pre) 603 366 303 486
total cow days 2nd (full) 2325 1312 1227 2134
total cow days 2nd (next) 165 20 86 114
Pooled Analysis; Primiparous Control 2501 5001 7501
N (# cows) (full) 87 34 95 34
N (# cows) (next) 49 5 40 5
total cow days (full) 22217 9895 25094 9913
total cow days (next) 2410 88 1963 95
Pooled Analysis; Multiparous
N (# cows) (full) 201 52 212 52
N (# cows) (next) 126 11 109 9
total cow days (full) 48138 13146 53336 13415
total cow days (next) 6145 187 5235 167
1 Sometribove dose (mg/14 days)
For all conditions, the number of cows affected and the total days observed were analyzed. The TAS study analysis included two additional variables. The first was the total number of cases. For a given condition, a new case was defined when consecutive incidents were separated by at least seven days. Cases which extended between study periods (i.e., between the pretreatment and the treatment periods) were counted in the period in which they began. The second variable, total duration of cases, was defined as the sum of the case lengths within a given condition.
Poisson regression was performed on total days observed, total cases observed, and total duration of cases, each with an appropriately calculated denominator, reflecting days at risk. When an analysis involved more than two doses, a residual chi square P-value was calculated. Analysis of the number of cows affected varied depending on the number of doses and the number of trials included in the analysis. The Cochran-Armitage trend test was used in the individual TAS and Dose-IM studies. Additionally, a residual chi square P-value was reported for these studies. The Cochran-Mantel-Haenszel nonzero correlation test was used for combined data across several locations. This included the individual Single Dose-IM and 4 Dose-SC study analyses as well as the pooled analyses.
Analysis of data from physical examinations was performed separately. Number of cows affected was the only variable analyzed because examinations were not conducted on a daily basis. Data were analyzed for each period of study that examinations were scheduled. Statistical methods identical to those previously discussed were used for the number of cows affected.
Results
There were no adverse effects of sometribove administration on the circulatory/lymphatic system or the integumentary system, nor did sometribove cause increased metabolic disorders or eye disorders/conjunctivitis.
Sometribove-treated cows had a greater incidence of disorders of the digestive system than controls. Within this system, various subsystems and categories were affected, for example, bloat and diarrhea (Tables 75 and 76).
(Eds. note: The following table consists of 8 columns.)
Table 75. Bloat
TAS; Primiparous Period Control 6001 18001 30001 A2 B3
# cows affected 1st (full) 0 0 2 3 .015 .869
days observed 1st (full) 0 0 13 28 .000 .020
total cases 1st (full) 0 0 9 13 .000 .025
# cows affected 2nd (full) 0 0 0 0 1.000 1.000
TAS; Multiparous
# cows affected 1st (full) 2 1 3 1 .865 .384
days observed 1st (full) 3 2 7 4 .397 .155
total cases 1st (full) 2 1 6 2 .537 .048
# cows affected 2nd (full) 0 0 0 0 1.000 1.000
Pooled Analysis; Primiparous Control 2501 5001 7501 A2 B3
# cows affected (full) 0 0 4 2 .038
days observed (full) 0 0 9 3 .007 .073
Pooled Analysis; Multiparous
# cows affected (full) 5 1 8 2 .370
days observed (full) 11 2 12 2 .752 .779
1 Sometribove dose (mg/14 days)
2 Probability A: Significance probability for test statistic
from Cochran-Armitage test (# cows affected) or Poisson regression (days
observed, total cases). N = Non-convergence.
3 Probability B: Significance probability for residual lack of
fit from Cochran-Armitage test (# cows affected) or Poisson regression (days
observed, total cases). N = Non-convergence.
(Eds. note: The following table consists of 8 columns.)
Table 76. Diarrhea1
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 3 4 4 5 .450 .951
days observed 1st (full) 5 9 7 15 .050 .638
total cases 1st (full) 4 8 6 13 .062 .638
# cows affected 2nd (full) 2 2 1 0 .382 .339
days observed 2nd (full) 2 3 1 0 .552 .468
total cases 2nd (full) 2 2 1 0 .587 .705
TAS; Multiparous
# cows affected 1st (full) 5 8 7 7 .674 .419
days observed 1st (full) 10 16 34 23 .013 .001
total cases 1st (full) 6 10 18 20 .004 .242
# cows affected 2nd (full) 5 2 4 3 .935 .231
days observed 2nd (full) 6 5 6 5 .899 .358
total cases 2nd (full) 6 3 6 4 .866 .242
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 19 3 24 3 .685
days observed (full) 33 4 44 5 .422 .000
Pooled Analysis; Multiparous
# cows affected (full) 59 2 60 3 .288
days observed (full) 92 2 134 4 .622 .000
1 See Table 75 footnotes.
In the musculoskeletal system, sometribove-treated cows had more disorders of the hock (Table 77), which were primarily manifested as swellings or enlargements. This effects was also suggested in the physical examination data (not shown). Sometribove-treated multiparous cows tended to have more disorders of the hoof and foot region (e.g., bruises, infections, swellings) in the daily observation database (Table 78), but not in the physical examination database (no observations). Similarly, there was a trend for increased lameness in treated cows in the daily observation database (Table 79), but not in the physical examination data. The physical examination data indicated that treated cows had more lesions such as lacerations, enlargements, and calluses of the knee (carpal region) (Table 80). Because of the inconsistencies in these data, the lameness clinical field study, described in Section 6.f, was conducted to more thoroughly evaluate the effects of sometribove on the musculoskeletal system.
(Eds. note: The following table consists of 8 columns.)
Table 77. Hock disorders1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 0 0 1 1 .198 .838
days observed 1st (full) 0 0 2 2 .110 .350
total cases 1st (full) 0 0 2 1 .242 .216
# cows affected 2nd (full) 0 0 0 0 1.000 1.000
TAS; Multiparous
# cows affected 1st (full) 1 2 1 4 .172 .492
days observed 1st (full) 3 3 1 4 .875 .538
total cases 1st (full) 1 3 1 4 .349 .420
# cows affected 2nd (full) 1 2 3 1 .787 .067
days observed 2nd (full) 1 2 4 1 .853 .034
total cases 2nd (full) 1 2 4 1 .853 .034
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 2 0 5 2 .091
days observed (full) 7 0 32 2 .031 .000
Pooled Analysis; Multiparous
# cows affected (full) 7 3 19 4 .018
days observed (full) 19 9 89 11 .000 .000
1 See Table 75 footnotes.
(Eds. note: The following table consists of 8 columns.)
Table 78. Foot disorders1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 1 0 1 2 .297 .549
days observed 1st (full) 1 0 1 3 .147 .377
total cases 1st (full) 1 0 1 3 .147 .377
# cows affected 2nd (full) 0 0 0 0 1.000 1.000
TAS; Multiparous
# cows affected 1st (full) 2 3 1 4 .539 .383
days observed 1st (full) 6 7 3 11 .342 .297
total cases 1st (full) 6 4 1 6 .842 .197
# cows affected 2nd (full) 2 1 1 4 .147 .703
days observed 2nd (full) 3 4 3 13 .011 .558
total cases 2nd (full) 2 2 1 4 .443 .753
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 8 1 5 2 .322
days observed (full) 15 3 23 5 .740 .112
Pooled Analysis; Multiparous
# cows affected (full) 9 8 19 7 .126
days observed (full) 25 17 46 35 .000 .001
1 See Table 75 footnotes.
(Eds. note: The following table consists of 8 columns.)
Table 79. Lameness1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 0 1 2 3 .051 .961
days observed 1st (full) 0 2 3 5 .040 .567
total cases 1st (full) 0 2 2 5 .042 .550
# cows affected 2nd (full) 2 1 0 0 .167 .842
days observed 2nd (full) 3 2 0 0 .229 .684
total cases 2nd (full) 2 2 0 0 .317 .544
TAS; Multiparous
# cows affected 1st (full) 4 4 4 5 .696 .987
days observed 1st (full) 9 9 5 18 .097 .196
total cases 1st (full) 6 7 4 10 .450 .551
# cows affected 2nd (full) 1 1 3 3 .098 .332
days observed 2nd (full) 5 1 8 10 .042 .102
total cases 2nd (full) 2 1 7 8 .019 .071
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 7 3 8 3 .749
days observed (full) 14 5 19 6 .769 .704
Pooled Analysis; Multiparous
# cows affected (full) 19 9 33 7 .127
days observed (full) 52 21 62 24 .177 .152
1 See Table 75 footnotes.
(Eds. note: The following table consists of 7 columns.)
Table 80. Knee calluses (physical examination data).
Pooled Analysis; Primiparous Control 250 500 750 P1
# cows affected (180 d) 2 1 6 2 .181
# cows affected (end lac) 1 1 5 0 .430
Pooled Analysis; Multiparous
# cows affected (180 d) 19 6 33 7 .052
# cows affected (end lac) 6 3 21 4 .001
1 Significance probability for test statistic from
Cochran-Mantel-Haenszel nonzero correlation test.
For the genito-urinary system, sometribove-treated cows experienced increased disorders of the uterus (e.g., fluid in the uterus, adhesions; Table 81).
(Eds. note: The following table consists of 8 columns.)
Table 81. Uterine disorders1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 0 2 0 2 .448 .150
days observed 1st (full) 0 2 0 2 .463 .194
total cases 1st (full) 0 2 0 2 .463 .194
# cows affected 2nd (full) 0 0 0 0 1.000 1.000
TAS; Multiparous
# cows affected 1st (full) 1 2 4 4 .112 .729
days observed 1st (full) 1 2 8 5 .068 .049
total cases 1st (full) 1 2 4 5 .093 .706
# cows affected 2nd (full) 1 2 0 0 .201 .193
days observed 2nd (full) 1 3 0 0 .178 .041
total cases 2nd (full) 1 2 0 0 .260 .171
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 5 1 10 4 .159
days observed (full) 5 1 15 6 .025 .298
Pooled Analysis; Multiparous
# cows affected (full) 12 6 29 3 .059
days observed (full) 16 15 44 10 .007 .009
1 See Table 75 footnotes.
For the respiratory system, there appeared to be an increase in the incidence of congestion and abnormal breathing in multiparous cows. However, the majority of these incidents occurred at the Dardenne Single Dose-IM trial. Because this disorder primarily occurred at one trial and was significant for only multiparous cows, FDA concluded that it was not a real effect of the drug.
Treated multiparous cows had an increased duration of udder dermatitis, but this was attributed to a small number of cows with long cases at the Cornell Single Dose-IM and SQ-Dose trials. Multiparous cows treated with sometribove had a greater incidence of udder swellings or edema than controls. However, these incidents were primarily associated with mastitis, dermatitis, and similar disorders.
Under the miscellaneous category, there was an increase in incidence of elevated body temperature in sometribove-treated cows. This observation is more fully discussed in Section 6.m.3. There was an increase in the number of observations of "off-feed" (feed refusal) and total days medicated for sometribove-treated cows (Tables 82 and 83).
(Eds. note: The following table consists of 8 columns.)
Table 82. Off-feed (not eating)1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 1 1 3 6 .003 .717
days observed 1st (full) 1 4 9 19 .000 .747
# cows affected 2nd (full) 2 0 0 0 .174 .503
days observed 2nd (full) 4 0 0 0 N N
TAS; Multiparous
# cows affected 1st (full) 6 3 3 5 .832 .414
days observed 1st (full) 18 5 6 9 .132 .037
# cows affected 2nd (full) 0 2 1 2 .283 .302
days observed 2nd (full) 0 5 1 4 .400 .005
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 5 10 20 5 .113
days observed (full) 9 15 37 9 .015 .004
Pooled Analysis; Multiparous
# cows affected (full) 26 16 31 11 .740
days observed (full) 43 31 66 17 .187 .000
1 See Table 75 footnotes.
(Eds. note: The following table consists of 8 columns.)
Table 83. Total days medicated1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 1st (full) 6 7 7 7 1.000 1.000
days observed 1st (full) 27 39 55 114 .000 .446
# cows affected 2nd (full) 3 2 1 1 .958 .413
days observed 2nd (full) 49 21 17 34 .000 .000
TAS; Multiparous
# cows affected 1st (full) 14 13 13 14 1.000 1.000
days observed 1st (full) 109 79 114 330 .000 .000
# cows affected 2nd (full) 9 6 3 8 .926 .041
days observed 2nd (full) 100 149 26 319 .000 .000
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (full) 42 16 58 21 .005
days observed (full) 199 74 295 78 .223 .000
Pooled Analysis; Multiparous
# cows affected (full) 132 36 154 34 .036
days observed (full) 669 238 1212 221 .000 .000
1 See Table 75 footnotes.
During the dry period and in the first sixty days of the next lactation there were no effects on cows previously administered sometribove with the exception that the incidence of metabolic disorders, primarily milk fever, was reduced in multiparous cows (Table 84). A trend toward increased numbers of cows with retained placenta was evident in the pooled analysis (Table 85). The data from the five individual trials contributing to this data set (i.e., the Single Dose-IM Study trials and the IM Dose-Determination Study) were analyzed using a stratified analysis based on the Mantel-Haenszel Test. Analyses were conducted comparing controls and the 500 mg sometribove-treated cows with parities separated and with parities pooled, using a one-tailed test. The probability of the observed increase being due to chance, if there was no difference between the treatments, was .0209 for the analysis where the parities were kept separate and .0256 where parities were pooled. Thus, FDA concluded that the increase in the incidence of retained placenta in the subsequent post-calving period was a repeatable effect.
(Eds. note: The following table consists of 8 columns.)
Table 84. Metabolic disorders1(Eds. note: The following table consists of 8 columns.)TAS; Primiparous Period Control 600 1800 3000 A B # cows affected 2nd (pre) 0 0 0 0 1.000 1.000 # cows affected 2nd (next) 1 0 0 .453 .575 TAS; Multiparous # cows affected 2nd (pre) 5 0 0 1 .089 .062 # cows affected 2nd (next) 3 0 0 0 .057 .647 Pooled Analysis; Primiparous Control 250 500 750 A B # cows affected (next) 2 0 1 0 .735 Pooled Analysis; Multiparous # cows affected (next) 37 1 10 0 .000 1 See Table 75 footnotes.
Table 85. Retained placenta1.
TAS; Primiparous Period Control 600 1800 3000 A B
# cows affected 2nd (pre) 0 1 0 0 .782 .145
# cows affected 2nd (next) 0 0 0 1.000 1.000
TAS; Multiparous
# cows affected 2nd (pre) 4 1 1 2 .567 .614
# cows affected 2nd (next) 0 0 1 0 .711 .163
Pooled Analysis; Primiparous Control 250 500 750 A B
# cows affected (next) 6 1 9 1 .155
Pooled Analysis; Multiparous
# cows affected (next) 20 3 25 1 .158
1 See Table 75 footnotes.
Conclusions
Sometribove use is associated with increased frequency of use of medication in cows. Use of sometribove may result in an increase in digestive disorders such as indigestion, bloat, and diarrhea. Treated cows may have more disorders of the uterus, and there may be an increase in the number of cows experiencing periods of "off-feed" (reduced feed intake) during treatment with sometribove. Also, the incidence of retained placenta may be higher following subsequent calving. These effects are provided on the product labeling.
l. Calf Birth Traits, Growth, and Health
Analysis of health data from calves born to cows treated with sometribove was conducted. Cows received sometribove for approximately the first 7 months of the 9-month gestation. The following studies were included in the 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)
The experimental design of each of these studies is described in Sections 6.b, 5.a, 6.e, and 6.d, respectively. A pooled analysis was conducted using studies that contained the control and 500 mg dosage groups. The calves from the TAS study were evaluated separately because of the higher doses administered to study cows.
The methods of gathering and analyzing health observations for calves were similar to those described for cows (Section 6.k). Birth traits measured were calving difficulty, gestation length, sex ratio, birth weight, height (TAS only), and girth (TAS only). Health data were analyzed separately by categories which are listed in Table 86. In addition, certain health observations were considered to be birth abnormalities (italicized in Table 86). Physical examinations were generally performed on calves within 72 hours of birth. Calves were observed for variable periods of time after birth depending upon the study. In the TAS study, all calves were observed for five weeks. In the 4 Dose-SC study, male calves were observed for one week and female calves for four weeks. In the Single Dose-IM study, all calves were observed for nine weeks. In the Dose-IM study, female calves (only) were observed for four weeks.
For purposes of the birth trait analyses all available data for calves were utilized. These included birth data from calves that were born alive or stillborn and calves from breedings that occurred beyond the breeding cut-off dates for each study. Data for the growth analyses included only the calves that completed the observation period as specified for each study. However, in the health and birth abnormality analyses, all calves observed for any part of the observation period were included.
Calf Performance in the Multi-lactation Chronic Toxicity Study (TAS)
There was no effect of sometribove on the birth traits with the exception of a trend for average calf birth weight, height, and girth to be reduced for the calves for both years from the multiparous cows treated at the two highest levels of sometribove compared to calves from control multiparous cows.
Average daily gains and feed intake were unaffected by the cow's previous treatment (Table 87). Gains were as expected for calves in this age group and breed. Similarly, hematology and blood chemistry variables were unaffected by sometribove treatment of the cow.
(Eds. note: The following table consists of 4 columns.)
Table 86. Categories of birth abnormalities used for analysis
Category Birth Abnormality Category Birth Abnormality
Nervous System Disorientation Heart/ Anemia
Circulatory Heart Murmur*
Redness gums
Elevated heart rate
Skeletal Underdeveloped tail Septicemia/Toxemia
Toed in or Toed out*
Sickle hock Urogenital Female twin to male
Bench knee Undescended testicle*
Curvature* Underdeveloped uterus
Conformation Urogenital
Swollen limb Underdeveloped vulva
Pain Underdeveloped ovary
Abnormal Sound/Abnormal Enlarged
Enlarged Head*
Fracture/Cracked Sensory Hematoma eye
Arthritis/ (eye,ear nose) Opacity*
joint inflammation Watery eye
Hematoma Congestion eye
Muscle Contracted tendons* Redness/bloody nose
Hernia - inguinal* Bloody eye
Hyperextension
Lameness/Limping/Weak Skin/hair Extra teats
Enlarged umbilical
Alimentary/ Hernia - umbilical* Abnormal umbilical
Digestive Underdeveloped teeth*
Over or under bite*
Atresia Endocrine glands
Pain abdominal
Hard/firm abdominal
Ulcer/erosion Abnormal placenta
Abnormal suckling
Abnormal sounds
Swollen/enlarged/edema Abnormal Depressed
Atony appearance Underdeveloped
Respiratory Elevated rate Stillbirths
Difficult breathing
Panting
* Birth Abnormalities
(Eds. note: The following table consists of 6 columns.)
Table 87.
The effect of sometribove administered to the cow during the TAS
study at dosages of 0, 600, 1800, and 3000 mg on 4-week average daily gain and
dry matter intake of calves.
Year 1
------------------ Sometribove Dosage (mg) --------------
Parity1 0 600 1800 3000 Prob2
----Mean Average Daily Gain3 (kg/d) ± standard error (n)----
1 0.39±0.03 (4) 0.58±0.16 (2) 0.21 (1) (0) NA
2,3 0.34±0.05 (9) 0.33±0.05 (6) 0.31±0.06 (5) 0.35±0.05 (8) .965
-----Mean Dry Matter Intake3 (kg/d) ± standard error (n)-----
1 0.84±0.01 (4) 1.25±0.06 (2) 0.73 (1) (0) NA
2,3 0.75±0.05 (9) 0.89±0.06 (6) 0.72±0.07 (5) 0.78±0.05 (8) .223
Year 2
-------------- Sometribove Dosage (mg) ---------
Parity1 0 600 1800 3000 Prob2
----Mean Average Daily Gain3 (kg/d) ± standard error (n)----
2 0.31±0.07 (4) 0.33±0.01 (2) 0.13 (1) (0) NA
3,4 0.19±0.06 (10) 0.17±0.19 (1) 0.25±0.07 (7) 0.25±0.07 (7) .845
-----Mean Dry Matter Intake3 (kg/d) ± standard error (n)-----
2 0.82±0.02 (4) 1.05±0.08 (2) 0.64 (1) (0) NA
3,4 0.68±0.06 (10) 0.93±0.20 (1) 0.77±0.07 (7) 0.69±0.07 (7) .555
1 Parity refers to the cow's parity.
2 Prob = probability that F-value exceeds calculated F-statistic
for treatment main effect. NA = not statistically analyzed.
3 Average daily gain is the regression coefficient of body weight
on days of age through 4 weeks of age. Dry matter intake is average daily
intake from birth to 4 weeks, excluding days when colostrum was fed. In Year
1, means are presented for parity 1, and in Year 2, means are presented for
parity 2. Least-squares means are presented for remaining parity groups. The
model included treatment, parity, treatment-by-parity interaction, and sex for
Year 1, and treatment, parity, and sex for Year 2. Analyses of dry matter
intake excluded days colostrum was fed.
Total days affected with high body temperature and pneumonia could not be evaluated due to inaccuracies in the recording of the duration of these clinical signs and, therefore, the overall category of days with clinical signs also could not be evaluated. Numbers of calves affected by these variables, however, were accurately captured and, thus, the overall category of numbers of calves with clinical signs was evaluated. In general, days that calves were medicated were accurately recorded. Therefore, total days medicated was a more appropriate indicator of sometribove's effect on overall health of offspring than days of clinical signs.
In the TAS study, total days medicated for female and male calves over the 29-day period for offspring of treated primiparous cows was increased in year one of the study. There was an increase in total days medicated for female calves of sometribove-treated multiparous cows for the 29-day observation period in year one of treatment and for males and females in year two of the TAS study. However, since the number of calves in the TAS study was small, this effect was better evaluated in the pooled analyses of the clinical trials, which had greater numbers of animals.
In the TAS study there were no significant results noted from the physical examinations for any of the parameters analyzed for either parity group.
Heifer calves from the first lactation were monitored from birth through reproductive maturity and breeding (approximately 16 months of age or until confirmed pregnant at day 60 of gestation or later). Administration of sometribove to pregnant cows did not affect health and performance of resulting female offspring, except that wither height was lower for heifers from 14 to 16 months of age for heifers born to cows dosed with 600 and 1800 mg sometribove. Growth rates through 16 months of age averaged approximately .84 kg/day and were unaffected by sometribove. Size and growth of all animals fell within the range of growth standards reported for Holstein heifers. Conception rates were control: 8/8, 600 mg: 2/3, 1800 mg: 3/3, and 3000 mg: 3/3.
Bull calves born to treated cows were not monitored through reproductive maturity in this study; therefore, no conclusions were made regarding the effect of the cow's dose of sometribove on the reproductive performance of bull calves. Thus, the product labeling states that safety to replacement bulls from dairy cows injected with sometribove has not been established.
Calf Performance in the Pooled Analyses
Effect of sometribove on birth traits in the pooled analysis (4 Dose-SC, Single Dose-IM, and Dose-IM Studies) for the 0 and 500 mg dose groups are presented in Table 88. Calving difficulty and sex ratio of calves were unaffected by administration of sometribove to their dams during gestation. Gestation length was reduced in those cows receiving sometribove versus the controls. This reduction was approximately 2.6 days for primiparous cows and 3.1 days for multiparous cows. Birth weight of calves from cows administered sometribove was reduced by approximately 1.5 kilograms in both parity groups. This effect was independent of rate of twinning.
Growth rate and average daily gain were measured for the offspring. The growth data could not be pooled across studies since length of observation and sex of calves monitored varied by study location. The evaluation of calf growth utilized all available data for each study. Cow's treatment with sometribove did not affect growth of calves born subsequent to the lactation of treatment. These data were highly variable since body weights taken within the first weeks of life can vary markedly.
(Eds. note: The following table consists of 4 columns.)
Table 88.
Effect of sometribove on birth traits in the pooled analysis.
-----Dose (mg)-----
Variable 0 500 Probability
Calving Difficulty1
Primiparous 1.00
High 16 (23.2)2 15 (22.7)
Low 53 (76.8) 51 (77.3)
Multiparous .347
High 44 (27.3) 30 (22.2)
Low 117 (72.7) 105 (77.8)
Sex Ratio of Calves
Primiparous .741
Female 32 (40.5) 27 (37.5)
Male 47 (59.5) 45 (62.5)
Multiparous .442
Female 78 (45.1) 77 (49.4)
Male 95 (54.9) 79 (50.6)
Gestation length (days)3,4
Primiparous 280.4 ± .773 277.8 ± .902 .028
n 71 55
Multiparous 280.5 ± .805 277.4 ± .850 .020
n 155 124
Birth weight (kg)3,4
Multiple births included
Primiparous 37.9 ± .780 36.4 ± .731 .083
n 76 69
Multiparous 40.5 ± .529 39.0 ± .523 .007
n 172 149
Multiple births excluded
Primiparous 43.9 ± .579 41.9 ± .660 .023
n 69 55
Multiparous 46.2 ± .585 43.2 ± .644 .003
n 154 120
1 High calving difficulty includes calving ease scores of 2, 3,
and 4. Low calving difficulty includes calving ease score of 1.
2 Numbers in parenthesis are percentages.
3 Location by treatment dose was used as the error term.
4 Results are reported as least squares means ± standard error
of least squares means.
n = number of calves.
There was a decrease in total days medicated for female calves of sometribove-treated primiparous cows for the 29-day observation period. There was an increase in total days medicated for male calves from treated primiparous cows over the 9-day observation period, but a decrease in total days medicated for male calves from treated multiparous cows compared to values from calves of control cows. These differences in response indicated that there was no clear effect of sometribove treatment of the cow on days of medication for the calves.
A decrease in diarrhea was noted for calves from primiparous cows over the 29 day observation period. There was an increase in abnormal lung sounds for female calves from primiparous cows treated with sometribove; however, this was the result of only two observations in the 750 mg group and no observations in the other dose groups. Also, there were no similar trends in female calves of multiparous cows or in male calves of either parity group. There were additional statistically significant effects (both increases and decreases) due to sometribove treatment of cow on some additional clinical signs. However, these effects were not consistent across male and female calves and/or parity group of the cow, and FDA therefore did not consider these to be of biological importance.
Calf Abnormalities
Birth abnormalities which were observed from the pooled data are listed in Table 86. When all calves of control vs. 500 mg primiparous cows from the IM and SC trials were pooled there were increased overall birth abnormalities in female (12 vs. 6 for controls) and male (15 vs. 9) calves of 500 mg sometribove dosed primiparous cows, due primarily to increased hernias (2 treated vs. 0 for controls for females, and 5 treated vs. 2 controls for males) within the "Alimentary" category.
When selected important birth abnormalities considered to represent those which may affect animal health and survival (italicized in Table 86) were analyzed comparing calves of controls and 500 mg sometribove-treated cows, there was no increase in overall incidence of selected abnormalities. When all of the calves examined from 500 mg primiparous cows were considered (N=32 for female controls, N=42 for male controls, N=26 for female 500 mg calves, N=41 for male 500 mg calves), there was a slight increase in umbilical hernias for female (P=0.099) and for male (P=0.079) calves of treated primiparous cows. There was a numerical reduction for hernias in male calves of sometribove-treated multiparous cows (5 controls vs. 3 treatment group calves). When sex and parity were stratified and all control vs. 500 mg calves were compared, there was weak significance (P=0.093) for increased hernias (13 control vs. 21 treatment group calves). However, most of the hernias reported were of minimal size (the minimum being 2 cm). None of the hernias was serious enough to require surgery and, due to their small size, they were expected to resolve spontaneously. FDA concluded that a slight predisposition for calves of treated primiparous cows to have small hernias would be of no biological consequence.
There was an increase in contracted tendons for calves of treated primiparous cows (one male and one female calf compared to no control calves affected). There was no increase in calves of multiparous cows nor for combined parity and sex. Due to the small numbers of calves involved and the inconsistency of effect, this result was considered to be due to chance.
Conclusions
FDA concluded that cows administered sometribove may have small decreases in gestation length and birth weight of calves, and they may have increased twinning rates. This information is provided on product labeling. Sometribove treatment of the cow during gestation had no adverse effects on the health of resulting offspring.
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