For Increasing Production of Marketable Milk in Lactating Dairy Cows
Sponsored by The Animal Sciences Division of Monsanto Company
® Registered trademark of Monsanto Company
1. General Information
NADA Number: 140-872
Sponsor:
Animal Sciences Division
of Monsanto Company
800 N. Lindbergh Blvd.
St. Louis, MO 63167
Generic Name: Recombinant DNA-derived methionyl bovine somatotropin
Trade Name: POSILAC® (sterile sometribove zinc suspension)(® Registered trademark of Monsanto Company)
Marketing Status: Over-the-counter (OTC)
Date Stamped: November 5, 1993
2. Indications for Use: For increased production of marketable milk in lactating dairy cows.
Sterile, prolonged-release injectable formulation in single-dose syringes each containing 500 mg sometribove zinc.
Routes of Administration:
Subcutaneous injection in the postscapular region (behind the shoulders) or ischiorectal fossa (depression on either side of the tailhead).
Recommended Dosage:
One syringe every 14 days beginning during the 9th week after calving and continuing until the end of lactation.
4. Overview of Studies Evaluated to Provide Pivotal Effectiveness and Animal Safety Data
Throughout the Freedom of Information (FOI) Summary, the term "sometribove" is used to represent the formulated drug product, sterile sometribove zinc suspension.
The general presentation of the results from the Chronic Animal Toxicity Study and full-lactation clinical studies consists of a discussion of study design, data analysis, pathology results (Chronic Animal Toxicity Study), and production results for each individual study in Sections 5.a and 6.b - 6.e. Results of other variables, such as reproduction, cow health, and mastitis, were pooled across most of these studies for evaluation and are provided in Sections 6.f - 6.m.
The following table indicates the pivotal studies evaluated to determine effectiveness and animal safety of sometribove, and the specific data derived from each study.
(Eds. note: The following table consists of 1 column and 25 headings.)
OVERVIEW OF STUDIES EVALUATED TO PROVIDE PIVOTAL EFFECTIVENESS AND ANIMAL SAFETY DATA
Study and ID Number*
Cornell #87-034:
Efficacy
Lameness
Injection Site Reactions
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Florida #87-029:
Efficacy
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Utah #87-024:
Lameness
Injection Site Reactions
Nutrient Intake, Body Weight and Condition
Reproduction
Cow Health **
Offspring
Arizona #89-075:
Efficacy
Idaho #88-129:
Efficacy
14-Day Drug Tolerance Study #86-011:
Pathology
Injection Site Reactions
Nutrient Intake, Body Weight and Condition
Cow Health **
Blood Variables
Body Temp.
Multi-lactation Chronic Animal Toxicity Study #85-010:
Pathology
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Circulating Anti-Somatotropin Binding
Blood Variables
Body Temp.
Urinalyis
IM/SC Bridging #86-032:
Lameness
Injection Site Reactions
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Circulating Anti-Somatotropin Binding
Blood Variables
Body Temp.
Urinalyis
IM-Dose Titration Study #86-023:
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Blood Variables
Body Temp.
Urinalyis
Arizona #85-039:
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Circulating Anti-Somatotropin Binding
Blood Variables
Cornell #85-038:
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Circulating Anti-Somatotropin Binding
Blood Variables
Dardenne #85-021:
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Mastitis
Cow Health **
Offspring
Circulating Anti-Somatotropin Binding
Blood Variables
Urinalyis
Utah #86-003:
Lameness
Nutrient Intake, Body Weight and Condition
Reproduction
Cow Health **
Offspring
Circulating Anti-Somatotropin Binding
Blood Variables
Lameness Study #92-007:
Lameness
Injection Site Reaction Field Study #91-072:
Injection Site Reactions
Non-Clinical Injection Site Reaction Study #91-068:
Injection Site Reactions
Vermont #86-031:
Injection Site Reactions
Arizona #89-075:
Injection Site Reactions
Preclinical #92-003:
Injection Site Reactions
Carcass Evaluation Study #89-049:
Injection Site Reactions
**Includes data from daily health observations and routine physical examinations, except for the Multi-location SC Dose Response Study, where routine physical examinations were not performed.
SC = Subcutaneous
IM = Intramuscular
The indication for use of this product is: "For increased production of marketable milk in lactating dairy cows."
Increased production refers to an increase in weight of milk produced. Dairy producers in the U.S. measure (and describe) milk production per cow or per farm in weight units, not volume. Thus, in the pivotal effectiveness and animal safety studies, weight of milk produced (not volume) was measured.
The term "marketable" milk refers to the milk that the dairy producer can legally sell. (The term "salable" milk is used interchangeably with "marketable" milk in this section of the FOI Summary.) Milk produced the first few days after a cow has a calf, also called colostrum, is not marketable as its composition is considerably different from true milk. Also, milk produced from cows after receiving certain therapeutic drugs cannot be sold legally if the milk contains residues of the drug above the FDA-established tolerance. In determining the effectiveness of sometribove, milk produced by a cow during the "withdrawal period" for any drug she had been administered therapeutically was excluded. (In the case of extra-label drug use, specific drug withdrawal periods were specified by the firm for purposes of the calculation, with CVM's concurrence.) Thus, on any day that a cow's milk should have been discarded because of a withdrawal period, the cow's production of "marketable/salable" milk was considered to be zero. Therefore, the evaluation of the effectiveness of the drug was based on production of marketable milk.
The evaluation of the effectiveness of sometribove was also based upon production of salable "3.5 % fat-corrected milk" or "FCM." The content of fat in milk typically varies among cows from about 2.0 to 6 % and is affected by factors such as the breed of the cow, stage of lactation, and its diet. The current pricing system in the U.S. generally favors milk of higher fat and other "solids" content, such as protein, because more cheese and other manufactured dairy products can be produced from the same unit of milk if solids content is higher. (For example, producers may get a bonus for milk of higher fat or solids content.) A long-standing practice in the dairy industry and the field of dairy science is to express milk production in terms of how much milk would have been produced if it was standardized to 3.5 % fat content (i.e., FCM). Thus, a cow that produced 100 lbs of milk with 2.5 % fat content would be calculated as having produced only about 84 lbs of FCM, whereas another cow producing 100 lbs of milk with 5 % fat content would be said to have produced 124 lbs of FCM. The actual equation for the calculation of FCM is provided on page 12.
Other calculation procedures are discussed in Section 5.a of the FOI Summary, including standardization to a specific length of lactation. All of these steps were taken to remove any potential biases in the calculation of the effectiveness of sometribove and also to evaluate milk production as it typically is evaluated in the dairy industry.
a. Multi-location SC Dose Response Clinical Study (4 Dose-SC)
Clinical studies were conducted at four separate locations (University of Arizona, Cornell University, University of Florida, and Utah State University) to determine the effective dose range of sometribove when administered subcutaneously (SC) commencing 60 ± 3 days postpartum and continuing until the end of lactation. The same study protocol was employed at each location with minor variations to allow for differences in management practices.
Investigators: J. T. Huber, Ph.D.
University of Arizona
Tucson, AZ 85721
D. E. Bauman, Ph.D.
Cornell University
Ithaca, NY 14853
H. H. Head, Ph.D.
University of Florida
Gainesville, FL 32611
R. C. Lamb, Ph.D.
Utah State University
Logan, UT 84322
Materials and Methods:
One hundred nine primiparous (first calf heifer) and 145 multiparous (mature) Holstein cows were randomly assigned within the two parity groupings to treatments of 0 (excipient), 250, 500, or 750 mg of sometribove every 14 days. Animals calved on location to allow acclimation prior to study initiation. At approximately 40 days postpartum, each cow was given a general physical examination by a veterinarian. Selection criteria for study cows included acceptable body and udder conformation, disposition, and body condition, adequate milk production and general health, vaccinations for IBR, PI3, BVD, and leptospirosis, and a negative test for brucellosis and tuberculosis. An additional requirement at Cornell was a negative test for Johne's Disease (bovine paratuberculosis).
The 0 mg dose consisted of the formulation ingredients (excipient) minus the active ingredient. Sometribove was administered via subcutaneous injection in one of four postscapular sites: right upper, right lower, left upper, or left lower. Injections were rotated among these four sites so that eight weeks elapsed prior to reinjection in a particular site, except at Florida, where due to a protocol misinterpretation each site was used twice consecutively before rotating to the next site. Treatments were administered using 16-gauge 1-inch hypodermic needles. Within each study location, cows were injected on the same day of the week, and all cows receiving treatment on a given day were injected in the same postscapular site.
Treatment was initiated at 60 ± 3 days postpartum and continued at 14-day intervals throughout lactation. In pregnant animals, treatment ceased at least 74 days prior to expected calving date to allow for a dry period of approximately 60 days or when average daily milk production decreased below 8.2 kg/day (unless low milk production was due to temporary ill health), whichever occurred first. Open (non-pregnant) animals continued on treatment for 25 treatment cycles (approximately 400-day lactation), or when average daily milk production decreased below 8.2 kg/day (unless low milk production was due to temporary ill health), whichever occurred first. In all cows, injections ceased as closely as possible to 14 days prior to dry off.
The distribution of cows started on treatment at each study location is provided below:
(Eds. note: The following table consists of 7 columns.)
Table 1.
Number of Cows Started on Treatment
Location and Study No. Parity* 0 mg 250 mg 500 mg 750 mg Totals
Arizona P/M 4/12 4/12 5/10 4/12 17/46
100-ARI-COW-LK-87-023
Cornell P/M 6/6 6/7 5/6 6/6 23/25
100-COR-COW-VKM-87-034
Florida P/M 9/8 9/8 10/9 9/9 37/34
100-UFL-COW-WAS-87-029
Utah P/M 8/10 8/10 8/9 8/11 32/40
100-UTA-COW-LK-87-024
POOLED P/M 27/36 27/37 28/34 27/38 109/145
*P=Primiparous; M=Multiparous
Within each parity group (primiparous and multiparous), blocks consisting of random permutations of the four treatments were generated for each location prior to the start of the study. Cows were assigned to blocks in order of calving dates. Within a block the maximum range in average daily milk production per cow during weeks 4 through 6 of lactation was ¾ to 9.1 kg/day (with the exception of one multiparous block at 15.8 kg/day). The range in the first day of treatment for the first and last cows entering a block was no greater than 56 calendar days.
All cows were milked twice daily at approximately 12-hour intervals except at Florida where intervals were 11 and 13 hours. All locations followed the same general milking procedures. Udders were washed and dried with individual paper towels. In addition, at Arizona and Utah, teats were predipped with an approved iodine teat dip and dried. Milk was forestripped onto the floor from each quarter to detect abnormal milk before milking machines were attached. The appearance of mastitic/abnormal milk was recorded. After milking was complete, teats were dipped with an approved iodine teat dip. Weight of milk yield was recorded for each cow at each milking throughout lactation. Individual cows' milkings that were discarded (withheld from human consumption) because the animal was administered med ion that had a milk withdrawal period were identified.
Milk fat, protein, and lactose percentages and somatic cell counts were determined from milk samples collected weekly from each cow on consecutive PM and AM milkings throughout lactation. Consistent days of the week were used at each location. Across the four locations, samples were collected three to four and 10 to 11 days post-injection during the treatment period.
Content of milk minerals (ash, calcium, and phosphorus) was determined on samples collected at consecutive PM and AM milkings from each cow during treatment weeks -2, -1, 3, 15, and 27. Consistent days of the week were used at each location. Across the four locations, samples were collected three to six days post-injection during the specified treatment weeks.
Diets at each location were formulated to meet or exceed nutritional requirements recommended by the National Research Council (NRC; 1978). All cows were fed total mixed rations (TMR) ad libitum with sufficient feed offered to allow for approximately 5 % refusal. Amount of feed offered and refused was recorded daily throughout lactation.
Feeding practices were according to established management at each location. At all locations, cows were fed a high energy diet from freshening to at least 90 days postpartum. Thereafter, cows were switched to lower energy density diets depending on level of milk production. Because the dietary formulations for different levels of milk production were based on typical levels of ad libitum intake, it was also necessary to consider body condition in making dietary shifts. At the discretion of the herd manager in consultation with the investigator, the timing of a cow's shift to a lower energy density diet may have been modified. If actual feed consumption was such that a cow was underconditioned for that stage of lactation, she may have remained on the higher energy density diet for a longer period than that indicated by her level of milk production.
At each location, diets and components were sampled weekly and composited monthly. Analyses of these samples were performed at appropriate testing facilities.
Cows were weighed weekly throughout the entire lactation. Within a study location, weights were taken at approximately the same time of day on a consistent day of the week such that during the treatment period, across the 4 locations, weighings occurred on days three to five and 10 to 12 post-injection. Body condition was scored at each weighing using a scale of 1 to 5 (1 = excessive underconditioning; 5 = excessive overconditioning) in quarter point increments (Wildman et al., 1982, Journal of Dairy Science 65:495).
The incidence of subclinical mastitis was evaluated from microbiological cultures of duplicate milk samples collected from each quarter of each cow once during the two-week pretreatment period, at 56-day intervals thereafter throughout lactation, and at dry-off. All cows at a location were sampled on the same day relative to injection.
For cases of clinical mastitis, duplicate samples were to be collected for microbiological culture before antibiotic treatment, if any, was administered. Adherence to this provision varied from location to location, and some discretion regarding treatment regimen was allowed at each location. However, the Utah location rarely treated clinical mastitis, resulting in unacceptably long cases. The lack of any attempt to control clinical mastitis did not reflect accepted mastitis management practices and could have resulted in mastitis organisms being shed from infected quarters to other quarters and/or cows, therefore confounding attempts to evaluate the effect of sometribove on mastitis incidence at this location. Mastitis data from the Utah location were therefore eliminated from analysis. Cows received intramammary dry cow treatment in each quarter after their last milking of the lactation (end of sometribove treatment period) at Arizona, Cornell, and Florida locations.
General herd health programs were followed at all locations. Current guidelines (National Institutes of Health), entitled "Guide for the Care and Use of Laboratory Animals," were followed. Cows were observed daily for signs of disease, injuries, or other disorders. Minor disorders were treated by farm personnel according to standard animal care procedures. A veterinarian was consulted when necessary. Cows were treated with approved medications which were used according to label direction unless the herd veterinarian or designee deemed the extra-label use of medication necessary. All health related observations and medications administered were documented. All available practical means were taken to diagnose the cause of any illness or injury. Cows received a general physical examination by a veterinarian during the last injection cycle. Sick or injured animals were removed from study if deemed necessary by the attending veterinarian and the investigator or herd manager. Necropsies were usually performed on clinical trial animals that died or were euthanized while on study. Any gross lesions observed at necropsy were collected for histopathological examination. All aborted fetuses of at least 100 days gestation and stillborn calves were examined externally and internally for malformations. If possible, the cause of abortion was determined.
Estrus detection was according to existing location practices and was based on visual observation and tail head marking. All observed heats were recorded and scored as described in Section 6.i on Reproduction.
Prostaglandins were not used as a reproductive aid in normal cycling cows until after 120 days postpartum. Prostaglandin use was allowed to treat pyometra or cystic ovarian disease at any time if prescribed by a veterinarian.
Cows received a veterinary examination to evaluate reproductive health prior to initiation of treatment. All breeding was by artificial insemination commencing at the first observed estrus after treatment initiation. Pregnancy was confirmed by rectal palpation at least 30 days after breeding. Breeding was continued through 400 (305 at Cornell) days postpartum. Sire selection was according to location practices.
Injection sites were observed for any swellings or adverse reactions three and ten days post injection and scored (see Section 6.g for description of the scoring system). If a visible swelling remained, scoring continued weekly until the swelling disappeared, or up to 8 weeks, whichever occurred first.
All calves born after the initial lactation of treatment were weighed after birth. Birth weight, sex of the calf, and a calving ease score (as described in Section 6.i on Reproduction) were recorded, in addition to any unusual observations (surgical intervention or stillbirth) noted during calving. After birth, the navel was treated with tincture of iodine. All calves were fed 4 to 6 quarts of colostrum within 24 hours of birth. At Florida, calves may have been allowed to nurse for up to 24 hours. Calves were then fed whole milk until weaned after at least 35 days of age. Free choice feeding of calf-starter began 2 days after birth except at Cornell, where calf-starter was begun 5 days after birth. All calves were given a general physical examination, usually within 72 hours of birth. Female calves were weighed during the second and fourth weeks of life.
Data Handling:
All cows started on treatment were included in the analysis of clinical health, mastitis (excluding Utah, see below), and injection site reactions (excluding Florida, see Section 6.g) for the period of time in which they were on study. Thus, every incident that occurred in these categories during the study was included in the evaluation of the effect of the drug. However, the evaluation of effectiveness, reproduction, nutrient intake, and body weight and condition generally involved the calculation of average values over the treatment period. Therefore, to be included in these latter analyses, cows had to complete greater than two-thirds of the 252-day standard treatment period (i.e., > or = 169 days of treatment) to provide sufficient data to accurately estimate effects over an entire treatment period. Reasons for not completing > or = 169 days of treatment included low production, health problems, administered an incorrect dose, and incorrect blocking. Also, a block had to include at least two cows so that an estimate of within block variation was possible. The following cows did not complete at least 169 days on treatment:
(Eds. note: The following table consists of 6 columns.)
Table 2.
Dose Parity* Study Cow ID Days on Reason
Location Treatment
0 mg P Florida 0010 154 ¾ 2/3 treatment period
due to low production
M Arizona 8540 14 Incomplete block
250 mg M Arizona 74 70 Lameness
1134 42 Misinjected (Wrong dose)
Cornell 3951 6 Incomplete Block
500 mg P Arizona 210 140 Incomplete Block
M Cornell 3449 68 Toxic mastitis
Florida 2942 168 ¾ 2/3 treatment period
due to low production
750 mg P Florida 0004 154 ¾ 2/3 treatment period
due to low production
Utah 306 22 Died due to Right Displaced
Abomasum
M Arizona 133 112 Incomplete Block
2071 14 Misinjected (Wrong Dose)
Utah 6096 37 Multiparous Cow Assigned to
Primiparous Cow Block
*P=Primiparous; M=Multiparous
Daily milk yield for each cow was the sum of two milkings per treatment day and was set to missing if the yield at either milking was not recorded due to mechanical or human error. An average daily AM milk yield for each cow was calculated for each treatment week from all of her non-missing daily AM milk weights that week. The same calculation was performed for all non-missing PM milk weights to obtain an average daily PM milk yield per week for each cow. Each cow's average daily AM and PM milk yields per week were summed to determine her average daily milk yield for the week.
An average daily 3.5 % fat-corrected milk (FCM) yield for each week was calculated for each cow as follows.
1. Each cow's average AM milk fat percent value and average daily AM milk yield during a week were used in the following equation to determine her average daily AM FCM yield for that week:
AM FCM (kg/d) = AM Milk (kg/d) X (0.43237 + (.16218 X AM fat % ))
2. A cow's average daily PM FCM yield for the week was calculated using the same equation and the animal's average PM milk fat percent value and average daily PM milk yield during the week.
3. A cow's average daily AM and PM FCM yields for the week were summed to obtain her average daily FCM yield for that week.
4. Any milk fat percent value greater than 8 % was designated as missing because such a high value would generally represent a laboratory error. During the pretreatment period, missing weekly AM or PM milk fat percent values (e.g., sample not collected or laboratory error) were estimated from the average of the adjacent weeks' AM or PM fat percent values, respectively. However, during the treatment period, weekly milk fat percent values tended to be cyclic. Thus, if a cow's AM or PM milk fat percent value was missing during an even week of the treatment period, the average of her adjacent even weeks' respective AM or PM milk fat values was used as a replacement for purposes of calculating a FCM value for the week. Missing values during odd numbered treatment weeks were similarly estimated.
The actual period of time in which cows remained on treatment varied depending on conception date, milk yield, and health conditions. Thus, an average daily standardized FCM (SFCM) yield per cow was calculated, adjusting to a 252-day treatment period (i.e., 36 weeks) according to the following procedures.
1. For cows on treatment > or = 252 days, the average daily FCM yields during each of the first 36 weeks of treatment were averaged.
2. For cows dried off at < 252 days due to low milk production, an average daily FCM yield of 0 kg/day was assigned to the weeks following the last injection cycle through 36 weeks of treatment. The average daily FCM yields for each of the 36 weeks were then averaged.
3. For cows dried off at < 252 days to allow a 60-day dry period (i.e., early conception) or because of non-treatment related removal from study, data were extended beyond the last complete injection cycle by linear regression. Individual cow regressions were estimated from the last six completed injection cycles, excluding cycles for which milk production was judged to be atypical for the general trend. Average daily FCM yield for the cycles was regressed on median treatment day of the cycle. The resulting equation for each cow was used to estimate her production during each week after the last completed injection cycle through 36 weeks of treatment. The average daily FCM yields for each of the 36 weeks were then averaged.
Average daily salable standardized FCM (SSFCM) yield was calculated for each cow. Each cow's average daily standardized FCM (SFCM) yield was multiplied by 252 days to obtain her total standardized FCM yield. The sum of all FCM discarded during the treatment period was subtracted from the total standardized FCM yield. The result was then divided by 252 days.
For the purposes of evaluating the effect of treatment on milk composition (milk fat, lactose, and protein percent and somatic cell counts), each week's AM and PM milk component values for each cow were weighted by the daily AM and PM milk yields within the week to calculate a weekly milk component value. Any PM or AM fat percent value greater than 8 % again was set to missing. If any of a cow's AM and/or PM milk component values were missing, her week's average milk component value was designated as missing so that, for the evaluation of effects on milk composition, only actual data (i.e., no estimated values) were used in the analysis. Somatic cell count data were converted to log base 10 prior to any statistical analysis.
Milk mineral values (ash, calcium, and phosphorus) were calculated for each cow during each sampled week by averaging replicates for each sampling, and then averaging values for consecutive milkings sampled during that week.
The amount of feed consumed by each cow was calculated for each day by subtracting the feed refused from the feed offered. The consumed value was set to missing if any offered or refused value was missing.
Results of laboratory analysis of TMR and feed ingredient samples were used to calculate feed composition for each day that a particular TMR (also hay at Utah) was fed. Estimated composition for days with missing composition data was the average of values for two adjacent periods.
Net energy of lactation (NE) for TMRs was calculated from NE of the components based on the proportion of each in the total diet. Values for NE for grains and by-products were those documented by NRC (1978). Values for NE for forages were those reported by the feed analysis laboratory for that sample. Dry matter content and all other nutrient values for each sample were also those reported in the feed composition analysis.
Amount consumed and composition for each day were combined to calculate dry matter, net energy, protein, calcium, and phosphorus intakes. These intakes were calculated separately for each feedstuff consumed and summed to obtain total nutrient intake per cow per day. Total daily intake was set to missing on any day that an individual feed consumed was missing.
Average daily dry matter, net energy, protein, calcium, and phosphorus intakes per cow per treatment week were calculated as the mean of non-missing daily intakes.
Energy, protein, calcium, and phosphorus balances were calculated for each cow as follows:
1. The requirements for these nutrients for milk production were calculated from average AM and PM milk yield per treatment week and weekly AM and PM fat test separately, then summed for the average daily requirement per treatment week. The equations for these requirements are as follows (derived from 1978 NRC):
NE Required for Milk Production (Mcal/d):
< or = 3.00 % fat: milk (kg/d) * ((fat ( % )*.044)+.158)*2.205
> or = 3.01 and < or = 4.00 % fat: milk (kg/d) * ((fat ( % )*.046)+.152)*2.205
> or = 4.01 and < or = 4.50 % fat: milk (kg/d) * ((fat ( % )*.036)+.192)*2.205
> or = 4.51 and < or = 8.00 % fat: milk (kg/d) * ((fat ( % )*.046)+.147)*2.205
Protein Required for Milk Production (g/d):
< 4.5 % fat: milk (kg/d) * ((fat ( % )*10)+47)
> or = 4.5 and <5 % fat: milk (kg/d) * ((fat ( % )*12)+38)
> or = 5 and < or = 8 % fat: milk (kg/d) * ((fat ( % )*10)+48)
Calcium Required for Milk Production (g/d):
< or = 8 % fat: milk (kg/d) * ((fat ( % )*.2)+1.9)
Phosphorus Required for Milk Production (g/d):
< 5 % fat: milk (kg/d) * ((fat ( % )*.1)+1.4)
> or = 5 and <5.5 % fat: milk (kg/d) * ((fat ( % )*.2)+0.9)
> or = 5.5 and < or = 8 % fat: milk (kg/d) * ((fat ( % )*.1)+1.45)
2. The daily maintenance requirement was calculated as (1978 NRC):
net energy (Mcal/d) = .08 * (body weight)^3/4
protein (g/d) = 3.61 * (body weight)^3/4 + 50.06
calcium (g/d) = 0.185 * (body weight)^3/4 -1.256
phosphorus (g/d) = 0.137 * (body weight)^3/4 + .411
where body weight was in kilograms and weekly weights were estimated by interpolation between actual weekly weights.
3. Total nutrient requirement for milk and maintenance was the sum of the two individual parts. Nutrient balance was calculated on a weekly basis as the net nutrient intake minus the sum of the nutrient requirements for milk and maintenance.
Statistical Analyses:
Because primiparous cows are generally still growing and have a lactation curve shaped differently from multiparous cows, analyses of all effectiveness data and animal safety data (excluding injection site reaction and body temperature data) were performed separately for the two parity groups. Statistical analyses were conducted using the Statistical Analysis System (SAS). Data were analyzed using analysis of variance. The pooled analyses used the linear model Y(i,j,k) = U + T(i) + S (j) + T(s,i,j) + B(k)(S (j)) + b*PRE(i,j,k) + e(i,j,k), where U = overall mean, T(i) = treatment effect, S (j) = location effect, T(s,i,j) = treatment by location interaction, B(k)(S (j)) = block (within location) effect, PRE(i,j,k) = covariate, b = regression coefficient for PRE(i,j,k), and e(i,j,k) = residual. The treatment by location interaction, when significant (P < 0.25), was used as the error term to test the significance of the treatment effect. Treatment effects were deemed to be significant when P < 0.05 for effectiveness data and P < 0.10 for safety data. Each cow's average 14-day pretreatment value for each variable was expressed as the deviation from the location and parity mean and included as a covariate in the analysis for that variable to reduce experimental variation. Variables not covariately adjusted (e.g., somatic cell counts) are so indicated where results are tabulated.
Analyses of effectiveness data were first performed on average daily values computed up to 18 completed cycles (252 days of treatment). Variables were first subjected to tests for normality for information only; no transformations were made for non-normal data. Bartlett's test for homogeneity of variance across locations was also performed. For pretreatment effectiveness data, Bartlett's test was based on a model that did not include treatment or the treatment by location interaction. For treatment period data, the full model was used for Bartlett's test. Significant heterogeneity (P<0.005) required that analyses be weighted using the reciprocal of the residual variance for each location.
Nutritional parameters, body weight, and body condition score data were also analyzed as daily averages calculated over four 56-day periods of treatment and for the four periods combined (224 days). Pretreatment values were used to reduce experimental variation in each analysis, and each was weighted if the 252 day average for that variable had significant heterogeneity of variance across locations. Treatment effects were determined for each period separately. Although not analyzed by repeated measures techniques, these analyses allowed for comparison of treatment effects during different time intervals of the entire lactation.
Linear-plateau modelling (Anderson and Nelson, 1975 and 1984) was used to determine the effective dose range of sometribove. The relationship examined was between the dose administered and average daily SSFCM and adjusted for the effects of location, block, and pretreatment production (deviations from within location by parity mean used as a covariate). Five types of models were used with notation following Anderson and Nelson (1975) and dose = 0, 1, 2, 3 for the 0, 250, 500, 750 mg/14 day treatments, respectively:
1. Model II - a straight line where response = [[beta(0)]] + [[beta(1)]] *dose + [[epsilon]].
2. Model III - a linear plateau model where response = [[beta(0)]] + [[beta(1)]] *dose + [[epsilon]]. Two submodels were tested, III-1 with plateau beginning at dose 1 (250 mg/14 days) and III-2 with plateau beginning at dose 2 (500 mg/14 days).
3. Model IV - A linear plateau model where response = [[beta(0)]] + [[beta(1)]] *dose, + [[beta(2)]] *dose + [[epsilon]]. Two submodels were tested, IV-1 with plateau beginning after dose 1 (250 mg/14 days) and IV-2 with plateau beginning after dose 2 (500 mg/14 days).
4. Model V - two sloping lines where response = [[beta(0)]] + [[beta(1)]] *dose, + [[beta(2)]] *dose + [[epsilon]]. Two submodels were tested, V-1 with lines intersecting at dose 1 (250 mg/14 days) and V-2 with lines intersecting at dose 2 (500 mg/14 days).
5. Quad - a quadratic model where response = [[beta(0)]] + [[beta(1)]] *dose + [[beta(2)]] *dose* + [[epsilon]].
Four models were excellent candidates to fit the results for each parity separately. These are the linear, quadratic, IV-2, and V-1. All had R^2 values greater than 0.96. However, the quadratic model was not appropriate since all coefficients in the model were not significantly different from zero, and the model degenerates to the linear model. For model V-1, the slopes of the two line segments do not differ, leaving a linear model. For model IV-2, the breakpoint to a plateau can be calculated to occur above the highest administered dose. This violates the assumption that the plateau occurs before the highest administered dose, and causes the model to degenerate to the linear model. Therefore, the linear model was chosen as the best candidate for an appropriate dose titration over this dose range. The linear model mean squared error also best approximates the ANOVA mean squared error.
Results:
Data from the four locations were intended to be pooled to evaluate the measure of effectiveness, salable standardized FCM (SSFCM). However, the SSFCM data from the Utah location were excluded from this analysis. As discussed previously, most mastitis cases at the Utah location were not treated, thus, it was not possible to quantitate the amount of milk that would have been discarded due to mastitis therapy. Also, the incidence and duration of mastitis cases may have been affected by the lack of treatment, which would have also affected the calculation of SSFCM. Thus, the Utah data were excluded from the analysis of effectiveness in increasing the production of SSFCM.
Average SSFCM yields by parity for the remaining three study locations are provided in the following table:
(Eds. note: The following table consists of 5 columns.)
Table 3.
Sometribove Dosage (mg/14 days)
Study 0 250 500 750
Primiparous
Arizona 26.2a ± 1.79* 28.6a ± 1.72 28.3a ± 1.74 32.8b ± 1.75
Cornell 25.2a ± 0.80 27.5ab ± 0.78 27.4ab ± 0.88 29.9b ± 0.82
Florida 19.1a ± 1.16 21.4ab ± 1.06 23.4bc ± 1.00 26.2c ± 1.16
Multiparous
Arizona 25.4a ± 1.85 28.6a ± 1.88 26.9a ± 1.94 31.4b ± 1.90
Cornell 27.6a ± 1.16 30.9ab ± 1.16 33.4b ± 1.31 33.9b ± 1.22
Florida 19.3a ± 1.25 25.0b ± 1.32 24.6b ± 1.23 26.8b ± 1.13
a,b,c Means with unlike letters (a,b,or c) are significantly different
(P < 0.05).
* Results represent least-squares means (kg/day) ±
standard errors of the mean.
As shown in the following table, statistical analysis of the SSFCM data pooled across the three locations showed a linear response in SSFCM in both parity groups. The response at 250 mg per biweekly administration was significantly greater than in controls, and the response was linear through the highest dose tested, 750 mg per biweekly administration. The dose requested by the sponsor, 500 mg administered every 14 days, was within the range of effectiveness and therefore approvable for use.
(Eds. note: The following table consists of 5 columns.)
Table 4.
The effect of sometribove administered at 0, 250, 500, and 750
mg/14 days on salable standardized 3.5 % fat-corrected milk production (SSFCM)
in primiparous and multiparous cows; pooled analysis of the three
locations.
------Sometribove Dosage (mg/14 days)----------
Parameter* 0 mg 250 mg 500 mg 750 mg
--------Mean SSFCM Production (kg/day)---------
Primiparous Cows** (N) 22.7 (18) 25.0 (19) 26.0 (19) 28.8 (18)
Multiparous Cows** (N) 24.2 (25) 27.7 (24) 28.1 (23) 30.8 (25)
*Results are reported as least-squares means.
**Overall treatment effect and linear contrast were significant
(P<.0001).
The milk yield response in the pooled analysis of all four locations exhibited a cyclic pattern for all sometribove doses throughout each 14-day injection cycle, peaking on approximately day 8 and having the lowest response at the beginning and end of each cycle. As seen in Table 5, the difference between the daily milk yield at the lowest point of response and the peak of the cycle was approximately 10-12 percent.
(Eds. note: The following table consists of 5 columns.)
Table 5.
Milk yield cyclicity of the 500 mg/14 day sometribove group
pooled 4-location study
-----------Average Daily Yield Actual Milk (kg/d)--------------
Day of Controls 500 mg/14 days 500 mg/14 days 500 mg/14 days
Cycle Pooled Pooled Primiparous Multiparous
1 25.74 27.57 26.27 28.68
2 25.98 28.64 27.40 29.69
3 25.74 28.97 27.48 30.25
4 25.56 29.30 27.93 30.48
5 25.60 29.15 27.66 30.43
6 25.59 29.91 28.34 31.27
7 25.59 30.11 28.68 31.34
8 25.49 30.49* 28.97* 31.79*
9 25.49 30.23 28.77 31.45
10 25.21 29.80 28.32 31.07
11 25.15 29.25 28.01 30.30
12 25.10 28.36 27.12 29.43
13 25.20 27.96 26.65 29.04
14 25.21 27.34 26.32 28.21
* Peak value
All four locations were included in an evaluation of the effects of sometribove treatment on milk composition through 252 days of treatment. As shown in Tables 6 and 7, there was no significant effect on overall milk composition in either parity group.
(Eds. note: The following table consists of 5 columns.)
Table 6.
Sometribove Dosage (mg/14 days)
Variable* 0 250 500 750
Number of Primiparous Cows 26 27 27 25
Fat, % 3.66 3.57 3.58 3.62
Protein, % 3.21 3.28 3.20 3.23
Lactose, % 4.94 4.94 4.97 4.97
Ash,** % 0.74 0.76 0.74 0.75
Calcium,** ppm 1081 1139 1071 1056
Phosphorus,** ppm 904 964 924 927
*Results reported as least squares means.
**Excludes one 250 mg cow missing pretreatment value to use as
covariate.
(Eds. note: The following table consists of 5 columns.)
Table 7.
Sometribove Dosage (mg/14 days)
Variable * 0 250 500 750
Number of Multiparous
Cows 35 34 32 35
Fat,** % 3.59 3.49 3.52 3.48
Protein,*** % 3.22 3.28 3.24 3.20
Lactose,*** % 4.76 4.78 4.77 4.77
Ash,% 0.74 0.75 0.73 0.74
Calcium, ppm 1050 1048 1019 1020
Phosphorus, ppm 854 899 885 896
*Results reported as least squares means.
**Excludes two 0 mg and one 250 mg cows missing pretreatment
value to use as covariate.
***Excludes one 0 mg and one 250 mg cows missing pretreatment
value to use as covariate.
There was a small effect on cyclicity of fat, protein, and lactose content in milk.
Figure 1 - Effect of varying doses of sometribove on percent milk fat of primiparous cows.
Figure 2 - Effect of varying doses of sometribove on percent milk fat of multiparous cows
Follow this link to view Figures 1 and 2.
Figure 3 - Effect of varying doses of sometribove on percent milk protein of primiparous cows.
Figure 4 - Effect of varying doses of sometribove on percent milk protein of multiparous cows.
Follow this link to view Figures 3 and 4.
Figure 5 - Effect of varying doses of sometribove on percent milk lactose of primiparous cows.
Figure 4 - Effect of varying doses of sometribove on percent milk lactose of multiparous cows.
Follow this link to view Figures 5 and 6.
At the 500 mg dose, fat and protein percents were slightly increased for both parity groups (0.14 and 0.06 percentage units, respectively) and lactose percent was slightly decreased (0.02 percentage units) for primiparous cows in the second week compared to the first week of the treatment cycle. However, because cows within a herd are generally at various stages of lactation, and stage of lactation had a greater impact on milk composition than cyclicity due to treatment with sometribove, these minor effects would be expected to have no impact on average milk composition of bulk tank milk.
Dry matter intake increased for both primiparous and multiparous cows (see Table 44 in Section 6.h). Feed efficiency could not be evaluated in this study since the change in body condition over the treatment period was not similar across treatment groups for each parity for the cows treated at the 500 and 750 mg level. For further discussion of body condition see Section 6.h. Mastitis data are reviewed in Section 6.j. Reproduction data are discussed in Section 6.i. Health data are discussed in Section 6.k. Data on offspring are discussed in Section 6.l.
Conclusions:
The increase in marketable (salable) milk in response to sometribove in lactating dairy cows was linear in both parity groups. The response at 250 mg every 14 days was significantly greater than in controls, and the response was linear through the highest dose tested, 750 mg every 14 days. The dose requested by the sponsor, 500 mg administered every 14 days, was within the range of effectiveness and therefore approvable for use. The milk yield response exhibited a cyclic pattern during each 14-day injection cycle, with greatest response during the middle of each cycle; this effect is described in the product labeling so that dairy producers are aware of the pattern in milk yield during treatment. Administration of sometribove had no significant effect on the overall composition of milk.
Figures 1-6 go here
b. Tailhead Versus Postscapular Subcutaneous Administration Studies
Two field studies were conducted to evaluate the effectiveness of sometribove by SC administration in the ischiorectal fossa (depression on either side of the tailhead region, subsequently referred to as tailhead) compared to the postscapular region in increasing the production of 3.5 % fat-corrected milk. Results from these studies, as well as histopathological data (see Section 6.g), were used to determine whether the tailhead was an acceptable SC route of administration for sometribove.
Study No. 100-AZF-COW-JAD-89-075
Investigators: D. Armstrong, Ph.D.
A. Burgos, M.S.
University of Arizona
Tucson, AZ 85721
Eighty-eight Jersey cows from a commercial dairy farm in Arizona were assigned to one of three treatment groups: control; 500 mg sometribove administered SC in the postscapular (PS) region every 14 days; or 500 mg sometribove administered SC in the tailhead (TH) region every 14 days. The distribution of cows started on treatment is provided below:
(Eds. note: The following table consists of 5 columns.)
Table 8. Parity Control 500 mg-PS 500 mg-TH Totals Primiparous 9 8 8 25 Multiparous 31 16 16 63Following a 14-day pretreatment period, a 14-week (98-day) treatment period was initiated in which controls were untreated and the sometribove treatment groups received a maximum of 7 injections. Treatment was initiated on the same calendar day for all animals, and cows ranged from 59 to 179 days postpartum on this date.
Cows were housed in an open-lot corral throughout the study and fed a total mixed ration which met or exceeded nutritional requirements recommended by NRC (1989).
The cows were milked twice a day. Daily milk yield per cow was measured once every week, with consecutive PM and AM milk weights recorded on days -10 and -3 relative to treatment initiation during the pretreatment period, and then on days 3 and 10 following each treatment injection. Milk was also sampled on these days, and daily PM and AM samples were composited and analyzed to estimate the average weekly milk fat percent value for each cow. Each cow's milk fat percent and average daily milk yield for the week were used to calculate an average daily FCM yield per week as described in Section 5.a.
Two primiparous cows (one in each sometribove treatment group) and 9 multiparous cows (six 500 mg-PS; three 500 mg-TH) missed one of the 7 injections during the treatment period. Average daily FCM yield for these cows during these weeks of the treatment period was considered missing.
During even-numbered treatment weeks, milk fat percents or milk weights that were not recorded (human or mechanical error) were estimated from the average of the cow's adjacent even weeks' values; missing values during odd-number treatment weeks were similarly estimated. One multiparous control cow was excluded from analysis because her milk yields were not recorded for three consecutive weeks.
An average daily FCM yield during the treatment period was calculated for each cow from all treatment weeks in which injections were not missed. Results were analyzed using analysis of variance, fitting the model Y(i,j,k) = U + T(i) + B(j) + b*PRE(i,j,k) + e(i,j,k), where U = overall mean, T(i) = treatment effect, B(j) = block effect, PRE(i,j,k) = covariate (14-day pretreatment FCM yield), b = regression coefficient for covariate, and e(i,j,k) = residual. Results are provided in Table 9. There was no difference in FCM response in dairy cows administered sometribove subcutaneously in either the postscapular or tailhead region.
(Eds. note: The following table consists of 4 columns.)
Table 9.
Effect of sometribove on 3.5 % fat-corrected milk (FCM) production
(kg/d) during the treatment period.
-------Sometribove-------
Control Postscapular Tailhead
Primiparous (N) 19.9a(9) 24.3b(8) 24.3b(8)
Multiparous (N) 21.9a(30) 27.4b(16) 27.5b(16)
a,b Means with different letters (a or b) are significantly different (P<.05)
Study No. 100-IDA-COW-GAG-88-129
Investigator: G. A. Green, D.V.M.
Monsanto Company
St. Louis, MO 63198
Forty-eight Holstein cows from a commercial dairy farm in Idaho were assigned to one of three treatment groups: control; 500 mg sometribove administered SC in the PS region every 14 days; or 500 mg sometribove administered SC in the TH region every 14 days. The distribution of cows started on treatment is provided below:
(Eds. note: The following table consists of 5 columns.)
Table 10. Parity Control 500 mg-PS 500 mg-TH Totals Primiparous 9 6 3 18 Multiparous 15 6 9 30Following a 14-day pretreatment period, a 12-week (84-day) treatment period was initiated in which controls were untreated and the sometribove treatment groups received a total of 6 injections. Treatment was initiated on the same calendar day for all animals, and cows ranged from 65 to 175 days postpartum on this date.
Cows were housed in free-stall lots throughout the study and fed one of four total mixed rations balanced to meet or exceed nutritional requirements recommended by NRC (1989) depending on stage of lactation, parity, production, and body condition score.
The cows were milked three times a day. Weight of milk yield was recorded for each cow at each milking during the pretreatment and treatment period. Daily milk yield for each cow was the sum of the three milkings per day and was set to missing if the yield at any milking was not recorded. An average daily milk yield was calculated for each cow during each treatment week from all non-missing daily milk yields measured that week. Beginning the week prior to treatment initiation, each cow's milk was sampled once a week (days 2 and 9 post-injection) during the three milkings that day. The three samples were composited and analyzed to estimate the animal's average weekly milk fat percent value. Each cow's milk fat percent and average daily milk yield for the week were used to calculate an average daily FCM yield per week as described in Section 5.a.
During even-numbered treatment weeks when a cow's milk fat percent value was missing, the average of her adjacent even weeks' values was used as a replacement; missing values during odd-number treatment weeks were similarly estimated.
An average daily FCM yield during the treatment period was calculated for each cow from her weekly values. Results were analyzed using the model described for the Arizona Jersey study (#100-AZF-COW-JAD-89-075). One multiparous 500 mg-TH treated cow was diagnosed with lymphosarcoma on day 63 of treatment and was excluded from analysis. Results are provided in Table 11. There was no difference in FCM response in dairy cows administered sometribove subcutaneously in either the postscapular or tailhead region.
(Eds. note: The following table consists of 4 columns.)
Table 11.
Effect of sometribove on 3.5 % fat-corrected milk (FCM) production (kg/d)
during the treatment period.
--------Sometribove--------
Control Postscapular Tailhead
Primiparous (N) 37.1a(9) 42.9b(6) 46.0b(3)
Multiparous (N) 41.0a(15) 44.2ab(6) 47.5b(8)
a,b Means with different letters (a or b) are significantly different (P<.05)
The results of these two studies demonstrated no difference in the FCM response in dairy cows to administration of sometribove when injected subcutaneously in either the postscapular or tailhead region.
Continue to the next section || back to BST Table of Contents