Joined
·
8 Posts
I use trifexis (spinosad + milbemycin oxime) on my dogs for heartworm and flea preventative. According to the company, use in breeding females should be used with caution and only under vet supervision, yet the study of effects on breed males has not been conducted at all. My vet only says dont use on your female during breeding, but Im concerned more about possible sterility in males as well as effects on females, specifically malformations in pups. The receptionist at the vet said she believes its more of a concern over litter size/health/defects etc. A fellow breeder friend worked several years as a vet tech and claims she has given comfortis (spinosad, main ingredient in trifexis) to her dogs since they were pups, never stopped treatment for breedings, and has NOT noticed a discernable difference in litters or pups. I've tried to read some information and it seems most of the breeding issues happen when doses are administered in much higher volume than what is prescribed by vets. However, Ive gotten a link to an information sheet from the FDA that describes the study conditions from the study on breeding females, but I was hoping someone with either experience with this medication or who might have a more scientific mind than I do could interpret the data from the study or describe their experiences. The following is the information I was able to obtain from the FDA. Thanks!
a. Title: Non-clinical laboratory study (GLP): A Reproductive Safety Study of a
Spinosad and Milbemycin Oxime Combination Administered Orally to Female
Beagle Dogs
b. Study Director: Edwin Goldenthal, PhD, ATS
Mattawan, MI
c. Study Design
Objective: Evaluate the safety of TRIFEXIS Chewable Tablets administered to breeding female dogs at 1X and 3X the upper half of the recommended therapeutic dose band.
1) Number of Animals: 39 adult female Beagles were randomized to treatment groups and received study treatment. The first 30 females confirmed to be pregnant were selected to continue on study for evaluation of reproductive variables. The remaining nine adult female dogs received study treatment until all treatment groups had ten pregnant females. The 18 breeding males and the pups did not receive study treatment. Females and males had to be healthy and to have had at least four pups in each of their previous two litters, with no congenital malformations in any pup within either litter.
2) Treatment Groups:
Table 25. Study T9A260803 Treatment Groups
3) Drug Administration: All treatments were administered orally with food.
Animals were re-dosed if they vomited within one hour. The 30 adult female dogs selected for evaluation of reproductive variables continued to receive study treatment, until their pups were 6 weeks old.
4) Variables Measured: Adult clinical pathology at baseline, clinical observations, physical examinations, body weight, litter size at birth and weaning, stillbirths, pup mortality, gross pathology, and histopathology
d. Statistical Methods: Repeated measurement endpoints, body weights of female adult dogs at each phase (gestation or lactation) and litter average body weight were analyzed using a linear mixed model with the baseline as a covariate and the fixed effects for treatment, time, and the treatment by time interaction. Acovariance matrix which minimizes the Akaike’s Information Criterion (AIC) was used. Weight gain of female adult dogs between Study Days -2 and 40 was analyzed using a linear mixed effect model with treatment as fixed effect and block and treatment by block as random effects.
For numerical parameters such as number of pups at birth, a linear one-way analysis of variance (ANOVA) was used to test for treatment differences. For binary outcomes such as proportion of pups with malformation, a generalized linear model with fixed effect treatment, binomial error distribution and logit link function was used to test treatment effect.
e. Results:
1) Clinical Findings in Adult Females: No treatment-related adverse reactions or signs of avermectin toxicosis were noted for adult females.
2) Body Weights in Adult Females: Between Study Day -2 (prior to the first study treatment on Study Day 0) and Study Day 40 (prior to the first mating on Study Day 42) there was a significant difference (p = 0.0406) in weight gain between the 3X group and the 0X group. The 0X group gained weight and the 3X group lost weight. The body weights of the treated groups were comparable to the control group during the gestation and post-parturition phases of the study.
3) Selection of Pregnant Females: The first ten confirmed pregnant dogs in each treatment group remained in the study. One 3X and one 1X group dog did not become pregnant.
4) Gestation and Litter Variables: Gestation length, litter size, stillborn pups, pup survival, and litter average body weight were comparable between treated and control dam groups.
5) Pups with Malformations: The proportion of pups with malformations was comparable between groups, with the types of malformations differing between groups. Malformations in the 1X group included a pup with cleft palate and a littermate with anophthalmia (one eye missing), fused single nares (single nostril), misshapen palate, hydrocephalus (fluid in the skull), omphalocele (organs outside of body), and small testes malpositioned cranial to kidneys; a pup with a malformation of the anterior tip of the urinary bladder and umbilical blood vessel; and a 4-day-old pup with patent ductus arteriosus (PDA). Malformations in the 3X group included three 2- to 3-day-old littermates with PDA (a fourth 2-day-old littermate had a very slightly patent ductus considered to be normal). Malformations in the control group included a pup with a malformed sternum (pectus excavatum), and a 2-day-old pup with PDA and a malpositioned superior vena cava. The incidence of cleft palate is not unexpected based on the historical data collected at the breeding site.
6) Pup Clinical Findings: No treatment-related effects were noted, with the exception of one 1X group pup. From three weeks of age on, one 1X group pup was smaller in size and less coordinated than its littermates, and received daily food and subcutaneous fluid supplements. It had tremors when excited.
f. Conclusions: With the exception of weight loss in the first six weeks at the 3X dose, spinosad and milbemycin oxime administration throughout the female reproductive cycle was clinically well-tolerated in adult Beagle dogs. The relationship between spinosad and milbemycin oxime treatment and the 1X and 3X dogs that did not become pregnant, the specific pup malformations, and the unthrifty 1X group pup are unknown.
a. Title: Non-clinical laboratory study (GLP): A Reproductive Safety Study of a
Spinosad and Milbemycin Oxime Combination Administered Orally to Female
Beagle Dogs
b. Study Director: Edwin Goldenthal, PhD, ATS
Mattawan, MI
c. Study Design
Objective: Evaluate the safety of TRIFEXIS Chewable Tablets administered to breeding female dogs at 1X and 3X the upper half of the recommended therapeutic dose band.
1) Number of Animals: 39 adult female Beagles were randomized to treatment groups and received study treatment. The first 30 females confirmed to be pregnant were selected to continue on study for evaluation of reproductive variables. The remaining nine adult female dogs received study treatment until all treatment groups had ten pregnant females. The 18 breeding males and the pups did not receive study treatment. Females and males had to be healthy and to have had at least four pups in each of their previous two litters, with no congenital malformations in any pup within either litter.
2) Treatment Groups:
Table 25. Study T9A260803 Treatment Groups
3) Drug Administration: All treatments were administered orally with food.
Animals were re-dosed if they vomited within one hour. The 30 adult female dogs selected for evaluation of reproductive variables continued to receive study treatment, until their pups were 6 weeks old.
4) Variables Measured: Adult clinical pathology at baseline, clinical observations, physical examinations, body weight, litter size at birth and weaning, stillbirths, pup mortality, gross pathology, and histopathology
d. Statistical Methods: Repeated measurement endpoints, body weights of female adult dogs at each phase (gestation or lactation) and litter average body weight were analyzed using a linear mixed model with the baseline as a covariate and the fixed effects for treatment, time, and the treatment by time interaction. Acovariance matrix which minimizes the Akaike’s Information Criterion (AIC) was used. Weight gain of female adult dogs between Study Days -2 and 40 was analyzed using a linear mixed effect model with treatment as fixed effect and block and treatment by block as random effects.
For numerical parameters such as number of pups at birth, a linear one-way analysis of variance (ANOVA) was used to test for treatment differences. For binary outcomes such as proportion of pups with malformation, a generalized linear model with fixed effect treatment, binomial error distribution and logit link function was used to test treatment effect.
e. Results:
1) Clinical Findings in Adult Females: No treatment-related adverse reactions or signs of avermectin toxicosis were noted for adult females.
2) Body Weights in Adult Females: Between Study Day -2 (prior to the first study treatment on Study Day 0) and Study Day 40 (prior to the first mating on Study Day 42) there was a significant difference (p = 0.0406) in weight gain between the 3X group and the 0X group. The 0X group gained weight and the 3X group lost weight. The body weights of the treated groups were comparable to the control group during the gestation and post-parturition phases of the study.
3) Selection of Pregnant Females: The first ten confirmed pregnant dogs in each treatment group remained in the study. One 3X and one 1X group dog did not become pregnant.
4) Gestation and Litter Variables: Gestation length, litter size, stillborn pups, pup survival, and litter average body weight were comparable between treated and control dam groups.
5) Pups with Malformations: The proportion of pups with malformations was comparable between groups, with the types of malformations differing between groups. Malformations in the 1X group included a pup with cleft palate and a littermate with anophthalmia (one eye missing), fused single nares (single nostril), misshapen palate, hydrocephalus (fluid in the skull), omphalocele (organs outside of body), and small testes malpositioned cranial to kidneys; a pup with a malformation of the anterior tip of the urinary bladder and umbilical blood vessel; and a 4-day-old pup with patent ductus arteriosus (PDA). Malformations in the 3X group included three 2- to 3-day-old littermates with PDA (a fourth 2-day-old littermate had a very slightly patent ductus considered to be normal). Malformations in the control group included a pup with a malformed sternum (pectus excavatum), and a 2-day-old pup with PDA and a malpositioned superior vena cava. The incidence of cleft palate is not unexpected based on the historical data collected at the breeding site.
6) Pup Clinical Findings: No treatment-related effects were noted, with the exception of one 1X group pup. From three weeks of age on, one 1X group pup was smaller in size and less coordinated than its littermates, and received daily food and subcutaneous fluid supplements. It had tremors when excited.
f. Conclusions: With the exception of weight loss in the first six weeks at the 3X dose, spinosad and milbemycin oxime administration throughout the female reproductive cycle was clinically well-tolerated in adult Beagle dogs. The relationship between spinosad and milbemycin oxime treatment and the 1X and 3X dogs that did not become pregnant, the specific pup malformations, and the unthrifty 1X group pup are unknown.
