Moxidectin (Page 2 of 5)

7 DRUG IN TERACTIONS

Midazolam (CYP3A4 substrate)

In healthy subjects, concomitant administration of a single 8 mg oral dose of Moxidectin Tablets did not have an effect on the pharmacokinetics of midazolam [ see Clinical Pharmacology ( 12.3) ]. Moxidectin can be co-administered with CYP3A4 substrates.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from clinical trials on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is a moxidectin-associated risk for major birth defects and miscarriage . Moxidectin administered orally to pregnant rats during the period of organogenesis was not associated with significant embryo-fetal developmental effects at doses of approximately 15 times the recommended human dose based on body surface area (BSA) comparison. When moxidectin was dosed orally to pregnant rabbits during the period of organogenesis, no embryo-fetal developmental effects were observed at oral doses of moxidectin up to 24 times the recommended human dose based on BSA comparison ( see Data).

Daily administration of moxidectin by oral gavage to maternal female rats during organogenesis and through lactation was associated with decreased survival, adverse clinical signs, and decreased body weights in first-generation offspring during the lactation period at a moxidectin dose less than 2-times the recommended human dose based on BSA comparison. Additional findings in first-generation offspring at the same dose included delays in pinna unfolding, eye opening, and vaginal opening. Other parameters, including reproduction and neurological development in first-generation offspring were not affected at any moxidectin dose ( see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In a rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of 8 mg based on BSA comparison) during Gestation Days (GDs) 6 to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of a skeletal variation, wavy ribs, at a maternally toxic dose. Mean maternal food consumption, body weights, and body weight gain were significantly decreased at moxidectin doses of 10 and 12 mg/kg/day compared to control values. The no observed adverse effect level (NOAEL) value for maternal and fetal toxicity was considered to be 5 and 10 mg/kg/day respectively (approximately 6 and 12 times, respectively, the recommended human dose based on BSA comparison). In the rabbit, daily oral administration of moxidectin at ≥ 5 mg/kg/day from GD 7 to GD 19 was not associated with fetal weight loss or malformations but resulted in significantly decreased maternal food consumption and body weight gains. The NOAEL values for maternal and fetal toxicity in the rabbit was 1 mg/kg/day and 10 mg/kg/day respectively (approximately 2 times and 24 times, respectively, the recommended human dose based on BSA comparison).

In a pre-postnatal study, moxidectin doses of 0.2 and 0.5 mg/kg/day were administered by oral gavage to maternal female rats from GD 6 throughout the lactation period until LD 21. A third dose group that received maternal doses of 1.5 mg/kg/day moxidectin (less than 2-times the recommended human dose based on BSA comparison) was divided into two cohorts with Cohort 1 receiving maternal doses from GD 6 until LD 10 and Cohort 2 receiving maternal doses from GD 6 until each individual animal littered, but not during the lactation period. First-generation offspring in Cohort 1 had adverse clinical signs (small body size, thin, weak, subdued/sluggish, pale, cold to touch, respiratory distress, blue coloration and/or no visible milk in stomach) and decreased survival and body weights during the lactation period. However, first-generation offspring in Cohort 2 did not experience adverse clinical signs, body weight loss, or reduced survival suggesting moxidectin in lactation milk was responsible for the adverse effects in offspring in Cohort 1. Additional findings included delays in pinna unfolding and eye opening in male and female offspring in both cohorts and delay of vaginal opening in female offspring in Cohort 2. No adverse effects were noted in offspring at a maternal dose of 0.5 mg/kg/day (approximately 0.6 times the recommended human dose based on BSA comparison). Reproductive performance based on mating and fertility indices and neurological development were not affected in male and female first-generation offspring at any of the administered moxidectin doses.

In another pre-postnatal study in rats, parental oral administration of dietary moxidectin prior to mating, through mating, gestation, and lactation did not produce adverse effects in first-generation or second-generation offspring at a maternal NOAEL dose of 0.824 mg/kg/day (approximately equivalent to the recommended human dose based on BSA comparison). However, at moxidectin doses ≥ 1.1 mg/kg/day (approximately equivalent to 1.3 times the recommended human dose based on BSA comparison), the survival and body weights of first-generation offspring were significantly decreased during the lactation period, and the number of live fetuses at birth was significantly decreased with a maternal moxidectin dose of 11 mg/kg/day (approximately equivalent to 13 times the recommended human dose based on BSA comparison). In this study, offspring were assessed for survival, body weights, and fertility, and developmental milestones were not assessed.

8.2 Lactation

Risk Summary

Moxidectin was detected in the milk of lactating women following a single 8 mg dose of Moxidectin Tablets ( see Data). There are no data on the effects of Moxidectin Tablets on the breast-fed infant or milk production. In a pre-postnatal study in rats, oral gavage administration of moxidectin at a dose less than 2-times the recommended human dose based on BSA comparison during the lactation period resulted in adverse clinical signs, weight loss, and increased mortality in rat pups suggesting moxidectin in lactation milk was responsible for the adverse effects [ see Use in Specific Populations ( 8.1), and Data].

Because of serious findings from the rat pre-postnatal study including weight loss and death, advise women that breastfeeding is not recommended at the time of treatment with Moxidectin Tablets and for 7 days after treatment.

Data

A pharmacokinetic study in twelve healthy adult lactating women who were 21 to 100 weeks post partum evaluated the concentrations of moxidectin in plasma and breast milk collected over a period of 28 days following a single 8 mg dose of Moxidectin Tablets. The mean (± SD) exposure ratio of moxidectin present in human breast milk to that of human plasma was approximately 1.77 (± 0.66) over a collection period of 28 days. The estimated mean (± SD) total infant dose, assuming the infants would consume all the breast milk collected during the study, was 0.056 mg (± 0.024 mg), which would be approximately 0.70% (± 0.30%) of the maternal dose. Relative infant dose was estimated to be 8.73% (± 0.024 mg). The effects of moxidectin or its metabolites on the breast-fed child or milk production were not evaluated.

8.4 Pediatric Use

The safety and effectiveness of Moxidectin Tablets have been established in pediatric patients 12 years of age and older. In Trial 1, (n = 53 patients aged 12 to 17 years), the safety and effectiveness was similar to that observed in adults [see Adverse Reactions ( 6.1), and Clinical Studies ( 14)]. The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.

8.5 Geriatric Use

Of the total number of patients included in Trial 1 that were treated with Moxidectin Tablets, 83 were aged 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Studies ( 14) and Clinical Pharmacology ( 12.3)].

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2023. All Rights Reserved.