GERIATRIC USE SECTION.


8.5 Geriatric Use Of the total number of patients included in Trial 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 )].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Moxidectin Tablets containing mg moxidectin are white to pale yellow uncoated oval-shaped tablets, debossed on one side with AKKA. Each high-density polyethylene bottle contains 500 tablets (NDC 71705-050-01), silica gel desiccant and polyester coil.Store below 30C (86F). Protect from light. Once open, the full contents of the container should be used within 24 hours with any unused content discarded.. Protect from light. Once open, the full contents of the container should be used within 24 hours with any unused content discarded.

OVERDOSAGE SECTION.


10 OVERDOSAGE No specific antidote is available for overdose with Moxidectin Tablets. If overdose occurs, the patient should be monitored for evidence of toxicity. Treatment of overdose with Moxidectin Tablets consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANELNDC 71705-050-01moxidectintablets2 mg500 tabletsRx Only NDC 71705-050-01moxidectintablets2 mg500 tabletsRx Only.

PEDIATRIC USE SECTION.


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.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics Cardiac ElectrophysiologyAt dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics The pharmacokinetic parameters of moxidectin following single mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4. Mean moxidectin Cmax and AUC increased approximately proportionally to dose over dose range of to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions. Table 4: Mean (+- SD) Pharmacokinetic Parameters of Moxidectin Following Single mg Oral Dose of Moxidectin Tablets to Healthy Subjects and Patients with Onchocerciasis Under Fasted ConditionsPK ParameterHealthy Subjects(N 27)Patients with Onchocerciasis(N 31)Cmax (ng/mL)58.9 +- 12.563.1 +- 20.0Tmax (hours)4 (2, 8)4 (1, 4)AUCinf (ngoh/mL)3387 +- 13282738 +- 1606Half-life (hours)784 +- 347559 +- 525Cmax maximum plasma concentration; Tmax time to reach Cmax; AUCinf area under the plasma concentration-time curve from time to infinity; Median (range)AbsorptionEffect of Food Moxidectin mean Cmax and AUC increased on average by 34% and 39%, respectively, when administered with standard high fat meal (900 calories, with nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions [see Dosage and Administration 2.1 )]. DistributionThe apparent mean +- SD volume of distribution of moxidectin is 2421 +- 1658 in patients with onchocerciasis. The plasma protein binding in humans is unknown.EliminationThe mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following single mg dose of Moxidectin Tablets. The apparent mean +- SD total clearance of moxidectin is approximately 3.50 +- 1.23 L/hour in patients with onchocerciasis.MetabolismThe hepatic metabolism of moxidectin is minimal. ExcretionFollowing administration of single mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligible.Specific PopulationsIn clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.Patients with Renal ImpairmentBased on population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin. The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.Drug Interaction StudiesClinical Study with Midazolam (CYP3A4 substrate) Co-administration of single mg dose of Moxidectin Tablets with single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam. In Vitro Studies CYP Enzymes: Moxidectin is not substrate or inhibitor of CYP enzymes. Uridine 5-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not UGT substrate.Transporter Systems: Moxidectin is not substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein (BCRP1).

PREGNULLNCY SECTION.


8.1 Pregnancy Risk SummaryAvailable data from clinical trials on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is 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 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 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.DataAnimal DataIn rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of mg based on BSA comparison) during Gestation Days (GDs) to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of skeletal variation, wavy ribs, at 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 and 10 mg/kg/day respectively (approximately and 12 times, respectively, the recommended human dose based on BSA comparison). In the rabbit, daily oral administration of moxidectin at >= mg/kg/day from GD 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 mg/kg/day and 10 mg/kg/day respectively (approximately times and 24 times, respectively, the recommended human dose based on BSA comparison). In 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 throughout the lactation period until LD 21. 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 receiving maternal doses from GD until LD 10 and Cohort receiving maternal doses from GD until each individual animal littered, but not during the lactation period. First-generation offspring in Cohort 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 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 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 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 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.

SPL UNCLASSIFIED SECTION.


2.1 Recommended Dosage in Patients Aged 12 Years and Older. The recommended dosage of Moxidectin Tablet is single dose of mg (four mg tablets) taken orally with or without food [see Clinical Pharmacology 12.3 )].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended during treatment with Moxidectin Tablets and for days after treatment. (8.2). Lactation: Breastfeeding not recommended during treatment with Moxidectin Tablets and for days after treatment. (8.2). 8.1 Pregnancy Risk SummaryAvailable data from clinical trials on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is 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 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 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.DataAnimal DataIn rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of mg based on BSA comparison) during Gestation Days (GDs) to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of skeletal variation, wavy ribs, at 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 and 10 mg/kg/day respectively (approximately and 12 times, respectively, the recommended human dose based on BSA comparison). In the rabbit, daily oral administration of moxidectin at >= mg/kg/day from GD 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 mg/kg/day and 10 mg/kg/day respectively (approximately times and 24 times, respectively, the recommended human dose based on BSA comparison). In 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 throughout the lactation period until LD 21. 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 receiving maternal doses from GD until LD 10 and Cohort receiving maternal doses from GD until each individual animal littered, but not during the lactation period. First-generation offspring in Cohort 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 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 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 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 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 SummaryMoxidectin was detected in the milk of lactating women following single 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 pre-postnatal study in rats, oral gavage administration of moxidectin at 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 days after treatment. DataA 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 period of 28 days following single 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 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 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 )].. 8.6 Renal Impairment. No dose adjustment of Moxidectin Tablets is necessary for patients with mild (creatinine clearance (CrCL) 60 to 89 mL/min) to moderate (CrCL 30 to 59 mL/min) renal impairment. The safety of Moxidectin Tablets in patients with severe renal impairment (CrCL 15 to 29 mL/min) or end stage renal disease, is unknown see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Cutaneous, Ophthalmological and/or Systemic Adverse Reactions of Varying Severity (Mazzotti Reaction): This may occur in patients with onchocerciasis following treatment with Moxidectin Tablets. Monitor patients for symptoms, including symptomatic orthostatic hypotension. (5.1) Symptomatic Orthostatic Hypotension: Episodes of symptomatic orthostatic hypotension including inability to stand without support may occur in patients following treatment with Moxidectin Tablets. (5.2) Encephalopathy in Loa loa Co-Infected Patients: Serious or even fatal encephalopathy following treatment with Moxidectin Tablets may occur in patients co-infected with Loa loa. Assess patients for loiasis in Loa loa endemic areas prior to treatment. (5.3) Edema and Worsening of Onchodermatitis: Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and aggravation of onchodermatitis. (5.4). Cutaneous, Ophthalmological and/or Systemic Adverse Reactions of Varying Severity (Mazzotti Reaction): This may occur in patients with onchocerciasis following treatment with Moxidectin Tablets. Monitor patients for symptoms, including symptomatic orthostatic hypotension. (5.1) Symptomatic Orthostatic Hypotension: Episodes of symptomatic orthostatic hypotension including inability to stand without support may occur in patients following treatment with Moxidectin Tablets. (5.2) Encephalopathy in Loa loa Co-Infected Patients: Serious or even fatal encephalopathy following treatment with Moxidectin Tablets may occur in patients co-infected with Loa loa. Assess patients for loiasis in Loa loa endemic areas prior to treatment. (5.3) Edema and Worsening of Onchodermatitis: Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and aggravation of onchodermatitis. (5.4). 5.1 Cutaneous, Ophthalmological and/or Systemic Adverse Reactions. Treatment with Moxidectin Tablets may cause cutaneous, ophthalmological and/or systemic reactions of varying severity (Mazzotti reaction). These adverse reactions are due to allergic and inflammatory host responses to the death of microfilariae [see Adverse Reactions 6.1 )]. There is trend toward an increased incidence of these adverse reactions in patients with higher microfilarial burden. The clinical manifestations of Mazzotti reaction includes pruritus, headache, pyrexia, rash, urticaria, hypotension (including symptomatic orthostatic hypotension and dizziness) [see Warnings and Precautions 5.2 )], tachycardia, edema, lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia. Ophthalmological manifestations include conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, photophobia, changes in visual acuity, hyperemia, ocular discomfort and watery eyes. These adverse reactions generally occur and resolve in the first week post-treatment. Laboratory changes include eosinophilia, eosinopenia, lymphocytopenia, neutropenia, and increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH). Proteinuria has also been reported. Treatment of severe Mazzotti reactions has not been evaluated in controlled clinical trials. Symptomatic treatments such as oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat orthostatic hypotension. Antihistamines and/or analgesics have been used for most mild to moderate cases. 5.2 Symptomatic Orthostatic Hypotension. An increased number of patients who received Moxidectin Tablets developed symptomatic orthostatic hypotension with inability to stand without support after lying down for minutes (in an orthostatic hypotension provocation test); 47/978 (5%) compared with 8/494 (2%) who received ivermectin. The decreases in blood pressure were transient, managed by resumption of recumbency and most commonly occurred on Days and post-treatment. Advise patients that if they feel dizzy or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve. 5.3 Encephalopathy in Loa loa Co-infected Patients. Patients with onchocerciasis who are also infected with Loa loa may develop serious or even fatal encephalopathy following treatment with Moxidectin Tablets. Moxidectin Tablets have not been studied in patients co-infected with Loa loa. Therefore, it is recommended that individuals who warrant treatment with Moxidectin Tablets and have had exposure to Loa loa-endemic areas undergo diagnostic screening for loiasis prior to treatment. 5.4 Edema and Worsening of Onchodermatitis Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and worsening of onchodermatitis following the use of Moxidectin Tablets. Symptomatic treatment has been used to manage patients who have experienced edema and worsening of onchodermatitis.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Midazolam (CYP3A4 substrate)In healthy subjects, concomitant administration of single 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.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other labeling sections:Cutaneous, Ophthalmological and/or Systemic Adverse Reactions [see Warnings and Precautio ns 5.1 )] Symptomatic Orthostatic Hypotension [see Warnings and Precautions 5.2 )] Encephalopathy in Loa loa Co-infection [see Warnings and Precautions 5.3 )] Edema and Worsening of Onchodermatitis [see Warnings and Precautions 5.4 )] Cutaneous, Ophthalmological and/or Systemic Adverse Reactions [see Warnings and Precautio ns 5.1 )] Symptomatic Orthostatic Hypotension [see Warnings and Precautions 5.2 )] Encephalopathy in Loa loa Co-infection [see Warnings and Precautions 5.3 )] Edema and Worsening of Onchodermatitis [see Warnings and Precautions 5.4 )] The most common adverse reactions (incidence 10%) were: eosinophilia, pruritus, musculoskeletal pain, headache, lymphopenia, tachycardia, rash, abdominal pain, hypotension, pyrexia, leukocytosis, influenza-like illness, neutropenia, cough, lymph node pain, dizziness, diarrhea, hyponatremia and peripheral swelling. (6)To report SUSPECTED ADVERSE REACTIONS, contact Medicines Development for Global Health at 800 MDGH 456 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under varying controlled conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety of Moxidectin Tablets was evaluated in two randomized, double-blind, active-controlled studies (Trial and Trial 2) [see Clinical Studies 14 )]. In Trial 1, 978 patients received Moxidectin Tablets as single oral dose of mg and 494 patients received ivermectin as single oral dose of approximately 150 mcg/kg. In Trial 2, 127 patients received Moxidectin Tablets as single oral dose ranging from mg (this is not an approved dose) to mg (38 received the recommended mg dose) and 45 patients received ivermectin as single oral dose of approximately 150 mcg/kg.Most Common Adverse ReactionsNo patients withdrew from either trial due to adverse reactions. Adverse Reactions reported in Trial in 10% of patients are summarized in Table 1. Most were related to physical, vital signs and laboratory changes associated with Mazzotti reaction [see Warnings and Precautions 5.1 )]. Table 1: Adverse Reactions Occurring in 10% of Moxidectin-treated Patients with Onchocerciasis in Trial Adverse ReactionMoxidectinN 978n (%)IvermectinN 494n (%)Eosinophilia721 (74)390 (79)Pruritus640 (65)268 (54)Musculoskeletal pain 623 (64)257 (52)Headache566 (58)267 (54)Lymphocytopenia470 (48)215 (44)Tachycardia 382 (39)148(30) Orthostatic tachycardia 333 (34)130 (26) Non-orthostatic tachycardia 179 (18)57 (12)Rash 358 (37)103 (21)Abdominal pain 305 (31)173 (35)Hypotension 289 (30)125 (25) Orthostatic hypotension 212 (22)81 (16)Pyrexia/Chills268 (27)88 (18)Leukocytosis240 (25)125 (25)Influenza like illness226 (23)102 (21)Neutropenia197 (20)112 (23)Cough168 (17)88 (18)Lymph node pain129 (13)28 (6)Dizziness121 (12)44 (9)Diarrhea/Gastroenteritis/Enteritis144 (15)84 (17)Hyponatremia112 (12)65 (13)Peripheral swelling107 (11)30 (6)a Includes myalgia, arthralgia, musculoskeletal pain, pain and back painb Includes orthostatic heart rate increased, postural orthostatic tachycardia syndrome, heart rate increased and sinus tachycardiac Includes orthostatic heart rate increased and postural orthostatic tachycardia syndromed Includes heart rate increased, tachycardia, and sinus tachycardiae Includes rash, papular rash and urticariaf Includes abdominal pain, abdominal pain upper and abdominal pain lowerg Includes orthostatic hypotension, blood pressure orthostatic decreased, blood pressure decreased, mean arterial pressure decreased, hypotensionh Includes orthostatic hypotension, and blood pressure orthostatic decreasedLymphocytopenia is defined as absolute lymphocyte count less than x 109/LNeutropenia is defined as absolute neutrophil count less than x 109/LThe most common adverse reactions in patients (n 38) treated with mg moxidectin in Trial were similar to the adverse reactions noted in Trial described in Table above.Other Adverse Reactions Reported in Clinical TrialsThe following adverse reactions occurred in less than 10% of subjects receiving Moxidectin Tablets in Trial 1:Ocular Adverse Reactions: In Trial 1, the most common ocular adverse reactions (occurring in >= 0.5% of patients) is shown in Table 2.Table 2: Ocular Adverse Reactions Occurring in >= 0.5% Moxidectin-treated PatientsAdverse ReactionMoxidectinN 978n (%)IvermectinN 494n (%)Eye pain78 (8)28 (6)Eye pruritus64 (7)26 (5)Visual impairment25 (3)9 (2)Eyelid edema21 (2)5 (1)Conjunctivitis allergic19 (2)11 (2)Ocular discomfort18 (2)11 (2)Ocular and conjunctival hyperemia17 (2)3 (1)Lacrimation increased13 (1)10 (2)Includes visual impairment, blurred vision and low vision acuity Includes foreign body sensation, ocular discomfort and abnormal sensation in the eye Hepatobiliary Adverse ReactionsMore patients in the moxidectin arm experienced elevation in bilirubin above the upper limit of normal and elevation in transaminases 5x upper limit of normal. Twenty-seven (2.8%) patients in the moxidectin arm and (0.6%) patients in the ivermectin arm had hyperbilirubinemia. Most of the patients had single measurements of hyperbilirubinemia without concurrent elevation in transaminases.Nine (1%) patients in the moxidectin arm and (0.4%) patients in the ivermectin arm had elevation in ALT of more than 5x upper limit of normal; ten (1%) patients in the moxidectin arm and (0.6%) patients in the ivermectin arm had elevation in AST to more than 5x upper limit of normal.Laboratory Abnormalities Laboratory abnormalities occurring in at least 1% of patients in the Trial are described in Table 3.Table 3: Laboratory Abnormalities in at least 1% of Moxidectin-treated PatientsParameterMOXIDECTIN(N 978)n (%)Ivermectin(N 494)n (%)HematologySevere eosinophilia (> x109/L)173 (18)111 (23)Grade lymphocytopenia (< 0.5 x109/L)220 (23)98 (20)Grade Neutrophils (< 0.5 x109/L)65 (7)46 (9)Eosinopenia (<0.045 x109/L)51 (5)21 (4)HepatobiliaryGGT (> 5x upper limit of normal)26 (3)16 (3)Bilirubin (> 2x upper limit of normal)14 (1.4)2 (0.4)AST (> 5x upper limit of normal)10 (1)3 (0.6)ALT (> 5x upper limit of normal)9 (1)2 (0.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year carcinogenicity studies in mice and rats were conducted with moxidectin. Mice were administered mean dietary dose of 8.7 mg/kg/day moxidectin which is approximately equivalent to times the recommended human dose based on body surface area comparison. Rats were administered mean dietary dose of 6.1 mg/kg/day moxidectin which is approximately equivalent to times the recommended human dose based on body surface area comparison. There was no evidence of tumorigenicity in either study. MutagenesisMoxidectin was shown to be negative for genotoxicity in battery of in vitro assays including bacterial mutagenicity assay, mouse lymphoma cell mutagenicity assay, unscheduled DNULL synthesis assay, and chromosome aberration assay, as well as in vivo in micronucleus assay in mice and chromosome aberration assay in rats.Impairment of FertilityIn fertility evaluations, male and female mating and fertility indices were not inhibited by oral-dietary moxidectin doses of approximately 0.86 mg/kg/day which is approximately equivalent to the recommended human dose based on body surface area comparison.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Moxidectin, macrocyclic lactone, is an anthelmintic drug [see Microbiology 12.4 )].. 12.2 Pharmacodynamics Cardiac ElectrophysiologyAt dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics The pharmacokinetic parameters of moxidectin following single mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4. Mean moxidectin Cmax and AUC increased approximately proportionally to dose over dose range of to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions. Table 4: Mean (+- SD) Pharmacokinetic Parameters of Moxidectin Following Single mg Oral Dose of Moxidectin Tablets to Healthy Subjects and Patients with Onchocerciasis Under Fasted ConditionsPK ParameterHealthy Subjects(N 27)Patients with Onchocerciasis(N 31)Cmax (ng/mL)58.9 +- 12.563.1 +- 20.0Tmax (hours)4 (2, 8)4 (1, 4)AUCinf (ngoh/mL)3387 +- 13282738 +- 1606Half-life (hours)784 +- 347559 +- 525Cmax maximum plasma concentration; Tmax time to reach Cmax; AUCinf area under the plasma concentration-time curve from time to infinity; Median (range)AbsorptionEffect of Food Moxidectin mean Cmax and AUC increased on average by 34% and 39%, respectively, when administered with standard high fat meal (900 calories, with nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions [see Dosage and Administration 2.1 )]. DistributionThe apparent mean +- SD volume of distribution of moxidectin is 2421 +- 1658 in patients with onchocerciasis. The plasma protein binding in humans is unknown.EliminationThe mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following single mg dose of Moxidectin Tablets. The apparent mean +- SD total clearance of moxidectin is approximately 3.50 +- 1.23 L/hour in patients with onchocerciasis.MetabolismThe hepatic metabolism of moxidectin is minimal. ExcretionFollowing administration of single mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligible.Specific PopulationsIn clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.Patients with Renal ImpairmentBased on population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin. The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.Drug Interaction StudiesClinical Study with Midazolam (CYP3A4 substrate) Co-administration of single mg dose of Moxidectin Tablets with single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam. In Vitro Studies CYP Enzymes: Moxidectin is not substrate or inhibitor of CYP enzymes. Uridine 5-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not UGT substrate.Transporter Systems: Moxidectin is not substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein (BCRP1).. 12.4 Microbiology Mechanism of ActionThe mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters. This leads to increased permeability, influx of chloride ions, hyperpolarization and muscle paralysis. Additionally, there is reduction in motility of all stages of the parasite, excretion of immunomodulatory proteins, and the fertility of both male and female adult worms. Antimicrobial activityMoxidectin is active against the microfilariae of O. volvulus [see Clinical Studies 14 )]. Studies suggest that moxidectin is not effective in killing the adult worms, however, it inhibits intra-uterine embryogenesis and release of microfilariae from the adult worms.ResistanceStudies in vitro and in infected animals suggest potential for development of resistance to moxidectin and cross-resistance with other macrocyclic lactones, such as ivermectin. However, the clinical relevance of these findings is not known.The mechanism of resistance may be multifactorial that include alteration in the target GluCl, GABA receptors and/or ABC transporters.

CLINICAL STUDIES SECTION.


6.1 Clinical Trials Experience Because clinical trials are conducted under varying controlled conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety of Moxidectin Tablets was evaluated in two randomized, double-blind, active-controlled studies (Trial and Trial 2) [see Clinical Studies 14 )]. In Trial 1, 978 patients received Moxidectin Tablets as single oral dose of mg and 494 patients received ivermectin as single oral dose of approximately 150 mcg/kg. In Trial 2, 127 patients received Moxidectin Tablets as single oral dose ranging from mg (this is not an approved dose) to mg (38 received the recommended mg dose) and 45 patients received ivermectin as single oral dose of approximately 150 mcg/kg.Most Common Adverse ReactionsNo patients withdrew from either trial due to adverse reactions. Adverse Reactions reported in Trial in 10% of patients are summarized in Table 1. Most were related to physical, vital signs and laboratory changes associated with Mazzotti reaction [see Warnings and Precautions 5.1 )]. Table 1: Adverse Reactions Occurring in 10% of Moxidectin-treated Patients with Onchocerciasis in Trial Adverse ReactionMoxidectinN 978n (%)IvermectinN 494n (%)Eosinophilia721 (74)390 (79)Pruritus640 (65)268 (54)Musculoskeletal pain 623 (64)257 (52)Headache566 (58)267 (54)Lymphocytopenia470 (48)215 (44)Tachycardia 382 (39)148(30) Orthostatic tachycardia 333 (34)130 (26) Non-orthostatic tachycardia 179 (18)57 (12)Rash 358 (37)103 (21)Abdominal pain 305 (31)173 (35)Hypotension 289 (30)125 (25) Orthostatic hypotension 212 (22)81 (16)Pyrexia/Chills268 (27)88 (18)Leukocytosis240 (25)125 (25)Influenza like illness226 (23)102 (21)Neutropenia197 (20)112 (23)Cough168 (17)88 (18)Lymph node pain129 (13)28 (6)Dizziness121 (12)44 (9)Diarrhea/Gastroenteritis/Enteritis144 (15)84 (17)Hyponatremia112 (12)65 (13)Peripheral swelling107 (11)30 (6)a Includes myalgia, arthralgia, musculoskeletal pain, pain and back painb Includes orthostatic heart rate increased, postural orthostatic tachycardia syndrome, heart rate increased and sinus tachycardiac Includes orthostatic heart rate increased and postural orthostatic tachycardia syndromed Includes heart rate increased, tachycardia, and sinus tachycardiae Includes rash, papular rash and urticariaf Includes abdominal pain, abdominal pain upper and abdominal pain lowerg Includes orthostatic hypotension, blood pressure orthostatic decreased, blood pressure decreased, mean arterial pressure decreased, hypotensionh Includes orthostatic hypotension, and blood pressure orthostatic decreasedLymphocytopenia is defined as absolute lymphocyte count less than x 109/LNeutropenia is defined as absolute neutrophil count less than x 109/LThe most common adverse reactions in patients (n 38) treated with mg moxidectin in Trial were similar to the adverse reactions noted in Trial described in Table above.Other Adverse Reactions Reported in Clinical TrialsThe following adverse reactions occurred in less than 10% of subjects receiving Moxidectin Tablets in Trial 1:Ocular Adverse Reactions: In Trial 1, the most common ocular adverse reactions (occurring in >= 0.5% of patients) is shown in Table 2.Table 2: Ocular Adverse Reactions Occurring in >= 0.5% Moxidectin-treated PatientsAdverse ReactionMoxidectinN 978n (%)IvermectinN 494n (%)Eye pain78 (8)28 (6)Eye pruritus64 (7)26 (5)Visual impairment25 (3)9 (2)Eyelid edema21 (2)5 (1)Conjunctivitis allergic19 (2)11 (2)Ocular discomfort18 (2)11 (2)Ocular and conjunctival hyperemia17 (2)3 (1)Lacrimation increased13 (1)10 (2)Includes visual impairment, blurred vision and low vision acuity Includes foreign body sensation, ocular discomfort and abnormal sensation in the eye Hepatobiliary Adverse ReactionsMore patients in the moxidectin arm experienced elevation in bilirubin above the upper limit of normal and elevation in transaminases 5x upper limit of normal. Twenty-seven (2.8%) patients in the moxidectin arm and (0.6%) patients in the ivermectin arm had hyperbilirubinemia. Most of the patients had single measurements of hyperbilirubinemia without concurrent elevation in transaminases.Nine (1%) patients in the moxidectin arm and (0.4%) patients in the ivermectin arm had elevation in ALT of more than 5x upper limit of normal; ten (1%) patients in the moxidectin arm and (0.6%) patients in the ivermectin arm had elevation in AST to more than 5x upper limit of normal.Laboratory Abnormalities Laboratory abnormalities occurring in at least 1% of patients in the Trial are described in Table 3.Table 3: Laboratory Abnormalities in at least 1% of Moxidectin-treated PatientsParameterMOXIDECTIN(N 978)n (%)Ivermectin(N 494)n (%)HematologySevere eosinophilia (> x109/L)173 (18)111 (23)Grade lymphocytopenia (< 0.5 x109/L)220 (23)98 (20)Grade Neutrophils (< 0.5 x109/L)65 (7)46 (9)Eosinopenia (<0.045 x109/L)51 (5)21 (4)HepatobiliaryGGT (> 5x upper limit of normal)26 (3)16 (3)Bilirubin (> 2x upper limit of normal)14 (1.4)2 (0.4)AST (> 5x upper limit of normal)10 (1)3 (0.6)ALT (> 5x upper limit of normal)9 (1)2 (0.4).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.


11 DESCRIPTION Moxidectin Tablets contain moxidectin, an anthelmintic drug and macrocyclic lactone of the milbemycin class derived from the actinomycete Streptomyces cyanogriseus. The chemical name of moxidectin is (2aE,4E,5R,6R,6S,8E,11R,13S,15S,17aR,20R,20aR,20bS)-6-[(E)-1,3-dimethyl-1-butenyl]-5,6,6,7,10,11,14,15,17a,20,20a,20b-dodecahydro-20,20b-dihydroxy-5,6,8,19-tetramethylspiro[11,15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2-[2H]pyran]-4,17(3H)-dione 4-(E)-(O-methyloxime). The structural formula is:Figure 1: Moxidectin StructureMoxidectin is white or pale-yellow, amorphous powder. The empirical formula is C37H53NO8 and the molecular weight is 639.82 Dalton. Moxidectin is readily soluble in organic solvents such as methylene chloride, diethyl ether, ethanol, acetonitrile, and ethyl acetate. It is only slightly soluble in water (0.51 mg/L) and the melting point range for moxidectin powder is 145C to 154C.Moxidectin Tablets are for oral administration. Each tablet contains mg of moxidectin. The tablets are uncoated and include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. Figure 1: Moxidectin Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION - Patients aged 12 years and older: Take mg (four mg tablets) as single oral dose, with or without food. (2.1) 2.1 Recommended Dosage in Patients Aged 12 Years and Older. The recommended dosage of Moxidectin Tablet is single dose of mg (four mg tablets) taken orally with or without food [see Clinical Pharmacology 12.3 )].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Moxidectin Tablets are available as white to pale yellow uncoated oval-shaped tablets, debossed on one side with AKKA. Each tablet contains mg of moxidectin. Tablets: mg. (3).

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older see Clinical Studies 14 ]. Limitations of Use:Moxidectin Tablets do not kill adult . volvulus. Follow-up evaluation is advised.The safety and efficacy of repeat administration of Moxidectin Tablets in patients with . volvulus has not been studied. Moxidectin is an anthelmintic indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. (1) Limitations of Use:Moxidectin Tablets do not kill adult O. volvulus parasites. Follow-up is advised. The safety and efficacy of repeat administration of Moxidectin Tablets in patients with . volvulus has not been studied.. Moxidectin Tablets do not kill adult O. volvulus parasites. Follow-up is advised. The safety and efficacy of repeat administration of Moxidectin Tablets in patients with . volvulus has not been studied.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Signs and Symptoms Associated with Microfilarial DeathAdvise patients that they are likely to have flu like symptoms including malaise, myalgia, headache, tachycardia, hypotension and pruritus, most commonly during the first week after treatment. Symptomatic Orthostatic HypotensionAdvise patients that if they feel dizzy, faint or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve. Absence of Macrofilarial ActivityAdvise patients that treatment with Moxidectin Tablets does not kill adult . volvulus and that follow up evaluation is usually required. Edema and Worsening of OnchodermatitisAdvise patients with hyper-reactive onchodermatitis that they may be more likely to experience severe adverse reactions.Encephalopathy in Loa loa Co-infected PatientsAdvise patients to report any symptoms of encephalopathy to their healthcare provider. Lactation Advise women that breastfeeding is not recommended at the time of treatment with Moxidectin Tablets and for days after treatment.Manufactured for: Medicines Development for Global Health, Melbourne, Victoria, Australia (C) 2021 Medicines Development for Global Health. All rights reserved.

LACTATION SECTION.


8.2 Lactation Risk SummaryMoxidectin was detected in the milk of lactating women following single 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 pre-postnatal study in rats, oral gavage administration of moxidectin at 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 days after treatment. DataA 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 period of 28 days following single 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 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.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Moxidectin, macrocyclic lactone, is an anthelmintic drug [see Microbiology 12.4 )].

MICROBIOLOGY SECTION.


12.4 Microbiology Mechanism of ActionThe mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters. This leads to increased permeability, influx of chloride ions, hyperpolarization and muscle paralysis. Additionally, there is reduction in motility of all stages of the parasite, excretion of immunomodulatory proteins, and the fertility of both male and female adult worms. Antimicrobial activityMoxidectin is active against the microfilariae of O. volvulus [see Clinical Studies 14 )]. Studies suggest that moxidectin is not effective in killing the adult worms, however, it inhibits intra-uterine embryogenesis and release of microfilariae from the adult worms.ResistanceStudies in vitro and in infected animals suggest potential for development of resistance to moxidectin and cross-resistance with other macrocyclic lactones, such as ivermectin. However, the clinical relevance of these findings is not known.The mechanism of resistance may be multifactorial that include alteration in the target GluCl, GABA receptors and/or ABC transporters.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year carcinogenicity studies in mice and rats were conducted with moxidectin. Mice were administered mean dietary dose of 8.7 mg/kg/day moxidectin which is approximately equivalent to times the recommended human dose based on body surface area comparison. Rats were administered mean dietary dose of 6.1 mg/kg/day moxidectin which is approximately equivalent to times the recommended human dose based on body surface area comparison. There was no evidence of tumorigenicity in either study. MutagenesisMoxidectin was shown to be negative for genotoxicity in battery of in vitro assays including bacterial mutagenicity assay, mouse lymphoma cell mutagenicity assay, unscheduled DNULL synthesis assay, and chromosome aberration assay, as well as in vivo in micronucleus assay in mice and chromosome aberration assay in rats.Impairment of FertilityIn fertility evaluations, male and female mating and fertility indices were not inhibited by oral-dietary moxidectin doses of approximately 0.86 mg/kg/day which is approximately equivalent to the recommended human dose based on body surface area comparison.. 13.2 Animal Toxicology and/or Pharmacology. Moxidectin was associated with transient CNS-related clinical signs. In rats, single dose of 20 mg/kg (equivalent to approximately 24 times the recommended human dose based on body surface area comparison) moxidectin was associated with piloerection, reduced arousal and body tone, abnormal gait, slowed breathing, and impaired righting reflex. In dogs, repeated doses of 1.6 mg/kg/day moxidectin (equivalent to approximately times the recommended human dose based on body surface area comparison) was associated with lacrimation, languid appearance, tremors, slight salivation, and slight ataxia.