Included as part of the PRECAUTIONS section.
Cutaneous, Ophthalmological And/Or Systemic Adverse
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]. There is a 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 Symptomatic Orthostatic Hypotension],
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.
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 5 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 1 and 2 post-treatment. Advise patients that
if they feel dizzy or light-headed after taking Moxidectin Tablets, they should
lie down until the symptoms resolve.
Encephalopathy In Loa loa Co-infected Patients
Patients with onchocerciasis who are also infected with Loa
loa may develop a serious or even fatal encephalopathy following treatment with
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.
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
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity effects for moxidectin have not
Moxidectin was shown to be negative for genotoxicity in a
battery of in vitro assays including a bacterial mutagenicity assay, mouse
lymphoma cell mutagenicity assay, unscheduled DNA synthesis assay, and a chromosome
aberration assay, as well as in vivo in a micronucleus assay in mice and a
chromosome aberration assay in rats.
In 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.
Use In Specific Populations
Limited available data 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 (Gestation Days (GD) 6 to 15),
was not associated with significant embryo-fetal developmental effects at doses
of approximately 15 times the recommended human dose based on body surface
area. When moxidectin was dosed orally to pregnant rabbits during the period of
organogenesis (GD 7 - 19), no embryo-fetal developmental effects were observed
at oral doses of moxidectin up to 24 times the recommended human dose based on
body surface area [see Data].
Daily parental oral administration of dietary moxidectin
to rats prior to mating, and through mating, gestation, and lactation was
associated with decreased survival and body weights for first-generation
offspring without maternal toxicity at moxidectin doses less than 2-times the
recommended human dose based on body surface area comparison. Daily dietary
moxidectin did not produce maternal toxicity or adverse effects for first- and second-generation
offspring at doses approximately equivalent to the recommended human dose based
on body surface area comparison. Offspring were assessed for survival, body
weights, and fertility. Developmental milestones were not assessed in this
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.
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 body surface area 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 body surface area
comparison). In the rabbit, daily oral administration of moxidectin at ≥ 5
mg/kg/day from GD7 to GD19 was not associated with fetal weight loss or malformations
but resulted in significantly decreased maternal food consumption and body
weight gains. The NOAEL value 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 body surface area comparison).
In a 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 secondgeneration offspring at a
maternal NOAEL dose of 0.824 mg/kg/day (approximately equivalent to the recommended
human dose based on body surface area comparison). However, at moxidectin doses
≥ 1.1 mg/kg/day (approximately equivalent to 1.3 times the recommended
human dose based on body surface area 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 body surface area
comparison). In this study, offspring were assessed for survival, body weights,
and fertility, and developmental milestones were not assessed.
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. The developmental and health benefits of breastfeeding should be
considered along with the mother's clinical need for Moxidectin Tablets and any
potential adverse effects on the breastfed child from Moxidectin Tablets or
from the underlying maternal condition.
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. The effects of moxidectin
or its metabolites on the breast-fed child or milk production were not evaluated.
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, and Clinical
Studies]. The safety and effectiveness of Moxidectin Tablets in pediatric
patients under 12 years of age has not been established.
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 and CLINICAL PHARMACOLOGY].
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].