Included as part of the PRECAUTIONS section.
Neostigmine has been associated with bradycardia.
Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to
lessen the risk of bradycardia [see DOSAGE AND ADMINISTRATION].
Serious Adverse Reactions In Patients With Certain Coexisting
BLOXIVERZ should be used with caution in patients with
coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or
myasthenia gravis. Because of the known pharmacology of neostigmine
methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such
as bradycardia, hypotension or dysrhythmia would be anticipated. In patients
with certain cardiovascular conditions such as coronary artery disease, cardiac
arrhythmias or recent acute coronary syndrome, the risk of blood pressure and
heart rate complications may be increased. Risk of these complications may also
be increased in patients with myasthenia gravis. Standard antagonism with
anticholinergics (e.g., atropine) is generally successful to mitigate the risk
of cardiovascular complications.
Because of the possibility of hypersensitivity, atropine
and medications to treat anaphylaxis should be readily available.
Large doses of BLOXIVERZ administered when neuromuscular
blockade is minimal can produce neuromuscular dysfunction. The dose of
BLOXIVERZ should be reduced if recovery from neuromuscular blockade is nearly
It is important to differentiate between myasthenic
crisis and cholinergic crisis caused by overdosage of BLOXIVERZ. Both
conditions result in extreme muscle weakness but require radically different treatment
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to
evaluate the carcinogenic potential of neostigmine.
Neostigmine methylsulfate was not mutagenic or
clastogenic when evaluated in an in vitro bacterial reverse mutation assay
(Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration
assay, or an in vivo mouse bone marrow micronucleus assay.
Impairment Of Fertility
In a fertility and early embryonic development study in
rats, male rats were treated for 28 days prior to mating and female rats were
treated for 14 days prior to mating with intravenous neostigmine methylsulfate
(human equivalent doses of 1.6, 4, and 8.1 mcg/kg/day, based on body surface
area). No adverse effects were reported at any dose (up to 0.1 times the MRHD
of 5 mg/60 kg person based on a body surface area comparison).
Use In Specific Populations
There are no adequate or well-controlled studies of
BLOXIVERZ in pregnant women. It is not known whether BLOXIVERZ can cause fetal
harm when administered to a pregnant woman or can affect reproductive capacity.
The incidence of malformations in human pregnancies has not been established for
neostigmine as the data are limited. All pregnancies, regardless of drug
exposure, have a background risk of 2 to 4% for major birth defects, and 15 to
20% for pregnancy loss.
No adverse effects were noted in rats or rabbits treated
with human equivalent doses of neostigmine methylsulfate doses up to 8.1 and 13
mcg/kg/day, respectively, during organogenesis (0.1 to 0.2-times the maximum
recommended human dose of 5 mg/60 kg person/day based on body surface area comparisons).
Anticholinesterase drugs, including neostigmine may cause
uterine irritability and induce premature labor when administered to pregnant
women near term.
BLOXIVERZ should be given to a pregnant woman only if
In embryofetal development studies, rats and rabbits were
administered neostigmine methylsulfate at human equivalent doses (HED, on a
mg/m² basis) of 1.6, 4 and 8.1 mcg/kg/day and 3.2, 8.1, and 13 mcg/kg/day,
respectively, during the period of organogenesis (Gestation Days 6 through 17
for rats and Gestation Days 6 through 18 for rabbits). There was no evidence
for a teratogenic effect in rats and rabbits up to HED 8.1 and 13 mcg/kg/day,
which are approximately 0.097 times and 0.16 times the MRHD of 5 mg/60 kg,
respectively in the presence of minimal maternal toxicity (tremors, ataxia, and
prostration). The studies resulted in exposures in the animals well below
predicted exposures in humans.
In a pre- and postnatal development study in rats,
neostigmine methylsulfate was administered to pregnant female rats at human
equivalent doses (HED) of 1.6, 4 and 8.1 mcg/kg/day from Day 6 of gestation through
Day 20 of lactation, with weaning on Day 21. There were no adverse effects on
physical development, behavior, learning ability, or fertility in the offspring
at HED doses up to 8.1 mcg/kg/day which is 0.097 times the MRHD of 5 mg/60 kg
on a mg/m² basis in the presence of minimal maternal toxicity (tremors, ataxia,
and prostration). The studies resulted in exposures in the animals well below predicted
exposures in humans.
Labor And Delivery
The effect of BLOXIVERZ on the mother and fetus with
regard to labor, delivery, the need for forceps delivery or other intervention
or resuscitation of the newborn, is not known.
Cholinesterase inhibitor drugs may induce premature labor
when given intravenously to pregnant women near term.
It is not known whether neostigmine methylsulfate is
excreted in human milk. Caution should be exercised when BLOXIVERZ is
administered to a nursing woman.
BLOXIVERZ is approved for the reversal of the effects of
non-depolarizing neuromuscular blocking agents after surgery in pediatric
patients of all ages.
Recovery of neuromuscular activity occurs more rapidly
with smaller doses of cholinesterase inhibitors in infants and children than in
adults. However, infants and small children may be at greater risk of
complications from incomplete reversal of neuromuscular blockade due to
decreased respiratory reserve. The risks associated with incomplete reversal
outweigh any risk from giving higher doses of BLOXIVERZ (up to 0.07 mg/kg or up
to a total of 5 mg, whichever is less).
The dose of BLOXIVERZ required to reverse neuromuscular
blockade in children varies between 0.03 mg - 0.07 mg/kg, the same dose range
shown to be effective in adults, and should be selected using the same criteria
as used for adult patients [see CLINICAL PHARMACOLOGY].
Since the blood pressure in pediatric patients,
particularly infants and neonates, is sensitive to changes in heart rate, the
effects of an anticholinergic agent (e.g., atropine) should be observed prior
to administration of neostigmine to lessen the probability of bradycardia and
Because elderly patients are more likely to have
decreased renal function, BLOXIVERZ should be used with caution and monitored
for a longer period in elderly patients. The duration of action of neostigmine methylsulfate
is prolonged in the elderly; however, elderly patients also experience slower spontaneous
recovery from neuromuscular blocking agents. Therefore, dosage adjustments are
not generally needed in geriatric patients; however, they should be monitored
for longer periods than younger adults to assure additional doses of BLOXIVERZ
are not required. The duration of monitoring should be predicated on the
anticipated duration of action for the NMBA used on the patient [see DOSAGE
Elimination half-life of neostigmine methylsulfate was
prolonged in anephric patients compared to normal subjects.
Although no adjustments to BLOXIVERZ dosing appear to be
warranted in patients with impaired renal function, they should be closely
monitored to assure the effects of the neuromuscular blocking agent, particularly
one cleared by the kidneys, do not persist beyond those of BLOXIVERZ. In this
regard, the interval for re-dosing the neuromuscular blocking agent during the
surgical procedure may be useful in determining whether, and to what extent,
post-operative monitoring needs to be extended.
The pharmacokinetics of neostigmine methylsulfate in
patients with hepatic impairment have not been studied. Neostigmine
methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments
to the dosing of BLOXIVERZ appear to be warranted in patients with hepatic
insufficiency. However, patients should be carefully monitored if hepatically
cleared neuromuscular blocking agents were used during their surgical procedure
as their duration of action may be prolonged by hepatic insufficiency whereas
BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This
could result in the effects of the neuromuscular blocking agent outlasting
those of BLOXIVERZ. This same situation may arise if the neuromuscular blocking
agent has active metabolites. In this regard, the interval for re-dosing the
neuromuscular blocking agent during the surgical procedure may be useful in determining
whether, and to what extent, post-operative monitoring needs to be extended.