Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/591
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Protopam Chloride (Injection)
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Organophosphate
Poisoning: ���Pralidoxime is most effective if administered immediately
after poisoning. Generally, little is accomplished if the drug
is given more than 36 hours after termination of exposure. When
the poison has been ingested, however, exposure may continue for some time due to slow absorption from the lower bowel, and fatal
relapses have been reported after initial improvement. Continued
administration for several days may be useful in such patients.
Close supervision of the patient is indicated for at least 48 to
72 hours. If dermal exposure has occurred, clothing should be
removed and the hair and skin washed thoroughly with sodium
bicarbonate or alcohol as soon as possible. Diazepam may be
given cautiously if convulsions are not controlled by atropine.���[7] Severe
poisoning (coma, cyanosis, respiratory depression) requires
intensive management. This includes the removal of secretions,
airway management, the correction of acidosis, and hypoxemia.
Atropine should be given as soon as possible after hypoxemia is
improved. Atropine should not be given in the presence of
significant hypoxia due to the risk of atropine-induced
ventricular fibrillation. In adults, atropine may be given
intravenously in doses of 2 to 4 mg. This should be repeated at
5 to 10-minute intervals until full atropinization (secretions
are inhibited) or signs of atropine toxicity appear (delirium,
hyperthermia, muscle twitching). Some degree
of atropinization should be maintained for at least 48 hours,
and until any depressed blood cholinesterase activity is
reversed. Morphine,
theophylline, aminophylline, and succinylcholine are
contraindicated. Tranquilizers of the reserpine or phenothiazine
type are to be avoided. After the effects of atropine
become apparent, PROTOPAM (pralidoxime chloride) may be
administered.<br/>PROTOPAM Chloride
Injection: Parenteral
drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever
solution and container permit. Discard
unused solution after a dose has been withdrawn. In adults, inject an initial
dose of 1 to 2 g of PROTOPAM, preferably as an infusion in 100
mL of saline, over a 15- to 30-minute period. If this is not
practical or if pulmonary edema is present, the dose should be
given slowly by intravenous injection as a 5 percent solution in
water over not less than five minutes. After about an hour, a
second dose of 1 to 2 g will be indicated if muscle weakness has
not been relieved. Additional doses may be given cautiously if
muscle weakness persists. Too-rapid
administration may result in temporary worsening of cholinergic
manifestations. Injection rate should not exceed 200 mg/minute.
If intravenous administration is not feasible, intramuscular or
subcutaneous injection should be used. In severe
cases, especially after ingestion of the poison, it may be
desirable to monitor the effect of therapy
electrocardiographically because of the possibility of heart
block due to the anticholinesterase. Where the poison has been
ingested, it is particularly important to take into account the
likelihood of continuing absorption from the lower bowel since
this constitutes new exposure. In such cases, additional doses of PROTOPAM (pralidoxime) may be needed every three to eight
hours. In effect, the patient should be���titrated���with PROTOPAM
as long as signs of poisoning recur. As in all cases of
organophosphate poisoning, care should be taken to keep the
patient under observation for at least 24 hours. If convulsions interfere with respiration, they may be controlled
by the slow intravenous injection of diazepam, up to 20 mg in
adults.<br/>Anticholinesterase
Overdosage: As an
antagonist to such anticholinesterases as neostigmine,
pyridostigmine, and ambenonium, which are used in the treatment
of myasthenia gravis, PROTOPAM may be given in a dosage of 1 to
2 g intravenously followed by increments of 250 mg every five
minutes.
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Chemical name:
2-formyl-1-methylpyridinium chloride oxime. Available in the United
States as PROTOPAM Chloride, pralidoxime chloride is frequently referred
to as 2-PAM Chloride. Structural formula: Pralidoxime
chloride occurs as an odorless, white, nonhygroscopic, crystalline
powder which is soluble in water. Stable in air, it melts between 215��and 225��C, with decomposition. The specific
activity of the drug resides in the 2-formyl-1-methylpyridinium ion and
is independent of the particular salt employed. The chloride is
preferred because of physiologic compatibility, excellent water
solubility at all temperatures, and high potency per gram, due to its
low molecular weight. Pralidoxime
chloride is a cholinesterase reactivator. PROTOPAM Chloride
for intravenous injection or infusion is prepared by cryodesiccation.
Each vial contains 1 g of sterile pralidoxime chloride, and NaOH to
adjust pH, to be reconstituted with 20 mL of Sterile Water for
Injection, USP. The pH of the reconstituted solution is 3.5 to 4.5.
Intramuscular or subcutaneous injection may be used when intravenous
injection is not feasible.
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The principal
action of pralidoxime is to reactivate cholinesterase (mainly outside of
the central nervous system) which has been inactivated by
phosphorylation due to an organophosphate pesticide or related compound.
The destruction of accumulated acetylcholine can then proceed, and
neuromuscular junctions will again function normally. Pralidoxime also
slows the process of���aging���of phosphorylated cholinesterase to a
nonreactivatable form, and detoxifies certain organophosphates by direct
chemical reaction. The drug has its most critical effect in relieving
paralysis of the muscles of respiration. Because pralidoxime is less
effective in relieving depression of the respiratory center, atropine is
always required concomitantly to block the effect of accumulated
acetylcholine at this site. Pralidoxime relieves muscarinic signs and
symptoms, salivation, bronchospasm, etc., but this action is relatively
unimportant since atropine is adequate for this purpose. Pralidoxime is
distributed throughout the extracellular water; it is not bound to
plasma protein. The drug is rapidly excreted in the urine partly
unchanged, and partly as a metabolite produced by the liver.
Consequently, pralidoxime is relatively short acting, and repeated doses
may be needed, especially where there is any evidence of continuing
absorption of the poison. The minimum
therapeutic concentration of pralidoxime in plasma is 4��g/mL; this
level is reached in about 16 minutes after a single injection of 600 mg
PROTOPAM Chloride. The apparent half-life of PROTOPAM Chloride is 74 to
77 minutes. It has been
reported [1]
that the supplemental use of oxime cholinesterase reactivators (such as
pralidoxime) reduces the incidence and severity of developmental defects
in chick embryos exposed to such known teratogens as parathion, bidrin,carbachol, and neostigmine. This protective effect of the oximes was
shown to be dose related.
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There are no known
absolute contraindications for the use of PROTOPAM. Relative
contraindications include known hypersensitivity to the drug and other
situations in which the risk of its use clearly outweighs possible
benefit .
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NDC
60977-141-01���Hospital
Package: This contains six 20 mL vials of 1 g each of sterile
PROTOPAM Chloride (pralidoxime chloride) white to off-white porous
cake*, without diluent or syringe. Solution may be prepared by adding 20
mL of Sterile Water for Injection, USP. These are single-dose vials for
intravenous injection or for intravenous infusion after further dilution
with physiologic saline. Intramuscular or subcutaneous injection may be
used when intravenous injection is not feasible.<br/>Storage: Store at 20��-25��C (68��-77��F),
excursions permitted to 15��-30��C (59��-86��F) [see USP Controlled Room Temperature].
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General: Pralidoxime
has been very well tolerated in most cases, but it must be
remembered that the desperate condition of the
organophosphate-poisoned patient will generally mask such minor
signs and symptoms as have been noted in normal subjects. Intravenous
administration of PROTOPAM should be carried out slowly and,
preferably, by infusion, since certain side effects, such as
tachycardia, laryngospasm, and muscle rigidity, have been
attributed in a few cases to a too-rapid rate of injection. (SeeDOSAGE AND
ADMINISTRATION.) PROTOPAM
should be used with great caution in treating organophosphate
overdosage in cases of myasthenia gravis since it may
precipitate a myasthenic crisis. Because
pralidoxime is excreted in the urine, a decrease in renal
function will result in increased blood levels of the drug.
Thus, the dosage of pralidoxime should be reduced in the
presence of renal insufficiency.<br/>Laboratory Tests: Treatment
of organophosphate poisoning should be instituted without
waiting for the results of laboratory tests. Red blood cell,
plasma cholinesterase, and urinary paranitrophenol measurements
(in the case of parathion exposure) may be helpful in confirming
the diagnosis and following the course of the illness. A
reduction in red blood cell cholinesterase concentration to
below 50% of normal has been seen only with organophosphate
ester poisoning.<br/>Drug Interactions: When
atropine and pralidoxime are used together, the signs of
atropinization (flushing, mydriasis, tachycardia, dryness of the
mouth and nose) may occur earlier than might be expected when
atropine is used alone. This is especially true if the total
dose of atropine has been large and the administration of
pralidoxime has been delayed. [2-4] The
following precautions should be kept in mind in the treatment of
anticholinesterase poisoning, although they do not bear directly
on the use of pralidoxime: since barbiturates are potentiated by
the anticholinesterases, they should be used cautiously in the
treatment of convulsions; morphine, theophylline, aminophylline,
succinylcholine, reserpine, and phenothiazine-type tranquilizers
should be avoided in patients with organophosphate
poisoning.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Since
pralidoxime chloride is indicated for short-term emergency use
only, no investigations of its potential for carcinogenesis,
mutagenesis, or impairment of fertility have been conducted by
the manufacturer, or reported in the literature.<br/>Pregnancy:<br/>Teratogenic
Effects���Pregnancy Category C: Animal reproduction studies have not been conducted
with pralidoxime. It is also not known whether
pralidoxime can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity.
Pralidoxime should be given to a pregnant woman only if
clearly needed.<br/>Nursing Mothers: It is not
known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised
when pralidoxime is administered to a nursing woman.<br/>Pediatric Use: Safety and
effectiveness in pediatric patients have not been
established.<br/>Geriatric Use: Clinical
studies of PROTOPAM did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical
experience has not identified differences in responses between
the elderly and younger patients. In general, dose selection for
an elderly patient should be cautious, usually starting at the
low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of
concomitant or other drug therapy.
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Manifestations of
Overdosage: Observed in
normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In
therapy it has been difficult to differentiate side effects due
to the drug from those due to the effects of the
poison.<br/>Treatment of
Overdosage: Artificial
respiration and other supportive therapy should be administered
as needed.<br/>Acute Toxicity: IV���man
TDLo: 14 mg/kg (toxic effects: CNS) IV���rat
LD: 96 mg/kg IM���rat
LD: 150 mg/kg ORAL���mouse LD: 4100 mg/kg IP���mouse
LD: 155 mg/kg IV���mouse
LD: 90 mg/kg IM���mouse
LD: 180 mg/kg IV���rabbit
LD: 95 mg/kg IM���guinea
pig LD: 168 mg/kg
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pralidoxime chloride
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Protopam Chloride (Injection)
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Forty to 60 minutes
after intramuscular injection, mild to moderate pain may be experienced
at the site of injection. Pralidoxime may
cause blurred vision, diplopia and impaired accommodation, dizziness,
headache, drowsiness, nausea, tachycardia, increased systolic and
diastolic blood pressure, hyperventilation, and muscular weakness when
given parenterally to normal volunteers who have not been exposed to
anticholinesterasepoisons. In patients, it is very difficult to
differentiate the toxic effects produced by atropine or the
organophosphate compounds from those of the drug. Elevations in SGOT
and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers
given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6
volunteers given 1800 mg intramuscularly. Levels returned to normal in
about 2 weeks. Transient elevations in creatine phosphokinase were
observed in all normal volunteers given the drug. A single intramuscular
injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation,
and hemorrhage. When atropine and
pralidoxime are used together, the signs of atropinization may occur
earlier than might be expected when atropine is used alone. This is
especially true if the total dose of atropine has been large and the
administration of pralidoxime has been delayed. [2-4]
Excitement and manic behavior immediately following recovery of
consciousness have been reported in several cases. However, similar
behavior has occurred in cases of organophosphate poisoning that were
not treated with pralidoxime. [3,5,6]
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PROTOPAM is not
effective in the treatment of poisoning due to phosphorus, inorganic
phosphates, or organophosphates not having anticholinesterase activity. PROTOPAM is not indicated as an antidote for
intoxication by pesticides of the carbamate class since it may increase
the toxicity of carbaryl.
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PROTOPAM is
indicated as an antidote: (1) in the treatment of poisoning due to those
pesticides and chemicals of the organophosphate class which have
anticholinesterase activity and (2) in the control of overdosage by
anticholinesterase drugs used in the treatment of myasthenia gravis. The principal
indications for the use of pralidoxime are muscle weakness and
respiratory depression. In severe poisoning, respiratory depression may
be due to muscle weakness.
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Protopam Chloride
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