PYRIDOSTIGMINE BROMIDE
DESCRIPTION:
Mestinon (pyridostigmine bromide) Injectable is an active cholinesterase
inhibitor. Chemically, pyridostigmine bromide is 3-hydroxy- 1-methylpyridinium
bromide dimethylcarbamate.
Each ml contains 5 mg pyridostigmine bromide compounded with 0.2% parabens
(methyl and propyl) as preservatives, 0.02% sodium citrate and pH adjusted to
approximately 5.0 with citric acid and, if necessary, sodium hydroxide.
ACTIONS/CLINICAL PHARMACOLOGY:
Mestinon facilitates the transmission of impulses across the myoneural junction
by inhibiting the destruction of acetylcholine by cholinesterase. Pyridostigmine
is an analog of neostigmine (Prostigmin(R)) but differs from it clinically by
having fewer side effects. Currently available data indicate that pyridostigmine
may have a significantly lower degree and incidence of bradycardia, salivation
and gastrointestinal stimulation. Animal studies using the injectable form of
pyridostigmine and human studies using the oral preparation have indicated that
pyridostigmine has a longer duration of action than does neostigmine measured
under similar circumstances.
INDICATIONS AND USAGE:
Mestinon Injectable is useful in the treatment of myasthenia gravis and as a
reversal agent or antagonist to nondepolarizing muscle relaxants such as
curariform drugs and gallamine triethiodide.
CONTRAINDICATIONS:
Known hypersensitivity to anticholinesterase agents; intestinal and urinary
obstructions of mechanical type.
WARNINGS:
Mestinon Injectable should be used with particular caution in patients with
bronchial asthma or cardiac dysrhythmias. Transient bradycardia may occur and be
relieved by atropine sulfate. Atropine should also be used with caution in
patients with cardiac dysrhythmias. When large doses of Mestinon are
administered, as during reversal of muscle relaxants, the prior or simultaneous
injection of atropine sulfate is advisable. Because of the possibility of
hypersensitivity in an occasional patient, atropine and antishock medication
should always be readily available.
As is true of all cholinergic drugs, overdosage of Mestinon may result in
cholinergic crisis, a state characterized by increasing muscle weakness which,
through involvement of the muscles of respiration, may lead to death. Myasthenic
crisis due to an increase in the severity of the disease is also accompanied by
extreme muscle weakness and thus may be difficult to distinguish from
cholinergic crisis on a symptomatic basis. Such differentiation is extremely
important, since increases in doses of Mestinon or other drugs in this class in
the presence of cholinergic crisis or of a refractory or "insensitive" state
could have grave consequences. Osserman and Genkins (REF. 1) indicate that the
two types of crisis may be differentiated by the use of Tensilon(R) (edrophonium
chloride) as well as by clinical judgment. The treatment of the two conditions
obviously differs radically. Whereas the presence of Myasthenic Crisis requires
more intensive anticholinesterase therapy, Cholinergic Crisis, according to
Osserman and Genkins, (REF. 1) calls for the prompt withdrawal of all drugs of
this type. The immediate use of atropine in cholinergic crisis is also
recommended. A syringe containing 1 mg of atropine sulfate should be immediately
available to be given in aliquots intravenously to counteract severe cholinergic
reactions.
Atropine may also be used to abolish or obtund gastrointestinal side effects or
other muscarinic reactions; but such use, by masking signs of overdosage, can
lead to inadvertent induction of cholinergic crisis.
For detailed information on the management of patients with myasthenia gravis,
the physician is referred to one of the excellent reviews such as those by
Osserman and Genkins, (REF. 2) Grob (REF. 3) or Schwab. (REF. 4, 5)
When used as an antagonist to nondepolarizing muscle relaxants, adequate
recovery of voluntary respiration and neuromuscular transmission must be
obtained prior to discontinuation of respiratory assistance and there should be
continuous patient observation. Satisfactory recovery may be defined by a
combination of clinical judgment, respiratory measurements and observation of
the effects of peripheral nerve stimulation. If there is any doubt concerning
the adequacy of recovery from the effects of the nondepolarizing muscle
relaxant, artificial ventilation should be continued until all doubt has been
removed.
Usage In Pregnancy: The safety of Mestinon during pregnancy or lactation in
humans has not been established. Therefore, use of Mestinon in women who may
become pregnant requires weighing the drug's potential benefits against its
possible hazards to mother and child.
ADVERSE REACTIONS:
The side effects of Mestinon are most commonly related to overdosage and
generally are of two varieties, muscarinic and nicotinic. Among those in the
former group are nausea, vomiting, diarrhea, abdominal cramps, increased
peristalsis, increased salivation, increased bronchial secretions, miosis and
diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps,
fasciculation and weakness. Muscarinic side effects can usually be counteracted
by atropine, but for reasons shown in the preceding section the expedient is not
without danger. As with any compound containing the bromide radical, a skin rash
may be seen in an occasional patient. Such reactions usually subside promptly
upon discontinuance of the medication. Thrombophlebitis has been reported
subsequent to intravenous administration.
DOSAGE AND ADMINISTRATION:
For Myasthenia Gravis--To supplement oral dosage, pre- and postoperatively,
during labor and postpartum, during myasthenic crisis, or whenever oral therapy
is impractical, approximately 1/30th of the oral dose of Mestinon may be given
parenterally, either by intramuscular or Very Slow intravenous injection. The
Patient Must Be Closely Observed For Cholinergic Reactions, Particularly If The
Intravenous Route Is Used.
For details regarding the management of myasthenic patients who are to undergo
major surgical procedures, see the article by Foldes. (REF. 6)
Neonates of myasthenic mothers may have transient difficulty in swallowing,
sucking and breathing. Injectable Mestinon may be indicated--by symptomatology
and use of the Tensilon(R) (edrophonium chloride) test--until Mestinon Syrup can
be taken. To date the world literature consists of less than 100 neonate
patients. (REF. 7) Of these only 5 were treated with injectable pyridostigmine,
with the vast majority of the remaining neonates receiving neostigmine. Dosage
requirements of Mestinon Injectable are minute, ranging from 0.05 mg to 0.15
mg/kg of body weight given intramuscularly. It is important to differentiate
between cholinergic and myasthenic crises in neonates. (See WARNINGS.)
Mestinon given parenterally one hour before completion of second stage labor
enables patients to have adequate strength during labor and provides protection
to infants in the immediate postnatal state. For further information on the use
of Mestinon Injectable in neonates of myasthenic mothers, see the article by
Namba. (REF. 7)
NOTE: For information on a diagnostic test for myasthenia gravis, and on the
evaluation and stabilization of therapy, please see product information on
Tensilon(R) (edrophonium chloride).
For Reversal Of Nondepolarizing Muscle Relaxants: When Mestinon Injectable is
given intravenously to reverse the action of muscle relaxant drugs, it is
recommended that atropine sulfate (0.6 to 1.2 mg) also be given intravenously
immediately prior to the Mestinon. Side effects, notably excessive secretions
and bradycardia, are thereby minimized. Usually 10 or 20 mg of Mestinon will be
sufficient for antagonism of the effects of the nondepolarizing muscle
relaxants. Although full recovery may occur within 15 minutes in most patients,
others may require a half hour or more. Satisfactory reversal can be evident by
adequate voluntary respiration, respiratory measurements and use of a peripheral
nerve stimulator device. It is recommended that the patient be well ventilated
and a patent airway maintained until complete recovery of normal respiration is
assured. Once satisfactory reversal has been attained, recurarization has not
been reported. For additional information on the use of Mestinon for antagonism
of nondepolarizing muscle relaxants see the article by Katz (REF. 8) and McNall.
(REF. 9)
Failure of Mestinon Injectable to provide prompt (within 30 minutes) reversal
may occur, e.g., in the presence of extreme debilitation, carcinomatosis, or
with concomitant use of certain broad spectrum antibiotics or anesthetic agents,
notably ether. Under these circumstances ventilation must be supported by
artificial means until the patient has resumed control of his respiration.
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