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NEOSTIGMINE METHYLSULFATE INJECTION USP 0.5mg/ml
1.3.1 SUMMARY PRODUCT CHARACTERISTICS (SmPC)
1 Name of the Finished Medicinal Product:
1.1 Product Name: Neostigmine Methylsulfate Injection USP 0.5mg/ml
1.2 Strength : 0.5 mg/ml
1.3 Pharmaceutical Form: Injection
2 Qualitative and Quantitative Compositions:
Qualitative Declaration:
Active component
INN Name: Neostigmine Methylsulfate
Quantitative Declaration:
Each ml contains:
Neostigmine Methylsulfate USP….0.5 mg
Water for Injection USP...........................Q.S.
Qty in
Sr. No. Content Name Quality Standard
mg/ ml
1. Neostigmine Methylsulfate USP 0.50 mg
2. Glacial Acetic Acid USP q.s.
3. Water for Injection USP q.s. to 1.00 ml
USP: United States Pharmacopoeia
3 Pharmaceutical Form: Injection
A clear, colourless solution
4 Clinical Particulars:
4.1 Therapeutic Indications:
Neostigmine Methylsulfate Injection, USP is indicated for:
• The symptomatic control of myasthenia gravis when oral therapy is impractical.
• The prevention and treatment of postoperative distention and urinary retention after
mechanical obstruction has been excluded.
Reversal of effects of nondepolarizing neuromuscular blocking agents (e.g., tubocurarine,
metocurine, gallamine or pancuronium) after surgery.
4.2 Posology and Method of Administration
DOSAGE AND ADMINISTRATION:
Symptomatic Control of Myasthenia Gravis
One mL of the 1:2000 solution (0.5 mg) IM or SC. Sub-sequent doses should be based on
the individual patient’s response.
Prevention of Postoperative Distention and Urinary Retention
One mL of the 1:4000 solution (0.25 mg) IM or SC as soon as possible after operation;
repeat every four to six hours for two or three days.
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NEOSTIGMINE METHYLSULFATE INJECTION USP 0.5mg/ml
Treatment of Postoperative Distention
One mL of the 1:2000 solution (0.5 mg) IM or SC, as required.
Treatment of Urinary Retention
One mL of the 1:2000 solution (0.5 mg) IM or SC. If urination does not occur within an
hour, the patient should be catheterized. After the patient has voided, or the bladder has been
emptied, continue the 0.5 mg injections every three hours for at least five injections.
Reversal of Effects of Nondepolarizing Neuromus-cular Blocking Agents
When Neostigmine Methylsulfate is administered IV, it is recommended that atropine sulfate
(0.6 to 1.2 mg) also be given IV using separate syringes. Some authorities have
recommended that the atropine be injected several minutes before the neostigmine
methylsulfate rather than concomitantly.
The usual dose is 0.5 to 2 mg Neostigmine Methylsulfate given by slow IV injection,
repeated as required. Only in exceptional cases should the total dose of neostigmine
methylsulfate exceed 5 mg. It is recommended that the patient be well ventilated and a patent
airway maintained until complete recovery of normal respiration is assured. The optimum
time for administration of the drug is during hyperventilation when the carbon dioxide level
of the blood is low. It should never be administered in the presence of high concentrations of
halothane or cyclopropane. In the presence of bradycardia, the pulse rate should be increased
to about 80/min with atropine before administering Neostigmine Methylsulfate.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
4.3 Contra-indications:
Neostigmine Methylsulfate Injection is contraindicated in patients with known
hypersensitivity to the drug. It is also contraindicated in patients with peritonitis or
mechanical obstruction of the intestinal or urinary tract.
4.4 Special warning and precautions for use:
WARNING
Neostigmine Methylsulfate Injection should be used with caution in patients with epilepsy,
bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism,
cardiac arrhythmias or peptic ulcer. When large doses of Neostigmine Methylsulfate
Injection are administered, the prior or simultaneous injection of atropine sulfate may be
advisable. Separate syringes should be used for the Neostigmine Methylsulfate and atropine.
Because of the possibility of hypersensitivity in an occasional patient, atropine and antishock
medication should always be readily available.
PRECAUTIONS
General
It is important to differentiate between myasthenic crisis and cholinergic crisis caused by
overdosage of Neostigmine Methylsulfate Injection. Both conditions result in extreme
muscle weakness but require radically different treatment.
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NEOSTIGMINE METHYLSULFATE INJECTION USP 0.5mg/ml
4.5 Interaction with other drugs, other forms of interactions:
Neostigmine Methylsulfate Injection does not antagonize, and may in fact prolong, the Phase
I block of depolarizing muscle relaxants such as succinylcholine or decamethonium. Certain
antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite
nondepolarizing blocking action which may accentuate neuromuscular block. These
antibiotics should be used in the myasthenic patient only when definitely indicated, and then
careful adjustment should be made of the anti-cholinesterase dosage. Local and some general
anesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular
transmission should be used cautiously, if at all, in patients with myasthenia gravis; the dose
of Neostigmine Methylsulfate may have to be increased accordingly.
4.6 Usage in pregnancy& Lactation
Pregnancy
Teratogenic Effects: Pregnancy Category C
There are no adequate or well-controlled studies of Neostigmine Methylsulfate in either
laboratory animals or in pregnant women. Neostigmine Methylsulfate should be given to a
pregnant woman only if clearly needed.
Nonteratogenic Effects-Anticholinesterase drugs may cause uterine irritability and induce
premature labor when given IV to pregnant women near term.
Lactation
It is not known whether Neostigmine Methylsulfate is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for serious adverse
reactions from Neostigmine Methylsulfate in nursing infants, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
4.7 Effects on ability to drive and operate machine:
Not applicable
4.8 Undesirable effects:
Side effects are generally due to an exaggeration of pharmacological effects of which
salivation and fasciculation are the most common. Bowel cramps and diarrhea may also
occur.
The following additional adverse reactions have been reported following the use of either
neostigmine bromide or neostigmine methysulfate.
Allergic reactions and anaphylaxis, dizziness, convulsions, loss of consciousness,
drowsiness, headache, dysarthria, miosis and visual changes, cardiac arrhythmias (including
bradycardia, tachycardia, atrioventricular block and nodal rhythm). These have been
predominantly noted following the use of the injectable form of Neostigmine Methylsulfate.
Increased oral, pharyngeal and bronchial secretions, respiratory arrest and bronchospasm,
rash and urticaria, nausea, emesis, flatulence and increased peristalsis, urinary frequency,
arthralgia.
4.9 Overdose and special antidotes :
Overdosage of Neostigmine Methylsulfate can cause cholinergic crisis, which is
characterized by increasing muscle weakness, and through involvement of the muscles of
respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the
disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish
from cholingeric crisis on a symptomatic basis. However, such differentiation is extremely
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NEOSTIGMINE METHYLSULFATE INJECTION USP 0.5mg/ml
important because increases in the dose of Neostigmine Methylsulfate or other drugs in this
class, in the presence of cholinergic crisis or of a refractory or ‘‘insensitive’’ state, could
have grave consequences. The two types of crisis may be differentiated by the use of
edrophonium chloride as well as by clinical judgment.
Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis
requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt
withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is
also recommended.
Atropine may also be used to abolish or minimize gastrointestinal side effects or other
muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent
induction of cholinergic crisis.
5 Pharmacological Properties:
5.1 Pharmacodynamic Properties:
Pharmacotherapeutic Group (ATC Code) : N07AA01
Neostigmine inhibits the hydrolysis of acetylcholine by competing with acetylcholine for
attachment to acetylcholinesterase at sites of cholinergic transmission. It enhances
cholinergic action by facilitating the transmission of impulses across neuromuscular
junctions. It also has a direct cholinomimetic effect on skeletal muscle and possibly on
autonomic ganglion cells and neurons of the central nervous system (CNS). Neostigmine
undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in
the liver. Protein binding to human serum albumin ranges from 15 to 25%.
The clinical effects of neostigmine usually begin within 20 to 30 minutes after IM injection
and last from 2.5 to 4 hours.
5.2 Pharmacokinetic Properties:
Following IM administration, Neostigmine is rapidly absorbed and eliminated. In a study of
five patients with myasthenia gravis, peak plasma levels were observed at 30 minutes, and
the half-life ranged from 51 to 90 minutes. Approximately 80% of the drug was eliminated
in urine within 24 hours; approximately 50% as the unchanged drug, and 30% as
metabolites. Following IV administration, plasma half-life ranges from 47 to 60 minutes
have been reported with a mean half-life of 53 minutes.
5.3 Preclinical Safety Data :
Long-term animal studies have not been performed to evaluate the carcinogenic potential of
neostigmine.
Neostigmine methylsulfate was not mutagenic in an in vitro bacterial reverse mutation assay
(Ames test).
6. Pharmaceuticals Particulars:
6.1 List of Excipients:
Glacial Acetic Acid USP
Water for Injection USP
6.2 Incompatibilities: Do not mix Neostigmine Injection with any other product.
6.3 Shelf life: 24 Months
6.4 Special precautions for storage:
Store below 30°C. Protect from light.
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MODULE 1 –ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION
NEOSTIGMINE METHYLSULFATE INJECTION USP 0.5mg/ml
6.5 Nature and contents of container:
1 ml: Neostigmine Methylsulfate Injection USP 0.5mg/ml is packed in 1ml USP Type I
glass ampoule with black ring. 5 such ampoules are packed in a blister. 5 such blisters are
packed in a carton with pack insert.
5 ml: Neostigmine Methylsulfate Injection USP 0.5mg/ml is packed in 5ml USP Type I
glass ampoule with black ring. 5 such ampoules in blister packed in a carton with pack
insert.
6.6 Special precaution for disposal : Not Applicable
7 Registrant:
Marketing Authorisation Holder:
M/s PHILLIPS PHARMACEUTICALS (NIGERIA) LTD.
Address : Afprint Industrial Estate, Plot 122-132,
Apapa Oshodi Expressway Lagos.
Country : Nigeria.
Telephone : +234 806761764
Fax : ---
E-mail : ---
Manufacturing Site Address:
M/s THEMIS MEDICARE LIMITED
Address : Sector 6 A, Plot No. 16,17& 18, IIE
SIDCUL,HARIDWAR-249 403,
Uttarakhand
Country : India
Telephone : 91-1334-239322/21
Telefax : 91-1334-239217
E-Mail : hwdgmtech@[Link]
8 Date of Revision of the Text: Not Applicable
9 Dosimetry (if applicable): Not Applicable
10 Instruction for preparations of Radiopharmaceutical (if applicable): Not Applicable
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