Prostigmin (neostigmine bromide), an anticholinesterase agent, is available for oral administration in 15-mg tablets. Each tablet also contains gelatin, lactose, corn starch, stearic acid, sugar and talc.

Chemically, neostigmine bromide is ( m  -hydroxyphenyl)trimethylammonium bromide dimethylcarbamate. It is a white, crystalline, bitter powder, soluble 1:1 in water, with a molecular weight of 303.20.

Prostigmin is indicated for the symptomatic treatment of myasthenia gravis. Its greatest usefulness is in prolonged therapy where no difficulty in swallowing is present. In acute myasthenic crisis where difficulty in breathing and swallowing is present, the parenteral form (neostigmine methylsulfate) should be used. The patient can be transferred to the oral form as soon as it can be tolerated.

The onset of action of Prostigmin given orally is slower than when given parenterally, but the duration of action is longer and the intensity of action more uniform. Dosage requirements for optimal results vary from 15 mg to 375 mg per day. In some instances it may be necessary to exceed these dosages, but the possibility of cholinergic crisis must be recognized. The average dose is 10 tablets (150 mg) administered over a 24-hour period. The interval between doses is of paramount importance. The dosage schedule should be adjusted for each patient and changed as the need arises. Frequently, therapy is required day and night. Larger portions of the total daily dose may be given at times when the patient is more prone to fatigue (afternoon, mealtimes, etc.). The patient should be encouraged to keep a daily record of his or her condition to assist the physician in determining an optimal therapeutic regimen.

Scored, white tablets containing 15 mg neostigmine bromide bottles of 100(NDC 0187-3100-10). Imprint on tablets: (front) PROSTIGMIN 15: (back) ICN.

Manufactured for ICN Pharmaceuticals, Inc.
Costa Mesa, CA 92626
by Hoffmann-La Roche Inc.

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 methylsulfate:

Allergic:   Allergic reactions and anaphylaxis.

Neurologic:   Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes.

Cardiovascular:   Cardiac arrhythmias (including bradycardia, tachycardia, A-V block and nodal rhythm) and nonspecific EKG changes have been reported, as well as cardiac arrest, syncope and hypotension. These have been predominantly noted following the use of the injectable form of Prostigmin.

Respiratory:   Increased oral, pharyngeal and bronchial secretions, and dyspnea. Respiratory depression, respiratory arrest and bronchospasm have been reported following the use of the injectable form of Prostigmin.

Dermatologic:   Rash and urticaria.

Gastrointestinal:   Nausea, emesis, flatulence and increased peristalsis.

Genitourinary:   Urinary frequency.

Musculoskeletal:   Muscle cramps and spasms, arthralgia.

Miscellaneous:   Diaphoresis, flushing and weakness.

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 where definitely indicated, and then careful adjustment should be made of adjunctive anticholinesterase 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 Prostigmin may have to be increased accordingly.

Prostigmin should be used with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer. As a rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract. Large doses should be avoided in situations where there might be an increased absorption rate from the intestinal tract. It should be used with caution when co-administered with anticholinergic drugs, in order to avoid reduction of intestinal motility.

General:   It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Prostigmin. Both conditions result in extreme muscle weakness but require radically different treatment. (See OVERDOSAGE section.)

Drug Interactions:    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 where definitely indicated, and then careful adjustment should be made of adjunctive anticholinesterase 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 Prostigmin may have to be increased accordingly.

Carcinogenesis, Mutagenesis and Impairment of Fertility: There have been no studies with Prostigmin which would permit an evaluation of its carcinogenic or mutagenic potential. Studies on the effect of Prostigmin on fertility and reproduction have not been performed.

Pregnancy:

Teratogenic Effects:  Pregnancy Category C. There are no adequate or well-controlled studies of Prostigmin in either laboratory animals or in pregnant women. It is not known whether Prostigmin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Prostigmin 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 intravenously to pregnant women near term.

Nursing Mothers:   It is not known whether Prostigmin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Prostigmin 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.

Pediatric Use:   Safety and effectiveness in children have not been established.

Overdosage of Prostigmin 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 cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of Prostigmin 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 crises may be differentiated by the  use  of  Tensilon®  (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.

The LD ₅₀ of neostigmine methylsulfate in mice is 0.3 ± 0.02 mg/kg intravenously, 0.54 ± 0.03 mg/kg subcutaneously, and 0.395 ± 0.025 mg/kg intramuscularly; in rats the LD ₅₀ is 0.315 ± 0.019 mg/kg intravenously, 0.445 ± 0.032 mg/kg subcutaneously, and 0.423 ± 0.032 mg/kg intramuscularly.

Prostigmin is contraindicated in patients with known hypersensitivity to the drug. Because of the presence of the bromide ion, it should not be used in patients with a previous history of reaction to bromides. It is contraindicated in patients with peritonitis or mechanical obstruction of the intestinal or urinary tract.

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. 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 percent.

Neostigmine bromide is poorly absorbed from the gastrointestinal tract following oral administration. As a rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract. In a study in fasting myasthenic patients, the extent of absorption was estimated to be 1 to 2 percent of the ingested 30-mg single oral dose. Peak concentrations in plasma occurred 1 to 2 hours following drug ingestion, with considerable individual variations. The half-life ranged from 42 to 60 minutes with a mean half-life of 52 minutes.

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IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NEOSTIGMINE BROMIDE - ORAL

(nee-oh-STIG-min)

COMMON BRAND NAME(S): Prostigmin

USES: Neostigmine is used to improve muscle strength in patients with a certain muscle disease (myasthenia gravis). It works by preventing the breakdown of a certain natural substance (acetylcholine) in your body. Acetylcholine is needed for normal muscle function.

HOW TO USE: Take this medication by mouth with or without food as directed by your doctor. Taking this medication with food or milk may help to decrease side effects.

Dosage is based on your medical condition and response to therapy. Talk with your doctor about how you respond to the medication and about when you feel the most tired or weak so that your doctor can make the proper dosage changes.

Do not increase your dose or take this medication more often than prescribed. Doing so may increase the risk of serious side effects.

Tell your doctor if your condition persists or worsens or if the medication stops working well.

SIDE EFFECTS: Nausea, vomiting, diarrhea, abdominal cramps, increased saliva/mucus, decreased pupil size, increased urination, or increased sweating may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: new or increased muscle cramps/weakness/twitching, new or increased difficulty swallowing, slow/fast/irregular heartbeat, dizziness, shortness of breath, headache, seizures.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking neostigmine, tell your doctor or pharmacist if you are allergic to it; or to other anticholinesterase medications (e.g., pyridostigmine); or to bromides; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: stomach/intestinal blockage, urinary blockage, a certain abdominal problem (peritonitis).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: seizures, asthma, heart disease (e.g., slow/irregular heartbeat, coronary artery disease), a certain nerve disorder (vagotonia), overactive thyroid (hyperthyroidism), stomach/intestinal problems (e.g., severe constipation, ulcer, megacolon).

Before having surgery, tell your doctor or dentist that you are using this medication.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Tell your doctor of all prescription and nonprescription medication you may use, especially: aminoglycoside antibiotics (e.g., gentamicin), antiarrhythmic medications (e.g., quinidine), drugs that decrease the movements of the stomach (e.g., antihistamines such as diphenhydramine, antispasmodics such as dicyclomine, narcotic pain medications such as morphine).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: nausea, vomiting, diarrhea, fast/slow heartbeat, dizziness, greatly increased saliva/sweating, blurred vision, agitation, muscle cramps/weakness, inability to move, trouble breathing, loss of consciousness.

NOTES: Do not share this medication with others.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.