Myo-Pyrolate

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Myo-Pyrolate uses

Myo-Pyrolate consists of Glycopyrrolate, Neostigmine Methylsulfate.

Glycopyrrolate:


INDICATIONS AND USAGE

For use as adjunctive therapy in the treatment of peptic ulcer.

CONTRAINDICATIONS

Glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus; intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis. Myo-Pyrolate (Glycopyrrolate) tablets are contraindicated in those patients with a hypersensitivity to Myo-Pyrolate (Glycopyrrolate).

WARNINGS

In the presence of a high environmental temperature, heat prostration can occur with use of Myo-Pyrolate (Glycopyrrolate).

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomyor colostomy. In this instance treatment with this drug would be inappropriate and possibly harmful.

Myo-Pyrolate (Glycopyrrolate) may produce drowsiness and blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug.

Theoretically, with overdosage, a curare-like action may occur, i.e., neuro-muscular blockade leading to muscular weakness and possible paralysis.

Pregnancy

The safety of this drug during pregnancy has not been established. The use of any drug during pregnancy requires that potential benefits of the drug be weighed against possible hazards to mother and child. Reproduction studies in rats revealed no teratogenic effects from Myo-Pyrolate (Glycopyrrolate); however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of Myo-Pyrolate (Glycopyrrolate). Information on possible adverse effects in the pregnant female is limited to uncontrolled data derived from marketing experience. Such experience has revealed no reports of teratogenic or other fetus-damaging potential. No controlled studies to establish the safety of the drug in pregnancy have been performed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Pediatric Use

Since there is no adequate experience in pediatric patients who have received this drug, safety and efficacy in pediatric patients have not been established.

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PRECAUTIONS

Use Myo-Pyrolate (Glycopyrrolate) with caution in the elderly and in all patients with:

  • Autonomic neuropathy.
  • Hepatic or renal disease.
  • Ulcerative colitis-large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason may precipitate or aggravate “toxic megacolon,” a serious complication of the disease.
  • Hyperthyrodism, coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, hypertension and prostatic hypertrophy.
  • Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition.

ADVERSE REACTIONS

Anticholinergics produce certain effects, most of which are extensions of their fundamental pharmacological actions. Adverse reactions to anticholinergics in general may include xerostomia; decreased sweating; urinary hesitancy and retention; blurred vision; tachycardia; palpitations; dilatation of the pupil; cycloplegia; increased ocular tension; loss of taste; headaches; nervousness; mental confusion; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; constipation; bloated feeling; impotence; suppression of lactation; severe allergic reaction or drug idiosyncrasies including anaphylaxis, urticaria and other dermal manifestations.

Myo-Pyrolate (Glycopyrrolate) is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier, is limited in contrast to atropine sulfate and scopolamine hydrobromide. For this reason the occurrence of CNS related side effects is lower, in comparison to their incidence following administration of anticholinergics which are chemically tertiary amines that can cross this barrier readily.

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OVERDOSAGE

The symptoms of overdosage of Myo-Pyrolate (Glycopyrrolate) are peripheral in nature rather than central.

  • To guard against further absorption of the drug-use gastric lavage, cathartics and/or enemas.
  • To combat peripheral anticholinergic effects (residual mydriasis, dry mouth, etc.)-utilize a quaternary ammonium anticholinesterase, such as neostigmine methylsulfate.
  • To combat hypotension-use pressor amines (norepinephrine, metaraminol) i.v.; and supportive care.
  • To combat respiratory depression-administer oxygen; utilize a respiratory stimulant such as Dopram®* i.v.; artificial respiration.

DOSAGE AND ADMINISTRATION

The dosage of Myo-Pyrolate (Glycopyrrolate) should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions. The presently recommended maximum daily dosage of Myo-Pyrolate (Glycopyrrolate) is 8 mg.

Myo-Pyrolate (Glycopyrrolate) Tablets 1 mg. The recommended initial dosage of Myo-Pyrolate (Glycopyrrolate) for adults is one tablet three times daily (in the morning, early afternoon, and at bedtime). Some patients may require two tablets at bedtime to assure overnight control of symptoms. For maintenance, a dosage of one tablet twice a day is frequently adequate.

Myo-Pyrolate (Glycopyrrolate) Tablets 2 mg. The recommended dosage of Myo-Pyrolate (Glycopyrrolate) for adults is one tablet two or three times daily at equally spaced intervals.

Myo-Pyrolate (Glycopyrrolate) tablets are not recommended for use in pediatric patients under the age of 12 years.

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DRUG INTERACTIONS

There are no known drug interactions.

HOW SUPPLIED

Myo-Pyrolate (Glycopyrrolate) tablets 1 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “400” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-065-01).

Myo-Pyrolate (Glycopyrrolate) tablets 2 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “401” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-066-01).

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F).

Dispense in tight container.

Rx only

* Dopram® is a registered trademark of Baxter Healthcare Corporation.

Manufactured by:

Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977

Rev: 07/2010

OS065-01-1-02

Myo-Pyrolate (Glycopyrrolate) 2mg Tablet

Neostigmine Methylsulfate:



Myo-Pyrolate (Neostigmine Methylsulfate) is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.

Myo-Pyrolate (Neostigmine Methylsulfate), a cholinesterase inhibitor, is indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery (1).

2. DOSAGE AND ADMINISTRATION

  • Should be administered by trained healthcare providers
  • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when Myo-Pyrolate (Neostigmine Methylsulfate) should be initiated and if additional doses are needed (2.2)
    • For reversal of NMBAs with shorter half-lives, when first twitch response is substantially greater than 10% of baseline, or when a second twitch is present: 0.03 mg/kg by intravenous route (2.2)
    • For reversal of NMBAs with longer half-lives or when first twitch response is close to 10% of baseline: 0.07 mg/kg by intravenous route (2.2)
  • Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg (whichever is less) (2.2)
  • An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with Myo-Pyrolate (Neostigmine Methylsulfate) (2.4)

2.1. Important Dosage Information

Myo-Pyrolate (Neostigmine Methylsulfate) should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of Myo-Pyrolate (Neostigmine Methylsulfate) should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Myo-Pyrolate (Neostigmine Methylsulfate) and should be used to determine the need for additional doses.

Myo-Pyrolate (Neostigmine Methylsulfate) is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Myo-Pyrolate (Neostigmine Methylsulfate) dosage is weight-based .

Prior to Myo-Pyrolate (Neostigmine Methylsulfate) administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation.

An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with Myo-Pyrolate (Neostigmine Methylsulfate)

2.2. Dosage in Adults

  • Peripheral nerve stimulation devices capable of delivering a train-of-four stimulus are essential to effectively using Myo-Pyrolate (Neostigmine Methylsulfate).
  • There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of Myo-Pyrolate (Neostigmine Methylsulfate).
  • Prior to administration, visually inspect Myo-Pyrolate (Neostigmine Methylsulfate) for particulate matter and discoloration.
  • Myo-Pyrolate (Neostigmine Methylsulfate) should be injected slowly by intravenous route over a period of at least 1 minute.
  • A 0.03 mg/kg to 0.07 mg/kg dose of Myo-Pyrolate (Neostigmine Methylsulfate) will generally achieve a TOF twitch ratio of 90% (TOF0.9) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA.
    • The 0.03 mg/kg dose is recommended for:
      • Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
      • When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present.
    • The 0.07 mg/kg dose is recommended for
      • NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
      • When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
      • There is need for more rapid recovery.
  • TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of Myo-Pyrolate (Neostigmine Methylsulfate).
  • TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation.
  • Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used.
  • The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.

2.3. Dosage in Pediatric Patients, including Neonates

Adult guidelines should be followed when Myo-Pyrolate (Neostigmine Methylsulfate) is administered to pediatric patients. Pediatric patients require Myo-Pyrolate (Neostigmine Methylsulfate) doses similar to those for adult patients.

2.4. Anticholinergic Administration

An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with Myo-Pyrolate (Neostigmine Methylsulfate). The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to Myo-Pyrolate (Neostigmine Methylsulfate).

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3. DOSAGE FORMS AND STRENGTHS

Myo-Pyrolate (Neostigmine Methylsulfate) is available as

  • Injection: 0.5 mg/mL, 5 mg of Myo-Pyrolate (Neostigmine Methylsulfate) in 10 mL multiple- dose vials
  • Injection: 1 mg/mL, 10 mg of Myo-Pyrolate (Neostigmine Methylsulfate) in 10 mL multiple-dose vials

Injection: 0.5 mg/mL and 1 mg/mL in 10 mL multiple-dose vials (3)

4. CONTRAINDICATIONS

Myo-Pyrolate (Neostigmine Methylsulfate) is contraindicated in patients with:

  • known hypersensitivity to Myo-Pyrolate (Neostigmine Methylsulfate) (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis).
  • peritonitis or mechanical obstruction of the intestinal or urinary tract.
  • Hypersensitivity to neostigmine (4)
  • Peritonitis or mechanical obstruction of the intestinal or urinary tract (4)

5. WARNINGS AND PRECAUTIONS

  • Bradycardia: Atropine or glycopyrrolate should be administered prior to Myo-Pyrolate to lessen risk of bradycardia. (5.1)
  • Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. (5.2)
  • Neuromuscular Dysfunction: Can occur if large doses of Myo-Pyrolate (Neostigmine Methylsulfate) are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. (5.4)

5.1. Bradycardia

Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Myo-Pyrolate (Neostigmine Methylsulfate) to lessen the risk of bradycardia .

5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions

Myo-Pyrolate 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 Myo-Pyrolate (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.

5.3. Hypersensitivity

Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available.

5.4. Neuromuscular Dysfunction

Large doses of Myo-Pyrolate administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Myo-Pyrolate (Neostigmine Methylsulfate) should be reduced if recovery from neuromuscular blockade is nearly complete.

5.5. Cholinergic Crisis

It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Myo-Pyrolate (Neostigmine Methylsulfate). Both conditions result in extreme muscle weakness but require radically different treatment .

6. ADVERSE REACTIONS

Most common adverse reactions during treatment: bradycardia, nausea and vomiting.

To report SUSPECTED ADVERSE REACTIONS, contact Avadel Legacy Pharmaceuticals, LLC at 1-877-622-2320 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1. Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions to Myo-Pyrolate (Neostigmine Methylsulfate) are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions.

Quantitative adverse event data are available from trials of Myo-Pyrolate (Neostigmine Methylsulfate) in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater.

System Organ Class Adverse Reaction
Cardiovascular Disorders bradycardia, hypotension, tachycardia/heart rate increase
Gastrointestinal Disorders dry mouth, nausea, post-procedural nausea, vomiting
General Disorders and Administration

Site Conditions

incision site complication, pharyngolaryngeal pain, procedural

complication, procedural pain

Nervous System Disorders dizziness, headache, postoperative shivering, prolonged

neuromuscular blockade

Psychiatric Disorders insomnia
Respiratory, Thoracic and Mediastinal

Disorders

dyspnea, oxygen desaturation <90%
Skin and Subcutaneous Tissue Disorders pruritus

6.2. Post Marketing Experience

The following adverse reactions have been identified during parenteral use of Myo-Pyrolate (Neostigmine Methylsulfate). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

System Organ Class Adverse Reaction
Allergic Disorders allergic reactions, anaphylaxis
Nervous System Disorders convulsions, drowsiness, dysarthria, fasciculation, loss of

consciousness, miosis, visual changes

Cardiovascular Disorders cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm),

hypotension, nonspecific EKG changes, syncope

Respiratory, Thoracic and Mediastinal

Disorders

bronchospasm; increased oral, pharyngeal and bronchial

secretions; respiratory arrest; respiratory depression

Skin and Sub-cutaneous Tissue Disorders rash, urticaria
Gastrointestinal Disorders bowel cramps, diarrhea, flatulence, increased peristalsis
Renal and Urinary Disorders urinary frequency
Musculoskeletal and Connective Tissue

Disorders

arthralgia, muscle cramps, spasms, weakness
Miscellaneous diaphoresis, flushing

7. DRUG INTERACTIONS

The pharmacokinetic interaction between Myo-Pyrolate (Neostigmine Methylsulfate) and other drugs has not been studied. Myo-Pyrolate (Neostigmine Methylsulfate) is metabolized by microsomal enzymes in the liver. Use with caution when using Myo-Pyrolate (Neostigmine Methylsulfate) with other drugs which may alter the activity of metabolizing enzymes or transporters.

8. USE IN SPECIFIC POPULATIONS

  • Pregnancy: No human data and limited animal data exist. Use only if clearly needed.

8.1. Pregnancy

Risk Summary

There are no adequate or well-controlled studies of Myo-Pyrolate in pregnant women. It is not known whether Myo-Pyrolate (Neostigmine Methylsulfate) 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 Myo-Pyrolate (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.

Myo-Pyrolate (Neostigmine Methylsulfate) should be given to a pregnant woman only if clearly needed.

Data

Animal Data

In embryofetal development studies, rats and rabbits were administered Myo-Pyrolate (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, Myo-Pyrolate (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.

8.2. Labor and Delivery

The effect of Myo-Pyrolate (Neostigmine Methylsulfate) 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.

8.3. Nursing Mothers

It is not known whether Myo-Pyrolate is excreted in human milk. Caution should be exercised when Myo-Pyrolate (Neostigmine Methylsulfate) is administered to a nursing woman.

8.4. Pediatric Use

Myo-Pyrolate (Neostigmine Methylsulfate) 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 Myo-Pyrolate (Neostigmine Methylsulfate) (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less).

The dose of Myo-Pyrolate (Neostigmine Methylsulfate) 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 .

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 hypotension.

8.5. Geriatric Use

Because elderly patients are more likely to have decreased renal function, Myo-Pyrolate should be used with caution and monitored for a longer period in elderly patients. The duration of action of Myo-Pyrolate (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 Myo-Pyrolate (Neostigmine Methylsulfate) are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient .

8.6. Renal Impairment

Elimination half-life of Myo-Pyrolate (Neostigmine Methylsulfate) was prolonged in anephric patients compared to normal subjects.

Although no adjustments to Myo-Pyrolate (Neostigmine Methylsulfate) 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 Myo-Pyrolate (Neostigmine Methylsulfate). 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.

8.7. Hepatic Impairment

The pharmacokinetics of Myo-Pyrolate (Neostigmine Methylsulfate) in patients with hepatic impairment have not been studied. Myo-Pyrolate (Neostigmine Methylsulfate) is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of Myo-Pyrolate (Neostigmine Methylsulfate) 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 Myo-Pyrolate (Neostigmine Methylsulfate), which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of Myo-Pyrolate (Neostigmine Methylsulfate). 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.

10. OVERDOSAGE

Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of Myo-Pyrolate (Neostigmine Methylsulfate) (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored.

Overdosage of Myo-Pyrolate (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 cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of Myo-Pyrolate (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 crises 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 lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.

11. DESCRIPTION

Myo-Pyrolate (Neostigmine Methylsulfate), a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:

Myo-Pyrolate (Neostigmine Methylsulfate) is a white crystalline powder and is very soluble in water and soluble in alcohol. Myo-Pyrolate (Neostigmine Methylsulfate) is a sterile, nonpyrogenic solution intended for intravenous use.

Each mL of the 0.5 mg/mL strength contains Myo-Pyrolate (Neostigmine Methylsulfate) 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.

Each mL of the 1 mg/mL strength contains Myo-Pyrolate (Neostigmine Methylsulfate) 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

Myo-Pyrolate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, Myo-Pyrolate (Neostigmine Methylsulfate) induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.

12.2. Pharmacodynamics

Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Myo-Pyrolate (Neostigmine Methylsulfate) does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system.

12.3. Pharmacokinetics

Distribution: Following intravenous injection, the observed Myo-Pyrolate (Neostigmine Methylsulfate) volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of Myo-Pyrolate (Neostigmine Methylsulfate) to human serum albumin ranges from 15 to 25%.

Metabolism: Myo-Pyrolate (Neostigmine Methylsulfate) is metabolized by microsomal enzymes in the liver.

Elimination: Following intravenous injection, the reported elimination half-life of Myo-Pyrolate (Neostigmine Methylsulfate) is between 24 and 113 minutes. Total body clearance of Myo-Pyrolate (Neostigmine Methylsulfate) is reported between 1.14 and 16.7 mL/min/kg.

Renal impairment: Elimination half-life of Myo-Pyrolate (Neostigmine Methylsulfate) was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively.

Hepatic impairment: The pharmacokinetics of Myo-Pyrolate (Neostigmine Methylsulfate) in patients with hepatic impairment has not been studied.

Pediatrics: Elimination half-life of Myo-Pyrolate (Neostigmine Methylsulfate) in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed Myo-Pyrolate (Neostigmine Methylsulfate) clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively.

Drug Interaction Studies: The pharmacokinetic interaction between Myo-Pyrolate (Neostigmine Methylsulfate) and other drugs has not been studied.

13. NONCLINICAL TOXICOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine.

Genotoxicity: 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 Myo-Pyrolate (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).

14. CLINICAL STUDIES

The evidence for the efficacy of Myo-Pyrolate (Neostigmine Methylsulfate) for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with Myo-Pyrolate (Neostigmine Methylsulfate) treatment compared to spontaneous recovery.

16. HOW SUPPLIED/STORAGE AND HANDLING

Myo-Pyrolate (Neostigmine Methylsulfate) (Neostigmine Methylsulfate Injection, USP) is available in the following:

NDC No. Strength Vial Size
76014-002-10 0.5 mg/mL 10 mL multiple-dose vials (supplied in packages of 10)
76014-003-10 1 mg/mL 10 mL multiple-dose vials (supplied in packages of 10)

The vial stopper is not made with natural rubber latex.

Myo-Pyrolate (Neostigmine Methylsulfate) should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Store in carton until time of use.


Avadel

Manufactured for:

Avadel Legacy Pharmaceuticals, LLC

Chesterfield, MO 63005

Rev. 01/17

Myo-Pyrolate pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Myo-Pyrolate available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Myo-Pyrolate destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Myo-Pyrolate Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Myo-Pyrolate pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."GLYCOPYRROLATE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."BLOXIVERZ (NEOSTIGMINE METHYLSULFATE) INJECTION [AVADEL LEGACY PHARMACEUTICALS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "NEOSTIGMINE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Myo-Pyrolate?

Depending on the reaction of the Myo-Pyrolate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Myo-Pyrolate not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Myo-Pyrolate addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Myo-Pyrolate, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Myo-Pyrolate consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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