Setisin

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Setisin uses



Setisin is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.

Setisin, 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

2.1. Important Dosage Information

Setisin 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 Setisin should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Setisin and should be used to determine the need for additional doses.

Setisin is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Setisin dosage is weight-based .

Prior to Setisin 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 Setisin

2.2. Dosage in Adults

2.3. Dosage in Pediatric Patients, including Neonates

Adult guidelines should be followed when Setisin is administered to pediatric patients. Pediatric patients require Setisin 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 Setisin. 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 Setisin.

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3. DOSAGE FORMS AND STRENGTHS

Setisin is available as


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

4. CONTRAINDICATIONS

Setisin is contraindicated in patients with:

5. WARNINGS AND PRECAUTIONS

5.1. Bradycardia

Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Setisin to lessen the risk of bradycardia .

5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions

Setisin 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 Setisin 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 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 Setisin administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Setisin 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 Setisin. Both conditions result in extreme muscle weakness but require radically different treatment .

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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 Setisin 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 Setisin 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 Setisin. 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
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7. DRUG INTERACTIONS

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

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

Risk Summary

There are no adequate or well-controlled studies of Setisin in pregnant women. It is not known whether Setisin 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 Setisin doses up to 8.1 and 13 mcg/kg/day, respectively, during organogenesis.

Anticholinesterase drugs, including neostigmine may cause uterine irritability and induce premature labor when administered to pregnant women near term.

Setisin should be given to a pregnant woman only if clearly needed.

Data

Animal Data

In embryofetal development studies, rats and rabbits were administered Setisin 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, Setisin 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 Setisin 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 Setisin is excreted in human milk. Caution should be exercised when Setisin is administered to a nursing woman.

8.4. Pediatric Use

Setisin 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 Setisin.

The dose of Setisin 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, Setisin should be used with caution and monitored for a longer period in elderly patients. The duration of action of Setisin 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 Setisin 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 Setisin was prolonged in anephric patients compared to normal subjects.

Although no adjustments to Setisin 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 Setisin. 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 Setisin in patients with hepatic impairment have not been studied. Setisin is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of Setisin 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 Setisin, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of Setisin. 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.

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10. OVERDOSAGE

Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of Setisin (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 Setisin 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 Setisin 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

Setisin, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:

Setisin is a white crystalline powder and is very soluble in water and soluble in alcohol. Setisin is a sterile, nonpyrogenic solution intended for intravenous use.

Each mL of the 0.5 mg/mL strength contains Setisin 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 Setisin 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

Setisin is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, Setisin 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. Setisin 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 Setisin volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of Setisin to human serum albumin ranges from 15 to 25%.

Metabolism: Setisin is metabolized by microsomal enzymes in the liver.

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

Renal impairment: Elimination half-life of Setisin 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 Setisin in patients with hepatic impairment has not been studied.

Pediatrics: Elimination half-life of Setisin 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 Setisin 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 Setisin 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 Setisin (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 Setisin 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 Setisin treatment compared to spontaneous recovery.

16. HOW SUPPLIED/STORAGE AND HANDLING

Setisin (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.

Setisin 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

Setisin 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.


Setisin 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.


Setisin 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.


Setisin 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.


Setisin 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."BLOXIVERZ (NEOSTIGMINE METHYLSULFATE) INJECTION [AVADEL LEGACY PHARMACEUTICALS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "NEOSTIGMINE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "NEOSTIGMINE". http://www.drugbank.ca/drugs/DB0140... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Setisin?

Depending on the reaction of the Setisin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Setisin 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 Setisin 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 Setisin, 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 Setisin 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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