PREVDUO neostigmine methylsulfate and glycopyrrolate 1 mg/mL; .2 mg/mL Injection
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Anticholinergic class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Patient education
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 7FLD91C86K
Edetate disodium is a chemical compound that binds and removes certain metal ions. In medicines, it acts as a preservative and stabilizer by preventing metals like calcium from interfering with the product's shelf life and consistency.
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UNII QTT17582CB
A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
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UNII N762921K75
A colorless, odorless gas that makes up most of the air we breathe. In medicines, it's used as a packaging gas or propellant to protect products from oxidation and maintain freshness.
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UNII 451W47IQ8X
Sodium chloride is common table salt. It's used in medicines as a buffer to maintain proper pH, as a filler to add bulk, or to adjust the osmotic balance in liquid formulations.
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UNII 55X04QC32I
A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
6 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Prevduo 1 mg/mL; .2 mg/mLthis 42023-0269-05 | Endo | 5 syringes | — | — | FDA listed | — |
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⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 11110054 ↗ | Drug product | — | Oct 25, 2038 |
| US 11938217 ↗ | Drug product | — | Oct 25, 2038 |
| US 10456354 ↗ | Drug product | — | Oct 25, 2038 |
| US 12151020 ↗ | Drug product | — | Oct 25, 2038 |
| US 12383491 ↗ | Drug product | — | Oct 25, 2038 |
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 42023-0269-05 You're viewing this | 5 SYRINGE, PLASTIC in 1 CARTON (42023-269-05) / 3 mL in 1 SYRINGE, PLASTIC (42023-269-01) | 2023-05-15 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE PREVDUO ® , a fixed dose combination of cholinesterase inhibitor and antimuscarinic agent, is indicated in patients age two years and above for the reversal of the effects of nondepolarizing neuromuscular blocking agents (NMBA) after surgery, while decreasing the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration. PREVDUO ® , a fixed dose combination of a cholinesterase inhibitor and antimuscarinic agent, is indicated in patients age two years and above for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery, while decreasing the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration ( 1 ).
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • Should be administered by trained healthcare providers ( 2.1 ) • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when PREVDUO ® should be initiated and if additional doses are needed ( 2.2 ) • For reversal of NMBAs with shorter half-lives in patients age 2 years and up, when first twitch response is substantially greater than 10% of baseline, or when a second twitch is present: 0.03 mg/kg of neostigmine methylsulfate (0.006 mg/kg of glycopyrrolate) by intravenous route ( 2.2 ) • For reversal of NMBAs with longer half-lives or when first twitch response is close to 10% of baseline in patients age 2 years and up: 0.07 mg/kg of neostigmine methylsulfate (0.014 mg/kg of glycopyrrolate) by intravenous route ( 2.2 ) • Maximum total dosage is 0.07 mg/kg of neostigmine methylsulfate or up to a total of 5 mg neostigmine methylsulfate (whichever is less) ( 2.2 )
2.1Important Dosage and Administration Information • PREVDUO ® 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 PREVDUO ® should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of PREVDUO ® and should be used to determine the need for additional doses. • PREVDUO ® is for intravenous use only and should be injected slowly over a period of at least 1 minute.
The PREVDUO ® dosage is weight-based [ see Dosage and Administration ( 2.2 ) ]. • Prior to PREVDUO ® 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. • Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using PREVDUO ® . • 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 PREVDUO ® . • Prior to administration, visually inspect PREVDUO ® for particulate matter and discoloration. • 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 PREVDUO ® . • 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.
2.2Dosage in Adults A 0.03 mg/kg to 0.07 mg/kg dose of Neostigmine methylsulfate (0.006 mg/kg to 0.014 mg/kg dose of Glycopyrrolate) Injection will generally achieve a TOF twitch ratio of 90% (TOF 0.9 ) within 10 to 20 minutes of administration, with minimization of neostigmine-induced bradycardia due to the included 0.2 mg of glycopyrrolate per 1 mg neostigmine. 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 of neostigmine methylsulfate (0.006 mg/kg of glycopyrrolate) 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 of neostigmine methylsulfate (0.014 mg/kg of glycopyrrolate) dose is recommended for: • Reversal of NMBAs wit…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS PREVDUO ® is a clear, colorless solution available as: • Injection: 3 mg/3 mL of neostigmine methylsulfate and 0.6 mg/3 mL of glycopyrrolate (1 mg/mL of neostigmine methylsulfate and 0.2 mg/mL of glycopyrrolate) in a single-dose 3 mL prefilled syringe. Injection: Clear, colorless solution available as 3 mg/3 mL of neostigmine methylsulfate and 0.6 mg/3 mL of glycopyrrolate (1 mg/mL of neostigmine methylsulfate and 0.2 mg/mL of glycopyrrolate) in a single-dose 3 mL Prefilled Syringe. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS PREVDUO ® is contraindicated in patients with: • known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis) and glycopyrrolate or any inactive ingredients [ see Warnings and Precautions ( 5.3 ) ]. • peritonitis or mechanical obstruction of the intestinal or urinary tract. • 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. • Hypersensitivity to neostigmine, glycopyrrolate, or nonactive ingredients ( 4 ) • Peritonitis or mechanical obstruction of the intestinal or urinary tract ( 4 ) • Patients with glaucoma; obstructive uropathy; obstructive disease of the gastrointestinal tract; 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 ( 4 ).
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Bradycardia : consideration should be given to administration of glycopyrrolate prior to neostigmine (i.e., as separate products) in patients with bradycardia or in patients in whom bradycardia, a known risk of neostigmine methysulfate, may cause hemodynamic instability. ( 5.1 ) • Serious Reactions with Coexisting Conditions : Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome, hyperthyroidism or myasthenia gravis. ( 5.2 ) • Hypersensitivity : Because of the possibility of hypersensitivity, medications to treat anaphylaxis should be readily available.
( 5.3 ) • Neuromuscular Dysfunction : Can occur if large doses of PREVDUO ® are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. ( 5.4 ) • Cholinergic Crisis : It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine. ( 5.5 ) • Precipitation of Acute Glaucoma : Glycopyrrolate may cause mydriasis and increase intraocular pressure in patients with glaucoma.
Advise patients with glaucoma to promptly seek medical care if they experience symptoms of acute angle closure glaucoma. ( 5.6 ) • Drowsiness and Blurred Vision : Warn patients about participating in activities requiring mental alertness. ( 5.7 ) • Heat Prostration : Advise patients to avoid exertion and high environmental temperatures after receiving PREVDUO ® .
( 5.8 ) • Intestinal Obstruction : Diarrhea may be an early symptom of incomplete intestinal obstruction. Avoid use in patients with diarrhea and ileostomy or colostomy. ( 5.9 ) • Tachycardia : Increase in heart rate may occur.
Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism. ( 5.10 )
5.1Bradycardia Neostigmine, a component of PREVDUO ® , is associated with bradycardia. Consideration should be given to administration of glycopyrrolate prior to neostigmine (i.e., as separate products) in patients with bradycardia or in patients in whom bradycardia, a known risk of neostigmine methysulfate, may cause hemodynamic instability.
5.2Serious Adverse Reactions in Patients with Certain Coexisting Conditions PREVDUO ® should be used with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, recent acute coronary syndrome, hypertension, myasthenia gravis and hyperthyroidism. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such as bradycardia, hypotension or dysrhythmia would be anticipated. In patients with acute 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.
5.3Hypersensitivity Because of the possibility of hypersensitivity, medications to treat anaphylaxis should be readily available.
5.4Neuromuscular Dysfunction Large doses of PREVDUO ® administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of PREVDUO ® should be reduced if recovery from neuromuscular blockade is nearly complete.
5.5Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine. Both conditions result in extreme muscle weakness but require radically different treatment. [ see Overdosage ( 10 ) ].
5.6Precipitation of Acute Glaucoma Glycopyrrolate, a component of PREVDUO ® , is contraindicated in patients with glaucoma because it may cause mydriasis and increase intraocular pressure. Advise patients with glaucoma to promptly seek medical care in the event that they experience symptoms of acute angle closure glaucoma (pain and reddening of t…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS • Most common adverse reactions to neostigmine during treatment: bradycardia, nausea, vomiting, blurred vision and photophobia. ( 6 ) • Most common adverse reactions to glycopyrrolate are related to anticholinergic pharmacology and may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; bradycardia; palpitation; and decreased sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Neostigmine Methylsulfate 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 neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The addition of glycopyrrolate to the neostigmine-glycopyrrolate prefilled syringe may prevent or mitigate these reactions.
Quantitative adverse event data are available from trials of 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. S y s t e m 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 Glycopyrrolate 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.
Anticholinergics, including glycopyrrolate, can produce certain effects, most of which are extensions of their pharmacologic actions. Adverse reactions may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; palpitation; decreased sweating; loss of taste; headache; nervousness; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; impotence; suppression of lactation; constipation; bloated feeling; severe allergic reactions including anaphylactic/anaphylactoid reactions; hypersensitivity; urticaria, pruritus, dry skin, and other dermal manifestations; some degree of mental confusion and/or excitement, especially in elderly persons.
6.2Post Marketing Experience Neostigmine Methylsulfate The following adverse reactions have been identified during post-approval parenteral use of 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. S y s t e m 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; resp…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Neostigmine Methylsulfate The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using neostigmine methylsulfate with other drugs which may alter the activity of metabolizing enzymes or transporters.
Glycopyrrolate The concurrent use of glycopyrrolate with other anticholinergics or medications with anticholinergic activity, such as phenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. The concurrent use of glycopyrrolate with other anticholinergics or medications with anticholinergic activity may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. ( 7 )
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary Neostigmine Methylsulfate There are no adequate or well-controlled studies of neostigmine in pregnant women. It is not known whether neostigmine 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 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.
Glycopyrrolate Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data). In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose (MRHD) of 1 mg (on a mg/m 2 basis), respectively (see Data).
The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively.
PREVDUO @ should be only given to a pregnant woman if the benefit outweighs the risk. Data Human Data Neostigmine Methylsulfate: There are no adequate or well-controlled studies of neostigmine methylsulfate in pregnant women. Glycopyrrolate: Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes.
In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts.
There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data Neostigmine Methylsulfate: In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m 2 basis) of 1.6, 4 and 8.1 mcg/kg/day 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 ma…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Neostigmine Methylsulfate There are no adequate or well-controlled studies of neostigmine in pregnant women. It is not known whether neostigmine 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 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.
Glycopyrrolate Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data). In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose (MRHD) of 1 mg (on a mg/m 2 basis), respectively (see Data).
The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively.
PREVDUO @ should be only given to a pregnant woman if the benefit outweighs the risk. Data Human Data Neostigmine Methylsulfate: There are no adequate or well-controlled studies of neostigmine methylsulfate in pregnant women. Glycopyrrolate: Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes.
In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts.
There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data Neostigmine Methylsulfate: In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m 2 basis) of 1.6, 4 and 8.1 mcg/kg/day 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, atax…
🧒 Pediatric Use ▾
8.4Pediatric Use PREVDUO @ is not recommended to be used in pediatric patients less than 2 years of age, as the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate. In these patients, a formulation that allows for glycopyrrolate to be administered prior to neostigmine to lessen the probability of bradycardia and hypotension is recommended. Neostigmine Methylsulfate 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 neostigmine (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). The dose of neostigmine 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 [ see Clinical Pharmacology ( 12.3 ) ].
Glycopyrrolate Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses of anticholinergics including glycopyrrolate. Infants and young children are especially susceptible to the toxic effects of anticholinergics.
🧓 Geriatric Use ▾
8.5Geriatric Use Because elderly patients are more likely to have decreased renal function, PREVDUO @ should be used with caution and monitored for a longer period in elderly patients. The duration of action of PREVDUO @ 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 PREVDUO @ are not required.
The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient.
🆘 Overdosage ▾
10 OVERDOSAGE Neostigmine Methylsulfate Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of neostigmine methylsulfate (cholinergic crisis), but are minimized by the presence of glycopyrrolate in the prefilled syringe. 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 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 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.
Glycopyrrolate If CNS symptoms (e.g., excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the blood–brain barrier) may be used. Physostigmine 0.5 to 2 mg should be slowly administered intravenously and repeated as necessary up to a total of 5 mg in adults. Proportionately smaller doses should be used in pediatric patients.
To combat hypotension, administer IV fluids and/or pressor agents along with supportive care. Fever should be treated symptomatically. Following overdosage, a curare-like action may occur, i.e., neuromuscular blockade leading to muscular weakness and possible paralysis.
In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Neostigmine methylsulfate, a component of PREVDUO @ , is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, 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. Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation.
These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions. Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.
12.2Pharmacodynamics The addition of glycopyrrolate to neostigmine (in the PREVDUO @ prefilled syringe) mitigates neostigmine-induced bradycardia. Neostigmine Methylsulfate 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.
Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system. Glycopyrrolate The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to highly non-polar tertiary amines which penetrate lipid barriers easily. With intravenous injection, the onset of action is generally evident within one minute.
The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine.
12.3Pharmacokinetics Distribution Neostigmine Methylsulfate Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and
1.4L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%. Glycopyrrolate The mean volume of distribution of glycopyrrolate was estimated to be 0.42±0.22 L/kg.
Metabolism Neostigmine Methylsulfate Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Glycopyrrolate While over 80% of glycopyrrolate is eliminated unchanged in urine and bile the in vivo metabolism of glycopyrrolate in humans has not been studied. Elimination Neostigmine Methylsulfate Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes.
Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg. Glycopyrrolate The mean clearance and mean half-life values were reported to be 0.54±0.14 L/kg/hr and 0.83±0.13 hr, respectively post IV administration. After IV administration of a 0.2 mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine 48 hours postdose and some of the radioactivity was also recovered in bile.
After IM administration of glycopyrrolate to adults, the mean half-life value is reported to be between 0.55 to 1.25 hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from a study. Group t 1/2 (hr) V ss (L/kg) CL (L/kg/hr) T m ax (min) C m ax (mcg/L) AUC (mcg/L•hr) (6 mcg/kg IV) 0.83±0.27 0.42±0.22 0.54±0.14 – – 8.64±1.49* (8 mcg/kg IM) – – – 27.48±6.12 3.47±1.48 6.…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Neostigmine methylsulfate, a component of PREVDUO @ , is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, 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. Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation.
These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions. Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING PREVDUO @ (neostigmine methylsulfate and glycopyrrolate) injection is a clear, colorless solution available in the following: NDC No. Strength Pack Size 42023-269-05 1 mg of Neostigmine Methylsulfate USP and 0.2 mg of Glycopyrrolate USP per mL 5 X 3 mL prefilled syringe in one carton 42023-269-01 1 mg of Neostigmine Methylsulfate USP and 0.2 mg of Glycopyrrolate USP per mL 3 mL Single dose prefilled syringe PREVDUO @ (neostigmine methylsulfate and glycopyrrolate) injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Protect from light. Store in carton until time of use.
📋 Description ▾
11 DESCRIPTION PREVDUO @ (neostigmine methylsulfate and glycopyrrolate) injection is a clear colorless solution available as a prefilled syringe that contains a fixed dose combination of neostigmine methylsulfate, a cholinesterase inhibitor and glycopyrrolate, an anticholinergic agent, for intravenous administration. PREVDUO @ is available as a sterile solution in 3 mL Prefilled Syringe. Each mL contains Neostigmine Methylsulfate USP (1 mg), Glycopyrrolate USP (0.2 mg), edetate disodium dihydrate USP (0.5 mg), sodium chloride USP (8 mg) in water for injection.
The pH is adjusted, when necessary, with Hydrochloric acid/sodium hydroxide to achieve a value of 3.6. Neostigmine Methylsulfate USP Neostigmine methylsulfate, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The molecular formula is C 13 H 22 N 2 O 6 S, a molecular weight is 334.39 g/mol and the following structural formula is: Glycopyrrolate USP Glycopyrrolate is a quaternary ammonium salt (anticholinergic agent) with a chemical name of 3[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide.
The molecular formula is C 19 H 28 BrNO 3 and the molecular weight is 398.33 and the structural formula is: Neo-structure Glyco-structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Increased Intraocular Pressure: Glycopyrrolate in the PREVDUO @ may cause mydriasis and increase intraocular pressure in patients with glaucoma. Advise patients with glaucoma to promptly seek medical care in the event that they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated pupils) [ see Warnings and Precautions ( 5.6 ) ]. Drowsiness and Blurred Vision : Inform patients that PREVDUO @ may cause drowsiness or blurred vision.
Warn patients not to operate a motor vehicle or other machinery or perform hazardous work until these issues resolve. [ see Warnings and Precautions ( 5.7 ) ]. PREVDUO @ is a registered trademark of Slayback Pharma LLC. Manufactured for: Endo USA Malvern, PA 19355 Revised: 04/2024