Neostigmine (Bloxiverz)

ED / ICU / Transport

• Reversal of residual nondepolarizing neuromuscular blockade. Some paralysis is still left over after surgery or procedural paralysis with rocuronium, vecuronium, pancuronium, atracurium or cisatracurium. The FDA label covers every age, neonates included.
• Minimal-depth block (train-of-four (TOF) ratio 0.4 to <0.9). Here, and only here, the 2023 American Society of Anesthesiologists (ASA) guideline suggests neostigmine as a reasonable alternative to sugammadex.
• Atracurium or cisatracurium block: sugammadex does not bind benzylisoquinolines. That leaves neostigmine as the reversal agent (ASA 2023: at minimal depth).

Other Uses

• Acute colonic pseudo-obstruction (ACPO, Ogilvie syndrome): this is for when conservative care fails (up to 72 hr), when the patient is not a candidate for it, or when perforation risk is high. Exclude mechanical obstruction and perforation first. It is off-label, recommended by the American Society for Gastrointestinal Endoscopy (ASGE) 2020 guideline.
• Myasthenia gravis, postoperative intestinal atony and urinary retention: injectable neostigmine carries IM or subcut labels outside the US. In the US, that injection is off-label for these uses. Oral pyridostigmine is the usual chronic myasthenia therapy.

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

• Vials: 0.5 mg/mL in 10 mL (5 mg) and 1 mg/mL in 10 mL (10 mg) multiple-dose vials, preserved with phenol. Both strengths come in the same vial size, so read the mg/mL on every vial.
• Prefilled syringe: 1 mg/mL in 5 mL (5 mg) single-dose syringe (Bloxiverz).
• Combination syringe (Prevduo): neostigmine 1 mg/mL plus glycopyrrolate 0.2 mg/mL in a 3 mL single-dose syringe (3 mg / 0.6 mg), labeled for age 2 yr and older.
• Route: the US labels allow IV use only.

Adult Dosing

Differs from FDA label: the label triggers on the first twitch reaching about 10% of baseline, and it allows 0.03–0.07 mg/kg (max 5 mg). ASA 2023 keeps neostigmine to a TOF ratio of 0.4 to below 0.9. For deeper rocuronium or vecuronium block, it recommends sugammadex.

Pediatric Dosing

Weight-based dose checks: pediatric weight-based dosing.

Preparation & Administration

• Monitor first: use a peripheral nerve stimulator, ideally quantitative TOF at the adductor pollicis, to choose the time and dose and to judge the need for more.
• Push rate: NMB reversal, slow IV over at least 1 min; ACPO, over 3–5 min.
• Anticholinergic: give it before or with neostigmine through a separate syringe (US and New Zealand labeling); in bradycardia, give it first and let the heart rate rise (New Zealand labeling: to about 80 bpm) before neostigmine.
• Airway: keep ventilating until spontaneous ventilation is fully adequate.
• Inspect: do not use if particles or discoloration are present.

Contraindications

• Hypersensitivity to neostigmine (urticaria, angioedema, bronchospasm, anaphylaxis reported)
• Peritonitis or mechanical obstruction of the intestinal or urinary tract
• Combination syringe (Prevduo) also: hypersensitivity to glycopyrrolate or any inactive ingredient; glaucoma; obstructive uropathy; obstructive GI disease; paralytic ileus or intestinal atony of the elderly or debilitated; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis or toxic megacolon; myasthenia gravis

Precautions

• Cardiac disease: coronary artery disease, arrhythmias or a recent acute coronary syndrome make bradycardia, hypotension and dysrhythmia more likely.
• Myasthenia gravis: expect more cardiovascular complications and a higher chance of cholinergic crisis.
• Bronchial asthma, recent intestinal or bladder surgery: extreme caution (New Zealand labeling).
• Epilepsy, Parkinsonism, peptic ulcer, hyperthyroidism, vagotonia, Addison disease, renal impairment: use with caution (New Zealand labeling).
• Heart failure, hypertension: use with caution (Prevduo labeling).
• Near-complete recovery: large doses can cause weakness. At a TOF ratio above 0.6, use 0.015–0.03 mg/kg. Once the measured ratio reaches 0.9 or higher, give none, per ASA 2023.

Hold / Reassess If

• TOF count <4 or TOF ratio <0.4 per ASA 2023 (ESAIC: ratio ≤0.2): wait for recovery, or use sugammadex for rocuronium or vecuronium. ASA 2023 allows neostigmine at deeper block only with quantitative monitoring and clinical judgment. Expect a longer wait to TOF ≥0.9. With fewer than 4 twitches, full reversal within 10 min is unlikely
• NMB reversal with bradycardia: give the anticholinergic first and confirm the heart rate rises
• ACPO pre-dose screen: do not give if HR <60 bpm (or on a β-blocker), SBP <90 mmHg, active bronchospasm, creatinine >3 mg/dL, active GI bleeding or pregnancy (exclusion criteria of NCT04951726)
• ACPO: peritoneal signs, free air, suspected ischemia or mechanical obstruction call for surgical evaluation instead

Common

• Cardiovascular: bradycardia, hypotension; tachycardia when paired with an anticholinergic
• GI: nausea, vomiting, abdominal cramping, salivation, diarrhea
• Other: dry mouth, dizziness, headache, shivering, pruritus
• Respiratory: dyspnea, SpO₂ <90% (reported at 1% or more in trials)

Serious / Life-Threatening

Overdose & Toxicity Management

• Cholinergic crisis: muscarinic signs (salivation, sweating, bronchorrhea, vomiting, diarrhea, bradycardia, miosis) plus nicotinic signs (fasciculations, cramps, increasing weakness up to respiratory paralysis).
• Immediate management: stop all cholinesterase inhibitors; support ventilation until spontaneous breathing is adequate; continuous cardiac monitoring.
• Antidote: atropine for muscarinic effects (New Zealand labeling: 1–2 mg IV, repeated as needed), or glycopyrrolate. Atropine does not reverse nicotinic weakness. Masking the muscarinic signs can hide an overdose that is still going on.
• Myasthenic vs cholinergic crisis: both cause severe weakness, and they need opposite treatment. Involve neurology. Support the airway before you add more cholinesterase inhibitor.

Clinically Significant Interactions

IV Compatibility

• Anticholinergic: US neostigmine labeling says to give atropine or glycopyrrolate through a separate syringe. The Prevduo syringe is the only premixed product.
• Prefilled syringes: do not add any other fluid.
• Dilution: given undiluted, by slow IV push. The label lists no infusion admixture.
• Verify with an institutional compatibility resource.

• Pediatrics: FDA-labeled for all ages. ASA 2023 limits apply at every age. In infants, the anticholinergic goes first (see the Pediatric Dosing table).
• Neonates: Blood pressure depends on heart rate. Give the anticholinergic first, then watch its effect. Skip the combination syringe under 2 yr.
• Pregnancy: Several decades of published data, mostly from exposure at cesarean section or delivery, have not found a drug-associated risk of major birth defects, miscarriage, or adverse maternal or infant outcomes (Bloxiverz label, section 8.1). Near term, IV cholinesterase inhibitors may cause uterine irritability and preterm labor (New Zealand labeling). Don't hold reversal back when it is needed. For non-obstetric surgery in pregnancy, neostigmine may cross the placenta while glycopyrrolate crosses poorly. Fetal bradycardia has been reported with this pair (case report). Consider atropine as the anticholinergic, and monitor the fetal heart rate where feasible.
• Lactation: US labeling calls the data insufficient on presence in milk and on infant effects. New Zealand labeling says only negligible amounts enter breast milk. It is a quaternary amine with a short half-life. A single reversal dose is unlikely to affect a breastfed infant more than briefly.
• Older Adults: Older adults get a longer duration of action, and spontaneous NMBA recovery is slower too. No routine dose change. Monitor longer for recurrent weakness.
• Renal Impairment: The half-life stretches out: mean 80 min normal, 105 min after transplant, 181 min anephric. No dose adjustment. Monitor until a renally cleared NMBA can't outlast neostigmine.
• Hepatic Impairment: Not studied, so no adjustment. A hepatically cleared NMBA, or one with active metabolites, may outlast neostigmine. Extend monitoring.
• Obesity / Dosing Weight: US labeling names no dosing weight. The 5 mg total cap applies.
• Myasthenia Gravis: Higher risk of cardiovascular complications and cholinergic crisis. Involve neurology and favor quantitative monitoring.

• Scope: Anesthesia, ICU and critical-care transport clinicians (RN/CCT) give it under orders. It is not an EMS drug. Scope varies by state and agency protocol.
• Reversal in Transport: Patients moved while paralyzed stay sedated and ventilated. Reversal is a destination decision, unless the sending team orders it with monitoring available.
• Storage & Stability: 20–25°C (68–77°F), protected from light, in the carton until use.
• Carried Concentration: Vials come in 0.5 mg/mL and 1 mg/mL, both in the same 10 mL size. Confirm mg and mL before you draw up. ISMP lists neostigmine and Neo-Synephrine (phenylephrine) as a confused pair.
• Handoff Essentials: NMBA, last dose and time; neostigmine and anticholinergic dose and time; last TOF count or ratio; heart rate response; for ACPO, response and any repeat dose.

Mechanism of Action

• Reversible (carbamate) inhibition of acetylcholinesterase leaves more acetylcholine in every cholinergic synapse.
• At the neuromuscular junction, acetylcholine outcompetes the nondepolarizing NMBA at nicotinic receptors. Muscle strength comes back.
• Muscarinic sites: bradycardia, bronchoconstriction, secretions, miosis and more gut motility. The gut effect is the basis of the ACPO response. The rest of that list is why the anticholinergic goes in.
• Quaternary ammonium. At usual doses it does not cross the blood-brain barrier.

Pharmacokinetics

• Half-life: 24–113 min after IV injection (US label; 47–60 min in New Zealand labeling); infants 39 min, children 48 min, adults 67 min; 181 min in anephric patients.
• Metabolism: hepatic microsomal enzymes and ester hydrolysis.
• Elimination: the kidneys do the work. About 80% of an IM dose shows up in urine within 24 hr, roughly half of it unchanged.
• Distribution: volume of distribution 0.12–1.4 L/kg; protein binding 15–25%.

Generic Name

Neostigmine methylsulfate

Brand Names

Bloxiverz (US); Prevduo (with glycopyrrolate, US); Prostigmin (historical brand); many generics

Pharmacologic Class

Reversible acetylcholinesterase inhibitor (quaternary carbamate)

Therapeutic Class

Neuromuscular blockade reversal agent; parasympathomimetic

Controlled Substance

Not controlled

ISMP High-Alert

No (the ISMP list covers the neuromuscular blockers, not their reversal agents)

Look-Alike / Sound-Alike

neostigmine / Neo-Synephrine (phenylephrine), a recent addition to the ISMP Confused Drug Names list (updated through June 2024); do not confuse with PHYSostigmine or pyRIDostigmine