Glycopyrrolate and Neostigmine methylsulfate

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.

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.

• Should be administered by trained healthcare providers. • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when PREVDUO ® should be initiated and if additional doses are needed. • 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. • 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. • Maximum total dosage is 0.07 mg/kg of neostigmine methylsulfate or up to a total of 5 mg neostigmine methylsulfate (whichever is less)

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. • peritonitis or mechanical obstruction of the intestinal or urinary tract.

• 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. • Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome, hyperthyroidism or myasthenia gravis. • Hypersensitivity: Because of the possibility of hypersensitivity, medications to treat anaphylaxis should be readily available. • 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.

• Most common adverse reactions to neostigmine during treatment: bradycardia, nausea, vomiting, blurred vision and photophobia. • 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.

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.

Store in carton until time of use.