GLYCOPYRROLATE

Glycopyrrolate Injection, USP is a synthetic anticholinergic agent. Each 1 mL contains: Glycopyrrolate, USP 0.2 mg Water for Injection, USP q.s. Benzyl Alcohol, NF 0.9% (preservative) pH adjusted, when necessary, with hydrochloric acid. For Intramuscular (IM) or Intravenous (IV) administration. Glycopyrrolate is a quaternary ammonium salt with the following chemical name: 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. Its structural formula is as follows: Glycopyrrolate occurs as a white, odorless crystalline powder. It is soluble in water and alcohol, and practically insoluble in chloroform and ether. Unlike atropine, glycopyrrolate is completely ionized at physiological pH values. Glycopyrrolate Injection, USP, is a clear, colorless, sterile liquid; pH 2.0 to 3.0. The partition coefficient of glycopyrrolate in a n-octanol/water system is 0.304 (log 10 P= -1.52) at ambient room temperature (24°C). Glycopyrrolate Structure

In Anesthesia Glycopyrrolate Injection, USP is indicated for use as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions; and to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation. When indicated, Glycopyrrolate Injection, USP may be used intraoperatively to counteract surgically or drug-induced or vagal reflexes associated arrhythmias. Glycopyrrolate protects against the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing muscle relaxants. In Peptic Ulcer For use in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated. Limitations of Use Glycopyrrolate Injection is not indicated as monotherapy for the treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established.

NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS ) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Glycopyrrolate Injection may be administered intramuscularly, or intravenously, without dilution, in the following indications. Adults PREANESTHETIC MEDICATION The recommended dose of Glycopyrrolate Injection is 0.004 mg/kg by intramuscular injection, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered. INTRAOPERATIVE MEDICATION Glycopyrrolate Injection may be used during surgery to counteract drug-induced or vagal reflexes and their associated arrhythmias (e.g., bradycardia). It should be administered intravenously as single doses of 0.1 mg and repeated, as needed, at intervals of 2 to 3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed. REVERSAL OF NEUROMUSCULAR BLOCKADE The recommended dose of Glycopyrrolate Injection is 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe. PEPTIC ULCER The usual recommended dose of Glycopyrrolate Injection is 0.1 mg administered at 4-hour intervals, 3 or 4 times daily intravenously or intramuscularly. Where more profound effect is required, 0.2 mg may be given. Some patients may need only a single dose, and frequency of administration should be dictated by patient response up to a maximum of four times daily. Glycopyrrolate Injection is not recommended for the treatment of peptic ulcer in pediatric patients (see PRECAUTIONS - Pediatric Use ). Pediatric Patients (see PRECAUTIONS - Pediatric Use ) PREANESTHETIC MEDICATION The recommended dose of Glycopyrrolate Injection in pediatric patients is 0.004 mg/kg intramuscularly, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered. INFANTS (1 month to 2 years of age) may require up to 0.009 mg/kg. INTRAOPERATIVE MEDICATION Because of the long duration of action of Glycopyrrolate Injection if used as preanesthetic medication, additional Glycopyrrolate Injection for anticholinergic effect intraoperatively is rarely needed; in the event it is required the recommended pediatric dose is 0.004 mg/kg intravenously, not to exceed 0.1 mg in a single dose which may be repeated, as needed, at intervals of 2 to 3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed. REVERSAL OF NEUROMUSCULAR BLOCKADE The recommended pediatric dose of Glycopyrrolate Injection is 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe. PEPTIC ULCER Glycopyrrolate Injection is not recommended for the treatment of peptic ulcer in pediatric patients (see PRECAUTIONS - Pediatric Use ). Diluent Compatibilities Dextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringer’s Injection. Diluent Incompatibilities Lactated Ringer’s solution Admixture Compatibilities PHYSICAL COMPATIBILITY This list does not constitute an endorsement of the clinical utility or safety of co-administration of glycopyrrolate with these drugs. Glycopyrrolate Injection is compatible for mixing and injection with the following injectable dosage forms: atropine sulfate, USP; Antilirium ® (physostigmine salicylate); Benadryl ® (diphenhydramine HCl); codeine phosphate, USP; Emete-Con ® (benz-quinamide HCl); hydromorphone HCl, USP; Inapsine ® (droperidol); Levo-Dromoran ® (levorphanol tartrate); lidocaine, USP; meperidine HCl, USP; Mestinon ® /Regonol ® (pyridostigmine bromide); morphine sulfate, USP; Nubain ® (nalbuphine HCl); Numorphan ® (oxymorphone HCl); procaine HCl, USP; promethazine HCl, USP; Prostigmin ® (neostigmine methylsulfate, USP); scopolamine HBr, USP; Stadol ® (butorphanol tartrate); Sublimaze ® (fentanyl citrate); Tigan ® (trimethobenzamide HCl); and Vistaril ® (hydroxyzine HCl). Glycopyrrolate Injection may be administered via the tubing of a running infusion of normal saline. Admixture Incompatibilities PHYSICAL INCOMPATIBILITY Since the stability of glycopyrrolate is questionable above a pH of 6.0 do not combine Glycopyrrolate Injection in the same syringe with Brevital ® (methohexital Na); Chloromycetin ® (chloramphenicol Na succinate); Dramamine ® (dimenhydrinate); Nembutal ® (pentobarbital Na); Pentothal ® (thiopental Na); Seconal ® (secobarbital Na); sodium bicarbonate (Abbott); Valium ® (diazepam); Decadron ® (dexamethasone Na phosphate); or Talwin ® (pentazocine lactate). These mixtures will result in a pH higher than 6.0 and may result in gas production or precipitation.

Known hypersensitivity to glycopyrrolate or any of its inactive ingredients. In addition, in the management of peptic ulcer patients, because of the longer duration of therapy, Glycopyrrolate Injection may be contraindicated in patients with the following concurrent conditions: 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.

Anticholinergics, including Glycopyrrolate Injection, 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. In addition, the following adverse events have been reported from post-marketing experience with glycopyrrolate: malignant hyperthermia; cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation); cardiac arrest; hypertension; hypotension; seizures; and respiratory arrest. Post-marketing reports have included cases of heart block and QTc interval prolongation associated with the combined use of glycopyrrolate and an anticholinesterase. Injection site reactions including pruritus, edema, erythema, and pain have also been reported. 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.

The concurrent use of Glycopyrrolate Injection 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. Concomitant administration of Glycopyrrolate Injection and potassium chloride in a wax matrix may increase the severity of potassium chloride-induced gastrointestinal lesions as a result of a slower gastrointestinal transit time.