GLYCOPYRROLATE INJECTION, USP

For Intramuscular or Intravenous Administration

Rx Only

NOT FOR USE IN NEONATES
CONTAINS BENZYL ALCOHOL

Glycopyrrolate Injection, USP is a clear, colorless, sterile solution of Glycopyrrolate, USP with Benzyl Alcohol, NF in Water for Injection, USP. The formulation is used for intramuscular or intravenous administration.

Each mL contains:

•  Glycopyrrolate, USP……………………………….0.2 mg
•  Benzyl Alcohol, NF (preservative)………………......0.9%
•  Water for Injection, USP…………………………........q.s.

When necessary, pH (2.0 to 3.0) adjusted with hydrochloric acid and/or sodium hydroxide.

Glycopyrrolate is a quaternary ammonium salt with the following chemical name: 3[(cyclopentylhydroxyphenylacetyl)oxy]-1, 1-dimethyl pyrrolidinium bromide. Glycopyrrolate is a synthetic anticholinergic agent that has the following molecular structure and molecular weight.

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. The partition coefficient of glycopyrrolate in a n-octanol/water system is 0.304 (log₁₀ P= -1.52) at ambient room temperature (24°C).

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.

The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are highly non-polar tertiary amines which penetrate lipid barriers easily.

With intravenous injection, the onset of action is generally evident within one minute. Following intramuscular administration, the onset of action is noted in 15 to 30 minutes, with peak effects occurring within approximately 30 to 45 minutes. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine.

The following pharmacokinetic information and conclusions were obtained from published studies that used nonspecific assay methods.

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.

This drug should be used with great caution, if at all, in patients with glaucoma.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use).

Glycopyrrolate injection may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug.

In addition, in the presence of fever, high environmental temperature and/or during physical exercise, heat prostration can occur with use of anticholinergic agents including glycopyrrolate (due to decreased sweating), particularly in children and the elderly.

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with glycopyrrolate injection would be inappropriate and possibly harmful.

Because glycopyrrolate injection may produce drowsiness or blurred vision, the patient should be cautioned not to engage in activities requiring mental alertness and/or visual acuity such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug (see WARNINGS).

The patient also should be cautioned about the use of this drug during exercise or hot weather since overheating may result in heat stroke.

The patient may experience a possible sensitivity of the eyes to light.

Due to its benzyl alcohol span, glycopyrrolate injection should not be used in neonates, i.e., patients less than 1 month of age.

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer.

Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients.

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 injection. Infants and young children are especially susceptible to the toxic effects of anticholinergics.

Benzyl alcohol, a component of this drug product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hemotologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Clinical Studies of glycopyrrolate injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy.

Anticholinergics, including gylcopyrrolate 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 exclient, 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.

To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulfate (which does not cross the blood-brain barrier) may be given intravenously in increments of 0.25 mg in adults. This dosage may be repeated every five to ten minutes until anticholinergic overactivity is reversed or up to a maximum of 2.5 mg. Proportionately smaller doses should be used in pediatric patients. Indication for repetitive doses of neostigmine should be based on close monitoring of the decrease in heart rate and the return of bowel sounds.

If CNS symptoms (e.g., exclient, 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.

NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS)

Glycopyrrolate injection may be administered intramuscularly, or intravenously, without dilution, in the following indications:

Dextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringer's Injection.

Lactated Ringer's solution

Physical Compatibility: This ul does not constitute an endorsement of the clinical utility or safety of co-administration of glycopyrrolate injection 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.

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.

Glycopyrrolate Injection, USP 0.2 mg/mL is available as follows:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).

AMERICAN REGENT, INC.
SHIRLEY, NY 11967

IN4601
Rev. 8/06
MG #14273