Glycopyrrolate

General Injectables & Vaccines, Inc

Glycopyrrolate 0.2mg/mL 5ml multi-dose vial

FULL PRESCRIBING INFORMATION: CONTENTS*

• GLYCOPYRROLATE DESCRIPTION
• CLINICAL PHARMACOLOGY
• PHARMACOKINETICS
• INDICATIONS & USAGE
• GLYCOPYRROLATE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• GLYCOPYRROLATE ADVERSE REACTIONS
• OVERDOSAGE
• DOSAGE & ADMINISTRATION
• HOW SUPPLIED
• PACKAGE LABEL

FULL PRESCRIBING INFORMATION

DESCRIPTION

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.

CLINICAL PHARMACOLOGY

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 nonpolar 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.

PHARMACOKINETICS

The following pharmacokinetic information and conclusions were obtained from published studies that used nonspecific assay
methods.
Distribution: The mean volume of distribution of glycopyrrolate was estimated to be 0.42 ± 0.22 L/kg.
Metabolism: The in vivo metabolism of glycopyrrolate in humans has not been studied.
Excretion: The mean clearance and mean T1/2 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 radioactivity was also recovered in bile. After IM administration of glycopyrrolate to adults, the
mean T1/2 value is reported to be between 0.55 to 1.25 hrs. Over 80% of IM dose administered was recovered in urine and the bile as
unchanged drug and half the IM dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation of
pharmacokinetic parameters from a study.

INDICATIONS & USAGE

In Anesthesia: Glycopyrrolate injection 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 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 as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or
when oral medication is not tolerated.

GLYCOPYRROLATE CONTRAINDICATIONS

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.

WARNINGS

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.

PRECAUTIONS

General
Investigate any tachycardia before giving glycopyrrolate injection since an increase in the heart rate may occur.
Use with caution in patients with: coronary artery disease; congestive heart failure; cardiac arrhythmias; hypertension;
hyperthyroidism.
Use with caution in patients with renal disease since the renal elimination of glycopyrrolate may be severely impaired in patients with
renal failure. Dosage adjustments may be necessary (see Pharmacokinetics-Renally Impaired).
Use glycopyrrolate with caution in the elderly and in all patients with autonomic neuropathy, hepatic or renal disease, ulcerative
colitis, prostatic hypertrophy, or hiatal hernia, since anticholinergic drugs may aggravate these conditions.
The use of anticholinergetic drugs in the treatment of gastric ulcer may produce a delay in gastric emptying due to antral statis.

Information for Patients
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.
Drug Interactions
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to evaluate the mutagenic potential
of glycopyrrolate have not been conducted. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in
diminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal
secretion which is evident at high doses of glycopyrrolate.
Pregnancy
Teratogenic Effects
Pregnancy Category B: Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/
kg/day (exposure was approximately 320 times the maximum recommended daily human dose of 2 mg on a mg/m2 basis) and rabbits
at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 5 times the maximum recommended daily human dose
on a mg/m2 basis). These studies produced no teratogenic effects to the fetus. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Single-dose studies in humans found that very small amounts of glycopyrrolate passed the placental barrier.
Nonteratogenic Effects
Published literature suggest the following regarding the use of glycopyrrolate during pregnancy. Unlike atropine, glycopyrrolate
in normal doses (0.004 mg/kg) does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree.
Concentrations of glycopyrrolate in umbilical venous and aterial 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. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rats of pup survival in a doserelated
manner.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when glycopyrrolate injection is administered to a nursing woman. As with other anticholinergics, glycopyrrolate may cause
suppression of lactation (see ADVERSE REACTIONS).
Pediatric Use
Due to its benzyl alcohol content, 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.
Geriatric Use
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.

GLYCOPYRROLATE ADVERSE REACTIONS

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 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. Postmarketing 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.

OVERDOSAGE

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., excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the bloodbrain
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.

DOSAGE & ADMINISTRATION

NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS)
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 1.0 mg of neostigmine or 5.0 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 ulcers 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.
lntraoperative 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 1.0 mg of neostigmine or 5.0 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).
NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever
solution and container permit.
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 coadministration 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.

HOW SUPPLIED

Glycopyrrolate Injection, USP 0.2 mg/mL is available as follows:
NDC-0517-4601-25 1 mL fill in 2 mL single dose vials Packages of 25
NDC-0517-4602-25 2 mL single dose vials Packages of 25
NDC-0517-4605-25 5 mL multiple dose vials Packages of 25
NDC-0517-4620-25 20 mL multiple dose vials Packages of 25
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. 1/09

PACKAGE LABEL