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 forInjection, USP. The formulation is used for intramuscular or intravenous administration.Each mL contains:Glycopyrrolate, USP................................0.2 mgBenzyl 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 agentthat 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 noctanol/

water system is 0.304 (log10 P= -1.52) at ambient room temperature (24degC).

CLINICAL PHARMACOLOGY

Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated bypostganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. Theseperipheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, theatrioventricular node, exocrine glands, and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and freeacidity 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-brainbarrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are highly nonpolar tertiary amines which penetrate lipidbarriers easily.With intravenous injection, the onset of action is generally evident within one minute. Following intramuscular administration, theonset of action is noted in 15 to 30 minutes, with peak effects occurring within approximately 30 to 45 minutes. The vagal blockingeffects 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 assaymethods.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 postIV administration. After IV administration of a 0.2 mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine48 hours postdose and some of radioactivity was also recovered in bile. After IM administration of glycopyrrolate to adults, themean 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 asunchanged drug and half the IM dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation ofpharmacokinetic parameters from a study.

*0-12 hr * *0-8 hr

SPECIAL POPULATIONS

Gender: Gender differences in pharmacokinetics of glycopyrrolate have not been investigated.

Renal Impairment: In one study glycopyrrolate was administered IV in uremic patients undergoing renal transplantation. The

mean elimination half-life was significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean area-underthe-

concentration-time curve (10.6 hr-mg/L), mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for

glycopyrrolate were also significantly different than those of controls (3.73 hr-mg/L, 1.14 L/hr/kg, and 50%, respectively). These

results suggest that elimination of glycopyrrolate is severely impaired in patients with renal failure.

Hepatic Impairment: Pharmocokinetic information in patients with hepatic impairment is unavailable.

Pediatrics: Following IV administration (5 mg/kg glycopyrrolate) to infants and children, the mean T1/2 values were reported to be

between 21.6 and 130.0 minutes and between 19.2 and 99.2 minutes, respectively.

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 becontraindicated in patients with the following concurrent conditions: glaucoma; obstructive uropathy (for example, bladder neckobstruction 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; severeulcerative 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), particularlyin 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 frommedications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administrationof 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 dosagesor other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from thesecombined sources (see PRECAUTIONS, Pediatric Use).Glycopyrrolate injection may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiringmental 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 withuse 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 thisinstance treatment with glycopyrrolate injection would be inappropriate and possibly harmful.

PRECAUTIONS

GeneralInvestigate 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 withrenal 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, ulcerativecolitis, 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 PatientsBecause glycopyrrolate injection may produce drowsiness or blurred vision, the patient should be cautioned not to engage in activitiesrequiring mental alertness and/or visual acuity such as operating a motor vehicle or other machinery, or performing hazardous workwhile 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 heatstroke.The patient may experience a possible sensitivity of the eyes to light.Drug InteractionsThe concurrent use of glycopyrrolate injection with other anticholinergics or medications with anticholinergic activity, such asphenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and may result in anincrease in anticholinergic side effects.Concomitant administration of glycopyrrolate injection and potassium chloride in a wax matrix may increase the severity of potassiumchloride-induced gastrointestinal lesions as a result of a slower gastrointestinal transit time.Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to evaluate the mutagenic potentialof glycopyrrolate have not been conducted. In reproduction studies in rats, dietary administration of glycopyrrolate resulted indiminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminalsecretion which is evident at high doses of glycopyrrolate.PregnancyTeratogenic EffectsPregnancy 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 rabbitsat intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 5 times the maximum recommended daily human doseon a mg/m2 basis). These studies produced no teratogenic effects to the fetus. Because animal reproduction studies are not alwayspredictive 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 EffectsPublished literature suggest the following regarding the use of glycopyrrolate during pregnancy. Unlike atropine, glycopyrrolatein 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 intramuscularadministration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significantamounts. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rats of pup survival in a doserelatedmanner.Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should beexercised when glycopyrrolate injection is administered to a nursing woman. As with other anticholinergics, glycopyrrolate may causesuppression of lactation (see ADVERSE REACTIONS).Pediatric UseDue 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 inpediatric patients.Infants, patients with Down's syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increasedresponse to anticholinergics, thus increasing the potential for side effects.A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses of anticholinergicsincluding 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 pediatricpatients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, andhigh levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99mg/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 substantiallylower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicitymay occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely todevelop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined dailymetabolic load of benzyl alcohol from all sources.Geriatric UseClinical Studies of glycopyrrolate injection did not include sufficient numbers of subjects aged 65 and over to determine whether theyrespond differently from younger subjects. Other reported clinical experience has not identified differences in responses between theelderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end ofthe dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or othertherapy.

OVERDOSAGE

To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulfate (whichdoes not cross the blood-brain barrier) may be given intravenously in increments of 0.25 mg in adults. This dosage may be repeatedevery five to ten minutes until anticholinergic overactivity is reversed or up to a maximum of 2.5 mg. Proportionately smaller dosesshould be used in pediatric patients. Indication for repetitive doses of neostigmine should be based on close monitoring of the decreasein heart rate and the return of bowel sounds.If CNS symptoms (e.g., excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the bloodbrainbarrier) may be used. Physostigmine 0.5 to 2 mg should be slowly administered intravenously and repeated as necessary up to atotal 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 possibleparalysis. In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained untileffective 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, given30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative areadministered.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 3minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulationsnecessary 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 tominimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may bemixed 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 intravenouslyor intramuscularly. Where more profound effect is required, 0.2 mg may be given. Some patients may need only a single dose, andfrequency 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-PediatricUse).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 sedativeare 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 glycopyrrolateinjection for anticholinergic effect intraoperatively is rarely needed; in the event it is required the recommended pediatric dose is 0.004mg/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 usualattempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correctparasympathetic 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. Inorder to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection andmay be mixed in the same syringe.Peptic Ulcer:Glycopyrrolate injection is not recommended for the treatment of peptic ulcer in pediatric patients (see PRECAUTIONS-PediatricUse).NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration wheneversolution and container permit.DILUENT COMPATIBILITIESDextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringer's Injection.DILUENT INCOMPATIBILITIESLactated Ringer's solutionADMIXTURE COMPATIBILITIESPhysical Compatibility: This list does not constitute an endorsement of the clinical utility or safety of coadministration ofglycopyrrolate with these drugs. Glycopyrrolate injection is compatible for mixing and injection with the following injectabledosage forms: atropine sulfate, USP; Antilirium(r) (physostigmine salicylate); Benadryl(r) (diphenhydramine HCl); codeinephosphate, USP; Emete-Con(r) (benz-quinamide HCl); hydromorphone HCl, USP; Inapsine(r) (droperidol); Levo-Dromoran(r)(levorphanol tartrate); lidocaine, USP; meperidine HCl, USP; Mestinon(r)/Regonol(r) (pyridostigmine bromide); morphine sulfate,USP; Nubain(r) (nalbuphine HCl); Numorphan(r) (oxymorphone HCl); procaine HCl, USP; promethazine HCl, USP; Prostigmin(r)(neostigmine methylsulfate, USP); scopolamine HBr, USP; Stadol(r) (butorphanol tartrate); Sublimaze(r) (fentanyl citrate); Tigan(r)(trimethobenzamide HCl); and Vistaril(r) (hydroxyzine HCl). Glycopyrrolate injection may be administered via the tubing of a runninginfusion of normal saline.ADMIXTURE INCOMPATIBILITIESPhysical Incompatibility: Since the stability of glycopyrrolate is questionable above a pH of 6.0 do not combine glycopyrrolateinjection in the same syringe with Brevital(r) (methohexital Na); Chloromycetin(r) (chloramphenicol Na succinate); Dramamine(r)

(dimenhydrinate); Nembutal(r) (pentobarbital Na); Pentothal(r) (thiopental Na); Seconal(r) (secobarbital Na); sodium bicarbonate(Abbott); Valium(r) (diazepam); Decadron(r) (dexamethasone Na phosphate); or Talwin(r) (pentazocine lactate). These mixtures willresult 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 25NDC-0517-4602-25 2 mL single dose vials Packages of 25NDC-0517-4605-25 5 mL multiple dose vials Packages of 25NDC-0517-4620-25 20 mL multiple dose vials Packages of 25Store at 20deg to 25degC (68deg to 77degF); excursions permitted to 15deg to 30degC (59deg to 86degF) (See USP Controlled Room Temperature).AMERICANREGENT, INC.SHIRLEY, NY 11967IN4601Rev. 1/09

PACKAGE LABEL