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 and/or sodium hydroxide.





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 C19H28BrNO3 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 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 (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.





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 the 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.

*0 to 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-under-the-concentration-time curve (10.6 hr-μg/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-μg/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that the elimination of glycopyrrolate is severely impaired in patients with renal failure.

Hepatic Impairment

Pharmacokinetic information in patients with hepatic impairment is unavailable.

Pediatrics

Following IV administration (5 μg/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.

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.

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.

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.

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 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)





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 1.0 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 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 1.0 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).





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.

Glycopyrrolate injection USP, 0.2 mg/mL, is a sterile clear, colorless solution and supplied as single and multiple dose vials available in following strengths and package sizes:





0.2 mg/mL vial

Single dose vial:         NDC 70700-165-22

25 single dose vials in a carton: NDC 70700-165-25





0.4 mg/2 mL (0.2 mg/mL) vial

Single dose vial:         NDC 70700-166-22

25 single dose vials in a carton: NDC 70700-166-25





1 mg/5 mL (0.2 mg/mL) vial

Multiple dose vial:         NDC 70700-167-22

25 multiple dose vials in a carton: NDC 70700-167-25





4 mg/20 mL (0.2 mg/mL) vial

Multiple dose vial:         NDC 70700-168-22

10 multiple dose vials in a carton: NDC 70700-168-23





Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].





To report SUSPECTED ADVERSE REACTIONS, contact Xiromed LLC at 1-844-XIROMED (844-947-6633) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.





All trademarks are the property of their respective owner.



Manufactured for:

Xiromed, LLC,

Florham Park, NJ 07932

Product of India

February 2020

PI-165-00

LEA-020360-00

Glycopyrrolate Injection USP, 0.2 mg/mL

1 mL Single Dose Vial

NDC 70700-165-22

Glycopyrrolate Injection USP, 0.2 mg/mL

25 x 1 mL Single Dose Vials

NDC 70700-165-25

Glycopyrrolate Injection USP, 0.4 mg/2 mL (0.2 mg/mL)

2 mL Single Dose Vial

NDC 70700-166-22

Glycopyrrolate Injection USP, 0.4 mg/2 mL (0.2 mg/mL)

25 x 2 mL Single Dose Vials

NDC 70700-166-25

Glycopyrrolate Injection USP, 1 mg/5 mL (0.2 mg/mL)

5 mL Multiple Dose Vial

NDC 70700-167-22

Glycopyrrolate Injection USP, 1 mg/5 mL (0.2 mg/mL)

25 x 5 mL Multiple Dose Vials

NDC 70700-167-25

Glycopyrrolate Injection USP, 4 mg/20 mL (0.2 mg/mL)

20 mL Multiple Dose Vial

NDC 70700-168-22

Glycopyrrolate Injection USP, 4 mg/20 mL (0.2 mg/mL)

10 x 20 mL Multiple Dose Vials

NDC 70700-168-23