Get your patient on Glycopyrrolate - Glycopyrrolate injection (Glycopyrrolate)

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

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 ^® (benzquinamide 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 injection: 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 report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800‑FDA‑1088 or www.fda.gov/medwatch.

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.

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 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 – 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, 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 T _1/2 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.

•0-8 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 T _1/2 values were reported to be between 21.6 and 130.0 minutes and between 19.2 and 99.2 minutes, respectively.

Glycopyrrolate Injection, USP 0.2 mg/mL, is supplied as clear, colorless non pyrogenic solution as follows;

1 mL single dose vials packaged in 25s          (NDC 65145-102-25)

2 mL single dose vials packaged in 25s          (NDC 65145-103-25)

5 mL multiple dose vials packaged in 25s      (NDC 65145-104-25)

20 mL multiple dose vials in 10s                    (NDC 65145-105-10)

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

Manufactured by:

Caplin Steriles Limited,

Gummidipoondi – 601 201,

INDIA.

February, 2019
CP4/AWC/088-01