ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. 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 exctextent, 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 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 Amneal Biosciences at 1-855-266-3251 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

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 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 to hours and the antisialagogue effects persist up to hours, periods longer than for atropine.PharmacokineticsThe following pharmacokinetic information and conclusions were obtained from published studies that used nonspecific assay methods.DISTRIBUTIONThe mean volume of distribution of glycopyrrolate was estimated to be 0.42+-0.22 L/kg.METABOLISMThe in vivo metabolism of glycopyrrolate in humans has not been studied.EXCRETIONThe 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 (Intravenous) administration. After IV (Intravenous) administration of 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 (Intramuscular) 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 (Intramuscular) dose administered was recovered in urine and the bile as unchanged drug and half the IM (Intramuscular) dose is excreted within hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from study.SPECIAL POPULATIONSGenderGender differences in pharmacokinetics of glycopyrrolate have not been investigated.Renal ImpairmentIn one study glycopyrrolate was administered IV (Intravenous) 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-mcg/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-mcg/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 ImpairmentPharmacokinetic information in patients with hepatic impairment is unavailable.PediatricsFollowing IV (Intravenous) administration (5 mcg/kg glycopyrrolate) to infants and children, the mean T1/2 values were reported to be between 21.6 and 130 minutes and between 19.2 and 99.2 minutes, respectively.. Image1.jpg.

DESCRIPTION SECTION.

Description Glycopyrrolate injection, USP is synthetic anticholinergic agent. Each mL contains:Glycopyrrolate, USP ........................................................0.2 mgWater 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 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:C19H28BrNO3 MW 398.33Glycopyrrolate, USP occurs as 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 clear, colorless, sterile liquid; pH 2.0 to 3.0. The partition coefficient of glycopyrrolate in n-octanol/water system is 0.304 (log10 P= -1.52) at ambient room temperature (24C).. Formula1.jpg.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. 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.AdultsPREANESTHETIC MEDICATIONThe 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 MEDICATIONGlycopyrrolate 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 to 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 BLOCKADEThe recommended dose of glycopyrrolate injection is 0.2 mg for each mg of neostigmine or 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 ULCERThe usual recommended dose of glycopyrrolate injection is 0.1 mg administered at 4-hour intervals, or times daily intravenously or intramuscularly. Where more profound effect is required, 0.2 mg may be given. Some patients may need only single-dose, and frequency of administration should be dictated by patient response up to 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 MEDICATIONThe 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 years of age) may require up to 0.009 mg/kg.INTRAOPERATIVE MEDICATIONBecause 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 single-dose which may be repeated, as needed, at intervals of to 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 BLOCKADEThe recommended pediatric dose of glycopyrrolate injection is 0.2 mg for each mg of neostigmine or 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 ULCERGlycopyrrolate injection is not recommended for the treatment of peptic ulcer in pediatric patients (see PRECAUTIONS Pediatric Use).Diluent CompatibilitiesDextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringers Injection.Diluent IncompatibilitiesLactated Ringers solutionAdmixture CompatibilitiesPHYSICAL COMPATIBILITYThis list 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(R) (physostigmine salicylate); Benadryl(R) (diphenhydramine HCl); codeine phosphate, 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 running infusion of normal saline.Admixture IncompatibilitiesPHYSICAL INCOMPATIBILITYSince the stability of glycopyrrolate is questionable above pH of 6.0 do not combine glycopyrrolate injection 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 will result in pH higher than 6.0 and may result in gas production or precipitation.

OVERDOSAGE SECTION.

OVERDOSAGE. To combat peripheral anticholinergic effects, 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 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., exctextent, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the blood-brain barrier) may be used. Physostigmine 0.5 to mg should be slowly administered intravenously and repeated as necessary up to total of mg in adults. Proportionately smaller doses should be used in pediatric patients.To combat hypotension, administer IV (Intravenous) fluids and/or pressor agents along with supportive care.Fever should be treated symptomatically.Following overdosage, curare-like action may occur, i.e., neuromuscular blockade leading to muscular weakness and possible paralysis. In the event of curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.

WARNINGS SECTION.

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 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.