Glycopyrrolate

1 INDICATIONS AND USAGE Glycopyrrolate Injection is an anticholinergic indicated: in anesthesia (adult and pediatric patients) • for reduction of salivary, tracheobronchial, and pharyngeal secretions, reduction of volume and acidity of gastric secretions, and blockade of cardiac inhibitory reflexes during induction of anesthesia and intubation. • intraoperatively to counteract surgically or drug-induced or vagal reflex-associated arrhythmias. • for protection against peripheral muscarinic effects of cholinergic agents. ( 1 ) in peptic ulcer (adults) • To reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer when rapid anticholinergic effect is desired or oral medication is not tolerated. Limitations of Use Glycopyrrolate Injection is not indicated as monotherapy for the treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established. ( 1 ) 1.1 Preanesthetic Glycopyrrolate Injection is indicated in adults and pediatric patients for reduction of salivary, tracheobronchial, and pharyngeal secretions, reduction of volume and acidity of gastric secretions, and blockade of cardiac inhibitory reflexes during induction of anesthesia and intubation. 1.2 Intraoperative Glycopyrrolate Injection is indicated in adults and pediatric patients to counteract surgically or drug-induced or vagal reflex-associated arrhythmias. 1.3 Reversal of Neuromuscular Blockade Glycopyrrolate Injection is indicated in adults and pediatric patients for protection against peripheral muscarinic effects of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing agents. 1.4 Peptic Ulcer Glycopyrrolate Injection is indicated in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated. • Limitations of Use Glycopyrrolate Injection is not indicated as monotherapy for the treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established.

2 DOSAGE AND ADMINISTRATION Glycopyrrolate Injection may be administered intramuscularly, or intravenously, without dilution, in the following indications: Adults ( 2.2 ) Preanesthetic Medication: 0.004 mg/kg IM, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia Intraoperative Medication: single doses of 0.1 mg IV and repeated, as needed, at intervals of 2 to 3 minutes Reversal of Neuromuscular Blockade: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine Peptic Ulcer: 0.1 mg IV or IM at 4-hour intervals, 3 or 4 times daily Pediatric patients ( 2.3 ) Preanesthetic Medication: 0.004 mg/kg IM, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia. Patients under 2 years of age may require up to 0.009 mg/kg Intraoperative Medication: 0.004 mg/kg IV, not to exceed 0.1 mg in a single dose and repeated, as needed, at intervals of 2 to 3 minutes Reversal of Neuromuscular Blockade: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine Peptic Ulcer: Glycopyrrolate Injection is not indicated for the treatment of peptic ulcer in pediatric patients Do not use prefilled syringe to administer a dose of less than 0.1 mg (0.5 mL). ( 2.3 ) See Full Prescribing Information for preparation, handling, and instructions for use of pre-filled syringe ( 2.4 , 2.5 ) 2.1 General Dosing and Administration Information 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. Do not introduce any other fluid into the syringe at any time. Do not dilute for IV push. Do not re-sterilize the syringe. Do not use this product on a sterile field. This product is for single dose only. 2.2 Dosing in 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. Attempt to determine the etiology of the arrhythmia, and perform the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance. Reversal of Neuromuscular Blockade The recommended dose of Glycopyrrolate Injection is 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine. 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. Frequency of administration should be dictated by patient response up to a maximum of four times daily. 2.3 Dosing in Pediatric Patients 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. Patients under 2 years of age may require up to 0.009 mg/kg. Do not use this prefilled syringe to administer a dose of less than 0.1 mg (0.5 mL). 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 minute …

3 DOSAGE FORMS AND STRENGTHS Glycopyrrolate Injection, USP is a clear, colorless, solution for injection available as 0.2 mg per mL glycopyrrolate in presentation of 0.2 mg per mL single-dose vials, 0.4 mg per 2 mL (0.2 mg per mL) single-dose vials, 1 mg per 5 mL (0.2 mg per mL) multi-dose vials, and 4 mg per 20 mL (0.2 mg per mL) multi-dose vials. Injection: 0.2 mg per mL glycopyrrolate in presentation of 0.2 mg per 1 mL single-dose vials, 0.4 mg per 2 mL single-dose vials, 1 mg per 5 mL multi-dose vials, and 4 mg per 20 mL multi-dose vials. ( 3 )

4 CONTRAINDICATIONS Glycopyrrolate Injection is contraindicated in: • patients with known hypersensitivity to Glycopyrrolate Injection or any of its inactive ingredients. • peptic ulcer 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. • Known hypersensitivity to glycopyrrolate or any of its inactive ingredients. ( 4 ) • Peptic ulcer patients with glaucoma; obstructive uropathy; obstructive disease of the gastrointestinal tract; 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. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions to anticholinergics 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. 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. Most common adverse reactions are related to anticholinergic pharmacology and 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; bradycardia; palpitation; and decreased sweating. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-888-808-5529, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-844-824-8426.

7 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 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. Other anticholinergics or drugs with anticholinergic activity : May intensify the antimuscarinic effects and result in an increase in anticholinergic side effects. ( 7 ) Potassium Chloride in a Wax Matrix : May increase severity of potassium chloride-induced gastrointestinal lesions. ( 7 )

8 USE IN SPECIFIC POPULATIONS Pediatric Use : 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. Large doses may cause hyperexcitability. ( 8.4 ) 8.1 Pregnancy Risk Summary Limited available data over decades of use with glycopyrrolate in pregnant women have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data) . In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 320-times and 5-times the maximum recommended human dose (MRHD) of 2 mg (on a mg/m 2 basis), respectively (see Data) . The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial 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. There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data 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/m 2 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/m 2 basis). These studies produced no teratogenic effects to the fetus. A preclinical study on reproductive performance of rats given glycopyrrolate resulted in a decreased rate of conception and survival at weaning. 8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergics, glycopyrrolate may cause suppression of lactation [see Adverse Reactions ( 6 )] . The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for glycopyrrolate injection and any potential adverse effects on the breastfed child from glycopyrrolate injection or from the underlying maternal condition. 8.4 Pediatric Use Glycopyrrolate injection is indicated in pediatric patients: for reduction of salivary, tracheobronchial, and pharyngeal secretions, reduction of volume and acidity of gastric secretions, and blockade of cardiac inhibitory reflexes during induction of anesthesia and intubation intraoperatively to counteract surgically …

12.1 Mechanism of Action 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.

DESCRIPTION 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: C 19 H 28 BrNO 3 MW 398.33 Glycopyrrolate, USP 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 to 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). structure

10 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 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 intravenous (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.

HOW SUPPLIED GLYCOPYRROLATE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1425-1 GLYCOPYRROLATE INJECTION, USP 0.2mg/mL 1mL VIAL NDC 51662-1431-1 GLYCOPYRROLATE INJECTION, USP 1mg/mL (0.2mg/mL) 5mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Glycopyrrolate injection USP, 0.2 mg/mL, is supplied as single and multiple-dose vials available in following strengths and package sizes: 0.2 mg/mL, 1 mL vial Single-dose vial: NDC 70121-1394-1 25 single-dose vials in a carton: NDC 70121-1394-5 0.2 mg/mL, 2 mL vial Single-dose vial: NDC 70121-1395-1 25 single-dose vials in a carton: NDC 70121-1395-5 0.2 mg/mL, 5 mL vial Multiple-dose vial: NDC 70121-1396-1 25 multiple-dose vials in a carton: NDC 70121-1396-5 0.2 mg/mL, 20 mL vial Multiple-dose vial: NDC 70121-1397-1 10 multiple-dose vials in a carton: NDC 70121-1397-7 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. All trademarks are the property of their respective owner. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Parenteral Unit Ahmedabad 382213, INDIA Distributed by: Amneal Biosciences LLC Bridgewater, NJ 08807 Rev. 07-2018-01