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 (IM), or intravenously (IV) without dilution, in the following indications. Adults ( 2.2 , 2.3 , 2.4 , 2.5 ) 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 ( 2.2 , 2.3 , 2.4 ) 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 IV 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 2.2 Recommended Dosage of Preanesthetic Medication in Adults and Pediatric Patients 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. Patients less than 2 years of age may require up to 0.009 mg/kg. 2.3 Recommended Dosage as Intraoperative Medication to Counteract Drug-induced or Vagal Reflexes and Their Associated Arrhythmias (e.g., bradycardia) in Adults and Pediatric Patients The recommended adult dose of Glycopyrrolate injection is 0.1 mg intravenously. Repeat this dose, as needed, at intervals of 2 to 3 minutes. The recommended pediatric dosage is 0.004 mg/kg intravenously, not to exceed 0.1 mg in a single dose, repeated every 2 to 3 minutes. Attempt to determine the etiology of the arrhythmia, and perform the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance. 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. 2.4 Recommended Dosage for Reversal of Neuromuscular Blockade in Adults and Pediatric Patients The recommended dose of Glycopyrrolate injection is 0.2 mg IV for each 1 mg of neostigmine or 5 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection. 2.5 Recommended Dosage for Peptic Ulcer in Adults The recommended dosage 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. 2.6 Preparation and Handling 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 injection with these drugs. Glycopyrrolate injection is compatible for mixing and injection with the following injectable dosage forms: atropine sulfate, USP; physostigmine salicylate; diphenhydramine HCl; codeine phosphate, USP; benz-quinamide HCl; hydromorphone HCl, USP; droperidol; levorphanol tartrate; lidocaine, USP; meperidine HCl, USP; pyridostigmine bromide; morphine sulfate, USP; nalbuphine HCl; oxymorphone HCl; procaine HCl, USP; promethazine HCl, USP; neostigmine methylsulfate, USP; scopolamine HBr, USP; butorphanol tartrate; fentanyl citrate; trimethobenzamide HCl; and hydroxyzine HCl. Glycopyrrolate injection may be administered via the tubing of a running infusion of normal saline. Admixture Incompatibilities Physical Incompatibility Because the stability of glycopyrrolate is questionable above a pH of 6.0 do not combine Glycopyrrolate injection in the same syringe with methohexital Na; chloramphenicol Na succinate; dimenhydrinate; pentobarbital Na; thiopental Na; secobarbital Na; sodium bicarbonate; diazepam; dexamethasone Na phosphate; or pentazocine lactate. These mixtures will result in a pH higher than 6.0 and may result in gas production or precipitation.

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 )

5 WARNINGS AND PRECAUTIONS Precipitation of Acute Glaucoma : May cause mydriasis and increase intraocular pressure in patients with glaucoma. Advise patients with glaucoma to promptly seek medical care if they experience symptoms of acute angle closure glaucoma. ( 5.1 ) Drowsiness or Blurred Vision : May cause drowsiness or blurred vision. Advise patients not to drive or perform hazardous work until resolved. ( 5.2 ) Heat Prostration : Advise patients to avoid exertion and high environmental temperatures after receiving glycopyrrolate injection. ( 5.3 ) Intestinal Obstruction : Diarrhea may be an early symptom of incomplete intestinal obstruction. Avoid use in patients with diarrhea and ileostomy or colostomy. ( 5.4 ) Tachycardia : Increase in heart rate may occur. Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism. ( 5.5 ) 5.1 Precipitation of Acute Glaucoma Glycopyrrolate injection may cause mydriasis and increase intraocular pressure in patients with glaucoma. Advise patients with glaucoma to promptly seek medical care in the event that they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated pupils). 5.2 Drowsiness or Blurred Vision Glycopyrrolate injection may cause drowsiness or blurred vision. Warn patients not to participate in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work, until these issues resolve. 5.3 Heat Prostration In the presence of fever, high environmental temperature, and/or during physical exercise, heat prostration can occur with use of anticholinergic agents including glycopyrrolate injection (due to decreased sweating), particularly in children and the elderly. Advise patients to avoid exertion and high environmental temperature after receiving glycopyrrolate injection. 5.4 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with glycopyrrolate injection is inappropriate and possibly harmful. Glycopyrrolate is contraindicated in patients with these conditions. 5.5 Tachycardia Investigate any tachycardia before giving glycopyrrolate injection because an increase in the heart rate may occur. Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism. 5.6 Risk of Use in Patients with Renal Impairment Renal elimination of glycopyrrolate may be significantly reduced in patients with renal failure. Dosage adjustments may be necessary in this population [ see Clinical Pharmacology ( 12.3 ) ]. 5.7 Autonomic Neuropathy, Hepatic Disease, Ulcerative Colitis, Prostatic Hypertrophy, or Hiatal Hernia Use glycopyrrolate injection with caution in the elderly and in all patients with autonomic neuropathy, hepatic disease, ulcerative colitis, prostatic hypertrophy, or hiatal hernia, because anticholinergic drugs may aggravate these conditions. Consider dose reduction and closely monitor the elderly and patients with autonomic neuropathy, hepatic disease, ulcerative colitis, prostatic hypertrophy, or hiatal hernia. 5.8 Delayed Gastric Emptying/Gastric Stasis The use of anticholinergic drugs, including glycopyrrolate injection, in the treatment of peptic ulcer may produce a delay in gastric emptying due to antral stasis. Monitor patients for symptoms such as vomiting, dyspepsia, early satiety, abdominal distention, and increased abdominal pain. Discontinue glycopyrrolate injection treatment if these symptoms develop or worsen on treatment. 5.9 Light Sensitivity Patients may experience sensitivity of the eyes to light. Advise patients to protect their eyes from light after receiving glycopyrrolate injection.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Glycopyrrolate Injection, USP is a clear, colorless solution and is supplied as follows: NDC Glycopyrrolate Injection, USP (0.2 mg per mL) Package Factor 71288- 414 -03 0.2 mg per 1 mL Single-Dose Vial 25 vials per carton 71288- 414 -04 0.4 mg per 2 mL Single-Dose Vial 25 vials per carton 71288- 415 -06 1 mg per 5 mL Multi-Dose Vial 25 vials per carton 71288- 415 -21 4 mg per 20 mL Multi-Dose Vial 10 vials per carton Storage Conditions Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. For single-dose vials only, discard unused portion. Sterile. The container closure is not made with natural rubber latex.