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 NOTE: CONTAINS BENZYL ALCOHOL [see Use in Specific Populations ( 8.4 )]. Glycopyrrolate Injection may be administered intramuscularly (IM), or intravenously (IV) without dilution, in the following indications. ( 2.1 ): 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 2.1 Important Dosage and Administration Instructions • 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. • This product is for both single dose and multiple dose. 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 th…

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 ) • Benzyl Alcohol Toxicity: Due to its benzyl alcohol content, glycopyrrolate injection should not be used in neonates, i.e., patients less than 1 month of age. ( 5.10 ) 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 protec…

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 )

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 )

8.1 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.

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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 866-770-7144, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .