Glycopyrrolate

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Precipitation of Acute Glaucoma [ see Warnings and Precautions (5.1) ] Partial or Complete Mechanical Intestinal Obstruction [ see Warnings and Precautions (5.2 ) ] Gastrointestinal Adverse Reactions due to Decreased Gastrointestinal Motility [ see Warnings and Precautions (5.3) ] Cognitive and Visual Adverse Reactions [ see Warnings and Precautions (5.4 )] Heat Prostration at High Environmental Temperatures [ see Warnings and Precautions (5.5) ] Other Conditions Exacerbated by Anticholinergic Adverse Reactions [ see Warnings and Precautions (5.6) ] Increased Risk of Anticholinergic Adverse Reactions in Geriatric Patients [ see Warnings and Precaution (5.7) ] The following adverse reactions associated with the use of glycopyrrolate, or other anticholinergic drugs, were identified in clinical studies or postmarketing reports. Because some of these reactions are 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. Cardiac Disorders: chest, pain, hypertension, tachycardia Endocrine Disorders: decreased sweating Eye Disorders: blurred vision, cycloplegia, dilatation of the pupil, increased ocular tension Gastrointestinal Disorders: bloated feeling, constipation, dry mouth, dysgeusia, nausea, vomiting Immune System Disorders: anaphylaxis [ see Contraindications (4) ] Nervous System Disorders: agitation, dizziness, drowsiness, headache, insomnia, mental confusion, nervousness, weakness Respiratory Disorders: respiratory depression, throat irritation Renal and Urinary Disorders: urinary hesitancy, urinary retention Reproductive System and Breast Disorders: impotence, suppression of lactation Vascular Disorders: flushing Adverse reactions include blurred vision, drowsiness, decreased sweating, flushing, vomiting, constipation, dry mouth, tachycardia, and urinary retention. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

4 CONTRAINDICATIONS Glycopyrrolate tablets are contraindicated in: Patients at risk for anticholinergic toxicity due to an underlying medical condition, including: Glaucoma [ see Warnings and Precautions (5.1) ] Obstructive uropathies, including prostatic hypertrophy Mechanical obstructive diseases of the gastrointestinal tract (e.g., pyloroduodenal stenosis, strictures) [ see Warnings and Precautions (5.2) ] Gastrointestinal motility disorders (e.g., achalasia, paralytic ileus, intestinal atony) [ see Warnings and Precautions (5.3) ] Bleeding gastrointestinal ulcer Active inflammatory or infectious colitis which can lead to toxic megacolon History of or current toxic megacolon Myasthenia gravis Patients with a hypersensitivity to glycopyrrolate or any of the inactive ingredients in glycopyrrolate tablets [ see Adverse Reactions (6) and Description (11) ]. Patients at risk for anticholinergic toxicity due to various underlying medical conditions. ( 4 , 5.1 , 5.2 , 5.3 ) Hypersensitivity to glycopyrrolate or the inactive ingredients. ( 4 )

11 DESCRIPTION Glycopyrrolate tablets contain synthetic anticholinergic glycopyrrolate. Glycopyrrolate is a quaternary ammonium compound with the following chemical name: 3-[(cyclopentyl hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. The molecular formula for glycopyrrolate is C 19 H 28 BrNO 3 , the molecular weight is 398.3 g/mol, and the structural formula is: Each glycopyrrolate tablets, USP contains glycopyrrolate, USP 1 mg or 2 mg as the active ingredient. The inactive ingredients are dibasic calcium phosphate, lactose, magnesium stearate, povidone, and sodium starch glycolate. glycco-structure

2 DOSAGE AND ADMINISTRATION Important Dosing Information ( 2.1 ) Glycopyrrolate tablets 2 mg are not recommended for patients initiating treatment or receiving maintenance treatment with glycopyrrolate tablets 1 mg or another 1 mg dosage strength of oral glycopyrrolate tablets. Recommended Dosage ( 2.2 ) The recommended initial dosage of glycopyrrolate tablets 1 mg is 1 mg three times daily (in the morning, early afternoon, and at bedtime). Some patients may require 2 mg at bedtime to assure overnight control of symptoms. For maintenance, a dosage of 1 mg twice a day is frequently adequate. The recommended dosage of glycopyrrolate tablets 2 mg for adults is 2 mg two or three times daily at equally spaced intervals. The maximum recommended daily dosage is 8 mg. Use the lowest effective dosage of glycopyrrolate to control symptoms. If patients can be titrated to a lower dose, switch from glycopyrrolate tablets 2 mg to glycopyrrolate tablets 1 mg or another 1 mg oral tablet of glycopyrrolate. 2.1 Important Dosing Information Glycopyrrolate tablets 2 mg are not recommended for patients in whom a lower dosage strength of oral glycopyrrolate (e.g., 1 mg tablet strength) is appropriate for initial or maintenance treatment because the dosage strength of glycopyrrolate tablets 2 mg may exceed the recommended initial and maintenance dosage of oral glycopyrrolate tablets. 2.2 Recommended Dosage The recommended initial dosage of glycopyrrolate tablets 1 mg for adults is 1 mg three times daily (in the morning, early afternoon, and at bedtime). Some patients may require 2 mg at bedtime to assure overnight control of symptoms. For maintenance, a dosage of 1 mg twice a day is frequently adequate. The recommended dosage of glycopyrrolate tablets 2 mg for adults is 2 mg two or three times daily at equally spaced intervals. The maximum recommended daily dosage of glycopyrrolate is 8 mg. Use the lowest effective dosage of glycopyrrolate to control symptoms. If patients can be titrated to a lower dose, switch from glycopyrrolate tablets 2 mg to glycopyrrolate tablets 1 mg or another 1 mg oral tablet of glycopyrrolate.

1 INDICATIONS AND USAGE Glycopyrrolate is indicated in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer. Limitations of Use Glycopyrrolate is not indicated as monotherapy for the treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established. Glycopyrrolate is anticholinergics indicated in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer. Limitations of Use: Not indicated as monotherapy for the treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established.

10 OVERDOSAGE Signs and symptoms of glycopyrrolate overdosage are related to excessive anti-muscarinic anticholinergic activity and are generally peripheral (e.g., flushing, hyperthermia, tachycardia, ileus, urinary retention, loss of ocular accommodation, and light sensitivity due to mydriasis), but central nervous system toxicity (agitation, seizures, hyperthermia) may also occur. If over-exposure occurs, call the Poison Control Center at 1-800-222-1222 for current information on the management of glycopyrrolate poisoning and overdosage. Management of glycopyrrolate overdosage is based upon presenting signs and symptoms, including close observation for severe or life-threatening complications which may require respiratory and cardiovascular monitoring and support. Consider administration of activated charcoal and/or use of a reversible anticholinesterase as appropriate or recommended by Poison Control.

7 DRUG INTERACTIONS Other Anticholinergic Drugs: Concomitant use is not recommended. ( 5.3 , 5.4 , 5.6 , 7.1 ) Drugs with Altered Absorption due to Decreased GI Motility: Concomitant use is not recommended. ( 7.2 ) GI Toxicity with Solid Oral Dosage Forms of Potassium Chloride: Concomitant use is not recommended. ( 7.3 ) 7.1 Other Anticholinergic Drugs There is potential for an additive interaction between glycopyrrolate and concomitantly used anticholinergic drugs (e.g., tricyclic antidepressants, anti-epileptics, class I antiarrhythmics, anti-spasmodics, amantadine) resulting in increased anticholinergic adverse reactions. Co-administration of antipsychotics with glycopyrrolate may lead to worsening of tardive dyskinesia. Glycopyrrolate tablets are not recommended in patients taking other anticholinergic drugs [ see Warnings and Precautions (5.3 , 5.4 , 5.6) ]. 7.2 Drugs with Altered Absorption due to Decreased Gastrointestinal Motility and Increased Transit Time Decreased gastrointestinal motility by glycopyrrolate may impact absorption of other drugs leading to increased or decreased drug exposure. Glycopyrrolate tablets are not recommended in patients taking other drugs that are affected by altered gastrointestinal motility [ see Warnings and Precautions (5.3) ]. 7.3 Gastrointestinal Toxicity with Solid Dosage Forms of Potassium Chloride Oral glycopyrrolate may worsen gastrointestinal mucosal injury reported with solid oral dosage forms of potassium chloride due to decreased gastric motility and increased transit time, leading to prolonged contact with the gastrointestinal mucosa. Glycopyrrolate tablets are not recommended in patients taking solid oral dosage forms of potassium chloride.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Glycopyrrolate, an anticholinergic (antimuscarinic) agent, inhibits the action of acetylcholine on parietal cells in the stomach and decreases the volume and acidity of gastric secretions. 12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with glycopyrrolate. 12.3 Pharmacokinetics Patients with Renal Impairment In the published literature, glycopyrrolate 4 mcg/kg was administered intravenously (glycopyrrolate tablets are not recommended for intravenous use) in uremic patients undergoing renal transplantation surgery. The mean AUC (10.6 mcg·h/L) and 24-hour urinary excretion (7%) for glycopyrrolate were significantly different from normal healthy adult subjects undergoing general surgery (3.7 mcg·h/L, and 65%, respectively) [ see Use in Specific Populations (8.6) ].

12.1 Mechanism of Action Glycopyrrolate, an anticholinergic (antimuscarinic) agent, inhibits the action of acetylcholine on parietal cells in the stomach and decreases the volume and acidity of gastric secretions.

12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with glycopyrrolate.

12.3 Pharmacokinetics Patients with Renal Impairment In the published literature, glycopyrrolate 4 mcg/kg was administered intravenously (glycopyrrolate tablets are not recommended for intravenous use) in uremic patients undergoing renal transplantation surgery. The mean AUC (10.6 mcg·h/L) and 24-hour urinary excretion (7%) for glycopyrrolate were significantly different from normal healthy adult subjects undergoing general surgery (3.7 mcg·h/L, and 65%, respectively) [ see Use in Specific Populations (8.6) ].

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3 DOSAGE FORMS AND STRENGTHS Tablets: Glycopyrrolate Tablets USP, 1 mg are white to off-white, round, flat beveled edge tablet debossed with “MCR 117” separated by break line on one side and plain on other side. Each tablet contains: Glycopyrrolate, USP 1 mg. Glycopyrrolate Tablets USP, 2 mg are white to off white, round, flat beveled edge tablet debossed with “AC 108” separated by break line on one side and plain on other side. Each tablet contains: Glycopyrrolate, USP 2 mg. Tablets: 1 mg (functionally scored) and 2 mg (functionally scored) ( 3 )

Glycopyrrolate Glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE LACTOSE MAGNESIUM STEARATE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO MCR;117 Glycopyrrolate Glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE LACTOSE MAGNESIUM STEARATE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO AC;108

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Reproduction studies in rats resulted in diminished rates of conception in a dose-related manner. Studies in dogs suggest that diminished rates of conception may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate.

13 NONCLINICAL TOXICOLOGY 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Reproduction studies in rats resulted in diminished rates of conception in a dose-related manner. Studies in dogs suggest that diminished rates of conception may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate.

ANDA207201

Glycopyrrolate

Glycopyrrolate

23155-607

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL glyco-spl-100mg glyco-2mg-spl-100

17 PATIENT COUNSELING INFORMATION Precipitation of Acute Glaucoma Advise patients to discontinue glycopyrrolate tablets and promptly seek medical care if they experience symptoms of acute angle-closure glaucoma (pain and reddening of the eyes accompanied by dilated pupils) [ see Warnings and Precautions (5.1) ]. Partial or Complete Mechanical Intestinal Obstruction Advise patients to contact their healthcare provider if diarrhea occurs, especially in patients with ileostomy or colostomy [ see Warnings and Precautions (5.2) ]. Gastrointestinal Adverse Reactions Due to Decreased Gastrointestinal Motility Inform patients that glycopyrrolate tablets may cause adverse reactions related to decreased gastrointestinal motility and report to their healthcare provider if they experience symptoms such as vomiting, early satiety, abdominal distention, and constipation [ see Warnings and Precautions (5.3) ]. Cognitive and Visual Adverse Reactions Inform patients that glycopyrrolate tablets may cause cognitive or visual impairment and not operate motor vehicles or other dangerous machinery or perform other hazardous tasks until they are reasonably certain that glycopyrrolate tablets do not affect them adversely. Advise patients to discontinue glycopyrrolate tablets immediately and contact their healthcare provider if symptoms develop (e.g., drowsiness or blurred vision) [ see Warnings and Precautions (5.4) ]. Heat Prostration at High Environmental Temperatures Inform patients that glycopyrrolate tablets can reduce sweating, leading to the possibility of heat exhaustion or heat stroke. Advise patients to avoid exposure to hot or very warm environmental temperatures [ see Warnings and Precautions (5.5) ]. Distributed by: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) 200146 Revised: 10/2022 avet-logo-spl

8.5 Geriatric Use Geriatric patients 65 years of age and older may be more sensitive to the anticholinergic adverse reactions of glycopyrrolate leading to complications of urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures; therefore, glycopyrrolate tablets are not recommended in geriatric patients and may be contraindicated in some geriatric patients with underlying medical conditions [ see Contraindications (4) and Warnings and Precautions (5) ].

8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergic drugs, glycopyrrolate may cause suppression of lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for glycopyrrolate tablets and any potential adverse effects on the breastfed infant from glycopyrrolate tablets.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Over decades of use, there is an absence of published data on orally administered glycopyrrolate in pregnant women, including an absence of any reports of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, at non-maternally toxic doses of oral glycopyrrolate, there were no adverse developmental effects in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean bodyweight that recovered post nursing, with no other developmental effects observed ( see Data ). The estimated background risk of 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 clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data At non-maternally toxic doses of oral glycopyrrolate, there were no effects on embryo-fetal development or toxicity in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean bodyweight that recovered post nursing, with no other developmental effects observed. In a published reproductive and developmental study, male and female rats were administered glycopyrrolate in the diet at 0 mg/kg/day, 32.5 mg/kg/day, 63 mg/kg/day, and 130 mg/kg/day for 3 weeks to 5 weeks and through up to three consecutive litters. There was no indication of abnormalities in the pups of treated dams. There was a decreased rate of conception and in survival rate at weaning for all treated animals in a dose-related manner. Diminished rates of conception may be due to diminished seminal secretion [ see NonclinicalToxicology (13.1) ].

8 USE IN SPECIFIC POPULATIONS Renal Impairment: Monitor patients with renal impairment; if anticholinergic adverse reactions occur, discontinue use. ( 8.6 ) 8.1 Pregnancy Risk Summary Over decades of use, there is an absence of published data on orally administered glycopyrrolate in pregnant women, including an absence of any reports of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, at non-maternally toxic doses of oral glycopyrrolate, there were no adverse developmental effects in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean bodyweight that recovered post nursing, with no other developmental effects observed ( see Data ). The estimated background risk of 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 clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data At non-maternally toxic doses of oral glycopyrrolate, there were no effects on embryo-fetal development or toxicity in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean bodyweight that recovered post nursing, with no other developmental effects observed. In a published reproductive and developmental study, male and female rats were administered glycopyrrolate in the diet at 0 mg/kg/day, 32.5 mg/kg/day, 63 mg/kg/day, and 130 mg/kg/day for 3 weeks to 5 weeks and through up to three consecutive litters. There was no indication of abnormalities in the pups of treated dams. There was a decreased rate of conception and in survival rate at weaning for all treated animals in a dose-related manner. Diminished rates of conception may be due to diminished seminal secretion [ see NonclinicalToxicology (13.1) ]. 8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergic drugs, glycopyrrolate may cause suppression of lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for glycopyrrolate tablets and any potential adverse effects on the breastfed infant from glycopyrrolate tablets. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Geriatric patients 65 years of age and older may be more sensitive to the anticholinergic adverse reactions of glycopyrrolate leading to complications of urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures; therefore, glycopyrrolate tablets are not recommended in geriatric patients and may be contraindicated in some geriatric patients with underlying medical conditions [ see Contraindications (4) and Warnings and Precautions (5) ]. 8.6 Renal Impairment Glycopyrrolate is substantially excreted by the kidney [ see Clinical Pharmacology (12.3) ]. Monitor patients with renal impairment for anticholinergic adverse reactions [ see Adverse Reactions (6) ]. If anticholinergic adverse reactions occur, discontinue glycopyrrolate tablets.

16 HOW SUPPLIED/STORAGE AND HANDLING Glycopyrrolate Tablets USP, 1 mg are white to off-white, round, flat beveled edge tablet debossed with “MCR 117” separated by break line on one side and plain on other side. Packaged in bottles of 100 tablets. Glycopyrrolate Tablets USP, 1 mg in bottles of 100 (NDC 23155-606-01). Glycopyrrolate Tablets USP, 2 mg are white to off white, round, flat beveled edge tablet debossed with “AC 108” separated by break line on one side and plain on other side. Packaged in bottles of 100 tablets. Glycopyrrolate Tablets USP, 2 mg in bottles of 100 (NDC 23155-607-01). Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° C to 30°C (59° F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. Dispense in tight container.