GLYCOPYRROLATE

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

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., glycopyrrolate tablets 1 mg or another 1 mg tablet strength) is appropriate for initial or maintenance treatment because the dosage strength of glycopyrrolate tablets 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.

5 WARNINGS AND PRECAUTIONS Precipitation of Acute Glaucoma : May increase intraocular pressure; if symptoms occur, discontinue use and promptly seek medical care. ( 4 , 5.1 ) Partial or Complete Mechanical Intestinal Obstruction : Diarrhea may be an early symptom, especially in patients with ileostomy or colostomy. If the obstruction is suspected, discontinue use and evaluate the patient for obstruction. ( 4 , 5.2 ) GI Adverse Reactions Due to Decreased GI Motility : Delayed gastric emptying, constipation, and intestinal pseudo-obstruction may occur and precipitate or aggravate paralytic ileus and toxic megacolon; not recommended for use with anticholinergics or other medications that decrease GI peristalsis. ( 4 , 5.3 , 7.1 ) Cognitive and Visual Adverse Reactions : May impair mental and/or physical function. Inform patients not to operate motor vehicles or perform other hazardous tasks until reasonably certain they are not adversely affected; discontinue use if signs or symptoms develop. ( 5.4 , 7.1 ) Heat Prostration at High Environmental Temperatures : Heat prostration resulting in fever and heatstroke can occur, especially in geriatric patients. Avoid exposure to hot or very warm environmental temperatures. ( 5.5 , 5.7 ) Other Conditions Exacerbated by Anticholinergic Adverse Reactions : Use is not recommended in patients with autonomic neuropathy, hyperthyroidism, cardiac disease, hiatal hernia, etc. ( 5.6 , 7.1 ) Increased Risk of Anticholinergic Adverse Reactions in Geriatric Patients : Complications include urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures. Not recommended in geriatric patients and may be contraindicated in some patients with underlying medical conditions. ( 4 , 5.7 , 8.5 ) 5.1 Precipitation of Acute Glaucoma Glycopyrrolate may cause increased intraocular pressure in patients with glaucoma and reduce the effects of antiglaucoma agents. Instruct patients to discontinue glycopyrrolate 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 Contraindications (4) ] . 5.2 Partial or Complete Mechanical Intestinal Obstruction Glycopyrrolate may worsen intestinal mechanical obstruction, and diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. If partial or complete intestinal obstruction is suspected, discontinue the use of glycopyrrolate and evaluate for potential intestinal obstruction [see Contraindications (4) ] . 5.3 Gastrointestinal Adverse Reactions Due to Decreased Gastrointestinal Motility Glycopyrrolate reduces gastrointestinal motility and may result in delayed gastric emptying, constipation, and intestinal pseudo-obstruction and may precipitate or aggravate paralytic ileus and toxic megacolon [see Contraindications (4) ] . The risk of gastrointestinal adverse reactions is further increased with the use of other anticholinergics and other medications that decrease gastrointestinal peristalsis. Monitor patients for symptoms of decreased gastrointestinal motility. Concomitant use of glycopyrrolate and other anticholinergics or other medications that decrease GI peristalsis is not recommended [see Drug Interactions (7.2) ] . 5.4 Cognitive and Visual Adverse Reactions Glycopyrrolate may produce drowsiness and blurred vision and impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle, operating machinery, or performing other hazardous work [see Adverse Reactions (6) ] . Concomitant use of other drugs that have anticholinergic properties may increase these effects [see Drug Interactions (7.1) ] . Inform patients not to operate motor vehicles or other dangerous machinery or perform other hazardoustasks until they are reasonably certain that glycopyrrolate does not affect them adversely. Discontinue glycopyrrolate if …

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 o 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 )

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. Coadministration of antipsychotics with glycopyrrolate may lead to worsening of tardive dyskinesia. Glycopyrrolate is 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 toincreased or decreased drug exposure. Glycopyrrolate is 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 is not recommended in patients taking solid oral dosage forms of potassium chloride.

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 Nonclinical Toxicology (13.1) ] .

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 Precautions (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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch