Glycopyrrolate Oral Solution

5 WARNINGS AND PRECAUTIONS 5.1 Constipation or Intestinal Pseudo-obstruction Constipation is a common dose-limiting adverse reaction which sometimes leads to glycopyrrolate discontinuation [see Adverse Reactions (6.1)]. Assess patients for constipation, particularly within 4-5 days of initial dosing or after a dose increase. Intestinal pseudo-obstruction has been reported and may present as abdominal distention, pain, nausea or vomiting. 5.2 Incomplete Mechanical Intestinal Obstruction Diarrhea may be an early symptom of incomplete mechanical intestinal obstruction, especially in patients with ileostomy or colostomy. If incomplete mechanical intestinal obstruction is suspected, discontinue treatment with glycopyrrolate oral solution and evaluate for intestinal obstruction. 5.3 High Ambient Temperatures In the presence of high ambient temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with the use of anticholinergic drugs such as glycopyrrolate oral solution. Advise patients/caregivers to avoid exposure of the patient to hot or very warm environmental temperatures. 5.4 Operating Machinery or an Automobile Glycopyrrolate oral solution may produce drowsiness or blurred vision. As appropriate for a given age, warn the patient not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking glycopyrrolate oral solution. 5.5 Anticholinergic Drug Effects Use glycopyrrolate oral solution with caution in patients with conditions that are exacerbated by anticholinergic drug effects including: Autonomic neuropathy Renal disease Ulcerative colitis – Large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason may precipitate or aggravate “toxic megacolon”, a serious complication of the disease. Hyperthyroidism Coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, and hypertension Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Constipation or intestinal pseudo-obstruction [see Warnings and Precautions (5.1)] Incomplete mechanical intestinal obstruction [see Warnings and Precautions (5.2)] The most common adverse reactions reported with glycopyrrolate oral solution are dry mouth, vomiting, constipation, flushing, and nasal congestion 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to glycopyrrolate oral solution in 151 subjects, including 20 subjects who participated in an 8-week placebo-controlled study (Study 1) and 137 subjects who participated in a 24-week open-label study (six subjects who received glycopyrrolate oral solution in the placebo-controlled study and 131 new subjects). Table 2 presents adverse reactions reported by ≥ 15% of glycopyrrolate oral solution -treated subjects from the placebo-controlled clinical trial. Table 2: Adverse Reactions Occurring in ≥ 15% of Glycopyrrolate oral solution Treated Subjects and at a Greater Frequency than Placebo in Study 1 Glycopyrrolate oral solution (N=20) n (%) Placebo (N=18) n (%) Dry Mouth 8 (40%) 2 (11%) Vomiting 8 (40%) 2 (11%) Constipation 7 (35%) 4 (22%) Flushing 6 (30%) 3 (17%) Nasal Congestion 6 (30%) 2 (11%) Headache 3 (15%) 1 (6%) Sinusitis 3 (15%) 1 (6%) Upper Respiratory Tract Infection 3 (15%) 0 Urinary Retention 3 (15%) 0 The following adverse reactions occurred at a rate of <2% of patients receiving glycopyrrolate oral solution in the open-label study. Gastrointestinal: Abdominal distention, abdominal pain, stomach discomfort, chapped lips, flatulence, retching, dry tongue General Disorders: Irritability, pain Infections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract infection Investigations: Heart rate increase Metabolism and Nutrition: Dehydration Nervous System: Headache, convulsion, dysgeusia, nystagmus Psychiatric: Agitation, restlessness, abnormal behavior, aggression, crying, impulse control disorder, moaning, mood altered Respiratory: Increased viscosity of bronchial secretion, nasal congestion, nasal dryness Skin: Dry skin, pruritus, rash Vascular: Pallor 6.2 Post Marketing Experience The following adverse reactions have been identified during postapproval use of other formulations of glycopyrrolate for other indications. Because 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. Additional adverse reactions identified during postapproval use of glycopyrrolate tablets include: loss of taste and suppression of lactation.

<table border="1" cellpadding="0" cellspacing="0"><caption>Table 2: Adverse Reactions Occurring in &#x2265; 15% of Glycopyrrolate oral solution Treated Subjects and at a Greater Frequency than Placebo in Study 1</caption><tbody><tr><td/><td><paragraph>Glycopyrrolate oral solution (N=20)</paragraph><paragraph>n (%)</paragraph></td><td><paragraph>Placebo (N=18)</paragraph><paragraph>n (%)</paragraph></td></tr><tr><td><paragraph>Dry Mouth</paragraph></td><td><paragraph>8 (40%)</paragraph></td><td><paragraph>2 (11%)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>8 (40%)</paragraph></td><td><paragraph>2 (11%)</paragraph></td></tr><tr><td><paragraph>Constipation</paragraph></td><td><paragraph>7 (35%)</paragraph></td><td><paragraph>4 (22%)</paragraph></td></tr><tr><td><paragraph>Flushing</paragraph></td><td><paragraph>6 (30%)</paragraph></td><td><paragraph>3 (17%)</paragraph></td></tr><tr><td><paragraph>Nasal Congestion</paragraph></td><td><paragraph>6 (30%)</paragraph></td><td><paragraph>2 (11%)</paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph>3 (15%)</paragraph></td><td><paragraph>1 (6%)</paragraph></td></tr><tr><td><paragraph>Sinusitis</paragraph></td><td><paragraph>3 (15%)</paragraph></td><td><paragraph>1 (6%)</paragraph></td></tr><tr><td><paragraph>Upper Respiratory Tract Infection</paragraph></td><td><paragraph>3 (15%)</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Urinary Retention</paragraph></td><td><paragraph>3 (15%)</paragraph></td><td><paragraph>0</paragraph></td></tr></tbody></table>