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 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. Advise patients/caregivers to avoid exposure of the patient to hot or very warm environmental temperatures.

5.4 Operating Machinery or an Automobile

Glycopyyrolate 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.

5.5 Anticholinergic Drug Effects

Use glycopyrrolate 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

6.1 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 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 in the placebo-controlled study and 131 new subjects).

Table 2 presents adverse reactions reported by ≥ 15% of glycopyrrolate-treated subjects from the placebo-controlled clinical trial.

Table 2: Adverse Reactions Occurring in ≥ 15% of Glycopyrrolate -Treated Subjects
               and at a Greater Frequency than Placebo in Study 1

The following adverse reactions occurred at a rate of <2% of patients receiving glycopyrrolate 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 Postmarketing 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.

8.1 Pregnancy

Risk Summary
There are no available data in pregnant women for glycopyrrolate to inform decisions concerning any drug-associated risks. In pregnant rats, daily oral administration of glycopyrrolate during organogenesis at dose exposures 2.5 to 113 times the exposure at the maximum recommended human dose (MRHD) did not result in an increased incidence of gross external or visceral defects [see Data]. When glycopyrrolate was administered intravenously to pregnant rabbits during organogenesis at dose exposures equivalent to up to approximately 7.8 times the exposure at the MRHD, no adverse effects on embryo-fetal development were seen. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data
Glycopyrrolate was orally administered to pregnant rats at dosages of 50, 200, and 400 mg/kg/day during the period of organogenesis. These dosages resulted in systemic exposures (estimated AUC0-inf values) approximately 2.5, 23, and 113 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses). Glycopyrrolate had no effect on maternal survival, but significantly reduced mean maternal body weight gain over the period of dosing at all dosages evaluated. Mean fetal weight was significantly reduced in the 200 and 400 mg/kg/day dose groups. There were two litters with all resorbed fetuses in the 400 mg/kg/day dose group. There were no effects of treatment on the incidence of gross external or visceral defects. Minor treatment-related skeletal effects included reduced ossification of various bones in the 200 and 400 mg/kg/day dose groups; these skeletal effects were likely secondary to maternal toxicity.

Glycopyrrolate was intravenously administered to pregnant rabbits at dosages of 0.1, 0.5, and 1.0 mg/kg/day during the period of organogenesis. These dosages resulted in systemic exposures (estimated AUC0-inf values) approximately 0.8, 4.6, and 7.8 times, respectively, the estimated systemic exposure in humans at the MRHD. Glycopyrrolate did not affect maternal survival under the conditions of this study. Mean maternal body weight gain and mean food consumption over the period of dosing were lower than the corresponding control value in the 0.5 and 1.0 mg/kg/day treatment groups. There were no effects of treatment on fetal parameters, including fetal survival, mean fetal weight, and the incidence of external, visceral, or skeletal defects.

Female rats that were pregnant or nursing were orally dosed with glycopyrrolate daily at dosages of 0, 50, 200, or 400 mg/kg/day, beginning on day 7 of gestation, and continuing until day 20 of lactation. These dosages resulted in systemic exposures (estimated AUC0-inf values) approximately 2.5, 23, and 113 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses). Mean body weight of pups in all treatment groups was reduced compared to the control group during the period of nursing, but eventually recovered to be comparable to the control group, post-weaning. No other notable delivery or litter parameters were affected by treatment in any group, including no effects on mean duration of gestation or mean numbers of live pups per litter. No treatment-related effects on survival or adverse clinical signs were observed in pups. There were no effects of maternal treatment on behavior, learning, memory, or reproductive function of pups.

8.2 Lactation

Risk Summary
There are no data on the presence of glycopyrrolate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for glycopyrrolate and any potential adverse effects on the breastfed infant from glycopyrrolate or from the underlying maternal condition.

8.4 Pediatric Use

Glycopyrrolate was evaluated for chronic severe drooling in patients aged 3-16 years with neurologic conditions associated with problem drooling. Glycopyrrolate has not been studied in subjects under the age of 3 years.

8.5 Geriatric Use

Clinical studies of glycopyrrolate did not include subjects aged 65 and over.

8.6 Renal Impairment

Because glycopyrrolate is largely renally eliminated, glycopyrrolate should be used with caution in patients with renal impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Glycopyrrolate is a competitive inhibitor of acetylcholine receptors that are located on certain peripheral tissues, including salivary glands. Glycopyrrolate indirectly reduces the rate of salivation by preventing the stimulation of these receptors.

12.2 Pharmacodynamics

Glycopyrrolate inhibits the action of acetylcholine on salivary glands thereby reducing the extent of salivation.

12.3 Pharmacokinetics

Absorption
In a parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery, subjects received either intravenous (IV) or oral glycopyrrolate as a premedication. The mean absolute bioavailability of oral glycopyrrolate tablets was low (approximately 3%) and highly variable among subjects (range 1.3 to 13.3%). A similar pattern of low and variable relative bioavailability is seen in adults.

Analysis of population pharmacokinetic data from normal adults and children with cerebral palsy associated chronic moderate to severe drooling failed to demonstrate linear pharmacokinetics across the dose range. In the same analysis, population estimates of the apparent oral clearance (scaled by weight in children and adults) ranged from 5.28 - 38.95 L/hr/kg for healthy adults and 8.07 - 25.65 L/hr/kg for patients with cerebral palsy, a reflection of the low and highly variable oral bioavailability of glycopyrrolate.

Absorption of glycopyrrolate (fasting) was compared to that of a marketed glycopyrrolate oral tablet. The Cmax after oral solution administration was 23% lower compared to tablet administration and AUC0-inf was 28% lower after oral solution administration. Mean Cmax after oral solution administration in the fasting state was 0.318 ng/mL, and mean AUC0-24 was 1.74 ng•hr/mL. Mean time to maximum plasma concentration for glycopyrrolate was 3.1 hours, and mean plasma half-life was 3.0 hours.

In healthy adults, a high fat meal was shown to significantly affect the absorption of glycopyrrolate oral solution (10 mL, 1 mg/5 mL). The mean Cmax under fed high fat meal conditions was approximately 74% lower than the Cmax observed under fasting conditions. Similarly, mean AUC0-T was reduced by about 78% by the high fat meal compared with the fasting AUC0-T. A high fat meal markedly reduces the oral bioavailability of glycopyrrolate. Therefore, glycopyrrolate should be dosed at least one hour before or two hours after meals. Pharmacokinetic results (mean ± SD) are described in Table 3.

Table 3: Pharmacokinetic Parameters (mean±SD) for Glycopyrrolate, Fasting and Fed, in Healthy Adults

*n=35

Distribution
After IV administration, glycopyrrolate has a mean volume of distribution in children aged 1 to 14 years of approximately 1.3 to 1.8 L/kg, with a range from 0.7 to 3.9 L/kg. In adults aged 60-75 years, the volume of distribution was lower (0.42 L/kg +/- 0.22).

Metabolism
In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of tritiated glycopyrrolate, approximately 85% of total radioactivity was excreted in urine and <5% was present in T-tube drainage of bile. In both urine and bile, >80% of the radioactivity corresponded to unchanged drug. These data suggest a small proportion of IV glycopyrrolate is excreted as one or more metabolites.

Elimination
Approximately 65-80% of an IV glycopyrrolate dose was eliminated unchanged in urine in adults. In two studies, after IV administration to pediatric patients ages 1-14 years, mean clearance values ranged from 1.01- 1.41 L/kg/hr (range 0.32 -2.22 L/kg/hr). In adults, IV clearance values were 0.54 ± 0.14 L/kg/hr.

Pediatrics
The estimated apparent clearance of glycopyrrolate from a population pharmacokinetic analysis (scaled by weight in children and adults) of oral and IV data was found to be 13.2 L/hr/kg or 92.7 L/hr for a typical 70 kg subject. In the same population based analysis, gender was not identified as having an effect on either glycopyrrolate clearance or systemic exposure.

Gender
Population pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or systemic exposure.

Race
The pharmacokinetics of glycopyrrolate by race has not been characterized.

Elderly
Glycopyrrolate pharmacokinetics have not been characterized in the elderly.

Renal Impairment
In one study, glycopyrrolate 4 mcg/kg was administered intravenously in uremic patients undergoing renal transplantation surgery. Mean AUC (10.6 mcg•h/L), mean plasma clearance (0.43 L/hr/kg) and mean 3-hour urinary excretion (0.7%) for glycopyrrolate were significantly different than those of control patients (3.73 µg•h/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that elimination of glycopyrrolate is severely impaired in patients with renal failure.

Hepatic Impairment
Glycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

When glycopyrrolate was administered via oral gavage to mice for up to 24 months at dosages of 2.5, 7, and 20 mg/kg/day in both genders, resulting in systemic exposures (estimated AUC0-inf values) approximately 0.1, 0.3, and 0.8 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses), no significant changes in tumor incidence were observed when compared to control.

When glycopyrrolate was administered via oral gavage to rats for up to 24 months at dosages of 5, 15, and 40 mg/kg/day in both genders, resulting in systemic exposures approximately 0.2, 0.8, and 2 times, respectively, the estimated systemic exposure in humans at the MRHD, no significant changes in tumor incidence were observed when compared to control.

Glycopyrrolate did not elicit any genotoxic effects in the Ames mutagenicity assay, the human lymphocyte chromosome aberration assay, or the micronucleus assay.

Glycopyrrolate was assessed for effects on fertility or general reproductive function in rats. Rats of both genders received glycopyrrolate at dosages up to 100 mg/kg/day via oral gavage, resulting in systemic exposures (estimated AUC0-inf values) in males and females up to approximately 11 and 15 times, respectively, the estimated systemic exposure in humans at the MRHD. No treatment-related effects on fertility or reproductive parameters were observed in either gender in this study.