ADVERSE REACTIONS SECTION.

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 are dry mouth, vomiting, constipation, flushing, and nasal congestion.. 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 (incidence >=30%) are dry mouth, vomiting, constipation, flushing, and nasal congestion. (6)To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 1-844-469-6379 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 24-week open-label study (six subjects who received glycopyrrolate in the placebo-controlled study and 131 new subjects).Table 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 Greater Frequency than Placebo in Study 1Glycopyrrolate(N=20)n (%)Placebo (N=18) (%)Dry Mouth8 (40%)2 (11%)Vomiting8 (40%)2 (11%)Constipation7 (35%)4 (22%)Flushing6 (30%)3 (17%)Nasal Congestion6 (30%)2 (11%)Headache3 (15%)1 (6%)Sinusitis3 (15%)1 (6%)Upper Respiratory Tract Infection3 (15%)0Urinary Retention3 (15%)0The following adverse reactions occurred at rate of <2% of patients receiving glycopyrrolate in the open-label study.Gastrointestinal: Abdominal distention, abdominal pain, stomach discomfort, chapped lips, flatulence, retching, dry tongueGeneral Disorders: Irritability, painInfections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract infectionInvestigations: Heart rate increase Metabolism and Nutrition: DehydrationNervous System: Headache, convulsion, dysgeusia, nystagmusPsychiatric: Agitation, restlessness, abnormal behavior, aggression, crying, impulse control disorder, moaning, mood alteredRespiratory: Increased viscosity of bronchial secretion, nasal congestion, nasal drynessSkin: Dry skin, pruritus, rashVascular: 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Additional adverse reactions identified during postapproval use of glycopyrrolate tablets include: loss of taste and suppression of lactation.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Glycopyrrolate is 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. AbsorptionIn parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery, subjects received either intravenous (IV) or oral glycopyrrolate as premedication. The mean absolute bioavailability of oral glycopyrrolate tablets was low (approximately 3%) and highly variable among subjects (range 1.3 to 13.3%). 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, reflection of the low and highly variable oral bioavailability of glycopyrrolate.Absorption of glycopyrrolate oral solution (fasting) was compared to that of 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 nghr/mL. Mean time to maximum plasma concentration for glycopyrrolate oral solution was 3.1 hours, and mean plasma half-life was 3.0 hours.In healthy adults, high fat meal was shown to significantly affect the absorption of glycopyrrolate oral solution (10 mL, 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. 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 Oral Solution, Fasting and Fed, in Healthy AdultsCmax (ng/mL)Tmax (hrs)AUC0-T (nghr/mL)AUC0-Inf (nghr/mL)T1/2 (hrs)Fasting (n=37)0.318 +- 0.1903.10 +- 1.081.74 +- 1.071.81 +- 1.093.0 +- 1.2Fed (n=36)0.084 +- 0.0812.60 +- 1.120.38 +- 0.140.46 +- 0.13n=35 3.2 +- 1.1 DistributionAfter IV administration, glycopyrrolate has mean volume of distribution in children aged to 14 years of approximately 1.3 to 1.8 L/kg, with 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).. MetabolismIn adult patients who underwent surgery for cholelithiasis and were given 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 small proportion of IV glycopyrrolate is excreted as one or more metabolites.. EliminationApproximately 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.. PediatricsThe estimated apparent clearance of glycopyrrolate from 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 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.. GenderPopulation pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or systemic exposure.. RaceThe pharmacokinetics of glycopyrrolate by race has not been characterized.. ElderlyGlycopyrrolate pharmacokinetics have not been characterized in the elderly.. Renal ImpairmentIn one study, glycopyrrolate mcg/kg was administered intravenously in uremic patients undergoing renal transplantation surgery. Mean AUC (10.6 mcgh/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 ugh/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 ImpairmentGlycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Glycopyrrolate was evaluated in multi-center, randomized, double-blind, placebo-controlled, parallel, eight-week study for the control of pathologic drooling in children (Study 1). The study enrolled 38 subjects aged 3-23 years; thirty-six subjects were aged 3-16 years and two patients were greater than 16 years. The subjects were male or female, weighed at least 13 kg (27 lbs), and had cerebral palsy, mental retardation, or another neurologic condition associated with problem drooling defined as drooling in the absence of treatment so that clothing became damp on most days (approximately five to seven days per week). Subjects were randomized in 1:1 fashion to receive glycopyrrolate or placebo. Doses of study medication were titrated over 4-week period to optimal response beginning at 0.02 mg/kg three times day increasing doses in increments of approximately 0.02 mg/kg three times per day every 5-7 days, not to exceed the lesser of approximately 0.1 mg/kg three times per day or mg three times per day.Subjects were evaluated on the 9-point modified Teachers Drooling Scale (mTDS), which is presented below. The mTDS evaluations were recorded by parents/caregivers times daily approximately two hours post-dose on evaluation days during pre-treatment baseline and at Weeks 2, 4, and of therapy.Modified Teachers Drooling Scale1= Dry: never drools 2= Mild: only the lips are wet; occasionally 3= Mild: only the lips are wet; frequently 4= Moderate: wet on the lips and chin; occasionally 5= Moderate: wet on the lips and chin; frequently 6= Severe: drools to the extent that clothing becomes damp; occasionally 7= Severe: drools to the extent that clothing becomes damp; frequently 8= Profuse: clothing, hands, tray, and objects become wet; occasionally 9= Profuse: clothing, hands, tray, and objects become wet; frequentlyResponders were defined as subjects with at least 3-point reduction in mean daily mTDS scores from baseline to Week 8. Table presents the proportion of responders at Week and Figure presents the mean mTDS values from baseline through Week 8.Table 4: Percentage of Responders at Week 8Glycopyrrolate Group(N=20)Placebo Group(N=18)15/20 (75%)2/18 (11%)Figure 1. Mean (+- Standard Errors) mDTS Scores. Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 24-week open-label study (six subjects who received glycopyrrolate in the placebo-controlled study and 131 new subjects).Table 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 Greater Frequency than Placebo in Study 1Glycopyrrolate(N=20)n (%)Placebo (N=18) (%)Dry Mouth8 (40%)2 (11%)Vomiting8 (40%)2 (11%)Constipation7 (35%)4 (22%)Flushing6 (30%)3 (17%)Nasal Congestion6 (30%)2 (11%)Headache3 (15%)1 (6%)Sinusitis3 (15%)1 (6%)Upper Respiratory Tract Infection3 (15%)0Urinary Retention3 (15%)0The following adverse reactions occurred at rate of <2% of patients receiving glycopyrrolate in the open-label study.Gastrointestinal: Abdominal distention, abdominal pain, stomach discomfort, chapped lips, flatulence, retching, dry tongueGeneral Disorders: Irritability, painInfections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract infectionInvestigations: Heart rate increase Metabolism and Nutrition: DehydrationNervous System: Headache, convulsion, dysgeusia, nystagmusPsychiatric: Agitation, restlessness, abnormal behavior, aggression, crying, impulse control disorder, moaning, mood alteredRespiratory: Increased viscosity of bronchial secretion, nasal congestion, nasal drynessSkin: Dry skin, pruritus, rashVascular: Pallor.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Glycopyrrolate is contraindicated in:Patients with medical conditions that preclude anticholinergic therapy (e.g., glaucoma, paralytic ileus, unstable cardiovascular status in acute hemorrhage, severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, myasthenia gravis).Patients taking solid oral dosage forms of potassium chloride. The passage of potassium chloride tablets through the gastrointestinal (GI) tract may be arrested or delayed with coadministration of glycopyrrolate.. Patients with medical conditions that preclude anticholinergic therapy (e.g., glaucoma, paralytic ileus, unstable cardiovascular status in acute hemorrhage, severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, myasthenia gravis).. Patients taking solid oral dosage forms of potassium chloride. The passage of potassium chloride tablets through the gastrointestinal (GI) tract may be arrested or delayed with coadministration of glycopyrrolate.. Medical conditions that preclude anticholinergic therapy. (4)Concomitant use of solid oral dosage forms of potassium chloride. (4). Medical conditions that preclude anticholinergic therapy. (4). Concomitant use of solid oral dosage forms of potassium chloride. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Glycopyrrolate is an anticholinergic drug available as an oral solution containing mg glycopyrrolate per mL. The chemical name for glycopyrrolate is pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl) oxy]-1,1-dimethyl-,bromide. The chemical structure is:The empirical formula for glycopyrrolate is C19H28BrNO3 and the molecular weight is 398.33. The inactive ingredients in glycopyrrolate oral solution are: citric acid, glycerin, natural and artificial cherry flavor, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate, sorbitol solution, and purified water.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Glycopyrrolate must be measured and administered with an accurate measuring device [see Patient Counseling Information (17)].Initiate dosing at 0.02 mg/kg orally three times daily and titrate in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and adverse reactions. The maximum recommended dosage is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight. For greater detail, see Table 1.During the four-week titration period, dosing can be increased with the recommended dose titration schedule while ensuring that the anticholinergic adverse events are tolerable. Prior to each increase in dose, review the tolerability of the current dose level with the patients caregiver.Glycopyrrolate should be dosed at least one hour before or two hours after meals.The presence of high fat food reduces the oral bioavailability of glycopyrrolate if taken shortly after meal [see Clinical Pharmacology (12.3)].Table 1: Recommended Dose Titration Schedule (each dose to be given three times daily)WeightDose Level 1Dose Level 2Dose Level 3Dose Level 4Dose Level 5kglbs(~0.02 mg/kg)(~0.04 mg/kg)(~0.06 mg/kg)(~0.08 mg/kg)(~0.1 mg/kg)13-1727-380.3 mg1.5 mL0.6 mg3 mL0.9 mg4.5 mL1.2 mg6 mL1.5 mg7.5 mL18-2239-490.4 mg2 mL0.8 mL4 mL1.2 mg6 mL1.6 mg8 mL2.0 mg10 mL23-2750-600.5 mg2.5 mL1.0 mg5 mL1.5 mg7.5 mL2.0 mg10 mL2.5 mg12.5 mL28-3261-710.6 mg3 mL1.2 mg6 mL1.8 mg9 mL2.4 mg12 mL3.0 mg15 mL33-3772-820.7 mg3.5 mL1.4 mg7 mL2.1 mg10.5 mL2.8 mg14 mL3.0 mg15 mL38-4283-930.8 mg4 mL1.6 mg8 mL2.4 mg12 mL3.0 mg15 mL3.0 mg15 mL43-4794-1040.9 mg4.5 mL1.8 mg9 mL2.7 mg13.5 mL3.0 mg15 mL3.0 mg15 mL>=48>=1051.0 mg5 mL2.0 mg10 mL3.0 mg15 mL3.0 mg15 mL3.0 mg15 mL. Initiate dosing at 0.02 mg/kg three times daily and titrate in increments of 0.02 mg/kg every 5-7 days, based on therapeutic response and adverse reactions. (2)Maximum recommended dose is 0.1 mg/kg three times daily, not to exceed 1.5-3 mg per dose based upon weight. (2)Administer at least one hour before or two hours after meals. (2). Initiate dosing at 0.02 mg/kg three times daily and titrate in increments of 0.02 mg/kg every 5-7 days, based on therapeutic response and adverse reactions. (2). Maximum recommended dose is 0.1 mg/kg three times daily, not to exceed 1.5-3 mg per dose based upon weight. (2). Administer at least one hour before or two hours after meals. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Glycopyrrolate is available as 1mg/5 mL clear, cherry-flavored solution for oral administration in 16 ounce bottles.. mg/5 mL, oral solution in 16 ounce bottles. (3). mg/5 mL, oral solution in 16 ounce bottles. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Digoxin tablets: Use with glycopyrrolate can increase digoxin serum levels. Monitor patients and consider use of alternative dosage forms of digoxin. (7)Amantadine: Effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the dose of glycopyrrolate during concomitant use. (7)Atenolol or metformin: Glycopyrrolate may increase serum levels of atenolol or metformin. Consider dose reduction when used with glycopyrrolate. (7)Haloperidol or levodopa: Glycopyrrolate may decrease serum levels of haloperidol or levodopa. Consider dose increase when used with glycopyrrolate. (7). Digoxin tablets: Use with glycopyrrolate can increase digoxin serum levels. Monitor patients and consider use of alternative dosage forms of digoxin. (7). Amantadine: Effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the dose of glycopyrrolate during concomitant use. (7). Atenolol or metformin: Glycopyrrolate may increase serum levels of atenolol or metformin. Consider dose reduction when used with glycopyrrolate. (7). Haloperidol or levodopa: Glycopyrrolate may decrease serum levels of haloperidol or levodopa. Consider dose increase when used with glycopyrrolate. (7). Drugs Affected by Reduced GI Transit TimeGlycopyrrolate reduces GI transit time, which may result in altered release of certain drugs when formulated in delayed- or controlled-release dosage forms.The passage of potassium chloride tablets through the GI tract may be arrested or delayed with coadministration of glycopyrrolate. Solid dosage forms of potassium chloride are contraindicated [see Contraindications (4)].Digoxin administered as slow dissolution oral tablets may have increased serum levels and enhanced action when administered with glycopyrrolate. Monitor patients receiving slow dissolution digoxin for increased action if glycopyrrolate is coadministered regularly. Consider the use of other oral dosage forms of digoxin (e.g., elixir or capsules).. The passage of potassium chloride tablets through the GI tract may be arrested or delayed with coadministration of glycopyrrolate. Solid dosage forms of potassium chloride are contraindicated [see Contraindications (4)].. Digoxin administered as slow dissolution oral tablets may have increased serum levels and enhanced action when administered with glycopyrrolate. Monitor patients receiving slow dissolution digoxin for increased action if glycopyrrolate is coadministered regularly. Consider the use of other oral dosage forms of digoxin (e.g., elixir or capsules).. AmantadineThe anticholinergic effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the dose of glycopyrrolate during coadministration of amantadine.. Drugs Whose Plasma Levels May be Increased by GlycopyrrolateCoadministration of glycopyrrolate may result in increased levels of certain drugs.Atenolols bioavailability may be increased with coadministration of glycopyrrolate. reduction in the atenolol dose may be needed.Metformin plasma levels may be elevated with coadministration of glycopyrrolate, increasing metformins pharmacologic and toxic effects. Monitor clinical response to metformin with concomitant glycopyrrolate administration; consider dose reduction of metformin if warranted.. Atenolols bioavailability may be increased with coadministration of glycopyrrolate. reduction in the atenolol dose may be needed.. Metformin plasma levels may be elevated with coadministration of glycopyrrolate, increasing metformins pharmacologic and toxic effects. Monitor clinical response to metformin with concomitant glycopyrrolate administration; consider dose reduction of metformin if warranted.. Drugs Whose Plasma Levels May be Decreased by GlycopyrrolateCoadministration of glycopyrrolate may result in decreased levels of certain drugs.Haloperidols serum level may be decreased when coadministered with glycopyrrolate, resulting in worsening of schizophrenic symptoms, and development of tardive dyskinesia. Closely monitor patients if coadministration cannot be avoided.Levodopas therapeutic effect may be reduced with glycopyrrolate administration. Consider increasing the dose of levodopa.. Haloperidols serum level may be decreased when coadministered with glycopyrrolate, resulting in worsening of schizophrenic symptoms, and development of tardive dyskinesia. Closely monitor patients if coadministration cannot be avoided.. Levodopas therapeutic effect may be reduced with glycopyrrolate administration. Consider increasing the dose of levodopa.

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. NDC 0259-0502-16; mg/5mL clear, cherry-flavored solution; 16 oz. bottle.. Store at room temperature 20 25C (68 77F); excursions permitted to 15 30C (59 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Glycopyrrolate is indicated to reduce chronic severe drooling in patients aged to 16 years with neurologic conditions associated with problem drooling (e.g., cerebral palsy).. Glycopyrrolate is an anticholinergic indicated to reduce chronic severe drooling in patients aged 3-16 years with neurologic conditions associated with problem drooling (e.g., cerebral palsy). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information)Advise patients/caregivers to measure glycopyrrolate with an accurate measuring device. household teaspoon is not an accurate measuring device. Patients/caregivers should use dosing cup available in pharmacies to accurately measure the correct milliliter dose. An oral syringe, also available in pharmacies, should be used to dispense glycopyrrolate into the childs mouth from the cup. pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.Administering glycopyrrolate with high fat meal substantially reduces the amount of glycopyrrolate absorbed. Administer glycopyrrolate at least one hour before or two hours after meals.Glycopyrrolate is started at low dose and gradually titrated over period of weeks based on therapeutic response and adverse reactions. Patients/caregivers should not increase the dose without the physicians permission.Common adverse reactions from glycopyrrolate include overly dry mouth, constipation, vomiting, flushing of the skin or face, and urinary retention. Side effects can sometimes be difficult to detect in some patients with neurologic problems who cannot adequately communicate how they feel. If side effects become troublesome after increasing dose, decrease the dose to the prior one and contact your physician.Constipation is the most common side effect of glycopyrrolate, and if constipation occurs, stop administering glycopyrrolate to the patient and call their healthcare practitioner.Inability of the patient to urinate, dry diapers or undergarments, irritability or crying may be signs of urinary retention, and if urinary retention occurs, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner.If the patient develops skin rash, hives or an allergic reaction, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner as this could be sign of hypersensitivity to this product.Drugs like glycopyrrolate can reduce sweating, and if the patient is in hot environment and flushing of the skin occurs this may be due to overheating. Avoid exposure of the patient to hot or very warm environmental temperatures to avoid overheating and the possibility of heat exhaustion or heat stroke.. Advise patients/caregivers to measure glycopyrrolate with an accurate measuring device. household teaspoon is not an accurate measuring device. Patients/caregivers should use dosing cup available in pharmacies to accurately measure the correct milliliter dose. An oral syringe, also available in pharmacies, should be used to dispense glycopyrrolate into the childs mouth from the cup. pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.. Administering glycopyrrolate with high fat meal substantially reduces the amount of glycopyrrolate absorbed. Administer glycopyrrolate at least one hour before or two hours after meals.. Glycopyrrolate is started at low dose and gradually titrated over period of weeks based on therapeutic response and adverse reactions. Patients/caregivers should not increase the dose without the physicians permission.. Common adverse reactions from glycopyrrolate include overly dry mouth, constipation, vomiting, flushing of the skin or face, and urinary retention. Side effects can sometimes be difficult to detect in some patients with neurologic problems who cannot adequately communicate how they feel. If side effects become troublesome after increasing dose, decrease the dose to the prior one and contact your physician.. Constipation is the most common side effect of glycopyrrolate, and if constipation occurs, stop administering glycopyrrolate to the patient and call their healthcare practitioner.. Inability of the patient to urinate, dry diapers or undergarments, irritability or crying may be signs of urinary retention, and if urinary retention occurs, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner.. If the patient develops skin rash, hives or an allergic reaction, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner as this could be sign of hypersensitivity to this product.. Drugs like glycopyrrolate can reduce sweating, and if the patient is in hot environment and flushing of the skin occurs this may be due to overheating. Avoid exposure of the patient to hot or very warm environmental temperatures to avoid overheating and the possibility of heat exhaustion or heat stroke.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for glycopyrrolate and any potential adverse effects on the breastfed infant from glycopyrrolate or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Glycopyrrolate is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Because glycopyrrolate is quaternary amine which does not easily cross the blood-brain barrier, symptoms of glycopyrrolate overdosage are generally more peripheral in nature rather than central compared to other anticholinergic agents. In case of accidental overdose, therapy may include:Maintain an open airway, providing ventilation as necessary.Managing any acute conditions such as hyperthermia, coma and or seizures as applicable, and managing any jerky myoclonic movements or choreoathetosis which may lead to rhabdomyolysis in some cases of anticholinergic overdosage.Administering quaternary ammonium anticholinesterase such as neostigmine to help alleviate-peripheral anticholinergic effects such as anticholinergic induced ileus.Administering activated charcoal orally as appropriate.. Maintain an open airway, providing ventilation as necessary.. Managing any acute conditions such as hyperthermia, coma and or seizures as applicable, and managing any jerky myoclonic movements or choreoathetosis which may lead to rhabdomyolysis in some cases of anticholinergic overdosage.. Administering quaternary ammonium anticholinesterase such as neostigmine to help alleviate-peripheral anticholinergic effects such as anticholinergic induced ileus.. Administering activated charcoal orally as appropriate.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1 mg/5 mL Bottle Carton. NDC: 0259-0502-1616 fl. oz. (473 mL)Glycopyrrolate Oral Solution mg/5 mL (0.2 mg/mL)Rx Only For Oral Use OnlyManufactured for: Merz Pharmaceuticals, LLCManufactured by: Mikart, LLC Atlanta, GA 30318. PRINCIPAL DISPLAY PANEL 1 mg/5 mL Bottle Carton.

PEDIATRIC USE SECTION.

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 years.

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionIn parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery, subjects received either intravenous (IV) or oral glycopyrrolate as premedication. The mean absolute bioavailability of oral glycopyrrolate tablets was low (approximately 3%) and highly variable among subjects (range 1.3 to 13.3%). 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, reflection of the low and highly variable oral bioavailability of glycopyrrolate.Absorption of glycopyrrolate oral solution (fasting) was compared to that of 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 nghr/mL. Mean time to maximum plasma concentration for glycopyrrolate oral solution was 3.1 hours, and mean plasma half-life was 3.0 hours.In healthy adults, high fat meal was shown to significantly affect the absorption of glycopyrrolate oral solution (10 mL, 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. 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 Oral Solution, Fasting and Fed, in Healthy AdultsCmax (ng/mL)Tmax (hrs)AUC0-T (nghr/mL)AUC0-Inf (nghr/mL)T1/2 (hrs)Fasting (n=37)0.318 +- 0.1903.10 +- 1.081.74 +- 1.071.81 +- 1.093.0 +- 1.2Fed (n=36)0.084 +- 0.0812.60 +- 1.120.38 +- 0.140.46 +- 0.13n=35 3.2 +- 1.1 DistributionAfter IV administration, glycopyrrolate has mean volume of distribution in children aged to 14 years of approximately 1.3 to 1.8 L/kg, with 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).. MetabolismIn adult patients who underwent surgery for cholelithiasis and were given 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 small proportion of IV glycopyrrolate is excreted as one or more metabolites.. EliminationApproximately 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.. PediatricsThe estimated apparent clearance of glycopyrrolate from 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 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.. GenderPopulation pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or systemic exposure.. RaceThe pharmacokinetics of glycopyrrolate by race has not been characterized.. ElderlyGlycopyrrolate pharmacokinetics have not been characterized in the elderly.. Renal ImpairmentIn one study, glycopyrrolate mcg/kg was administered intravenously in uremic patients undergoing renal transplantation surgery. Mean AUC (10.6 mcgh/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 ugh/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 ImpairmentGlycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.

POSTMARKETING EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Additional adverse reactions identified during postapproval use of glycopyrrolate tablets include: loss of taste and suppression of lactation.

PREGNANCY SECTION.

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 DataGlycopyrrolate 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 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.

RENAL IMPAIRMENT SUBSECTION.

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)].

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT and CAREGIVER INFORMATION. Glycopyrrolate Oral SolutionPlease read the Patient and Caregiver Information that comes with glycopyrrolate before you start giving it to your child, and each time you get refill. This leaflet does not take the place of talking with your doctor about your childs medical condition or treatment.What is Glycopyrrolate Oral SolutionGlycopyrrolate is prescription medicine used in children with medical conditions that cause too much (abnormal) drooling.Who should not take Glycopyrrolate Oral SolutionDo not give glycopyrrolate to anyone who:has problems urinatinghas bowel problem called paralytic ileuslacks normal bowel tone or tensionhas severe ulcerative colitis or certain other serious bowel problems with severe ulcerative colitishas myasthenia gravisWhat should tell my doctor before giving Glycopyrrolate Oral Solution to my childTell your doctor if your child:has any allergieshas any stomach or bowel problems, including ulcerative colitishas any problems with constipationhas thyroid problemshas high blood pressurehas heart problems or abnormal heart beatshas hiatal hernia with gastroesophageal reflux disease (GERD)has any eye problemshas any problems urinatinghas any other medical conditionsis pregnant or plans to become pregnant. It is not known if glycopyrrolate can harm an unborn baby.is breastfeeding or plans to breastfeed. It is not known if glycopyrrolate passes into breast milk and if it can harm the baby.Tell your doctor about all of the medicines that your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicine may affect the way glycopyrrolate works, and glycopyrrolate may affect how some other medicines work.How should give Glycopyrrolate Oral SolutionGive glycopyrrolate exactly as prescribed by your childs doctor.Give glycopyrrolate hour before or hours after meals.Your doctor will tell you how much (milliliters or mLs) of glycopyrrolate to give your child.Do not change the dose of glycopyrrolate unless your doctor tells you to.You must measure the dose of glycopyrrolate before giving it to your child. Use special marked dose measuring cup (available at most pharmacies) to measure the right dose of glycopyrrolate.To help make sure that your child swallows the dose, you should use an oral syringe to give the child each dose of glycopyrrolate, after you measure the dose needed with dose measuring cup. Oral syringes are also available at most pharmacies.If you have questions about how to measure the dose or how to use an oral syringe, ask your pharmacist or doctor.The dose of glycopyrrolate that is needed to control drooling may be different for each child. Glycopyrrolate is usually started at low dose, and slowly increased as directed by your doctor. This slow increase in dose continues until the best dose for your child is reached, to control drooling.During this time it is important to stay in close contact with your childs doctor, and tell the doctor about any side effects that your child has. See What are the possible side effects of glycopyrrolateWhat should avoid while taking Glycopyrrolate Oral SolutionGlycopyrrolate may cause sleepiness or blurred vision. Do not drive car, operate heavy machinery, or do other dangerous activities while taking glycopyrrolate.Avoid overheating. See What are the possible side effects of glycopyrrolateWhat are the possible side effects of Glycopyrrolate Oral SolutionGlycopyrrolate can cause serious side effects including:Constipation. Constipation is common with glycopyrrolate. Tell your doctor if your child strains with bowel movements, goes longer between bowel movements, cannot have bowel movement, or their stomach is firm and large. The dose of glycopyrrolate may need to be decreased or stopped.Diarrhea and intestinal blockage. Diarrhea can be an early symptom of blockage in the intestine. This is especially true if your child has colostomy or ileostomy. Tell your doctor if your child has any diarrhea while taking glycopyrrolate.Problems with control of body temperature (overheating or heat stroke). Glycopyrrolate can cause your child to sweat less. Your child can become overheated, and develop heat stroke if they are in an area that is very hot. Avoid overheating. Call your doctor right away if your child becomes sick and has any of these symptoms of heatstroke:hot, red skindecreased alertness or passing out (unconsciousness)fast, weak pulsefast, shallow breathingincreased body temperature (fever) The most common side effects of glycopyrrolate include:dry mouthvomitingflushing of the face or skinnasal congestionheadacheswollen sinuses (sinusitis)upper respiratory tract infectionproblems urinating, difficulty starting urinationTell your doctor if your child has any side effect that concerns you or that does not go away. These are not all the possible side effects of glycopyrrolate.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Glycopyrrolate Oral SolutionStore glycopyrrolate between 68F to 77F (20C to 25C).Keep glycopyrrolate out of the reach of children.General information about Glycopyrrolate Oral Solution:Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use glycopyrrolate for condition for which it was not prescribed. Do not give glycopyrrolate to other people even if they have the same condition. It may harm them.This leaflet summarizes the most important information about glycopyrrolate. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about glycopyrrolate that is written for health professionals.For more information, call 1-844-469-6379.What are the ingredients in Glycopyrrolate Oral SolutionActive Ingredient: glycopyrrolateInactive Ingredients: citric acid, glycerin, natural and artificial cherry flavor, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate, sorbitol solution, and purified waterIssued November 2021Manufactured by:Mikart, LLCAtlanta, GA 30318Manufactured for:Merz Pharmaceuticals, LLC Raleigh, NC 27615(C) 2021 Merz Pharmaceuticals, LLCAW01099-00Rev 11/2021. has problems urinating. has bowel problem called paralytic ileus. lacks normal bowel tone or tension. has severe ulcerative colitis or certain other serious bowel problems with severe ulcerative colitis. has myasthenia gravis. has any allergies. has any stomach or bowel problems, including ulcerative colitis. has any problems with constipation. has thyroid problems. has high blood pressure. has heart problems or abnormal heart beats. has hiatal hernia with gastroesophageal reflux disease (GERD). has any eye problems. has any problems urinating. has any other medical conditions. is pregnant or plans to become pregnant. It is not known if glycopyrrolate can harm an unborn baby.. is breastfeeding or plans to breastfeed. It is not known if glycopyrrolate passes into breast milk and if it can harm the baby.. Give glycopyrrolate exactly as prescribed by your childs doctor.. Give glycopyrrolate hour before or hours after meals.. Your doctor will tell you how much (milliliters or mLs) of glycopyrrolate to give your child.. Do not change the dose of glycopyrrolate unless your doctor tells you to.. You must measure the dose of glycopyrrolate before giving it to your child. Use special marked dose measuring cup (available at most pharmacies) to measure the right dose of glycopyrrolate.. To help make sure that your child swallows the dose, you should use an oral syringe to give the child each dose of glycopyrrolate, after you measure the dose needed with dose measuring cup. Oral syringes are also available at most pharmacies.. If you have questions about how to measure the dose or how to use an oral syringe, ask your pharmacist or doctor.. The dose of glycopyrrolate that is needed to control drooling may be different for each child. Glycopyrrolate is usually started at low dose, and slowly increased as directed by your doctor. This slow increase in dose continues until the best dose for your child is reached, to control drooling.. During this time it is important to stay in close contact with your childs doctor, and tell the doctor about any side effects that your child has. See What are the possible side effects of glycopyrrolate. Glycopyrrolate may cause sleepiness or blurred vision. Do not drive car, operate heavy machinery, or do other dangerous activities while taking glycopyrrolate.. Avoid overheating. See What are the possible side effects of glycopyrrolate. Constipation. Constipation is common with glycopyrrolate. Tell your doctor if your child strains with bowel movements, goes longer between bowel movements, cannot have bowel movement, or their stomach is firm and large. The dose of glycopyrrolate may need to be decreased or stopped.. Diarrhea and intestinal blockage. Diarrhea can be an early symptom of blockage in the intestine. This is especially true if your child has colostomy or ileostomy. Tell your doctor if your child has any diarrhea while taking glycopyrrolate.. Problems with control of body temperature (overheating or heat stroke). Glycopyrrolate can cause your child to sweat less. Your child can become overheated, and develop heat stroke if they are in an area that is very hot. Avoid overheating. Call your doctor right away if your child becomes sick and has any of these symptoms of heatstroke:hot, red skindecreased alertness or passing out (unconsciousness)fast, weak pulsefast, shallow breathingincreased body temperature (fever) hot, red skin. decreased alertness or passing out (unconsciousness). fast, weak pulse. fast, shallow breathing. increased body temperature (fever). dry mouth. vomiting. flushing of the face or skin. nasal congestion. headache. swollen sinuses (sinusitis). upper respiratory tract infection. problems urinating, difficulty starting urination.

SPL UNCLASSIFIED SECTION.

5.1 Constipation or Intestinal Pseudo-obstruction. Constipation is 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 dose increase. Intestinal pseudo-obstruction has been reported and may present as abdominal distention, pain, nausea or vomiting.

STORAGE AND HANDLING SECTION.

Store at room temperature 20 25C (68 77F); excursions permitted to 15 30C (59 86F) [See USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric use: The safety and effectiveness of glycopyrrolate has not been established in patients less than years of age. (8.4)Renal impairment: Use glycopyrrolate with caution in patients with renal impairment. (8.6). Pediatric use: The safety and effectiveness of glycopyrrolate has not been established in patients less than years of age. (8.4). Renal impairment: Use glycopyrrolate with caution in patients with renal impairment. (8.6). 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 DataGlycopyrrolate 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 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 SummaryThere 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 mothers 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 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Constipation or intestinal pseudo-obstruction: May present as abdominal distention, pain, nausea, or vomiting. Assess patients for constipation, particularly within 4-5 days of initial dosing or after dose increase. (5.1)Incomplete mechanical intestinal obstruction: May present as diarrhea. If obstruction is suspected, discontinue glycopyrrolate and evaluate. (5.2)High ambient temperature: To reduce the risk of heat prostration, avoid high temperatures. (5.3). Constipation or intestinal pseudo-obstruction: May present as abdominal distention, pain, nausea, or vomiting. Assess patients for constipation, particularly within 4-5 days of initial dosing or after dose increase. (5.1). Incomplete mechanical intestinal obstruction: May present as diarrhea. If obstruction is suspected, discontinue glycopyrrolate and evaluate. (5.2). High ambient temperature: To reduce the risk of heat prostration, avoid high temperatures. (5.3). 5.1 Constipation or Intestinal Pseudo-obstruction. Constipation is 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 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. Glycopyrrolate may produce drowsiness or blurred vision. As appropriate for given age, warn the patient not to engage in activities requiring mental alertness such as operating 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 neuropathyRenal diseaseUlcerative colitis Large doses may suppress intestinal motility to the point of producing paralytic ileus and for this reason may precipitate or aggravate toxic megacolon, serious complication of the diseaseHyperthyroidismCoronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, and hypertensionHiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition. Autonomic neuropathy. Renal disease. Ulcerative colitis Large doses may suppress intestinal motility to the point of producing paralytic ileus and for this reason may precipitate or aggravate toxic megacolon, 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.