GLYCOPYRROLATE_- glycopyrrolate_solution

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. Glycopyrrolate inhibits the action of acetylcholine on salivary glands thereby reducing the extent of salivation. Absorption In a parallel study of children (n=6 per group) aged 7 to 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. 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. 95 L/hr/kg for healthy adults and 8. 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 C max 0-inf max 0-24 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 C max max 0-T 0-T Table 3: Pharmacokinetic Parameters (mean+/-SD) for Glycopyrrolate, Fasting and Fed, in Healthy Adults * n=35 C max (ng/mL ) T max (hrs) AUC 0-T (ng·hr/mL) AUC 0-Inf T 1/2 (hrs) Fasting (n=37) 0. 2 Fed (n=36) 0. 1* Distribution After IV administration, glycopyrrolate has a mean volume of distribution in children aged 1 to 14 years of approximately 1. 8 L/kg, with a range from 0. In adults aged 60 to 75 years, the volume of distribution was lower (0. 42 L/kg +/- 0. 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 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 to 80% of an IV glycopyrrolate dose was eliminated unchanged in urine in adults. In two studies, after IV administration to pediatric patients ages 1 to 14 years, mean clearance values ranged from 1. 41 L/kg/hr (range 0. 22 L/kg/hr). In adults, IV clearance values were 0. 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 mcg·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.

Glycopyrrolate oral solution is indicated to reduce chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling (e. , cerebral palsy). Glycopyrrolate is an anticholinergic indicated to reduce chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling (e.

Glycopyrrolate oral solution 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 to 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 to 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 patient’s caregiver. Glycopyrrolate oral solution 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 oral solution if taken shortly after a meal [see Clinical Pharmacology (12. 3) Table 1: Recommended Dose Titration Schedule (each dose to be given three times daily) Weight Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4 Dose Level 5 kg lbs (~0. 02 mg/kg) (~0. 04 mg/kg) (~0. 06 mg/kg) (~0. 08 mg/kg) (~0. 1 mg/kg) 13 to 17 27 to 38 0. 6 mg 3 mL 0. 2 mg 6 mL 1. 5 mL 18 to 22 39 to 49 0. 4 mg 2 mL 0. 8 mL 4 mL 1. 6 mg 8 mL 2 mg 10 mL 23 to 27 50 to 60 0. 5 mL 1 mg 5 mL 1. 5 mL 2 mg 10 mL 2. 5 mL 28 to 32 61 to 71 0. 6 mg 3 mL 1. 8 mg 9 mL 2. 4 mg 12 mL 3 mg 15 mL 33 to 37 72 to 82 0. 4 mg 7 mL 2. 8 mg 14 mL 3 mg 15 mL 38 to 42 83 to 93 0. 8 mg 4 mL 1. 6 mg 8 mL 2. 4 mg 12 mL 3 mg 15 mL 3 mg 15 mL 43 to 47 94 to 104 0. 5 mL 3 mg 15 mL 3 mg 15 mL >=48 >=105 1 mg 5 mL 2 mg 10 mL 3 mg 15 mL 3 mg 15 mL 3 mg 15 mL Initiate dosing at 0. 02 mg/kg three times daily and titrate in increments of 0. 02 mg/kg every 5 to 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. ( 2 Administer at least one hour before or two hours after meals.

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. The most common adverse reactions (incidence >=30%) are dry mouth, vomiting, constipation, flushing, and nasal congestion. ( 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. gov/medwatch. 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 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 Glycopyrrolate (N=20) Placebo (N=18) 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 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 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.

Glycopyrrolate oral solution is contraindicated in: Patients with medical conditions that preclude anticholinergic therapy (e. , 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 oral solution. Medical conditions that preclude anticholinergic therapy. ( 4 Concomitant use of solid oral dosage forms of potassium chloride.

Pediatric use: The safety and effectiveness of glycopyrrolate has not been established in patients less than 3 years of age. 4 Renal impairment: Use glycopyrrolate with caution in patients with renal impairment. 6 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] 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 AUC 0-inf Glycopyrrolate was intravenously administered to pregnant rabbits at dosages of 0. 5, and 1 mg/kg/day during the period of organogenesis. These dosages resulted in systemic exposures (estimated AUC 0-inf 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 AUC 0-inf Risk Summary Glycopyrrolate was evaluated for chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling. Glycopyrrolate has not been studied in subjects under the age of 3 years. Clinical studies of glycopyrrolate did not include subjects aged 65 and over. Because glycopyrrolate is largely renally eliminated, glycopyrrolate should be used with caution in patients with renal impairment [see Clinical Pharmacology (12.

Drugs Affected by Reduced GI Transit Time Glycopyrrolate 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. , elixir or capsules). Amantadine Drugs Whose Plasma Levels May be Increased by Glycopyrrolate Atenolol’s bioavailability may be increased with coadministration of glycopyrrolate. A reduction in the atenolol dose may be needed. Metformin plasma levels may be elevated with coadministration of glycopyrrolate, increasing metformin’s pharmacologic and toxic effects. Monitor clinical response to metformin with concomitant glycopyrrolate administration; consider a dose reduction of metformin if warranted. Drugs Whose Plasma Levels May be Decreased by Glycopyrrolate Haloperidol’s 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. Levodopa’s therapeutic effect may be reduced with glycopyrrolate administration. Consider increasing the dose of levodopa. 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 a dose increase when used with glycopyrrolate.

OVERDOSAGE
Because glycopyrrolate is a 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 a quaternary ammonium anticholinesterase such as neostigmine to help alleviate-peripheral anticholinergic effects such as anticholinergic induced ileus. Administering activated charcoal orally as appropriate.
NONCLINICAL TOXICOLOGY
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 AUC 0-inf 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 AUC 0-inf
CLINICAL STUDIES
Glycopyrrolate was evaluated in a 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 to 23 years; thirty-six subjects were aged 3 to 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 a 1:1 fashion to receive glycopyrrolate or placebo. Doses of study medication were titrated over a 4-week period to optimal response beginning at 0. 02 mg/kg three times a day increasing doses in increments of approximately 0. 02 mg/kg three times per day every 5 to 7 days, not to exceed the lesser of approximately 0. 1 mg/kg three times per day or 3 mg three times per day. Subjects were evaluated on the 9-point modified Teacher’s Drooling Scale (mTDS), which is presented below. The mTDS evaluations were recorded by parents/caregivers 3 times daily approximately two hours post-dose on evaluation days during pre-treatment baseline and at Weeks 2, 4, 6 and 8 of therapy. Modified Teacher’s Drooling Scale 1= 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; frequently Responders were defined as subjects with at least a 3-point reduction in mean daily mTDS scores from baseline to Week 8. Table 4 presents the proportion of responders at Week 8 and Figure 1 presents the mean mTDS values from baseline through Week 8. Table 4: Percentage of Responders at Week 8 Glycopyrrolate Group Placebo Group (N=20) (N=18) 15/20 (75%) 2/18 (11%) fig1.
PATIENT and CAREGIVER INFORMATION
Glycopyrrolate Oral Solution (GLYE koe PIR oh late) Please read the Patient and Caregiver Information that comes with glycopyrrolate oral solution before you start giving it to your child, and each time you get a refill. This leaflet does not take the place of talking with your doctor about your child’s medical condition or treatment. What is glycopyrrolate oral solution? Glycopyrrolate oral solution is a prescription medicine used in children with medical conditions that cause too much (abnormal) drooling. Who should not take glycopyrrolate oral solution? has problems urinating has a 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 What should I tell my doctor before giving glycopyrrolate oral solution to my child? Tell your doctor if your child: 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 a 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 oral solution 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 How should I give glycopyrrolate oral solution? Give glycopyrrolate oral solution exactly as prescribed by your child’s doctor. Give glycopyrrolate oral solution 1 hour before or 2 hours after meals. Your doctor will tell you how much (milliliters or mLs) of glycopyrrolate oral solution to give your child. Do not change the dose of glycopyrrolate oral solution unless your doctor tells you to. You must measure the dose of glycopyrrolate oral solution before giving it to your child. Use a special marked dose measuring cup (available at most pharmacies) to measure the right dose of glycopyrrolate oral solution. To help make sure that your child swallows the dose, you should use an oral syringe to give the child each dose of glycopyrrolate oral solution, after you measure the dose needed with a 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 oral solution that is needed to control drooling may be different for each child. Glycopyrrolate oral solution is usually started at a 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 child’s doctor, and tell the doctor about any side effects that your child has. See “What are the possible side effects of glycopyrrolate oral solution?” What should I avoid while taking glycopyrrolate oral solution? Glycopyrrolate oral solution may cause sleepiness or blurred vision. Do not drive a car, operate heavy machinery, or do other dangerous activities while taking glycopyrrolate oral solution. Avoid overheating. See “What are the possible side effects of glycopyrrolate oral solution?” What are the possible side effects of glycopyrrolate oral solution? Glycopyrrolate oral solution can cause serious side effects including: Constipation. Diarrhea and intestinal blockage. Problems with control of body temperature (overheating or heat stroke). hot, red skin decreased alertness or passing out (unconsciousness) fast, weak pulse fast, shallow breathing increased body temperature (fever) The most common side effects of glycopyrrolate oral solution include: dry mouth vomiting flushing of the face or skin nasal congestion headache swollen sinuses (sinusitis) upper respiratory tract infection problems urinating, difficulty starting urination Tell 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 oral solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store glycopyrrolate oral solution? Store glycopyrrolate oral solution between 68°F to 77°F (20°C to 25°C). Keep glycopyrrolate oral solution out of the reach of children. General information about glycopyrrolate oral solution: Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use glycopyrrolate oral solution for a condition for which it was not prescribed. Do not give glycopyrrolate oral solution to other people even if they have the same condition. It may harm them. This leaflet summarizes the most important information about glycopyrrolate oral solution. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about glycopyrrolate oral solution that is written for health professionals. For more information, call Aurobindo Pharma USA, Inc. 1-866-850-2876. Aurobindo Pharma USA, Inc. Aurobindo Pharma Limited

Aurobindo Pharma Limited

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