AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Glycopyrrolate

Glycopyrrolate is a synthetic quaternary ammonium antimuscarinic.365,366,367,368,369

Chronic Obstructive Pulmonary Disease

Glycopyrrolate

Glycopyrrolate is used alone or in fixed combination with formoterol fumarate or indacaterol for the long-term maintenance treatment of airflow obstruction associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.368,369,373,374,375 Glycopyrrolate is not indicated for the treatment of acute bronchospasm.368,369

Efficacy of glycopyrrolate oral inhalation powder has been evaluated in 2 randomized, double-blind, placebo-controlled, parallel-group trials in 867 adults 40 years of age or older with moderate to severe COPD.368,373,374 Patients were randomized to receive glycopyrrolate 15.6 mcg or placebo twice daily and were allowed to use their prescribed inhaled corticosteroid therapy.368,373,374 The primary outcome measure was the change from baseline in forced expiratory volume in 1 second (FEV₁) area under the curve (AUC) from 0-12 hours following the morning dose on day 85.368,373,374 In both trials, patients receiving glycopyrrolate experienced a greater change from baseline in FEV₁ AUC from 0-12 hours (treatment difference of 123-139 mL) compared with patients receiving placebo.368,373,374

Efficacy of glycopyrrolate oral inhalation solution has been evaluated in 2 randomized, double-blind, placebo-controlled, parallel-group trials in adults 40 years of age or older with COPD.369 Patients also had preexisting or concurrent cardiovascular disease.369 Patients were randomized to receive glycopyrrolate (25 or 50 mcg) or placebo twice daily and were allowed to use their prescribed respiratory medications (i.e., long-acting β₂-adrenergic agonists, with or without inhaled corticosteroids, and short-acting antimuscarinics).369 The primary outcome measure was the change from baseline in trough FEV₁ on day 84.369 In both trials, patients receiving glycopyrrolate experienced a greater change from baseline in trough FEV₁ compared with patients receiving placebo; the change from baseline in trough FEV₁ in patients receiving glycopyrrolate 25 mcg twice daily was 89-92 mL greater than that in patients receiving placebo.369 The additional benefit observed with glycopyrrolate 50 mcg twice daily compared with 25 mcg twice daily was not sufficient to warrant use of the higher dosage.369

Fixed Combination of Glycopyrrolate and Formoterol Fumarate

Glycopyrrolate in fixed combination with formoterol fumarate (glycopyrrolate/formoterol) is used as an oral inhalation aerosol for the long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.371,377 The fixed combination containing glycopyrrolate and formoterol fumarate is not indicated for the treatment of acute bronchospasm.371 The fixed combination also is not indicated for the treatment of asthma; safety and efficacy in asthma have not been established.371

Efficacy of glycopyrrolate in fixed combination with formoterol fumarate has been evaluated in 2 randomized, double-blind, placebo-controlled, parallel-group studies of 24 weeks' duration in 3699 patients 40 years of age or older with moderate to very severe COPD.371,377 Patients were randomized to receive orally inhaled glycopyrrolate/formoterol (glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg), glycopyrrolate 18 mcg alone, formoterol fumarate 9.6 mcg alone, or placebo twice daily and were allowed to use their prescribed respiratory medications (i.e., inhaled corticosteroids and/or phosphodiesterase type 4 inhibitors).371,377 The primary outcome measure was change from baseline in trough FEV₁ at week 24.371,377 In both trials, the change from baseline in trough FEV₁ at 24 weeks was greater in patients receiving glycopyrrolate/formoterol compared with patients receiving either drug alone or placebo.371,377

Fixed Combination of Glycopyrrolate and Indacaterol

Glycopyrrolate in fixed combination with indacaterol (glycopyrrolate/indacaterol) is used as an oral inhalation powder for the long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.370,376 The fixed combination containing glycopyrrolate and indacaterol is not indicated for the treatment of acute bronchospasm.370 The fixed combination is not indicated for the treatment of asthma; safety and efficacy in asthma have not been established.370

Efficacy of glycopyrrolate in fixed combination with indacaterol has been evaluated in 2 randomized, double-blind, placebo- and active-controlled studies of 12 weeks' duration in 2038 patients 40 years of age or older with moderate to severe COPD.370,376 Patients were randomized to receive therapy with orally inhaled glycopyrrolate 15.6 mcg/indacaterol 27.5 mcg in fixed combination, glycopyrrolate 15.6 mcg alone, indacaterol 27.5 mcg alone, or placebo twice daily and were allowed to use their prescribed inhaled corticosteroid therapy.370,376 The primary outcome measure was the change from baseline in FEV₁ AUC from 0-12 hours following the morning dose on day 85.370,376 Following administration of orally inhaled glycopyrrolate 15.6 mcg in fixed combination with indacaterol 27.5 mcg twice daily, the change from baseline in FEV₁ AUC from 0-12 hours following the morning dose on day 85 was larger than that observed with either drug alone or placebo in both trials.370,376

Drooling

Glycopyrrolate oral solution is used for the symptomatic management of chronic severe drooling in pediatric patients 3-16 years of age with neurologic conditions (e.g., cerebral palsy) associated with problematic drooling.367,372

In one randomized, placebo-controlled trial, 36 patients 3-16 years of age and 2 patients older than 16 years of age with cerebral palsy, mental retardation, or other neurologic conditions associated with problematic drooling (i.e., drooling in the absence of treatment so that clothing is damp approximately 5-7 days per week) achieved a clinical response (defined as at least a 3-point reduction in mean daily scores on the 9-point modified Teacher's Drooling Scale [mTDS]) following therapy with glycopyrrolate oral solution.367 Dosages of glycopyrrolate were titrated over a 4-week period to optimal patient response starting at 0.02 mg/kg 3 times daily with increasing dosage increments of approximately 0.02 mg/kg 3 times daily every 5-7 days, not to exceed the lesser of approximately 0.1 mg/kg 3 times daily or 3 mg per dose 3 times daily.367 Following 8 weeks of therapy, a positive response was observed in 75 or 11% of patients receiving glycopyrrolate oral solution or placebo, respectively.367

Peptic Ulcer Disease

Glycopyrrolate is used orally or parenterally as an adjunct in the treatment of peptic ulcer disease.365,366 Glycopyrrolate injection is used in patients with peptic ulcer disease when rapid antimuscarinic effect is desired or oral therapy is not tolerated.365 As with other antimuscarinics, there are no conclusive data from well-controlled studies which indicate that, in usually recommended dosage, glycopyrrolate aids in the healing, decreases the rate of recurrence, or prevents complications of peptic ulcers. In addition, in patients with gastric ulcer, antimuscarinics may delay gastric emptying and result in antral stasis.365 With the advent of more effective therapies for the treatment of peptic ulcer disease, antimuscarinics have only limited usefulness in this condition. (See Uses: Peptic Ulcer Disease and GI Hypersecretory States, in the Antimuscarinics/Antispasmodics General Statement 12:08.08)

Surgery

Glycopyrrolate injection is used parenterally as a preoperative medication to inhibit salivation and excessive secretions of the respiratory tract;365 however, the current practice of using thiopental (no longer commercially available in the US), halothane, or similar general anesthetics that do not stimulate the production of salivary or tracheobronchial secretions has reduced the need to control excessive respiratory secretions during surgery. Although glycopyrrolate injection has been used prophylactically to prevent acid-aspiration pneumonitis during surgery, antimuscarinics, including glycopyrrolate, have not been shown to be effective for this use. Glycopyrrolate injection may be used to prevent cholinergic effects during surgery, such as cardiac arrhythmias, hypotension, and bradycardia, which may result from traction on viscera (with resultant vagal stimulation), stimulation of the carotid sinus, or administration of drugs (e.g., succinylcholine).365 Glycopyrrolate injection is administered concurrently with anticholinesterase agents (e.g., neostigmine, pyridostigmine) to block the adverse muscarinic effects of these latter agents when they are used after surgery to terminate curarization.365 Unlike atropine or hyoscyamine (tertiary amine antimuscarinics), glycopyrrolate (quaternary ammonium antimuscarinic) does not readily penetrate the CNS365 and therefore will not reverse the central effects of physostigmine. Because glycopyrrolate does not have appreciable CNS effects, it may be preferred in some patients.365 For further discussion on the use of glycopyrrolate injection in surgery, see Uses: Surgery, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Administration

Glycopyrrolate is administered orally,366,367 IM, IV,365 or by oral inhalation.368,369,370,371

Oral Administration

Glycopyrrolate is administered orally as tablets366 or an oral solution.367

When the oral solution is used, it should be administered at least 1 hour before or 2 hours after meals.367 An accurate measuring device must be used to administer the oral solution.367

Parenteral Administration

For preoperative IM administration, glycopyrrolate may be administered in the same syringe with other compatible preoperative medications.

For IV administration, glycopyrrolate may be given by direct IV injection.365 Alternatively, glycopyrrolate may be administered via the tubing of a running IV infusion of 0.9% sodium chloride.365 When used concomitantly with neostigmine,365 physostigmine, or pyridostigmine,365 glycopyrrolate may be administered IV simultaneously with the anticholinesterase agent via the same syringe.365 (See Chemistry and Stability: Stability.)

Because glycopyrrolate injection contains benzyl alcohol as a preservative, the manufacturer recommends that the drug not be used in neonates younger than 1 month of age.365 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.359,360,361,362,363,364,365 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.359,360,361,362,363,364,365 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.359

Oral Inhalation via Dry-Powder Inhaler

Glycopyrrolate oral inhalation powder (Seebri^® Neohaler^®) is administered by oral inhalation only using a special oral inhalation device (Neohaler^®) that delivers powdered drug from capsules.368 Glycopyrrolate capsules for oral inhalation must not be taken orally (i.e., swallowed), as the intended effects on the lungs will not be obtained.368

Glycopyrrolate in fixed combination with indacaterol (glycopyrrolate/indacaterol; Utibron^® Neohaler^®) is administered by oral inhalation only using a special oral inhalation device (Neohaler^®) that delivers powdered drug from capsules.370 Glycopyrrolate/indacaterol capsules for oral inhalation must not be taken orally (i.e., swallowed), as the intended effects on the lungs will not be obtained.370

The Neohaler^® device should not be used to administer other drugs.368,370 The Neohaler^® device provided with each new prescription of glycopyrrolate or glycopyrrolate/indacaterol should be used to administer the drug.368,370 The capsules containing oral inhalation powder should be stored in the foil-wrapped sealed blisters, and only one capsule should be removed immediately before use; any unused additional capsules that are exposed to air should be discarded.368,370

To obtain optimal benefit, the patient should be given a copy of the patient information and instructions for use provided by the manufacturer.368,370 To use the Neohaler^® device, the cap should be removed, then the inhaler should be opened by holding the base firmly and tilting the mouthpiece.368,370 One blister should be separated from the blister card by tearing along the perforation.368,370 The protective backing should be pulled away to expose one capsule immediately before use; the capsule should not be pushed through the foil to remove it from the blister.368,370 The capsule should be removed from the blister with dry hands and placed into the capsule chamber of the device; the capsule should not be placed into the mouthpiece of the device.368,370 The inhaler should be closed fully until a click is heard.368,370 The inhaler should be held upright with the mouthpiece pointing upward, and both piercing buttons should be pressed together firmly at the same time only once (a click will be heard), then the piercing buttons should be released fully.368,370 Piercing the capsule may produce very small pieces, which may pass into the mouth; the pieces should not cause any harm if swallowed or inhaled.368,370

Before inhaling the dose, the patient should exhale completely, being careful not to exhale into the mouthpiece of the Neohaler^® device.368,370 The inhaler device should be held horizontally (piercing buttons facing left and right) and the mouthpiece placed in the mouth, with the lips closed firmly around it.368,370 The patient should then inhale rapidly, but steadily and as deeply as possible, without pressing the piercing buttons.368,370 During inhalation, a whirring noise created by the capsule spinning around in the chamber should be heard; a sweet flavor also may be detected.368,370 The patient should continue holding their breath for at least 5-10 seconds or as long as comfortably possible while removing the inhaler from the mouth, and then should exhale.368,370 The inhaler should be opened to see if any powder is left in the capsule.368,370 If powder remains, the inhaler should be closed and the steps for inhaling the drug should be repeated.368,370 Most patients are able to empty the capsule with 1 or 2 inhalations.368,370 Coughing may occur soon after inhaling the dose; however, coughing does not interfere with delivery of the full dose as long as the capsule is empty.368,370 After inhaling the dose, the mouthpiece should be opened and the device tipped to dispose of the used capsule, then the inhaler should be closed and the cap replaced.368,370 Used capsules should not be left in the device.368,370

If a whirring noise is not heard during inhalation of the drug, the capsule may be stuck in the capsule chamber.368,370 If this occurs, the inhaler should be opened and the capsule carefully loosened by tapping the base of the inhaler; the piercing buttons should not be pressed.368,370 The steps to inhale the drug should then be repeated.368,370

Routine cleaning of the inhaler is not necessary; if desired, the mouthpiece may be cleaned inside and outside with a clean, dry, lint-free cloth, or a clean, dry, soft brush may be used to wipe the inhaler and remove any powder residue.368,370 The inhaler should be kept dry, and the device should not be taken apart.368,370

Oral Inhalation via Solution

Glycopyrrolate oral inhalation solution (Lonhala^® Magnair^®) is administered by oral inhalation via nebulization only using a special oral inhalation device (Magnair^® nebulizer system).369 Glycopyrrolate solution for oral inhalation must not be injected or taken orally (i.e., swallowed), as the intended effects on the lungs will not be obtained.369

The Magnair^® nebulizer system should not be used to administer other drugs.369 The Magnair^® nebulizer system provided in the starter kit and the replacement handset provided with each new prescription should be used to administer the drug.369 The single-dose vials of glycopyrrolate oral inhalation solution should be stored in the sealed foil pouch; any unused vials should be discarded 7 days after the pouch is first opened.369

Prior to administration of glycopyrrolate oral inhalation solution for nebulization, the Magnair^® nebulizer system should be assembled according to the manufacturer's directions and checked to ensure it is working properly.369 To obtain optimal benefit, the patient should be given a copy of the patient information and instructions for use provided by the manufacturer.369

Immediately prior to use, the foil pouch should be opened and the two vials of oral inhalation solution removed and separated; one vial should be returned to the foil pouch and stored in the nebulizer system carrying bag.369 The vial to be used should be inserted into the bottom of the medication cap until it clicks.369 The medication cap with the vial should then be placed on top of the handset body (with the aerosol head already inserted without touching the part that pierces the vial) and turned in a clockwise direction until a click is heard.369 The notch in the medication cap should line up with the blue line on the handset body.369

To administer the treatment, the mouthpiece should be inserted into the mouth and the on/off button on the controller pressed.369 During the treatment, which should take about 2-3 minutes, the patient should breathe normally through the mouthpiece.369 Care should be taken to avoid tilting the handset, loosening or removing the medication cap, or unclasping the handset body until the treatment is complete.369 At the end of the treatment, a beep will sound and the controller will shut off automatically.369 After each treatment, the manufacturer's instructions for cleaning the handset should be followed.369

Oral Inhalation via Aerosol

Glycopyrrolate in fixed combination with formoterol fumarate (glycopyrrolate/formoterol; Bevespi^® Aerosphere^®) is administered by oral inhalation using an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant.371 The glycopyrrolate/formoterol oral inhalation aerosol should only be used with the actuator supplied with the product.371

The aerosol inhaler should be primed by releasing 4 test sprays into the air (away from the face) before initial use, and shaken well before each test spray.371 If the inhaler has not been used for more than 7 days, the priming process should be repeated (using only 2 sprays rather than 4).371 To administer a dose, the cap should be removed from the mouthpiece.371 Before each inhalation, the inhaler must be shaken well.371 The inhaler should be held with the mouthpiece pointing towards the face while the patient exhales through the mouth as fully and comfortably as possible.371 The lips should be closed around the mouthpiece and the head tilted back, keeping the tongue below the mouthpiece.371 While inhaling slowly and deeply, the center of the dose indicator should be pressed down until the canister stops moving in the actuator and a spray has been released, then the dose indicator should be released.371 Following inhalation, the mouthpiece should be removed from the mouth and the breath held as long as comfortably possible (up to 10 seconds) then the patient should exhale gently.371 The process should be repeated for the second inhalation.371 The cap should be replaced on the mouthpiece immediately after use.371

The Bevespi^® Aerosphere^® inhaler should be cleaned once weekly by removing the canister from the actuator; the canister should not be cleaned or allowed to get wet.371 The actuator should be held under warm running water for about 30 seconds.371 The actuator should then be turned upside down and water rinsed through the actuator again for about 30 seconds.371 The actuator should be allowed to dry overnight.371 When the actuator is dry, the canister should be pressed gently down into it; however, the canister should not be pressed down too hard since this may cause drug to be released.371 Priming of the inhaler should be repeated after each cleaning by shaking well and releasing 2 test sprays into the air away from the face.371 The inhaler should be discarded when the labeled number of inhalations has been used or within 3 months after removal from the foil pouch or when the dose indicator reads “0,” whichever comes first.371 The canister should never be immersed in water to determine the amount of drug remaining in the canister (“float test”).371

Dosage

Each capsule of glycopyrrolate oral inhalation powder (Seebri^® Neohaler^®) contains 15.6 mcg of glycopyrrolate.368 However, the actual amount of drug delivered to the lungs depends on factors such as the patient's inspiratory flow rate and inspiratory time.368 Under standardized in vitro testing at a fixed flow rate of 90 L/minute for 1.3 seconds, the Neohaler^® device delivered 13.1 mcg from the 15.6-mcg capsule (equivalent to 12.5 mcg of glycopyrronium) from the mouthpiece.368

Each capsule of glycopyrrolate/indacaterol oral inhalation powder (Utibron^® Neohaler^®) contains 15.6 mcg of glycopyrrolate and 27.5 mcg of indacaterol.370 However, the actual amount of drug delivered to the lungs depends on factors such as the patient's inspiratory flow rate and inspiratory time.370 Under standardized in vitro testing at a fixed flow rate of 90 L/minute for 1.3 seconds, the Neohaler^® device delivered 12.8 mcg of glycopyrrolate (equivalent to 12.5 mcg of glycopyrronium) and 20.8 mcg of indacaterol from the mouthpiece.370

Each single-dose vial of glycopyrrolate oral inhalation solution (Lonhala^® Magnair^®) contains 25 mcg of glycopyrrolate in 1 mL of solution.369 However, the actual amount of drug delivered to the lungs depends on patient factors.369 Under standardized in vitro testing, the Magnair^® device delivered approximately 14.2 mcg of glycopyrrolate (equivalent to 11.4 mcg of glycopyrronium) from the mouthpiece.369

After priming of the oral aerosol inhaler containing glycopyrrolate/formoterol, each actuation of the oral aerosol inhaler (Bevespi^® Aerosphere^®) delivers 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) and 5.5 mcg of formoterol fumarate from the valve.371 Dosage is expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 9 mcg of glycopyrrolate (equivalent to 7.2 mcg of glycopyrronium) and 4.8 mcg of formoterol fumarate from the mouthpiece.371 The actual amount of drug delivered to the lungs depends on factors such as the patient's coordination between actuation of the device and inspiration through the delivery system.371 Commercially available glycopyrrolate/formoterol aerosol inhaler delivers 28 or 120 metered sprays per 5.9- or 10.7-g canister, respectively.371

Chronic Obstructive Pulmonary Disease

Glycopyrrolate

For the long-term management of airflow obstruction associated with chronic obstructive pulmonary disease (COPD), the usual dosage of glycopyrrolate oral inhalation powder in adults is 15.6 mcg (the contents of one capsule) twice daily via the Neohaler^® device.368 More frequent administration or higher dosages are not recommended.368 Orally inhaled glycopyrrolate powder should not be used for the treatment of acute episodes of bronchospasm.368

For the long-term management of airflow obstruction associated with COPD, the usual dosage of glycopyrrolate oral inhalation solution in adults is 25 mcg (the contents of one single-dose vial) twice daily via the Magnair^® device.369 More frequent administration or higher dosages are not recommended.369 Orally inhaled glycopyrrolate solution should not be used for the treatment of acute episodes of bronchospasm.369

Fixed Combination of Glycopyrrolate and Formoterol Fumarate

For the long-term management of airflow obstruction associated with COPD, the usual dosage of glycopyrrolate in fixed combination with formoterol fumarate in adults is 18 mcg of glycopyrrolate and 9.6 mcg of formoterol fumarate (two inhalations of preparation containing 9 mcg of glycopyrrolate and 4.8 mcg of formoterol fumarate) twice daily via the Aerosphere^® device.371 More frequent administration or higher dosages are not recommended.371 Orally inhaled glycopyrrolate/formoterol should not be used for the treatment of acute episodes of bronchospasm.371

Fixed Combination of Glycopyrrolate and Indacaterol

For the long-term management of airflow obstruction associated with COPD, the usual dosage of glycopyrrolate in fixed combination with indacaterol in adults is 15.6 mcg of glycopyrrolate and 27.5 mcg of indacaterol (the contents of one capsule) twice daily via the Neohaler^® device.370 More frequent administration or higher dosages are not recommended.370 Orally inhaled glycopyrrolate/formoterol should not be used for the treatment of acute episodes of bronchospasm.370

Drooling

The initial recommended dosage of glycopyrrolate oral solution for the symptomatic management of chronic severe drooling in pediatric patients 3-16 years of age with neurologic conditions (e.g., cerebral palsy) associated with problematic drooling is 0.02 mg/kg 3 times daily; dosage may be titrated in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and tolerance.367 During dosage titration, tolerability of the current dose should be reviewed with the patient's caregiver prior to each increase in dosage.367 The maximum recommended dosage is 0.1 mg/kg 3 times daily (not to exceed 1.5-3 mg per dose based on weight).367

Peptic Ulcer Disease

The usual initial oral dosage of glycopyrrolate tablets for the adjunctive treatment of peptic ulcer disease in adults is 1 mg 3 times daily, in the morning, early afternoon, and at bedtime.366 Some patients may require 2 mg at bedtime to ensure overnight control of symptoms.366 Alternatively, an oral dosage for adults of 2 mg 2 or 3 times daily, given at equally spaced intervals, may be used.366 A maintenance dosage of 1 mg twice daily is adequate in most adults.366 The maximum adult oral dosage is 8 mg daily.366

The usual IM or IV dosage of glycopyrrolate for the adjunctive treatment of peptic ulcer disease in adults is 0.1 mg, administered every 4 hours, 3 or 4 times daily.365 When a more profound antimuscarinic effect is desired, 0.2 mg may be given IM or IV.365 Some patients may only require a single dose, and frequency of parenteral administration should be determined by the patient's response up to a maximum of 4 doses daily.365

As with other antimuscarinics, higher than recommended dosage may be required for therapeutic effect in patients with peptic ulcer disease. Dosage should be carefully titrated until therapeutic effect is achieved or adverse effects become intolerable, using the lowest possible effective dosage.366

Safety and efficacy of oral or parenteral glycopyrrolate for the treatment of peptic ulcer disease in pediatric patients have not been established;365,366 the tablets are not recommended in children younger than 12 years of age.365,366

Surgery

As a preoperative medication in adults or children 2 years of age and older, the usual dose of glycopyrrolate is 0.004 mg/kg, administered IM 30-60 minutes prior to the anticipated time of induction of anesthesia or at the time other preanesthetic medications (e.g., opiates, sedatives) are administered.365 Children 1-24 months of age may require a preoperative dose up to 0.009 mg/kg.365

When intraoperative use of glycopyrrolate is necessary to prevent cholinergic effects during surgery in adults or children, the usual IV dose is 0.1 mg or 0.004 mg/kg (not to exceed 0.1 mg), respectively; if necessary, the dose may be repeated at 2- to 3-minute intervals.365 Because of the long duration of antimuscarinic effects of the preoperative dose, intraoperative doses of glycopyrrolate are rarely needed in children.365

To block adverse muscarinic effects of anticholinesterase agents (i.e., neostigmine, pyridostigmine) when these agents are used to reverse the neuromuscular blockade produced by curariform agents in adults or children, the usual IV dose of glycopyrrolate is 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine administered; glycopyrrolate is administered concurrently in the same syringe with the anticholinesterase agent.365 Some clinicians recommend that, in the presence of bradycardia, antimuscarinics be administered IV before the anticholinesterase agent to increase the pulse rate to about 80 beats/minute.

Pharmacokinetics

Absorption

Glycopyrrolate, like other quaternary ammonium drugs, is incompletely absorbed from the GI tract since it is completely ionized;367 however, the rate and extent of absorption of glycopyrrolate following oral administration have not been fully characterized. Following administration of oral glycopyrrolate tablets in children, mean absolute bioavailability was low (about 3%) and variable (range 1-13%).367 The mean time to peak plasma glycopyrrolate concentrations following administration of the oral solution is about 3 hours.367 Administration with a high-fat meal has been shown to decrease the absorption of glycopyrrolate following administration of the oral solution; the oral solution should be administered at least 1 hour before or 2 hours after meals.367

Following oral inhalation of glycopyrrolate powder via the Neohaler^® device, the drug is rapidly absorbed with peak plasma concentrations occurring at 5 minutes.368 Following oral inhalation of the powder, the absolute bioavailability is about 40%, with 90% of systemic exposure resulting from lung absorption and 10% from GI absorption.368 Steady-state concentrations are achieved within 1 week with repeated once-daily oral inhalation; changes in glycopyrrolate pharmacokinetics over time have not been observed.368 Linear pharmacokinetics were observed following oral inhalation dosages of 31.2-249.6 mcg daily.368

Following oral inhalation of glycopyrrolate solution via the Magnair^® nebulizer system, the drug is rapidly absorbed with peak plasma concentrations occurring within 20 minutes.369 Steady-state plasma concentrations are achieved within 1 week of repeated twice-daily oral inhalation; 2- to 3-fold accumulation of systemic glycopyrrolate exposure has been observed at steady state following twice-daily dosing.369

Following IV administration of glycopyrrolate, the drug has an onset of action of about 1 minute.365 Following IM injection, pharmacologic effects are evident within 15-30 minutes and peak within 30-45 minutes.365 The vagal blocking effects of the drug persist for 2-3 hours and inhibition of salivation persists for up to 7 hours after parenteral administration of the drug.365 Following oral administration, the anticholinergic effects of glycopyrrolate may persist for up to 8-12 hours.

Distribution

Little information is available on the distribution of glycopyrrolate. Quaternary ammonium antimuscarinics are completely ionized and possess poor lipid solubility.365,366 Accordingly they do not readily penetrate the CNS or eye.365,366

Following IV administration of glycopyrrolate in animals, the drug is rapidly distributed throughout the body with highest concentrations appearing in the stomach and intestine. Following IV administration of a single 0.1 mg/kg dose of radiolabeled glycopyrrolate in dogs, peak CSF concentrations of the drug were 0.9 ng/mL, about 10% of the peak serum concentration. Glycopyrrolate is distributed into bile. Following surgery for cholelithiasis in patients who had T-tube drains placed into the common bile duct, peak biliary concentrations of drug were reached within 30-60 minutes after IV administration and persisted for up to 48 hours in some patients.

In vitro, plasma protein binding of 38-41% has been reported at concentrations of 1-10 ng/mL following IV administration.368,369

Glycopyrrolate crosses the placental barrier to a limited extent.365 Following IV administration of a single 0.1 mg/kg dose of radiolabeled drug in pregnant dogs, peak fetal concentrations were 0.63 ng/mL, about 4% of the peak maternal serum concentration. It is not known if glycopyrrolate distributes into milk.365

Elimination

Following IV administration of glycopyrrolate, serum concentrations of the drug decline rapidly, with less than 10% of the dose remaining in serum after 5 minutes and essentially no drug remaining during the period of 0.5-3 hours after administration. Following IV administration, the elimination half-life of glycopyrrolate is approximately 50 minutes, 19-99 minutes, and 22-130 minutes in adults, children, and infants, respectively.365 Following IM administration in adults, the elimination half-life is 33-75 minutes.365

Following administration of the oral solution, a mean elimination half-life of 3 hours was reported.367

Following oral inhalation of glycopyrrolate powder via the Neohaler^® device, a mean elimination half-life of 33-53 hours was reported.368

In vitro studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9).368,369 Multiple cytochrome P-450 (CYP) isoenzymes appear to contribute to the oxidative biotransformation of glycopyrrolate; hydrolysis to M9 is likely catalyzed by members of the cholinesterase family presystemically and/or via first-pass metabolism from the swallowed dose fraction of orally inhaled drug.368,369 Following repeated oral inhalation, glucuronide and/or sulfate conjugates, accounting for about 3% of the inhaled dose, were found in urine.368 Renal elimination of parent drug accounts for about 60-70% of systemically available glycopyrrolate following oral inhalation; active tubular secretion contributes to renal clearance.368,369 Nonrenal clearance is mainly thought to result from metabolism, with biliary clearance contributing a small role.368,369

Small amounts of IV glycopyrrolate are metabolized to one or more metabolites.367 Glycopyrrolate is excreted mainly as unchanged drug in feces via biliary elimination and in urine.365 In adults, approximately 65-80% of an IV dose was eliminated in urine as unchanged drug.367 In animals, 70-90% of a dose was eliminated in feces. Following IV administration of the drug in patients who had undergone surgery for cholelithiasis, about 85% of the dose was excreted in urine within 48 hours and less than 5% of the dose was distributed into T-tube drainage of bile, principally as unchanged drug.367

In patients undergoing renal transplantation receiving IV glycopyrrolate, the half-life was prolonged to 47 minutes compared with 19 minutes in healthy individuals.365 Elimination of glycopyrrolate appears to be severely impaired in patients with renal failure.367 In patients receiving glycopyrrolate by oral inhalation, total systemic glycopyrrolate exposure increased by up to 1.4- or 2.2-fold, respectively, in those with mild to moderate (estimated glomerular filtration rate [GFR] greater than or equal to 30 mL/minute) or severe to end-stage renal impairment (estimated GFR less than 30 mL/minute).368

Pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.367,368

There is no evidence that age, body weight, race, gender, or smoking status has any effect on the pharmacokinetics of glycopyrrolate oral inhalation powder.368

Chemistry and Stability

Chemistry

Glycopyrrolate is a synthetic quaternary ammonium antimuscarinic.365,366 Glycopyrrolate is an aminoalcohol ester. The drug occurs as a white, crystalline powder and has solubilities of approximately 238 mg/mL in water and 33.3 mg/mL in alcohol at 25°C.

Commercially available glycopyrrolate for injection is a clear, colorless, sterile solution of the drug in water for injection.365 Sodium hydroxide and/or hydrochloric acid may be added during the manufacture of the injection to adjust the pH to 2-3.365 Commercially available glycopyrrolate injection also contains 0.9% benzyl alcohol as a preservative.365

Stability

Commercially available glycopyrrolate injection should be stored in single-dose or multiple-dose containers, preferably of USP Type I glass, at controlled room temperature between 20 and 25°C.365 .

Glycopyrrolate is stable under ordinary conditions of temperature, heat, and light. The drug is most stable at an acid pH. Glycopyrrolate is unstable at a pH greater than 6.365 Ester hydrolysis is the major cause of decomposition of glycopyrrolate; the rate of hydrolysis increases with increasing pH.

Solutions containing glycopyrrolate concentrations of 0.8 mg/L are stable for 48 hours at room temperature in the following IV infusion solutions: 5% dextrose, 5% dextrose and 0.45% sodium chloride, 0.9% sodium chloride, or Ringer's injection.365,378

The manufacturer of glycopyrrolate injection states that the drug is stable in dextrose 10% solution.365 In addition, the manufacturer states that glycopyrrolate may be administered via the tubing of a running IV infusion of 0.9% sodium chloride.365

When combined in the same syringe, admixtures containing glycopyrrolate have been reported to be stable for 48 hours at room temperature with the following injections: atropine sulfate, chlorpromazine hydrochloride, codeine phosphate, diphenhydramine hydrochloride, droperidol, droperidol and fentanyl citrate (Innovar^®, no longer commercially available in the US), hydromorphone hydrochloride, hydroxyzine hydrochloride, levorphanol tartrate, lidocaine hydrochloride, meperidine hydrochloride, meperidine hydrochloride and promethazine hydrochloride (Mepergan^®, no longer commercially available in the US), morphine sulfate, neostigmine methylsulfate, oxymorphone hydrochloride, procaine hydrochloride (no longer commercially available in the US), prochlorperazine edisylate, promazine hydrochloride (no longer commercially available in the US), promethazine hydrochloride, propiomazine hydrochloride (no longer commercially available in the US), pyridostigmine bromide, scopolamine hydrobromide, triflupromazine hydrochloride (no longer commercially available in the US), or trimethobenzamide hydrochloride.365

In addition, when combined in the same syringe, the manufacturer states that admixtures containing glycopyrrolate injection are reported to be stable with the following injections: butorphanol tartrate, fentanyl citrate, nalbuphine hydrochloride, and physostigmine salicylate.365

Since the compatibility of these and other admixtures with glycopyrrolate depends on several factors (e.g., concentration of the drugs, resulting pH, temperature), specialized references should be consulted for the specific conditions of compatibility. Chloramphenicol, dexamethasone sodium phosphate, diazepam, dimenhydrinate, methohexital sodium, pentazocine lactate, pentobarbital sodium, secobarbital sodium, sodium bicarbonate, or thiopental sodium (no longer commercially available in the US) are incompatible with glycopyrrolate when combined in the same syringe.365 Glycopyrrolate is physically incompatible with drugs having an alkaline pH; a gas may evolve or precipitation may occur if the drugs are mixed.365 Admixture with other drugs or solutions that results in a pH greater than 6 (e.g., dexamethasone sodium phosphate, a buffered solution of lactated Ringer's injection) will usually cause rapid ester hydrolysis of glycopyrrolate; however, glycopyrrolate may be administered via the tubing of a running IV infusion of lactated Ringer's injection.365,378

Commercially available glycopyrrolate tablets should be stored in tight containers at 20-25°C (may be exposed to 15-30°C).366

Commercially available glycopyrrolate oral solution containing 1 mg of glycopyrrolate per 5 mL should be stored at 20-25°C (may be exposed to 15-30°C).367

Commercially available dry-powder capsules for oral inhalation containing glycopyrrolate alone or in fixed combination with indacaterol (glycopyrrolate/indacaterol) should be stored at 25°C (may be exposed to 15-30°C).368,370 The capsules should be stored in the foil-sealed blisters until immediately before use.368,370 Only one capsule should be removed immediately before use or effectiveness of the drug may be reduced.368,370 Capsules should be discarded if opened and exposed to air (i.e., not used immediately).368,370

Commercially available single-dose vials containing glycopyrrolate oral inhalation solution should be stored at 20-25°C.369 Single-dose vials should be stored in the protective foil pouch.369 After the pouch is opened, unused vials should be returned to the pouch for stora any vials not used within 7 days of opening the pouch should be discarded.369 Any vial containing solution that is not colorless should be discarded.369

Commercially available oral inhalation aerosol containing glycopyrrolate in fixed combination with formoterol fumarate (glycopyrrolate/formoterol) should be stored at 20-25°C (may be exposed to 15-30°C).371 The inhalation aerosol should be discarded 3 months after the foil pouch is opened or when the dose indicator reaches “0”, whichever comes first.371

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

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360. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-1.

361. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR Morb Mortal Wkly Rep . 1982; 31:290-1. [PubMed 6810084]

362. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8. [PubMed 7133084]

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365. West-ward Pharmaceuticals. Robinul^® (glycopyrrolate) injection prescribing information. Eatontown, NJ; 2011 Dec.

366. Shionogi Inc. Robinul^® (glycopyrrolate) and Robinul Forte^® (glycopyrrolate) tablets prescribing information. Florham Park, NJ; 2011 Dec.

367. Merz Pharmaceuticals, LLC. Cuvposa^® (glycopyrrolate) oral solution prescribing information. Raleigh, NC; 2016 May.

368. Sunovion Pharmaceuticals, Inc. Seebri^® Neohaler^® (glycopyrrolate) inhalation powder prescribing information. Marlborough, MA; 2017 Jul.

369. Sunovion Pharmaceuticals, Inc. Lonhala^® Magnair^® (glycopyrrolate) inhalation solution prescribing information. Marlborough, MA; 2017 Dec.

370. Sunovion Pharmaceutials, Inc. Utibron^® Neohaler^® (indacaterol/glycopyrrolate) inhalation powder prescribing information. Marlborough, MA; 2017 Jan.

371. AstraZeneca Pharmaceuticals LP. Bevespi^® Aerosphere^® (glycopyrrolate and formoterol fumarate) inhalation aerosol prescribing information. Wilmington, DE; 2017 Jun.

372. Parr JR, Todhunter E, Pennington L et al. Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability. Arch Dis Child . 2018; 103:371-376. [PubMed 29192000]

373. LaForce C, Feldman G, Spangenthal S et al. Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study. Int J Chron Obstruct Pulmon Dis . 2016; 11:1233-43. [PubMed 27354782]

374. Kerwin E, Siler TM, Korenblat P et al. Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study. Chronic Obstr Pulm Dis . 2016; 3:549-559. [PubMed 28848879]

375. Mahler DA, Gifford AH, Satti A et al. Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3). Respir Med . 2016; 115:39-45. [PubMed 27215502]

376. Mahler DA, Kerwin E, Ayers T et al. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med . 2015; 192:1068-79. [PubMed 26177074]

377. Martinez FJ, Rabe KF, Ferguson GT et al. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD. Chest . 2017; 151:340-57. [PubMed 27916620]

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