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Glycopyrrolate

Pronunciation

Pronunciation

(glye koe PYE roe late)

Index Terms

  • Glycopyrronium Bromide
  • NVA237
  • Seebri Neohaler

Pharmacologic Category

  • Anticholinergic Agent

Pharmacology

Blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS; indirectly reduces the rate of salivation by preventing the stimulation of acetylcholine receptors

In COPD, competitively and reversibly inhibits the action of acetylcholine at muscarinic receptor subtypes 1-3 (greater affinity for subtypes 1 and 3) in bronchial smooth muscle thereby causing bronchodilation

Absorption

Oral tablet: Poor (~3%); variable and erratic; Oral solution: 23% lower compared to tablet; Oral powder for inhalation: Rapid

Distribution

Vd: Children (1 to 14 years): Mean range: 1.3-1.8 L/kg; Adults: 0.2-0.62 L/kg

Metabolism

Hepatic (minimal)

Excretion

Urine (as unchanged drug, IM: 80%, IV: 85%); bile (as unchanged drug)

Clearance: Children (1 to 14 years): Mean range: 1 to 1.4 L/kg/hour; Adults: Mean range: 0.4 to 0.68 L/kg/hour

Onset of Action

Oral: 50 minutes; IM: 15-30 minutes; IV: ~1 minute

Peak effect: Oral: ~1 hour; IM: 30-45 minutes

Time to Peak

Plasma: Oral powder for inhalation: 5 minutes

Duration of Action

Vagal effect: 2-3 hours; Inhibition of salivation: Up to 7 hours; Anticholinergic: Oral: 8-12 hours; Parenteral: 7 hours

Half-Life Elimination

Infants: 22-130 minutes; Children 19-99 minutes; Adults: ~60-75 minutes; Oral solution: Adults: 3 hours; Oral powder for inhalation: 13-22 hours (Sechaud, 2012)

Special Populations: Renal Function Impairment

AUC of IV is 10.6 mcg•h/L in renally impaired patients. Elimination is severely impaired in patients with renal failure with plasma clearance of IV lowering to 0.43 L/h/kg.

Use: Labeled Indications

Inhibit salivation and excessive secretions of the respiratory tract preoperatively; control of upper airway secretions; intraoperatively to counteract drug-induced or vagal mediated bradyarrhythmias; adjunct in treatment of peptic ulcer (indication listed in product labeling but currently has no place in management of peptic ulcer disease)

Cuvposa: Reduce chronic, severe drooling in those with neurologic conditions (eg, cerebral palsy) associated with drooling

Seebri Breezhaler [Canadian product]: Maintenance treatment of chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema

Use: Unlabeled

Adjunct with acetylcholinesterase inhibitors (eg, neostigmine, edrophonium, pyridostigmine) to antagonize cholinergic effects

Contraindications

Hypersensitivity to glycopyrrolate or any component of the formulation; medical conditions that preclude use of anticholinergic medication; severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, paralytic ileus, obstructive disease of GI tract (eg, pyloric stenosis), intestinal atony in the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; narrow-angle glaucoma; acute hemorrhage; tachycardia; obstructive uropathy; myasthenia gravis

Oral solution: Additional contraindication: Concomitant use of potassium chloride in a solid oral dosage form

Seebri Breezhaler [Canadian product]: Hypersensitivity to glycopyrronium bromide or any component of the formulation

Dosage

Children:

Reduction of secretions (preanesthetic):

Oral (off-label): 40-100 mcg/kg/dose 3-4 times/day

IM, IV (off-label): 4-10 mcg/kg/dose every 3-4 hours; maximum: 0.2 mg/dose or 0.8 mg/24 hours

Intraoperative: IV: 4 mcg/kg not to exceed 0.1 mg; repeat at 2- to 3-minute intervals as needed

Preoperative: IM:

<2 years: 4-9 mcg/kg 30-60 minutes before procedure

>2 years: 4 mcg/kg 30-60 minutes before procedure

Drooling, chronic: Children 3-16 years: Oral solution (Cuvposa™): Initial: 0.02 mg/kg 3 times/day; titrate in increments of 0.02 mg/kg every 5-7 days as tolerated, up to a maximum dose of 0.1 mg/kg 3 times/day, not to exceed 1.5-3 mg/dose

Children and Adults: Reverse neuromuscular blockade: IV: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine administered or 5-15 mcg/kg glycopyrrolate with 25-70 mcg/kg of neostigmine or 0.1-0.3 mg/kg of pyridostigmine (agents usually administered simultaneously, but glycopyrrolate may be administered first if bradycardia is present)

Adults:

COPD: Oral powder for inhalation: Seebri® Breezhaler® [Canadian product]: 50 mcg (contents of one capsule) once daily

Reduction of secretions:

Intraoperative: IV: 0.1 mg repeated as needed at 2- to 3-minute intervals

Preoperative: IM: 4 mcg/kg 30-60 minutes before procedure

Dosage adjustment in renal impairment: No dosage adjustment provided in manufacturer’s labeling. However, data suggest renal impairment reduces glycopyrrolate elimination; use with caution.

Dosage adjustment in hepatic impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Extemporaneously Prepared

A 0.5 mg/mL oral suspension may be made with 1 mg tablets and a 1:1 mixture of Ora-Plus® and either Ora-Sweet® or Ora-Sweet® SF. Crush thirty 1 mg tablets in a mortar and reduce to a fine powder. Prepare diluent by mixing 30 mL of Ora-Plus® with 30 mL of either Ora-Sweet® or Ora-Sweet® SF and stir vigorously. Add 30 mL of diluent (via geometric dilution) to powder until smooth suspension is obtained. Transfer suspension to 60 mL amber bottle. Rinse contents of mortar into bottle with sufficient quantity of remaining diluent to obtain 60 mL (final volume). Label “shake well”. Stable at room temperature for 90 days. Due to bitter aftertaste, chocolate syrup may be administered prior to or mixed (1:1 v/v) with suspension immediately before administration (Cober, 2011).

A 0.5 mg/mL oral solution can be made from tablets. Crush fifty 1 mg tablets in a mortar and reduce to a fine powder. Add enough distilled water to make about 90 mL, mix well. Transfer to a bottle, rinse mortar with water, and add a quantity of water sufficient to make 100 mL. Label “shake well” and “protect from light”. Stable at room temperature for 25 days (Gupta, 2001).

A 0.1 mg/mL oral solution may be made using glycopyrrolate 0.2 mg/mL injection without preservatives. Withdraw 50 mL from vials with a needle and syringe, add to 50 mL of a 1:1 mixture of Ora-Sweet® and Ora-Plus® in a bottle. Label “shake well”, “protect from light,” and “refrigerate”. Stable refrigerated for 35 days (Landry, 2005).

Cober MP, Johnson CE, Sudekum D, et al, “Stability of Extemporaneously Prepared Glycopyrrolate Oral Suspensions,” Am J Health Syst Phar,. 2011, 68(9):843-5.21515869Gupta VD, “Stability of an Oral Liquid Dosage Form of Glycopyrrolate Prepared from Tablets,” IJPC 2001, 5(6):480-1.Landry C, “Stability and Subjective Taste Acceptability of Four Glycopyrrolate Solutions for Oral Administration,” IJPC, 2005, 9(5):396-98.

Administration

IV: Administer IV at a rate of 0.2 mg over 1-2 minutes. May be administered IM or IV without dilution. May also be administered via the tubing of a running IV infusion of a compatible solution. May be administered IV in the same syringe with neostigmine or pyridostigmine.

Oral: Administer oral solution on an empty stomach, 1 hour before or 2 hours after meals

Oral inhalation [Canadian product]: Administer once daily preferably at the same time each day using the Seebri® Breezhaler® only. Remove capsule from foil blister immediately before use. Do not swallow capsule. Avoid getting powder into eyes. Place capsule in the capsule-chamber in the base of the Seebri® Breezhaler®. A click is heard as it fully closes. Hold inhaler with mouthpiece in upright position and pierce capsule within chamber by simultaneously pressing piercing buttons on base of inhaler (click is heard as capsule is pierced). Release buttons. Exhale fully. Do not exhale into inhaler. Tilt head slightly back and place mouthpiece in mouth with piercing buttons on base of inhaler in horizontal position and not up and down. Do not press piercing buttons. Inhale (rapidly, steadily and deeply); the capsule vibration should be heard within the device. Hold breath for at least 5-10 seconds or as long as possible. Remove mouthpiece prior to exhalation. Patient should not breathe out through the mouthpiece. If any powder remains in capsule, exhale and inhale again. Repeat until capsule is empty. Throw away empty capsule; do not leave in inhaler. Always keep capsules and inhaler dry. Note: If a dose is missed, take as soon as possible on that day; do not take 2 doses on the same day.

Compatibility

Stable in D51/2NS, D5W, D10W, NS, R; incompatible in LR

Compatibility in syringe: Incompatible with chloramphenicol, dexamethasone sodium phosphate, diazepam, dimenhydrinate, methohexital, pentazocine, pentobarbital, secobarbital, sodium bicarbonate, thiopental.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Oral capsules for inhalation [Canadian product]: Store at 15°C to 25°C (59°F to 77°F) in blister. Capsules should be stored in the blister pack and only removed immediately before use. Once protective foil is peeled back and/or removed the capsule should be used immediately; if capsule is not used immediately, it should be discarded. Do not store capsules in Seebri® Breezhaler®. Protect from moisture.

Drug Interactions

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Amantadine: May enhance the anticholinergic effect of Glycopyrrolate. Monitor therapy

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Anticholinergic Agents: May enhance the anticholinergic effect of Glycopyrrolate. Avoid combination

Atenolol: Glycopyrrolate may increase the serum concentration of Atenolol. Monitor therapy

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Digoxin: Glycopyrrolate may increase the serum concentration of Digoxin. This effect is specific to digoxin administered as slow dissolution oral tablets. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Haloperidol: Glycopyrrolate may decrease the serum concentration of Haloperidol. Management: Monitor patients closely for signs/symptoms of reduced clinical response to haloperidol if concurrent use with glycopyrrolate is required. When possible, consider avoiding concurrent use. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Levodopa: Glycopyrrolate may decrease the serum concentration of Levodopa. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

MetFORMIN: Glycopyrrolate may increase the serum concentration of MetFORMIN. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Potassium Chloride: Glycopyrrolate may enhance the adverse/toxic effect of Potassium Chloride. This is specific to solid oral dosage forms of potassium chloride. Management: Concurrent use of solid oral dosage forms of potassium chloride are contraindicated with glycopyrrolate. Consider using a non-solid oral dosage form or another alternative therapy as appropriate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Adverse Reactions

>10% (as reported with Cuvposa™):

Cardiovascular: Flushing (30%)

Central nervous system: Headache (15%)

Gastrointestinal: Vomiting (40%), xerostomia (40%), constipation (35%)

Genitourinary: Urinary retention (15%)

Respiratory: Nasal congestion (30%), sinusitis (15%), upper respiratory tract infection (15%)

<10% (frequency not always defined):

Cardiovascular: Pallor (≤2%), arrhythmias, cardiac arrest, heart block, hyper-/hypotension, malignant hyperthermia, palpitation, QTc-interval prolongation, tachycardia

Central nervous system: Aggressiveness (≤2%), agitation (≤2%), crying (abnormal; ≤2%), irritability (≤2%), mood changes (≤2%), pain (≤2%), restlessness (≤2%), confusion, dizziness, drowsiness, excitement, insomnia, nervousness, seizure

Dermatologic: Dry skin (≤2%), pruritus (≤2%), rash (≤2%), urticaria

Endocrine & metabolic: Dehydration (≤2%), lactation suppression

Gastrointestinal: Abdominal distention (≤2%), abdominal pain (≤2%), flatulence (≤2%), retching (≤2%), bloated feeling, intestinal obstruction, loss of taste, nausea, pseudo-obstruction

Genitourinary: Urinary tract infection (≤2%), impotence, urinary hesitancy

Local: Injection site reactions (edema, erythema, pain)

Neuromuscular & skeletal: Weakness

Ocular: Nystagmus (≤2%), blurred vision, cycloplegia, mydriasis, ocular tension increased, photophobia, sensitivity to light increased

Respiratory: Bronchial secretion (thickening; ≤2%), nasal dryness (≤2%), pneumonia (≤2%), respiratory depression

Miscellaneous: Anaphylactoid reactions, diaphoresis decreased, hypersensitivity reactions

As reported with Seebri® Breezhaler® [Canadian product]:

1% to 10%:

Central nervous system: Headache (elderly: 2%)

Gastrointestinal: Xerostomia (2% to 3%), gastroenteritis (1% to 3%), dyspepsia (1%), vomiting (1%)

Genitourinary: Urinary tract infection (elderly: 3%), dysuria (1%)

Neuromuscular & skeletal: Musculoskeletal pain (2%)

Respiratory: Nasopharyngitis (9%), rhinitis (2%)

<1% (Limited to important or life-threatening): Cough, cystitis, dental caries, diabetes mellitus, epistaxis, fatigue, hypoesthesia, palpitations, rash, throat irritation, urinary retention, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Bronchospasm: Rarely, paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; discontinue use of inhaler and consider other therapy if bronchospasm occurs.

• CNS effects: May cause drowsiness and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Diarrhea: May be a sign of incomplete intestinal obstruction, treatment should be discontinued if this occurs.

• GI transit: Slowing of GI muscular action can occur resulting in constipation or intestinal pseudo-obstruction. Constipation is a common dose-limiting adverse event. Intestinal pseudo-obstruction can result in abdominal distention, pain, nausea, or vomiting.

• Heat prostration: May occur in the presence of increased environmental temperature; use caution in hot weather and/or exercise.

• Mechanical obstruction (incomplete): Diarrhea may be a sign of incomplete intestinal obstruction, especially in patients with an ileostomy or colostomy. Discontinue treatment if this occurs.

• Pigment effects: Caution should be used in individuals demonstrating decreased pigmentation (skin and iris coloration, dark versus light) since there has been some evidence that these individuals have an enhanced sensitivity to the anticholinergic response.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with coronary artery disease, tachyarrhythmias, heart failure, or hypertension; evaluate tachycardia prior to administration.

• Hiatal hernia: Use with caution in patients with hiatal hernia with reflux.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism.

• Narrow-angle glaucoma: Use with caution in patients with narrow-angle glaucoma; patients using Seebri® Breezhaler® [Canadian product] should avoid getting powder in eyes. Monitor for signs/symptoms of glaucoma and instruct patient to contact healthcare provider immediately with onset of symptoms.

• Neuropathy: Use with caution in patients with autonomic neuropathy.

• Prostatic hyperplasia/bladder neck obstruction: Glycopyrrolate may worsen the symptoms (eg, urinary retention) of prostatic hyperplasia and/or bladder neck obstruction; use with caution.

• Renal impairment: Elimination is severely impaired in renal failure; dosage adjustment may be necessary.

• Ulcerative colitis: Use with caution as large doses suppress intestinal motility; may precipitate/exacerbate an ileus or toxic megacolon.

Special populations:

• Elderly: Use with caution in the elderly; increased risk for anticholinergic effects, confusion, and hallucinations.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Oral inhaler [Canadian product]: Not indicated for the initial (rescue) treatment of acute episodes of bronchospasm or with acutely deteriorating COPD; after initiation of therapy, patients should use short-acting bronchodilators only on an as needed basis for acute symptoms.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Zar, 2007).

Monitoring Parameters

Heart rate; anticholinergic effects; bowel sounds; bowel movements; effects on drooling

Oral inhalation: FEV1, peak flow (or other pulmonary function studies)

Pregnancy Risk Factor

B (injection) / C (oral solution)

Pregnancy Considerations

Adverse effects were not observed in animal reproduction studies. Small amounts of glycopyrrolate cross the human placenta. Glycopyrrolate in doses of 0.004 mg/kg has not been found to affect fetal heart rate.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, asthenia, constipation, blurred vision, flushing, xerostomia, xeroderma, dysgeusia, nausea, rhinitis, rhinorrhea, pharyngitis, or injection site irritation. Have patient report immediately to prescriber severe dizziness, syncope, illogical thinking, urinary retention, angina, tachycardia, arrhythmia, diarrhea, abdominal edema, dyspepsia, vision changes, considerable headache, tachypnea, significant asthenia, mood changes, or sexual dysfunction (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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