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Glycopyrrolate (Systemic)

Pronunciation

(glye koe PYE roe late)

Index Terms

  • Glycopyrronium Bromide
  • NVA237

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Robinul: 0.2 mg/mL (1 mL); 0.4 mg/2 mL (2 mL); 1 mg/5 mL (5 mL); 4 mg/20 mL (20 mL) [contains benzyl alcohol]

Generic: 0.2 mg/mL (1 mL); 0.4 mg/2 mL (2 mL); 1 mg/5 mL (5 mL); 4 mg/20 mL (20 mL)

Solution, Oral:

Cuvposa: 1 mg/5 mL (473 mL [DSC]) [contains methylparaben, propylene glycol, propylparaben, saccharin sodium]

Cuvposa: 1 mg/5 mL (473 mL) [contains methylparaben, propylene glycol, propylparaben, saccharin sodium; cherry flavor]

Tablet, Oral:

Glycate: 1.5 mg [DSC] [dye free]

Robinul: 1 mg [scored]

Robinul-Forte: 2 mg [scored]

Generic: 1 mg, 2 mg

Brand Names: U.S.

  • Cuvposa
  • Glycate [DSC]
  • Robinul
  • Robinul-Forte

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

Absorption

Oral tablet: Poor (~3%); variable and erratic; Oral solution: 23% lower compared to tablet; high-fat meal markedly reduces the oral bioavailability

Distribution

Vd: Children:1.3 to 1.8 L/kg; Adults: 0.4 ± 0.22 L/kg

Excretion

Urine (as unchanged drug, IM: 65% to >80%, IV: 85%); bile (as unchanged drug, <5%)

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

IM: 15 to 30 minutes; IV: Within 1 minute; Peak effect: IM: Within ~30 to 45 minutes

Time to Peak

3.1 hours

Duration of Action

Vagal effect: 2 to 3 hours; Inhibition of salivation: Up to 7 hours; Parenteral: 7 hours

Half-Life Elimination

Infants: 21.6 to 130 minutes; Children 19.2 to 99.2 minutes; IM: Adults: 0.55 to 1.25 hours; IV: 0.83 ± 0.13 hour; Oral solution: Adults: 3 hours

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

Chronic drooling (Cuvposa only): To reduce chronic, severe drooling in pediatric patients 3 to 16 years with neurologic conditions (eg, cerebral palsy) associated with problem drooling

Reduction of secretions (Robinul injection only): To reduce salivary, tracheobronchial, and pharyngeal secretions preoperatively; to reduce the volume and free acidity of gastric secretions

Reversal of bradycardia, vagal reflexes (Robinul injection only): To block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation; intraoperatively to counteract surgically or drug-induced or vagal reflexes associated arrhythmias

Reversal of muscarinic effects of cholinergic agents (Robinul injection only): Protects against the peripheral muscarinic effects (eg, bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing muscle relaxants

Contraindications

Hypersensitivity to glycopyrrolate or any component of the formulation; medical conditions that preclude use of anticholinergic medication (eg, severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, paralytic ileus, obstructive disease of GI tract [eg, achalasia, pyloroduodenal, stenosis], intestinal atony in elderly or debilitated patients, unstable cardiovascular status in acute hemorrhage, glaucoma, obstructive uropathy [eg, bladder neck obstruction due to prostatic hypertrophy], myasthenia gravis)

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

Dosing: Adult

Reduction of secretions (preoperative): IM: 4 mcg/kg 30 to 60 minutes before anesthesia or when the preanesthetic opioid and/or sedative are administered

Reversal of bradycardia, vagal reflexes (intraoperative): IV: 0.1 mg as a single dose; repeat as needed at 2- to 3-minute intervals

Reversal of muscarinic effects of cholinergic agents: IV: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine administered

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic drooling: Children and Adolescents 3 to 16 years: Oral solution (Cuvposa): Initial: 0.02 mg/kg 3 times daily; titrate in increments of 0.02 mg/kg every 5 to 7 days as tolerated, up to a maximum dose of 0.1 mg/kg 3 times daily, not to exceed 3 mg/dose

Reduction of secretions (preoperative):

Infants and Children ≤2 years: IM: 4 to 9 mcg/kg 30 to 60 minutes before anesthesia or when the preanesthetic opioid and/or sedative are administered

Children >2 years and Adolescents: Refer to adult dosing

Reversal of bradycardia, vagal reflexes (intraoperative): Infants, Children, and Adolescents: IV: 4 mcg/kg/dose (maximum dose: 0.1 mg); repeat at 2- to 3-minute intervals as needed

Reversal of muscarinic effects of cholinergic agents: Infants, Children, and Adolescents: IV: Refer to adult dosing.

Control of secretions (chronic) (off-label use): Limited data available (Nelson 1996): Children:

Oral: 40 to 100 mcg/kg/dose 3 to 4 times daily

IM, IV: 4 to 10 mcg/kg/dose every 3 to 4 hours

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; elimination is severely impaired in renal failure; use with caution; dosage adjustment may be necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Reconstitution

IV: May further dilute in a compatible solution.

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

IM: May administer undiluted.

IV: May be administered IV without dilution or may dilute in a compatible solution. In perioperative setting, usually administered over 1 to 2 minutes (eg, in adults: 0.2 mg over 1 to 2 minutes). May also be administered via the tubing of a running IV infusion of a NS. May be administered IV in the same syringe with neostigmine or pyridostigmine for reversal of neuromuscular blockade. For chronic pediatric uses, consider further dilution and infusing over 20 to 30 minutes (Nelson 1996).

Oral: Administer oral solution 1 hour before or 2 hours after meals. Measure oral solution with an accurate measuring device (eg, dosing cup or oral syringe).

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

Injection: Store at 20°C to 25°C (68°F to 77°F).

Oral: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

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 (Systemic). 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 adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Atenolol: Glycopyrrolate (Systemic) 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 (Systemic) may increase the serum concentration of Digoxin. 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 (Systemic) 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 (Systemic) may decrease the serum concentration of Levodopa. Monitor therapy

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

MetFORMIN: Glycopyrrolate (Systemic) 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

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

Potassium Chloride: Glycopyrrolate (Systemic) may enhance the adverse/toxic effect of Potassium Chloride. This is specific to solid oral dosage forms of potassium chloride. 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

Frequency not always defined.

Cardiovascular: Flushing (30%), pallor (≤2%), cardiac arrhythmias, heart block, hypertension, hypotension, palpitation, tachycardia

Central nervous system: Headache (15%), aggressiveness (≤2%), agitation (≤2%), crying (abnormal; ≤2%), irritability (≤2%), mood changes (≤2%), pain (≤2%), restlessness (≤2%), confusion, dizziness, drowsiness, excitement (higher incidence in older adults), insomnia, nervousness

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

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

Gastrointestinal: Vomiting (40%), xerostomia (40%), constipation (35%), abdominal distention (≤2%), abdominal pain (≤2%), flatulence (≤2%), retching (≤2%), intestinal obstruction, loss of taste, nausea, pseudo-obstruction

Genitourinary: Urinary retention (15%), urinary tract infection (≤2%), impotence, urinary hesitancy

Neuromuscular & skeletal: Weakness

Ocular: Nystagmus (≤2%), blurred vision, cycloplegia, increased intraocular pressure, mydriasis

Respiratory: Nasal congestion (30%), sinusitis (15%), upper respiratory tract infection (15%), bronchial secretion (thickening; ≤2%), nasal dryness (≤2%), pneumonia (≤2%)

<1% (Limited to important or life-threatening): Arrhythmias, hypertension, hypotension, malignant hyperthermia, seizure

Warnings/Precautions

Concerns related to adverse effects:

• 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).

• 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, particularly in children and the elderly; 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 incomplete mechanical intestinal obstruction is suspected or if diarrhea occurs.

Disease-related concerns:

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

• Hepatic impairment: Use with caution in patients with hepatic impairment.

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

• Hyperthyroidism: Use with caution in patients with hyperthyroidism.

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

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

• Renal impairment: Use with caution in patients with renal impairment; elimination is severely impaired in renal failure; dosage adjustment may be necessary.

• Ulcerative colitis: Use with caution in patients with ulcerative colitis; large doses may suppress intestinal motility; may precipitate/exacerbate an ileus or toxic megacolon. Use is contraindicated in patients with severe ulcerative colitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

• Pediatric: Infants, patients with Down syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, increasing the potential for adverse events. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses. Infants and young children are especially susceptible to the toxic effects of anticholinergics.

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.

• 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

Pregnancy Risk Factor

B (injection)

Pregnancy Considerations

Adverse effects have not been 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, loss of strength and energy, blurred vision, flushing, dry mouth, dizziness, change in taste, headache, rhinitis, anxiety, or insomnia. Have patient report immediately to prescriber lack of sweating, confusion, difficult urination, tachycardia, abnormal heartbeat, enlarged pupils, vision changes, eye pain, severe eye irritation, diarrhea, bloating, constipation, abdominal edema, abdominal pain, severe nausea, severe vomiting, muscle weakness, 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 health care 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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