Glyrx-Pf (glycopyrrolate/PF)

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

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

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

After priming of the oral aerosol inhaler containing glycopyrrolate/formoterol, each actuation of the oral aerosol inhaler (Bevespi(R) Aerosphere(R)) delivers 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) and 5.5 mcg of formoterol fumarate from the valve. 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. 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. Commercially available glycopyrrolate/formoterol aerosol inhaler delivers 28 or 120 metered sprays per 5.9- or 10.7-g canister, respectively.

Glycopyrrolate is administered orally, IM, IV, or by oral inhalation.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anticholinergics/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6)

CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5)

PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Anticholinergics/Glucagon (DIAGNOSTIC)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1)

CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility.

DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1)

Anticholinergics; Opioids/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticholinergics/Select Antipsychotics;Select Phenothiazines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multiple mechanisms may be involved: 1. additive peripheral and CNS blockade of muscarinic receptors. 2. anticholinergic-induced inhibition of gastrointestinal absorption of phenothiazines. 3. antagonism of the dopamine blocking effects of selected antipsychotics and phenothiazines.

CLINICAL EFFECTS: The dopamine blocking effects of selected antipsychotic agents or phenothiazines may be decreased while anticholinergic adverse effects may be increased.

PREDISPOSING FACTORS: The risk for severe anticholinergic toxicities, e.g. delirium, hyperthermia, paralytic ileus is increased in the elderly and in patients on multiple anticholinergic agents.

PATIENT MANAGEMENT: Anticholinergic agents may be required to treat or prevent antipsychotic induced extrapyramidal symptoms. When other indications lead to co-prescribing of the combination, assess patient response to the combination. Review patient medication list for other anticholinergic agents. When needed, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly.

DISCUSSION: Although numerous studies have been published regarding a possible interaction between phenothiazines and anticholinergics, the earlier reports were not double-blind or placebo controlled and patients may have received other drugs concomitantly. These earlier investigations reported increased side effects as well as increased, decreased and no effect on the therapeutic outcome. Double-blind studies have also reported conflicting results. Anticholinergic therapy varied from having no effect on phenothiazine concentration or patient outcome, to increasing phenothiazine levels. The discrepancies reported may be due to interpatient variability including age of the patient, type and duration of illness and treatment setting.

Anticholinergics/Topiramate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)

Anticholinergics/Zonisamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Beta-Agonists; Anticholinergics; Theophylline/Methacholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway.(1)

CLINICAL EFFECTS: The result of the methacholine challenge test may not be accurate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The following drugs should be held before a methacholine challenge for the the duration indicated:(1) - short-acting beta-agonists: 6 hours - long-acting beta-agonists: 36 hours - short-acting anti-cholinergics: 12 hours - long-acting anti-cholinergics: at least 168 hours (7 days) - oral theophylline: 12-48 hours

DISCUSSION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway and cause inaccurate test results.

There is no enhanced messaging for this drug.

• Glaucoma
• Hemorrhagic shock
• Paralytic ileus
• Pyloroduodenal obstruction
• Toxic megacolon

• Benign prostatic hyperplasia
• Gastrointestinal obstruction
• Myasthenia gravis
• Toxin-mediated diarrhea
• Ulcerative colitis
• Urinary tract obstructive uropathy

• Autonomic neuropathy
• Chronic heart failure
• Coronary artery disease
• Hiatal hernia
• Hyperthyroidism
• Tachyarrhythmia

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Less Frequent

• Bradycardia

Rare or Very Rare

• Abdominal distension
• Acute cognitive impairment
• Acute respiratory failure
• Anaphylaxis
• Cardiac arrest
• Cardiac arrhythmia
• Dehydration
• Heart block
• Heat stroke
• Hypersensitivity drug reaction
• Hypertension
• Hypotension
• Ileus
• Injection site sequelae
• Ocular hypertension
• Pneumonia
• Seizure disorder
• Skin rash
• Tachycardia
• Urticaria

More Frequent

• Blurred vision
• Constipation
• Decreased sweating
• Drowsy
• Flushing
• Mydriasis
• Nasal congestion
• Palpitations
• Photophobia
• Vomiting
• Xerostomia

Less Frequent

• Breast milk flow decreased
• Urinary hesitancy
• Urinary retention
• Urinary tract infection

Rare or Very Rare

• Acute abdominal pain
• Agitation
• Anticholinergic toxicity
• Cheilosis
• Cycloplegia
• Dizziness
• Dry nose
• Dry skin
• Dysgeusia
• Erectile dysfunction
• Fever
• Flatulence
• General weakness
• Headache disorder
• Impulse control disorder
• Injection site erythema
• Injection site pain
• Insomnia
• Irritability
• Loss of taste
• Mood changes
• Nausea
• Nervousness
• Nystagmus
• Pallor
• Pruritus of skin
• Sinusitis
• Sore throat
• Thick bronchial secretions
• Upper respiratory infection

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