Breztri Aerosphere (budesonide/glycopyrrolate/formoterol fumarate)

Each 2-mL single-dose vial of formoterol fumarate oral inhalation solution contains 20 mcg of formoterol fumarate. The oral inhalation solution does not require dilution prior to administration by nebulization. The actual amount of drug delivered to the lungs will depend on patient factors and the type of nebulization system used and its performance.

Each actuation of the oral aerosol inhaler containing the fixed combination of formoterol fumarate dihydrate and budesonide delivers 5.1 mcg of formoterol fumarate dihydrate and 91 or 181 mcg of budesonide from the valve and delivers 4.5 mcg of formoterol fumarate dihydrate and 80 or 160 mcg of budesonide from the actuator per metered spray, depending on the preparation used. The strength of formoterol/budesonide preparations and dosage of the fixed combination are expressed in terms of drug delivered from the mouthpiece of the actuator. The actual amount of drug delivered to the lungs depends on factors such as the patient's coordination between the actuation of the inhaler and inspiration through the delivery system. The commercially available formoterol/budesonide aerosol inhaler delivers 60 metered sprays per 6- or 6.9-g canister and 120 metered sprays per 10.2-g canister.

After priming of the oral aerosol inhaler containing the fixed combination of formoterol fumarate and glycopyrrolate, each actuation of the oral aerosol inhaler (Bevespi(R) Aerosphere(R)) delivers 5.5 mcg of formoterol fumarate and 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) from the valve. Dosage is expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 4.8 mcg of formoterol fumarate and 9 mcg of glycopyrrolate (equivalent to 7.2 mcg of glycopyrronium) from the actuator. 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 formoterol/glycopyrrolate aerosol inhaler delivers 28 or 120 metered sprays per 5.9- or 10.7-g canister, respectively.

Each actuation of the oral aerosol inhaler containing the fixed combination of formoterol fumarate dihydrate and mometasone furoate delivers 5.5 mcg of formoterol fumarate dihydrate and 115 or 225 mcg of mometasone furoate from the valve and delivers 5 mcg of formoterol fumarate dihydrate and 100 or 200 mcg of mometasone furoate from the actuator per metered spray, depending on the preparation used. The strength of formoterol/mometasone preparations and dosage of the fixed combination are expressed in terms of drug delivered from the mouthpiece of the actuator. The actual amount of drug delivered to the lungs may depend on factors such as the patient's coordination between actuation of the device and inspiration through the delivery system. Commercially available formoterol/mometasone aerosol inhaler delivers 60 or 120 metered sprays per 8.8- or 13-g canister, respectively.

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.

Budesonide is administered orally as delayed-release capsules. For oral inhalation, budesonide is available as an inhalation powder administered via an inhaler device (Flexhaler(R)), as a micronized suspension administered via nebulization, and as an inhalation aerosol containing budesonide in fixed combination with formoterol fumarate (Symbicort(R)) administered via an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant. Patients receiving orally inhaled budesonide should rinse their mouth with water after each dose to remove residual drug in the oropharyngeal area and to minimize the development of fungal overgrowth and/or infection.

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

No dosing information is available for this tab.

The following information addresses potential interactions with formoterol fumarate. When formoterol fumarate is used in fixed combination with budesonide, glycopyrrolate, or mometasone furoate, interactions associated with budesonide, glycopyrrolate, and mometasone also should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparations containing formoterol fumarate and budesonide, glycopyrrolate, or mometasone.

The following information addresses potential interactions with budesonide. When budesonide is used in fixed combination with formoterol fumarate, interactions associated with formoterol fumarate should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing budesonide and formoterol fumarate.

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)

Agents Affecting Plasma Cortisol Levels/Cosyntropin

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 plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1)

DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

Glucocorticoids/Desmopressin

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: Glucocorticoids increase the risk of hyponatremia.(1-4)

CLINICAL EFFECTS: Concurrent use of glucocorticoids may increase the risk of hyponatremia with desmopressin.(1-4)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (carbamazepine, chlorpromazine, lamotrigine, loop diuretics, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants).

PATIENT MANAGEMENT: The concurrent use of systemic or inhaled glucocorticoids with desmopressin is contraindicated.(1-4) Desmopressin may be initiated 3 days or 5 half-lives after glucocorticoid discontinuation, whichever is longer. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Sympathomimetics/Dihydroergotamine

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: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

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

Agents That Affect Catecholamines/Iobenguane I 123

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Agents That Affect Iodide/Radioactive Iodide

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

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Agents That Affect Iodide/Sodium Iodide I 131

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

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

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)

Beta-2 Agonists/Non-Cardioselective Beta-Blockers

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

MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other.

CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm.

PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm.

PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. For timolol ophthalmic drops, counsel patients to apply pressure to the inner corner of the eye after administration to prevent systemic absorption. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure.

DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20)

Inhaled Anticholinergics/Pramlintide

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

MECHANISM OF ACTION: Pramlintide slows gastric emptying. Anticholinergics may result in additive or synergistic effects.(1)

CLINICAL EFFECTS: Concurrent use of pramlintide and anticholinergics may result in additive or synergistic effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pramlintide states that pramlintide therapy should not be considered in patients requiring the use of drugs that stimulate gastrointestinal motility or in patients taking drugs that alter gastrointestinal motility.(1) Patients receiving inhaled anticholinergics should be evaluated for signs of systemic effects, which may include constipation.

DISCUSSION: Patients using drugs that alter gastrointestinal motility have not been studied in clinical trials for pramlintide.(1) Constipation has been reported as a side effect of inhaled anticholinergic agents such as ipratropium(2) and tiotropium.(3)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

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

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Selected Steroids/Antiretroviral Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Antiretroviral CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4. Dexamethasone may induce metabolism of agents that are substrates of CYP3A4.(1-13,50)

CLINICAL EFFECTS: Concurrent use of antiretroviral CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression. Concurrent dexamethasone may result in decreased levels and effectiveness of CYP3A4 substrates.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy of corticosteroids metabolized by CYP3A4 with antiretroviral CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued. Patients receiving concurrent therapy with dexamethasone and substrates of CYP3A4 should also be monitored for decreased effectiveness of the CYP3A4 substrate. The manufacturers of nasal fluticasone(14-16) and fluticasone for inhalation(17) state that concurrent use of fluticasone and atazanavir, indinavir, nelfinavir, ritonavir or saquinavir is not recommended. The US manufacturers of atazanavir,(1) fosamprenavir,(5) indinavir(6) and nelfinavir(8) recommend caution with concurrent use of inhaled or nasal fluticasone. Consider alternatives to fluticasone if long-term use is required.

DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(2) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(18) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,14) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(6,14-16) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(19) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(19-20) dexamethasone,(22) injectable triamcinolone,(23-26) nasal fluticasone.(28-46) Hepatitis has also been reported with concurrent budesonide and ritonavir.(47) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(48) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(49) Selected steroids metabolized by CYP3A4 are linked to this monograph.(50) Selected CYP3A4 inhibitors and substrates linked to this monograph include: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lenacapavir, lopinavir, nelfinavir, saquinavir, and tipranavir.(50)

Selected Steroids/Selected Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy between corticosteroids metabolized by CYP3A4 and strong CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued.

DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(3) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(4) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(6-8) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(6) The cortisol AUC decreased by 86%.(10-13) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(14) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(15-16) dexamethasone,(17) injectable triamcinolone,(18-21) nasal fluticasone.(23-41) Hepatitis has also been reported with concurrent budesonide and ritonavir.(42) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(43) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(44) Selected steroids metabolized by CYP3A4 are linked to this monograph.(45) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, erythromycin, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, nefazodone, paritaprevir, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1-2,45)

Sympathomimetics/Ergot Alkaloids

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

MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.

CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary.

DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine.

Sympathomimetics/Selected Inhalation Anesthetic Agents

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

MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1)

CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1)

DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics.

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.

Corticosteroids/Quinolones

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

MECHANISM OF ACTION: Quinolone-induced arthropathy is a class effect of the quinolones.(1) Exactly how corticosteroid use increases the risk of tendon rupture is unknown.

CLINICAL EFFECTS: Concurrent use of quinolones and corticosteroids may increase the risk of tendonitis and/or tendon rupture. This affect is most common in the Achilles tendon, but has been reported in the rotator cuff (shoulder), hand, biceps, thumb, and other tendons.(2-9)

PREDISPOSING FACTORS: Risk factors for tendinitis and tendon rupture include age greater than 60; a history of kidney, heart, or lung transplantation, strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis.

PATIENT MANAGEMENT: Quinolone use should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients experiencing discomfort or pain should be instructed to rest and refrain from exercise until the diagnosis of tendonitis tendon rupture has been excluded.(2-9)

DISCUSSION: Ruptures of the shoulder, hand, Achilles tendon, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving ciprofloxacin,(2) gatifloxacin,(3) levofloxacin,(4) lomefloxacin,(5) moxifloxacin,(6) nalidixic acid,(7) norfloxacin,(8) and ofloxacin.(9) A retrospective review of the IMS Health database examined quinolone use use from July 1, 1992 to June 30, 1998. The adjusted relative risk of tendon disorder with concurrent quinolone use was 1.9. Relative risk increased to 3.2 in patients aged 60 or older compared to 0.9 in patients aged less than 60. In patients aged 60 or older who used corticosteroids and quinolones concurrently, relative risk increased to 6.2.(10) In contrast, another retrospective review examined patients from a health insurance claims database and found no apparent effect from concurrent quinolone and corticosteroid use.(11) In a review of the follow-up to 42 spontaneously reported case of quinolone-associated tendon disorders in the Netherlands between January, 1988 and January, 1998, risk factors for tendon disorders included age older than 60, oral corticosteroid use, and existing joint problems.(12) In a review of the Swiss Drug Monitoring system, four of seven cases of levofloxacin-associated tendon problems also involved concurrent oral or inhaled corticosteroids.(13) In a review of the Medline database from 1966-2001, 98 case reports of tendinopathy associated with quinolones were located. Thirty-two (32.7%) of the patients had received systemic or inhaled corticosteroids before and during quinolone therapy. Of the 40 patients who suffered a tendon rupture, 21 (52.5%) were receiving corticosteroids.(14) Other authors have reported cases of tendon disorders in patients receiving concurrent corticosteroids and ciprofloxacin,(15) levofloxacin, (16-20) and ofloxacin.(21)

Inhaled Anticholinergics/Solid Oral Potassium Capsules

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

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with inhaled anticholinergics could potentially result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) Constipation has been reported as a side effect of inhaled anticholinergic agents such as ipratropium(22) and tiotropium.(23)

Inhaled Anticholinergics/Solid Oral Potassium Tablets

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

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with inhaled anticholinergics could potentially result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) Constipation has been reported as a side effect of inhaled anticholinergic agents such as ipratropium(22) and tiotropium.(23)

Inhaled Direct-Acting Sympathomimetics/Tricyclic Compounds

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

MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake.

CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics. Similarity between cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Selected Corticosteroids/Levoketoconazole

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

MECHANISM OF ACTION: Levoketoconazole may inhibit the CYP3A4 mediated metabolism of some corticosteroids, resulting in increased systemic exposure. Levoketoconazole may also suppress endogenous cortisol output. Levoketoconazole is the enantiomer of ketoconazole.

CLINICAL EFFECTS: Concurrent use of levoketoconazole may result in elevated levels of and effects from the corticosteroid, including Cushing syndrome. These effects have been seen with systemic as well as inhaled corticosteroids.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should be carefully monitored with concurrent administration of these agents, or when levoketoconazole is added to corticosteroid therapy. The dose of the corticosteroid may need to be adjusted or alternative therapy considered.

DISCUSSION: The concurrent use of ketoconazole has been shown to increase budesonide area-under-curve (AUC) by eight-fold. In a study in eight healthy subjects, the simultaneous administration of ketoconazole increased budesonide AUC by 6.5-fold. Administering the two agents 12 hours apart increased budesonide AUC by 3.8-fold. In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily) increased the AUC of a single intravenous dose of methylprednisolone (20 mg) by 135% and decreased its clearance by 60%. Concurrent ketoconazole also increased the reduction in 24-hour cortisol AUC and suppressed morning cortisol concentrations. In a study in 8 healthy subjects, ketoconazole decreased the clearance of methylprednisolone by 46% and increased mean residence time by 37%. In a randomized, cross-over study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily for 6 days) had no effect on the pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg). In a study, concurrent oral ketoconazole increased the AUC of des-ciclesonide from orally inhaled ciclesonide by 3.6-fold. There were no changes in ciclesonide levels. In a study in 24 healthy subjects, subjects were randomized to receive either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course of mometasone (400 mcg BID). No subject had mometasone levels greater than 150 pcg/ml on Day 3. Four of 12 subjects who received ketoconazole had mometasone Cmax levels greater than 200 mcg/ml on Day 9. Plasma cortisol levels appeared to decrease as well. In a cross-over study in 15 healthy subjects, subjects were randomized to receive fluticasone furoate and vilanterol on days 5-11 with either ketoconazole (200mg once daily) or placebo for days 1-11 with a washout period of 7-14 days. Fluticasone furoate AUC was increased by 36%, Cmax was increased by 33%, and decreased systemic cortisol levels by 27%. There were no effects on heart rate and blood potassium levels. There was a small increase in QTc which was 7.6ms greater when compared to placebo; however, ketoconazole has been reported to increase QTc by 5-6ms. Vilanterol AUC was increased by 65% and Cmax was increased by 22%. There were no effects on heart rate and blood potassium levels. No serious adverse events occurred and no subjects withdrew from the study due to adverse events. The most common adverse event reported was headache. Coadministration of orally inhaled fluticasone (1000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC.

Selected Sensitive Cyp3a4 Substrates/Schisandra

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

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Selected Steroids/Ensitrelvir; Nirmatrelvir-Ritonavir

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

MECHANISM OF ACTION: Ensitrelvir and nirmatrelvir/ritonavir may inhibit the metabolism of corticosteroids metabolized by CYP3A4.(1,2)

CLINICAL EFFECTS: Ensitrelvir and nirmatrelvir/ritonavir may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration with corticosteroids of all routes of administration of which exposures are significantly increased by strong CYP3A4 inhibitors can increase the risk of Cushing's syndrome and adrenal suppression. However, the risk of Cushing's syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is low.(1) The manufacturer of nirmatrelvir/ritonavir recommends considering alternative corticosteroids including beclomethasone, prednisone, and prednisolone.(1)

DISCUSSION: Concurrent use of a single dose of midazolam 2 mg, a CYP3A4 substrate, with nirmatrelvir-ritonavir (300 mg/100 mg twice daily for nine doses) increased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam by 37% and 143%, respectively.(1) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,13) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(4-7) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(8) In a clinical study, ensitrelvir (750 mg on day 1 and 250 mg on days 2-5) increased the Cmax and AUC of dexamethasone 1 mg single dose by 1.47-fold and 3.47-fold, respectively.(2) Selected steroids linked to this monograph include: budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and triamcinolone.(9)

Formoterol fumarate and fixed combinations containing formoterol fumarate are contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.

Because of the risk of asthma-related death and hospitalization, use of formoterol for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated. (See Asthma-related Death and Serious Asthma-related Events under Warnings/Precautions: Warnings, in Cautions and also see Uses: Bronchospasm.)

Formoterol fumarate in fixed combination with budesonide (formoterol/budesonide; Symbicort(R)) and formoterol fumarate in fixed combination with mometasone furoate (formoterol/mometasone; Dulera(R)) are contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required.

Formoterol fumarate in fixed combination with glycopyrrolate (formoterol/glycopyrrolate; Bevespi(R) Aerosphere(R)) is not indicated for the treatment of asthma.

Known hypersensitivity to budesonide or any ingredient in the formulation.

Orally inhaled budesonide is contraindicated as primary treatment of acute asthmatic attacks or status asthmaticus when intensive measures (e.g., an orally inhaled beta2adrenergic agonist, an orally inhaled anticholinergic agent, subcutaneous epinephrine, IV aminophylline, and/or an oral/IV glucocorticoid) are required.

Orally inhaled budesonide powder (Pulmicort(R) Flexhaler(R)) is contraindicated in patients with severe hypersensitivity to milk proteins.

Budesonide in fixed combination with formoterol fumarate (Symbicort(R)) is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required.

When budesonide is used in fixed combination with formoterol fumarate, contraindications associated with formoterol fumarate should be considered.

There are no contraindication contraindications for this drug.

• Fungal infection
• Ocular hypertension
• Osteoporosis
• Parasitic infection

• Active tuberculosis
• Angle-closure glaucoma
• Benign prostatic hyperplasia
• Bladder outflow obstruction
• Cardiac arrhythmia
• Cataracts
• Chickenpox
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Chronic myocardial ischemia
• Diabetes mellitus
• Disease of liver
• Glaucoma
• Hypertension
• Hypokalemia
• Hypothalamic-pituitary insufficiency
• Immunosuppression
• Measles
• Osteopenia
• Pheochromocytoma
• Seizure disorder
• Thyrotoxicosis
• Urinary retention

Adverse effects occurring in 2% or more of adults in clinical trials receiving formoterol fumarate oral inhalation solution for the treatment of COPD include diarrhea, nausea, vomiting, nasopharyngitis, dry mouth, dizziness, and insomnia.

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with budesonide for the treatment of asthma include nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis.

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with budesonide for the treatment of COPD include nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection.

Adverse effects occurring in 2% or more of patients receiving formoterol fumarate in fixed combination with glycopyrrolate for the treatment of COPD and more frequently than in those receiving placebo include urinary tract infection and cough.

Adverse effects occurring in 3% or more of patients receiving formoterol fumarate in fixed combination with mometasone furoate for the treatment of asthma and more frequently than in those receiving placebo include nasopharyngitis, sinusitis, and headache.

Adverse effects occurring in at least 5% of patients receiving budesonide oral capsules include headache, dizziness, nausea, vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, sinusitis, respiratory infection, viral infection, pain (including back pain), arthralgia, and fatigue. Adverse effect profile in long-term treatment was similar to that of short-term treatment.

Adverse effects occurring in 1% or more of patients receiving budesonide by oral inhalation (as a powder using a Flexhaler(R) or a Turbuhaler(R) (no longer commercially available in the US) or as an inhalation suspension, administered via nebulization) include infections (e.g., respiratory infection, ocular infection), nasopharyngitis, pharyngitis, nasal congestion, allergic rhinitis, sinusitis, viral infection (e.g., herpes simplex), cough, voice alteration, stridor, earache, otitis (media or externa), viral infection, flu-like syndrome, moniliasis, oral candidiasis, flu syndrome, fever, headache, migraine, insomnia, dysphonia, hyperkinesia, asthenia, fatigue, emotional lability, pain (e.g., back pain), arthralgia, myalgia, hypertonia, fractures, dyspepsia, gastroenteritis, nausea, vomiting, diarrhea, abdominal pain, dry mouth, taste perversion, weight gain, anorexia, epistaxis, ecchymosis, purpura, cervical lymphadenopathy, conjunctivitis, rash (may be pustular), pruritus, allergic reaction, contact dermatitis, syncope, and chest pain.

Less Frequent

• Chest pain
• Tremor

Rare or Very Rare

• Adrenocortical insufficiency
• Aggravated glaucoma
• Anaphylaxis
• Anaphylaxis
• Angina
• Angioedema
• Angioedema
• Angioedema
• Asthma exacerbation
• Atrial fibrillation
• Atrial fibrillation
• Cardiac arrhythmia
• Cataracts
• Diabetes mellitus
• Drug-induced psychosis
• Eosinophilic granulomatosis with polyangiitis
• Gastroenteritis
• Glaucoma
• Hypercortisolism
• Hyperglycemia
• Hypertension
• Hypokalemia
• Hypotension
• Immunosuppression
• Influenza
• Malaise
• Metabolic acidosis
• Ocular hypertension
• Osteopenia
• Paradoxical bronchospasm
• Paradoxical bronchospasm
• Paradoxical bronchospasm
• Skin rash
• Tachycardia
• Urticaria
• Ventricular premature beats

More Frequent

• Allergic rhinitis
• Cough
• Diarrhea
• Dizziness
• Dyspepsia
• Gastroenteritis
• Headache disorder
• Insomnia
• Nasal congestion
• Nausea
• Oral candidiasis
• Pharyngitis
• Pharyngitis
• Sinusitis
• Sore throat
• Upper respiratory infection
• Upper respiratory infection
• Voice change
• Vomiting
• Xerostomia

Less Frequent

• Abdominal pain with cramps
• Acute bacterial otitis media
• Arthralgia
• Back pain
• Bronchitis
• Bronchitis
• Bruising
• Cough
• Cough
• Cramps
• Diarrhea
• Dysgeusia
• Dyspnea
• Dyspnea
• Ecchymosis
• Fatigue
• Fever
• General weakness
• Headache disorder
• Insomnia
• Muscle spasm
• Nausea
• Pain
• Pain
• Pharyngitis
• Pneumonia
• Rhinitis
• Sinusitis
• Skin rash
• Sore throat
• Syncope
• Urinary retention
• Urinary tract infection
• Vomiting
• Wheezing
• Xerostomia

Rare or Very Rare

• Aggressive behavior
• Arthralgia
• Contact dermatitis
• Depression
• Dysuria
• Esophageal candidiasis
• Fatigue
• Flu-like symptoms
• Gastroesophageal reflux disease
• Hyperglycemia
• Insomnia
• Irritability
• Nausea
• Nervousness
• Nervousness
• Pain in oropharynx
• Palpitations
• Pruritus of skin
• Pruritus of skin
• Skin rash
• Symptoms of anxiety
• Symptoms of anxiety
• Upper abdominal pain
• Urticaria
• Voice change

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Formoterol fumarate oral inhalation solution (Perforomist(R)) and formoterol fumarate in fixed combination with glycopyrrolate (Bevespi(R) Aerosphere(R)) are not indicated for use in children. Safety and efficacy of these preparations in children have not been established.

Safety and efficacy of formoterol fumarate in fixed combination with budesonide (Symbicort(R)) in pediatric patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration. Safety and efficacy of formoterol/budesonide in pediatric patients 6 to less than 12 years of age with asthma have been established in studies of up to 12 weeks' duration; however, the manufacturer states that safety and efficacy of the fixed-combination preparation in children younger than 6 years of age with asthma have not been established.

Safety and efficacy of formoterol fumarate in fixed combination with mometasone furoate (Dulera(R)) in pediatric patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration.

Available data from controlled clinical trials suggest that monotherapy with long-acting beta2-adrenergic agonists increases the risk of asthma-related hospitalization in pediatric and adolescent patients. (See Asthma-related Death and Serious Asthma-related Events under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of oral budesonide delayed-release capsules have not been established in pediatric patients younger than 18 years of age with Crohn's disease. Oral budesonide (using preparations other than Entecort(R) EC) has been used for the management of mild to moderately active Crohn's disease in a limited number of pediatric patients without unusual adverse effects. Benign intracranial hypertension has been reported in at least one pediatric patient with Crohn's disease receiving the drug.

Safety and efficacy of budesonide inhalation powder have not been established in children younger than 6 years of age. Efficacy of budesonide inhalation suspension has not been established in children younger than 1 year of age, while safety of the suspension has not been established in children younger than 6 months of age. Safety and efficacy of budesonide in fixed combination with formoterol fumarate (Symbicort(R)) inhalation aerosol in patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration; in addition, safety and efficacy of the fixed-combination preparation in children 6 to less than 12 years of age with asthma have been established in studies of up to 12 weeks' duration. The manufacturer states that safety and efficacy of the fixed-combination preparation in children younger than 6 years of age with asthma have not been established. Use of corticosteroids may lead to suppression of growth in children and adolescents. Therefore, children receiving prolonged therapy with orally inhaled budesonide should be monitored periodically for possible adverse effects on growth and development. (See Cautions: Pediatric Precautions, in the Corticosteroids General Statement 68:04.)

Category C. (See Users Guide.) Formoterol may interfere with uterine contractility; carefully weigh benefit versus risk in labor.

There is an increased risk of adverse perinatal outcomes (e.g., preeclampsia, premature birth, low birth weight, and neonates small for gestational age) in women with poorly or moderately controlled asthma. Pregnant women with asthma should be closely monitored and therapy adjusted as necessary to maintain optimal asthma control.

The effects of formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate during labor and delivery are not known. Because of the potential for beta-agonist interference with uterine contractility, use of formoterol in fixed combination with budesonide, glycopyrrolate, or mometasone during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Category B (orally inhaled powder and inhalation suspension); category C (oral capsules and the fixed combination of budesonide and formoterol fumarate oral inhalation aerosol). (See Users Guide.) Hypoadrenalism may occur in infants of women receiving corticosteroid therapy during pregnancy. These infants should be carefully monitored.

Formoterol is distributed into milk in rats; it is not known whether formoterol is distributed into human milk. Effects of formoterol fumarate on breast-fed infants or milk production also are not known.

The benefits of breast-feeding and the woman's clinical need for formoterol fumarate alone or in fixed combination with budesonide or mometasone should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Because many drugs are distributed into human milk, caution should be exercised when formoterol fumarate in fixed combination with glycopyrrolate is administered to nursing women. Since there are no data from controlled clinical studies, the manufacturer of formoterol/glycopyrrolate states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Like other corticosteroids, budesonide is distributed into milk; however, data are not available on the effects of the drug on the breast-fed child or on milk production. The benefits of breast-feeding and the importance of budesonide to the woman should be considered along with any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition. The manufacturer of budesonide oral inhalation powder (Pulmicort(R) Flexhaler(R)) states that the drug should be used in nursing women only if clinically appropriate and that therapy should be titrated to the lowest effective dosage. In addition, budesonide powder inhaler should be used immediately after nursing to minimize infant exposure to the drug.

The manufacturers of formoterol fumarate and formoterol fumarate in fixed combination with budesonide, glycopyrrolate, or mometasone furoate state that dosage adjustment is not required in geriatric patients.

No substantial differences in safety and efficacy of formoterol alone or in fixed combination with budesonide, glycopyrrolate, or mometasone furoate have been observed in geriatric patients relative to younger adults. However, the manufacturers state that the possibility that some geriatric patients may exhibit increased sensitivity to formoterol or fixed combinations containing formoterol cannot be ruled out. (See Dosage and Administration: Special Populations.)

Clinical studies of oral budesonide delayed-release capsules or budesonide oral inhalation powder did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. While other clinical experience with budesonide inhalation powder or inhalation suspension or with the inhalation aerosol containing budesonide in fixed combination with formoterol fumarate has not revealed age-related differences in response, oral drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. Safety of budesonide inhalation powder in patients 65 years of age or older was similar to that observed in younger adults. No substantial differences in safety and efficacy of budesonide in fixed combination with formoterol fumarate were observed in geriatric patients relative to younger adults. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. (See Dosage and Administration: Special Populations.)