Serevent Diskus (salmeterol xinafoate)

Dosage of salmeterol xinafoate is expressed in terms of salmeterol. Although each blister of the double-foil blister strip in the Serevent(R) Diskus(R) device contains 50 mcg of salmeterol as salmeterol xinafoate inhalation powder, the precise amount of drug delivered to the lungs with each activation of the Diskus(R) device depends on factors such as the patient's inspiratory flow. (See Chemistry and Stability: Chemistry.)

Each blister of the foil blister strip in the Advair(R) Diskus(R) device contains 50 mcg of salmeterol as salmeterol xinafoate and 100, 250, or 500 mcg of fluticasone propionate; however, the precise amount of each drug delivered to the lungs with each activation of the Diskus(R) device depends on factors such as the patient's inspiratory flow. (See Chemistry and Stability: Chemistry.)

Each actuation of the AirDuo(R) RespiClick(R) device contains 14 mcg of salmeterol as salmeterol xinafoate and 55, 113, or 232 mcg of fluticasone propionate; however, the precise amount of each drug delivered to the lungs with each actuation of the RespiClick(R) device depends on factors such as the patient's inspiratory flow.

Each actuation of the oral aerosol inhaler of the fixed combination of salmeterol and fluticasone propionate (Advair(R) HFA) delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol from the valve. Dosages of salmeterol and fluticasone propionate in the fixed-combination inhalation aerosol are expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 45, 115, or 230 mcg of fluticasone propionate and 21 mcg of salmeterol from the mouthpiece. The commercially available inhalation aerosol of salmeterol in fixed combination with fluticasone propionate delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.

The manufacturer states that adjustment of salmeterol dosage alone or in fixed combination with fluticasone propionate is not necessary in geriatric patients.

The pharmacokinetics of salmeterol or salmeterol in fixed combination with fluticasone have not been studied in patients with hepatic impairment. Since salmeterol and fluticasone propionate are cleared predominantly by hepatic metabolism, impaired liver function theoretically may lead to accumulation of the drugs in plasma. Therefore, the manufacturers recommend that patients with hepatic disease be monitored closely while receiving salmeterol therapy.

The pharmacokinetics of salmeterol in fixed combination with fluticasone have not been studied in patients with renal impairment. Therefore, there are no specific dosage recommendations for such patients.

Salmeterol xinafoate is administered by oral inhalation using a special preloaded oral inhaler (Serevent(R) or Advair(R) Diskus(R), or AirDuo(R) RespiClick(R)) that delivers powdered drug alone or in fixed combination with fluticasone propionate. The manufacturer of the Diskus(R) devices states that spacer devices should not be used with Serevent(R) or Advair(R) Diskus(R). The manufacturer of the RespiClick(R) device states that spacers or volume holding chambers should not be used with AirDuo(R) RespiClick(R).

Salmeterol/fluticasone propionate inhalation aerosol (Advair(R) HFA) should only be used with the actuator supplied with the product. Before each inhalation, the inhaler must be shaken well for 5 seconds. The aerosol inhaler should be test sprayed 4 times into the air (away from the face) before initial use, and shaken well for 5 seconds before each spray. If the inhaler has not been used for more than 4 weeks or if the inhaler was dropped, the inhaler should be test sprayed twice into the air (away from the face) and shaken well for 5 seconds before each spray.

The cap covering the mouthpiece should be slipped off the mouthpiece; the strap on the cap will stay attached to the mouthpiece. The patient should look for foreign objects inside the inhaler prior to use, and should check to see that the canister is fully seated within the actuator. After exhaling as completely as possible, the patient should place the mouthpiece of the inhaler well into the mouth and close the lips firmly around it. Then the patient should inhale deeply through the mouth while actuating the inhaler. The patient should remove the mouthpiece from the mouth and hold the breath for as long as possible, up to 10 seconds, and exhale slowly. It is recommended that 30 seconds elapse between inhalations. Rinsing the mouth after inhalation of salmeterol/fluticasone propionate inhalation aerosol and spitting out the water are advised. The opening for the spray of the metal canister and the mouthpiece should be wiped with a dry cotton swab and dampened tissue, respectively, at least once a week after the evening dose. The actuator should be allowed to air-dry overnight. When the dose counter on the inhaler reads ''020,'' the patient should contact the pharmacy for a refill or consult their clinician to determine whether a refill is needed. The inhaler should be discarded when the dose counter reads ''000.'' The counter should never be altered or removed from the canister.

For administration of salmeterol xinafoate alone (Serevent(R)) or in combination with fluticasone propionate (Advair(R)) inhalation powder via the Diskus(R) device, the patient should hold the device in one hand, put the thumb of the other hand on the thumbgrip, and push the thumbgrip until the mouthpiece appears and snaps into position. The lever on the Diskus(R) should then be depressed in a direction away from the patient while the inhaler is held in a level, horizontal position; the lever pierces the foil blister and releases the powdered drug into an exit port. To avoid releasing and wasting additional doses of the drug, the patient should not tilt or close the Diskus(R) device, play with the lever, or advance the lever more than once at this point. A dose counter will advance each time the lever is depressed. Before inhaling the dose, the patient should exhale as completely as possible; the patient should not exhale into the Diskus(R) device because pressure from the exhalation will interfere with proper inhaler operation. The patient should then place the mouthpiece of the inhaler between the lips and inhale deeply and quickly through the inhaler with a steady, even breath; pressure from the inhalation will disperse drug from the exit port into the air stream created by the patient's inhalation. The patient should remove the inhaler from the mouth, hold his or her breath for 10 seconds (or as long as comfortable), and then exhale slowly. While most patients can taste or feel a dose of drug delivered from the Diskus(R) device, they should be instructed not to use another dose even if they do not perceive that the dose has been delivered. Rinsing the mouth after inhalation of salmeterol in fixed combination with fluticasone propionate is advised. The Diskus(R) device may be closed and reset for the next dose by sliding the thumbgrip towards the patient as far as it will go. The inhaler should not be washed but should be stored in a dry place away from direct heat or sunlight. The inhaler should be discarded when every blister has been used, or 4 or 6 weeks after removal of the Advair(R) Diskus(R) or Serevent(R) Diskus(R), respectively, from its foil overwrap pouch. The inhaler should not be taken apart.

For instructions on use of the AirDuo(R) RespiClick(R) oral inhaler, the manufacturer's labeling should be consulted.

To obtain optimal benefit, the patient should be given a copy of the product-specific patient instructions and medication guide provided by the manufacturer. (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects.)

No dosing information is available for this tab.

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

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

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

Salmeterol/Cobicistat; Protease Inhibitors

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

MECHANISM OF ACTION: Some protease inhibitors may inhibit the metabolism of the portion of salmeterol that is swallowed, resulting in significant systemic absorption.(1-14)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in systemic effects of salmeterol, including palpitations and sinus tachycardia.(1-14)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of salmeterol and the protease inhibitors state that the concurrent use of salmeterol with HCV or HIV protease inhibitors is not recommended.(1-14) The National Institutes of Health COVID-19 treatment guidelines recommend holding salmeterol during and for at least 2-3 days after completion of nirmatrelvir/ritonavir therapy.(15) The Canadian manufacturer of salmeterol states that concurrent use of atazanavir, indinavir, nelfinavir, ritonavir, and saquinavir is not recommended.(16) Canadian labeling contraindicates concurrent use of atazanavir/ritonavir, darunavir/cobicistat, and lopinavir/ritonavir with salmeterol.(18-21) Consider the use of alternative agents.

DISCUSSION: In a study in 20 healthy subjects, concurrent administration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a strong inhibitor of CYP3A4) for 7 days increased the plasma area-under-curve (AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold, respectively. Concurrent use did not result in clinically significant changes in heart rate, mean blood potassium, mean blood glucose or mean QTc; however, concurrent use was associated with more frequent increases in QTc duration. Three subjects were withdrawn from the study because of systemic salmeterol effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia).(1) An in vitro study showed that ketoconazole completely inhibited the formation of alpha-hydroxysalmeterol by CYP3A4.(1,22) Protease inhibitors linked to this monograph include: amprenavir, atazanavir, boceprevir, cobicistat, darunavir, ensitrelvir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, saquinavir, telaprevir, and tipranavir.

Salmeterol/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. 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)

Salmeterol/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 the portion of salmeterol that is swallowed, resulting in significant systemic absorption.(1) An in vitro study showed that ketoconazole completely inhibited the formation of alpha-hydroxysalmeterol by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in systemic effects of salmeterol, including palpitations and sinus tachycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that the concurrent use of salmeterol with strong inhibitors of CYP3A4 is not recommended.(1) The Canadian manufacturer of salmeterol states that concurrent use of itraconazole should be approached with caution.(2) The US manufacturer of itraconazole states that concurrent administration with salmeterol is not recommended during and two weeks after itraconazole treatment.(4) Consider the use of alternative agents.

DISCUSSION: In a study in 20 healthy subjects, concurrent administration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily) for 7 days increased the plasma area-under-curve (AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold, respectively. Concurrent use did not result in clinically significant changes in heart rate, mean blood potassium, mean blood glucose or mean QTc; however, concurrent use was associated with more frequent increases in QTc duration. Three subjects were withdrawn from the study because of systemic salmeterol effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia).(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, idelalisib, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telithromycin, troleandomycin, tucatinib, and voriconazole.(5,6)

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.

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.

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.

There is no enhanced messaging for this drug.

• Acute asthma attack

• Congenital long QT syndrome
• Hypokalemia
• Prolonged QT interval

• Chronic myocardial ischemia
• Diabetes mellitus
• Hypertension
• Seizure disorder
• Thyrotoxicosis

There is no enhanced messaging for this drug.

Rare or Very Rare

• Anaphylaxis
• Angina
• Angioedema
• Asthma exacerbation
• Atrial fibrillation
• Bronchitis
• Cardiac arrhythmia
• Chest pain
• Conjunctivitis
• Edema
• Extrasystoles
• Hypercortisolism
• Hyperglycemia
• Hypersensitivity drug reaction
• Hypertension
• Hypokalemia
• Hypotension
• Keratitis
• Laryngismus
• Paradoxical bronchospasm
• Seizure disorder
• Sinusitis
• Stridor
• Upper respiratory infection
• Ventricular tachycardia

More Frequent

• Headache disorder

Less Frequent

• Cough
• Cramps
• Dizziness
• Influenza
• Nasal congestion
• Nausea
• Nervousness
• Palpitations
• Rhinitis
• Sore throat
• Tachycardia
• Tremor

Rare or Very Rare

• Arthralgia
• Contact dermatitis
• Dyspepsia
• Earache
• Eczema
• Fatigue
• Fever
• Insomnia
• Laryngitis
• Malaise
• Myalgia
• Oral candidiasis
• Paresthesia
• Skin rash
• Symptoms of anxiety
• Toothache
• Urticaria
• Vomiting

No enhanced messaging available.

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There are no adequate and well-controlled studies of salmeterol in pregnant women. Because of the potential for beta-agonist interference with uterine contractility, use of salmeterol during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. The drug should be used during other stages of pregnancy only if the potential benefit justifies the potential risk to the fetus. Salmeterol in fixed combination with fluticasone propionate inhalation aerosol (Advair(R) HFA) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant women with poorly or moderately controlled asthma, there is an increased risk of adverse perinatal events such as preeclampsia in the mother, and prematurity, low birth weight, and small size for gestational age in the neonate. Pregnant women with asthma should be closely monitored and dosage of medications should be adjusted as needed to maintain optimal asthma control.

Reproduction studies in male and female rats using oral salmeterol dosages of up to 2 mg/kg daily (representing 160 times the recommended clinical dosage on a mg/m2 basis) have not revealed evidence of harm to the fetus. Dutch rabbit fetuses exposed to oral salmeterol dosages of at least 1 mg/kg (representing 50 times the maximum recommended daily inhalation dosage based on comparison of AUC data) exhibited characteristic effects of beta-receptor stimulation, including precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No teratogenic effects were observed at oral salmeterol doses of 0.6 mg/kg (20 times the maximum recommended daily inhalation dosage based on comparison of AUC data). Delayed ossification of the frontal bones was seen in the fetuses of New Zealand White rabbits given oral salmeterol dosages of 10 mg/kg (representing 1600 times the maximum recommended daily inhalation dosage on a mg/m2 basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to use in humans.

In reproduction studies in mice and rats, no evidence of an increased toxicity was associated with the use of salmeterol combined with fluticasone propionate when compared with toxicity observed from the components administered separately. Teratogenicity (i.e., cleft palate), fetal death, or increased implantation loss has been observed in mice receiving a subcutaneous dosage of 150 mcg/kg of fluticasone propionate (representing approximately less than the maximum recommended daily inhalation dosage in adults on a mcg/m2 basis) combined with a 10 mg/kg oral dosage of salmeterol (representing approximately 410 times the maximum recommended daily inhalation dosage in adults on a mg/m2 basis), but these effects did not occur when lower dosages of fluticasone propionate (up to 40 mcg/kg subcutaneously, representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m2 basis) were combined with lower dosages of salmeterol (up to 1.4 mg/kg orally, representing approximately 55 times the maximum recommended daily inhalation dosage in adults on a mg/m2 basis). Reproduction studies in rats receiving subcutaneous dosages of fluticasone propionate of up to 30 mcg/kg (representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m2 basis) combined with dosages of up to 1 mg/kg of salmeterol (approximately 80 times the recommended daily inhalation dosage in adults on a mg/m2 basis) did not reveal evidence of teratogenicity. Delayed ossification, changes in the occipital bone, umbilical hernia, decreased placental or fetal weight, and maternal toxicity have been observed in rats receiving subcutaneous dosages of fluticasone propionate 100 mcg/kg (representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m2 basis) combined with oral salmeterol dosages of 10 mg/kg (approximately 810 times the maximum recommended daily inhalation dosage in adults on a mg/m2 basis).

It is not known whether salmeterol xinafoate or fluticasone propionate is distributed into human milk. However, salmeterol is distributed into milk in rats. Corticosteroids, other than fluticasone propionate, are distributed into human milk. Effects of salmeterol xinafoate or fluticasone propionate on breast-fed infants or milk production also are not known. The benefits of breast-feeding and the woman's clinical need for salmeterol xinafoate or fluticasone propionate should be considered along with any potential adverse effects on the breast-fed infant from the drugs or from the underlying maternal condition. Since no data from controlled trials are available on the use of such preparations in nursing women, caution is advised if salmeterol alone or salmeterol in fixed combination with fluticasone propionate is administered in nursing women.

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