Fluticasone-Salmeterol (fluticasone propionate/salmeterol xinafoate)

Unless otherwise stated, the dose of fluticasone propionate administered as an aerosol via metered-dose inhaler with a hydrofluoroalkane (HFA) propellant is expressed as the amount of drug delivered from the actuator of the inhaler per metered spray; the dose of fluticasone propionate (and of salmeterol in the combination preparation Advair(R)) administered as an oral inhalation powder is expressed as the nominal (labeled) dose contained in each foil-wrapped blister. The manufacturer states that spacer devices should not be used with Advair(R) or Flovent(R) Diskus(R).

Each actuation of the commercially available fluticasone propionate HFA oral inhalation aerosol labeled as containing 44, 110, or 220 mcg of fluticasone propionate per metered spray delivers 50, 125, or 250 mcg from the valve, respectively, and 44, 110, or 220 mcg from the actuator, respectively. The 10.6-g (labeled as containing 44 mcg of fluticasone propionate) or 12-g canister (labeled as containing 110 or 220 mcg of fluticasone propionate) delivers 120 metered sprays of fluticasone propionate.

Each actuation of the oral aerosol inhaler containing the fixed combination of fluticasone propionate and salmeterol xinafoate delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol from the valve. Dosages of fluticasone propionate and salmeterol 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 fluticasone propionate in fixed combination with salmeterol delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.

With commercially available fluticasone propionate inhalation powder (Flovent(R) Diskus(R), Advair(R) Diskus(R)) delivered via the Diskus(R) device, the amount of drug delivered to the lungs depends on factors such as the patient's inspiratory flow. Using standardized in vitro testing at a flow rate of 60 L per minute for 2 seconds, the Flovent(R) Diskus(R) labeled as containing 50, 100, or 250 mcg of fluticasone propionate delivers 46, 94, or 235 mcg of fluticasone propionate, respectively. In adults with obstructive lung disease and severely compromised lung function (FEV1 20-30% of predicted), mean peak inspiratory flow through the Diskus(R) device was 82.4 L/minute. In children 4 and 8 years of age with asthma, mean peak inspiratory flow through the Diskus(R) device was 70 and 104 L/minute, respectively. Using standardized in vitro testing at a flow rate of 60 L per minute for 2 seconds, the Advair(R) Diskus(R) device delivered 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol per activation from a Diskus(R) labeled as containing 100, 250, or 500 mcg of fluticasone propionate and 50 mcg of salmeterol, respectively. In adults with obstructive lung disease and severely compromised lung function (FEV1 20-30% of predicted), mean peak inspiratory flow through the Diskus(R) device was 82.4 L/minute for Advair(R). In adults and adolescents with asthma, mean peak inspiratory flow through the Diskus(R) device was 122.2 L/minute. In a group of children 4 years of age, mean peak inspiratory flow through the Advair(R) Diskus(R) device averaged 75.5 L/minute; in children 8 years of age, mean peak inspiratory flow averaged 107.3 L/minute.

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.

Fluticasone propionate alone and in fixed combination with salmeterol is administered as a microcrystalline suspension by oral inhalation using an oral aerosol inhaler with hydrofluoroalkane (HFA; non-chlorofluorocarbon) propellant or as the inhalation powder using the Diskus(R) device that delivers the drug from foil-wrapped blisters. Fluticasone propionate in fixed combination with salmeterol xinafoate is also administered as an inhalation powder using the Diskus(R) device that delivers the drugs from foil-wrapped blisters.

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.)

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

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.

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)

Salmeterol Combinations/Selected Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the CYP3A4 metabolism of the portion of both the corticosteroid (budesonide or fluticasone) and salmeterol that is swallowed, resulting in significant systemic absorption.(1-18)

CLINICAL EFFECTS: Inhibitors of CYP3A4 may result in increased systemic exposure and effects of budesonide or fluticasone, including Cushing's syndrome and adrenal suppression. Systemic effects of salmeterol, including palpitations and sinus tachycardia, may also occur.(1-18)

PREDISPOSING FACTORS: The risk of Cushing's syndrome and adrenal suppression may be higher in patients with concurrent use of systemic glucocorticoids.

PATIENT MANAGEMENT: Concurrent therapy of budesonide-salmeterol or fluticasone-salmeterol with strong CYP3A4 inhibitors is not recommended.(18) Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone. Canadian labeling contraindicates concurrent use of atazanavir/ritonavir, darunavir/cobicistat, and lopinavir/ritonavir with salmeterol.(19-22) If concurrent therapy is warranted, patients should be closely monitored for systemic effects. Advise patients receiving concurrent therapy to rinse their mouth thoroughly after administering budesonide-salmeterol or fluticasone-salmeterol to limit the amount of drug that is swallowed.

DISCUSSION: 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, maximum concentration (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.(8,13,17) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively. The cortisol AUC decreased by 86%.(18) There have been many case reports of Cushing's syndrome in patients treated concurrently with ritonavir and fluticasone.(23-41) 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 AUC and 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).(18) An in vitro study showed that ketoconazole completely inhibited the metabolism of salmeterol to alpha-hydroxysalmeterol by CYP3A4.(42) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(43)

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)

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.

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 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.

Primary treatment of severe acute asthmatic attacks or status asthmaticus when intensive measures (e.g., oxygen, parenteral bronchodilators, IV corticosteroids) are required.

Fluticasone propionate in fixed combination with salmeterol 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.

Known hypersensitivity to fluticasone propionate or any ingredient (e.g., milk protein) in the formulation.

When fluticasone propionate is used in fixed combination with salmeterol, contraindications associated with salmeterol should be considered.

There are no contraindication contraindications for this drug.

• Acute asthma attack
• Congenital long QT syndrome
• Hypokalemia
• Prolonged QT interval

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

Adverse effects occurring in more than 3% of patients older than 12 years of age receiving fluticasone propionate HFA oral inhalation aerosol in controlled clinical trials include upper respiratory tract infection, headache, throat irritation, upper respiratory inflammation, sinusitis/sinus infection, candidiasis (including oral candidiasis), cough, hoarseness/dysphonia, and bronchitis. Adverse effects reported in clinical trials with fluticasone propionate HFA inhalation aerosol in pediatric patients (4-11 years of age) generally were similar to those observed in adolescents and adults.

Adverse effects occurring in more than 3% of patients receiving fluticasone propionate oral inhalation powder in controlled clinical trials include upper respiratory tract infection, throat irritation, sinusitis/sinus infection, upper respiratory inflammation, rhinitis, viral respiratory infection, cough, bronchitis, oral candidiasis, nausea and vomiting, GI discomfort and pain, viral GI infection, musculoskeletal pain, muscle injury, headache, fever, and viral infection.

Rare or Very Rare

• Adrenocortical insufficiency
• Anaphylaxis
• Anaphylaxis
• Angina
• Angioedema
• Angioedema
• Asthma exacerbation
• Atrial fibrillation
• Bronchitis
• Cardiac arrhythmia
• Cataracts
• Central serous chorioretinopathy
• Chest pain
• Conjunctivitis
• Edema
• Esophageal candidiasis
• Extrasystoles
• Glaucoma
• Hypercortisolism
• Hypercortisolism
• Hyperglycemia
• Hyperglycemia
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypertension
• Hypokalemia
• Hypotension
• Hypothalamic-pituitary insufficiency
• Immunosuppression
• Influenza
• Keratitis
• Laryngismus
• Ocular pain
• Osteopenia
• Osteoporosis
• Paradoxical bronchospasm
• Paradoxical bronchospasm
• Pneumonia
• Seizure disorder
• Sinusitis
• Skin and skin structure infection
• Skin rash
• Stridor
• Upper respiratory infection
• Urticaria
• Ventricular tachycardia

More Frequent

• Bronchitis
• Cough
• Headache disorder
• Headache disorder
• Myalgia
• Oral candidiasis
• Pharyngeal candidiasis
• Pharyngitis
• Sinusitis
• Upper respiratory infection

Less Frequent

• Back pain
• Cough
• Cramps
• Dizziness
• Influenza
• Nasal congestion
• Nausea
• Nervousness
• Palpitations
• Rhinitis
• Sore throat
• Tachycardia
• Tremor
• Voice change

Rare or Very Rare

• Aggressive behavior
• Agitation
• Arthralgia
• Arthralgia
• Blurred vision
• Bruising
• Contact dermatitis
• Dental caries
• Dental discoloration
• Depression
• Diarrhea
• Dizziness
• Drowsy
• Dyspepsia
• Dyspepsia
• Dyspnea
• Earache
• Ecchymosis
• Eczema
• Eosinophilia
• Facial edema
• Fatigue
• Fatigue
• Fever
• Fever
• Hyperkinesis
• Hypertension
• Insomnia
• Insomnia
• Irritability
• Laryngitis
• Laryngitis
• Malaise
• Muscle rigidity
• Musculoskeletal pain
• Myalgia
• Nausea
• Oral candidiasis
• Pain in oropharynx
• Paresthesia
• Pruritus of skin
• Rhinitis
• Rhinorrhea
• Skin rash
• Sleep disorder
• Sore throat
• Symptoms of anxiety
• Symptoms of anxiety
• Thrombophlebitis
• Toothache
• Toothache
• Urinary tract infection
• Urticaria
• Viral infection
• Vomiting
• Vomiting
• Weight gain
• Xerostomia

No enhanced messaging available.

Safety and efficacy of fluticasone propionate inhalation aerosol or powder alone in children younger than 4 years of age have not been established. Safety and efficacy of the inhalation powder containing fluticasone propionate in fixed combination with salmeterol (Advair(R) Diskus(R)) in children younger than 4 years of age have not been established. Safety and efficacy of the inhalation aerosol containing fluticasone propionate in fixed combination with salmeterol (Advair(R) HFA) in children younger than 12 years of age have not been established. Use of the inhalation powder containing fluticasone propionate in children 4-11 years of age is supported by data from several clinical trials. Use of fluticasone propionate inhalation aerosol or the inhalation powder containing fluticasone propionate in fixed combination with salmeterol (Advair(R) Diskus(R)) in children 4-11 years of age is supported by data from several clinical trials and by extrapolation of efficacy data from older patients. The adverse effect profile of Flovent(R) HFA in pediatric patients (4-11 years of age) generally is similar to that observed in adolescents and adults.

Use of corticosteroids or inadequate control of chronic diseases (e.g., asthma) may lead to suppression of growth in children and adolescents. Therefore, children receiving prolonged therapy with orally inhaled fluticasone propionate should be monitored periodically (e.g., via stadiometry) for possible adverse effects on growth and development. The benefits of corticosteroid therapy should be weighed against the possibility of growth suppression and the risks associated with alternative therapies. Children should be maintained on the lowest possible dosage of fluticasone propionate that controls asthma symptoms.

Category C.

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).

While it is not known whether fluticasone propionate is distributed into milk in humans, the drug is distributed into milk in rats. In addition, other corticosteroids are distributed into milk. Data also are not available on the effects of the drug on the breast-fed child or on milk production. Since data are not available on the use of fluticasone propionate oral inhalation aerosol in nursing women, caution is advised if the drug is administered in nursing women. The benefits of breast-feeding should be considered along with the woman's clinical need for fluticasone propionate oral inhalation and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

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.

Although no overall differences in safety and efficacy of orally inhaled fluticasone propionate alone or fluticasone propionate in fixed combination with salmeterol as the inhalation aerosol (Advair(R) HFA) were observed relative to younger adults, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Experience with the inhalation powder containing fluticasone propionate in fixed combination with salmeterol (Advair(R) Diskus(R)) in those 65 years of age or older with asthma is insufficient to determine whether geriatric patients respond differently than younger patients. In clinical studies evaluating the inhalation powder containing fluticasone propionate in fixed combination with salmeterol for COPD, patients 65 years of age or older experienced a higher incidence of serious adverse effects compared with those younger than 65 years of age, although the distribution of adverse effects was similar in the two groups. Dosage of fluticasone propionate HFA inhalation aerosol in geriatric patients should be selected with caution, reflecting the greater frequency of decreased hepatic function, presence of coexisting conditions, or other drug therapies in such patients. Dosage adjustments based solely on age are not recommended in geriatric patients receiving fluticasone propionate inhalation powder alone or fluticasone propionate inhalation powder or aerosol in fixed combination with salmeterol.