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Fluticasone and Salmeterol

Pronunciation

Pronunciation

(floo TIK a sone & sal ME te role)

Index Terms

  • Fluticasone Propionate and Salmeterol Xinafoate
  • Fluticasone/Salmeterol
  • Salmeterol and Fluticasone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol, for oral inhalation:

Advair HFA:

45/21: Fluticasone propionate 45 mcg and salmeterol 21 mcg per inhalation (8 g) [chlorofluorocarbon free]

45/21: Fluticasone propionate 45 mcg and salmeterol 21 mcg per inhalation (12 g) [chlorofluorocarbon free]

115/21: Fluticasone propionate 115 mcg and salmeterol 21 mcg per inhalation (8 g) [chlorofluorocarbon free]

115/21: Fluticasone propionate 115 mcg and salmeterol 21 mcg per inhalation (12 g) [chlorofluorocarbon free]

230/21: Fluticasone propionate 230 mcg and salmeterol 21 mcg per inhalation (8 g) [chlorofluorocarbon free]

230/21: Fluticasone propionate 230 mcg and salmeterol 21 mcg per inhalation (12 g) [chlorofluorocarbon free]

Powder, for oral inhalation:

Advair Diskus:

100/50: Fluticasone propionate 100 mcg and salmeterol 50 mcg (14s, 60s) [contains lactose]

250/50: Fluticasone propionate 250 mcg and salmeterol 50 mcg (14s, 60s) [contains lactose]

500/50: Fluticasone propionate 500 mcg and salmeterol 50 mcg (14s, 60s) [contains lactose]

Brand Names: U.S.

  • Advair Diskus
  • Advair HFA

Pharmacologic Category

  • Beta2 Agonist
  • Beta2-Adrenergic Agonist, Long-Acting
  • Corticosteroid, Inhalant (Oral)

Pharmacology

Combination of fluticasone (corticosteroid) and salmeterol (long-acting beta2-agonist) designed to improve pulmonary function and control over what is produced by either agent when used alone. Because fluticasone and salmeterol act locally in the lung, plasma levels do not predict therapeutic effect.

Fluticasone: The mechanism of action for all topical corticosteroids is believed to be a combination of three important properties: Anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions. Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity.

Salmeterol: Relaxes bronchial smooth muscle by selective action on beta2-receptors with little effect on heart rate

Use: Labeled Indications

Asthma: Treatment of asthma in patients 4 years and older (Diskus) and in patients 12 years and older (HFA).

Chronic obstructive pulmonary disease (Diskus only): Twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Fluticasone 250 mcg/salmeterol 50 mcg Diskus is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

Fluticasone 250 mcg/salmeterol 50 mcg Diskus twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength fluticasone 500 mcg/salmeterol 50 mcg Diskus over fluticasone 250 mcg/salmeterol 50 mcg Diskus has not been demonstrated.

General information: Fluticasone/salmeterol is not indicated for the relief of acute bronchospasm.

Contraindications

Hypersensitivity to fluticasone, salmeterol, or any component of the formulation; status asthmaticus; acute episodes of asthma or COPD; severe hypersensitivity to milk proteins (Advair Diskus)

Documentation of allergenic cross-reactivity for corticosteroids and sympathomimetics are limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Do not use to transfer patients from systemic corticosteroid therapy. Patients receiving fluticasone/salmeterol should not use additional salmeterol or other inhaled, long-acting beta2-agonists (eg, formoterol, arformoterol) for any other reason.

COPD: Oral Inhalation: Advair Diskus:

US labeling: Fluticasone 250 mcg/salmeterol 50 mcg twice daily, 12 hours apart. Note: This is the maximum dose.

Canadian labeling: Fluticasone 250 mcg/salmeterol 50 mcg or fluticasone 500 mcg/salmeterol 50 mcg twice daily, 12 hours apart.

Asthma (maintenance): Oral inhalation:

Advair Diskus: One inhalation twice daily, morning and evening, 12 hours apart

Maximum dose: Fluticasone 500 mcg/salmeterol 50 mcg per inhalation (2 inhalations/day)

Advair HFA: Two inhalations twice daily, morning and evening, 12 hours apart

Maximum dose: Fluticasone 230 mcg/salmeterol 21 mcg per inhalation (4 inhalations/day)

Advair 125 or Advair 250 [Canadian products]: Two inhalations twice daily, morning and evening, 12 hours apart

Note: Initial dose prescribed should be based upon asthma severity. Dose should be increased after 2 weeks if adequate response is not achieved. Patients should be titrated to lowest effective dose once stable.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Patients receiving fluticasone/salmeterol should not use additional salmeterol or other inhaled, long-acting beta2-agonists (eg, formoterol, arformoterol) for any other reason.

Asthma: Oral inhalation:

Children 4 to 11 years: Advair Diskus: Fluticasone 100 mcg/salmeterol 50 mcg twice daily, 12 hours apart. Note: This is the maximum dose.

Children ≥12 years: Refer to adult dosing.

Dosing: Renal Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling: No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment required; manufacturer suggests close monitoring of patients with hepatic impairment.

Administration

Advair Diskus: After removing from box and foil pouch, write the “Pouch opened” and “Use by” dates on the label on top of the Diskus. The “Use by” date is 1 month from date of opening the pouch. Every time the lever is pushed back, a dose is ready to be inhaled. Do not close or tilt the Diskus after the lever is pushed back. Do not play with the lever or move the lever more than once. The dose indicator tells you how many doses are left. When the numbers 5 to 0 appear in red, only a few doses remain. Discard device 1 month after you remove it from the foil pouch or when the dose counter reads “0” (whichever comes first). Rinse mouth with water after use and spit to reduce risk of oral candidiasis.

Advair HFA: Shake well for 5 seconds before each spray. Prime with 4 test sprays (into air and away from face) before using for the first time. If canister is dropped or not used for >4 weeks, prime with 2 sprays. Patient should contact pharmacy for refill when the dose counter reads “020”. Discard device when the dose counter reads “000”. Do not spray in eyes. Rinse mouth with water after use and spit to reduce risk of oral candidiasis.

Dietary Considerations

Advair Diskus powder for oral inhalation contains lactose; very rare anaphylactic reactions have been reported in patients with severe milk protein allergy.

Storage

Advair Diskus: Store at 20°C to 25°C (68°F to 77°F). Store in a dry place out of direct heat or sunlight. Diskus device should be discarded 1 month after removal from foil pouch, or when dosing indicator reads “0” (whichever comes first); device is not reusable.

Advair HFA: Store at 20°C to 25°C (68°F to 77°F), excursions permitted from 15°C to 30°C (59°F to 86°F). Store with mouthpiece down. Discard after 120 inhalations. Discard device when the dose counter reads “000”. Device is not reusable.

Drug Interactions

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination

Amphotericin B: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cobicistat: May increase the serum concentration of Fluticasone (Oral Inhalation). Avoid combination

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Salmeterol. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Salmeterol. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Long-Acting Beta2-Agonists: May enhance the adverse/toxic effect of other Long-Acting Beta2-Agonists. Avoid combination

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loop Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Telaprevir: May increase the serum concentration of Salmeterol. Avoid combination

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tipranavir: May increase the serum concentration of Salmeterol. Avoid combination

Tipranavir: May increase the serum concentration of Fluticasone (Oral Inhalation). Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Headache (12% to 21%)

Respiratory: Upper respiratory tract infection (16% to 27%), pharyngitis (9% to 13%)

>3% to 10%:

Central nervous system: Dizziness (1% to 4%), pain (1% to 4%)

Gastrointestinal: Nausea (3% to 6%), vomiting (3% to 6%), gastrointestinal infection (≤4%; including viral), diarrhea (2% to 4%), oral candidiasis (1% to 4%)

Neuromuscular & skeletal: Musculoskeletal pain (2% to 7%), myalgia (≤4%)

Respiratory: Throat irritation (7% to 9%), bronchitis (2% to 8%), upper respiratory tract inflammation (4% to 7%), lower respiratory tract infection (1% to 7%; COPD diagnosis and age >65 years increase risk), cough (3% to 6%), sinusitis (4% to 5%), viral respiratory tract infection (3% to 5%), hoarseness (1% to 5%)

1% to 3%:

Cardiovascular: Cardiac arrhythmia, chest symptoms, edema, myocardial infarction, palpitations, syncope, tachycardia

Central nervous system: Migraine, mouth pain, sleep disorder

Dermatologic: Dermatitis, diaphoresis, eczema, exfoliation of skin, urticaria, viral skin infection

Endocrine & metabolic: Fluid retention, hypothyroidism, weight gain

Gastrointestinal: Constipation, dysgeusia, oral mucosa ulcer

Genitourinary: Urinary tract infection

Hematologic & oncologic: Hematoma

Hepatic: Abnormal hepatic function tests

Hypersensitivity: Hypersensitivity reaction

Infection: Candidiasis (≤3%), bacterial infection, viral infection

Neuromuscular & skeletal: Muscle injury (≤3%), arthralgia, bone disease, bone fracture, muscle cramps, muscle rigidity, muscle spasm, ostealgia, rheumatoid arthritis, tremor

Ophthalmic: Conjunctivitis, eye redness, keratitis, xerophthalmia

Respiratory: Chest congestion, ENT infection, epistaxis, laryngitis, lower respiratory signs and symptoms (hemorrhage), nasal signs and symptoms (irritation), rhinitis, rhinorrhea, sneezing

Miscellaneous: Burn, laceration, wound

<1% (Limited to important or life-threatening): Aggressive behavior, atrial fibrillation, cataract, Churg-Strauss syndrome, Cushing's syndrome, decreased linear skeletal growth rate, depression, dysmenorrhea, ecchymoses, esophageal candidiasis, exacerbation of asthma (serious and some fatal), glaucoma, hyperactivity, hyperglycemia, hypersensitivity reaction (immediate and delayed), hypertension, hypokalemia, hypothyroidism, influenza, irritability, lassitude, myositis, osteoporosis, pallor, paranasal sinus disease, paresthesia, pelvic inflammatory disease, photodermatitis, skin rash, supraventricular tachycardia, syncope, tracheitis, ventricular tachycardia, vulvovaginitis

ALERT: U.S. Boxed Warning

Asthma-related death:

Long-acting beta-2 adrenergic agonists such as salmeterol may increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths of 13,176 patients treated for 28 weeks on salmeterol vs 3 deaths of 13,179 patients on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma-control drugs mitigates the increased risk of asthma-related death from long-acting beta-2 adrenergic agonists. Available data from controlled clinical trials suggest that long-acting beta-2 adrenergic agonists increase the risk of asthma-related hospitalization in pediatric patients and adolescents.

Therefore, when treating patients with asthma, only prescribe fluticasone/salmeterol for patients not adequately controlled on a long-term asthma-control medication (eg, inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and long-acting beta-2 adrenergic agonist. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (eg, discontinue fluticasone/salmeterol) if possible without loss of asthma control, and maintain the patient on a long-term asthma-control medication, such as an inhaled corticosteroid. Do not use fluticasone/salmeterol for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: Fluticasone may cause hypercorticism or suppression of hypothalamic-pituitary-adrenal (HPA) axis in sensitive patients. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Patients receiving ≥20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections.

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-agonists (LABAs), such as salmeterol, increase the risk of asthma-related deaths; fluticasone/salmeterol should only be used in patients not adequately controlled on a long-term asthma control medication (ie, inhaled corticosteroid) or whose disease severity requires initiation of two maintenance therapies. In a large, randomized, placebo-controlled US clinical trial (SMART 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use; however, current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2015; NIH/NHLBI 2007). Assess patients at regular intervals once asthma control is maintained on combination therapy to determine if step-down therapy is appropriate (without loss of asthma control), and the patient can be maintained on an inhaled corticosteroid only. LABAs are not appropriate in patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. In a more recent multicenter, randomized, double-blinded trial, the use of salmeterol and an inhaled corticosteroid (ie, fluticasone) combined in a single inhaler in a large number of adolescent and adult patients with persistent asthma (non-life threatening and stable) did not increase the risk of serious asthma-related events compared with fluticasone alone; in addition, patients receiving fluticasone/salmeterol had fewer severe asthma exacerbations compared with patients receiving fluticasone alone (Stempel 2016).

• Bronchospasm: Rarely, paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response.

• Hypersensitivity reactions: Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm) have been reported.

• Immunosuppression: Prolonged use of corticosteroids may also increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Avoid use if possible in patients with ocular herpes; active or quiescent tuberculosis infections of the respiratory tract; or untreated viral, fungal, or bacterial or parasitic systemic infections. Exposure to chickenpox or measles should be avoided; if the patient is exposed, prophylaxis with varicella zoster immune globulin or pooled intramuscular immunoglobulin, respectively, may be indicated; if chickenpox develops, treatment with antiviral agents may be considered. With oral inhalation, local yeast infections (eg, oropharyngeal candidiasis) may occur; patient should rinse mouth with water and spit after each use to reduce incidence.

• Lower respiratory infections: Pneumonia and other lower respiratory tract infections have been reported in patients with COPD following the use of inhaled corticosteroids; monitor COPD patients closely since pneumonia symptoms may overlap symptoms of exacerbations.

• Oral candidiasis: Infections with Candida albicans in the mouth and throat (thrush) have been reported with use.

• Psychiatric manifestations: Corticosteroid use may cause psychiatric manifestations, including depression, euphoria, insomnia, mood swings, and personality changes. Preexisting psychiatric conditions may be exacerbated by corticosteroid use.

• Serious effects/fatalities: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.

• Upper airway symptoms: There have been reports of laryngeal spasm, irritation, and swelling (stridor, choking) with use.

• Vasculitis: Rare cases of vasculitis (Churg-Strauss syndrome) or other systemic eosinophilic conditions can occur; often associated with decrease and/or withdrawal of oral corticosteroid therapy following initiation of inhaled corticosteroid.

Disease-related concerns:

• Asthma: Appropriate use: Do not use for acute bronchospasm. Short-acting beta2-agonist (eg, albuterol) should be used for acute symptoms and symptoms occurring between treatments. Do not initiate in patients with significantly worsening or acutely deteriorating asthma.

• Bone mineral density: Use with caution in patients with major risk factors for decreased bone mineral count such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants or oral corticosteroids); high doses and/or long-term use of inhaled corticosteroids have been associated with decreases in bone mineral density.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, hypertension, or HF); beta-agonists may cause elevation in blood pressure, heart rate, and result in CNS stimulation/excitation. Beta2-agonists may also increase risk of arrhythmias.

• COPD: Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Data are not available to determine if LABA use increases the risk of death in patients with COPD.

• Diabetes: Use with caution in patients with diabetes mellitus; beta2 agonists may increase serum glucose.

• Hepatic impairment: Use with caution in patients with hepatic impairment; may lead to accumulation of fluticasone in plasma; monitor closely.

• Hypokalemia: Use with caution in patients with hypokalemia; beta2 agonists may decrease serum potassium.

• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged fluticasone use. Consider routine eye exams in chronic users.

• Seizure disorders: Use with caution in patients with seizure disorders; beta-agonists may result in CNS stimulation/excitation.

• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in patients with hyperthyroidism and decreases in hypothyroidism.

Concurrent drug therapy issues:

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

Special populations:

• Pediatric: [U.S. Boxed Warning]: LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Orally-inhaled and intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 centimeter per year [range 0.3-1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally-inhaled and intranasal corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.

Dosage form specific issues:

• Lactose: Powder for oral inhalation (Advair Diskus) contains lactose; very rare anaphylactic reactions have been reported in patients with severe milk protein allergy.

Other warnings/precautions:

• Discontinuation of systemic corticosteroids: Withdraw systemic corticosteroid therapy with gradual tapering of dose; consider reducing the daily prednisone dose by 2.5 to 5 mg on a weekly basis beginning after at least 1 week of inhalation therapy. Monitor lung function, beta-agonist use, asthma symptoms, and for signs and symptoms of adrenal insufficiency (fatigue, lassitude, weakness, nausea and vomiting, hypotension) during withdrawal.

• Patient information: Patients must be instructed to use short-acting beta2-agonist (eg, albuterol) for acute asthmatic or COPD symptoms and to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use of inhaled short-acting beta2-agonist may indicate deterioration of asthma, and medical evaluation must not be delayed. Therapy should not be used more than twice daily; do not use with other long-acting beta 2-agonists.

Monitoring Parameters

FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation; glaucoma and cataracts. Monitor for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating asthma condition. The growth of pediatric patients receiving inhaled corticosteroids should be monitored routinely (eg, via stadiometry).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies using this combination. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), nausea, vomiting, illogical thinking, signs of infection, signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, anxiety, behavioral changes, vision changes, burning or numbness feeling, choking, change in voice, seizures, bone pain, severe dizziness, severe headache, insomnia, loss of strength and energy, vaginitis, weight gain, mouth sores, redness or white patches in mouth or throat, or difficulty breathing, wheezing, or coughing after use (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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