April 2008
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ADVAIR DISKUS safely and effectively. See full prescribing information
`for ADVAIR DISKUS.
`
`ADVAIR DISKUS® 100/50 (fluticasone propionate 100 mcg and
`salmeterol 50 mcg inhalation powder)
`ADVAIR DISKUS® 250/50 (fluticasone propionate 250 mcg and
`salmeterol 50 mcg inhalation powder)
`ADVAIR DISKUS® 500/50 (fluticasone propionate 500 mcg and
`salmeterol 50 mcg inhalation powder)
`FOR ORAL INHALATION
`Initial U.S. Approval: 2000
`WARNING: RISK OF ASTHMA-RELATED DEATH
`See full prescribing information for complete boxed warning.
`• Long-acting beta2-adrenergic agonists, such as salmeterol, one of the
`active ingredients in ADVAIR DISKUS, may increase the risk of
`asthma-related death. A US study showed an increase in asthma-
`related deaths in patients receiving salmeterol (13 deaths out of
`13,176 patients treated for 28 weeks on salmeterol versus 3 out of
`13,179 patients on placebo). (5.1)
`• When treating patients with asthma, only prescribe ADVAIR
`DISKUS for patients not adequately controlled on other asthma-
`controller medications or whose disease severity clearly warrants
`initiation of treatment with 2 maintenance therapies. (1.1, 5.1)
`---------------------------RECENT MAJOR CHANGES --------------------
`Indications and Usage, Maintenance Treatment of Chronic
`April 2008
`Obstructive Pulmonary Disease (1.2)
`Dosage and Administration, Chronic Obstructive
`Pulmonary Disease, (2.2)
`April 2008
`Warnings and Precautions, Pneumonia (5.5)
`Drug Interactions, Inhibitors of Cytochrome P450 3A4 (7.1) April 2008
`----------------------------INDICATIONS AND USAGE---------------------
`ADVAIR DISKUS is a combination product containing a corticosteroid and a
`long-acting beta2-adrenergic agonist indicated for:
`• Maintenance treatment of asthma in patients 4 years of age and older.
`(1.1)
`• Maintenance treatment of airflow obstruction and reducing exacerbations
`in patients with chronic obstructive pulmonary disease (COPD). (1.2)
`Important limitations:
`• Not indicated for patients whose asthma can be managed by inhaled
`corticosteroids with occasional use of inhaled short-acting beta2-agonists.
`(1.1)
`• Not indicated for the relief of acute bronchospasm. (1.1, 1.2)
`----------------------- DOSAGE AND ADMINISTRATION ----------------
`For oral inhalation only.
`• Maintenance treatment of asthma in patients ≥12 years: 1 inhalation of
`ADVAIR DISKUS 100/50, 250/50, or 500/50 twice daily. Starting dosage
`is based on asthma severity. (2.1)
`• Maintenance treatment of asthma in patients 4 to 11 years: 1 inhalation of
`ADVAIR DISKUS 100/50 twice daily. (2.1)
`• Maintenance treatment of COPD: 1 inhalation of ADVAIR DISKUS
`250/50 twice daily. (2.2)
`--------------------- DOSAGE FORMS AND STRENGTHS --------------
`DISKUS® device containing a combination of fluticasone propionate (100,
`250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder. (3)
`-------------------------------CONTRAINDICATIONS------------------------
`• Primary treatment of status asthmaticus or acute episodes of asthma or
`COPD requiring intensive measures. (4)
`• Severe hypersensitivity to milk proteins. (4)
`----------------------- WARNINGS AND PRECAUTIONS-----------------
`• Asthma-related death: Long-acting beta2-adrenergic agonists may increase
`the risk. Prescribe only for recommended patient populations. (5.1)
`• Deterioration of disease and acute episodes: Do not initiate in acutely
`deteriorating asthma or to treat acute symptoms. (5.2)
`
`
`
`1
`
`•
`
`• Use with additional long-acting beta2-agonist: Do not use in combination
`because of risk of overdose. (5.3)
`• Localized infections: Candida albicans infection of the mouth and throat
`may occur. Monitor patients periodically for signs of adverse effects on
`the oral cavity. Advise patients to rinse the mouth following inhalation.
`(5.4)
`• Pneumonia: Increased risk in patients with COPD. Monitor patients for
`signs and symptoms of pneumonia. (5.5)
`Immunosuppression: Potential worsening of infections (e.g., existing
`tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular
`herpes simplex). Use with caution in patients with these infections. More
`serious or even fatal course of chickenpox or measles can occur in
`susceptible patients. (5.6)
`• Transferring patients from systemic corticosteroids: Risk of impaired
`adrenal function when transferring from oral steroids. Taper patients
`slowly from systemic corticosteroids if transferring to ADVAIR DISKUS.
`(5.7)
`• Hypercorticism and adrenal suppression: May occur with very high
`dosages or at the regular dosage in susceptible individuals. If such
`changes occur, discontinue ADVAIR DISKUS slowly. (5.8)
`• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased
`systemic corticosteroid and cardiovascular effects. Use not recommended
`with ADVAIR DISKUS. (5.9)
`• Paradoxical bronchospasm: Discontinue ADVAIR DISKUS and institute
`alternative therapy if paradoxical bronchospasm occurs. (5.10)
`• Patients with cardiovascular or central nervous system disorders: Use with
`caution because of beta-adrenergic stimulation. (5.12)
`• Decreases in bone mineral density: Assess bone mineral density initially
`and periodically thereafter. (5.13)
`• Effects on growth: Monitor growth of pediatric patients. (5.14)
`• Glaucoma and cataracts: Close monitoring is warranted. (5.15)
`• Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and
`hyperglycemia. (5.16, 5.18)
`• Coexisting conditions: Use with caution in patients with convulsive
`disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17)
`------------------------------ ADVERSE REACTIONS -----------------------
`Most common adverse reactions (incidence ≥3%) are:
`• Asthma: upper respiratory tract infection or inflammation, pharyngitis,
`dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and
`vomiting. (6.1)
`• COPD: pneumonia, oral candidiasis, throat irritation, dysphonia, viral
`respiratory infections, headaches, musculoskeletal pain. (6.2)
`To report SUSPECTED ADVERSE REACTIONS, contact
`GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------
`•
`Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use not
`recommended. May cause systemic corticosteroid and cardiovascular
`effects. (7.1)
`• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with
`extreme caution. May potentiate effect of salmeterol on vascular system.
`(7.2)
`Beta-blockers: Use with caution. May block bronchodilatory effects of
`beta-agonists and produce severe bronchospasm. (7.3)
`Diuretics: Use with caution. Electrocardiographic changes and/or
`hypokalemia associated with nonpotassium-sparing diuretics may
`worsen with concomitant beta-agonists. (7.4)
`----------------------- USE IN SPECIFIC POPULATIONS ----------------
`Hepatic impairment: Monitor patients for signs of increased drug exposure.
`(8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`MEDICATION GUIDE.
`
`•
`
`•
`
`Revised: April 2008
`ADD:3PI
`
`MYLAN - EXHIBIT 1036
`Mylan et al. v. AstraZeneca
`IPR2015-01340
`
`

`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF ASTHMA- ELATED DEATH
`R
`1
`INDICATIONS AND USAGE
`1.1 Maintenance Treatment of Asthma
`1.2 Maintenance Treatment of Chronic
`Obstructive Pulmonary Disease
`2 DOSAGE AN ADMINISTRATION
`D
`2.1 Asthma
`2.2 Chronic Obstructive Pulmonary D sease
`i
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WA
`S AND PRECAUTIONS
`RNING
`5.1 Risk of Asthma-Related Death With Long-
`Acting Beta2-Adrenergic Agonists
`5.2 Deterioration of Disease and Acute
`Episodes
`5.3 Excessive Use of ADVAIR DISKUS and Use
`With Other L ng-Acting Beta2-Agonists
`o
`5.4 Local Effec
`ts
`5.5 Pneumonia
`5.6
`Immunosuppression
`5.7 Transferring Patients From Systemic
`Corticosteroid Therapy
`5.8 Hypercorticism and Adrenal Suppression
`5.9 Drug Interactions With Strong Cytochrome
`P450 3A4 Inhibitors
`5.10 Paradoxical Bronchospasm and Upper
`Airway Symptoms
`5.11 Immediate Hypersensitivity Reactions
`5.12 Cardiovascular and Central Nervous System
`Effects
`5.13 Reduction in Bone Mineral Density
`5.14 Effect on Growth
`5.15 Glaucoma and Cataracts
`5.16 Eosinophilic Conditions and Churg-Strauss
`Syndrome
`5.17 Coexisting Conditions
`5.18 Hypokalemia and Hyperglycemia
`6 AD ERSE REACTIONS
`V
`6.1 Clinical Trials Experience in Asthma
`
`6.2 Clinical Trials Experience in Chronic
`Obstructive Pulmonary Disease
`6.3 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1
`Inhibitors of Cytochrome P450 3A4
`7.2 Monoamine Oxidase Inhibitors and Tricyclic
`Antidepressants
`7.3 Beta-Adrenergic Receptor Blocking Agents
`7.4 Diuretics
`8 USE IN SPECIFI
` POPULATIONS
`C
`8.1 Pregnancy
`8.2 Labor and Delive y
`r
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Actio n
`12.2 Pharmacodynami s
`c
`12.3 Pharmacokinetics
`13 NON LINICAL TOXICOLOGY
`C
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL ST DIES
`U
`14.1 Asthma
`14.2 Chronic Obstructive Pulmonary Disease
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INF RMATION
`O
`17.1 Asthma-Related Death
`17.2 Not for Acute Symptoms
`17.3 Do Not Use Additional Long-Acting Beta2-
`Agonists
`17.4 Risks Associated With Corticosteroid
`Therapy
`17.5 Risks Associated With Beta-Agonist
`Therapy
`17.6 Medication Guide
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`2
`
`

`
`______________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: RISK OF ASTHMA-RELATED DEATH
`Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active
`
`ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death.
`Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR
`DISKUS for patients not adequately controlled on other asthma-controller medications
`(e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly
`warrants initiation of treatment with 2 maintenance therapies. Data from a large placebo-
`controlled US study that compared the safety of salmeterol (SEREVENT® Inhalation
`Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related
`deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for
`28 weeks on salmeterol versus 3 deaths out of 13,179 patients on placebo) [see Warnings
`and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`1
`1.1 Maintenance Treatment of Asthma
`
`ADVAIR DISKUS is indicated for the long-term, twice-daily, maintenance treatment of
`asthma in patients 4 years of age and older.
`
`Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients
`in ADVAIR DISKUS, may increase the risk of asthma-related death [see Warnings and
`Precautions (5.1)]. Therefore, when treating patients with asthma, physicians should only
`prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller
`medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity
`clearly warrants initiation of treatment with 2 maintenance therapies.
`Important Limitations of Use:
`
`• ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.
`• ADVAIR DISKUS is not indicated in patients whose asthma can be successfully managed by
`inhaled corticosteroids along with occasional use of inhaled, short-acting beta2-agonists.
`1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease
`
`ADVAIR DISKUS 250/50 is indicated for the twice-daily maintenance treatment of
`airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including
`chronic bronchitis and/or emphysema. ADVAIR DISKUS 250/50 is also indicated to reduce
`exacerbations of COPD in patients with a history of exacerbations. ADVAIR DISKUS 250/50
`twice daily is the only approved dosage for the treatment of COPD because an efficacy
`advantage of the higher strength ADVAIR DISKUS 500/50 over ADVAIR DISKUS 250/50 has
`not been demonstrated.
`Important Limitations of Use: ADVAIR DISKUS is NOT indicated for the relief of
`
`acute bronchospasm.
`
`
`
`3
`
`

`
`DOSAGE AND ADMINISTRATION
`2
`ADVAIR DISKUS should be administered twice daily every day by the orally inhaled
`
`route only. After inhalation, the patient should rinse the mouth with water without swallowing
`[see Patient Counseling Information (17.4)].
`
`More frequent administration or a higher number of inhalations (more than 1 inhalation
`twice daily) of the prescribed strength of ADVAIR DISKUS is not recommended as some
`patients are more likely to experience adverse effects with higher doses of salmeterol. Patients
`using ADVAIR DISKUS should not use additional long-acting beta2-agonists for any reason.
`[See Warnings and Precautions (5.3, 5.12).]
`2.1 Asthma
`
`If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-
`agonist should be taken for immediate relief.
`Adult and Adolescent Patients 12 Years of Age and Older: For patients 12 years of
`
`age and older, the dosage is 1 inhalation twice daily (morning and evening, approximately
`12 hours apart).
`
`The recommended starting dosages for ADVAIR DISKUS for patients 12 years of age
`and older are based upon patients’ asthma severity. For patients not currently on inhaled
`corticosteroids whose disease severity clearly warrants initiation of treatment with 2
`maintenance therapies, or patients inadequately controlled on an inhaled corticosteroid, the
`recommended starting dosage is ADVAIR DISKUS 100/50 or 250/50 twice daily.
`
`The maximum recommended dosage is ADVAIR DISKUS 500/50 twice daily.
`
`For all patients it is desirable to titrate to the lowest effective strength after
`adequate asthma stability is achieved.
`
`Improvement in asthma control following inhaled administration of ADVAIR DISKUS
`can occur within 30 minutes of beginning treatment, although maximum benefit may not be
`achieved for 1 week or longer after starting treatment. Individual patients will experience a
`variable time to onset and degree of symptom relief.
`
`For patients who do not respond adequately to the starting dosage after 2 weeks of
`therapy, replacing the current strength of ADVAIR DISKUS with a higher strength may provide
`additional improvement in asthma control.
`
`If a previously effective dosage regimen of ADVAIR DISKUS fails to provide adequate
`improvement in asthma control, the therapeutic regimen should be reevaluated and additional
`therapeutic options (e.g., replacing the current strength of ADVAIR DISKUS with a higher
`strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be
`considered.
`Pediatric Patients 4 to 11 Years of Age: For patients with asthma aged 4 to 11 years
`
`who are symptomatic on an inhaled corticosteroid, the dosage is 1 inhalation of ADVAIR
`DISKUS 100/50 twice daily (morning and evening, approximately 12 hours apart).
`2.2 Chronic Obstructive Pulmonary Disease
`
`
`
`4
`
`

`
`
`The recommended dosage for patients with COPD is 1 inhalation of ADVAIR DISKUS
`250/50 twice daily (morning and evening, approximately 12 hours apart).
`
`If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-
`agonist should be taken for immediate relief.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Disposable purple device with 60 blisters containing a combination of fluticasone
`
`propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder
`formulation. An institutional pack containing 28 blisters is also available.
`
`CONTRAINDICATIONS
`4
`
`The use of ADVAIR DISKUS is contraindicated in the following conditions:
`• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where
`intensive measures are required.
`• Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.11), Description
`(11)].
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Risk of Asthma-Related Death With Long-Acting Beta2-Adrenergic Agonists
`
`Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active
`ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore,
`when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for
`patients not adequately controlled on other asthma-controller medications (e.g., low- to
`medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of
`treatment with 2 maintenance therapies.
`
`A large placebo-controlled US study that compared the safety of salmeterol with placebo,
`each added to usual asthma therapy, showed an increase in asthma-related deaths in patients
`receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a
`randomized, double-blind study that enrolled long-acting beta2-agonist–naive patients with
`asthma to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily
`over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim
`analysis was conducted when approximately half of the intended number of patients had been
`enrolled (N = 26,355), which led to premature termination of the study. The results of the interim
`analysis showed that patients receiving salmeterol were at increased risk for fatal asthma events
`(see Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred
`in patients treated with salmeterol than those treated with placebo (0.10% vs. 0.02%, relative risk
`4.37 [95% CI: 1.25, 15.34]).
`
`Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death
`occurred at a higher rate in patients treated with salmeterol than in patients treated with placebo
`(0.07% vs. 0.01%, relative risk 5.82 [95% CI: 0.70, 48.37]). In African Americans also,
`asthma-related death occurred at a higher rate in patients treated with salmeterol than those
`
`
`
`5
`
`

`
`treated with placebo (0.31% vs. 0.04%, relative risk 7.26 [95% CI: 0.89, 58.94]). Although the
`relative risks of asthma-related death were similar in Caucasians and African Americans, the
`estimate of excess deaths in patients treated with salmeterol was greater in African Americans
`because there was a higher overall rate of asthma-related death in African American patients (see
`Table 1). Given the similar basic mechanisms of action of beta2-agonists, it is possible that the
`findings seen in the SMART study represent a class effect.
`
`The data from the SMART study are not adequate to determine whether concurrent use of
`inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in ADVAIR
`DISKUS, or other asthma-controller therapy modifies the risk of asthma-related death.
`
`Table 1. Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research
`Trial (SMART)
`
`Placebo
`n (%*)
`
`
`3 (0.02%)
`
`
`1 (0.01%)
`
`Excess Deaths
`Expressed per
`10,000 Patients‡
`Relative Risk†
`(95% Confidence
`Salmeterol
`(95% Confidence
`n (%*)
`Interval)
`Interval)
`
`Total Population§
`
`
`
`8 (3, 13)
`4.37 (1.25, 15.34)
`13 (0.10%)
`Salmeterol: N = 13,176
`Placebo: N = 13,179
`
`
`
`Caucasian
`
`
`
`6 (1, 10)
`5.82 (0.70, 48.37)
`6 (0.07%)
`Salmeterol: N = 9,281
`
`
`
`Placebo: N = 9,361
`African American
`
`
`
`27 (8, 46)
`7.26 (0.89, 58.94)
`
`7 (0.31%)
`Salmeterol: N = 2,366
`
`
`1 (0.04%)
`
`Placebo: N = 2,319
`* Life-table 28-week estimate, adjusted according to the patients’ actual lengths of exposure to
`study treatment to account for early withdrawal of patients from the study.
`† Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the
`rate in the placebo group. The relative risk indicates how many more times likely an
`asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week
`treatment period.
`‡ Estimate of the number of additional asthma-related deaths in patients treated with salmeterol
`in SMART, assuming 10,000 patients received salmeterol for a 28-week treatment period.
`Estimate calculated as the difference between the salmeterol and placebo groups in the rates
`of asthma-related death multiplied by 10,000.
`§ The Total Population includes the following ethnic origins listed on the case report form:
`Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population
`includes those patients whose ethnic origin was not reported. The results for Caucasian and
`African American subpopulations are shown above. No asthma-related deaths occurred in the
`
`
`
`6
`
`

`
`Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149),
`or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death
`occurred in the placebo group in the subpopulation whose ethnic origin was not reported
`(salmeterol n = 130, placebo n = 127).
`
`
`Figure 1. Cumulative Incidence of Asthma-Related
`Deaths in the 28-Week Salmeterol Multi-center Asthma
`Research Trial (SMART), by Duration of Treatment
`
`
`
`
`7
`
`
`
`

`
`
`
`A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide
`Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate
`of asthma-related death was numerically, though not statistically significantly, greater in patients
`with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol
`(180 mcg 4 times daily) added to usual asthma therapy.
`
`The SNS and SMART studies enrolled patients with asthma. No studies have been
`conducted that were primarily designed to determine whether the rate of death in patients with
`COPD is increased by long-acting beta2-adrenergic agonists.
`5.2 Deterioration of Disease and Acute Episodes
`
`ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or
`potentially life-threatening episodes of asthma or COPD. ADVAIR DISKUS has not been
`studied in patients with acutely deteriorating asthma or COPD. The initiation of ADVAIR
`DISKUS in this setting is not appropriate.
`
`Serious acute respiratory events, including fatalities, have been reported when salmeterol,
`a component of ADVAIR DISKUS, has been initiated in patients with significantly worsening or
`acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma
`(e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation,
`mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma
`exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with
`significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists;
`decreasing response to usual medications; increasing need for systemic corticosteroids; recent
`emergency room visits; deteriorating lung function). However, these events have occurred in a
`few patients with less severe asthma as well. It was not possible from these reports to determine
`whether salmeterol contributed to these events.
`
`Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma.
`In this situation, the patient requires immediate reevaluation with reassessment of the treatment
`regimen, giving special consideration to the possible need for replacing the current strength of
`ADVAIR DISKUS with a higher strength, adding additional inhaled corticosteroid, or initiating
`systemic corticosteroids. Patients should not use more than 1 inhalation twice daily (morning and
`evening) of ADVAIR DISKUS.
`
`ADVAIR DISKUS should not be used for the relief of acute symptoms, i.e., as rescue
`therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting
`beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as
`shortness of breath. When prescribing ADVAIR DISKUS, the physician must also provide the
`patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute
`symptoms, despite regular twice-daily (morning and evening) use of ADVAIR DISKUS.
`
`When beginning treatment with ADVAIR DISKUS, patients who have been taking oral
`or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed
`to discontinue the regular use of these drugs.
`
`
`
`8
`
`

`
`5.3 Excessive Use of ADVAIR DISKUS and Use With Other Long-Acting Beta2-
`Agonists
`
`As with other inhaled drugs containing beta2-adrenergic agents, ADVAIR DISKUS
`should not be used more often than recommended, at higher doses than recommended, or in
`conjunction with other medications containing long-acting beta2-agonists, as an overdose may
`result. Clinically significant cardiovascular effects and fatalities have been reported in
`association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR
`DISKUS should not use an additional long-acting beta2-agonist (e.g., salmeterol, formoterol
`fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced
`bronchospasm (EIB) or the maintenance treatment of asthma or COPD.
`5.4
`Local Effects
`
`In clinical studies, the development of localized infections of the mouth and pharynx with
`Candida albicans has occurred in patients treated with ADVAIR DISKUS. When such an
`infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal)
`therapy while treatment with ADVAIR DISKUS continues, but at times therapy with ADVAIR
`DISKUS may need to be interrupted. Patients should rinse the mouth after inhalation of
`ADVAIR DISKUS.
`5.5 Pneumonia
`
`Physicians should remain vigilant for the possible development of pneumonia in patients
`with COPD as the clinical features of pneumonia and exacerbations frequently overlap.
`
`Lower respiratory tract infections, including pneumonia, have been reported in patients
`with COPD following the inhaled administration of corticosteroids, including fluticasone
`propionate and ADVAIR DISKUS. In 2 replicate 12-month studies of 1,579 patients with
`COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR
`DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of
`pneumonia in the patients treated with ADVAIR DISKUS was higher in patients over 65 years
`of age (9%) compared with the incidence in patients less than 65 years of age (4%). [See Adverse
`Reactions (6.2), Use in Specific Populations (8.5).]
`
`In a 3-year study of 6,184 patients with COPD, there was a higher incidence of
`pneumonia reported in patients receiving ADVAIR DISKUS 500/50 compared with placebo
`(16% with ADVAIR DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with
`salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year studies with
`ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in patients over 65 years of
`age (18% with ADVAIR DISKUS 500/50 vs. 10% with placebo) compared with patients less
`than 65 years of age (14% with ADVAIR DISKUS 500/50 vs. 8% with placebo). [See Adverse
`Reactions (6.2), Use in Specific Populations (8.5).]
`5.6
`Immunosuppression
`
`Persons who are using drugs that suppress the immune system are more susceptible to
`infections than healthy individuals. Chickenpox and measles, for example, can have a more
`serious or even fatal course in susceptible children or adults using corticosteroids. In such
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`children or adults who have not had these diseases or been properly immunized, particular care
`should be taken to avoid exposure. How the dose, route, and duration of corticosteroid
`administration affect the risk of developing a disseminated infection is not known. The
`contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not
`known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin
`(VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled
`intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for
`complete VZIG and IG prescribing information.) If chickenpox develops, treatment with
`antiviral agents may be considered.
`
`Inhaled corticosteroids should be used with caution, if at all, in patients with active or
`quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial,
`viral, or parasitic infections; or ocular herpes simplex.
`5.7
`Transferring Patients From Systemic Corticosteroid Therapy
`
`Particular care is needed for patients who have been transferred from systemically active
`corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have
`occurred in patients with asthma during and after transfer from systemic corticosteroids to less
`systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a
`number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
`
`Patients who have been previously maintained on 20 mg or more per day of prednisone
`(or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have
`been almost completely withdrawn. During this period of HPA suppression, patients may exhibit
`signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection
`(particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although
`ADVAIR DISKUS may provide control of asthma symptoms during these episodes, in
`recommended doses it supplies less than normal physiological amounts of glucocorticoid
`systemically and does NOT provide the mineralocorticoid activity that is necessary for coping
`with these emergencies.
`
`During periods of stress or a severe asthma attack, patients who have been withdrawn
`from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses)
`immediately and to contact their physicians for further instruction. These patients should also be
`instructed to carry a warning card indicating that they may need supplementary systemic
`corticosteroids during periods of stress or a severe asthma attack.
`
`Patients requiring oral corticosteroids should be weaned slowly from systemic
`corticosteroid use after transferring to ADVAIR DISKUS. Prednisone reduction can be
`accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy
`with ADVAIR DISKUS. Lung function (mean forced expiratory volume in 1 second [FEV1] or
`morning peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be
`carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma
`signs and symptoms, patients should be observed for signs and symptoms of adrenal
`insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
`
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`Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or
`
`ADVAIR DISKUS may unmask conditions previously suppressed by the systemic corticosteroid
`therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients
`may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or
`muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory
`function.
`5.8 Hypercorticism and Adrenal Suppression
`
`Fluticasone propionate, a component of ADVAIR DISKUS, will often help control
`asthma symptoms with less suppression of HPA function than therapeutically equivalent oral
`doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be
`systemically active at higher doses, the beneficial effects of ADVAIR DISKUS in minimizing
`HPA dysfunction may be expected only when recommended dosages are not exceeded and
`individual patients are titrated to the lowest effective dose. A relationship between plasma levels
`of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown
`after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual
`sensitivity to effects on cortisol production exist