Advair Diskus

Name: Advair Diskus

Advair Diskus and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Advair Diskus crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication.  Your doctor and you will decide if the benefits outweigh the risk of using Advair Diskus.

What other drugs will affect Advair Diskus (fluticasone and salmeterol)?

Many drugs can interact with this medicine. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

  • an antidepressant, heart or blood pressure medicine, a diuretic or "water pill";

  • antifungal medicine such as ketoconazole; or

  • ritonavir (Norvir) or lopinavir/ritonavir (Kaletra).

This list is not complete and many other drugs can interact with fluticasone and salmeterol. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

What are some other side effects of Advair Diskus?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Upset stomach or throwing up.
  • Throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

How do I store and/or throw out Advair Diskus?

  • Store at room temperature.
  • Store in foil pouch until ready for use.
  • Protect from heat and sunlight.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Dosage Forms and Strengths

Inhalation Powder. Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains a combination of fluticasone propionate 100, 250, or 500 mcg and salmeterol 50 mcg per blister.

Adverse Reactions

LABA, such as salmeterol, one of the active ingredients in Advair Diskus, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol [see Warnings and Precautions (5.1)]. 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)].

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection [see Warnings and Precautions (5.4)] • Pneumonia in patients with COPD [see Warnings and Precautions (5.5)] • Immunosuppression [see Warnings and Precautions (5.6)] • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] • Reduction in bone mineral density [see Warnings and Precautions (5.13)] • Growth effects [see Warnings and Precautions (5.14)] • Glaucoma and cataracts [see Warnings and Precautions (5.15)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

The incidence of adverse reactions associated with Advair Diskus in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (349 females and 356 males) previously treated with salmeterol or inhaled corticosteroids were treated twice daily with Advair Diskus (100/50- or 250/50-mcg doses), fluticasone propionate inhalation powder (100- or 250-mcg doses), salmeterol inhalation powder 50 mcg, or placebo. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group.

Table 2. Adverse Reactions with Advair Diskus with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma

Adverse Event

Advair Diskus

100/50

(n = 92)

%

Advair Diskus

250/50

(n = 84)

%

Fluticasone Propionate

100 mcg

(n = 90)

%

Fluticasone Propionate

250 mcg

(n = 84)

%

Salmeterol

50 mcg

(n = 180)

%

Placebo

(n = 175)

%

Ear, nose, and throat

  Upper respiratory tract infection

27

21

29

25

19

14

  Pharyngitis

13

10

7

12

8

6

  Upper respiratory inflammation

7

6

7

8

8

5

  Sinusitis

4

5

6

1

3

4

  Hoarseness/dysphonia

5

2

2

4

<1

<1

  Oral candidiasis

1

4

2

2

0

0

Lower respiratory

  Viral respiratory infections

4

4

4

10

6

3

  Bronchitis

2

8

1

2

2

2

  Cough

3

6

0

0

3

2

Neurology

  Headaches

12

13

14

8

10

7

Gastrointestinal

  Nausea and vomiting

4

6

3

4

1

1

  Gastrointestinal discomfort and pain

4

1

0

2

1

1

  Diarrhea

4

2

2

2

1

1

  Viral gastrointestinal infections

3

0

3

1

2

2

Non-site specific

  Candidiasis unspecified site

3

0

1

4

0

1

Musculoskeletal

  Musculoskeletal pain

4

2

1

5

3

3

The types of adverse reactions and events reported in Trial 3, a 28-week non-U.S. clinical trial in 503 subjects previously treated with inhaled corticosteroids who were treated twice daily with Advair Diskus 500/50, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg, were similar to those reported in Table 2.

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with Advair Diskus compared with subjects treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum.

Pediatric Subjects Aged 4 to 11 Years

The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks’ treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving inhaled corticosteroids at trial entry were randomized to either Advair Diskus 100/50 or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (greater than or equal to 3% and greater than placebo) seen in the pediatric subjects but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections.

Laboratory Test Abnormalities

Elevation of hepatic enzymes was reported in greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

Short-term (6 Months to 1 Year) Trials

The short-term safety data are based on exposure to Advair Diskus 250/50 twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, a total of 723 adult subjects (266 females and 457 males) were treated twice daily with Advair Diskus 250/50, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder, or placebo. The mean age of the subjects was 64, and the majority (93%) was Caucasian. In this trial, 70% of the subjects treated with Advair Diskus reported an adverse reaction compared with 64% on placebo. The average duration of exposure to Advair Diskus 250/50 was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month trial is shown in Table 3.

Table 3. Overall Adverse Reactions with Advair Diskus 250/50 with ≥3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis

Adverse Event

Advair Diskus

250/50

(n = 178)

%

Fluticasone Propionate

250 mcg

(n = 183)

%

Salmeterol

50 mcg

(n = 177)

%

Placebo

(n = 185)

%

Ear, nose, and throat

  Candidiasis mouth/throat

10

6

3

1

  Throat irritation

8

5

4

7

  Hoarseness/dysphonia

5

3

<1

0

  Sinusitis

3

8

5

3

Lower respiratory

  Viral respiratory infections

6

4

3

3

Neurology

  Headaches

16

11

10

12

  Dizziness

4

<1

3

2

Non-site specific

  Fever

4

3

0

3

  Malaise and fatigue

3

2

2

3

Musculoskeletal

  Musculoskeletal pain

9

8

12

9

  Muscle cramps and spasms

3

3

1

1

In the two 1-year trials, Advair Diskus 250/50 was compared with salmeterol in 1,579 subjects (863 males and 716 females). The mean age of the subjects was 65 years, and the majority (94%) was Caucasian. To be enrolled, all of the subjects had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the subjects treated with Advair Diskus and 86% of the subjects treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of greater than 5% and more frequently in the subjects treated with Advair Diskus were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the subjects treated with Advair Diskus and 25 (3%) of the subjects treated with salmeterol developed pneumonia.

The incidence of pneumonia was higher in subjects older than 65 years, 9% in the subjects treated with Advair Diskus compared with 4% in the subjects treated with Advair Diskus younger than 65 years. In the subjects treated with salmeterol, the incidence of pneumonia was the same (3%) in both age-groups. [See Warnings and Precautions (5.5), Use in Specific Populations (8.5).]

Long-term (3 Years) Trial

The safety of Advair Diskus 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year trial in 6,184 adult subjects with COPD (4,684 males and 1,500 females). The mean age of the subjects was 65 years, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with Advair Diskus 250/50. In addition, pneumonia was reported in a significantly increased number of subjects treated with Advair Diskus 500/50 and fluticasone propionate 500 mcg (16% and 14%, respectively) compared with subjects treated with salmeterol 50 mcg or placebo (11% and 9%, respectively). When adjusted for time on treatment, the rates of pneumonia were 84 and 88 events per 1,000 treatment-years in the groups treated with fluticasone propionate 500 mcg and with Advair Diskus 500/50, respectively, compared with 52 events per 1,000 treatment-years in the salmeterol and placebo groups. Similar to what was seen in the 1-year trials with Advair Diskus 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with Advair Diskus 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with Advair Diskus 500/50 versus 8% with placebo). [See Warnings and Precautions (5.5), Use in Specific Populations (8.5).]

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with COPD treated with Advair Diskus compared with subjects treated with placebo include the following: syncope; ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection; hypothyroidism; dry eyes; eye infections; gastrointestinal signs and symptoms; oral lesions; abnormal liver function tests; bacterial infections; edema and swelling; viral infections.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Advair Diskus, fluticasone propionate, and/or salmeterol or a combination of these factors.

Cardiac Disorders

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders

Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders

Glaucoma.

Gastrointestinal Disorders

Abdominal pain, dyspepsia, xerostomia.

Immune System Disorders

Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.

Infections and Infestations

Esophageal candidiasis.

Metabolic and Nutrition Disorders

Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, and Bone Disorders

Arthralgia, cramps, myositis, osteoporosis.

Nervous System Disorders

Paresthesia, restlessness.

Psychiatric Disorders

Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Reproductive System and Breast Disorders

Dysmenorrhea.

Respiratory, Thoracic, and Mediastinal Disorders

Chest congestion; chest tightness; dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin and Subcutaneous Tissue Disorders

Ecchymoses, photodermatitis.

Vascular Disorders

Pallor.

Advair Diskus Description

Advair Diskus 100/50, Advair Diskus 250/50, and Advair Diskus 500/50 are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Advair Diskus is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of Advair Diskus is salmeterol xinafoate, a beta2-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure:

Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Advair Diskus is a purple plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone propionate (100, 250, or 500 mcg) and micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, Advair Diskus delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from Advair Diskus 100/50, Advair Diskus 250/50, and Advair Diskus 500/50, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS® inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) subjects with asthma inhaling maximally through the DISKUS inhaler show mean PIF of 122.2 L/min (range: 81.6 to 152.1 L/min). Inhalation profiles for pediatric subjects with asthma inhaling maximally through the DISKUS inhaler show a mean PIF of 75.5 L/min (range: 49.0 to 104.8 L/min) for the 4-year-old subject set (N = 20) and 107.3 L/min (range: 82.8 to 125.6 L/min) for the 8-year-old subject set (N = 20).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone Propionate

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 4 and 10 times the MRHDID for adults and children, respectively, on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than and approximately equivalent to the MRHDID for adults and children, respectively, on a mg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHDID on a mg/m2 basis). Prostate weight was significantly reduced.

Salmeterol

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHDID for adults and children, respectively, on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m2 basis).

Animal Toxicology and/or Pharmacology

Preclinical

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

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