can produce paradoxical bronchospasm, which may be life threatening. If paradoxical
bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated
immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be
discontinued immediately; and alternative therapy should be instituted.
5. 11 Hypersensitivity Reactions Hypersensitivity reactions may occur after
administration of BREO ELLIPTA. There have been reports of anaphylactic reactions
in patients with severe milk protein allergy after inhalation of other powder products
containing lactose; therefore, patients with severe milk protein allergy should not
take BREO ELLIPTA [see Contraindications ( 4)].
5. 12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce
a clinically significant cardiovascular effect in some patients as measured by
increases in pulse rate, systolic or diastolic blood pressure, and also cardiac
arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects
occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have
been reported to produce electrocardiographic changes, such as flattening of the
T wave, prolongation of the QTc interval, and ST segment depression, although
the clinical significance of these findings is unknown. In healthy subjects, large
doses of inhaled fluticasone furoate/vilanterol ( 4 times the recommended dose of
vilanterol, representing a 12-fold higher systemic exposure than seen in patients
with COPD) have been associated with clinically significant prolongation of the QTc
interval, which has the potential for producing ventricular arrhythmias. Therefore,
BREO ELLIPTA, like other sympathomimetic amines, should be used with caution
in patients with cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension.
5. 13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD)
have been observed with long-term administration of products containing inhaled
corticosteroids. The clinical significance of small changes in BMD with regard to
long-term consequences such as fracture is unknown. Patients with major risk
factors for decreased bone mineral content, 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 (e.g.,
anticonvulsants, oral corticosteroids) should be monitored and treated with
established standards of care. Since patients with COPD often have multiple risk
factors for reduced BMD, assessment of BMD is recommended prior to initiating
BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are
seen and BREO ELLIPTA is still considered medically important for that patient’s
COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly
considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures
were reported by 2% of subjects receiving the fluticasone furoate/vilanterol
combination (50 mcg/25 mcg: 2% [ 14 of 820 subjects]; 100 mcg/25 mcg: 2% [ 19
of 806 subjects]; or 200 mcg/25 mcg: 2% [ 14 of 811 subjects]) than in subjects
receiving vilanterol 25 mcg alone (less than 1% [ 8 of 818 subjects]).
5. 14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and
cataracts have been reported in patients with COPD following the long-term
administration of inhaled corticosteroids. Therefore, close monitoring is warranted in
patients with a change in vision or with a history of increased intraocular pressure,
glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with
COPD, similar incidences of ocular effects (including glaucoma and cataracts) were
reported in subjects receiving the fluticasone furoate/vilanterol combination
(50 mcg/25 mcg: less than 1% [ 7 of 820 subjects]; 100 mcg/25 mcg: 1% [ 12 of
806 subjects]; 200 mcg/25 mcg: less than 1% [ 7 of 811 subjects]) as those
receiving vilanterol 25 mcg alone (1% [ 9 of 818 subjects]).
5. 15 Coexisting Conditions BREO ELLIPTA, like all medicines containing
sympathomimetic amines, should be used with caution in patients with convulsive
disorders or thyrotoxicosis and in those who are unusually responsive to
sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol,
when administered intravenously, have been reported to aggravate preexisting
diabetes mellitus and ketoacidosis.
5. 16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may
produce significant hypokalemia in some patients, possibly through intracellular
shunting, which has the potential to produce adverse cardiovascular effects. The
decrease in serum potassium is usually transient, not requiring supplementation.
Beta-agonist medications may produce transient hyperglycemia in some patients. In
4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with
COPD, there was no evidence of a treatment effect on serum glucose or potassium.
6 ADVERSE REACTIONS
LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase
the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of
asthma. [See Boxed Warnings and Warnings and Precautions ( 5. 1).] Systemic and
local corticosteroid use may result in the following: Increased risk of pneumonia in
COPD [see Warnings and Precautions ( 5. 5)] ; Increased risk for decrease in bone
mineral density [see Warnings and Precautions ( 5. 13)].
6. 1 Clinical Trials Experience 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. The clinical program for BREO ELLIPTA
included 7,700 subjects with COPD in two 6-month lung function trials, two
12-month exacerbation trials, and 6 other trials of shorter duration. A total of
2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg,
and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The
safety data described below are based on the confirmatory 6-month and 12-month
trials. Adverse reactions observed in the other trials were similar to those observed
in the confirmatory trials.
6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA
in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2;
n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and
84% were Caucasian. They had a mean age of 62 years and an average smoking
history of 44 pack years, with 54% identified as current smokers. At screening,
the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to
87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47%
(range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to
152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA
100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/
vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg,
vilanterol 25 mcg, or placebo.
Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo
With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease
Adverse Event
BREO ELLIPTA
100 mcg/25 mcg
(n = 410)
%
Vilanterol
25 mcg
(n = 408)
%
Fluticasone
Furoate
100 mcg
(n = 410)
%
Placebo
(n = 412)
%
Infections and
infestations
Nasopharyngitis 9 10 8 8
Upper respiratory
tractinfection 7 5 4 3
Oropharyngeal
candidiasisa 5 2 3 2
Nervous system
disorders
Headache 7 9 7 5
a Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and
oropharyngitis fungal.
12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and
4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of
which 57% were male and 85% were Caucasian. They had a mean age of 64 years
and an average smoking history of 46 pack years, with 44% identified as current
smokers. At screening, the mean postbronchodilator percent predicted FEV1 was
45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46%
(range: 17% to 81%), indicating that the subject population had moderate to very
severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the
following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25
mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition
to the events shown in Table 1, adverse reactions occurring in greater than or equal
to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included
COPD, back pain, pneumonia [see Warnings and Precautions ( 5. 5)], bronchitis,
sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis,
diarrhea, peripheral edema, and pyrexia.
7 DRUG INTERACTIONS
7. 1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol,
the individual components of BREO ELLIPTA, are both substrates of CYP3A4.
Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases
the systemic exposure to fluticasone furoate and vilanterol. Caution should be
exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir,
clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir,
saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and
Precautions ( 5. 9) and Clinical Pharmacology ( 12. 3) of full prescribing information].
7. 2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol,
like other beta2-agonists, should be administered with extreme caution to patients
being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs
known to prolong the QTc interval or within 2 weeks of discontinuation of such
agents, because the effect of adrenergic agonists on the cardiovascular system may
be potentiated by these agents. Drugs that are known to prolong the QTc interval
have an increased risk of ventricular arrhythmias.
7. 3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the
pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA,
but may produce severe bronchospasm in patients with reversible obstructive
airways disease. Therefore, patients with COPD should not normally be treated
with beta-blockers. However, under certain circumstances, there may be no
acceptable alternatives to the use of beta-adrenergic blocking agents for these
patients; cardioselective beta-blockers could be considered, although they should
be administered with caution.
7. 4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/
or hypokalemia that may result from the administration of non–potassium-sparing
diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Although the clinical significance of these effects is not known, caution is advised in
the coadministration of beta-agonists with non–potassium-sparing diuretics.
8 USE IN SPECIFIC POPULATIONS
8. 1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate
and well-controlled trials with BREO ELLIP TA in pregnant women. Corticosteroids
and beta2-agonists have been shown to be teratogenic in laboratory animals when
administered systemically at relatively low dosage levels. Because animal studies
are not always predictive of human response, BREO ELLIPTA should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Women should be advised to contact their physicians if they become pregnant while
