considering the coadministration of ANORO ELLIPTA with 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. 4), 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 ANORO
ELLIPTA, but may produce severe bronchospasm in patients with COPD. 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, such as vilanterol,
a component of ANORO ELLIPTA, 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 ANORO ELLIPTA
with non–potassium-sparing diuretics.
7. 5 Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid
coadministration of ANORO ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase
in anticholinergic adverse effects [see Warnings and Precautions ( 5. 9, 5. 10), Adverse Reactions ( 6)].
8 USE IN SPECIFIC POPULATIONS
8. 1 Pregnancy
Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials of ANORO ELLIP TA or
its individual components, umeclidinium and vilanterol, in pregnant women. Because animal reproduction studies
are not always predictive of human response, ANORO 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 taking ANORO ELLIP TA.
Umeclidinium: There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times,
respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal
inhaled doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).
Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 70 times, respectively,
the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC
basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in
rabbits at approximately 450 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses
of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in
cervical vertebral centrum and metacarpals.
Nonteratogenic Effects: Umeclidinium: There were no effects on perinatal and postnatal developments in rats at
approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).
Vilanterol: There were no effects on perinatal and postnatal developments in rats at approximately 3,900 times the
MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).
8. 2 Labor and Delivery
There are no adequate and well-controlled human trials that have investigated the effects of ANORO ELLIPTA during
labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, ANORO ELLIPTA should be used during
labor only if the potential benefit justifies the potential risk.
8. 3 Nursing Mothers
ANORO ELLIP TA: It is not known whether ANORO ELLIP TA is excreted in human breast milk. Because many drugs
are excreted in human milk, caution should be exercised when ANORO ELLIP TA is administered to a nursing woman.
Since there are no data from well-controlled human studies on the use of ANORO ELLIPTA by nursing mothers,
based on the data for the individual components, a decision should be made whether to discontinue nursing or to
discontinue ANORO ELLIPTA, taking into account the importance of ANORO ELLIP TA to the mother.
Umeclidinium: It is not known whether umeclidinium is excreted in human breast milk. However, administration
to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium
in 2 pups, which may indicate transfer of umeclidinium in milk.
Vilanterol: It is not known whether vilanterol is excreted in human breast milk. However, other beta2-agonists have
been detected in human milk.
8. 4 Pediatric Use
ANORO ELLIPTA is not indicated for use in children. The safety and efficacy in pediatric patients have not been
8. 5 Geriatric Use
Based on available data, no adjustment of the dosage of ANORO ELLIPTA in geriatric patients is necessary, but
greater sensitivity in some older individuals cannot be ruled out.
Clinical trials of ANORO ELLIPTA for COPD included 2,143 subjects aged 65 and older and, of those, 478 subjects
were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects
and younger subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger subjects.
8. 6 Hepatic Impairment
Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC,
nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls.
Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology ( 12. 3)
of full Prescribing Information].
8. 7 Renal Impairment
There were no significant increases in either umeclidinium or vilanterol exposure in subjects with severe renal
impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with
renal impairment [see Clinical Pharmacology ( 12. 3) of full Prescribing Information].
No case of overdose has been reported with ANORO ELLIP TA.
ANORO ELLIP TA contains both umeclidinium and vilanterol; therefore, the risks associated with overdosage for the
individual components described below apply to ANORO ELLIPTA. Treatment of overdosage consists of discontinuation
of ANORO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious
use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce
bronchospasm. Cardiac monitoring is recommended in cases of overdosage.
High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic
anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium ( 16 times
the maximum recommended daily dose) for 14 days in subjects with COPD.
10. 2 Vilanterol
The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic
stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation
(e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias,
nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue,
malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic
medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.
13 NONCLINICAL TOXICOLOGY
13. 1 Carcinogenesis, Mutagenesis, Impairment of Fertility
ANORO ELLIP TA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ANORO
ELLIP TA; however, studies are available for individual components, umeclidinium and vilanterol, as described below.
Umeclidinium: Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year
inhalation studies in rats and mice at inhaled doses up to 137 mcg/kg/day and 295/200 mcg/kg/day (male/female),
respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).
Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma
assay, and in vivo rat bone marrow micronucleus assay.
No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/
kg/day and inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the
MRHDID in adults on an AUC basis).
Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian
tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 7,800 times the
MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/day
(approximately 210 times the MRHDID in adults on an AUC basis).
In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas
in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/
day (greater than or equal to approximately 20 times the MRHDID in adults on an AUC basis). No tumors were seen at
an inhalation dose of 10. 5 mcg/kg/day (approximately 1 time the MRHDID in adults on an AUC basis).
These tumor 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.
Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow
micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell
assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.
No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at
inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,500 times,
respectively, the MRHDID in adults on a mcg/m2 basis).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Asthma-Related Death: Inform patients that LABA, such as vilanterol, one of the active ingredients in ANORO ELLIP TA,
increase the risk of asthma-related death. ANORO ELLIP TA is not indicated for the treatment of asthma.
Not for Acute Symptoms: Inform patients that ANORO ELLIP TA is not meant to relieve acute symptoms of COPD and extra
doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol.
Provide patients with such medicine and instruct them in how it should be used.
Instruct patients to seek medical attention immediately if they experience any of the following:
• Symptoms get worse
• Need for more inhalations than usual of their rescue inhaler
Patients should not stop therapy with ANORO ELLIP TA without physician/provider guidance since symptoms may
recur after discontinuation.
Do Not Use Additional Long-Acting Beta2-Agonists: Instruct patients to not use other medicines containing a LABA.
Patients should not use more than the recommended once-daily dose of ANORO ELLIP TA.
Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the
regular use of these products and use them only for the symptomatic relief of acute symptoms.
Paradoxical Bronchospasm: As with other inhaled medicines, ANORO ELLIP TA can cause paradoxical bronchospasm.
If paradoxical bronchospasm occurs, instruct patients to discontinue ANORO ELLIP TA.
Risks Associated With Beta-Agonist Therapy: Inform patients of adverse effects associated with beta2-agonists,
such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a physician
immediately should any of these signs or symptoms develop.
Worsening of Narrow-Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle
glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes
from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of
these signs or symptoms develop.
Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty
passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or
ANORO and ELLIPTA are trademarks of GSK group of companies.
ANORO ELLIP TA was developed in collaboration with .
Research Triangle Park, NC 27709
©2013, GSK group of companies. All rights reserved.
Revised 12/2013 ANR:1BRS
©2014 GSK group of companies.
All rights reserved. Printed in USA. ANR025R0 March 2014