Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

ANORO ELLIPTA (NDA-203975)

(UMECLIDINIUM BROMIDE; VILANTEROL TRIFENATATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

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06/02/2023 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Blurred vision, eye pain, glaucoma, increased intraocular pressure.

…

10/20/2022 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

ANORO ELLIPTA is contraindicated in:

patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.6), Description (11)].
use of a long-acting beta2-adrenergic agonist (LABA), including vilanterol, one of the active ingredients in ANORO ELLIPTA, without an inhaled corticosteroid (ICS), in patients with asthma [see Warnings and Precautions (5.1)]. ANORO ELLIPTA is not indicated for the treatment of asthma.

5 Warnings and Precautions

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

Additions and/or revisions underlined:

The safety and effectiveness of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma [see Contraindications (4)].

…

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including vilanterol, one of the active ingredients in ANORO ELLIPTA.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted.

Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.10 Worsening of Urinary Retention

Additions and/or revisions underlined:

ANORO ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

5.2 Deterioration of Disease and Acute Episodes

Additions and/or revisions underlined:

ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. ANORO ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of ANORO ELLIPTA in this setting is not appropriate.

If ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. The daily dose of ANORO ELLIPTA should not be increased. Increasing use of inhaled, short-acting beta2-agonists is a signal of deteriorating disease. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation of ANORO ELLIPTA once daily.

ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with ANORO ELLIPTA, 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 and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

5.3 Avoid Excessive Use of ANORO ELLIPTA and Avoid Use with Other Long-acting Beta2-agonists

Subsection title revised

5.4 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Additions and/or revisions underlined:

Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.6 Hypersensitivity Reactions, including Anaphylaxis

Subsection title revised

5.7 Cardiovascular Effects

Additions and/or revisions underlined:

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, ANORO 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 [see Clinical Pharmacology (12.2)]. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

ANORO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for ANORO ELLIPTA (n = 2,070). Adjudicated on-treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving ANORO ELLIPTA.

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in labeling:

…

6.1 Clinical Trials Experience

Extensive changes/revisions; please refer to label

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Labor or Delivery: ANORO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

…

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ANORO ELLIPTA have not been established in pediatric patients. ANORO ELLIPTA is not indicated for use in pediatric patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Instruct patients not to use other LABAs for COPD. [See Warnings and Precautions (5.3).]

…

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 healthcare practitioner immediately should any of these signs and symptoms develop. [See Warnings and Precautions (5.7).]

…

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 physician immediately if any of these signs or symptoms develop. [See Warnings and Precautions (5.9).]

…

PATIENT INFORMATION

Extensive changes; please refer to label

06/06/2019 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Cardiovascular Effects

Newly added information

In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100 mcg/62.5 mcg/100 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100 mcg/25 mcg (n = 4,134), and 2.2 per 100 patient-years for ANORO ELLIPTA (n = 2,070). Adjudicated on-treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving ANORO ELLIPTA.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The safety data described below are based on the four 6-month and two 12-month trials.

6-Month Trials

The incidence of adverse reactions associated with ANORO ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trial 1, NCT #01313650 and Trial 2 NCT #01313637); N = 1,532 and N = 1,489, respectively) and 2 active-controlled trials (Trial 3, NCT #01316900 and Trial 4, NCT #01316913); N = 843 and N = 869, respectively).

12-Month Trials

In a long-term safety trial (Trial 5, NCT #01316887), 335 subjects … Adverse reactions observed with a frequency of greater than or equal to 1% …

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; please refer to label for complete information.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is ANORO ELLIPTA?

ANORO ELLIPTA combines 2 medicines in one inhaler, an anticholinergic …

Anticholinergic medicines such as umeclidinium and LABA medicines such as vilanterol help the muscles …

ANORO ELLIPTA is a prescription medicine used long term (chronic) to treat people …
ANORO ELLIPTA is used as 1 inhalation 1 time each day to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days).
ANORO ELLIPTA is not approved for the treatment of asthma. It is not known if ANORO ELLIPTA is safe and effective in people with asthma. ANORO ELLIPTA contains vilanterol. LABA medicines such as vilanterol when used alone increase the risk of hospitalizations and death from asthma problems.
ANORO ELLIPTA is not used to relieve sudden breathing problems and will not replace a rescue inhaler. Always have a rescue inhaler (an inhaled, short-acting bronchodilator) with you to treat sudden breathing problems. If you do not have a rescue inhaler, contact your healthcare provider …

05/29/2019 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

(addition underlined)

…

Use of a LABA without an inhaled corticosteroid (ICS) is contraindicated in patients with asthma. ANORO ELLIPTA is not indicated for the treatment of asthma.

5 Warnings and Precautions

5.1 Serious Asthma-Related Events—Hospitalizations, Intubations, Death

(additions underlined)

ANORO ELLIPTA is not indicated for the treatment of asthma.

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

…

Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

6 Adverse Reactions

(additions underlined)

The following adverse reactions are described in greater detail in other sections:

Serious asthma-related events–hospitalizations, intubations, death. LABA, such as vilanterol (one of the active ingredients in ANORO ELLIPTA), as monotherapy (without ICS) for asthma increase the risk of asthma-related events. ANORO ELLIPTA is not indicated for the treatment of asthma.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Serious Asthma-Related Events

ANORO ELLIPTA is not indicated for the treatment of asthma. Inform patients that LABA, such as vilanterol (one of the active ingredients in ANORO ELLIPTA), when used alone (without ICS) for asthma increase the risk of asthma-related hospitalization or asthma-related death

PATIENT INFORMATION

(replacement for Medication Guide, Please refer to label for more information)

10/17/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Worsening of Urinary Retention

(Additions and/or revisions are underlined)

…Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

5.9 Worsening of Narrow-Angle Glaucoma

(Additions and/or revisions are underlined)

… Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Respiratory, Thoracic, and Mediastinal Disorders Dysphonia, paradoxical bronchospasm.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Pregnancy Category C…Women should be advised to contact their healthcare providers if they become pregnant while taking ANORO ELLIPTA.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Not for Acute Symptoms

…Tell patients they should not stop therapy with ANORO ELLIPTA without healthcare provider guidance since symptoms may recur after discontinuation.

Worsening of Narrow-Angle Glaucoma

…Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Worsening of Urinary Retention

…Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

ANORO® ELLIPTA® [a-nor’oh e-LIP-ta] (umeclidinium and vilanterol inhalation powder) for oral inhalation

General information about the safe and effective use of ANORO ELLIPTA.

Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide… This Medication Guide summarizes the most important information about ANORO ELLIPTA. If you would like more information, talk with your healthcare provider or pharmacist…

03/22/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Cardiovascular Effects

(Additions and/or revisions are underlined)

…Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Eye Disorders

Blurred vision, glaucoma, increased intraocular pressure.

Renal and Urinary Disorders

Dysuria, urinary retention

Respiratory, Thoracic, and Mediastinal Disorders

Paradoxical bronchospasm

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ANORO ELLIPTA and certain other medicines may interact with each other. This may cause serious side effects.

Especially tell your healthcare provider if you take:

anticholinergics (including tiotropium, ipratropium, aclidinium)
atropine
antifungal or anti-HIV medicines

02/24/2016 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of ANORO ELLIPTA. 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 ANORO ELLIPTA or a combination of these factors.

Cardiac Disorders: Palpitations.
Immune System Disorders: Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria.
Nervous System Disorders: Dysgeusia, tremor.
Psychiatric Disorders: Anxiety