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.

ADVAIR DISKUS 100/50 (NDA-021077)

(FLUTICASONE PROPIONATE; SALMETEROL XINAFOATE)

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

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01/07/2019 (SUPPL-61)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Glaucoma and Cataracts

(additions underlined)

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of ICS, including fluticasone propionate, a component of ADVAIR DISKUS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ADVAIR DISKUS long term.

…

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

…

Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma.

Labor and Delivery: There are no human studies evaluating the effects of ADVAIR DISKUS during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of ADVAIR DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

…

8.2 Lactation

(additions underlined)

…

Data

Data: Subcutaneous administration of tritiated fluticasone propionate at a dose of 10 mcg/kg/day to lactating rats resulted in measurable levels in milk. Oral administration of

salmeterol at a dose of 10,000 mcg/kg/day to lactating rats resulted in measurable levels in milk.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Glaucoma and Cataracts

Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

…

PATIENT INFORMATION

(additions underlined)

…

Before using ADVAIR DISKUS, tell your healthcare provider about all of your medical conditions, including if you:

…

have or have had eye problems such as glaucoma, increased pressure in your eye, cataracts, or other changes in vision.

…

What are the possible side effects of ADVAIR DISKUS?

ADVAIR DISKUS can cause serious side effects, including:

…

eye problems including glaucoma, increased pressure in your eye, cataracts, or other changes in vision. You should have regular eye exams while using ADVAIR DISKUS.
…

12/20/2017 (SUPPL-56)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

The use of ADVAIR DISKUS is contraindicated in the following conditions:

Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients

5 Warnings and Precautions

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

(Additions and/or revisions are underlined)

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)]. 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 (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists

Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared fluticasone propionate/salmeterol inhalation powder (ADVAIR DISKUS) with fluticasone propionate inhalation powder, 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled, U.S. trial that compared the safety of 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 versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

6 Adverse Reactions

(Additions and/or revisions are underlined)

Use of LABA may result in the following:

Serious asthma-related events – hospitalizations, intubations, death
Cardiovascular and central nervous system effects

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to labeling)

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADVAIR DISKUS and any potential adverse effects on the breastfed child from ADVAIR DISKUS or from the underlying maternal condition.

Data

Animal Data: Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.08 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk. Oral administration of salmeterol at a dose in lactating rats approximately 973 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Serious Asthma-Related Events

Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with ADVAIR DISKUS, there is not a significant increase in the risk of these events.

PATIENT INFORMATION ADVAIR DISKUS [AD vair DISK us] (fluticasone propionate and salmeterol inhalation powder) for oral inhalation

(Extensive changes; please refer to labeling)

12/20/2017 (SUPPL-57)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

The use of ADVAIR DISKUS is contraindicated in the following conditions:

Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients

5 Warnings and Precautions

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

(Additions and/or revisions are underlined)

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists

Salmeterol Multicenter Asthma Research Trial (SMART)

6 Adverse Reactions

(Additions and/or revisions are underlined)

Use of LABA may result in the following:

Serious asthma-related events – hospitalizations, intubations, death
Cardiovascular and central nervous system effects

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to labeling)

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

Data

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Serious Asthma-Related Events

PATIENT INFORMATION ADVAIR DISKUS [AD vair DISK us] (fluticasone propionate and salmeterol inhalation powder) for oral inhalation

(Extensive changes; please refer to labeling)

02/28/2017 (SUPPL-58)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Deterioration of Disease and Acute Episodes

Additions and/or revisions underlined:

ADVAIR HFA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ADVAIR HFA 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 ADVAIR HFA, patients …