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.

ALVESCO (NDA-021658)

(CICLESONIDE)

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

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02/16/2023 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Oropharyngeal Candidiasis

(Additions and/or revisions underlined)

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans occurred in 32 of 3038 patients treated with ALVESCO. Of the 32 reported cases,

20 occurred in 1394 patients treated with a total daily dose of 320 mcg of ALVESCO or higher. Most cases of Candida infection were mild to moderate. When such an infection occurs, treat it with appropriate local or systemic (i.e., oral antifungal) therapy and discontinue ALVESCO. Patients should rinse the mouth after inhalation of ALVESCO.

5.3 Immunosuppression and Risk of Infections

(Additions and/or revisions underlined)

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The safety and effectiveness of ALVESCO have not been established in pediatric patients less than 12 years of age and ALVESCO is not indicated for use in this population. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See Prescribing Information for VZIG and IG) If chickenpox develops, treatment with antiviral agents may be considered.

5.4 Transferring Patients from Systemic Corticosteroid Therapy

(Additions and/or revisions underlined)

HPA Suppression/Adrenal Insufficiency

Particular care is needed for patients who are transferred from systemically active corticosteroids to ALVESCO because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically-available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

…

Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids

Transfer of patients from systemic steroid therapy to ALVESCO may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

Corticosteroid Withdrawal Symptoms

During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression

(Additions and/or revisions underlined)

ALVESCO will often help control asthma symptoms with less suppression of HPA function than therapeutically similar oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ALVESCO. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

Hypercorticism and adrenal suppression may occur when corticosteroids, including ALVESCO, are used at higher-than-recommended dosages [see Dosage and Administration (2)] or patients at risk for such effects.

5.7 Effect on Growth

(Additions and/or revisions underlined)

Orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of ALVESCO have not been established in pediatric patients less than 12 years of age and ALVESCO is not indicated for use in this population. Monitor the growth of pediatric patients receiving ALVESCO routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ALVESCO, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].

6 Adverse Reactions

(Additions and/or revisions underlined)

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

Oropharyngeal Candidiasis [see Warnings and Precautions (5.1)]
Immunosuppression and Risk of Infections [see Warnings and Precautions (5.3)]
Hypercorticism and Adrenal Suppression [see Warnings and Precautions (5.5)]
Reduction in Bone Mineral Density [see Warnings and Precautions (5.6)]
Growth Effects [see Warnings and Precautions (5.7)]
Glaucoma and Cataracts [see Warnings and Precautions (5.8)]

6.1 Clinical Trial Experience

(Additions and/or revisions underlined)

The safety data described below for adult and pediatric patients 12 years of age and older reflect exposure to ALVESCO in doses ranging from 80 mcg to 640 mcg twice daily in five double- blind placebo-controlled clinical trials. Studies with once daily dosing are omitted from the safety database because the doses studied once daily are lower than the highest recommended twice daily doses. The five studies were of 12 to 16 weeks treatment duration, one of which included a safety extension follow-up of one year. In the 12 to 16 week treatment studies,

…

Adults and Pediatric Patients 12 Years of Age and Older

Four of the five trials included a total of 624 patients ages 12 years and older (359 females and 265 males) with asthma of varying severity who were treated with ALVESCO 80 mcg, 160 mcg, or 320 mcg twice daily for 12 to 16 weeks. These studies included patients previously using either controller therapy (predominantly inhaled corticosteroids) or reliever therapy (bronchodilator therapy alone). In these trials, the mean age was 39.1 years, and the majority of the patients (79.0%) were Caucasian. In these trials, 52.3%, 59.8% and 54.1% of the patients in the ALVESCO 80 mcg, 160 mcg, and 320 mcg treatment groups, respectively, had at least one adverse event compared to 58.0% in the placebo group.

Table 2 includes adverse reactions for the recommended doses of ALVESCO that occurred at an incidence of greater than or equal to 3% in any of the ALVESCO groups and which were more frequent with ALVESCO compared to placebo.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.2 Lactation

(Pregnancy Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of ALVESCO for the maintenance treatment of asthma as prophylactic therapy have been established in pediatric patients aged 12 years and older. Use of ALVESCO for this indication is supported by evidence from randomized, double-blind, placebo- controlled, parallel-group clinical trials in adult and pediatric patients 12 years of age and older with mild persistent to severe persistent asthma [see Clinical Studies (14)].

The safety and effectiveness of ALVESCO have not been established in pediatric patients younger than 12 years of age.

Pediatric Patients 4 to 11 years of age

Effectiveness was not demonstrated in two randomized, double-blind, placebo-controlled studies that were conducted to evaluate the efficacy of ALVESCO 40, 80, or 160 mcg administered once daily for 12 weeks in patients 4 to 11 years of age with asthma. These studies included 1018 patients previously using either controller therapy (predominately inhaled corticosteroids) or reliever therapy (bronchodilator therapy alone). The patients had a mean baseline percent predicted FEV1 of 68%. The primary efficacy endpoint was morning pre-dose FEV1. Other measures of efficacy included AM PEF, asthma symptoms, and rescue albuterol use. The studies showed inconsistent results and did not establish the efficacy of ALVESCO in patients 4 to 11 years of age.

Pediatric Patients 2 to 6 years of age

Effectiveness was not demonstrated in one randomized, double-blind, placebo-controlled study that was conducted to evaluate the efficacy of ALVESCO 40, 80, and 160 mcg administered once daily for 24 weeks in 992 patients 2 to 6 years of age with persistent asthma. The primary efficacy endpoint was time to the first severe asthma exacerbation [defined as worsening of asthma which required treatment with systemic (including oral) steroids or any other asthma medication besides treatment medication and rescue medication] or lack of improvement, whichever occurred first. No statistically significant differences were observed for the individual comparisons of ALVESCO 40, 80, and 160 mcg to placebo. Results from this study did not establish efficacy of ALVESCO in patients 2 to 6 years of age.

Studies in children under 2 years of age have not been conducted given the lack of efficacy observed in patients 2 to 11 years of age.

Effect on Growth

Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure…

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Oropharyngeal Candidiasis

Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with ALVESCO therapy, but at times therapy with the ALVESCO inhaler may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)].

Acute Asthma Episodes

Patients should be advised that ALVESCO is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. The patient should be instructed to contact their physician immediately if there is deterioration of their asthma [see Warnings and Precautions (5.2)].

Immunosuppression and Risk of Infections

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.3)].

Hypercorticism and Adrenal Suppression

Patients should be advised that ALVESCO may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ALVESCO [see Warnings and Precautions (5.5)].

Reduction in Bone Mineral Density

Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and where appropriate, be treated for this condition [see Warnings and Precautions (5.6)].

Effect on Growth

Patients should be informed that orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.7)].