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.

ARIDOL (NDA-022368)

(MANNITOL)

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

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08/13/2021 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reaction is described elsewhere in the labeling:

Severe Bronchospasm [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population for the ARIDOL bronchial challenge test consisted of 1,082 subjects (577 females and 505 males) including patients with asthma, symptoms suggestive of asthma, and healthy individuals from 6 to 83 years of age who participated in the two clinical trials (Studies 1 and 2). The racial distribution of subjects was 84% Caucasian, 5% Asian, 4% Black, and 7% Other. Pediatric and adolescent patients comprised 23% of the total study population with 118 pediatric patients aged 6-11 years and 128 adolescents aged 12-17 years.

Adverse reactions were reported at the time of the testing procedure and for one day thereafter. No serious adverse reactions were reported following bronchial challenge testing with ARIDOL in either trial.

Five adult subjects (0.6%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of cough, decreased lung function, feeling jittery, sore throat, and throat irritation. One adult subject (0.3%) discontinued following the methacholine bronchial challenge test because of dizziness. One pediatric subject (0.4%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of retching.

Table 2 displays the combined common adverse reactions (greater than or equal to 1%) within a day after bronchial challenge testing with ARIDOL or methacholine in the overall population for Studies 1 and 2.

…

There were no differences in the incidence of adverse reactions based on gender or race. The clinical trials did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently compared to subjects below 65 years of age.

Pediatric Patients Aged 6 to 17 Years: Overall, the types and severities of adverse reactions in children were similar to those observed in the adult population. As in the adult population, the adverse reactions of pharyngolaryngeal pain, nausea, and headache were the more common with incidences of 4%, 3%, and 3%, respectively. There were no major differences in the types of adverse reactions observed in children 6-11 years of age compared to adolescents 12-17 years old.

The decrease in FEV1 in pediatric patients and adolescents who received the ARIDOL bronchial challenge test was similar to that of the adult population with 5%, 15% and 9% of pediatric patients who had bronchial challenge testing with ARIDOL, methacholine and exercise, respectively, experiencing reduction in FEV1 greater than or equal to 30%. No patient who had bronchial challenge testing with ARIDOL or exercise had a decrease in FEV1 greater than or equal to 60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV1 greater than or equal to 60%.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no available human data regarding inhaled mannitol to evaluate a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was orally administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively

Data

Animal Data

In animal reproduction studies, oral administration of mannitol to pregnant rats and mice during the period of organogenesis did not cause fetal structural alterations. The mannitol dose in rats and mice was approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRDID) in humans, respectively, (on a mg/m2 basis at maternal doses of 1600 mg/kg/day in both species).

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of mannitol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARIDOL bronchial challenge test and any potential adverse effects on the breastfed child from ARIDOL or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of ARIDOL for the assessment of bronchial hyperresponsiveness in adult and pediatric patients 6 years of age or older who do not have clinically apparent asthma have been established. The use of ARIDOL for this indication is supported by evidence from two clinical studies that included 246 pediatric patients 6 to 17 years of age [see Clinical Studies (14)].

The mean and median maximum percentage reduction in FEV1 in patients with a positive ARIDOL challenge test in pediatric patients 6 to 17 years of age (19% and 18%, respectively) showed no apparent difference compared to the adult population (19% and 18%, respectively).

The safety profile of the ARIDOL bronchial challenge test in pediatric patients 6 to 17 years of age was similar to the adult population in two clinical studies [see Adverse Reactions (6)].

Safety and effectiveness of ARIDOL have not been established in pediatric patients less than 6 years old. Bronchial challenge testing with ARIDOL should not be performed in children less than 6 years of age due to their inability to provide reliable spirometric measurements.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Clinical studies of ARIDOL did not include sufficient numbers of patients 50 years of age and older to determine whether they respond differently from younger adult patients.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Severe Bronchospasm

Prior to administration patients should be informed of the potential for bronchial challenge testing with ARIDOL to cause severe bronchospasm and of the potential symptoms they may experience [see Warnings and Precautions (5.1)].

Patients with Certain Co-morbid Conditions

Bronchial challenge testing with ARIDOL should be performed with caution in patients having severe cough, ventilatory impairment, spirometry-induced bronchoconstriction, hemoptysis of unknown origin, pneumothorax, recent abdominal or thoracic surgery, recent intraocular surgery, unstable angina, or active upper or lower respiratory tract infection or other conditions that may worsen with the use of a bronchial irritant [see Warnings and Precautions (5.2)].