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.

FLOVENT HFA (NDA-021433)

(FLUTICASONE PROPIONATE)

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

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01/07/2019 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Glaucoma and Cataracts

(additions underlined)

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT HFA long term.

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

Risk Summary

There are insufficient data on the use of FLOVENT HFA in pregnant women. There are clinical considerations with the use of FLOVENT HFA in pregnant women. (See Clinical Considerations.)

…

Data

Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

…

8.2 Lactation

(additions underlined)

…

Data

Animal Data: Subcutaneous administration of tritiated fluticasone propionate at a dose of 10 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 FLOVENT HFA, 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 FLOVENT HFA?

FLOVENT HFA 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 FLOVENT HFA.

…

07/19/2017 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Tabl e 2 renamed Table 1

8 Use in Specific Populations

8.4 Pediatric Use

Table 3 renamed Table 2

10/05/2016 (SUPPL-32)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(additions and/or revisions are underlined)

Risk Summary

… However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mg/m2 basis.

Data

Animal Data

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.14 times the MRHDID (on a mg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however,there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

07/28/2016 (SUPPL-31)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation (PLLR Conversion)

Risk Summary

There are no available data on the presence of fluticasone propionate 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 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 FLOVENT HFA and any potential adverse effects on the breastfed child from FLOVENT HFA or from the underlying maternal condition.

Data

Animal Data

Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.05 times the MRHDID for adults (on a mg/m2 basis) resulted in measurable levels in milk.

Pregnancy (PLLR Conversion)

Risk Summary

There are no randomized clinical studies of FLOVENT HFA in pregnant women. There are clinical considerations with the use of FLOVENT HFA in pregnant women. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mg/m2 basis. However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose approximately 0.5 times the MRHDID on a mg/m2 basis. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Pregnancy (PLLR Conversion)

Data

Animal Data

In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately 0.17 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).
In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mg/m2 basis with a maternal inhalation dose of 91 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.13 times the MRHDID (on a mg/m2 basis with a maternal inhalation dose of 23 mcg/kg/day).
In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).
Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at dose approximately 0.04 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.3 times the MRHDID (on a mg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).