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.

LOTRISONE (NDA-018827)

(BETAMETHASONE DIPROPIONATE; CLOTRIMAZOLE)

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

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06/14/2019 (SUPPL-50)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion, additions and/or revisions are underlined)

Risk Summary

There are no available data on topical betamethasone dipropionate or clotrimazole use in pregnant women to identify a LOTRISONE cream associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Observational studies suggest an increased risk of low birthweight infants with the use of potent or very potent topical corticosteroid during pregnancy. Advise pregnant women that LOTRISONE cream may increase the risk of having a low birthweight infant and to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible.

There have been no reproduction studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. In an animal reproduction study, betamethasone dipropionate caused malformations (i.e., umbilical hernias, cephalocele, and cleft palate) in pregnant rabbits when given by the intramuscular route during organogenesis. The available data do not allow the calculation of relevant comparisons between the systemic exposure of clotrimazole and/or betamethasone dipropionate observed in the animal studies to the systemic exposure that would be expected in humans after topical use of LOTRISONE cream.

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 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.

Data

Animal Data

Clotrimazole

Studies in pregnant rats treated during organogenesis with intravaginal doses up to 100 mg/kg/day revealed no evidence of fetotoxicity due to clotrimazole exposure.

No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation Days 6 to 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights), and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day was maternally lethal, and therefore, fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day had no adverse effects on dams or fetuses. However, in the combined fertility, embryofetal development, and postnatal development study conducted in rats, 50 mg/kg/day clotrimazole was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks.

Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day did not cause malformations in pregnant mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally during organogenesis with 60, 120, or 180 mg/kg/day.

Betamethasone Dipropionate

Betamethasone dipropionate caused malformations when given to pregnant rabbits during organogenesis by the intramuscular route at doses of 0.05 mg/kg/day. The abnormalities observed included umbilical hernias, cephalocele, and cleft palates.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion, additions and/or revisions are underlined)

Advise pregnant women that LOTRISONE cream may increase the risk of having a low birthweight infant and to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible.

Lactation

Advise a woman to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply LOTRISONE cream directly to the nipple and areola to avoid direct infant exposure.

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). Inform the patient of the following:

Pregnancy

Advise pregnant women that LOTRISONE cream may increase the risk of having a low birthweight infant and to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible.

Lactation

05/21/2018 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Ophthalmic Adverse Reactions

(Additions and/or revisions are underlined)

Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported in postmarketing experience with the use of topical corticosteroid products, including topical betamethasone products.

Avoid contact of LOTRISONE cream with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…Ophthalmic adverse reactions of blurred vision, cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy have been reported with the use of topical corticosteroids, including topical betamethasone products…

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).

Advise patients to report any visual symptoms to their healthcare providers.