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.

AVAGE (NDA-021184)

(TAZAROTENE)

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

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07/21/2017 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Local Irritation and Hypersensitivity Reactions

Additions and/or revisions underlined:

Local tolerability reactions (including blistering and skin desquamation) and hypersensitivity adverse reactions

(including urticaria) have been observed with topical tazarotene. Application of AVAGE Cream …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Overall, 20/567 (3.5%) subjects in the AVAGE Cream group and 16/564 (2.8%) subjects in the vehicle group reported adverse events (including edema, irritation, and inflammation) directly related to the eye or eyelid. The majority of these conditions were mild.

Newly added subsection:

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tazarotene. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: blister, dermatitis, urticaria, skin exfoliation, skin discoloration (including skin hyperpigmentation or skin hypopigmentation), swelling at or near application sites, and pain.

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

PATIENT COUNSELING INFORMATION

Important Administration Instructions

Additions and/or revisions underlined:

AVAGE Cream is for topical use only. Do not apply to eyes and mouth, or other mucous membranes. The cream may cause severe redness, itching, burning, stinging, and peeling. Avoid accidental transfer of AVAGE Cream into eyes, mouth, or other mucous membranes. If contact with mucous membranes occurs, rinse thoroughly with water. Seek medical attention if eye irritation continues. Wash hands thoroughly after applying AVAGE Cream.

09/16/2016 (SUPPL-8)

Approved Drug Label (PDF)

4 Contraindications

AVAGE Cream is contraindicated in: (Additions underlined)

Pregnancy. Retinoids may cause fetal harm when administered to a pregnant female.
Individuals who have known hypersensitivity to any of its components.

5 Warnings and Precautions

5.1 Embryofetal Toxicity

(additional information from PLR Conversion)

Based on data from animal reproduction studies, retinoid pharmacology and the potential for systemic

absorption, AVAGE Cream may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Safety in pregnant females has not been established. The potential risk to the fetus outweighs the potential benefit to the mother from AVAGE Cream use during pregnancy; therefore, discontinue AVAGE Cream as soon as pregnancy is recognized. Tazarotene elicits malformations and developmental effects associated with retinoids after topical and oral administration to pregnant rats and rabbits during organogenesis. However, limited case reports of pregnancy in females enrolled in clinical trials for AVAGE Cream have not reported a clear association with tazarotene and major birth defects or miscarriage risk.

… tazarotene is a teratogenic substance in animals, and it is not known what level of exposure is required for teratogenicity in humans.

Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to AVAGE Cream therapy. Initiate AVAGE Cream therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with AVAGE Cream.

5.2 Local Irritation and Hypersensitivity Reactions

Local tolerability reactions and hypersensitivity adverse reactions have been observed with topical tazarotene.

…If these adverse reactions occur, discontinue the medication until the integrity of the skin is restored, or reduce the dosing to an interval the patient can tolerate …

Closely monitor the frequency of application by carefully observing the therapeutic response and skin tolerance. (additions underlined)

5.3 Photosensitivity and Risk of Sunburn

Because of heightened burning susceptibility, minimize exposure to ultraviolet rays (including sunlight and sun lamps) during the use of AVAGE Cream … Advise patients with sunburn not to use AVAGE Cream until the sunburn is fully recovered … Avoid using AVAGE Cream if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. (additions underlined)

5.4 Lentigo Maligna (new subsection added)

Some facial pigmented lesions are not lentigines, but rather lentigo maligna, a type of melanoma. Before application of AVAGE Cream, carefully assess facial pigmented lesions of concern by a qualified physician (e.g., dermatologist) to exclude a diagnosis of lentigo maligna.

6 Adverse Reactions

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

Embryofetal toxicity
Photosensitivity and Risk of Sunburn

6.1 Clinical Trials Experience

The most frequent adverse reactions reported with AVAGE Cream, 0.1% that occurred in greater than 10% of subjects, included desquamation, erythema, burning sensation, and dry skin (in descending order). Reactions that occurred in 1 to 10% of subjects, included skin irritation, pruritus, irritant contact dermatitis, stinging, rash, and cheilitis (in descending order). Common adverse events that occurred at a rate of at least 1% and at a higher rate in the AVAGE Cream group than in the vehicle group in the clinical trials are presented in the following table. (additions underlined)

TABLE OF ADVERSE EVENTS SEEN IN 24-WEEK CLINICAL TRIALS WITH AVAGE CREAM 0.1% (Additional table; please refer to label)

A few subjects reported adverse events at Week 0; however, for patients who were treated with AVAGE Cream, the highest number of new reports for each adverse event was at Week 2.

When combining data from the two trials, 5.3% of subjects in the AVAGE Cream group and 0.9% of subjects in the vehicle group discontinued because of adverse events.

The majority of these conditions were mild.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, AVAGE Cream may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Safety in pregnant females has not been established. The potential risk to the fetus outweighs the potential benefit to the mother from AVAGE Cream during pregnancy; therefore, AVAGE Cream should be discontinued as soon as pregnancy is recognized. Limited case reports of pregnancy in females enrolled in clinical trials for AVAGE Cream have not established a clear association with tazarotene and major birth defects or miscarriage risk. Because the exact timing and extent of exposure in relation to the gestational age are not certain, the significance of these findings is unknown.

In animal reproduction studies with pregnant rats, tazarotene dosed topically during organogenesis at 2times the maximum systemic exposure in subjects treated with the maximum recommended human dose (MRHD) of tazarotene cream, 0.1% resulted in reduced fetal body weights and reduced skeletal ossification. In animal reproduction studies with pregnant rabbits dosed topically with tazarotene gel at 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, there was a single incident of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies.

In animal reproduction studies with pregnant rats and rabbits, tazarotene dosed orally during organogenesis at 2 and 52 times, respectively, the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1% resulted in malformations, fetal toxicity, developmental delays, and/or behavioral delays. In pregnant rats, tazarotene dosed orally prior to mating through early gestation resulted in decreased litter size, decreased numbers of live fetuses, decreased fetal body weights, and increased malformations at doses approximately 7 times higher than the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. 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 rats, a tazarotene 0.05% gel formulation dosed topically during gestation days 6 through 17 at 0.25 mg/kg/day, which represented 2 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1% (i.e., 2 mg/cm2 over a 15% body surface area), resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel, which represented 26 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, during gestation days 6 through 18, had a single incident of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies.

When tazarotene was given orally to animals, developmental delays were seen in rats, and malformations and post-implantation loss were observed in rats and rabbits at doses representing 2 and 52 times, respectively, 0.1% atthe maximum systemic exposure seen in subjects treated with the MRHD of tazarotene cream, 0.1%.

In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day

7, a7, which represented 7 times the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%, classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations was observed at that dose.

In a pre- and postnatal development toxicity study, topical administration of tazarotene gel (0.125 mg/kg/day) to pregnant female rats from gestation day 16 through lactation day 20 reduced pup survival, but did not affect the reproductive capacity of the offspring. Based on data from another study, the maximum systemic exposure in the rat would be equivalent to the maximum systemic exposure in subjects treated with the MRHD of tazarotene cream, 0.1%.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of tazarotene in human milk, the effects on the breastfed infant, or the effects on milk production. After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in rat milk. The lack of clinical data during lactation precludes a clear determination of the risk of AVAGE Cream to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVAGE Cream and any potential adverse effects on the breastfed child from AVAGE Cream or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential within 2 weeks prior to initiating AVAGE Cream therapy which should begin during a menstrual period.

Contraception

Females

Based on animal studies, AVAGE Cream may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with AVAGE Cream.

8.4 Pediatric Use

The safety and efficacy of tazarotene cream have not been established in patients under the age of 17 years with facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines. (additions and/or underlined)

8.5 Geriatric Use

In the studies of facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines, 44 male subjects and 180 female subjects out of the total population of 1131 subjects were older than 65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

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

Patient Counseling Information

Embryofetal Toxicity

Inform females of reproductive potential of the potential risk to a fetus. Advise these patients to use effective contraception during treatment with AVAGE Cream. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Photosensitivity and Risk of Sunburn

Advise patients to avoid excessive sun exposure and to use of sunscreens and protective measures (hat, visor).

Advise patients to avoid using AVAGE if also taking other medicines may increase sensitivity to sunlight.

Important Administration Instructions

Advise patients of the following:

Use AVAGE Cream on the face once per day, at bedtime.
Avoid contact with the eyes and mouth. The cream may cause severe redness, itching, burning, stinging, and peeling.
Gently wash face with a mild soap before applying the cream.
Dry skin before applying the cream.
Apply only a small pea sized amount (about 1/4 inch or 5 millimeter diameter) to lightly cover the entire face.
Apply emollients or moisturizers before or after tazarotene cream and ensure that the first cream or lotion has absorbed into the skin and dried completely.
In the morning, apply a moisturizing sunscreen.

Patient Information

Extensively updated; please refer to label.

Other

PLR conversion; please refer to label.